Articles tagged as "Combination prevention"

Phylogenetics - powerful new tools tied to ethical imperatives for key populations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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HIV-1 transmission networks across South Korea.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Asia, Latin America, Northern America
Brazil, Canada, China, Republic of Korea
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Post-exposure prophylaxis – does it matter which medicines we use?

Editor’s notes: Two studies this month looked at alternative post-exposure prophylaxis (PEP) regimens.  PEP is often not well tolerated and this leads to non-completion of the one month course.  In London a randomized trial by Milinkovic A and colleagues compared the tolerability and completion rates between 213 individuals given twice daily maraviroc or ritonavir-boosted lopinavir in addition to daily tenofovir disproxil fumarate with emitricitabine (TDF-FTC) daily.  Completion rates were very similar (71% vs. 65%) but maraviroc was associated with fewer mild-moderate side effects (70% vs. 91%) and less use of anti-diarrhoeal medication (25% vs. 67%).  There were no serious side effects in either arm and similar numbers of individuals stopped taking their medication (18%). In Australia, in an open label, non-randomized study, 100 individuals were offered once daily dolutegravir as the third drug (also with TDF-FTC). 90 people completed the one month course, 9 were lost to follow up and one stopped because of headaches.  Side effects were also common in this study (similar to the London study); around a quarter of people complained of fatigue, nausea or diarrhoea [Mcallister J et al.]. Although no seroconversions were seen in either study, despite well documented risks at entry to treatment, the studies are not large enough to shed much light on the effectiveness of the regimens.  They demonstrate the ongoing challenges in finding PEP regimens that have fewer side effects.  Whether completion rates would be as high in less controlled settings than a clinical trial is not clear.  Nonetheless it seems that dolutegravir daily or maraviroc twice daily may be a suitable replacement for ritonavir-boosted lopinavir as the third drug for use as PEP.

 

Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra® in combination with Truvada® for HIV post-exposure prophylaxis (MiPEP Trial).

Milinkovic A, Benn P, Arenas-Pinto A, Brima N, Copas A, ClarkeA, Fisher M, Schembri G, Hawkins D, Williams A, Gilson R; MiPEP Trial Team.J Antimicrob Chemother. 2017 Mar 20. doi: 10.1093/jac/dkx062. [Epub ahead ofprint]

Objectives: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir.

Methods: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3or 4 clinical or laboratory adverse events (AEs) related to the PEP medication.

Results: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P  =   0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra ® arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period.

Conclusions: The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.

Abstract access 

Dolutegravir with tenofovir disoproxil fumarate - emtricitabine as HIV post-exposure prophylaxis in gay and bisexual men.

Mcallister J, Towns JM, Mcnulty A, Pierce AB, Foster R, Richardson R, Carr A. AIDS. 2017 Mar 15. doi: 10.1097/QAD.0000000000001447. [Epub ahead of print]

Objectives: Completion rates for HIV post-exposure prophylaxis (PEP) are often low. We investigated the adherence and safety of dolutegravir (DTG 50 mg daily) with tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF-FTC) as3-drug PEP in gay and bisexual men (GBM).

Design: Open-label, single-arm study at 3 sexual health clinics and 2 emergency departments in Australia.

Methods: One hundred HIV-uninfected GBM requiring PEP received DTG plus TDF-FTC for 28 days. The primary endpoint was PEP failure (premature PEP cessation or primary HIV infection through Week 12). Additional endpoints were: adherence by self-report (n = 98) and pill count (n = 55); safety; and plasma drug levels at Day 28.

Results: PEP completion was 90% (95%CI 84% to 96%). Failures (occurring at a median 9 days, IQR 3-16) comprised loss to follow-up (9%) and adverse event resulting in study drug discontinuation (headache, 1%). No participant was found to acquire HIV through Week 12. Adherence to PEP was 98% by self-report and in the 55 participants with corresponding pill count data. The most common clinical adverse events (AEs) were fatigue (26%), nausea (25%), diarrhoea (21%), and headache (10%). There were only four Grade 3-4 subjective AEs. The most common laboratory AE was raised alanine aminotransferase (22%), but there was no case of clinical hepatitis. At Day 28, the mean estimated glomerular filtration rate (eGFR) decrease was 14 ml/min/1.73m (SD 17, p = 0.001); an eGFR of<60 ml/min/1.73m occurred in 3%.

Conclusions: DTG with TDF-FTC is a safe and well-tolerated option for once-daily PEP.

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Europe, Oceania
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Cure and vaccination – more steps forward in understanding persistence of HIV and how we might deal with it

Editor’s notes: CD32a is the exciting new marker for T-lymphocytes that seem to harbour the reservoir for HIV in peripheral blood.  These cells form a very small proportion of all CD4 T-lymphocytes, but they host copies of the virus in their DNA that can be woken up and start replicating again.  While this is still a discovery at the level of basic immunology, it raises important possibilities for measuring the reservoir and perhaps for intervening directly to drain it.  It may also lead on to further basic biological understanding of why this particular transmembrane protein should be so significantly expressed in latently infected cells but not in bystanders [Descours B et al., Richman DD].

Two papers are relevant to the push for an HIV vaccine.  A new mathematical model by Medlock J et al. highlights the potential contribution of a vaccine (or indeed other prevention technologies) over and above the impact of better diagnosis, linkage and treatment of people living with HIV as framed in the 90:90:90 treatment target of UNAIDS.  Of course, a significant advantage of a vaccine or a prevention technology is that primary prevention leads to a more rapid reduction in the number of people living with HIV and the associated costs of lifelong ART. UNAIDS strategy already includes a major push for those prevention tools that have been shown to work, with emphasis on combination prevention including structural (such as incentives to keep girls in school and improving access to condoms), behavioural (such as increasing condom usage) and biomedical (such as PrEP) elements within an approach that prioritizes the highest burdened locations and populations.  It is not clear that this new model has incorporated these wider prevention programmes in their baseline scenarios. Nonetheless the conclusion is still that we should maintain our enthusiasm for the ongoing and imminent large scale clinical trials of vaccine candidates!

And finally for this month, another encouraging immunotherapy study from NIAID.  In a macaque model using a humanized SHIV (a virus that still infects macaques but has been engineered to express HIV proteins), Nishimura Y et al. found a big difference when treatment was stopped between standard ART and infusions of broadly neutralizing antibodies infused around the time of infection.  Whereas the viral load rebounded soon after the ART was stopped, several of the macaques were able to continue to suppress the SHIV for up to two years after the infusion of antibodies.  The mechanism was shown to be through the CD8 T cell pathway, since removal of these cells led to rapid viral rebound in the antibody treated animals. With each new discovery in the animal and immunology laboratories, we get a little closer to understanding what it might take to develop an effective vaccine that could provide durable protection against HIV or provide effective treatment or therapeutic enhancement that allowed people living with HIV to no longer require ART.  That is a goal that we are all pushing towards!

CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses.

Descours B, Petitjean G, López-Zaragoza JL, Bruel T, Raffel R, Psomas C, Reynes J, Lacabaratz C, Levy Y, Schwartz O, Lelievre JD, Benkirane M. Nature. 2017 Mar 23;543(7646):564-567. doi: 10.1038/nature21710.Epub 2017 Mar15.

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.

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HIV: Finding latent needles in a haystack.

Richman DD. Nature. 2017 Mar 23;543(7646):499-500. doi: 10.1038/nature21899. Epub 2017 Mar15.

Antiretroviral therapy can keep HIV at bay, but a few cells remain infected, so the disease cannot be cured. The discovery of a protein that marks out these infected cells will facilitate crucial studies of this latent viral reservoir. 

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Effectiveness of UNAIDS targets and HIV vaccination across 127 countries.

Medlock J, Pandey A, Parpia AS, Tang A, Skrip LA, Galvani AP. Proc Natl Acad Sci U S A. 2017 Mar 20. pii: 201620788. doi:10.1073/pnas.1620788114. [Epub ahead of print]

The HIV pandemic continues to impose enormous morbidity, mortality, and economic burdens across the globe. Simultaneously, innovations in antiretroviral therapy, diagnostic approaches, and vaccine development are providing novel tools for treatment-as-prevention and prophylaxis. We developed a mathematical model to evaluate the added benefit of an HIV vaccine in the context of goals to increase rates of diagnosis, treatment, and viral suppression in 127 countries. Under status quo interventions, we predict a median of 49 million [first and third quartiles 44M, 58M] incident cases globally from 2015 to 2035. Achieving the Joint United Nations Program on HIV/AIDS 95-95-95 target was estimated to avert 25 million [20M, 33M] of these new infections, and an additional 6.3 million [4.8M, 8.7M] reduction was projected with the 2020 introduction of a 50%-efficacy vaccine gradually scaled up to 70% coverage. This added benefit of prevention through vaccination motivates imminent and ongoing clinical trials of viable candidates to realize the goal of HIV control.

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Early antibody therapy can induce long-lasting immunity to SHIV.

Nishimura Y, Gautam R, Chun TW, Sadjadpour R, Foulds KE, Shingai M, Klein F, Gazumyan A, Golijanin J, Donaldson M, Donau OK, Plishka RJ, Buckler-White A, Seaman MS, Lifson JD, Koup RA, Fauci AS, Nussenzweig MC, Martin MA. Nature. 2017 Mar 23;543(7646):559-563. doi: 10.1038/nature21435. Epub 2017 Mar13.

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

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Gender and sexuality are central considerations in voluntary medical male circumcision campaigns

Discourses of masculinity, femininity and sexuality in Uganda's Stand Proud, Get Circumcised campaign.

Rudrum S, Oliffe JL, Benoit C. Cult Health Sex. 2017 Feb;19(2):225-239. doi: 10.1080/13691058.2016.1214748. Epub 2016 Aug 11.

This paper analyses discourses of masculinity, femininity and sexuality in Stand Proud, Get Circumcised, a public health campaign promoting circumcision as an HIV-prevention strategy in Uganda. The campaign includes posters highlighting the positive reactions of women to circumcised men, and is intended to support the national rollout of voluntary medical male circumcision. We offer a critical discourse analysis of representations of masculinity, femininity and sexuality in relation to HIV prevention. The campaign materials have a playful feel and, in contrast to ABC (Abstain, Be faithful, Use condoms) campaigns, acknowledge the potential for pre-marital and extra-marital sex. However, these posters exploit male anxieties about appearance and performance, drawing on hegemonic masculinity to promote circumcision as an idealised body aesthetic. Positioning women as the campaign's face reasserts a message that women are the custodians of family health and simultaneously perpetuates a norm of estrangement between men and their health. The wives' slogan, 'we have less chance of getting HIV', is misleading, because circumcision only directly prevents female-to-male HIV transmission. Reaffirming hegemonic notions of appearance- and performance-based heterosexual masculinity reproduces existing unsafe norms about masculinity, femininity and sexuality. In selling male circumcision, the posters fail to promote an overall HIV-prevention message.

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Editor’s notes: In this article, the authors provide a feminist, critical discourse analysis of Uganda’s 2012 ‘Stand Proud, Get Circumcised’ campaign. The campaign promoted voluntary medical male circumcision as an HIV prevention strategy. The authors look at how masculinity, femininity, gender relations and acceptable sexuality are configured.

The authors note that even within this prevention strategy that is male-only, men were largely absent with women representing the campaign’s public face. They argue that this is in keeping with widespread messages about gender and HIV in the region that position women as the central actors. That said, messages about normative masculinity were evident and focussed on anxieties about men’s penises as a site for the physical assessment of masculine sexual prowess or failure. Together with a lack of reference to gay men, this positioning affirms dominant ideals of what a ‘man’ is: straight, circumcised, sexually active. The authors also observe that discourses of femininity, while departing from women-as-victims and introducing sexual pleasure, were relevant only for women’s ability to impose conditions for sex, thereby influencing men to circumcise. The authors therefore argue that the discourses around gender and sexuality, rather than being socially transformative, were instead positioned to produce existing norms around sex. This positioning offers little hope for creating structural changes to gender relations that might hinder HIV transmission. The authors also express concern that the posters sell circumcision, but neglect to highlight the evidence that women are not directly protected, or that other tools of prevention including condoms remain important. 

Africa
Uganda
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Sexual risk behaviour, HIV prevalence unchanged in Kenya as more men are circumcised

Changes in male circumcision prevalence and risk compensation in the Kisumu, Kenya population, 2008-2013.

Westercamp M, Jaoko W, Mehta S, Abuor P, Siambe P, Bailey RC. J Acquir Immune Defic Syndr. 2017 Feb 1;74(2):e30-e37. doi: 10.1097/QAI.0000000000001180.

Background: Three randomized controlled trials showed that voluntary medical male circumcision (VMMC) reduces the risk of female-to-male HIV transmission by approximately 60%. However, data from communities where VMMC programs have been implemented are needed to assess changes in circumcision prevalence and whether men and women compensate for perceived reductions in risk by increasing their HIV risk behaviors.

Methods: Scale-up of free VMMC began in Kisumu, Kenya in 2008. Between 2009 and 2013, a sequence of 3 unlinked cross-sectional surveys were conducted. All individuals 15-49 years of age residing in randomly selected households were interviewed and offered HIV testing. Male circumcision status was confirmed by examination. Design-adjusted bivariate comparisons and multivariable analyses were used for statistical inference.

Results: The prevalence of male circumcision increased from 32% (95% CI: 26% to 38%) in 2009 to 60% (95% CI: 56% to 63%) in 2013. The adjusted prevalence ratio of HIV and genital ulcer disease in circumcised compared with uncircumcised men was 0.48 (95% CI: 0.36 to 0.66) and 0.51 (95% CI: 0.37 to 0.69), respectively. There was no association between circumcision status and sexual behaviors, HIV knowledge, or indicators of risk perception.

Conclusions: The conditions necessary for the VMMC program to have a significant public health impact are present in Kisumu, Kenya. Between 2009 and 2013, circumcision prevalence increased from 30% to 60%; HIV prevalence in circumcised men was half that of uncircumcised men, and there was no or minimal sexual risk compensation.

Abstract access  

Editor’s notes: Evidence of the protective effect of male circumcision on HIV incidence has led many countries in sub-Saharan Africa to promote voluntary medical male circumcision (VMMC). Mathematical models have illustrated that VMMC programmes will reduce HIV prevalence over time when VMMC uptake is high, and when men who have had VMMC do not substantially increase their sexual risk behaviours. In Kenya, the VMMC programme has exceeded its targets, with over 1.1 million procedures conducted between 2008 and 2015. In this paper, the authors assessed the assumptions behind the models, using data from three population-based cross-sectional surveys conducted among male and female adult residents of Kisumu, Kenya between 2009 and 2013. During this time, VMMC prevalence among men almost doubled from 32% to 60%, yet, HIV prevalence did not change for men or women. In addition, men who had VMMC reported the same levels of sexual risk behaviours as men who were not circumcised, yet had half the prevalence of HIV and genital ulcer disease. This study re-confirms the individual benefit of VMMC in a non-trial population, while demonstrating no evidence for sexual risk compensation. This study is notable for its large sample size, population-based sampling design, visual confirmation of circumcision status, and HIV testing protocol. Studies of longer duration are required to confirm the population-level impacts of VMMC– i.e. a protection benefit beyond men who had VMMC - on HIV prevalence, and to monitor the longer-term trend in sexual risk behaviours.

Africa
Kenya
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The value of religious leaders in promoting healthy behaviour

Educating religious leaders to promote uptake of male circumcision in Tanzania: a cluster randomised trial.

Downs JA, Mwakisole AH, Chandika AB, Lugoba S, Kassim R, Laizer E, Magambo KA, Lee MH, Kalluvya SE, Downs DJ, Fitzgerald DW. Lancet. 2017 Mar 18;389(10074):1124-1132.doi: 10.1016/S0140-6736(16)32055-4. Epub 2017 Feb 15

Background: Male circumcision is being widely deployed as an HIV prevention strategy in countries with high HIV incidence, but its uptake in sub-Saharan Africa has been below targets. We did a study to establish whether educating religious leaders about male circumcision would increase uptake in their village.

Methods: In this cluster randomised trial in northwest Tanzania, eligible villages were paired by proximity (<60 km) and the time that a free male circumcision outreach campaign from the Tanzanian Ministry of Health became available in their village. All villages received the standard male circumcision outreach activities provided by the Ministry of Health. Within the village pairs, villages were randomly assigned by coin toss to receive either additional education for Christian church leaders on scientific, religious, and cultural aspects of male circumcision (intervention group), or standard outreach only (control group). Church leaders or their congregations were not masked to random assignment. The educational intervention consisted of a 1-day seminar co-taught by a Tanzanian pastor and a Tanzanian clinician who worked with the Ministry of Health, and meetings with the study team every 2 weeks thereafter, for the duration of the circumcision campaign. The primary outcome was the proportion of male individuals in a village who were circumcised during the campaign, using an intention-to-treat analysis that included all men in the village. This trial is registered with ClinicalTrials.gov, number NCT 02167776.

Findings: Between June 15, 2014, and Dec 10, 2015, we provided education for church leaders in eight intervention villages and compared the outcomes with those in eight control villages. In the intervention villages, 52.8% (30 889 of 58 536) of men were circumcised compared with 29.5% (25 484 of 86 492) of men in the eight control villages (odds ratio 3.2 [95% CI, 1.4-7.3]; p=0.006).

Interpretation: Education of religious leaders had a substantial effect on uptake of male circumcision, and should be considered as part of male circumcision programmes in other sub-Saharan African countries. This study was conducted in one region in Tanzania; however, we believe that our intervention is generalisable. We equipped church leaders with knowledge and tools, and ultimately each leader established the most culturally-appropriate way to promote male circumcision. Therefore, we think that the process of working through religious leaders can serve as an innovative model to promote healthy behaviour, leading to HIV prevention and other clinically relevant outcomes, in a variety of settings.

Abstract  Full-text [free] access 

Editor’s notes: Voluntary medical male circumcision is recommended for HIV prevention in settings with high prevalence of HIV. However, uptake of male circumcision has been lower in some settings than is optimal to reduce population-level HIV incidence. Religious beliefs can be an important barrier to acceptance of VMMC. In this community randomised trial, the investigators sought to improve uptake of male circumcision in Tanzania through an education programme delivered to religious leaders alongside a VMMC outreach campaign. Following educational seminars, each religious leader was asked to decide how best to address issues of male circumcision in his or her own community. Overall, there was a three-fold increase in uptake of male circumcision in the programme villages compared with control villages.

Deep commitment to religious faith and practices is common in many sub-Saharan countries. In this study, investigators used an innovative approach to promote healthy behaviour by tapping into the power of religious leaders. The impressive results illustrate the importance of addressing social and structural determinants of behaviour. This is a model that could be extended to address other challenging health behaviours in this and other similar settings. 

Africa
United Republic of Tanzania
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Mixed methods in biomedical intervention trials yield rich data – the VOICE-D qualitative study

How presentation of drug detection results changed reports of product adherence in South Africa, Uganda and Zimbabwe.

Musara P, Montgomery ET, Mgodi NM, Woeber K, Akello CA, Hartmann M, Cheng H, Levy L, Katz A, Grossman CI, Chirenje ZM, van der Straten A, Mensch B. AIDS Behav. 2017 Jan 21. doi: 10.1007/s10461-017-1685-x. [Epub ahead of print]

Accurate estimates of study product use are critical to understanding and addressing adherence challenges in HIV prevention trials. The VOICE trial exposed a significant gap between self-reported adherence and drug detection. The VOICE-D qualitative study was designed to better understand non-adherence during VOICE, and was conducted in 2 stages: before (stage 1) and after (stage 2) drug detection results were provided to participants. Transcripts from 44 women who participated in both stages were analysed to understand the effect of presenting drug detection data on narratives of product use. Thirty-six women reported high adherence in stage 1, yet admitted non-use in stage 2, three reported high adherence in both stages (contrary to their drug detection results) and five had consistent responses across both stages and drug results. Presenting objective measures of use may facilitate more accurate product use reporting and should be evaluated in future prevention trials.

Abstract access  

Editor’s notes: The VOICE trial looked at the effectiveness of PrEP and vaginal microbicides in women in three African countries. One of the findings of the study was low product adherence among some women, based on retrospective drug level testing. In this paper, the authors compare data on product adherence from before and after participants were given plasma drug detection results. The findings are revealing, not least because many of women interviewed explained why they had claimed to be adhering to the drug, when they were not. Women gave many reasons for not being open about taking their medicines/use of the microbicide. It is interesting that a few women continued to say that they were good adherers, even when presented with drug plasma data, which suggested otherwise. This, the authors note, requires further investigation. 

The findings provide valuable evidence of the shortcomings of collecting self-reported adherence data. The use of biomedical markers to reveal drug plasma levels is important. However, the qualitative research, which documented the discussion around those findings, is both fascinating and extremely useful. Perhaps in future there will be an even greater willingness to fund good qualitative research as a key component of trials?

Africa
South Africa, Uganda, Zimbabwe
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Getting to 80% male circumcision

Obtaining a male circumcision prevalence rate of 80% among adults in a short time: An observational prospective intervention study in the Orange Farm township of South Africa.

Marshall E, Rain-Taljaard R, Tsepe M, Monkwe C, Taljaard D, Hlatswayo F, Xaba D, Molomo T, Lissouba P, Puren A, Auvert B. Medicine (Baltimore). 2017 Jan;96(4):e5328. doi: 10.1097/MD.0000000000005328.

World Health Organization recommends a target for the male circumcision prevalence rate of 80%. This rate will have a substantial impact on the human immunodeficiency virus-acquired immunodeficiency syndrome epidemic in Eastern and Southern Africa. The objective of the study was to assess whether an innovative intervention can lead to an increased voluntary male medical circumcision (VMMC) uptake among adults in a short time. This prospective observational study of a demand generation intervention was conducted in the township of Orange Farm (South Africa) in August to November 2015. In this community male circumcision prevalence rate among adults was stable between 2010 and 2015 at 55% and 57%, despite regular VMMC campaigns at community level and the presence of a VMMC clinic that offered free VMMC. The intervention took place in a random sample of 981 households where 522 men aged 18 to 49 years accepted to participate in the study. Among the 226 uncircumcised men, 212 accepted to be enrolled in the intervention study. A personal male circumcision adviser trained in interpersonal communication skills was assigned to each uncircumcised participant. The male circumcision advisers were trained to explain the risks and benefits of VMMC, and to discuss 24 possible reasons given by men for not being circumcised. Participants were then followed for 9 weeks. Each participant had a maximum of 3 motivational interviews at home. Participants who decided to be circumcised received financial compensation for their time equivalent to 2.5 days of work at the minimum South African salary rate. Among the 212 uncircumcised men enrolled in the intervention, 69.8% (148/212; 95% confidence interval [CI]; 63.4%-75.7%) agreed to be circumcised, which defines the uptake of the intervention. The male circumcision prevalence rate of the sample increased from 56.7% (296/522) to 81.4% (425/522; 77.9%-84.6%), P < 0.001, corresponding to a relative increase of 43.6% (95% CI: 35.4%-53.7%). The reported reasons for accepting circumcision were motivational interviews with the male circumcision adviser (83.1%), and time compensation (39.4%). Increased uptake of VMMC uptake can be obtained in a short time among adult males but requires an intense intervention centered on uncircumcised men at an individual level and time compensation.

Abstract  Full-text [free] access

Editor’s notes: As there are diverse motives for and barriers to voluntary male medical circumcision (VMMC), a range of programmes are required to reach WHO’s target of 80% male circumcision. This demand-creation activity study took place in a setting where, following school talks, street animation, flyers and local radio advertising, circumcision prevalence had risen to 57% by 2010 but had then plateaued. The programme was based on the theory that saturation had not been reached and many men who remained uncircumcised were not opposed to it but needed the right opportunity and circumstances to motivate them. In just over two months the prevalence of adult male circumcision in the study sample increased to over 80%, (WHO goal) as a result of implementing up to three home-based motivational interviews, plus time compensation of half a week’s pay at minimum wage for men who had VMMC.

Uptake was highest among the oldest men (aged 40-49 years), who had the lowest prevalence of circumcision before the study. Possibly previous programmes that were primarily focussed on adolescents were less likely to affect them. The highest rates were achieved in the youngest age group (aged 18-24 years), who were the most likely to already be circumcised before the study. Time to think about their options at home was important to participants. Most men who opted for VMMC said it was very important to have discussed the situation with their partner (80%) and with relatives or friends (78%). The three motivational interviews produced diminishing yield; 112/212 men sought VMMC after the first interview, 28/78 after the second and 8/54 after the third. After one interview plus financial compensation, the male circumcision prevalence in the sample increased to 75%.

The study is an example of a locally developed and setting-appropriate activity, quickly and rigorously tested in a realistic setting. In this manner, research questions can be relevant to the context and the results can be put into practice. 

Africa
South Africa
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Benefits of including males living with HIV in voluntary medical male circumcision - modelling analysis

Could circumcision of HIV-positive males benefit voluntary medical male circumcision programs in Africa? Mathematical modeling analysis.

Awad SF, Sgaier SK, Lau FK, Mohamoud YA, Tambatamba BC, Kripke KE, Thomas AG, Bock N, Reed JB, Njeuhmeli E, Abu-Raddad LJ. PLoS One. 2017 Jan 24;12(1):e0170641. doi: 10.1371/journal.pone.0170641. eCollection 2017.

Background: The epidemiological and programmatic implications of inclusivity of HIV-positive males in voluntary medical male circumcision (VMMC) programs are uncertain. We modeled these implications using Zambia as an illustrative example.

Methods and findings: We used the Age-Structured Mathematical (ASM) model to evaluate, over an intermediate horizon (2010-2025), the effectiveness (number of VMMCs needed to avert one HIV infection) of VMMC scale-up scenarios with varying proportions of HIV-positive males. The model was calibrated by fitting to HIV prevalence time trend data from 1990 to 2014. We assumed that inclusivity of HIV positive males may benefit VMMC programs by increasing VMMC uptake among higher risk males, or by circumcision reducing HIV male-to-female transmission risk. All analyses were generated assuming no further antiretroviral therapy (ART) scale-up. The number of VMMCs needed to avert one HIV infection was projected to increase from 12.2 VMMCs per HIV infection averted, in a program that circumcises only HIV-negative males, to 14.0, in a program that includes HIV-positive males. The proportion of HIV-positive males was based on their representation in the population (e.g. 12.6% of those circumcised in 2010 would be HIV-positive based on HIV prevalence among males of 12.6% in 2010). However, if a program that only reaches out to HIV-negative males is associated with 20% lower uptake among higher-risk males, the effectiveness would be 13.2 VMMCs per infection averted. If improved inclusivity of HIV-positive males is associated with 20% higher uptake among higher-risk males, the effectiveness would be 12.4. As the assumed VMMC efficacy against male-to-female HIV transmission was increased from 0% to 20% and 46%, the effectiveness of circumcising regardless of HIV status improved from 14.0 to 11.5 and 9.1, respectively. The reduction in the HIV incidence rate among females increased accordingly, from 24.7% to 34.8% and 50.4%, respectively.

Conclusion: Improving inclusivity of males in VMMC programs regardless of HIV status increases VMMC effectiveness, if there is moderate increase in VMMC uptake among higher-risk males and/or if there is moderate efficacy for VMMC against male-to-female transmission. In these circumstances, VMMC programs can reduce the HIV incidence rate in males by nearly as much as expected by some ART programs, and additionally, females can benefit from the intervention nearly as much as males.

Abstract  Full-text [free] access

Editor’s notes: Evidence from randomised control trials and modelling studies suggest that voluntary male medical circumcision (VMMC) is a cost-effective HIV prevention programme. A deterministic compartmental age structured HIV model was used to assess benefits of including HIV positive males in VMMC programmes. The HIV model was parameterized using HIV biological and behavioural data for sub-Saharan Africa.  The model was fit to HIV prevalence for Zambia in the years between 1990 and 2014. The model used baseline circumcision coverages from Zambia Demographic and Health Survey 2007. The authors analysed the model for three VMMC programme scenarios; circumcising HIV negative males only, circumcising both HIV negative and HIV positive males, and circumcising males regardless of their HIV status. Sensitivity analysis was conducted to ascertain the robustness of key model assumptions on the study findings. The findings from the study suggest that, improving the inclusivity of all males is likely to improve the effectiveness of VMMC programmes.  This will be the case if there is moderate increase in uptake among higher-risk males and/or moderate VMMC efficacy in preventing male-to-female transmission. This is a very interesting modelling study which gives insights to policymakers on factors to consider in designing VMMC programmes. 

Africa
Zambia
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A step forward for HIV prevention in women

Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women.

Nel A, van Niekerk N, Kapiga S, Bekker LG, Gama C, Gill K, Kamali A, Kotze P, Louw C, Mabude Z, Miti N, Kusemererwa S, Tempelman H, Carstens H, Devlin B, Isaacs M, Malherbe M, Mans W, Nuttall J, Russell M, Ntshele S, Smit M, Solai L, Spence P, Steytler J, Windle K, Borremans M, Resseler S, Van Roey J, Parys W, Vangeneugden T, Van Baelen B, Rosenberg Z; Ring Study Team. N Engl J Med. 2016 Dec;375(22):2133-2143.

Background: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda.

Methods: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion.

Results: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified.

Conclusions: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .).

Abstract  Full-text [free] access

Editor’s notes: The need to develop safe, effective tools for women, particularly young women and adolescent girls, remains a high priority in sub-Saharan Africa. Self-inserted vaginal rings, which provide sustained release of antiretroviral drugs over time, offer an option that women can initiate themselves. Two large randomised trials have been conducted to assess the efficacy and safety of a vaginal ring containing dapivirine in preventing HIV infection in women. This trial is published in the same issue of the New England Journal of Medicine as the trial by Baeten et al. (reviewed by HIV This Month in March 2016). Both trials were conducted in eastern and southern Africa where the incidence of HIV remains high.

As in the Baeten trial, this trial found a moderate reduction in HIV infection (31% lower) among women using the dapivirine vaginal ring compared with placebo. In both trials, protection was higher among women older than 21 years of age, although, unlike the Baeten trial, the difference in efficacy between the two age groups in this trial was not statistically significant. Baeten et al noted that biological measurement of adherence was higher among women older than 21 years (more than 70% overall) which may partly explain the higher protection observed. The investigators of both trials note that the genital tract of younger women may make them more susceptible to HIV infection. This warrants further investigation. Differences in the frequency of vaginal and/or anal sex across different age groups may also be important. In an editorial to accompany publication of these two important trials, Adimora notes that “providers and women must ensure that the HIV interventions that women adopt match their sexual behaviours and needs. Different women – and women at different life stages – will require different types of HIV prevention.”  

Africa
South Africa, Uganda
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