Articles tagged as "Democratic Republic of the Congo"

Cryptoccal meningitis – the unacceptable consequence of leaving people behind during ART scale up

Editor’s notes: Cryptococcal meningitis is a severe disease that occurs in people with advanced immune suppression.  Its occurrence is an indicator that an HIV treatment programme is not working well, as it is rare in people whose CD4 count is above 100 cells per microlitre.  Rajasingham and colleagues have tried to estimate the current burden of disease.  This is not straightforward, as the number and proportion of people with advanced HIV disease is changing with the increasing scale up of antiretroviral therapy and earlier HIV diagnosis.  Nonetheless, severe immune suppression still occurs in those whose HIV infection remains undiagnosed or is diagnosed too late; among those who are not started on effective ARVs promptly and among those in whom ART fails and who are not managed effectively by the ART treatment programme.  The authors estimate that there could be more than 180 000 deaths from cryptococcal meningitis with the large majority (136 000) in Africa.  This makes Cryptococcus responsible for more than 15% of HIV-related deaths, second only to tuberculosis as a documented cause.  The authors emphasize the need for earlier diagnosis of HIV and better linkage to quality care programmes.  In the meantime, there are also advances in the screening, prophylaxis and treatment of Cryptococcus itself, which require investment in laboratory services and affordable medicines that can save lives until the effects of good ART improves the immune status.

Cassim and colleagues have developed a novel approach to costing different approaches to the roll out of technology for screening for cryptococcal antigen in the blood of people with advanced HIV infection.  Depending on the numbers of samples to be tested in the laboratory, a mix of single use lateral flow assays and automated enzyme immunoassays makes most sense.  The aim is to allow the more cost-effective high-volume sites to subsidize the low volume sites in order to ensure that as many people living with advanced HIV infection as possible can be screened.

Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis

Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A, Boulware DR. Lancet Infect Dis. 2017 Aug;17(8):873-881. doi: 10.1016/S1473-3099(17)30243-8. Epub 2017 May 5.

Background: Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease.

Methods: We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per μL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/μL not on ART, and those with CD4 less than 100 cells per μL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis.

Findings: We estimated an average global cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8-6·2) among people with a CD4 cell count of less than 100 cells per μL, with 278 000 (95% CI 195 500-340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600-282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600-193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400-234 300), with 135 900 (75%; [95% CI 93 900-163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10-19).

Interpretation: Our analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority.

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Estimating the cost-per-result of a national reflexed cryptococcal antigenaemia screening program: Forecasting the impact of potential HIV guideline changes and treatment goals

Cassim N, Coetzee LM, Schnippel K, Glencross DK. PLoS One. 2017 Aug 22;12(8):e0182154. doi: 10.1371/journal.pone.0182154. eCollection 2017.

Introduction: During 2016, the National Health Laboratory Service (NHLS) introduced laboratory-based reflexed Cryptococcal antigen (CrAg) screening to detect early Cryptococcal disease in immunosuppressed HIV+ patients with a confirmed CD4 count of 100 cells/μl or less.

Objective: The aim of this study was to assess cost-per-result of a national screening program across different tiers of laboratory service, with variable daily CrAg test volumes. The impact of potential ART treatment guideline and treatment target changes on CrAg volumes, platform choice and laboratory workflow are considered.

Methods: CD4 data (with counts ≤ 100 cells/μl) from the fiscal year 2015/16 were extracted from the NHLS Corporate Date Warehouse and used to project anticipated daily CrAg testing volumes with appropriately-matched CrAg testing platforms allocated at each of 52 NHLS CD4 laboratories. A cost-per-result was calculated for four scenarios, including the existing service status quo (Scenario-I), and three other settings (as Scenarios II-IV) which were based on information from recent antiretroviral (ART) guidelines, District Health Information System (DHIS) data and UNAIDS 90/90/90 HIV/AIDS treatment targets. Scenario-II forecast CD4 testing offered only to new ART initiates recorded at DHIS. Scenario-III projected all patients notified as HIV+, but not yet on ART (recorded at DHIS) and Scenario-IV forecast CrAg screening in 90% of estimated HIV+ patients across South Africa (also DHIS). Stata was used to assess daily CrAg volumes at the 5th, 10th, 25th, 50th, 75th, 90th and 95th percentiles across 52 CD4-laboratories. Daily volumes were used to determine technical effort/ operator staff costs (% full time equivalent) and cost-per-result for all scenarios.

Results: Daily volumes ranged between 3 and 64 samples for Scenario-I at the 5th and 95th percentile. Similarly, daily volumes ranges of 1-12, 2-45 and 5-100 CrAg-directed samples were noted for Scenario's II, III and IV respectively. A cut-off of 30 CrAg tests per day defined use of either LFA or EIA platform. LFA cost-per-result ranged from $8.24 to $5.44 and EIA cost-per-result between $5.58 and $4.88 across the range of test volumes. The technical effort across scenarios ranged from 3.2-27.6% depending on test volumes and platform used.

Conclusion: The study reported the impact of programmatic testing requirements on varying CrAg test volumes that subsequently influenced choice of testing platform, laboratory workflow and cost-per-result. A novel percentiles approach is described that enables an overview of the cost-per-result across a national program. This approach facilitates cross-subsidisation of more expensive lower volume sites with cost-efficient, more centralized higher volume laboratories, mitigating against the risk of costing tests at a single site.

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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.

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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.

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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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Thymidine analogue mutations associated with extensive resistance in African people failing on tenofovir

Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub-Saharan Africa: a retrospective multi-centre cohort study.

Gregson J, Kaleebu P, Marconi VC, van Vuuren C, Ndembi N, Hamers RL, Kanki P, Hoffmann CJ, Lockman S, Pillay D, de Oliveira T, Clumeck N, Hunt G, Kerschberger B, Shafer RW, Yang C, Raizes E, Kantor R, Gupta RK. Lancet Infect Dis. 2016 Nov 30. pii: S1473-3099(16)30469-8. doi: 10.1016/S1473-3099(16)30469-8. [Epub ahead of print]

Background: HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART.

Methods: We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs.

Findings: Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60.5 cells per µL [IQR 21.0-128.0] in patients with TAMS vs 95.0 cells per µL [37.0-177.0] in patients without TAMs; p=0.007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0.0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0.0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0.0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0.64 (p<0.0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1.29 (1.13-1.47; p<0.0001)

Interpretation: TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains.

Abstract  Full-text [free] access 

Editor’s notes: Since 2012, WHO has recommended that tenofovir should be included in first-line antiretroviral therapy, in place of the thymidine analogues, zidovudine and stavudine, which have more significant adverse effects. When therapy fails to maintain virologic control, tenofovir is associated with characteristic resistance mutations that are different from the thymidine analogue mutations (TAMs) associated with the older drugs. This study looked at the resistance patterns of people in Africa with virologic failure after starting on WHO recommended first-line combination including tenofovir and a non-nucleoside reverse transcriptase inhibitor (NNRTI).  TAMs were surprisingly common (16%) for a group who were not known to have received thymidine analogues. This is not what would be expected from this drug combination. The implication is that TAMs may have been present before tenofovir-containing treatment was started, possibly because of undeclared previous therapy. It is well known that TAMs make subsequent therapy with an NNRTI and nucleoside analogues very much more likely to fail. The presence of TAMs was associated with more extensive resistance to other drugs including lamivudine and NNRTIs, some of which may also have been present before the tenofovir based treatment.

Only people with treatment failure were studied. The total number entering into treatment is not recorded. However, based on other reports in Africa the authors speculate a failure rate of 15 to 35% and that they may therefore have found TAMs in two to six percent of people who started treatment. That seems a realistic figure for undeclared prior treatment and gives some perspective to the scale of this problem.

There is continuing concern about drug resistance in low- and middle-income countries.  As the thymidine analogues are phased out, people receiving them may be switched to tenofovir. In situations where there is no access to viral load monitoring, some people will have unrecognised virologic failure and may have developed resistance including TAMs. They are then likely to fail on tenofovir with additional resistance. Realistic strategies are necessary for the prompt detection of treatment failure.

Africa
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Profound effect of ART on mortality through reduction of opportunistic infections

Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low and middle income countries: a systematic review and meta-analysis. 

Low A, Gavriilidis G, Larke N, Lajoie MR, Drouin O, Stover J, Muhe L, Easterbrook P. Clin Infect Dis. 2016 Mar 6. pii: ciw125. [Epub ahead of print]

Background: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in HIV-infected adults in low and middle-income countries (LMIC).

Methods: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at CD4 ≥200 cells/µl was estimated using UNAIDS country estimates and global average OI treatment cost per case.

Results: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range 57-91%) except for tuberculosis, and was largest for oral candidiasis, PCP and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, 43.8-49.4).

Conclusions: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

Abstract  Full-text [free] access

Editor’s notes: Opportunistic infections (OIs) remain the major cause of HIV-associated mortality. OIs account for substantially higher mortality in low and middle income countries (LMICs) compared to high income countries (HICs).

This paper describes the results of a systematic review and meta-analysis including about 500 000 people on ART in LMICs across three regions (sub-Saharan Africa, Asia, and Latin America). These large numbers enabled the investigators to look at the effect of ART on the incidence of key OIs during and after the first year of treatment.

Not surprisingly they found that the effect of ART reduced the risk of all OIs during the first year after ART initiation, although the reduction was less for tuberculosis. The authors attribute this to the occurrence of tuberculosis across a wide range of CD4 cell counts, a smaller effect of early immune restoration and the contribution of TB as a manifestation of immune reconstitution syndrome during the first months after ART initiation. Beyond one year after ART initiation, the reduction in tuberculosis was greater.

They conclude that the effect of ART on the incidence of most HIV-associated OIs is the key reason for the global decline in HIV-associated mortality. However, a significant proportion of HIV-positive persons still continue to present with advanced disease. Besides timely ART initiation, additional measures such as CTX prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole prophylaxis should be considered for late presenters. 

Africa, Asia, Latin America
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Tenofovir resistance – need for caution but not panic

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.

TenoRes Study Group. Lancet Infect Dis. 2016 Jan 28. pii: S1473-3099(15)00536-8. doi: 10.1016/S1473-3099(15)00536-8. [Epub ahead of print]

Background: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.

Methods: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.

Findings: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per µL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]).

Interpretation: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial.

Abstract  Full-text [free] access 

Editor’s notes: Global surveillance for tenofovir (TDF) resistance is important at a time of expanding use of TDF-containing regimens for treatment and prevention. This collaborative analysis used data collated from several small studies in different settings. Overall, around one in three people who had failed on TDF-containing treatment had evidence of TDF resistance, although this frequency varied between 20% in Europe to almost 60% in Africa. Mutations associated with NNRTIs and lamivudine/emtricitabine resistance were more common overall and were present in most people with TDF resistance.

The regional variation probably reflects differences in clinical practice and study inclusion criteria. All European studies involved cohorts with frequent viral load monitoring, whereas half of the African cohorts had no routine viral load monitoring. All European studies included people with virologic failure but with low-level viraemia (viral load <1000 copies/ml) whereas almost all African studies included only people with viral load >1000 copies/ml.

While these data provide useful estimates of the frequency of drug resistance mutations in people with virologic failure on first-line ART, there should be caution about extrapolating beyond this. Reports from cohort studies with an accurate denominator of all people starting TDF-containing first-line ART would be useful to give more reliable estimates of overall incidence of acquired TDF resistance. Moreover, there remains a need for representative population-based surveillance for acquired and transmitted drug resistance. So far, global surveillance has detected limited evidence of transmitted TDF-associated mutations, but this needs to be monitored closely, especially in high incidence settings.

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Cash incentivises short-term retention in PMTCT services in Kinshasa

Conditional cash transfers and uptake of and retention in prevention of mother-to-child HIV transmission care: a randomised controlled trial.

Yotebieng M, Thirumurthy H, Moracco KE, Kawende B, Chalachala JL, Wenzi LK, Ravelomanana NL, Edmonds A, Thompson D, Okitolonda EW, Behets F. Lancet HIV. 2016 Feb;3(2):e85-93. doi: 10.1016/S2352-3018(15)00247-7.

Background: Novel strategies are needed to increase retention in and uptake of prevention of mother-to-child HIV transmission (PMTCT) services in sub-Saharan Africa. We aimed to determine whether small, increasing cash payments, which were conditional on attendance at scheduled clinic visits and receipt of proposed services can increase the proportions of HIV-infected pregnant women who accept available PMTCT services and remain in care.

Methods: In this randomised controlled trial, we recruited newly diagnosed HIV-infected women, who were 32 or less weeks pregnant, from 89 antenatal care clinics in Kinshasa, Democratic Republic of Congo, and randomly assigned (1:1) them to either the intervention group or the control group using computer-based randomisation with varying block sizes of four, six, and eight. The intervention group received compensation on the condition that they attended scheduled clinic visits and accepted offered PMTCT services (US$5, plus US$1 increment at every subsequent visit), whereas the control group received usual care. Outcomes assessed included retention in care at 6 weeks' post partum and uptake of PMTCT services, measured by attendance of all scheduled clinic visits and acceptance of proposed services up to 6 weeks' post partum. Analyses were by intention to treat. This trial is registered with ClinicalTrials.org, number NCT01838005.

Findings: Between April 18, 2013, and Aug 30, 2014, 612 potential participants were identified, 545 were screened, and 433 were enrolled and randomly assigned; 217 to the control group and 216 to the intervention group. At 6 weeks' post partum, 174 participants in the intervention group (81%) and 157 in the control group (72%) were retained in care (risk ratio [RR] 1.11; 95% CI 1.00-1.24). 146 participants in the intervention group (68%) and 116 in the control group (54%) attended all clinic visits and accepted proposed services (RR 1.26; 95% CI 1.08-1.48). Results were similar after adjustment for marital status, age, and education.

Interpretation: Among women with newly diagnosed HIV, small, incremental cash incentives resulted in increased retention along the PMTCT cascade and uptake of available services. The cost-effectiveness of these incentives and their effect on HIV-free survival warrant further investigation.

Abstract access

Editor’s notes: Eliminating new HIV infections in children and keeping their mothers alive is a crucial component in ending the AIDS epidemic. However, engaging and retaining women in prevention of mother-to-child transmission services can be problematic, with high rates of loss to follow up being documented in many sub-Saharan countries. Noting the success of financial incentives to promote positive health behaviours, this study applies this approach in antenatal care clinics in Kinshasa, Democratic Republic of Congo.   

Newly-diagnosed HIV-positive pregnant women were randomised to receive usual care versus small escalating cash payments. This payment started at $5, increasing by $1 each visit, on the proviso they attended scheduled appointments and adhered to medical advice until six weeks post-partum. This cash offer resulted in both increased attendance to all visits and increased retention at six weeks post-partum. As might be expected, the effect was strongest among the most vulnerable women, including women who walked to the clinic. This is in line with the rationale that addressing non-medical, structural barriers enables engagement with care.

It is worth noting that follow-up stopped at six weeks post-partum so the impact of the programme over a longer period needs further exploration. However, the study is reported to be the first of its kind in prevention of mother-to-child transmission of HIV and certainly supports the need for continued research into the use of financial incentives for prevention of mother-to-child transmission.

Africa
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The effects of trauma follow people on the move

A systematic review of HIV risk behaviors and trauma among forced and unforced migrant populations from low and middle-income countries: state of the literature and future directions.

Michalopoulos LM, Aifah A, El-Bassel N. AIDS Behav. 2016 Feb;20(2):243-61. doi: 10.1007/s10461-015-1014-1.

The aim of the current systematic review is to examine the relationship between trauma and HIV risk behaviors among both forced and unforced migrant populations from low and middle income countries (LMIC). We conducted a review of studies published from 1995 to 2014. Data were extracted related to (1) the relationship between trauma and HIV risk behaviors, (2) methodological approach, (3) assessment methods, and (4) differences noted between forced and unforced migrants. A total of 340 records were retrieved with 24 studies meeting inclusion criteria. Our review demonstrated an overall relationship between trauma and HIV risk behaviors among migrant populations in LMIC, specifically with sexual violence and sexual risk behavior. However, findings from 10 studies were not in full support of the relationship. Findings from the review suggest that additional research using more rigorous methods is critically needed to understand the nature of the relationship experienced by this key-affected population.

Abstract access

Editor’s notes: The number of forced and unforced migrants is growing globally. Refugees, asylum seekers, and internally displaced persons (IDP) are forced migrants who often migrate due to political violence or conflict. Labour migrants are seen as unforced migrants who choose to emigrate for economic reasons. About half of labour migrants worldwide are women who are increasingly migrating on their own being the sole income provider for their families. With respect to trauma exposure and HIV risk in settings of long-term political violence and conflict, the distinction between war migrant, non-war migrant, and long-term resident is blurred. This in-depth review of 24 studies related to low-and middle-income countries (LMIC), mostly from sub-Saharan Africa, found findings similar to those from non-migrant populations in high-income countries. These linked traumatic experiences among migrant populations with HIV risk behaviours. Sexual violence was consistently associated with HIV sexual risk behaviours and HIV infection across the studies. But there are big gaps in the scientific literature. For example, the relationship between trauma and HIV risks has been explored for female labour migrants who are sex workers but not among women who have other occupations. Most studies addressed sexual risk and alcohol dependence, but injecting drug risk behaviours and use of any illicit drugs were virtually ignored by most studies. Few studies examined a possible link for trauma that occurred pre-migration and post-migration. Three qualitative studies examined male migrants who have sex with men, finding that violent experiences and discrimination and stigma associated with homophobia, combined with other migrant-associated traumas, can compound their mental health outcomes and subsequent HIV risk behaviours – but all were only conducted in the last four years. No studies were found that focused on HIV prevention programmes to address trauma and HIV risks among migrant workers in LMIC. However, the studies do reveal important factors that prevention programmes would have to consider. For example, concerns among labour migrants about dangerous working conditions may take precedence over HIV risk perceptions and the need for safer sex. This systematic review presents a wealth of information while highlighting the need to improve the quality of scientific research examining the link between HIV and trauma among both forced and unforced migrants in LMIC. 

Africa, Asia, Europe, Latin America
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Time to consider older adults on ART

Risk factors for mortality during antiretroviral therapy in older populations in resource-limited settings.

O'Brien D, Spelman T, Greig J, McMahon J, Ssonko C, Casas E, Mesic A, Du Cros P, Ford N. J Int AIDS Soc. 2016 Jan 14;19(1):20665. doi: 10.7448/IAS.19.1.20665. eCollection 2016.

Introduction: An increasing proportion of adult patients initiating antiretroviral therapy (ART) in resource-limited settings are aged >50 years. Older populations on ART appear to have heightened risk of death, but little is known about factors influencing mortality in this population.

Methods: We performed a retrospective observational multisite cohort study including all adult patients (≥15 years) initiating ART between 2003 and 2013 in programmes supported by Medecins Sans Frontieres across 12 countries in Asia, Africa and Europe. Patients were stratified into two age groups, >50 years and 15 to 50 years. A Cox proportional hazards model was used to explore factors associated with mortality.

Results: The study included 41 088 patients: 2591 (6.3%) were aged >50 years and 38 497 (93.7%) were aged 15 to 50 years. The mortality rate was significantly higher in the age group >50 years [367 (14.2%) deaths; mortality rate 7.67 deaths per 100 person-years (95% confidence interval, CI: 6.93 to 8.50)] compared to the age group 15 to 50 years [3788 (9.8%) deaths; mortality rate 4.18 deaths per 100 person-years (95% CI: 4.05 to 4.31)], p<0.0001. Higher CD4 levels at baseline were associated with significantly reduced mortality rates in the 15 to 50 age group but this association was not seen in the >50 age group. WHO Stage 4 conditions were more strongly associated with increased mortality rates in the 15 to 50 age group compared to populations >50 years. WHO Stage 3 conditions were associated with an increased mortality rate in the 15 to 50 age group but not in the >50 age group. Programme region did not affect mortality rates in the >50 age group; however being in an Asian programme was associated with a 36% reduced mortality rate in populations aged 15 to 50 years compared to being in an African programme. There was a higher overall incidence of Stage 3 WHO conditions in people >50 years (12.8/100 person-years) compared to those 15 to 50 years (8.1/100 person-years) (p<0.01). The rate of Stage 4 WHO conditions was similar (5.8/100 versus 6.1/100 respectively, p=0.52). Mortality rates on ART associated with the majority of specific WHO conditions were similar between the 15 to 50 and >50 age groups.

Conclusions: Older patients on ART in resource-limited settings have increased mortality rates, but compared to younger populations this appears to be less influenced by baseline CD4 count and WHO clinical stage. HIV treatment programmes in resource-limited settings need to consider risk factors associated with mortality on ART in older populations, which may differ to those related to younger adults.

Abstract Full-text [free] access

Editor’s notes: This article reports on a retrospective multisite cohort analysis that examined mortality rates and factors associated with mortality on ART for older individuals (> 50 years). The authors found that mortality was nearly two times greater in populations aged >50 years compared with people aged 15 to 50 years.

Contrary to other recent research, they did not find that the effect of age on mortality was stronger at lower CD4 cell counts. However, the analysis used pooled data from very diverse settings, with the great majority of patients (77%) from Asian programmes, and only 22% from Africa (and from nine different countries). This makes it difficult to tease out risk factors for mortality.

Interestingly they found that being in an Asian programme was associated with a 36% reduction in mortality (aHR: 0.64, 95%CI 0.59-0.69) among populations between 15 and 50 years compared to being in an African programme. The authors suggest that this might be due to a lower incidence of co-morbidities including opportunistic infections in Asian populations below 50 years compared to African populations.

As little is known about what it is like living with HIV for older people in resource-limited settings, the authors conclude with suggesting further social science research to address this issue. 

Africa, Asia, Europe
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Violence experience of women living with HIV: a global study

Violence. Enough already: findings from a global participatory survey among women living with HIV.

Orza L, Bewley S, Chung C, Crone ET, Nagadya H, Vazquez M, Welbourn A. J Int AIDS Soc. 2015 Dec 1;18(6 Suppl 5):20285. doi: 10.7448/IAS.18.6.20285. eCollection 2015.

Introduction: Women living with HIV are vulnerable to gender-based violence (GBV) before and after diagnosis, in multiple settings. This study's aim was to explore how GBV is experienced by women living with HIV, how this affects women's sexual and reproductive health (SRH) and human rights (HR), and the implications for policymakers.

Methods: A community-based, participatory, user-led, mixed-methods study was conducted, with women living with HIV from key affected populations. Simple descriptive frequencies were used for quantitative data. Thematic coding of open qualitative responses was performed and validated with key respondents.

Results: In total, 945 women living with HIV from 94 countries participated in the study. Eighty-nine percent of 480 respondents to an optional section on GBV reported having experienced or feared violence, either before, since and/or because of their HIV diagnosis. GBV reporting was higher after HIV diagnosis (intimate partner, family/neighbours, community and health settings). Women described a complex and iterative relationship between GBV and HIV occurring throughout their lives, including breaches of confidentiality and lack of SRH choice in healthcare settings, forced/coerced treatments, HR abuses, moralistic and judgemental attitudes (including towards women from key populations), and fear of losing child custody. Respondents recommended healthcare practitioners and policymakers address stigma and discrimination, training, awareness-raising, and HR abuses in healthcare settings.

Conclusions: Respondents reported increased GBV with partners and in families, communities and healthcare settings after their HIV diagnosis and across the life-cycle. Measures of GBV must be sought and monitored, particularly within healthcare settings that should be safe. Respondents offered policymakers a comprehensive range of recommendations to achieve their SRH and HR goals. Global guidance documents and policies are more likely to succeed for the end-users if lived experiences are used.

Abstract  Full-text [free] access

Editor’s notes: Violence against women who are living with HIV is common globally. This paper reports on a study of 832 women living with HIV from 94 countries who participated in an online survey, recruited through a non-random snowball sampling model. The survey comprised quantitative and qualitative (free text) components. Participants included women who had ever or were currently using injection drugs (14%), who had ever or were currently selling sex (14%), and who had ever or were currently homeless (14%). Lifetime experience of violence among respondents was high (86%). Perpetrators included: intimate partner (59%), family member / neighbour (45%), community member (53%), health care workers (53%) and police, military, prison or detention services (17%). Findings suggest that violence is not a one off occurrence and cannot easily be packaged as a cause or a consequence of HIV. Instead violence occurs throughout women’s lives, takes multiple forms, and has a complex and iterative relationship with HIV.

The study population did not represent all women living with HIV, and was biased towards women with internet access who have an activist interest. Nonetheless, the study provides further evidence of the breadth and frequency of gender based violence experienced by women living with HIV. Key recommendations for policy makers include training of health care workers working in sexual and reproductive services to offer non-discriminatory services to women living with HIV and to effectively respond to disclosures of gender based violence (such as intimate partner violence) as part of the package of care.

Algeria, Angola, Argentina, Armenia, Australia, Austria, Azerbaijan, Belarus, Belgium, Belize, Bolivarian Republic of Venezuela, Bolivia, Botswana, Burkina Faso, Burundi, Cambodia, Cameroon, Canada, Chile, China, Colombia, Costa Rica, Côte d'Ivoire, Czech Republic, Democratic Republic of the Congo, Denmark, Dominican Republic, Ecuador, El Salvador, Estonia, Ethiopia, France, Gabon, Germany, Ghana, Greece, Guatemala, Honduras, Hungary, India, Indonesia, Ireland, Italy, Jamaica, Kazakhstan, Kenya, Kyrgyzstan, Lesotho, Malawi, Mali, Mexico, Moldova, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, New Zealand, Nicaragua, Nigeria, Norway, Panama, Paraguay, Peru, Poland, Republic of the Congo, Romania, Russian Federation, Rwanda, Serbia, South Africa, Spain, Sri Lanka, Sudan, Swaziland, Switzerland, Tajikistan, Togo, Transdniestria, Turkey, Uganda, Ukraine, United Kingdom, United Republic of Tanzania, United States of America, Uruguay, Uzbekistan, Viet Nam, Zambia, Zimbabwe
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Expanding ART access: increasing costs

The HIV treatment gap: estimates of the financial resources needed versus available for scale-up of antiretroviral therapy in 97 countries from 2015 to 2020.

Dutta A, Barker C, Kallarakal A. PLoS Med. 2015 Nov 24;12(11):e1001907. doi: 10.1371/journal.pmed.1001907. eCollection 2015.

Background: The World Health Organization (WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless of CD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected the global resources needed for rapid scale-up of ART. Under the Health Policy Project, we conducted modeling analyses for 97 countries to estimate eligibility for and numbers on ART from 2015 to 2020, along with the facility-level financial resources required. We compared the estimated financial requirements to estimated funding available.

Methods and findings: Current coverage levels and future need for treatment were based on country-specific epidemiological and demographic data. Simulated annual numbers of individuals on treatment were derived from three scenarios: (1) continuation of countries' current policies of eligibility for ART, (2) universal adoption of aspects of the WHO 2013 eligibility guidelines, and (3) expanded eligibility as per the WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS "90-90-90" ART targets. We modeled uncertainty in the annual resource requirements for antiretroviral drugs, laboratory tests, and facility-level personnel and overhead.

We estimate that 25.7 (95% CI 25.5, 26.0) million adults and 1.57 (95% CI 1.55, 1.60) million children could receive ART by 2020 if countries maintain current eligibility plans and increase coverage based on historical rates, which may be ambitious. If countries uniformly adopt aspects of the WHO 2013 guidelines, 26.5 (95% CI 26.0 27.0) million adults and 1.53 (95% CI 1.52, 1.55) million children could be on ART by 2020. Under the 90-90-90 scenario, 30.4 (95% CI 30.1, 30.7) million adults and 1.68 (95% CI 1.63, 1.73) million children could receive treatment by 2020. The facility-level financial resources needed for scaling up ART in these countries from 2015 to 2020 are estimated to be US$45.8 (95% CI 45.4, 46.2) billion under the current scenario, US$48.7 (95% CI 47.8, 49.6) billion under the WHO 2013 scenario, and US$52.5 (95% CI 51.4, 53.6) billion under the 90-90-90 scenario. After projecting recent external and domestic funding trends, the estimated 6-y financing gap ranges from US$19.8 billion to US$25.0 billion, depending on the costing scenario and the U.S. President's Emergency Plan for AIDS Relief contribution level, with the gap for ART commodities alone ranging from US$14.0 to US$16.8 billion. The study is limited by excluding above-facility and other costs essential to ART service delivery and by the availability and quality of country- and region-specific data.

Conclusions: The projected number of people receiving ART across three scenarios suggests that countries are unlikely to meet the 90-90-90 treatment target (81% of people living with HIV on ART by 2020) unless they adopt a test-and-offer approach and increase ART coverage. Our results suggest that future resource needs for ART scale-up are smaller than stated elsewhere but still significantly threaten the sustainability of the global HIV response without additional resource mobilization from domestic or innovative financing sources or efficiency gains. As the world moves towards adopting the WHO 2015 guidelines, advances in technology, including the introduction of lower-cost, highly effective antiretroviral regimens, whose value are assessed here, may prove to be "game changers" that allow more people to be on ART with the resources available.

Abstract Full-text [free] access

Editor’s notes: This is a complex and important paper that seeks to understand the financial requirements necessary to: a) continue countries’ current policies of eligibility for ART, b) roll out universal adoption of certain aspects of WHO 2013 eligibility guidelines, and c) expand eligibility as per WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS ‘90-90-90’ targets.

The authors estimated the number of adults and children eligible for and receiving HIV treatment, as well as the cost of providing ART in 97 countries across six regions, covering different income levels. They estimated that 25.7 million adults and 1.57 million children could receive ART by 2020 if countries maintain the current eligibility strategies. If countries adopted WHO 2013 eligibility guidelines, 26.5 million adults and 1.53 million children would be on ART by 2020, and if they adopted the 90-90-90 scenario, 30.4 million adults and 1.68 million children could receive treatment by then. The financial resources necessary for this scale up are estimated to be US$ 45.8 billion under current eligibility, US$ 48.7 billion under WHO 2013 scenario and US$ 52.5 billion under the 90-90-90 scenario. The estimated funding gap for the six year period ranges between US$ 20 and US$ 25 billion. In this study, the costs of commodities were taken directly from data collated by other organisations.  No empirical cost estimates of service delivery were made.  Nor was there an attempt to understand the cost implications of the development synergies and social and programme enablers that may be needed to increase the number of people living with HIV knowing their status.  The new WHO recommendations need to be actively pursued if we are to meet targets, rather than passively continuing with “business as usual”. 

Nonetheless, the findings of this study highlight the gap between guidelines written by WHO and very real programmatic obstacles on the ground. There is evidence to suggest that universal test-and-treat strategies could lead to substantially improved health outcomes at the population level, as well as potentially being cost-saving in the long-term. However, as the authors have illustrated, it would require increased levels of funding. What needs to be explored further now is how to overcome the logistical hurdles of rolling out such an initiative. Changing systems and practices is costly and takes time. Health workers will have to be retrained, data collection strategies will have to be revised. Expanding treatment may also mean increasing the number of health staff working on this initiative, which has an opportunity cost that may reverberate in other parts of the health system. Substantially altering health service provision, particularly in weak health systems, may have knock-on effects with unexpected and unintended consequences.

WHO guidelines serve a vital purpose of giving us a goal to aim for. But studies like this one help us know if and how we can get there. 

Africa, Asia, Europe, Latin America, Oceania
Algeria, Angola, Armenia, Azerbaijan, Bahamas, Bangladesh, Barbados, Belarus, Belize, Benin, Bhutan, Bolivia, Botswana, Bulgaria, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Côte d'Ivoire, Cuba, Democratic Republic of the Congo, Djibouti, Dominican Republic, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Georgia, Ghana, Guatemala, Guinea, Guinea-Bissau, Guyana, Haiti, Honduras, India, Indonesia, Iran (Islamic Republic of), Jamaica, Kazakhstan, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Malaysia, Mali, Mauritania, Mauritius, Moldova, Mongolia, Morocco, Mozambique, Myanmar, Namibia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Papua New Guinea, Philippines, Republic of the Congo, Romania, Russia, Rwanda, Senegal, Serbia and Montenegro, Sierra Leone, Somalia, South Africa, Sri Lanka, Sudan, Suriname, Swaziland, Tajikistan, Thailand, Togo, Trinidad and Tobago, Tunisia, Uganda, Ukraine, United Republic of Tanzania, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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