Articles tagged as "Biomedical interventions and prevention tools"

South Africa’s major cascade gap is between testing and treatment

Level of viral suppression and the cascade of HIV care in a South African semi-urban setting in 2012.

Jean K, Puren A, Cutler E, Singh B, Bouscaillou J, Rain-Taljaard R, Taljaard D, Gouws E, Lissouba P, Lewis DA, Peytavin G, Auvert B. AIDS. 2016 Aug 24;30(13):2107-16. doi: 10.1097/QAD.0000000000001155.

Objective: In 2012, 7 years after the introduction of antiretroviral treatment (ART) in the South African township of Orange Farm, we measured the proportion of HIV-positive people who were virally suppressed, especially among high-risk groups (women 18-29 years and men 25-34 years).

Design: A community-based cross-sectional representative survey was conducted among 3293 men and 3473 women.

Methods: Study procedures included a face-to-face interview and collection of blood samples that were tested for HIV, 11 antiretroviral drugs and HIV-viral load.

Results: HIV prevalence was 17.0% [95% confidence interval: 15.7-18.3%] among men and 30.1% [28.5-31.6%] among women. Overall, 59.1% [57.4-60.8%] of men and 79.5% [78.2-80.9%] of women had previously been tested for HIV. When controlling for age, circumcised men were more likely to have been tested compared with uncircumcised men (66.1 vs 53.6%; P < 0.001). Among HIV+, 21.0% [17.7-24.6%] of men and 30.5% [27.7-33.3%] of women tested positive for one or more antiretroviral drugs. Using basic calculations, we estimated that, between 2005 and 2012, ART programs prevented between 46 and 63% of AIDS-related deaths in the community. Among antiretroviral-positive, 91.9% [88.7-94.3%] had viral suppression (viral load <400 copies/ml). The proportion of viral suppression among HIV+ was 27.0% [24.3-29.9%] among women and 17.5% [14.4-20.9%] among men. These proportions were lower among the high-risk groups: 15.6% [12.1-19.7%] among women and 8.4% [5.0-13.1%] among men.

Conclusion: In Orange Farm, between 2005 and 2012, ART programs were suboptimal and, among those living with HIV, the proportion with viral suppression was still low, especially among the young age groups. However, our study showed that, in reality, antiretroviral drugs are highly effective in viral suppression at an individual level.

Abstract access  

Editor’s notes: The efficacy of antiretroviral treatment (ART) in preventing HIV transmission from HIV-positive to HIV-negative people is clearly established. However, HIV incidence remains stubbornly high in many settings, and the challenge is to find ways to implement ART at sufficient scale, in combination with other effective programmes, to make an impact on HIV incidence at community level.

In this study, the authors surveyed a representative sample of adults in a community near Johannesburg, South Africa, where HIV prevalence is high and ART has been widely available since 2005. A trial of voluntary male medical circumcision (VMMC) was run in this location between 2002 to 2004, and a programme of incentivised VMMC and community mobilisation have been in place since 2008. The proportion of adults who had ever tested for HIV was nearly 80% among women and 60% among men, similar to that reported at national level in South Africa. Among survey participants with detectable ART agents in their blood, 94% had an HIV viral load below 1000 copies per ml, 92% below 400 copies per ml and 78% below 50 copies per ml. However, because ART programmes were sub-optimal at the time of the study, only 24% of all HIV-positive people in the survey had an HIV viral load below 400 copies per ml.

This study presents data from a real-world setting in South Africa. During the time of the study (2005-2012) treatment programmes were still sub-optimal (using the WHO 2006 treatment guidelines) but it shows that for all people on ART, significant levels of viral suppression were obtained. Of critical importance for treatment programmes will be to make sure that people have access to testing services and that testing and treatment programmes are linked. 

Africa
South Africa
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Near elimination of HIV transmission with combined ART and PrEP

Integrated delivery of antiretroviral treatment and pre-exposure prophylaxis to HIV-1-serodiscordant couples: a prospective implementation study in Kenya and Uganda.

Baeten JM, Heffron R, Kidoguchi L, Mugo NR, Katabira E, Bukusi EA, Asiimwe S, Haberer JE, Morton J, Ngure K, Bulya N, Odoyo J, Tindimwebwa E, Hendrix C, Marzinke MA, Ware NC, Wyatt MA, Morrison S, Haugen H, Mujugira A, Donnell D, Celum C. PLoS Med. 2016 Aug 23;13(8):e1002099. doi: 10.1371/journal.pmed.1002099. eCollection 2016.

Background: Antiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical trials. We conducted a prospective implementation study to understand the feasibility and effectiveness of these interventions in delivery settings.

Methods and findings: Between November 5, 2012, and January 5, 2015, we enrolled and followed 1013 heterosexual HIV-1-serodiscordant couples in Kenya and Uganda in a prospective implementation study. ART and PrEP were offered through a pragmatic strategy, with ART promoted for all couples and PrEP offered until 6 mo after ART initiation by the HIV-1 infected partner, permitting time to achieve virologic suppression. One thousand thirteen couples were enrolled, 78% of partnerships initiated ART, and 97% used PrEP, during a median follow-up of 0.9 years. Objective measures of adherence to both prevention strategies demonstrated high use (≥85%). Given the low HIV-1 incidence observed in the study, an additional analysis was added to compare observed incidence to incidence estimated under a simulated counterfactual model constructed using data from a prior prospective study of HIV-1-serodiscordant couples. Counterfactual simulations predicted 39.7 HIV-1 infections would be expected in the population at an incidence of 5.2 per 100 person-years (95% CI 3.7-6.9). However, only two incident HIV-1 infections were observed, at an incidence of 0.2 per 100 person-years (95% CI 0.0-0.9, p < 0.0001 versus predicted). The use of a non-concurrent comparison of HIV-1 incidence is a potential limitation of this approach; however, it would not have been ethical to enroll a contemporaneous population not provided access to ART and PrEP.

Conclusions: Integrated delivery of time-limited PrEP until sustained ART use in African HIV-1-serodiscordant couples was feasible, demonstrated high uptake and adherence, and resulted in near elimination of HIV-1 transmission, with an observed HIV incidence of <0.5% per year compared to an expected incidence of >5% per year.

Abstract  Full-text [free] access 

Editor’s notes: Long-term follow-up of the landmark HPTN-052 trial of ART for prevention of HIV transmission between HIV serodiscordant couples was covered in a recent issue of HIV This Month. In that trial, of the few transmission events that did occur, half were during the first few months of ART use in the HIV-positive partner, before viral load suppression. This study from Kenya and Uganda now suggests that offering pre-exposure prophylaxis (PrEP) to the HIV-negative partner to bridge the gap until virologic suppression may be an effective way to almost eliminate the risk of transmission.

In this study there were significant delays in ART initiation in the HIV-positive partner. At the start of the study the recommendation for ART initiation was a CD4+ cell count <350, and only half of the HIV-positive partners had initiated ART by six months. PrEP uptake by the HIV-negative partner was high during this time period and high levels of adherence were sustained, suggesting that this was a feasible and acceptable strategy for discordant couples.

The activities were delivered using specific clinical research facilities and staff, so the logical next step would be to demonstrate scalability with delivery through routine health systems and through more innovative community-based systems.  

Africa
Kenya, Uganda
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‘Scared of going there’ – barriers to HIV treatment for pregnant women in Tanzania

Stigma, facility constraints, and personal disbelief: why women disengage from HIV care during and after pregnancy in Morogoro region, Tanzania.

McMahon SA, Kennedy CE, Winch PJ, Kombe M, Killewo J, Kilewo C. AIDS Behav. 2016 Aug 17. [Epub ahead of print]

Millions of children are living with HIV in sub-Saharan Africa, and the primary mode of these childhood infections is mother-to-child transmission. While existing interventions can virtually eliminate such transmission, in low- and middle-income settings, only 63% of pregnant women living with HIV accessed medicines necessary to prevent transmission. In Tanzania, HIV prevalence among pregnant women is 3.2%. Understanding why HIV-positive women disengage from care during and after pregnancy can inform efforts to reduce the impact of HIV on mothers and young children. Informed by the tenets of Grounded Theory, we conducted qualitative interviews with 40 seropositive postpartum women who had disengaged from care to prevent mother-to-child transmission (PMTCT). Nearly all women described antiretroviral treatment (ART) as ultimately beneficial but effectively inaccessible given concerns related to stigma. Many women also described how their feelings of health and vitality coupled with concerns about side effects underscored a desire to forgo ART until they deemed it immediately necessary. Relatively fewer women described not knowing or forgetting that they needed to continue their treatment regimens. We present a theory of PMTCT disengagement outlining primary and ancillary barriers. This study is among the first to examine disengagement by interviewing women who had actually discontinued care. We urge that a combination of intervention approaches such as mother-to-mother support groups, electronic medical records with same-day tracing, task shifting, and mobile technology be adapted, implemented, and evaluated within the Tanzanian setting.

Abstract access  

Editor’s notes: The push for universal access to antiretroviral therapy for everyone living with HIV faces many obstacles.  In many parts of the world, pregnant women are offered HIV testing as a part of antenatal care. Treatment is then offered if a woman is found to be HIV-positive. Many women accept this care, having been provided with the information that this is beneficial for their baby and also themselves. Some women who accept treatment take themselves out of care. This can be detrimental not only for the HIV status of their baby, but also for their general antenatal care. As the authors of this paper note, there is a growing body of literature that describes losses to care from the provider perspective. There are also a number of papers about women who have accepted care, who describe why others refuse treatment.  It is unusual to find detailed findings from interviews with women who have dropped out of or refused HIV treatment while pregnant. While the findings are not particularly surprising, the authors of this paper have captured the individual reasons why the 40 women interviewed in their study, left or never entered care. The reasons given underline the challenge of ‘prompt treatment’. Many women were not ready for immediate treatment.  Fears of the clinic layout ‘betraying’ a woman’s status are described. So too are the negative attitudes of health providers as well as family and community members. The authors provide an excellent example of how good qualitative research, conducted and analysed in an exemplary manner, offers valuable insights. This paper provides valuable information on an often hidden minority of women who are not ready or able ‘to test and treat’.

Africa
United Republic of Tanzania
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Antiretroviral therapy dramatically reduces transmission of HIV to sexual partners

Antiretroviral therapy for the prevention of HIV-1 transmission.

Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Cottle L, Zhang XC, Makhema J, Mills LA, Panchia R, Faesen S, Eron J, Gallant J, Havlir D, Swindells S, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano DD, Essex M, Hudelson SE, Redd AD, Fleming TR. N Engl J Med. 2016 Jul 18. [Epub ahead of print]

Background: An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission.

Methods: We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis.

Results: Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant.

Conclusions: The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Abstract access

Editor’s notes: The HPTN 052 trial has been a landmark study in establishing antiretroviral therapy as a strategy for preventing onward transmission of HIV. It was a study of more than 800 couples. More than half of the couples were in African countries. In each couple, one sexual partner was HIV positive and the other HIV negative.  The participants living with HIV were randomised either to receive immediate antiretroviral therapy or to delay until their CD4 count fell to 350, an approved approach at that time. The HIV negative partners were then monitored for acquisition of HIV.  When new HIV infections occurred, the virus was studied for genetic similarity to the virus of the known positive partner. The interim analysis was published in 2011.  It illustrated the programme to be so effective that the randomisation was ended and all the participants living with HIV were offered antiretroviral therapy. 

This article presents data after five years of follow-up, and if anything the results are even more remarkable. In more than 10 000 person-years of follow up, there were only eight transmissions of genetically linked virus from participants receiving antiretroviral therapy. Of these transmissions, four occurred early in treatment when the viral load would not be expected to be suppressed.  The other four occurred after treatment failure. In this enormous study, there were therefore no linked transmissions from participants who were stable on treatment without detectable viraemia. The study provides powerful support for the UNAIDS 90-90-90 treatment target.  The widest possible effective use of antiretroviral therapy will not only improve the health of people treated but could have a dramatic effect on new HIV infections.

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Weekend breaks on efavirenz-based ART non-inferior in adolescents

BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.

Butler K, Inshaw J, Ford D, Bernays S, Scott K, Kenny J, Klein N, Turkova A, Harper L, Nastouli E, Paparini S, Choudhury R, Rhodes T, Babiker A, Gibb D. Health Technol Assess. 2016 Jun;20(49):1-108. doi: 10.3310/hta20490.

Background: For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings.

Objectives: To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy.

Design: Open, randomised, non-inferiority trial.

Setting: Europe, Thailand, Uganda, Argentina and the USA.

Participants: Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months.

Interventions: Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART).

Main outcome measures: Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age.

Results: In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm3, respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial.

Conclusions: Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned.

Trial registration: Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.

Abstract  Full-text [free] access 

Editor’s notes: Adherence to ART has been shown to deteriorate in adolescence, with missed doses occurring particularly at weekends. Pharmacokinetic properties of some ART drugs, such as efavirenz, allow for a break in pill taking without a break in effective treatment. Non-inferiority trials evaluating five days on, two days off in adults have shown continuous ART to be non-inferior with low rates of virologic rebound.  This formed the rationale for this global, randomised Phase II/III trial in young people.

In the BREATHER trial, non-inferiority of viral suppression in adolescents on efavirenz-based first-line ART was shown for short-cycle treatment compared with continuous treatment. Overall 93% of adolescents remained virally suppressed. Findings from the two-year long-term follow-up phase will confirm if short-cycle treatment is effective and safe in this population.  Further studies are required to confirm the applicability of this strategy in real-life settings where viral load monitoring is likely to be less frequent than in a trial setting.

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Showing they care: lay-counsellors, home-based testing and the value of follow-up support

How home HIV testing and counselling with follow-up support achieves high testing coverage and linkage to treatment and prevention: a qualitative analysis from Uganda.

Ware NC, Wyatt MA, Asiimwe S, Turyamureeba B, Tumwesigye E, van Rooyen H, Barnabas RV, Celum CL. J Int AIDS Soc. 2016 Jun 28;19(1):20929. doi: 10.7448/IAS.19.1.20929. eCollection 2016.

Introduction: The successes of HIV treatment scale-up and the availability of new prevention tools have raised hopes that the epidemic can finally be controlled and ended. Reduction in HIV incidence and control of the epidemic requires high testing rates at population levels, followed by linkage to treatment or prevention. As effective linkage strategies are identified, it becomes important to understand how these strategies work. We use qualitative data from The Linkages Study, a recent community intervention trial of community-based testing with linkage interventions in sub-Saharan Africa, to show how lay counsellor home HIV testing and counselling (home HTC) with follow-up support leads to linkage to clinic-based HIV treatment and medical male circumcision services.

Methods: We conducted 99 semi-structured individual interviews with study participants and three focus groups with 16 lay counsellors in Kabwohe, Sheema District, Uganda. The participant sample included both HIV+ men and women (N=47) and HIV-uncircumcised men (N=52). Interview and focus group audio-recordings were translated and transcribed. Each transcript was summarized. The summaries were analyzed inductively to identify emergent themes. Thematic concepts were grouped to develop general constructs and framing propositional statements.

Results: Trial participants expressed interest in linking to clinic-based services at testing, but faced obstacles that eroded their initial enthusiasm. Follow-up support by lay counsellors intervened to restore interest and inspire action. Together, home HTC and follow-up support improved morale, created a desire to reciprocate, and provided reassurance that services were trustworthy. In different ways, these functions built links to the health service system. They worked to strengthen individuals' general sense of capability, while making the idea of accessing services more manageable and familiar, thus reducing linkage barriers.

Conclusions: Home HTC with follow-up support leads to linkage by building "social bridges," interpersonal connections established and developed through repeated face-to-face contact between counsellors and prospective users of HIV treatment and male circumcision services. Social bridges link communities to the service system, inspiring individuals to overcome obstacles and access care.

Abstract  Full-text [free] access 

Editor’s notes: How can people be encouraged once they have received a positive HIV-test result to link and stay in treatment? This is a crucial question as the momentum for everyone living with HIV to be on antiretroviral therapy grows.  The authors of this paper demonstrate clearly and succinctly the value of personal contact in supporting people to test and the link to care. Lay-counsellors paying visits to people’s homes provided the encouragement to help some people to link to care. The home visits were seen by people visited as a sign that ‘someone cared’.  The personal attention and information provided promoted trust. The visits also created a sense of obligation: the person visited felt they should do something in return to please the counsellor.

Increasing numbers of people living with HIV does not necessarily mean that it is easier for someone coping with a positive-test result to link to care. We should not underestimate the continued burden that an HIV-positive test result places on individuals.  Many barriers remain both to testing and sustaining a link to care. The authors of this paper provide examples of how to overcome some of those barriers. However, while this paper provides encouraging findings on the value of the home-based activity, the findings also pose a challenge. Can such follow-up support services, which demand more than a single visit, be provided widely enough to benefit all people who need such attention and support? 

Africa
Uganda
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The HIV prevention cascade – a new approach to guide HIV prevention programmes

Providing a conceptual framework for HIV prevention cascades and assessing feasibility of empirical measurement with data from east Zimbabwe: a case study.

Garnett GP, Hallett TB, Takaruza A, Hargreaves J, Rhead R, Warren M, Nyamukapa C, Gregson S. Lancet HIV. 2016 Jul;3(7):e297-306. doi: 10.1016/S2352-3018(16)30039-X.

Background: The HIV treatment cascade illustrates the steps required for successful treatment and is a powerful advocacy and monitoring tool. Similar cascades for people susceptible to infection could improve HIV prevention programming. We aim to show the feasibility of using cascade models to monitor prevention programmes.

Methods: Conceptual prevention cascades are described taking intervention-centric and client-centric perspectives to look at supply, demand, and efficacy of interventions. Data from two rounds of a population-based study in east Zimbabwe are used to derive the values of steps for cascades for voluntary medical male circumcision (VMMC) and for partner reduction or condom use driven by HIV testing and counselling (HTC).

Findings: In 2009 to 2011 the availability of circumcision services was negligible, but by 2012 to 2013 about a third of the population had access. However, where it was available only 12% of eligible men sought to be circumcised leading to an increase in circumcision prevalence from 3.1% to 6.9%. Of uninfected men, 85.3% did not perceive themselves to be at risk of acquiring HIV. The proportions of men and women tested for HIV increased from 27.5% to 56.6% and from 61.1% to 79.6%, respectively, with 30.4% of men tested self-reporting reduced sexual partner numbers and 12.8% reporting increased condom use.

Interpretation: Prevention cascades can be populated to inform HIV prevention programmes. In eastern Zimbabwe programmes need to provide greater access to circumcision services and the design and implementation of associated demand creation activities. Whereas, HTC services need to consider how to increase reductions in partner numbers or increased condom use or should not be considered as contributing to prevention services for the HIV-negative adults.

Abstract  Full-text [free] access 

Editor’s notes: UNAIDS has set an ambitious goal of reducing new adult HIV infections below 500 000 per year by 2020. Achieving this goal relies on increased coverage of primary HIV prevention programmes, including pre-exposure prophylaxis and voluntary medical male circumcision (VMMC). The HIV treatment cascade is a well known tool to monitor the performance of services for people living with HIV, and to identify gaps in care. An HIV prevention cascade could provide a similarly useful tool to inform prevention programmes. The tool would define the steps necessary for an effective HIV prevention programme, estimating the proportion of people lost at each step, and hence identifying the barriers to effective HIV prevention in populations. The authors propose a framework for HIV prevention cascades, differentiating between availability, uptake, adherence, and efficacy.  The framework would estimate the proportion of the population protected by a given strategy or combination of strategies. Population survey data from rural Zimbabwe are used to illustrate the prevention cascade for VMMC and behaviour change driven by HIV testing and counselling (HTC). These data are used to highlight the barriers impacting on reducing HIV incidence. As the authors acknowledge, there are limitations to the cascade approach for HIV prevention. The cascade is more difficult to define and to estimate for HIV prevention than for HIV treatment. In order for the cascade to be useful, it is necessary to have a good understanding of who is at risk of acquiring HIV.  However, the prevention needs of HIV negative adults change over time as people move in and out of risk. Although the authors illustrate the use of the cascade for an individual programme, it is more difficult to assess the combined effect of several prevention strategies. Still, the cascade approach may provide a useful tool to help guide HIV prevention efforts, by identifying gaps and prioritising areas for action.

Africa
Zimbabwe
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Demand-side activities are essential for achieving population level impact of HIV prevention tools

Interventions to strengthen the HIV prevention cascade: a systematic review of reviews.

Krishnaratne S, Hensen B, Cordes J, Enstone J, Hargreaves JR. Lancet HIV. 2016 Jul;3(7):e307-17. doi: 10.1016/S2352-3018(16)30038-8.

Background: Much progress has been made in interventions to prevent HIV infection. However, development of evidence-informed prevention programmes that translate the efficacy of these strategies into population effect remain a challenge. In this systematic review, we map current evidence for HIV prevention against a new classification system, the HIV prevention cascade.

Methods: We searched for systematic reviews on the effectiveness of HIV prevention interventions published in English from Jan 1, 1995, to July, 2015. From eligible reviews, we identified primary studies that assessed at least one of: HIV incidence, HIV prevalence, condom use, and uptake of HIV testing. We categorised interventions as those seeking to increase demand for HIV prevention, improve supply of HIV prevention methods, support adherence to prevention behaviours, or directly prevent HIV. For each specific intervention, we assigned a rating based on the number of randomised trials and the strength of evidence.

Findings: From 88 eligible reviews, we identified 1964 primary studies, of which 292 were eligible for inclusion. Primary studies of direct prevention mechanisms showed strong evidence for the efficacy of pre-exposure prophylaxis (PrEP) and voluntary medical male circumcision. Evidence suggests that interventions to increase supply of prevention methods such as condoms or clean needles can be effective. Evidence arising from demand-side interventions and interventions to promote use of or adherence to prevention tools was less clear, with some strategies likely to be effective and others showing no effect. The quality of the evidence varied across categories.

Interpretation: There is growing evidence to support a number of efficacious HIV prevention behaviours, products, and procedures. Translating this evidence into population impact will require interventions that strengthen demand for HIV prevention, supply of HIV prevention technologies, and use of and adherence to HIV prevention methods.

Abstract  Full-text [free] access

Editor’s notes: Demand, supply and use of programmes are crucial for the uptake and effective use of HIV prevention strategies. This paper presents an impressive undertaking in which the authors conducted a review of systematic reviews on the evidence for the effectiveness of HIV prevention programmes across the multiple steps in an HIV prevention cascade. This particular prevention cascade allocates programmes into demand-side, supply-side, adherence, and direct HIV prevention technologies. This was published in a separate paper in conjunction with this review. The review found that there is strong evidence with regards to which direct HIV prevention technologies are efficacious, as well as maps where adherence and supply-side programmes have been effective. A primary gap was noted on the demand-side of the cascade (e.g. information, education and communication, and peer-based activities to increase demand for medical male circumcision) where studies have not resulted in reducing HIV incidence or prevalence. There remains a need to understand why, despite supply, there is low uptake of some HIV prevention strategies, and for evaluation of novel activities to increase demand.  

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Improved survival with lymphoma in the antiretroviral therapy era

Evolution of HIV-associated lymphoma over 3 decades.

Ramaswami R, Chia G, Dalla Pria A, Pinato DJ, Parker K, Nelson M, Bower M. J Acquir Immune Defic Syndr. 2016 Jun 1;72(2):177-83. doi: 10.1097/QAI.0000000000000946.

Introduction: The emergence of combined antiretroviral therapy (cART) and improvements in the management of opportunistic infections have altered the HIV epidemic over the last 30 years. We aimed to assess changes to the biology and outcomes of HIV-associated lymphomas over this period at the national center for HIV oncology in the United Kingdom.

Methods: Clinical characteristics at lymphoma diagnosis have been prospectively collected since 1986, along with details of lymphoma treatment and outcomes. The clinical features and outcomes were compared between 3 decades: pre-cART decade (1986-1995), early-cART decade (1996-2005), and late-cART decade (2006-2015).

Results: A total of 615 patients with HIV-associated lymphoma were included in the study: 158 patients in the pre-cART era, 200 patients in the early-cART era, and 257 patients in the late-cART era. In more recent decades, patients were older (P < 0.0001) and had higher CD4 cell counts (P < 0.0001) at lymphoma diagnosis. Over time, there has also been a shift in lymphoma histological subtypes, with an increase in lymphoma subtypes associated with moderate immunosuppression. The overall survival for patients with HIV-associated lymphoma has dramatically improved over the 3 decades (P < 0.0001).

Conclusion: Over the last 30 years, the clinical demographic of HIV-associated lymphomas has evolved, and the outcomes have improved.

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Editor’s notes: Lymphomas are the second most common malignancy after Kaposi’s sarcoma among people living with HIV in Europe, Australia and northern America. This study examined how the biology and rates of survival have changed since combination antiretroviral therapy (cART) became available.

People living with HIV and diagnosed with lymphoma over the past thirty years in a specialist oncology centre in the United Kingdom were included in the study. The mean age at diagnosis of lymphoma increased over time, most likely reflecting improvement in life expectancy with cART. As would be expected, the mean CD4 count and the proportion of people with a suppressed viral load at lymphoma diagnosis increased, while proportion with an AIDS-defining illness before lymphoma diagnosis declined significantly.  

This study demonstrated a shift of the histological subtypes of lymphoma that are associated with less severe immunosuppression, for example the proportion of primary CNS lymphoma (PCNSL) and diffuse large B-cell lymphoma (DLBCL), which are associated with severe immunosuppression, declined, while the proportion of Burkitt’s lymphoma and Hodgkin’s lymphoma (associated with less profound immunosuppression) increased.

A key finding of this study was the significantly improved overall survival of people with lymphoma. The improved survival is not explained by changes in histological subtypes of lymphoma over time, as improvement in prognosis was observed for each histological subtype. The substantial improvement in overall survival is attributable to a number of factors. They include the availability of cART, attention to opportunistic infection prophylaxis, improved supportive care for people undergoing lymphoma treatment as well as improved modalities of lymphoma treatment. Such modalities include efficacious drugs that can be safely co-administered with cART, e.g., rituximab, novel agents and use of autologous stem cell transplants.  

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United Kingdom
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Oral PrEP reduces risk of HIV and does not result in riskier sex

Effectiveness and safety of oral HIV pre-exposure prophylaxis (PrEP) for all populations: A systematic review and meta-analysis.

Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O'Reilly K R, Koechlin FM, Rodolph M, Hodges-Mameletzis I, Grant RM. AIDS. 2016 May 5. [Epub ahead of print]

Objective: Pre-exposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate (TDF) as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes.

Design: Rigorous systematic review and meta-analysis.

Methods: A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis.

Results: Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared to placebo. Trials with PrEP use >70% demonstrated the highest PrEP effectiveness (RR = 0.30, 95% CI: 0.21-0.45, p < 0.001) compared to placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness.

Conclusion: PrEP is protective against HIV infection across populations, presents few significant safety risks, and no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV-risk.

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Editor’s notes: This systematic review is the first to aggregate data from across oral pre-exposure prophylaxis (PrEP) studies, including randomized control trials and observational studies, to present clear evidence on the effectiveness of oral PrEP use. The findings confirm that oral PrEP significantly reduces the risk of acquiring HIV if taken consistently and correctly across populations, countries, and most age groups. Differences in efficacy directly correlate with adherence, which accounts for the lower efficacy seen in some subgroups. Perhaps two of the most compelling analyses presented in this paper relate to resistance and behavioural disinhibition. The risk of resistance was shown to be quite low, and study participants exhibiting resistant HIV either enrolled in the studies during an acute infection stage or acquired resistant strains during the course of the research. Regarding behavioural disinhibition, indicators measured such as rates of sexually transmitted infections revealed that PrEP use in the efficacy trials was not associated with behavioural disinhibition and in some studies, resulted in even safer sexual behaviour than what was reported at baseline. Recently completed demonstration projects have reported increased rates of STIs among gay men and other men who have sex with men. However, in the open-label extensions included in this review, where counselling was more intensive, safer sex practices were maintained, thus suggesting that counselling can be effective in preventing behavioural disinhibition. 

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