Articles tagged as "Asia"

How are we going to get to our prevention targets? Old tools, new tools and a more nuanced understanding of transmission dynamics.

Editor’s notes: By 2020, the Fast-Track strategy is aiming to reduce new HIV infections to 200 000 per year.  There is increasing recognition that if we are to succeed, we will need to do much more than simply putting people onto HIV treatment.  Despite the massive impact of ART on infectiousness, the decline in new infections at the community level is still not fast enough, even in countries like Botswana (see above) where 90-90-90 has almost been reached.  Renewed enthusiasm for primary prevention has also followed key trials of biomedical prevention tools including voluntary medical male circumcision and ARV-based prevention.  It is all too easy for us to forget the crucial role that condoms have played from the early days of the epidemic.  More recently, with HIV seen as a less terrifying infection, many programmes suffer from “condom fatigue”.  So it is good to see papers on the key importance of condoms as well as perspectives on how they are perceived by young men.

The magic of ARVs does not end with treatment.  We are finally moving to wider use of pre-exposure prophylaxis (PrEP).  There is no doubt that PrEP works when taken, but there are still plenty of questions for policy-makers about how to adopt it whole-heartedly into their national strategic plans and for financiers about how to pay for it.  Papers this month cover a range of experiences with PrEP from the US, where the huge majority of PrEP users still live, to Europe and Australia, where policies are finally moving towards wider use.  Long acting PrEP remains a key objective for many, as it might improve regular adherence, which has proved the Achilles’ heel of oral and topical PrEP in several of the large studies.

One of the ways to make PrEP most cost-effective is to ensure that it is available to people who are most likely to acquire HIV.  So the hope continues that phylogenetic analyses will allow more sophisticated understanding of the dynamics of the multiple overlapping networks of HIV transmission in communities.  Papers this month cover Australia and the PANGEA consortium of African research sites along with a cautionary comment about establishing the ethical framework for such studies, particularly among populations who are already subject to discrimination and criminalization.

When used correctly and consistently, condoms are highly effective not only to prevent HIV but also to prevent pregnancy and to prevent sexually transmitted infections.  Stover and colleagues have tried to capture all three benefits in one model.  They explore three potential scenarios for condom programming between now and 2030 in 81 countries that are priorities for family planning or HIV programmers or both.  The benefits of greater investment in condoms are huge.  In their most optimistic scenario, the authors suggest that if the entire gap between people who would like to use condoms and people who currently use them was filled (almost 11 billion condoms over the period), this could prevent up to 400 million unwanted pregnancies; 16.8 million new HIV infections and more than 700 million sexually transmitted infections.  The costs are quite modest, and at $115 per DALY averted this is an investment that everyone should support.  There are of course limitations in such a broad brush model, but it provides an excellent starting point.

The challenges in provision of condoms to young people go well beyond the cost and effectiveness considerations that underpin the previous analysis.  In an interesting qualitative study in South Africa, de Bruin and Panday-Soobrayan report their findings from focus group discussions with learners in 33 public schools.  Most of the learners were not in favour of provision of condoms at school, although they were keen on more youth friendly sexual and reproductive health and rights services within the public sector.  Many thought that provision of condoms would lead to earlier and more frequent sexual contacts, despite considerable experience showing that this is not the case in other settings.

Multiple trials have shown that PrEP is extremely effective when it is used consistently and correctly.  Many countries in all continents are now beginning to work out where it fits within their combination prevention package.  To date, the large majority of PrEP users are in the United States of America (USA), where more than 140 000 people have started.  It is much harder to measure how many are still taking it regularly.  Patel and colleagues analysed utilization at three months after the initial prescription of PrEP in three major PrEP clinics in three states in the USA.  18% of the 201 people (90% male) seen at baseline did not use their PrEP and this was strongly predicted by insurance status, with around a four-fold risk of dropping out among those who were not insured.  Although the numbers are small, this is an important study.  The authors suggest that increased insurance cover might make PrEP have a greater impact.  More broadly it raises the challenge that PrEP is often needed most by people least able to access it.  This will be a real challenge in countries where people most at risk, such as gay men and other men who have sex with men and sex workers, are criminalized or discriminated against in many health care settings.

In Australia, PrEP has been provided through large demonstration projects while awaiting decisions about how to include it in routine practice.  Lal and colleagues report results from 114 (one transgender woman, the rest male) people taking PrEP in the Victorian PrEP Demonstration project.  Participants have to pay an equivalent of an insurance co-payment, in order to make the situation more like the “real world”.  The participants were recruited because they were at high risk of HIV engaging in condomless anal sex with partners who were known to be living with HIV or of unknown status.  Adherence to PrEP was excellent as measured by a variety of reported and biological measures.  They observed one seroconversion in a man with exposure two weeks before starting PrEP who was already in the process of seroconverting and whose virus was found to be resistant to emtricitabine.  The only other seroconversion occurred in someone who had not yet started PrEP.  The authors found a substantial increase in rates of gonorrhoea and chlamydia once participants were “stable” on PrEP after three months.  There was also a significant reduction in condom use with both regular and casual partners.  This is one of the first studies to document important risk compensation among PrEP users.  Of course, preventing HIV is a huge benefit that generally outweighs the harms of additional treatment for sexually transmitted infections.  However, the study emphasizes the importance of enhancing sexual health services alongside PrEP and reminds us that people most at risk of HIV are also at high risk of other infections (and also of pregnancy in the context of heterosexual transmission.)  If PrEP is integrated within a broad sexual health service, there could be considerable synergistic benefits.

Gay men and men who have sex with men who enrolled in the PrEP demonstration project in Amsterdam also had high concomitant rates of hepatitis C virus (HCV).  Hoorenborg and colleagues found that around 5% of the 375 men enrolled in the project were co-infected.  The HCV found among these men were genetically similar to those circulating in the population of gay men and other men who have sex with men living with HIV, and more distinct from HCV from other risk groups.  This is good evidence that HCV and HIV both circulate in this population, and emphasizes once again the need for more integrated services, including hepatitis screening.

The ÉCLAIR study is a phase 2a trial of cabotegravir injections in healthy HIV-negative male volunteers.  As noted, adherence is a major challenge in many PrEP trials; although notably less of a problem when people choose to take PrEP in demonstration projects.  It is hoped that cabotegravir could be the first long acting PrEP.  Markowitz and colleagues presented the results of this study at CROI 2017.  The authors point out that although the injections are painful, many men stated that they would be happy to continue if the injections were effective.  No serious safety challenges emerged. The pharmacokinetics suggests that a dose given more frequently will be needed – and subsequent trials will use a two monthly regimen. 

One group for whom PrEP has been recommended by WHO for some years are serodiscordant couples (SDCs).  The Partners PrEP study, which forms one of the cornerstones for the evidence that PrEP works for both men and women, was conducted in SDCs.  The idea is to protect the HIV-negative partner from infection until such time as the partner living with HIV has been on ART consistently and suppressed their viral load.  So a study from the Centers for Disease Control USA is relevant to discussions of PrEP.  Crepaz and colleagues found that around 6000 new HIV infections occur each year in the USA among men and women having heterosexual sex and are aware that their partner is living with HIV.  They point out that viral suppression is achieved by only around 50% of heterosexuals living with HIV and that an additional proportion does not know their HIV status.  So the importance of HIV testing, and of focusing efforts on serodiscordant couples is clear.  Such efforts include both improving HIV treatment effectiveness, and providing a range of prevention choices including PrEP until viral suppression is achieved.

While the study above used traditional epidemiological surveillance reports, phylogenetics may provide additional insights into the dynamics of transmission.  In Australia, where notifications with HIV are rising steadily,  Castley and colleagues have examined the sequence data from almost 5000 viruses collected across the country from 2005-2012.  This sample is drawn from around 1200 new HIV infections per year (and around 27 000 people living with HIV).  The sample is not random, but reflects samples that were sent for sequencing to determine drug resistance.  Around one quarter of sequences are found in tight clusters (pairs, triplets or more) with other sequences, making it likely that they are closely connected by transmission.  Of course, all HIV sequences have been transmitted, so a longer time period and complete sampling would be expected to give a much higher proportion in clusters.  Indeed the more recent samples are around twice as likely to be in clusters as those collected at the start of the time period. Nonetheless, the large sample and the time period of collection allows some clear observations to be made.  In all states, the proportion of non-B subtypes is increasing, which must relate to travel and migration to and from Asia and Africa.  There is little evidence that the C subtypes (originally from Africa) are found in all male clusters suggesting little spill over into the community of gay men and other men having sex with men.  Larger clusters are more common among younger, all male networks. Like most molecular epidemiological studies, there are a small number of large clusters which represent highly active transmission.  These clusters are also most likely to be all male.  Taken together, the results suggest that the steady rise in notifications in Australia is probably due to increasing migration and travel and to ongoing active transmission networks among young gay men.  The challenge is to turn this sort of analysis into clear policy recommendations that can improve HIV prevention.

UNAIDS joined an interesting meeting on the ethics of phylogenetic studies in Africa organised by the PANGEA consortium.  Many of the issues discussed are also covered in a comment by Cohen on the importance of thinking through the risks inherent in these studies.  A key issue is to ensure that systems are reinforced to monitor any unexpected harms and to establish mitigation strategies to minimize them.  The challenges are not necessarily different to traditional epidemiological studies which may highlight networks and locations of groups that are criminalized or discriminated against.  In community consultations, prior to agreeing to go forward with phylogenetic studies, some potential participants even say that they would be keen to “know who infected them” in order to punish them.  This is clearly NOT the aim of such studies and emphasizes the importance of clear information about the limitations of the techniques which cannot usually rule out the possibility of additional links in the transmission chain.  Issues of anonymised information and what to do if clinically relevant results such as drug resistance mutations are uncovered as incidental findings also need to be discussed.

Furthermore, Ratmann and colleagues, reporting on the first 4000 sequences from the PANGEA consortium (largely from the Rakai project in Uganda), also emphasize some of the technical challenges that may lead to erroneous results in creating phylogenies.  There is little doubt that as the cost of sequencing falls and as the technologies and software become increasingly straightforward, we will see more and more studies of sequence data.  It is likely that analysis of these data will lead to more nuanced approaches to HIV prevention, particularly as the overall incidence falls, and sharper tools are needed to dissect the pathways of ongoing transmission.

The case for investing in the male condom

Stover J, Rosen JE, Carvalho MN, Korenromp EL, Friedman HS, Cogan M, Deperthes B. PLoS One. 2017 May 16;12(5):e0177108. doi: 10.1371/journal.pone.0177108. eCollection 2017.

When used correctly and consistently, the male condom offers triple protection from unintended pregnancy and the transmission of sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). However, with health funding levels stagnant or falling, it is important to understand the cost and health impact associated with prevention technologies. This study is one of the first to attempt to quantify the cost and combined health impact of condom use, as a means to prevent unwanted pregnancy and to prevent transmission of STIs including HIV. This paper describes the analysis to make the case for investment in the male condom, including the cost, impact and cost-effectiveness by three scenarios (low in which 2015 condom use levels are maintained; medium in which condom use trends are used to predict condom use from 2016-2030; and high in which condom use is scaled up, as part of a package of contraceptives, to meet all unmet need for family planning by 2030 and to 90% for HIV and STI prevention by 2016) for 81 countries from 2015-2030. An annual gap between current and desired use of 10.9 billion condoms was identified (4.6 billion for family planning and 6.3 billion for HIV and STIs). Under a high scenario that completely reduces that gap between current and desired use of 10.9 billion condoms, we found that by 2030 countries could avert 240 million DALYs. The additional cost in the 81 countries through 2030 under the medium scenario is $1.9 billion, and $27.5 billion under the high scenario. Through 2030, the cost-effectiveness ratios are $304 per DALY averted for the medium and $115 per DALY averted for the high scenario. Under the three scenarios described above, our analysis demonstrates the cost-effectiveness of the male condom in preventing unintended pregnancy and HIV and STI new infections. Policy makers should increase budgets for condom programming to increase the health return on investment of scarce resources.

Abstract  Full-text [free] access

Learners' perspectives on the provision of condoms in South African public schools.

de Bruin WE, Panday-Soobrayan S. AIDS care. 2017 May 16:1-4. doi: 10.1080/09540121.2017.1327647. [Epub ahead of print]

A stubborn health challenge for learners in South African public schools concerns sexual and reproductive health and rights (SRHR). In 2015, the Department of Basic Education (DBE) proposed the provision of condoms and SRHR-services to learners in schools. This study aimed to contribute to the finalisation and implementation of DBE's policy by exploring learners' perspectives on the provision of condoms and SRHR-services in schools. Sixteen focus group discussions were conducted with learners (n = 116) from 33 public schools, to assess their attitudes, social influences, and needs and desires regarding condom provision and SRHR-services in schools. The majority of learners did not support condom provision in schools as they feared that it may increase sexual activity. Contrarily, they supported the provision of other SRHR-services as clinics fail to offer youth-friendly services. Learners' sexual behaviour and access to SRHR-services are strongly determined by their social environment, including traditional norms and values, and social-pressure from peers and adults. Learners' most pressing needs and desires to access condoms and SRHR-services in school concerned respect, privacy and confidentiality of such service provision. Implementation of DBE's policy must be preceded by an evidence-informed advocacy campaign to debunk myths about the risk of increased sexual activity, to advocate for why such services are needed, to shift societal norms towards open discussion of adolescent SRHR and to grapple with the juxtaposition of being legally empowered but socially inhibited to protect oneself from HIV, STIs and early pregnancy. Provision of condoms and other SRHR-services in schools must be sensitive to learners' privacy and confidentiality to minimise stigma and discrimination.

Abstract  Full-text [free] access

Impact of insurance coverage on utilization of pre-exposure prophylaxis for HIV prevention

Patel RR, Mena L, Nunn A, McBride T, Harrison LC, Oldenburg CE, Liu J, Mayer KH, Chan PA.  PLoS One. 2017 May 30;12(5):e0178737 . doi: 10.1371/journal.pone.0178737. eCollection 2017.

Pre-exposure prophylaxis (PrEP) can reduce U.S. HIV incidence. We assessed insurance coverage and its association with PrEP utilization. We reviewed patient data at three PrEP clinics (Jackson, Mississippi; St. Louis, Missouri; Providence, Rhode Island) from 2014-2015. The outcome, PrEP utilization, was defined as patient PrEP use at three months. Multivariable logistic regression was performed to determine the association between insurance coverage and PrEP utilization. Of 201 patients (Jackson: 34%; St. Louis: 28%; Providence: 28%), 91% were male, 51% were White, median age was 29 years, and 21% were uninsured; 82% of patients reported taking PrEP at three months. Insurance coverage was significantly associated with PrEP utilization. After adjusting for Medicaid-expansion and individual socio-demographics, insured patients were four times as likely to use PrEP services compared to the uninsured (OR: 4.49, 95% CI: 1.68-12.01; p = 0.003). Disparities in insurance coverage are important considerations in implementation programs and may impede PrEP utilization.

Abstract  Full-text [free] access

Medication adherence, condom use and sexually transmitted infections in Australian PrEP users: interim results from the Victorian PrEP demonstration project

Lal L, Audsley J, Murphy D, Fairley CK, Stoove M, Roth N, Moore R, Tee BK, Puratmaja N, Anderson PL, Leslie D, Grant RM, De Wit J, Wright E; VicPrEP Study Team. AIDS. 2017 May 1 doi: 10.1097/QAD.0000000000001519. [Epub ahead of print]

Objective: HIV Pre-exposure prophylaxis (PrEP) decreases risk of HIV acquisition however its efficacy is closely dependent on adherence. There is also concern that the preventive effect of PrEP may be offset by risk compensation, notably an increase in condomless anal sex.

Design: Multi-site, open-label demonstration study that recruited people at current or recent risk of HIV infection in Melbourne, Australia.

Methods: Participants were recruited from three general practice clinics and one sexual health clinic in Melbourne and consented to take daily tenofovir/emtricitabine for 30 months. Sexual practice data, HIV and sexually transmitted infection (STI) test results were collected at baseline and 3-monthly during follow up. PrEP adherence was evaluated by self-report at clinical visits, online surveys, refill-based assessments and dried blood spot (DBS) testing. We present a 12-month interim analysis.

Results: 114 people were recruited. We observed a significant decline in condom use which occurred concomitantly with a significant increase in STIs over the first 12 months of PrEP. Incidence (per 100PY) of any STI was 43.2 and 119.8 at m0-3 and M3-12, respectively (IRR 2.77 (1.52, 5.56)). Adherence to PrEP medication was high by all measures, including six month TDF-FTC levels in DBS.

Conclusions: We found significant reduction in condom use and an increase STIs over the first 12 months of follow-up. High medication adherence rates coupled with a decline in condom use and a rise in STIs, suggests that prevention, early detection and treatment of STIs is a chief research priority in the current era of HIV PrEP.

Abstract

Men who have sex with men starting pre-exposure prophylaxis (PrEP) are at risk of HCV infection: evidence from the Amsterdam PrEP study

Hoornenborg E, Achterbergh RC, Van Der Loeff MF, Davidovich U, Hogewoning A, de Vries HJ, Schinkel J, Prins M, Laar TJWV; Amsterdam PrEP Project team in the HIV Transmission Elimination AMsterdam Initiative, MOSAIC study group. AIDS. 2017 May 1. doi: 10.1097/QAD.0000000000001522. [Epub ahead of print].

Objectives and Design: Hepatitis C virus (HCV) has been recognised as an emerging sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). However, HIV-negative MSM at high risk for HIV might also be at increased risk for HCV. We studied the HCV prevalence in HIV-negative MSM who start pre-exposure prophylaxis (PrEP) in Amsterdam. Phylogenetic analysis was used to compare HCV strains obtained from HIV-negative and HIV-positive MSM.

Methods: At enrolment in the Amsterdam PrEP (AMPrEP) demonstration project, HIV-negative MSM were tested for the presence of HCV antibodies and HCV RNA. If positive for HCV RNA, an HCV NS5B gene fragment (709 bp) was sequenced and compared with HCV isolates from HIV-positive MSM (n = 223) and risk groups other than MSM (n = 153), using phylogenetic analysis.

Results: Of 375 HIV-negative MSM enrolled in AMPrEP, 18 (4.8%, 95%CI 2.9%-7.5%) of participants were anti-HCV and/or HCV RNA positive at enrolment; 15/18 (83%) had detectable HCV RNA. HCV genotyping showed genotype 1a (73%), 4d (20%) and 2b (7%). All HCV-positive MSM starting PrEP were part of MSM-specific HCV clusters containing MSM with and without HIV.

Conclusion: HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported. All HIV-negative HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status. Hence, routine HCV testing should be offered to MSM at high risk for HIV, especially for those enrolling in PrEP programs.

Abstract

Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial.

Markowitz M, Frank I, Grant RM, Mayer KH, Elion R, Goldstein D, Fisher C, Sobieszczyk ME, Gallant JE, Van Tieu H, Weinberg W, . Margolis DA, Hudson KJ, Stancil BS, Ford SL, Patel P, Gould E, Rinehart AR, Smith KY, Spreen WR. Lancet HIV. 2017 May 22. pii: S2352-3018(17)30068-1. doi: 10.1016/S2352-3018(17)30068-1. [Epub ahead of print]

Background: Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection.

Methods: We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178.

Findings: Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 μg/mL (95% CI 0·237-0·385), 0·331 μg/mL (0·253-0·435), and 0·387 μg/mL (0·296-0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration.

Interpretation: Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens.

Abstract

Examination of HIV infection through heterosexual contact with partners who are known to be HIV infected in the United States, 2010-2015

Crepaz N, Dong B, Chen M, Hall I. AIDS. 2017 Jul 17;31(11):1641-1644. doi: 10.1097/QAD.0000000000001526.

Using data from the National HIV Surveillance System, we examined HIV infections diagnosed between 2010 and 2015 attributed to heterosexual contact with partners previously known to be HIV infected. More than four in 10 HIV infections among heterosexual males and five in 10 HIV infections among heterosexual women were attributed to this group. Findings may inform the prioritization of prevention and care efforts and resource allocation modeling for reducing new HIV infection among discordant partnerships.

Abstract

A national study of the molecular epidemiology of HIV-1 in Australia 2005–2012

Castley A, Sawleshwarkar S, Varma R, Herring B, Thapa K, Dwyer D, Chibo D, Nguyen N, Hawke K, Ratcliff R, Garsia R, Kelleher A, Nolan D; Australian Molecular Epidemiology Network-HIV (AMEN-HIV).. PLoS One. 2017 May 10;12(5):e0170601. doi: 10.1371/journal.pone.0170601. eCollection 2017.

Introduction: Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia.

Methods: The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4873 patients who had genotypes performed during 2005-2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster).

Results: HIV-1 subtype B represented 74.5% of the 4873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p<0.001), being younger (p<0.001), being male (p = 0.023) and having a B subtype (p = 0.02). Being in a larger cluster (>3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008).

Conclusion: This nationwide HIV-1 study of 4873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia

Abstract  Full-text [free] access

HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences.

Ratmann O, Wymant C, Colijn C, Danaviah S, Essex M, Frost SD, Gall A, Gaiseitsiwe S, Grabowski M, Gray R, Guindon S, von Haeseler A, Kaleebu P, Kendall M, Kozlov A, Manasa J, Minh BQ, Moyo S, Novitsky V, Nsubuga R, Pillay S, Quinn TC, Serwadda D, Ssemwanga D, Stamatakis A, Trifinopoulos J, Wawer M, Leigh Brown A, de Oliveira T, Kellam P, Pillay D, Fraser C.. AIDS Res Hum Retroviruses. 2017 May 25. doi: 10.1089/AID.2017.0061. [Epub ahead of print].

To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
Afghanistan, Angola, Australia, Azerbaijan, Bangladesh, Benin, Bolivia, Botswana, Brazil, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Congo, Côte d'Ivoire, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, Haiti, India, Indonesia, Iran (Islamic Republic of), Iraq, Jamaica, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, Niger, Nigeria, Pakistan, Papua New Guinea, Peru, Philippines, Russian Federation, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Solomon Islands, Somalia, South Africa, South Sudan, Sudan, Swaziland, Tajikistan, Togo, Turkmenistan, Uganda, Ukraine, United Republic of Tanzania, United States of America, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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Key populations need so much more than HIV-specific services – involve them at every stage of planning and programming

Editor’s notes: This month sees a welcome set of papers covering female sex workers in West Africa; gay men and other men who have sex with men in the Middle East and in East Africa; people who inject drugs in the USA and eastern Europe.

Sex work is legal in Cote d’Ivoire although soliciting and pandering are criminalized, which creates legal barriers to practicing sex work.  Legalization does not necessarily prevent widespread abuse of power. Lyons and colleagues recruited 466 female sex workers in Abidjan through a respondent driven sampling approach.  A structured interview and rapid HIV test was performed.  Around 11% of the women were found to be living with HIV and it is clear that there are large unmet needs for HIV-specific services.  Only one quarter of those living with HIV reported that they knew their status and of these, only a few were already taking ART.  However, the focus of this study was on violence, both physical and sexual, which was alarmingly common, with around 54% of women reporting physical violence and 43% sexual violence.  The violence was most often perpetrated by spouses and boyfriends as well as by paying customers.  Other sex workers, pimps or managers and uniformed officers were also responsible for violence, both physical and sexual.  16% of women said that they had been tortured.  Collecting reliable data on sensitive areas with vulnerable populations is challenging.  The sampling method may introduce biases, and the interviews may lead to reported behaviours to “please” the interviewer.  However, this study included major efforts to work with the community of sex workers and their networks, and considerable trust has been built, so the results seem credible.  The authors call for structural interventions and policy reforms that have little to do with HIV directly, but would lead to an environment where HIV and other harms were greatly reduced.  There is also a direct need to ensure that sex workers have good access to HIV and other sexual and reproductive health services.

People who inject drugs also have many needs besides HIV services.  In the USA, the number of people who inject drugs is increasing.  This has led to a rising number of deaths from opioid overdose (around 30 000 in 2014), as well as increased HIV transmission, which makes the headlines of the news, when it occurs in settings where HIV is otherwise rare.  Cost-effective HIV prevention programmes for people who inject drugs are essential to the long-term health outcomes for this population and other high-risk groups in the USA.  Bernard and colleagues used a mathematical model and economic analysis to identify the most cost-effective interventions for HIV prevention programmes for people who inject drugs in the USA.

The authors found that under many likely assumptions about potential scale up, the best buy was always to provide opioid agonist therapy, which reduces injecting frequency and results in multiple, immediate quality-of-life improvements.  Needle and syringe exchange programmes are less expensive, but in these models produced fewer benefits, making them the next most cost-effective intervention, alone or in combination. PrEP was not likely to be cost-effective in this population except in the very highest risk settings.  This is in line with the values and preference expressed by many people who use drugs around the world.  The priority should be for “standard” harm reduction approaches, which will reduce HIV transmission, but have far wider benefits on the health and well-being of drug users and their communities.

Relatively little research is carried out with key populations in the Middle East.  Heimer and colleagues also used respondent driven sampling (with the same potential biases as above) to recruit 292 men who have sex with men in Beirut.  Although one quarter of the participants had been born in Syria and moved recently to Lebanon, the sampling method does reduce the precision of this estimate.  Of 36 people living with HIV identified, 32 were on HIV treatment, which is encouraging.  If the 32 on treatment were virally suppressed, the prevalence of “infectious HIV” in the survey was around 1.4%.  As we move forward into the viral load era, notions of risk for sexual behaviour will change, and we need to think about explicit descriptions such as “condomless sex” rather than simply referring to “unprotected sex”.  As stated above, the benefits of condoms for other sexually transmitted infections as well as for HIV need to be emphasized and the full range of ARV-based prevention made available in order to minimize the epidemic of HIV among gay men and other men who have sex with men in Lebanon and beyond.

The dynamics of the HIV epidemic in Ukraine are shifting.  Increasingly sexual transmission is becoming more common, and transmission through injecting drug use reducing.  Fearnhill and colleagues’ study of phylogenetics and recent infections among 876 newly diagnosed people living with HIV in Kiev highlights these trends.  The study also demonstrates plenty of uncertainty and suggests that the stigma associated with both injecting drug use and with gay men and other men having sex with men may lead to significant under-reporting of both in traditional epidemiological surveillance.  Although phylogenetics cannot prove misclassification, it is highly suggestive when large clusters of HIV from known gay men and other men who have sex with men include no women, but do include other men, who self-report to be heterosexual.  Transmission was most common among gay men and other men who have sex with men, and from those with recent infections.  HIV strains from women often cluster with those from people who inject drugs.  In a complex and dynamic environment with overlapping risk factors for HIV infection, phylogenetics adds a useful lens through which to examine what is happening.  Yet again, the challenge is to translate more granular understanding of the epidemics into clear public health policy and practice.

What do men who have sex with men in Kenya think about participating in HIV prevention research, such as a vaccine trial?  Doshi and colleagues used a social network-based approach to conduct in-depth interviews with 70 gay men and other men who have sex with men.  Here is what some of them said:

“He [the potential study participant] keeps hearing there is a research [study] that is starting, that there is money – one thousand or two, three thousand – he will run for the money…because it is someone’s life you have to be sure of what is going on…. You run for the better option because research comes in every type and researchers are everywhere in town.”

“Ok, you know most of the research coming to Kenya starts with MSM. Those are the ones that are tested on first so if there are side effects, those will be the first victims”

“It will benefit many of us…on my side…because sometimes I’m drunk I go out and meet people and they tell me they do not use condom…or… I’m drunk, I don’t know myself and I have already come to the bed with someone. Even I don’t know what he will do to me, if he will do me with a condom or if he will do me without a condom. Now the [HIV] vaccine…will be beneficial to me and the whole community”

This is a rich paper, giving insights into the reasons that people do or do not want to participate in vaccine trials.  It raises plenty of ethical questions about the balance between self-interest, altruism, coercion and consent.  It is encouraging that on the whole most participants saw the potential benefits to the wider community and would consider volunteering their time despite the associated risks.  Their perceptions were also coloured by previous research studies and how researchers had met their responsibilities for the care and well-being of their participants.  A good advertisement for the UNAIDS-AVAC Good Participatory Practice guidance!

Physical and sexual violence affecting female sex workers in Abidjan, Côte d'Ivoire: prevalence, and the relationship with the work environment, HIV, and access to health services

Lyons CE, Grosso A, Drame FM, Ketende S, Diouf D, Ba I, Shannon K, Ezouatchi R, Bamba A, Kouame A, Baral S. J Acquir Immune Defic Syndr. 2017 May 1;75(1):9-17. doi: 10.1097/QAI.0000000000001310.

Background: Violence is a human rights violation, and an important measure in understanding HIV among female sex workers (FSW). However, limited data exist regarding correlates of violence among FSW in Côte d'Ivoire. Characterizing prevalence and determinants of violence and the relationship with structural risks for HIV can inform development and implementation of comprehensive HIV prevention and treatment programs.

Methods: FSW > 18 years were recruited through respondent driven sampling (RDS) in Abidjan, Côte d'Ivoire. In total, 466 participants completed a socio-behavioral questionnaire and HIV testing. Prevalence estimates of violence were calculated using crude and RDS-adjusted estimates. Relationships between structural risk factors and violence were analyzed using χ2 tests and multivariable logistic regression.

Results: The prevalence of physical violence was 53.6% (250/466), and sexual violence was 43.2% (201/465) among FSW in this study. Police refusal of protection was associated with physical (adjusted Odds Ratio [aOR]: 2.8; 95% confidence interval [CI]: 1.7 to 4.4) and sexual violence (aOR: 3.0; 95% CI: 1.9 to 4.8). Blackmail was associated with physical (aOR: 2.5; 95% CI: 1.5 to 4.2) and sexual violence (aOR: 2.4; 95% CI: 1.5 to 4.0). Physical violence was associated with fear (aOR: 2.2; 95% CI: 1.3 to 3.1) and avoidance of seeking health services (aOR: 2.3; 95% CI: 1.5 to 3.8).

Conclusions: Violence is prevalent among FSW in Abidjan and associated with features of the work environment and access to care. These relationships highlight layers of rights violations affecting FSW, underscoring the need for structural interventions and policy reforms to improve work environments, and to address police harassment, stigma, and rights violations to reduce violence and improve access to HIV interventions.

Abstract

Estimation of the cost-effectiveness of HIV prevention portfolios for people who inject drugs in the United States: a model-based analysis

Bernard CL, Owens DK, Goldhaber-Fiebert JD, Brandeau ML. PLoS Med. 2017 May 24;14(5):e1002312 doi: 10.1371/journal.pmed.1002312. eCollection 2017 May.

Background: The risks of HIV transmission associated with the opioid epidemic make cost-effective programs for people who inject drugs (PWID) a public health priority. Some of these programs have benefits beyond prevention of HIV-a critical consideration given that injection drug use is increasing across most United States demographic groups. To identify high-value HIV prevention program portfolios for US PWID, we consider combinations of four interventions with demonstrated efficacy: opioid agonist therapy (OAT), needle and syringe programs (NSPs), HIV testing and treatment (Test & Treat), and oral HIV pre-exposure prophylaxis (PrEP).

Methods and Findings: We adapted an empirically calibrated dynamic compartmental model and used it to assess the discounted costs (in 2015 US dollars), health outcomes (HIV infections averted, change in HIV prevalence, and discounted quality-adjusted life years [QALYs]), and incremental cost-effectiveness ratios (ICERs) of the four prevention programs, considered singly and in combination over a 20-y time horizon. We obtained epidemiologic, economic, and health utility parameter estimates from the literature, previously published models, and expert opinion. We estimate that expansions of OAT, NSPs, and Test & Treat implemented singly up to 50% coverage levels can be cost-effective relative to the next highest coverage level (low, medium, and high at 40%, 45%, and 50%, respectively) and that OAT, which we assume to have immediate and direct health benefits for the individual, has the potential to be the highest value investment, even under scenarios where it prevents fewer infections than other programs. Although a model-based analysis can provide only estimates of health outcomes, we project that, over 20 y, 50% coverage with OAT could avert up to 22 000 (95% CI: 5200, 46 000) infections and cost US$18 000 (95% CI: US$14 000, US$24 000) per QALY gained, 50% NSP coverage could avert up to 35 000 (95% CI: 8900, 43 000) infections and cost US$25 000 (95% CI: US$7000, US$76 000) per QALY gained, 50% Test & Treat coverage could avert up to 6700 (95% CI: 1200, 16 000) infections and cost US$27 000 (95% CI: US$15 000, US$48 000) per QALY gained, and 50% PrEP coverage could avert up to 37 000 (22 000, 58 000) infections and cost US$300 000 (95% CI: US$162 000, US$667 000) per QALY gained. When coverage expansions are allowed to include combined investment with other programs and are compared to the next best intervention, the model projects that scaling OAT coverage up to 50%, then scaling NSP coverage to 50%, then scaling Test & Treat coverage to 50% can be cost-effective, with each coverage expansion having the potential to cost less than US$50 000 per QALY gained relative to the next best portfolio. In probabilistic sensitivity analyses, 59% of portfolios prioritized the addition of OAT and 41% prioritized the addition of NSPs, while PrEP was not likely to be a priority nor a cost-effective addition. Our findings are intended to be illustrative, as data on achievable coverage are limited and, in practice, the expansion scenarios considered may exceed feasible levels. We assumed independence of interventions and constant returns to scale. Extensive sensitivity analyses allowed us to assess parameter sensitivity, but the use of a dynamic compartmental model limited the exploration of structural sensitivities.

Conclusions: We estimate that OAT, NSPs, and Test & Treat, implemented singly or in combination, have the potential to effectively and cost-effectively prevent HIV in US PWID. PrEP is not likely to be cost-effective in this population, based on the scenarios we evaluated. While local budgets or policy may constrain feasible coverage levels for the various interventions, our findings suggest that investments in combined prevention programs can substantially reduce HIV transmission and improve health outcomes among PWID.

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HIV risk, prevalence, and access to care among men who have sex with men in Lebanon

Heimer R, Barbour R, Khoury D, Crawford FW, Shebl FM, Aaraj E, Khoshnood K. AIDS Res Hum Retroviruses. 2017 Jun 29 doi: 10.1089/AID.2016.0326. [Epub ahead of print].

Objective: Little is known about HIV prevalence and risk among men who have sex with men in much of the Middle East, including Lebanon. Recent national level surveillance has suggested an increase in HIV prevalence concentrated among men in Lebanon. We undertook a biobehavioral study to provide direct evidence for the spread of HIV.

Design: MSM were recruited by respondent driven sampling, interviewed, and offered HIV testing anonymously at sites located in Beirut, Lebanon from October 2014 through February 2015. The interview questionnaire was designed to obtain information on participants' sociodemographic situation, sexual behaviors, alcohol and drug use, health, HIV testing and care, experiences of stigma and discrimination. Individuals not reporting an HIV diagnosis were offered optional, anonymous HIV testing.

Results: Among the 292 MSM recruited, we identified 36 cases of HIV (12.3%). A quarter of the MSM were born in Syria and recently arrived in Lebanon. Condom use was uncommon; 65% reported unprotected sex with other men. Group sex encounters were reported by 22% of participants. Among the 32 individuals already aware of their infection, 30 were in treatment and receiving antiretroviral therapy.

Conclusions: HIV prevalence was substantially increased over past estimates. Efforts to control future increases will have to focus on reducing specific risk behaviors and experienced stigma and abuse, especially among Syrian refugees.

Abstract

A phylogenetic analysis of HIV-1 sequences in Kiev: findings among key populations

Fearnhill E, Gourlay A, Malyuta R, Simmons R, Ferns RB, Grant P, Nastouli E, Karnets I, Murphy G, Medoeva A, Kruglov Y, Yurchenko A, Porter K; CASCADE Collaboration in EuroCoord. Clin Infec Dis 2017 May 29: doi: 10.1093/cid/cix499. [Epub ahead of print].

Background: The HIV epidemic in Ukraine has been driven by a rapid rise among people who inject drugs, but recent studies have shown an increase through sexual transmission.

Methods: Protease and RT sequences from 876 new HIV diagnoses (April 2013 - March 2015) in Kiev were linked to demographic data. We constructed phylogenetic trees for 794 subtype A1 and 64 subtype B sequences and identified factors associated with transmission clustering. Clusters were defined as ≥ 2 sequences, ≥ 80% local branch support and maximum genetic distance of all sequence pairs in the cluster ≤ 2.5%. Recent infection was determined through the LAg avidity EIA assay. Sequences were analysed for transmitted drug resistance (TDR) mutations.

Results: 30% of subtype A1 and 66% of subtype B sequences clustered. Large clusters (maximum 11 sequences) contained mixed risk groups. In univariate analysis, clustering was significantly associated with subtype B compared to A1 (OR 4.38 [95% CI 2.56-7.50]), risk group (OR 5.65 [3.27-9.75]) for men who have sex with men compared to heterosexual males, recent, compared to long-standing, infection (OR 2.72 [1.64-4.52]), reported sex work contact (OR 1.93 [1.07-3.47]) and younger age groups compared to age ≥36 (OR 1.83 [1.10-3.05] for age ≤25). Females were associated with lower odds of clustering than heterosexual males (OR 0.49 [0.31-0.77]). In multivariate analysis, risk group, subtype and age group were independently associated with clustering (p<0.001, p=0.007 and p=0.033). 18 sequences (2.1%) indicated evidence of TDR.

Conclusions: Our findings suggest high levels of transmission and bridging between risk groups.

Abstract  Full-text [free] access

Contextualizing willingness to participate: recommendations for engagement, recruitment & enrolment of Kenyan MSM in future HIV prevention trials

Doshi M, Avery L, Kaddu RP, Gichuhi M, Gakii G, du Plessis E, Dutta S, Khan S, Kimani J, Lorway RR. BMC Public Health. 2017 May 18;17(1):469 doi: 10.1186/s12889-017-4395-4.

Background: The HIV epidemic among men who have sex with men (MSM) continues to expand globally. The addition of an efficacious, prophylactic vaccine to combination prevention offers immense hope, particularly in low- and middle- income countries which bear the greatest global impact. However, in these settings, there is a paucity of vaccine preparedness studies that specifically pertain to MSM. Our study is the first vaccine preparedness study among MSM and female sex workers (FSWs) in Kenya. In this paper, we explore willingness of Kenyan MSM to participate in HIV vaccine efficacy trials. In addition to individual and socio-cultural motivators and barriers that influence willingness to participate (WTP), we explore the associations or linkages that participants draw between their experiences with or knowledge of medical research both generally and within the context of HIV/AIDS, their perceptions of a future HIV vaccine and their willingness to participate in HIV vaccine trials.

Methods: Using a social network-based approach, we employed snowball sampling to recruit MSM into the study from Kisumu, Mombasa, and Nairobi. A field team consisting of seven community researchers conducted in-depth interviews with a total of 70 study participants. A coding scheme for transcribed and translated data was developed and the data was then analysed thematically.

Results: Most participants felt that an HIV vaccine would bring a number of benefits to self, as well as to MSM communities, including quelling personal fears related to HIV acquisition and reducing/eliminating stigma and discrimination shouldered by their community. Willingness to participate in HIV vaccine efficacy trials was highly motivated by various forms of altruism. Specific researcher responsibilities centred on safe-guarding the rights and well-being of participants were also found to govern WTP, as were reflections on the acceptability of a future preventive HIV vaccine.

Conclusion: Strategies for engagement of communities and recruitment of trial volunteers for HIV vaccine efficacy trials should not only be grounded in and informed by investigations into individual and socio-cultural factors that impact WTP, but also by explorations of participants' existing experiences with or knowledge of medical research as well as attitudes and acceptance towards a future HIV vaccine.

Abstract  Full-text [free] access

 

Africa, Asia, Northern America
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H*V – can we do better for HIV, HBV and HCV if we all work together?

Editor’s notes: The Sustainable Development Goals (SDGs) signal a major shift in the way that the United Nations and her development partners aim to shape the next decades.  Whereas the Millennium Development Goals reinforced specific programmes for HIV, tuberculosis and malaria, the SDGs call for a more integrated approach to health and well-being and encourage integration and synergy wherever it makes sense.  Hepatitis is one obvious area in which better collaboration and coordination could yield benefits.  Hepatitis B (HBV) and C (HCV) viruses are both more common in some of the populations most affected by HIV.  HCV can now be cured with drugs that derive directly from the HIV portfolio, while some ARVs have a direct effect on HBV.

Rwanda is one of the first countries in sub-Saharan Africa to set up a control programme for viral hepatitis, building on the infrastructure established for HIV. Umutesi and colleagues report on results of screening almost 120 000 people living with HIV who entered care for markers of HBV and HCV.  Around 5000 people (4.3%) were identified with a positive Hepatitis B surface antigen and a similar number (4.6%) were found to have antibodies against HCV.  There was marked variation geographically with a range by district from 2%-11% for HBV, higher in more urban areas and in men.  For HCV the range was from 3%-8% and was higher in more rural areas, and also in men.  This study provides a good platform to estimate numbers of people who might need treatment and to plan the next steps in an integrated programme.

People who inject drugs are particularly severely affected by HCV, and so co-infection with both HIV and HCV is common in areas where both viruses circulate.  Some estimates from Ho Chi Minh City in Viet Nam suggest that more than 40% of people who inject drugs are living with HIV and that essentially all of these people are also co-infected with HCV.  Birger R and colleagues developed a mathematical model to explore the likely impact of interventions aimed at HIV, HCV or broad harm reduction [with methadone maintenance treatment (MMT)] on future mortality and incidence of both infections.  While ART scale up reduces HIV incidence and mortality, it has no effect on HCV.  MMT is effective at reducing incidence of both HIV and HCV (and has morbidity and mortality benefits beyond these viruses).  However, MMT does not help the many people already living with HCV and so has little effect on HCV related mortality. So the model is clear that treatment for HCV needs to be an important part of a combined programme and that we urgently need to find ways to reduce the price of directly acting antivirals if we are to save more Vietnamese lives.

Haldane and colleagues have also focused on this intersection between HIV and substance use services.  They carried out a systematic review to understand the models and implications of integration of service delivery.  The authors expand their typology of integration models considering the point of entry of the client, and the degree to which services are co-located and delivered.  Integration can be considered as “clinical”, “service” or “systems”.  The first two can operate at the micro or meso level meaning that individual staff can deal with both situations, or that staff are trained to provide appropriate referrals.  Systems level integration operates at a macro level and implies that programmes for each service make collaborations and coordinate in ways that may affect staffing, funding and fragmentation of services. Although there are theoretical advantages to coordination and integration (as shown by the mathematical model above), there are few good empirical studies of integrated service delivery reported outside the USA.  The authors considered that most of the intervention studies had a risk of bias in the interpretation of their impact, although all demonstrated positive changes in outcomes.  Furthermore, almost all the studies focussed on integration at the clinic or individual provider level (meso or micro) rather than addressing the larger systemic challenges that we need to consider.  If we are to achieve the ideals laid out in the Sustainable Development Goals, we will need to overcome some of these systemic challenges, particularly for populations that are criminalized and marginalized by many of the public services.

Prevalence of hepatitis B and C infection in persons living with HIV enrolled in care in Rwanda.

Umutesi J, Simmons B, Makuza JD, Dushimiyimana D, Mbituyumuremyi A, Uwimana JM, Ford N, Mills EJ, Nsanzimana S. BMC Infect Dis. 2017 May 2;17(1):315. doi: 10.1186/s12879-017-2422-9.

Background: Hepatitis B (HBV) and C (HCV) are important causes of morbidity and mortality in people living with human immunodeficiency virus (HIV). The burden of these co-infections in sub-Saharan Africa is still unclear. We estimated the prevalence of the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCVAb) among HIV-infected individuals in Rwanda and identified factors associated with infection.

Methods: Between January 2016 and June 2016, we performed systematic screening for HBsAg and HCVAb among HIV-positive individuals enrolled at public and private HIV facilities across Rwanda. Results were analyzed to determine marker prevalence and variability by demographic factors.

Results: Overall, among 117 258 individuals tested, the prevalence of HBsAg and HCVAb was 4.3% (95% confidence interval [CI] (4.2-4.4) and 4.6% (95% CI 4.5-4.7) respectively; 182 (0.2%) HIV+ individuals were co-infected with HBsAg and HCVAb. Prevalence was higher in males (HBsAg, 5.4% [5.1-5.6] vs. 3.7% [3.5-3.8]; HCVAb, 5.0% [4.8-5.2] vs. 4.4% [4.3-4.6]) and increased with age; HCVAb prevalence was significantly higher in people aged ≥65 years (17.8% [16.4-19.2]). Prevalence varied geographically.

Conclusion: HBV and HCV co-infections are common among HIV-infected individuals in Rwanda. It is important that viral hepatitis prevention and treatment activities are scaled-up to control further transmission and reduce the burden in this population. Particular efforts should be made to conduct targeted screening of males and the older population. Further assessment is required to determine rates of HBV and HCV chronicity among HIV-infected individuals and identify effective strategies to link individuals to care and treatment.

Abstract  Full-text [free] access

The impact of HCV therapy in a high HIV-HCV prevalence population: A modeling study on people who inject drugs in Ho Chi Minh City, Vietnam.

Birger RB, Le T, Kouyos RD, Grenfell BT, Hallett TB. PLoS One. 2017 May 11;12(5):e0177195. doi: 10.1371/journal.pone.0177195. eCollection 2017.

Background: Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection is a major global health problem especially among people who inject drugs (PWID), with significant clinical implications. Mathematical models have been used to great effect to shape HIV care, but few have been proposed for HIV/HCV.

Methods: We constructed a deterministic compartmental ODE model that incorporated layers for HIV disease progression, HCV disease progression and PWID demography. Antiretroviral therapy (ART) and Methadone Maintenance Therapy (MMT) scale-ups were modeled as from 2016 and projected forward 10 years. HCV treatment roll-out was modeled beginning in 2026, after a variety of MMT scale-up scenarios, and projected forward 10 years.

Results: Our results indicate that scale-up of ART has a major impact on HIV though not on HCV burden. MMT scale-up has an impact on incidence of both infections. HCV treatment roll-out has a measurable impact on reductions of deaths, increasing multifold the mortality reductions afforded by just ART/MMT scale-ups.

Conclusion: HCV treatment roll-out can have major and long-lasting effects on averting PWID deaths on top of those averted by ART/MMT scale-up. Efficient intervention scale-up of HCV alongside HIV interventions is critical in Vietnam.

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Integrating HIV and substance use services: a systematic review

Haldane V, Cervero-Liceras F, Chuah FL, Ong SE, Murphy G, Sigfrid L, Watt N, Balabanova D, Hogarth S, Maimaris W, Buse K, Piot P, McKee M, Perel P, Legido-Quigley H. Journal of the International AIDS Society. 2017 May 30;20(1).http://dx.doi.org/10.7448/IAS.20.1.21585.

Introduction: Substance use is an important risk factor for HIV, with both concentrated in certain vulnerable and marginalized populations. Although their management differs, there may be opportunities to integrate services for substance use and HIV. In this paper we systematically review evidence from studies that sought to integrate care for people living with HIV and substance use problems.

Methods: Studies were included if they evaluated service integration for substance use and HIV. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias.

Results and discussion: 11 057 records were identified, with 7616 after removal of duplicates. After screening titles and abstracts, 51 met the inclusion criteria. Integration models were categorized by location (HIV, substance use and other facilities), level of integration from micro (integrated care delivered to individuals) to macro (system level integrations) and degree of integration from least (screening and counselling only) to most (care for HIV, substance use and/or other illnesses at the same facility). Most reported descriptive or cohort studies; in four randomized control trials integrated activities improved patient outcomes. There is potential for integrating services at all facility types, including mobile health services. While services offering screening only can achieve synergies, there are benefits from delivering integrated treatment for HIV and substance use, including ease of referral to other mental health and social services.

Conclusions: Our review used a wide range of databases and conference archives to increase representation of papers from low- and middle-income countries. Limitations include the overrepresentation of studies from the United States, and the descriptive nature of the majority of papers. The evidence reviewed shows that greater integration offers important benefits in both patient and service outcomes but further research and outcome reporting is needed to better understand innovative and holistic care models at the complex intersection of substance use and HIV services.

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Africa, Asia, Europe, Northern America
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Increasing HIV testing by sharing the load and updating tasks and traditions for traditional birth attendants and lay providers

Editor’s notes: Nigeria still has the highest number of new HIV infections among children in the world, around 40 000 annually, with the large majority arising from mother to child transmission.  In Nigeria, less than 20% of pregnant women receive HIV testing. This is due to several issues which include a limited number of HIV testing service delivery points and a limited number of deliveries taking place at health facilities.  Around two thirds of deliveries take place at home, traditionally supported by traditional birth attendants (TBAs).  Many TBAs in Nigeria have little knowledge of either the benefits or practice of HIV testing, nor of ways to reduce transmission of HIV to infants.

Chizoba and colleagues have developed and tested a model of antenatal care that aims to integrate TBAs within the government primary health care (PHC) network.  The intervention consisted of PHC clinics identifying a few TBAs who operated in the catchment area of the clinic. Between one and five of these TBAs was invited to the PHC clinic for a one-day training on HIV point of care testing, and asked to refer all women found to be positive to the clinic for confirmation and follow up.  Once a month TBAs came to the clinic for encouragement and to provide data on tests performed.  Once a quarter, the clinic visited the TBAs to provide supervision, mentoring and quality improvement training.  The TBAs were also paid $2 for every pregnant woman whom they tested for HIV, in order to compensate them for any loss of earnings from pregnant women living with HIV who would now be seen in the clinic rather than delivering at home. 

The authors used a quasi-experimental design for this study. Out of the 74 PEPFAR supported PHC clinics that provided HIV services in their antenatal clinics in Ebonyi state of Nigeria, 34 were interested in this new integrated approach, whereas 40 expressed no interest.  20 clinics were chosen at random from each of these categories, to avoid additional selection bias.  (Although as the authors state, there may already be considerable differences between the clinics that were interested and clinics that were not).  Comparisons were made before and after the programme was put in place, and also between clinics in the intervention group and those in the group that had not been interested to integrate services with the TBAs.

Despite this non-randomized design, the results are quite striking with more than twice as many women receiving HIV testing in the intervention clinics in the six months after the intervention began (going up from 2501 to 5346 across the 20 clinics).  There was no such increase in the non-intervention areas (which saw a change from 1770 to 1892 across the 20 clinics).  Furthermore the large majority of the increase was among women who had been tested by the TBAs. 

While this is hugely encouraging and a big increase, it will be important to see if the increase can be sustained as it is a significant change in the way that the TBAs and the PHC clinic staff work.  It is also not clear how much the increase is a result of the integration model and how much it relates to the additional payment that TBAs receive, which seems to amount to around $100 per TBA over the 6 month period of the assessment.

A thorough review of the role of trained lay providers in performing HIV tests was carried out as part of the WHO process that led to the guidance in 2015 that “Lay providers who are trained and supervised to use rapid diagnostic tests (RDTs) can independently conduct safe and effective HIV testing services.” Kennedy and colleagues now present the details of that systematic review.

Many national policies, particularly in African countries allow for HIV testing by trained lay providers using rapid diagnostic tests (RDTs) and even more allow lay providers to perform pre- and post-test counselling (around 80% of African countries in one survey of policies).  However, some countries limit these roles to trained healthcare providers due to concerns about lay providers’ ability to perform the tests accurately and reliably and to deliver high quality pre- and post-test counselling, linkage to appropriate prevention and clinical care services, and coordination with laboratory services to ensure the delivery of correct test results.

Despite widespread use of lay providers, there are actually rather few studies that directly compare the outcomes of testing between lay and professional providers.  The authors reviewed over 6000 titles, abstracts or full articles and found only five that allowed a direct comparison, while an additional six studies allowed the values and preferences of clients and providers to be assessed.

While this evidence base is very limited, findings from the single randomized trial (in the US) and one observational study (in Malawi), that compared pre- and post-intervention time periods, suggest that using trained lay providers can increase HIV testing uptake.  Three studies compared the quality of testing between lay providers and professional providers and found that both can achieve similar testing quality. Unfortunately, no studies measured adverse events following testing, nor linkage to care. The six values and preferences studies, also found support for lay providers.

This is the key evidence that underpins the strong recommendation from WHO and now also from many national authorities, that trained lay providers are an essential component in the efforts to scale up HIV testing in order to reach the first 90.

Increasing HIV testing among pregnant women in Nigeria: evaluating the traditional birth attendant and primary health center integration (TAP-In) model.

Chizoba AF, Pharr JR, Oodo G, Ezeobi E, Ilozumb J, Egharevba J, Ezeanolue EE, Nwandu A. AIDS Care. 2017 Apr 18:1-5. doi: 10.1080/09540121.2017.1317325. [Epub ahead of print]

Engaging Traditional Birth Attendants (TBAs) may be critical to preventing mother-to-child transmission of HIV (PMTCT) in Nigeria. We integrated TBAs into Primary Health Centers (PHCs) and provided the TBAs with HIV counseling and testing (HCT) training for PMTCT (TAP-In). The purpose of this study was to evaluate the impact of TAP-In on HCT uptake among pregnant women. A quasi-experimental design was used for this study. Twenty PHCs were assigned to the intervention group that integrated TAP-In and 20 were assigned to the control group. Data were collected six months prior to the initiation of TAP-In and six months post, using antenatal clinic registries. Intervention PHCs more than doubled the number of pregnant women who received HCT in their catchment area post TAP-In while control PHCs had no significant change. After initiating TAP-In, intervention PHCs provided almost three times more HCT than the control PHCs (p < 0.01) with TBA provided over half of the HCT post TAP-In. The TAP-In model was effective for increasing HCT among pregnant women.

Abstract access 

Should trained lay providers perform HIV testing? A systematic review to inform World Health Organization guidelines.

Kennedy CE, Yeh PT, Johnson C, Baggaley R. AIDS Care. 2017 Apr 24:1-7. doi:10.1080/09540121.2017.1317710. [Epub ahead of print.]

New strategies for HIV testing services (HTS) are needed to achieve UN 90-90-90 targets, including diagnosis of 90% of people living with HIV. Task-sharing HTS to trained lay providers may alleviate health worker shortages and better reach target groups. We conducted a systematic review of studies evaluating HTS by lay providers using rapid diagnostic tests (RDTs). Peer-reviewed articles were included if they compared HTS using RDTs performed by trained lay providers to HTS by health professionals, or to no intervention. We also reviewed data on end-users' values and preferences around lay providers preforming HTS. Searching was conducted through 10 online databases, reviewing reference lists, and contacting experts. Screening and data abstraction were conducted in duplicate using systematic methods. Of 6113 unique citations identified, 5 studies were included in the effectiveness review and 6 in the values and preferences review. One US-based randomized trial found patients' uptake of HTS doubled with lay providers (57% vs. 27%, percent difference: 30, 95% confidence interval: 27-32, p < 0.001). In Malawi, a pre/post study showed increases in HTS sites and tests after delegation to lay providers. Studies from Cambodia, Malawi, and South Africa comparing testing quality between lay providers and laboratory staff found little discordance and high sensitivity and specificity (≥98%). Values and preferences studies generally found support for lay providers conducting HTS, particularly in non-hypothetical scenarios. Based on evidence supporting using trained lay providers, a WHO expert panel recommended lay providers be allowed to conduct HTS using HIV RDTs. Uptake of this recommendation could expand HIV testing to more people globally.

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Africa, Asia
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How do we know which activities make a difference to HIV prevention?

Editor’s notes: In order to be fairly certain that an intervention is responsible for changes in HIV or HIV-related behaviours, the gold standard is randomization. This allows for fair comparisons between groups, since factors that might alter the outcomes will be more or less equally balanced between the study groups.  This is true whether such confounding factors are expected, but also importantly, even those factors that are unknown, unexpected and unmeasured will also be balanced between the arms. 

A second key determinant of high quality research is to use an approach that maximizes full engagement and follow-up of participants in the study.  One such approach that is widely recognized is to use Good Participatory Practice.  

Rhodes and colleagues study condom promotion and HIV testing among the Hispanic/Latino community of gay men and other men who have sex with men in North Carolina, USA.  Although gay men and other men who have sex with men represent approximately 4% of the adult male population in the United States of America, they account for more than 80% of new HIV infections among men.  Around one quarter of gay men and other men who have sex with men are Hispanic or Latino.  The authors therefore wanted to use research to make a difference to the HIV burden of the Hispanic/Latino gay men and other men who have sex with men community in North Carolina, USA.  They found that despite the impact of HIV on Hispanic/ Latino gay men and other men who have sex with men, they were only able to identify one evidence-based behavioural HIV prevention programme focussed on this population.

The authors used an extensive community based participatory research partnership, whose members represented the Hispanic/ Latino gay men and other men who have sex with men community, AIDS service organizations, Hispanic/Latino-serving community organizations, and universities to develop, implement, and evaluate a Spanish-language, small group intervention designed to increase condom use and HIV testing among Hispanic/Latino gay men and other men who have sex with men (HOLA en Grupos).

304 participants were randomly allocated to the HOLA en Grupos intervention, or to a general health education comparison intervention having the same number of sessions (4) and duration (16 hours in total) that focussed on prostate, lung, and colorectal cancers; diabetes; high cholesterol; cardiovascular disease; and alcohol misuse. These topics for the control group were identified on the basis of identified needs and priorities of Hispanic/Latino gay men and other men who have sex with men.

HOLA en Grupos is grounded on social cognitive theory, empowerment education, and traditional Hispanic/Latino cultural values and includes four interactive modules of four hours each delivered in groups.  Participants in both intervention and control arms received reimbursement for their time, certificates of completion and meals and a celebration at the completion of the course.  In other words this was an intensive intervention that might be hard to replicate in most settings, but it follows very high standards both for developing and conducting the research and also for determining the impact of the intervention.

The intervention was associated with a large effect on both condom usage (four-fold higher in the intervention arm than the control) and HIV test uptake (an astonishing 14-fold higher, reflecting the relatively low testing rate in the control group).

A major limitation in many HIV prevention studies, including this one, is that the outcome is based on reported behaviour.  The challenge is that the real outcome of interest, which is new HIV infections, is relatively rare in almost all communities so that studies have to be huge and expensive, and the large majority of participants in both intervention and control arms do not in fact acquire HIV.  This is in contrast to most studies of treatment, where there are clearly defined biological, standardized measures which many or all participants are likely to reach.  Nonetheless, there are many examples of studies that find changes in reported behaviour that are not associated with biological markers of such change (such as incidence of HIV or other sexually transmitted infections, or pregnancy). 

There are also many observational or ecological studies that report changes in new HIV infections but that cannot truly say why the number of infections fell and whether the interventions used in the study were responsible for the changes.  For example Nwokolo and colleagues report in a short research letter on the dramatic decline in new HIV diagnoses in the large London clinic where they work.  New infections in that clinic, and in fact in other large clinics in London, have dropped by a remarkable 40% from 2015 to 2016, as originally reported in the popular science press before any scientific publication or presentation. The authors of the research letter are suitably cautious about how to account for the impressive decline.  Various systems have been improved over the past few years in this clinic to make it easier to have an HIV test and start treatment immediately.  However, most of the clinic team (and many other commentators) assume that it is also due to the rapid rise in the use of PrEP.  Although it is still not available through the UK National Health Service, the clinic has been at the forefront of encouraging gay men and other men who have sex with men who might benefit from PrEP to purchase it from on-line pharmacies.  The clinic then provides the appropriate monitoring and follow up to ensure that their clients get the best possible PrEP service given the current constraints.  Whatever the cause, we should be celebrating the rapid fall in new HIV infections across London, which is home to a substantial proportion of the new HIV infections in the UK.

The challenges of demonstrating evidence of effectiveness for HIV prevention is also felt among black women in the USA.  Although they have the highest burden of HIV among women in the USA, the incidence rates are such that a traditional randomized trial design would need to be huge, and consequently hugely expensive.  Adimora and colleagues consider whether an alternative trial design might be to use data from high HIV incidence settings and then to develop proxies of protection, such as the concentration of a PrEP medicine to infer whether black women are protected.  An alternative that has been proposed for men who have sex with men would be to look for other markers of high risk, such as sexually transmitted infections, reported partners, age, and substance use and estimate the likely risk of HIV acquisition in the absence of PrEP from these parameters.  Then the observed incidence could be compared to this modelled counterfactual, much as was done in the open label extension of the Partners PrEP study in Kenyan and Ugandan sero-different couples.  However, translating risk factors for infection across populations, and even continents when there is such heterogeneity in risk of infection is not at all straightforward.  So there is still plenty to think about and no clear answers yet!

A useful addition to the tool box for designing studies and assessing the effectiveness of interventions, would be better tools for measuring recent infection.  There are several assays all with differing characteristics but increasingly these differences and how they interact with different clades of HIV are becoming clear.  Key determinants for each assay are the mean duration of recent infection (MDRI) estimate (which does seem to vary by clade) and the false recency rate (FRR) which needs to be less than 2% to be considered useful.  Hargrove and colleagues used three different assays to test samples from 101 women who seroconverted during the ZVITAMBO trial.  The MDRI measured using standard cut-off points, were considerably shorter than those published for the general population.  The authors point out that changes in antibody properties among women who have recently given birth or other unspecified physiological states, mean that incidence assays may give different results from those published and expected.  Yet more caution when comparing incidence estimates between studies.  As an endpoint in a comparison between two groups in the same population, the assays are still attractive. Although, given typical MDRIs of around six to nine months, these assays will still need to be embedded in very large samples to give reliable estimates of incidence and statistically significant differences between groups.

This month saw the production of a useful supplement on many aspects of how data from different sources, including incidence assays are used to inform the sophisticated models on which so much HIV planning, programming and financing is based.  An example is Mahiane and colleagues’ paper on the development of a new tool to fit existing programme data into the spectrum suite of models in order to estimate incidence.

Finally in this section, for those who are keen on laboratory studies, Richardson-Harman and colleagues describe the current state of ex-vivo challenge models for assessing potential candidates as microbicides.  In these models, biopsies of rectal, cervical or vaginal tissue, taken during other procedures, or from volunteers, are kept alive in the laboratory.  The tissues can then be challenged with HIV in the presence or absence of potential microbicide products.  The current model works best for rectal tissues, in which infection occurs promptly and consistently, so that the effect of a microbicide can clearly be seen by a reduction in the production of HIV p24 antigen.  However, for cervical and vaginal tissues, the infection (in the absence of any microbicide) was less consistent, slower and lasted longer making it less easy to determine statistical differences between those tissues with microbicide and those without.  Further work of this sort may help to streamline the choice of microbicide or PrEP products that can most sensibly be taken out of the laboratory and into the (almost) real world of clinical trials.

Small-group randomized controlled trial to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Rhodes SD, Alonzo J, Mann L, Song EY, Tanner AE, Arellano JE, Rodriguez-Celedon R, Garcia M, Freeman A, Reboussin BA, Painter TM. Am J Public Health. 2017 Jun;107(6):969-976. doi: 10.2105/AJPH.2017.303814. Epub 2017 Apr 20.

Objectives: To evaluate the HOLA en Grupos intervention, a Spanish-language small-group behavioral HIV prevention intervention designed to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Methods: In 2012 to 2015, we recruited and randomized 304 Hispanic/Latino men who have sex with men, aged 18 to 55 years in North Carolina, to the 4-session HOLA en Grupos intervention or an attention-equivalent general health education comparison intervention. Participants completed structured assessments at baseline and 6-month follow-up. Follow-up retention was 100%.

Results: At follow-up, relative to comparison participants, HOLA en Grupos participants reported increased consistent condom use during the past 3 months (adjusted odds ratio [AOR] = 4.1; 95% confidence interval [CI] = 2.2, 7.9; P < .001) and HIV testing during the past 6 months (AOR = 13.8; 95% CI = 7.6, 25.3; P < .001). HOLA en Grupos participants also reported increased knowledge of HIV (P < .001) and sexually transmitted infections (P < .001); condom use skills (P < .001), self-efficacy (P < .001), expectancies (P < .001), and intentions (P < .001); sexual communication skills (P < .01); and decreased fatalism (P < .001).

Conclusions: The HOLA en Grupos intervention is efficacious for reducing HIV risk behaviors among Hispanic/Latino men who have sex with men.

Abstract access 

Not just PrEP: other reasons for London's HIV decline.

Nwokolo N, Whitlock G, McOwan A. Lancet HIV. 2017 Apr;4(4):e153. doi: 10.1016/S2352-3018(17)30044-9.

The reduction in HIV diagnoses in London in 2016 is attributed to pre-exposure prophylaxis (PrEP). We believe that the causes of the 42% decline seen at our clinic are likely to be multifactorial. 56 Dean Street diagnoses one in four of London's HIV cases, 50% of whom have incident infection (ie, within 4 months of infection). Because of this, and following the results of the START study, we actively recommend treatment at, or close to, diagnosis, reducing the risk of transmission in people who would otherwise be highly infectious.

Abstract access 

US black women and HIV prevention: time for new approaches to clinical trials.

Adimora AA, Cole SR, Eron JJ Clin Infect Dis. 2017 Apr 5. doi: 10.1093/cid/cix313. [Epub ahead of print]. 

Black women bear the highest burden of HIV infection among US women. Tenofovir/ emtricitabine HIV prevention trials among women in Africa have yielded varying results. Ideally, a randomized controlled trial (RCT) among US women would provide data for guidelines for US women's HIV pre-exposure prophylaxis use. However, even among US black women at high risk for HIV infection, sample size requirements for an RCT with HIV incidence as its outcome are prohibitively high. We propose to circumvent this large sample size requirement by evaluating relationships between HIV incidence and drug concentrations measured among participants in traditional phase 3 trials in high incidence settings - and then applying these observations to drug concentrations measured among at risk individuals in lower incidence settings, such as US black women. This strategy could strengthen the evidence base to enable black women to fully benefit from prevention research advances and decrease racial disparities in HIV rates.

Abstract access 

Heightened HIV antibody responses in postpartum women as exemplified by recent infection assays: implications for incidence estimates.

Hargrove JW, van Schalkwyk C, Humphrey JH, Mutasa K, Ntozini R, Owen SM, Masciotra S, Parekh BS, Duong YT, Dobbs T, Kilmarx PH, Gonese E. AIDS Res Hum Retroviruses. 2017 May 24. doi: 10.1089/AID.2016.0319. [Epub ahead of print].

Laboratory assays that identify recent HIV infections are important for assessing impacts of interventions aimed at reducing HIV incidence. Kinetics of HIV humoral responses can vary with inherent assay properties, and between HIV subtypes, populations, and physiological states. They are important in determining mean duration of recent infection (MDRI) for antibody-based assays for detecting recent HIV infections. We determined MDRIs for multi-subtype peptide representing subtypes B, E and D (BED)-capture enzyme immunoassay, limiting antigen (LAg), and Bio-Rad Avidity Incidence (BRAI) assays for 101 seroconverting postpartum women, recruited in Harare from 1997 to 2000 during the Zimbabwe Vitamin A for Mothers and Babies trial, comparing them against published MDRIs estimated from seroconverting cases in the general population. We also compared MDRIs for women who seroconverted either during the first 9 months, or at later stages, postpartum. At cutoffs (C) of 0.8 for BED, 1.5 for LAg, and 40% for BRAI, estimated MDRIs for postpartum mothers were 192, 104, and 144 days, 33%, 32%, and 52% lower than published estimates of 287, 152 and 298 days, respectively, for clade C samples from general populations. Point estimates of MDRI values were 7%-19% shorter for women who seroconverted in the first 9 months postpartum than for those seroconverting later. MDRI values for three HIV incidence biomarkers are longer in the general population than among postpartum women, particularly those who recently gave birth, consistent with heightened immunological activation soon after birth. Our results provide a caution that MDRI may vary significantly between subjects in different physiological states.

Abstract access 

Improvements in Spectrum's fit to program data tool.

Mahiane SG, Marsh K, Grantham K, Crichlow S, Caceres K, Stover J.  AIDS. 2017 Apr;31 Suppl 1:S23-S30. doi: 10.1097/QAD.0000000000001359.

Objective: The Joint United Nations Program on HIV/AIDS-supported Spectrum software package (Glastonbury, Connecticut, USA) is used by most countries worldwide to monitor the HIV epidemic. In Spectrum, HIV incidence trends among adults (aged 15-49 years) are derived by either fitting to seroprevalence surveillance and survey data or generating curves consistent with program and vital registration data, such as historical trends in the number of newly diagnosed infections or people living with HIV and AIDS related deaths. This article describes development and application of the fit to program data (FPD) tool in Joint United Nations Program on HIV/AIDS' 2016 estimates round.

Methods: In the FPD tool, HIV incidence trends are described as a simple or double logistic function. Function parameters are estimated from historical program data on newly reported HIV cases, people living with HIV or AIDS-related deaths. Inputs can be adjusted for proportions undiagnosed or misclassified deaths. Maximum likelihood estimation or minimum chi-squared distance methods are used to identify the best fitting curve. Asymptotic properties of the estimators from these fits are used to estimate uncertainty.

Results: The FPD tool was used to fit incidence for 62 countries in 2016. Maximum likelihood and minimum chi-squared distance methods gave similar results. A double logistic curve adequately described observed trends in all but four countries where a simple logistic curve performed better.

Conclusion: Robust HIV-related program and vital registration data are routinely available in many middle-income and high-income countries, whereas HIV seroprevalence surveillance and survey data may be scarce. In these countries, the FPD tool offers a simpler, improved approach to estimating HIV incidence trends.

Abstract access 

Analytical advances in the ex vivo challenge efficacy assay.

Richardson-Harman N, Parody R, Anton P, McGowan I, Doncel G, Thurman AR, Herrera C, Kordy K, Fox J, Tanner K, Swartz G, Dezzutti CS. AIDS Res Hum Retroviruses. 2017 Apr;33(4):395-403. doi: 10.1089/AID.2016.0073. Epub 2016 Dec 16.

The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n = 502), cervical (n = 88), and vaginal (n = 110) tissues were challenged with HIV-1BaL ex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05), but a larger sample size was predicted to be needed for either cervical (n = 21) or vaginal (n = 10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.

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Short and sweet? Do study participants prefer shorter or longer consent forms? Do they understand the contents?

Editor’s notes: As described above in the HOLA en Grupos study, engagement and partnership is vital if HIV research is to produce useful and relevant results.  The ethics of research involving human subjects continues to evolve but the key principles laid out by Beauchamp and Childress in 1989 remain central.  The principles of autonomy, non-maleficence, beneficence, and justice, have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care.

Autonomy implies that research participants should be able to consent willingly to join a research study and a key part of that informed consent process is usually a written “consent form” that is signed by the participant.  However, a major challenge is often to ensure that on the one hand all relevant information about possible benefits and harms is included in the information and on the other hand that the consent process is manageable and appropriate for the participant.

In the largest study of its kind to date, Grady and colleagues embedded a randomized trial within the larger randomized START trial (comparing immediate with deferred start of antiretroviral medicines in people with early HIV infection).  Around 4000 participants in START were allocated according to their 154 research sites, which were randomly assigned to the original, lengthy and somewhat complicated consent form, or to a simplified, shorter consent form with much more attention paid to ease of comprehension and readability.  The shorter form was still around 1800 words long (compared to the almost 6000 of the original) and was only a little easier to read, because the sponsors of the study needed to be certain that all the information demanded by current guidelines was included.

Surprisingly, there was no overall difference in either the primary outcome (an understanding that participants’ treatment would be randomly allocated) or in overall comprehension of aspects of the study.  In other words, the authors did NOT find the advantages that they were expecting from the modified consent form.

However, various clear trends emerge from the data that are relevant to future research too.  Those with less education were clearly less able to understand the randomization approach.  73% of the 1240 participants who had not attended high school compared to more than 90% of the 935 who had completed a university degree or postgraduate education answered the primary question on randomization correctly. The START study team were diligent in explaining the study to potential participants before presenting the informed consent form, with around a half of participants reporting more than an hour of explanation prior to being asked for consent, and more than 80% of sites reporting that participants understood the study “very well” prior to the consent process.  There was also a clear trend for participants from sites that had been involved in previous HIV research to understand the process better (rising from 69% in those with no previous HIV studies to 85% in those with more than 10).

Increasingly HIV prevention researchers are aiming to work with populations that have high ongoing incidence of HIV.  In a world where treatment is increasingly widespread and overall numbers of infections have fallen somewhat, this means that researchers will tend to be working with more and more disadvantaged populations where many participants may be less well educated and less familiar with research.  This important study makes it clear that the ethical principle of autonomy requires an ongoing process that goes far beyond the choice of words in a consent form.  Research must build trust between researchers and participants.  The research team should explain carefully and in appropriate ways what is involved in the study and what options participants have. Study teams should build a governance process into the research so that participants can have confidence that any risks of the research, both for them as individuals, but also often for the community or group to which they belong, are monitored and mitigated.  In this way potentially vulnerable individuals may still be recruited into important research projects and contribute to the ways in which science can end the epidemic.

A randomized trial comparing concise and standard consent forms in the START trial.

Grady C, Touloumi G, Walker AS, Smolskis M, Sharma S, Babiker AG, Pantazis N, Tavel J, Florence E, Sanchez A, Hudson F, Papadopoulos A, Emanuel E, Clewett M, Munroe D, Denning E; INSIGHT START Informed Consent substudy Group PLoS One. 2017 Apr 26;12(4):e0172607. doi: 10.1371/journal.pone.0172607. eCollection 2017.

Background: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed.

Methods: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin).

Results: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups.

Conclusions: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient.

Trial registration: Informed consent substudy was registered as part of START study in clinicaltrials.gov #NCT00867048, and EudraCT # 2008-006439-12.

Abstract Full-text [free] access 

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Non-communicable diseases and co-morbidities – the flip side of successful ART programmes?

Editor’s notes: As the population of people living with HIV grows older and lives longer, the importance of non-communicable diseases is increasing.  Several studies this month explored various aspects of this intersection.

An encouraging study from Spain by Sorigué M et al., analysed the outcomes of patients with advanced stage Hodgkin’s lymphoma, a relatively common cancer both among people living with HIV and the HIV-negative population. The authors showed that, in the era of combined antiretroviral therapy, the complete response rate and ten year survival were not significantly different among people living with HIV (89% and 73%) and HIV negative people (91% and 68%).

Another broadly encouraging study from Ireland by Tinago W et al., followed up 384 people (176 living with HIV) to determine changes over three years in their bone mineral density (BMD).  BMD was somewhat lower in the people living with HIV, despite the group being younger on average.  As expected, BMD gradually fell with increasing age but the rate of bone loss was no different between people living with HIV and HIV negative people.  88% of the people living with HIV were on ART at the start of the study period.  Not having started ART among people living with HIV was associated with lower BMD and people who had started more recently showed the largest declines in BMD.  This suggests (as has previously been shown in cohorts of people living with HIV) that after an initial loss in BMD, the rate of loss stabilizes and is similar to HIV-negative people.  Interestingly, the authors did not show that overall exposure to tenofovir disproxil fumarate (TDF) was particularly associated with greater BMD loss over the course of follow up, despite several previous randomized trials confirming that TDF does cause BMD loss when it is started.

While on the subject of TDF, this month saw two important regulatory trials of tenofovir alafenamide (TAF), sponsored by the manufacturers Gilead Sciences.  630 people living with HIV on treatment with rilpivirine, emtricitabine and TDF whose viral load was supressed, were randomly allocated to remain on the same regimen or to swap the TDF for TAF.  TAF is a pro-drug, that reduces the plasma concentrations of tenofovir and is therefore expected to reduce the renal and bone toxicities associated with TDF while still delivering active drug to the cells where it is needed.  One year later, viral suppression was very similar in the two groups (94%).  There was also no significant difference seen in the side effects over this one year period, with no serious adverse events and 6% vs. 12% having some side effects in the TAF and TDF arms respectively [Orkin C and colleagues].

A related study by DeJesus E et al. with the same design was conducted among people taking efavirenz, emtricitabine and tenofovir, one of the most common first line regimens throughout the world. In this trial the efavirenz was switched to rilpivirine and the TDF to TAF.  875 people living with HIV whose viral load was supressed were randomized and after one year viral suppression was very similar in the two groups (90-92%).  There was also no significant difference seen in the side effects over this one year period, with no serious adverse events and 13% vs. 10% having some side effects in the rilpivirine -TAF and efavirenz-TDF arms respectively.

Returning to co-morbidities and non-communicable diseases, a study by Rodríguez-Arbolí E and colleagues in rural Tanzania has shown that 11.6% of people living with HIV who had not yet started ART had raised blood pressure.  A further 9.6% develop raised blood pressure during follow up, an incidence of 12 per 100 person years. The risk factors for developing hypertension were those well recognized in HIV-negative populations (age, renal disease and being overweight) and not specifically related to HIV infection, ART or immunological status.  The authors recommend integration of non-communicable disease screening and management into HIV care clinics but a larger conclusion might be to improve management of hypertension more generally, as it affects both people living with HIV and people without.

In contrast, a study by Pollack TM et al. from Viet Nam shows that smoking tobacco is associated with a higher viral load among people living with HIV presenting for ART.  As would be expected, other predictors of more advanced HIV disease such as lower CD4 counts and lower BMI and prior TB were all associated with a higher viral load at presentation.  Male sex was also significantly associated with a higher viral load.  The authors point out various other studies from Cameroon and the US that have shown similar and related interactions between smoking tobacco, viral load at presentation or viral load suppression or rebound on ART treatment.  Other studies in the US have not found this association.  One of the challenges is to separate behavioural factors that might be confounders – perhaps people who smoke are more likely to present late.  In this study there was not a clear dose response.  People who smoked more than ten cigarettes per day were actually somewhat less likely in this sample to have a higher viral load than people who smoked 1-10 cigarettes per day, but the numbers were too small to make statistically significant claims.  The authors suggest that oxidative stress and induction of the cytochrome P450 (CYP) pathway could explain the mechanism of smoking-related increased VL among HIV positive individuals.  While the study cannot prove cause and effect, there are already many reasons to promote tobacco cessation among people living with HIV and this may be an additional one.

The D:A:D study is a major prospective cohort that follows more than 49 000 people living with HIV in Europe, Australia and the USA.  Among the cohort, more than 4000 have developed chronic renal impairment.  A study by Ryom L et al. this month examined whether there was improvement, stabilisation or progression of renal impairment in the 2006 individuals who had additional measurements 2-3 years after renal impairment was first noted and explored risk factors for each.  On the one hand, they show that some ARVs (notably TDF and ritonavir-boosted atazanovir) are associated with worse renal outcomes, but on the other hand, they demonstrate that after stopping these nephrotoxic medicines, the kidneys recover or at least do not deteriorate further.  Once again, traditional risk factors (older age, high blood pressure and diabetes) are also important risk factors for the kidneys of people living with HIV.  As the population of people living with HIV gets older and lives longer, HIV care and traditional non-communicable disease management must overlap and coordinate.

HIV-infection has no prognostic impact on advanced-stage Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine and dacarbazine.

Sorigué M, García O, Tapia G, Baptista MJ, Moreno M, Mate JL, Sancho JM, FeliuE, Ribera JM, Navarro JT. AIDS. 2017 Mar 29. doi: 10.1097/QAD.0000000000001487. [Epub ahead of print]

Objective: Classical Hodgkin lymphoma (cHL) is a non-AIDS-defining cancer with good response to chemotherapy in the combined antiretroviral therapy (cART) era. The aim of the study was to compare the characteristics, the response with treatment and survival of advanced-stage cHL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) between cART-treated HIV-positive and HIV-negative patients.

Design and methods: We retrospectively analyzed advanced-stage cHL patients from a single institution, uniformly treated with ABVD. All HIV-positive patients received cART concomitantly with ABVD.

Results: A total of 69 patients were included in the study: 21 were HIV-positive and 48 were HIV-negative. HIV-positive patients had more aggressive features at cHL diagnosis, such as worse performance status, more frequent bone marrow involvement and mixed cellularity histologic subtype. There were no differences in complete response rate (89% in HIV-positive vs. 91% in HIV-negative), P = 1; disease-free survival 10-year disease-free survival 70% (41-99%) vs. 74% (57-91%), P = 0.907 and overall survival (OS) 10-year OS 73% (95% confidence interval52-94%) vs. 68% (51-85%), P = 0.904. On multivariate analysis, HIV infection did not correlate with worse OS.

Conclusion: Although HIV-positive patients with cHL had more aggressive baseline features in this series, there were no differences in response rate or survival between HIV-positive and HIV-negative patients.

Abstract access 

Predictors of longitudinal change in bone mineral density in a cohort of HIV-positive and negative patients.

Tinago W, Cotter AG, Sabin CA, Macken A, Kavanagh E, Brady JJ, McCarthy G,Compston J, Mallon PW; HIV UPBEAT Study Group.225. AIDS. 2017 Mar 13;31(5):643-652. doi: 10.1097/QAD.0000000000001372.

Objective: Although low bone mineral density (BMD) is prevalent in HIV, changes in BMD over time remain unclear. We aimed to compare rates of, and factors associated with, BMD change between HIV-positive and HIV-negative patients.

Methods: In a prospective, 3-year cohort, HIV-positive and HIV-negative patients provided annual demographic and clinical data, fasting bloods, and dual x-ray absorptiometry. Using longitudinal mixed models we compared and determined predictors of rate of change in BMD.

Results: Of 384 study participants (45.8% HIV positive), 120 contributed two and 264 contributed three BMD measurements. Those with HIV were younger [median interquartile range 39 (34-46) vs. 43 (35-50) years; P = 0.04], more often men (61 vs. 46%; P = 0.003), and less likely Caucasian (61 vs. 82%; P < 0.001).Although BMD was lower in those with HIV, BMD declined in both groups, with nonsignificant between-group difference in rate of BMD change over time. Within the HIV group, starting antiretroviral therapy (ART) within 3 months of enrolment was associated with greater BMD decline at all anatomical sites (all P < 0.001). Age more than 30 years, Caucasian ethnicity, and not being on ART during follow-up were associated with greater decline and higher parathyroid hormone associated with a smaller decline in BMD at the femoral neck. We found no association between BMD change and exposure to tenofovir disoproxil fumarate or protease inhibitors.

Conclusion: We observed no difference in rate of BMD decline regardless of HIV status and in HIV-positive patient, having started ART within the previous 3 months was the only factor associated with greater BMD decline at all three sites.

Abstract access 

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

Orkin C,  DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, Vandercam B, de Wet J, Rockstroh J, Lazzarin A, Rijnders B, Podzamczer D, Thalme A, Stoeckle M, Porter D, Liu HC, Cheng A, Quirk E, SenGupta D, Cao H. Lancet HIV. 2017 Mar 1. pii: S2352-3018(17)30031-0. doi:10.1016/S2352-3018(17)30031-0. [Epub ahead of print]

Background: Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per ml) on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 ml/min. Participants were randomly assigned(1:1) to receive a single-tablet regimen of either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per ml of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with clinicaltrials.gov, number NCT01815736.

Findings: Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per ml HIV-1 RNA (difference -0·3%, 95·001% CI-4·2 to 3·7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20(6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious.

Interpretation: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.

Abstract access 

Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, Martorell CT, de Wet J, Stellbrink HJ, Molina JM, Post FA, Valero IP, Porter D, Liu Y, Cheng A, Quirk E, SenGupta D, Cao H. Lancet HIV. 2017 Mar 1. pii: S2352-3018(17)30032-2. doi:10.1016/S2352-3018(17)30032-2. [Epub ahead of print]

Background: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine,and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned(1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine(200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226.

Findings: Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group.

Interpretation: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.

Abstract access 

Incidence and risk factors for hypertension among HIV patients in rural Tanzania - A prospective cohort study.

Rodríguez-Arbolí E, Mwamelo K, Kalinjuma AV, Furrer H, Hatz C, Tanner M, Battegay M, Letang E; KIULARCO Study Group. PLoS One. 2017 Mar 8;12(3):e0172089. doi: 10.1371/journal.pone.0172089.eCollection 2017.

Introduction: Scarce data are available on the epidemiology of hypertension among HIV patients in rural sub-Saharan Africa. We explored the prevalence, incidence and risk factors for incident hypertension among patients who were enrolled in a rural HIV cohort in Tanzania.

Methods: Prospective longitudinal study including HIV patients enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2013 and 2015. Non-ART naïve subjects at baseline and pregnant women during follow-up were excluded from the analysis. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on two consecutive visits. Cox proportional hazards models were used to assess the association of baseline characteristics and incident hypertension.

Results: Among 955 ART-naïve, eligible subjects, 111 (11.6%) were hypertensive at recruitment. Ten women were excluded due to pregnancy. The remaining 834 individuals contributed 7967 person-months to follow-up (median 231 days, IQR 119-421) and 80 (9.6%) of them developed hypertension during a median follow-up of 144 days from time of enrolment into the cohort [incidence rate 120.0 cases/1000 person-years, 95% confidence interval (CI) 97.2-150.0]. ART was started in 630 (75.5%) patients, with a median follow-up on ART of 7 months (IQR 4-14). Cox regression models identified age [adjusted hazard ratio (aHR) 1.34 per 10 years increase, 95% CI 1.07-1.68, p = 0.010], body mass index (aHR per 5 kg/m2 1.45, 95% CI 1.07-1.99, p = 0.018) and estimated glomerular filtration rate (aHR < 60 versus ≥ 60 ml/min/1.73 m2 3.79, 95% CI 1.60-8.99, p = 0.003) as independent risk factors for hypertension development.

Conclusions: The prevalence and incidence of hypertension were high in our cohort. Traditional cardiovascular risk factors predicted incident hypertension, but no association was observed with immunological or ART status. These data support the implementation of routine hypertension screening and integrated management into HIV programmes in rural sub-Saharan Africa.

Abstract  Full-text [free] access

Cigarette smoking is associated with high HIV viral load among adults presenting for antiretroviral therapy in Vietnam.

Pollack TM, Duong HT, Pham TT, Do CD, Colby D. PLoS One. 2017 Mar 7;12(3):e0173534. doi: 10.1371/journal.pone.0173534.eCollection 2017.

High HIV viral load (VL >100 000 cp/ml) is associated with increased HIV transmission risk, faster progression to AIDS, and reduced response to some antiretroviral regimens. To better understand factors associated with high VL, we examined characteristics of patients presenting for treatment in Hanoi, Vietnam. We examined baseline data from the Viral Load Monitoring in Vietnam Study, a randomized controlled trial of routine VL monitoring in a population starting antiretroviral therapy (ART) at a clinic in Hanoi. Patients with prior treatment failure or ART resistance were excluded. Characteristics examined included demographics, clinical and laboratory data, and substance use. Logistic regression was used to calculate crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Out of 636 patients, 62.7% were male, 72.9% were ≥30 years old, and 28.3% had a history of drug injection. Median CD4 was 132cells/mm3, and 34.9% were clinical stage IV. Active cigarette smoking was reported by 36.3% with 14.0% smoking >10 cigarettes per day. Alcohol consumption was reported by 20.1% with 6.1% having ≥5 drinks per event. Overall 53.0% had a VL >100 000 cp/ml. Male gender, low body weight, low CD4 count, prior TB, and cigarette smoking were associated with high VL. Those who smoked 1-10 cigarettes per day were more likely to have high VL (aOR = 1.99, 95% CI = 1.15-3.45), while the smaller number of patients who smoked >10 cigarettes per day had a non-significant trend toward higher VL (aOR = 1.41, 95% CI = 0.75-2.66). Alcohol consumption was not significantly associated with high VL. Tobacco use is increasingly recognized as a contributor to premature morbidity and mortality among HIV-infected patients. In our study, cigarette smoking in the last 30 days was associated with a 1.5 to 2-fold higher odds of having an HIV VL >100 000 cp/ml among patients presenting for ART. These findings provide further evidence of the negative effects of tobacco use among HIV-infected patients.

Abstract  Full-text [free] access 

Predictors of eGFR progression, stabilisation or improvement after chronic renal impairment in HIV-positive individuals.

Ryom L, Mocroft A, Kirk O, Reiss P, Ross M, Smith C, Moranne O, Morlat P, Fux CA, Sabin C, Phillips A, Law M, Lundgren JD; D:A:D study group. AIDS. 2017 Mar 28. doi: 10.1097/QAD.0000000000001464. [Epub ahead of print]

Objectives: The objectives of this analysis were to investigate predictors of progression, stabilisation or improvement in eGFR after development of chronic renal impairment (CRI) in HIV-positive individuals.

Design: Prospective observational study.

Methods: D:A:D study participants progressing to CRI defined as confirmed, ≥ 3 months apart, eGFR ≤70  mL/min/1.73m were included in the analysis. The median of all eGFRs measured 24-36 months post-CRI was compared to the median eGFR defining CRI, and changes were grouped into: improvement (>+10 mL/min/1.73m), stabilisation (-10 to +10 mL/min/1.73m) and progression (<-10 mL/min/1.73m). Adjusted polynomial regression models assessed odds of better eGFR outcomes after CRI, assuming eGFR improvement is better than stabilisation which in turn is better than progression.

Results: Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilised and 12% progressed. Individuals remaining on TDF or boosted atazanavir (ATV/r) 24 months post-CRI had worse eGFR outcomes compared to those unexposed (TDF: 0.47 [0.35-0.63], ATV/r: 0.63 [0.48-0.82]). Individuals off TDF for 12-24 months (0.75 [0.50-1.13]) or off ATV/r for >12 months (1.17 [0.87-1.57]) had similar eGFR outcomes as those unexposed to these ARVs. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes.

Conclusion: Current TDF and ATV/r use after a diagnosis of CRI was associated with worse eGFR outcomes. In contrast, TDF and ATV/r discontinuation lead to similar longer-term eGFR outcomes as in those unexposed suggesting these drug-associated eGFR declines may be halted or reversed after their cessation.

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Comorbidity, HIV Treatment
Africa, Asia, Europe, Northern America, Oceania
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Phylogenetics - powerful new tools tied to ethical imperatives for key populations

Editor’s notes: There are now well over half a million HIV isolates that have been sequenced and the data stored in public accessible Genbank.  A systematic review by Hassan AS and colleagues of the methods used to define phylogenetic trees and clusters within them demonstrates the importance of using the correct criteria for the hypothesis being tested. Most articles use the pol sequence, since this is what is sequenced for drug resistance testing.  Most analyses have been done using a phylogenetic approach that uses a probability to assess the likelihood that isolates are clustered, and so depends on the cut-off value chosen.  For example, a well-studied outbreak of HIV among drug users in Finland is clearly linked to an earlier outbreak in Sweden, but because the Finnish isolates were collected later, they had already diverged somewhat from the Swedish ones.  If the threshold was set too high, they would not be recognized to be part of the same outbreak.  However for active transmission chains, a high threshold is needed to avoid falsely linking isolates.  There is no consensus on what methods to use, so caution is needed when comparing different studies.

Mark Wainberg, Professor of Medicine and of Microbiology at McGill University and a giant of Canadian HIV science, passed away this month.  So, as a tribute to his work, we have chosen a study from the McGill AIDS Centre by Brenner BG and colleagues.  The team used phylogenetic analysis to classify pre-treatment HIV isolates from 3901 men who have sex with men in Quebec according to the likelihood of being an acute or recent infection and the likelihood of clustering with other isolates.  Over the period from 2002-2015, a larger and larger proportion of the infections in this population could be linked to larger clusters, particularly involving younger men and men with recent infection, many of whom did not know their HIV status.  At least 40% of the onward spread of the epidemic in Quebec can be ascribed to just thirty clusters, varying in size from 20–140 individuals.

Using phylogenetics to understand transmission patterns requires careful attention to ethics, confidentiality and stigmatization.  A study in South Korea by Ahn MY and colleagues aimed to define the risk factors for clustering within clusters among 143 people living with HIV in four cities.  In eight out of the nine clusters identified participants did not report the same risk factors. Clusters were small, eight pairs and one quartet.  In the two tightest clusters, where the isolates were indistinguishable on the sequences examined, one man stated that he had sex with women, but the paired isolate came from another man and in the other pair, both men chose not to disclose their risk factors.  With small studies where information can sometimes be inferred even when not disclosed, it is perhaps not surprising that more than half the participants chose not to report their risk factors.

Other phylogenetic studies this month have explored the evolution of HIV recombination and the spread of different clades in communities in North-Eastern Brazil [Delatorre E et al.] and China.  In the North-Eastern states of Brazil, 72% of HIV isolates were subtype B, but rare subtypes such as D (1%) and CRF02_AG (1%) appear to be spreading within the population rather than being introduced from outside. In China studies from Sichuan [Wang Y et al.], Yunnan [Li Y and colleagues] and Zhejiang [Wang H et al.] have shown new recombinant forms of HIV with elements that suggest that viruses from different countries in the region have combined.  The widening diversity of HIV brings challenges for vaccine development, and potentially for HIV assays, such as those for recent infection that may differ in their sensitivity and specificity between different sub-types.  Understanding the migration of people and their viruses could be useful for providing better services, but careful attention to messaging will be needed to prevent such data from being used to discriminate further against migrants.

The final phylogenetic paper this month also comes from China, where Hao M and colleagues reported a study of students living with HIV in Beijing. The study demonstrated that transmitted drug resistance is still low in this setting, with just 0.8% of 237 students having virus that was resistant to non-nucleoside reverse transcriptase inhibitors that form part of the backbone of first line treatment in China.  A further 1.3% has resistance to protease inhibitors that are used in second line treatment.

Defining HIV-1 transmission clusters based on sequence data: a systematic review and perspectives.

Hassan AS, Pybus OG, Sanders EJ, Albert J, Esbjörnsson J. AIDS. 2017 Mar 28. doi: 10.1097/QAD.0000000000001470. [Epub ahead of print]

Understanding HIV-1 transmission dynamics is relevant to both screening and intervention strategies of HIV-1 infection. Commonly, HIV-1 transmission chains are determined based on sequence similarity assessed either directly from a sequence alignment or by inferring a phylogenetic tree. This review is aimed at both nonexperts interested in understanding and interpreting studies of HIV-1transmission, and experts interested in finding the most appropriate cluster definition for a specific dataset and research question. We start by introducing the concepts and methodologies of how HIV-1 transmission clusters usually have been defined. We then present the results of a systematic review of 105 HIV-1 molecular epidemiology studies summarizing the most popular methods and definitions in the literature. Finally, we offer our perspectives on how HIV-1 transmission clusters can be defined and provide some guidance based on examples from real life datasets.

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Large cluster outbreaks sustain the HIV epidemic among MSM in Quebec.

Brenner BG, Ibanescu RI, Hardy I, Stephens D, Otis J, Moodie E, Grossman Z,Vandamme AM, Roger M, Wainberg MA; and the Montreal PHI, SPOT cohorts. AIDS. 2017 Mar 13;31(5):707-717. doi: 10.1097/QAD.0000000000001383.

Objective: HIV-1 epidemics among MSM remain unchecked despite advances in treatment and prevention paradigms. This study combined viral phylogenetic and behavioural risk data to better understand underlying factors governing the temporal growth of the HIV epidemic among MSM in Quebec (2002-2015).

Methods: Phylogenetic analysis of pol sequences was used to deduce HIV-1transmission dynamics (cluster size, size distribution and growth rate) in first genotypes of treatment-naïve MSM (2002-2015, n = 3901). Low sequence diversity of first genotypes (0-0.44% mixed base calls) was used as an indication of early-stage infection. Behavioural risk data were obtained from the Montreal rapid testing site and primary HIV-1-infection cohorts.

Results: Phylogenetic analyses uncovered high proportion of clustering of new MSM infections. Overall, 27, 45, 48, 53 and 57% of first genotypes within one (singleton, n = 1359), 2-4 (n = 692), 5-9 (n = 367), 10-19 (n = 405) and 20+ (n = 1277) cluster size groups were early infections (<0.44% diversity). Thirty viruses within large 20+ clusters disproportionately fuelled the epidemic, representing 13, 25 and 42% of infections, first genotyped in 2004-2007 (n = 1314), 2008-2011 (n = 1356) and 2012-2015 (n = 1033), respectively. Of note, 35, 21 and 14% of MSM belonging to 20+, 2-19 and one (singleton) cluster groups were under 30 years of age, respectively. Half of persons seen at the rapid testing site (2009-2011, n = 1781) were untested in the prior year. Poor testing propensity was associated with fewer reported partnerships.

Conclusion: Addressing the heterogeneity in transmission dynamics among HIV-1-infected MSM populations may help guide testing, treatment and prevention strategies.

Abstract access 

HIV-1 transmission networks across South Korea.

Ahn MY, Wertheim JO, Kim WJ, Kim SW, Lee JS, Ann HW, Jeon Y, Ahn JY, Song JE, Oh DH, Kim YC, Kim EJ), Jung IY, Kim MH, Jeong W, Jeong SJ, Ku NS, Kim JM, Smith DM, Choi JY. AIDS Res Hum Retroviruses. 2017 Mar 27. doi: 10.1089/aid.2016.0212. [Epub ahead of print]

Molecular epidemiology can help clarify the properties and dynamics of HIV-1 transmission networks in both global and regional scales. We studied 143 HIV-1-infected individuals recruited from four medical centers of three cities in South Korea between April 2013 and May 2014. HIV-1 env V3 sequence data were generated (337-793 bp) and analyzed using a pairwise distance-based clustering approach to infer putative transmission networks. Participants whose viruses were ≤2.0% divergent according to Tamura-Nei 93 genetic distance were defined as clustering. We collected demographic, risk, and clinical data and analyzed these data in relation to clustering. Among 143 participants, we identified nine putative transmission clusters of different sizes (range 2-4 participants). The reported risk factor of participants were concordant in only one network involving two participants, that is, both individuals reported homosexual sex as their risk factor. The participants in the other eight networks did not report concordant risk factors, although they were phylogenetically linked. About half of the participants refused to report their risk factor. Overall, molecular epidemiology provides more information to understand local transmission networks and the risks associated with these networks.

Abstract access 

HIV-1 Genetic diversity in northeastern Brazil: high prevalence of non-B subtypes.

Delatorre E, Couto-Fernandez JC, Bello G.AIDS Res Hum Retroviruses. 2017 Mar 22. doi: 10.1089/AID.2017.0045. [Epub ahead of print]

The Northeastern Brazilian region has experienced a constant increase in the number of newly reported AIDS cases over the last decade, but the genetic diversity of HIV-1 strains currently disseminated in this region remains poorly explored. HIV-1 pol sequences were obtained from 140 patients followed at outpatient clinics from four Northeastern Brazilian states (Alagoas, Bahia, Ceará and Piauí) between 2014 and 2015. Subtype B was the most prevalent HIV-1 clade (72%) detected in the Northeastern region, followed by subtypes F1 (6%), C (5%) and D (1%). The remaining strains (16%) displayed a recombinant structure and were classified as: BF1 (11%), BC (4%), BCF1 (1%) and CRF02_AG-like (1%). The 20 HIV-1 BF1 and BC recombinant sequences detected were distributed among 11 lineages classified as: CRF28/29_BF-like (n = 5), CRF39_BF-like (n = 1), URFs_BF (n = 9) and URFs_BC (n = 5). Non-B subtypes were detected in all Northeastern Brazilian states, but with variable prevalence, ranging from 16% in Ceará to 55% in Alagoas. Phylogenetics analyses support that subtype D and CRF02_AG strains detected in the Northeastern region resulted from the expansion of autochthonous transmission networks, rather than from exogenous introductions from other countries. These results reveal that HIV-1 epidemic spreading in the Northeastern Brazilian region is comprised by multiple subtypes and recombinant strains and that the molecular epidemiologic pattern in this Brazilian region is much more complex than originally estimated.

Abstract access 

Identification of a novel HIV type 1 CRF01_AE/B'/C recombinant isolate in Sichuan, China.

Wang Y, Kong D, Xu W, Li F, Liang S, Feng Y, Zhang F, Shao Y, Ma L. AIDS Res Hum Retroviruses. 2017 Mar 13. doi: 10.1089/aid.2017.0002. [Epub ahead of print]

We report in this study a novel HIV-1 unique recombinant virus (XC2014EU01) isolated from an HIV-positive man who infected through heterosexual sex in Sichuan, China. The near full-length genome analyses showed that XC2014EU01 harbored one subtype B segment in pol region and two subtype C segments in gag-pol region in a CRF01_AE backbone. The unique mosaic structure was distinctly different from the other CRF01_AE/B'/C recombinant forms reported. Phylogenetic tree analyses revealed that the subtype B region originated from a Thailand subtype B' lineage, the subtype C regions were from an India C lineage, and the backbone was from CRF01_AE. XC2014EU01 was still identified as CCR5-tropic, and plasma of XC2014EU01 infected person had the media neutralizing activity. The emergence of XC2014EU01 may increase the complexity of the HIV-1 epidemic among high-risk populations and the difficulty of vaccine research and development.

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Identification of a novel HIV type 1 circulating recombinant form (CRF86_BC) among heterosexuals in Yunnan, China.

Li Y, Miao J, Miao Z, Song Y, Wen M, Zhang Y, Guo S, Zhao Y, Feng Y, Xia X. AIDS Res Hum Retroviruses. 2017 Mar;33(3):279-283. doi: 10.1089/AID.2016.0188. Epub 2016 Oct 18.

In recent years, multiple circulating recombinant forms (CRFs) and unique recombinant forms of human immunodeficiency virus type 1 (HIV-1) have been described in Yunnan, China. Here, we identified a novel HIV-1 CRF (CRF86_BC) isolated from three heterosexuals with no obvious epidemiologic linkage in western Yunnan (Baoshan prefecture) in China. CRF86_BC had a subtype C backbone with four subtype B fragments inserted into the pol, vpr, vpu, env, and nef gene regions, respectively. Furthermore, subregion tree analysis revealed that subtype C backbone originated from an Indian C lineage and subtype B segment inserted was from a Thai B lineage. They are different from previously documented B/C forms in its distinct backbone, inserted fragment size, and break points. This highlighted the importance of continual monitoring of genetic diversity and complexity of HIV-1 strains in this region.

Abstract access 

Near full-length genomic characterization of a novel HIV-1 unique recombinant (CRF55_01B/CRF07_BC) from a Malaysian immigrant worker in Zhejiang, China.

Wang H, Luo P, Zhu H, Wang N, Hu J, Mo Q, Yang Z, Feng Y. AIDS Res Hum Retroviruses. 2017 Mar;33(3):275-278.doi: 10.1089/AID.2016.0100. Epub 2016 Aug 17.

Recombinant forms contribute substantially to the genetic diversity of human immunodeficiency virus type 1 (HIV-1). Here we report a novel HIV-1 recombinant detected from a comprehensive HIV-1 molecular epidemiologic study among cross-border populations in China. Near full-length genome (NFLG) phylogenetic analysis showed that the novel HIV-1 recombinant ZJCIQ15005, which was isolated from a Malaysian immigrant worker in Zhejiang, China, clustered with CRF55_01B reference sequences but set up a distinct branch. Recombinant analysis showed that the NFLG of ZJCIQ15005 composed of CRF55_01B (as the backbone) and CRF07_BC,with 12 recombinant break points observed in the pol, vif, vpr, tat, rev, env,nef, and 3'LTR regions. This is the first detection of a novel HIV-1 recombinant (CRF55_01B/CRF07_BC) in immigrant workers in China. The emergence of this recombinant may increase the complexity of the HIV-1 epidemic in China and suggests the importance of continuous surveillance of the dynamic changes of HIV-1.

Abstract access 

Low rates of transmitted drug resistances among treatment-naive HIV-1 infected students in Beijing, China.

Hao M, Wang J, Xin R, Li X, Hao Y, Chen J, Ye J, Wang Y, He X, Huang C, Lu H. AIDS Res Hum Retroviruses. 2017 Mar 22. doi: 10.1089/AID.2017.0053. [Epub ahead of print]

Beijing has seen a rising epidemic of HIV among students. However, little information was known about the molecular epidemiologic data among HIV-infected students. In this study, the diversity and the prevalence of TDR in pol sequences deriving from 237 HIV-infected students were analyzed. TDR mutations were found in 5 MSM among students. The overall prevalence of TDR in students was 2.1%, comprised of 1.3% to protease inhibitors and 0.8 % to non-nucleoside reverse transcriptase inhibitors. Our finding indicates a low-level prevalence of TDR mutations among students in Beijing.

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Asia, Latin America, Northern America
Brazil, Canada, China, Republic of Korea
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Infectious co-morbidities – why are people still dying of advanced HIV infections?

Editor’s notes: Tuberculosis remains the biggest reported killer of people living with HIV.  Studies from Guangxi, China and Nigeria examine risk factors for tuberculosis.  In the Chinese study, Cui Z and colleagues found almost one in six of 1019 people receiving care for HIV had active tuberculosis.  The risk factors that they found when comparing these 160 people with tuberculosis to matched controls living with HIV but without tuberculosis were well-known (low CD4 cell count, smoking and non-use of ART).  Long duration of HIV infection was also independently associated with developing tuberculosis, emphasising the need for tuberculosis specific measures in addition to ART.  The authors recommend standard approaches that need to be strengthened (active screening and case-finding with early initiation of ART; isoniazid preventive therapy and better infection control).  The most extraordinary statistic is how much higher the rate of tuberculosis is among this group of people receiving HIV care than it is among the general population of Guangxi.  173 times higher is pretty impressive!

The Pathmanathan I et al. study in Nigeria, carried out as part of a broader analysis of the outcomes of a nationally representative sample of people taking ART, is more optimistic.  The incidence rate for tuberculosis once people started on ART was 0.57 per 100 person years, which compares quite favourably with the estimated incidence for Nigeria from the WHO Global Tuberculosis 2016 report [link] of 0.32 per 100 person years.  Furthermore, most of the incident tuberculosis occurred soon after starting ART and (as might be expected) was most common in people with low CD4 count; previous tuberculosis or suspected but not diagnosed tuberculosis on starting ART.  Once people’s CD4 count was above 200 cells per ml, the incidence rate was 0.29 per 100 person-years.  This is encouraging, as it suggests that a good ART programme could have a significant impact on the overall risk of tuberculosis.  The aim of collaborative tuberculosis and HIV programme efforts must be to find people living with HIV before they are so immunocompromised.  In this study, the average CD4 count at enrolment was less than 200 cells per ml and around 5% of people already had tuberculosis at that time.

Late HIV diagnosis was also the subject of a study from Jiangsu province in China.  Hu H and colleagues looked at the trends in HIV testing and presentation to care before the CD4 count fell below 350 cells per ml.  From 2011-2014 in cross-sectional annual community based surveys among around 2500 men who have sex with men (MSM), there was a modest decline in the proportion who had had an HIV test within the last 12 months from 60% to 53%, and late presentation remained stable around 40%.  We have to shift from this plateau and the authors point out that HIV self-tests seem highly acceptable to MSM in China and that social media and internet based advocacy might also help.

There is increasing interest in co-infections with hepatitis B and C viruses in people living with HIV.  Hepatitis B is widespread in many countries in sub-Saharan Africa with “horizontal” transmission occurring in childhood.  Vaccination is now included as part of some countries programmes on expanded immunisation.  Co-infection with HIV and Hepatitis B leads to more rapid progression of liver damage and to liver cancer. Seremba E and colleagues tested stored sera from people living with HIV in the Rakai community and found that around half had already been infected with hepatitis B (in line with the high prevalence of infection in children).  During the follow up samples from people who were hepatitis B negative, new infections with hepatitis B occurred in 39 individuals, giving an incidence rate of 1.2 per 100 person years.  While hepatitis B vaccine is recommended for people living with HIV who are not infected, this study shows that ART is also protective, particularly if it contains lamivudine or tenofovir.  So this may be an added benefit of the wider scale-up of ART.

Despite advance in ART, too many people still die with HIV-associated infections that are only seen at low CD4 cell counts.  An important example is cryptococcal meningitis, which causes an insidious onset of symptoms. By the time patients are seen at the hospital with severe headache and signs of raised intracranial pressure it is often too late to prevent them from dying. This is because the best medicines (liposomal amphotericin and flucytosine) are expensive and often not available.  So WHO recommends pre-emptive treatment for people who are first seen at the health service with CD4 counts less than 100 cells per ml and with cryptococcal antigen (CRAG) detectable in the blood.  A modelling study by Ramachandran A et al. from Uganda and the US considered the likely costs and benefits of using a new lateral flow assay for CRAG for people living with HIV with a low CD4 count, with pre-emptive treatment with fluconazole for people found to be CRAG-positive. The results, including various sensitivity tests, are strongly in favour of widespread implementation of this strategy. The authors calculate that it would cost Uganda around US$650 000 per year and would avert more than a thousand deaths.  Like the tuberculosis discussions above, the real aim is to prevent people living with HIV reaching the stage where “old-fashioned” opportunistic infections can cause such misery.  However in the medium term, we are likely to continue to see many people presenting late in the course of their infections, and CRAG (and tuberculosis) screening and management are key ways to prevent mortality.

Risk factors associated with Tuberculosis (TB) among people living with HIV/AIDS: A pair-matched case-control study in Guangxi, China.

Cui Z, Lin M, Nie S, Lan R. PLoS One. 2017 Mar 30;12(3):e0173976. doi:10.1371/journal.pone.0173976.eCollection 2017.

Background: As one of the poorest provinces in China, Guangxi has a high HIV and TB prevalence, with the annual number of TB/HIV cases reported by health department among the highest in the country. However, studies on the burden of TB-HIV co-infection and risk factors for active TB among HIV-infected persons in Guangxi have rarely been reported.

Objective: To investigate the risk factors for active TB among people living with HIV/AIDS in Guangxi Zhuang autonomous region, China.

Methods: A surveillance survey was conducted of 1019 HIV-infected patients receiving care at three AIDS prevention and control departments between 2013 and 2015. We investigated the cumulative prevalence of TB during 2 years. To analyze risk factors associated with active TB, we conducted a 1:1 pair-matched case-control study of newly reported active TB/HIV co-infected patients. Controls were patients with HIV without active TB, latent TB infection or other lung disease, who were matched with the case group based on sex and age (± 3 years).

Results: A total of 1019 subjects were evaluated. 160 subjects (15.70%) were diagnosed with active TB, including 85 clinically diagnosed cases and 75 confirmed cases. We performed a 1:1 matched case-control study, with 82 TB/HIV patients and 82 people living with HIV/AIDS based on surveillance site, sex and age (±3) years. According to multivariate analysis, smoking (OR = 2.996, 0.992-9.053), lower CD4+ T-cell count (OR = 3.288, 1.161-9.311), long duration of HIV-infection (OR = 5.946, 2.221-15.915) and non-use of ART (OR = 7.775, 2.618-23.094) were independent risk factors for TB in people living with HIV/AIDS.

Conclusion: The prevalence of active TB among people living with HIV/AIDS in Guangxi was 173 times higher than general population in Guangxi. It is necessary for government to integrate control planning and resources for the two diseases. Medical and public health workers should strengthen health education for TB/HIV prevention and treatment and promote smoking cessation. Active TB case finding and early initiation of ART is necessary to minimize the burden of disease among patients with HIV, as is IPT and infection control in healthcare facilities.

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Incidence and predictors of tuberculosis among HIV-infected adults after initiation of antiretroviral therapy in Nigeria, 2004-2012.

Pathmanathan I, Dokubo EK, Shiraishi RW, Agolory SG, Auld AF, Onotu D, Odafe S, Dalhatu I, Abiri O, Debem HC, Bashorun A, Ellerbrock T. PLoS One. 2017 Mar 10;12(3):e0173309. doi: 10.1371/journal.pone.0173309.eCollection 2017.

Background: Nigeria had the most AIDS-related deaths worldwide in 2014 (170 000), and 46% were associated with tuberculosis (TB). Although treatment of people living with HIV (PLHIV) with antiretroviral therapy (ART) reduces TB-associated morbidity and mortality, incident TB can occur while on ART. We estimated incidence and characterized factors associated with TB after ART initiation in Nigeria.

Methods: We analyzed retrospective cohort data from a nationally representative sample of adult patients on ART. Data were abstracted from 3496 patient records, and analyses were weighted and controlled for a complex survey design. We performed domain analyses on patients without documented TB disease and used a Cox proportional hazard model to assess factors associated with TB incidence after ART.

Results: At ART initiation, 3350 patients (95.8%) were not receiving TB treatment. TB incidence after ART initiation was 0.57 per 100 person-years, and significantly higher for patients with CD4<50/μL (adjusted hazard ratio [AHR]:4.2, 95% confidence interval [CI]: 1.4-12.7) compared with CD4≥200/μL. Patients with suspected but untreated TB at ART initiation and those with a history of prior TB were more likely to develop incident TB (AHR: 12.2, 95% CI: 4.5-33.5 and AHR: 17.6, 95% CI: 3.5-87.9, respectively).

Conclusion: Incidence of TB among PLHIV after ART initiation was low, and predicted by advanced HIV, prior TB, and suspected but untreated TB. Study results suggest a need for improved TB screening and diagnosis, particularly among high-risk PLHIV initiating ART, and reinforce the benefit of early ART and other TB prevention efforts.

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Trends in late HIV diagnosis among men who have sex with men in Jiangsu province, China: Results from four consecutive community-based surveys, 2011-2014.

Hu H, Yan H, Liu X, Xu X, Xu J, Qiu T, Shi LE, Fu G, HuanX, McFarland W, Wei C). PLoS One. 2017 Mar 9;12(3):e0172664. doi:10.1371/journal.pone.0172664.eCollection 2017.

Objectives: To examine trends in HIV testing, late HIV diagnosis and associated factors among men who have sex with men (MSM) in Jiangsu province, China.

Methods: Four consecutive community-based cross-sectional surveys were conducted among MSM from 2011 to 2014 in eight cities in the province. Participants were recruited from MSM venues and via the internet. HIV bio-behavioral surveys were conducted to collect demographic and behavioral data and measure HIV infection. HIV-infected participants with CD4 counts less than 350 cells/µL were defined as having a late HIV diagnosis. Chi-square trend tests were used to compare temporal changes over the years and multivariable logistic regression analyses were used to identify factors associated with late diagnosis.

Results: A total of 2441, 2677, 2591 and 2610 participants were enrolled in 2011, 2012, 2013 and 2014, respectively. Testing for HIV in the last 12 months decreased over the time period, from 59.9% to 52.5% (p<0.001). Late HIV diagnosis remained high and steady, ranging from 33.3% to 44.2% over the years with no significant change over time (p = 0.418). MSM who were older than 24 years (aOR =1.748, p = 0.020 for 25-39 years old; aOR = 3.148, p<0.001 for 40 years old or older), were recruited via internet (aOR = 1.596, p = 0.024), and did not have an HIV test in the past 12 months (aOR = 3.385, p<0.001) were more likely to be late diagnosed.

Conclusions: Our study showed a plateau in HIV testing among MSM in China, in parallel to high levels of late diagnosis. Emerging and innovative strategies such as HIV self-testing and reaching more MSM by internet, both highly acceptable to MSM in China, may reduce late diagnosis.

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Hepatitis B incidence and prevention with antiretroviral therapy among HIV-positive individuals in Uganda.

Seremba E, Ssempijja V, Kalibbala S, Gray RH, Wawer MJ, Nalugoda F, Casper C, Phipps W, Ocama P, Serwadda D, Thomas DL, Reynolds SJ. 123. AIDS. 2017 Mar 27;31(6):781-786. doi: 10.1097/QAD.0000000000001399.

Objective: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda.

Methods: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs).

Results: Thirty-nine HBV infections occurred over 3342 person-years, incidence1.17/100 person-years. HBV incidence was significantly lower with ART use: 0.49/100 person-years with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1-0.5, P < 0.001], and with lamivudine (3TC) use: (0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI0.1-0.7, P =  < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2-19.0, P < 0.001); and with age: 15-29 years versus 40-50 years (aHR 3.2, 95% CI 1.2-9.0); 30-39 years versus 40-50 years (aHR 2.1, 95% CI 0.9-5.3).

Conclusion: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa.

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Cost-effectiveness of CRAG-LFA screening for cryptococcal meningitis among people living with HIV in Uganda.

Ramachandran A(1), Manabe Y(1,)(2), Rajasingham R(3), Shah M(4).141. BMC Infect Dis. 2017 Mar 23;17(1):225. doi: 10.1186/s12879-017-2325-9.

Background: Cryptococcal meningitis (CM) constitutes a significant source of mortality in resource-limited regions. Cryptococcal antigen (CRAG) can be detected in the blood before onset of meningitis. We sought to determine the cost-effectiveness of implementing CRAG screening using the recently developed CRAG lateral flow assay in Uganda compared to current practice without screening.

Methods: A decision-analytic model was constructed to compare two strategies for cryptococcal prevention among people living with HIV with CD4 < 100 in Uganda: No cryptococcal screening vs. CRAG screening with WHO-recommended preemptive treatment for CRAG-positive patients. The model was constructed to reflect primary HIV clinics in Uganda, with a cohort of HIV-infected patients withCD4 < 100 cells/µL. Primary outcomes were expected costs, DALYs, and incremental cost-effectiveness ratios (ICERs). We evaluated varying levels of programmatic implementation in secondary analysis.

Results: CRAG screening was considered highly cost-effective and was associated with an ICER of $6.14 per DALY averted compared to no screening (95% uncertainty range: $-20.32 to $36.47). Overall, implementation of CRAG screening was projected to cost $1.52 more per person, and was projected to result in a 40% relative reduction in cryptococcal-associated mortality. In probabilistic sensitivity analysis, CRAG screening was cost-effective in 100% of scenarios and cost saving (ie cheaper and more effective than no screening) in 30% of scenarios. Secondary analysis projected a total cost of $651 454 for 100%implementation of screening nationally, while averting 1228 deaths compared to no screening.

Conclusion: CRAG screening for PLWH with low CD4 represents excellent value for money with the potential to prevent cryptococcal morbidity and mortality in Uganda.

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Africa, Asia
China, Nigeria, Uganda
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Thai PrEP Open-label study illustrates better adherence in people at higher risk of HIV

Factors associated with the uptake of and adherence to HIV pre-exposure prophylaxis in people who have injected drugs: an observational, open-label extension of the Bangkok Tenofovir Study.

Martin M, Vanichseni S, Suntharasamai P, Sangkum U, Mock PA, Chaipung B, Worrajittanon D, Leethochawalit M, Chiamwongpaet S, Kittimunkong S, Gvetadze RJ, McNicholl JM, Paxton LA, Curlin ME, Holtz TH, Samandari T, Choopanya K, on behalf of the Bangkok Tenofovir Study Group. Lancet HIV. 2017 Feb;4(2):e59-e66. doi: 10.1016/S2352-3018(16)30207-7. Epub 2016 Nov 18.

Background: Results of the randomised, double-blind, placebo-controlled Bangkok Tenofovir Study (BTS) showed that taking tenofovir daily as pre-exposure prophylaxis (PrEP) can reduce the risk of HIV infection by 49% in people who inject drugs. In an extension to the trial, participants were offered 1 year of open-label tenofovir. We aimed to examine the demographic characteristics, drug use, and risk behaviours associated with participants' uptake of and adherence to PrEP.

Methods: In this observational, open-label extension of the BTS (NCT00119106), non-pregnant, non-breastfeeding, HIV-negative BTS participants, all of whom were current or previous injecting drug users at the time of enrolment in the BTS, were offered daily oral tenofovir (300 mg) for 1 year at 17 Bangkok Metropolitan Administration drug-treatment clinics. Participant demographics, drug use, and risk behaviours were assessed at baseline and every 3 months using an audio computer-assisted self-interview. HIV testing was done monthly and serum creatinine was assessed every 3 months. We used logistic regression to examine factors associated with the decision to take daily tenofovir as PrEP, the decision to return for at least one PrEP follow-up visit, and greater than 90% adherence to PrEP.

Findings: Between Aug 1, 2013, and Aug 31, 2014, 1348 (58%) of the 2306 surviving BTS participants returned to the clinics, 33 of whom were excluded because they had HIV (n=27) or grade 2-4 creatinine results (n=6). 798 (61%) of the 1315 eligible participants chose to start open-label PrEP and were followed up for a median of 335 days (IQR 0-364). 339 (42%) participants completed 12 months of follow-up; 220 (28%) did not return for any follow-up visits. Participants who were 30 years or older (odds ratio [OR] 1.8, 95% CI 1.4-2.2; p<0.0001), injected heroin (OR 1.5, 1.1-2.1; p=0.007), or had been in prison (OR 1.7, 1.3-2.1; p<0.0001) during the randomised trial were more likely to choose PrEP than were those without these characteristics. Participants who reported injecting heroin or being in prison during the 3 months before open-label enrolment were more likely to return for at least one open-label follow-up visit than those who did not report injecting heroin (OR 3.0, 95 % CI 1.3-7.3; p=0.01) or being in prison (OR 2.3, 1.4-3.7; p=0.0007). Participants who injected midazolam or were in prison during open-label follow-up were more likely to be greater than 90% adherent than were those who did not inject midazolam (OR 2.2, 95% CI 1.2-4.3; p=0.02) or were not in prison (OR 4.7, 3.1-7.2; p<0.0001). One participant tested positive for HIV, yielding an HIV incidence of 2.1 (95% CI 0.05-11.7) per 1000 person-years. No serious adverse events related to tenofovir use were reported.

Interpretation: More than 60% of returning, eligible BTS participants started PrEP, which indicates that a substantial proportion of PWID who are knowledgeable about PrEP might be interested in taking it. Participants who had injected heroin or been in prison were more likely to choose to take PrEP, suggesting that participants based their decision to take PrEP, at least in part, on their perceived risk of incident HIV infection.

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Editor’s notes: Following the clinical trials assessing the efficacy of oral pre-exposure prophylaxis (PrEP) for HIV prevention, several of the trial teams and others have undertaken open-label extension and implementation studies. These were conducted to investigate the ‘real-world’ delivery of PrEP among key populations in various settings throughout the world. This paper presents the open-label study following the Bangkok Tenofovir Study (BTS) where oral PrEP was offered to participants, people who inject (or injected) drugs, for one year in the BTS study clinics. Unique to this study was the element of observed daily dosing at the clinics where participants were required to attend in order to access their PrEP. Results of the study are largely in line with reports from other similar studies, where people with more HIV-associated risk factors tended to adhere better and were more likely to take up and use PrEP. Interestingly, having a casual partner was not associated with better adherence, however, the number of casual partners reported by participants decreased during the study period, and there was no observed increase in other risky behaviours such as injecting drug use or sharing needles. One other additional point of note was the relatively higher adherence seen among prisoners and other incarcerated people which could point to consistent and easy access as a strong motivator to take PrEP. These results are an important contribution to the growing body of evidence around PrEP implementation which seems to suggest that people with a higher risk will be appropriately self-selecting for uptake of the programme. 

Asia
Thailand
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