Articles tagged as "Sexual transmission and prevention"

The power of PEPFAR programmes: estimates of infections averted and life years gained in Africa

Estimating the impact of the US President's Emergency Plan for AIDS Relief on HIV treatment and prevention programmes in Africa.

Heaton LM, Bouey PD, Fu J, Stover J, Fowler TB, Lyerla R, Mahy M. Sex Transm Infect. 2015 Dec;91(8):615-20. doi: 10.1136/sextrans-2014-051991. Epub 2015 Jun 8.

Background: Since 2004, the US President's Emergency Plan for AIDS Relief (PEPFAR) has supported the tremendous scale-up of HIV prevention, care and treatment services, primarily in sub-Saharan Africa. We evaluate the impact of antiretroviral treatment (ART), prevention of mother-to-child transmission (PMTCT) and voluntary medical male circumcision (VMMC) programmes on survival, mortality, new infections and the number of orphans from 2004 to 2013 in 16 PEPFAR countries in Africa.

Methods: PEPFAR indicators tracking the number of persons receiving ART for their own health, ART regimens for PMTCT and biomedical prevention of HIV through VMMC were collected across 16 PEPFAR countries. To estimate the impact of PEPFAR programmes for ART, PMTCT and VMMC, we compared the current scenario of PEPFAR-supported interventions to a counterfactual scenario without PEPFAR, and assessed the number of life years gained (LYG), number of orphans averted and HIV infections averted. Mathematical modelling was conducted using the SPECTRUM modelling suite V.5.03.

Results: From 2004 to 2013, PEPFAR programmes provided support for a cumulative number of     24 565 127 adults and children on ART, 4 154 878 medical male circumcisions, and ART for PMTCT among 4 154 478 pregnant women in 16 PEPFAR countries. Based on findings from the model, these efforts have helped avert 2.9 million HIV infections in the same period. During 2004-2013, PEPFAR ART programmes alone helped avert almost 9 million orphans in 16 PEPFAR countries and resulted in 11.6 million LYG.

Conclusions: Modelling results suggest that the rapid scale-up of PEPFAR-funded ART, PMTCT and VMMC programmes in Africa during 2004-2013 led to substantially fewer new HIV infections and orphaned children during that time and longer lives among people living with HIV. Our estimates do not account for the impact of the PEPFAR-funded non-biomedical interventions such as behavioural and structural interventions included in the comprehensive HIV prevention, care and treatment strategy used by PEPFAR countries. Therefore, the number of HIV infections and orphans averted and LYG may be underestimated by these models.

Abstract access

Editor’s notes: The President’s Emergency Plan for AIDS Relief (PEPFAR) was initiated in 2004 with $42 billion spent up until the end of 2013. Despite limitations in monitoring the overall contribution of PEPFAR to individual programmes, this article attempts to provide an overview of PEPFAR support for ART, prevention of mother to child transmission and voluntary medical male circumcision (VMMC) programmes using the 2014 version of Spectrum Software model. The Spectrum modules used included DemProj, AIDS Impact Model (AIM) and Goals, which interact to model the impact and future course of the HIV epidemic at the population level.  An estimate of PEPFAR’s contribution was obtained by subtracting it from the total for the national programme statistics reported by UNAIDS on ART, PMTCT and VMMC.

The baseline scenario of PEPFAR-supported programmes in 2013 was compared to a counterfactual scenario, which subtracts the direct contribution of PEPFAR. The results estimate that the combined programmes have averted 2.7 million infections in Africa, with over 11.5 million life years gained and the aversion of almost nine million orphans. Other key population programmes that the funding supported including gender equity and health strengthening were not evaluated and therefore, the estimate for impact may be conservative. A limitation of the analysis is that it is unable to predict the national response without PEPFAR and the impact of ART calculated by the model is sensitive to the distribution of new ART patients by CD4 count at the initiation of treatment. In addition, few countries have sufficient death registration systems to validate mortality estimates, which may result in the accomplishments of PEPFAR’s impact being overestimated. However, with the operation of PEPFAR in a larger context of partnership consortiums, an improvement in evaluation methods will be necessary. 

Africa
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Sex and drugs: poppers and HIV risk

Poppers use and risky sexual behaviors among men who have sex with men in Beijing, China.

Zhang H, Teng T, Lu H, Zhao Y, Liu H, Yin L, Sun Z, He X, Qian HZ, Ruan Y, Shao Y, Vermund SH. Drug Alcohol Depend. 2015 Dec 10. pii:S0376-8716(15)01807-4. doi:10.1016/j.drugalcdep.2015.11.037. [Epub ahead of print]

Background: Although poppers are increasingly popular among MSM in China, little is known about the patterns of poppers use. The objectives of this study were to describe the patterns of poppers use and examine its association with sexual behaviors and HIV infection among MSM in Beijing, China.

Methods: As part of a multi-component HIV intervention trial, 3588 MSM were surveyed between March 2013 and March 2014 in Beijing, China. Blood samples were collected and tested for HIV and syphilis. The questionnaire collected information about socio-demographic and behavioral characteristics. Univariate and multivariable logistic regression analyses were performed to evaluate the correlates of poppers use.

Results: Over a quarter of men (27.5%) reported having used at least one type of drugs in the past three months. Poppers were the most popular one (26.8%). Poppers use was correlated with a higher HIV prevalence [odds ratio (OR): 1.38, 95% confidence interval (CI): 1.11-1.70]. Demographic and sexual behavioral factors associated with poppers use included: younger age [adjusted OR (AOR): 1.56, 95% CI: 1.25-1.94], higher education (AOR: 1.61, 95% CI: 1.33-1.96), alcohol use (AOR: 1.32, 95% CI: 1.10-1.60), seeking male partners mainly via the internet (AOR: 1.60, 95% CI: 1.28-2.00), multiple male sex partnership (AOR: 2.22, 95% CI: 1.90-2.60), and unprotected receptive anal intercourse (AOR: 1.52, 95% CI: 1.28-1.81).

Conclusions: In this study, poppers use was positively associated with HIV infection and unprotected anal intercourse. Intervention efforts should be devoted to promote safer sex and HIV testing and counseling among MSM who use poppers.

 Abstract access   

Editor’s notes: Poppers are butyl and other nitrites that were used in the past for heart pain. They can be inhaled to facilitate anal sex. Sniffing poppers relaxes the anal sphincter muscles, making anal intercourse easier and enhancing pleasure. Numerous studies have found an association between popper use and an increased risk of acquiring HIV. This may be due to the effect of poppers in dilating capillaries and increasing blood flow to the rectum. Such a biological effect may increase the risk to the receptive partner in anal sex, further to having less autonomy in determining whether a condom is used.

This large community-based study gathered information from adult men living in Beijing, who reported sex with men in the previous 12 months. The descriptive data reported in this paper were gathered in the first phase of what is intended to be a large multi-component HIV prevention intervention trial. These data illustrate high prevalence of popper use among gay men and other men who have sex with men in Beijing. Clearly, a priority of the trial should be testing strategies to address popper use in this population. The HIV epidemic in China has evolved to one in which sexual transmission predominates, with four out of five new infections in 2011 acquired through sexual exposure. In contrast to other drugs used to enhance sexual pleasure (such as methamphetamine, ecstasy, and ketamine), poppers are widely available in China at adult stores or through the internet. In light of the finding that popper users are more likely to use the internet, it may be possible to work with the community to design programmes using internet platforms to reach men most at risk. These could aim to raise awareness and encourage changes in sex and popper use norms to reduce HIV risk and make sex safer for gay men and other men who have sex with men in Beijing.

Asia
China
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A pill for HIV prevention: to take when you need it

On-demand preexposure prophylaxis in men at high risk for HIV-1 infection.

Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, Tremblay C, Le Gall JM, Cua E, Pasquet A, Raffi F, Pintado C, Chidiac C, Chas J, Charbonneau P, Delaugerre C, Suzan-Monti M, Loze B, Fonsart J, Peytavin G, Cheret A, Timsit J, Girard G, Lorente N, Preau M, Rooney JF, Wainberg MA, Thompson D, Rozenbaum W, Dore V, Marchand L, Simon MC, Etien N, Aboulker JP, Meyer L, Delfraissy JF, Group AIS. N Engl J Med. 2015 Dec 3;373(23):2237-46. doi: 10.1056/NEJMoa1506273. Epub 2015 Dec 1.

Background: Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen.

Methods: We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections.

Results: Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03).

Conclusions: The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events.

Abstract Full-text [free] access

Editor’s notes: The IPERGAY trial is the first trial to assess ‘on demand’ HIV pre-exposure prophylaxis (PrEP). It had a ‘take it when you need it’ approach, rather than a daily dosing approach where a pill is taken every day, regardless of sexual activity. In 2010, the iPrEx Trial of daily pills among gay men and other men who have sex with men reported a 42% relative reduction in HIV incidence. In participants with detectable drug in their blood (meaning that they had been taking the pills), the reduction was 92%. The IPERGAY researchers set out to prove or disprove the hypothesis that men would be more likely to take pills if pill-taking was associated with having sex. The hypothesis was that this might improve adherence and hence reduce the risk of HIV acquisition compared with daily dosing. Participants were randomly assigned to take a dose of two pills of TDF/FTC (tenofovir disoproxil fumarate/emtricitabine) or placebo with food between two and 24 hours before sex. A third pill was taken 24 hours after sex and a fourth pill 24 hours after that. If they continued to be sexually active, they were told to take one pill a day while sexually active and then the two post-exposure doses 24 hours apart. When the striking results of the PROUD trial in the United Kingdom, among gay men and other men who have sex with men, were made public [see HIV This Month February 2015], IPERGAY’s Data Safety and Monitoring Board (DSMB) asked for an unblinded interim analysis of the IPERGAY data. The results were so convincing (an 86% relative risk reduction) that the DSMB recommended that the trial be unblinded so that men in the placebo arm could be offered active drug. The next question was whether this highly effective preventive measure could be made available outside the trial setting. The Food and Drug Administration of the United States of America had approved TDF/FTC for HIV PrEP in 2012 but no country had followed suit. On November 23, 2015, France’s Minister for Social Affairs, Health, and Women’s Rights announced a temporary recommendation for the use of TDF/FTC HIV prophylaxis, opening the way to the authorisation of PrEP in other European countries. Before any other European country responded, South Africa’s Medicines Control Council announced on December 3, 2015 its approval of the fixed-dose combination of TDF/FTC for pre-exposure prophylaxis of HIV. Kenya’s Pharmacy & Poisons Board also approved once-daily use of TDF/FTC for HIV prevention on December 23, 2015. The scientific evidence has been building for years. Clearly it is time to act now to make this highly effective HIV prevention choice available to people at highest risk of HIV exposure.

Europe, Northern America
Canada, France
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Long-acting PrEP might offer a solution to the challenges of adherence

Potential clinical and economic value of long-acting preexposure prophylaxis for South African women at high-risk for HIV infection.

Walensky RP, Jacobsen MM, Bekker LG, Parker RA, Wood R, Resch SC, Horstman NK, Freedberg KA, Paltiel AD. J Infect Dis. 2015 Dec 17. pii: jiv523. [Epub ahead of print]

Background: For young South African women at risk for human immunodeficiency virus (HIV) infection, preexposure prophylaxis (PrEP) is one of the few effective prevention options available. Long-acting injectable PrEP, which is in development, may be associated with greater adherence, compared with that for existing standard oral PrEP formulations, but its likely clinical benefits and additional costs are unknown.

Methods: Using a computer simulation, we compared the following 3 PrEP strategies: no PrEP, standard PrEP (effectiveness, 62%; cost per patient, $150/year), and long-acting PrEP (effectiveness, 75%; cost per patient, $220/year) in South African women at high risk for HIV infection (incidence of HIV infection, 5%/year). We examined the sensitivity of the strategies to changes in key input parameters among several outcome measures, including deaths averted and program cost over a 5-year period; lifetime HIV infection risk, survival rate, and program cost and cost-effectiveness; and budget impact.

Results: Compared with no PrEP, standard PrEP and long-acting PrEP cost $580 and $870 more per woman, respectively, and averted 15 and 16 deaths per 1000 women at high risk for infection, respectively, over 5 years. Measured on a lifetime basis, both standard PrEP and long-acting PrEP were cost saving, compared with no PrEP. Compared with standard PrEP, long-acting PrEP was very cost-effective ($150/life-year saved) except under the most pessimistic assumptions. Over 5 years, long-acting PrEP cost $1.6 billion when provided to 50% of eligible women.

Conclusions: Currently available standard PrEP is a cost-saving intervention whose delivery should be expanded and optimized. Long-acting PrEP will likely be a very cost-effective improvement over standard PrEP but may require novel financing mechanisms that bring short-term fiscal planning efforts into closer alignment with longer-term societal objectives.

Abstract  Full-text [free] access

Editor’s notes: Standard oral pre-exposure prophylaxis (PrEP) is effective in preventing HIV and is one of the few proven prevention options available to young women at risk of HIV. However, daily adherence is key and trials have illustrated problems with adherence in several populations. Development of long-acting injectable formulations of PrEP may provide an option that does not require daily adherence to pills. In anticipation of new formulations of PrEP, this study modelled the potential clinical benefits, additional cost, cost-effectiveness and budget impact of existing and novel PrEP strategies. Given that the effectiveness and cost of long-acting PrEP is unknown, sensitivity analyses were conducted to look at varied effectiveness, HIV infection incidence, age at PrEP discontinuation and programmatic cost. The results suggest that long-acting PrEP is likely to be more clinically and cost-effective than standard oral PrEP. However, it will place an even greater strain on existing HIV prevention budgets. In addition to the research necessary to establish its clinical effectiveness, efforts to develop novel financing mechanisms are also required.         

Africa
South Africa
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Adolescents, safer sex and HIV-status disclosure in South Africa

Sex and secrecy: how HIV-status disclosure affects safe sex among HIV-positive adolescents.

Toska E, Cluver LD, Hodes R, Kidia KK. AIDS Care. 2015 Dec;27 Suppl 1:47-58. doi: 10.1080/09540121.2015.1071775.

HIV-positive adolescents who engage in unsafe sex are at heightened risk for transmitting or re-acquiring HIV. Disclosure of HIV-status to sexual partners may impact on condom use, but no study has explored the effects of (i) adolescent knowledge of one's HIV-status, (ii) knowledge of partner status and (iii) disclosure to partners, on safer sex behaviour. This study aimed to identify whether knowledge of HIV-status by HIV-positive adolescents and partners was associated with safer sex. Eight hundred and fifty eight HIV-positive adolescents (10-19 years old, 52% female, 68.1% vertically infected) who had ever initiated antiretroviral treatment in 41 health facilities in the Eastern Cape, South Africa, were interviewed using standardised questionnaires. Quantitative analyses used multivariate logistic regressions, controlling for confounders. Qualitative research included interviews, focus group discussions and observations with 43 HIV-positive teenagers and their healthcare workers. N = 128 (14.9%) of the total sample had ever had sex, while N = 109 (85.1%) of sexually active adolescents had boy/girlfriend. In total, 68.1% of the sample knew their status, 41.5% of those who were sexually active and in relationships knew their partner's status, and 35.5% had disclosed to their partners. For adolescents, knowing one's status was associated with safer sex (OR = 4.355, CI 1.085-17.474, p = .038). Neither knowing their partner's status, nor disclosing one's HIV-status to a partner, were associated with safer sex. HIV-positive adolescents feared rejection, stigma and public exposure if disclosing to sexual and romantic partners. Counselling by healthcare workers for HIV-positive adolescents focused on benefits of disclosure, but did not address the fears and risks associated with disclosure. These findings challenge assumptions that disclosure is automatically protective in sexual and romantic relationships for HIV-positive adolescents, who may be ill-equipped to negotiate safer sex. There is a pressing need for effective interventions that mitigate the risks of disclosure and provide HIV-positive adolescents with skills to engage in safe sex.

Abstract  Full-text [free] access

Editor’s notes: Ninety percent of the world’s adolescents living with HIV, live in sub-Saharan Africa.  Evidence illustrates high levels of condomless sex with other adolescents (27-90%) and low rates of disclosure to sexual partners. Negotiating safer sexual practices is particularly challenging for HIV-positive adolescents, exacerbated by HIV-associated factors, learning and accepting their status, and withholding or disclosing their HIV status to sexual partners. There is a dearth of evidence on associations between disclosure and negotiating safer sexual practices among adolescents. This study examines the extent to which disclosure to, and by, adolescents living with HIV is associated with safer sex.

This mixed-methods study employed an iterative approach whereby preliminary qualitative findings guided quantitative measures, particularly items on disclosure. Emerging quantitative findings framed the thematic focus of qualitative research. The study was conducted in the eastern Cape, South Africa. Some 858 adolescents aged 10-19 years were recruited for the quantitative arm of the study. Some 43 participants were included in the qualitative arm of the study. Data generation methods used were individual interviews, focus group discussions and direct observations.

The findings indicate that among adolescents living with HIV, knowledge of HIV-status was strongly associated with safer sex. Knowing one’s partner’s status or disclosing one’s status was not.  Qualitative findings suggest that fear of rejection, exposure, and stigma discouraged HIV-positive adolescents from disclosing to their partners as a strategy for negotiating safer sex. Disclosure counselling and support from healthcare professionals did not address these challenges. Guidelines on counselling HIV-positive adolescents should focus on promoting safer sex with all sexual partners as a first priority, rather than promoting disclosure to sexual partners. Disclosure counselling for HIV-positive adolescents could also be enhanced by improving patient confidentiality, addressing adolescent fears on the dangers of disclosure and by giving HIV-positive adolescents skills to negotiate safer sex.

Africa
South Africa
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Condomless sex + viral suppression = ‘safe(r)’ sex? Challenging the laws that criminalise HIV transmission

HIV transmission law in the age of treatment-as-prevention.

Haire B, Kaldor J. J Med Ethics. 2015 Dec;41(12):982-6. doi: 10.1136/medethics-2014-102122. Epub 2015 Sep 29.

Evidence that treating people with HIV early in infection prevents transmission to sexual partners has reframed HIV prevention paradigms. The resulting emphasis on HIV testing as part of prevention strategies has rekindled the debate as to whether laws that criminalise HIV transmission are counterproductive to the human rights-based public health response. It also raises normative questions about what constitutes 'safe(r) sex' if a person with HIV has undetectable viral load, which has significant implications for sexual practice and health promotion. This paper discusses a recent high-profile Australian case where HIV transmission or exposure has been prosecuted, and considers how the interpretation of law in these instances impacts on HIV prevention paradigms. In addition, we consider the implications of an evolving medical understanding of HIV transmission, and particularly the ability to determine infectiousness through viral load tests, for laws that relate to HIV exposure (as distinct from transmission) offences. We conclude that defensible laws must relate to appreciable risk. Given the evidence that the transmissibility of HIV is reduced to negligible level where viral load is suppressed, this needs to be recognised in the framing, implementation and enforcement of the law. In addition, normative concepts of 'safe(r) sex' need to be expanded to include sex that is 'protected' by means of the positive person being virally suppressed. In jurisdictions where use of a condom has previously mitigated the duty of the person with HIV to disclose to a partner, this might logically also apply to sex that is 'protected' by undetectable viral load.

Abstract access

Editor’s notes: The changing landscape of HIV treatment challenges assumptions about the HIV epidemic based on past knowledge and understanding. The authors of this paper set out why laws that criminalise HIV transmission may now need to change. This change is required because of the impact of antiretroviral therapy on the viral load of someone living with HIV and taking their treatment regularly. As the authors note ‘it is no longer reasonable to classify condomless sex as ‘unsafe’ if the partner with HIV has an undetectable viral load’ (p. 985).  What the authors do not discuss is whether someone on antiretroviral therapy does indeed have a suppressed viral load.  Indeed, whether the person’s viral load suppression may change between the act for which they are prosecuted, and the time of the prosecution, is not discussed. The viral load of someone living with HIV on treatment may not stay suppressed if there is a break in adherence. That said, this paper does very effectively highlight how the evolution of the HIV epidemic affects many areas of life and institutions; including laws that may be slow to adapt and change.

Oceania
Australia, New Zealand
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Predicting acute HIV infection in key populations

Targeted screening of at-risk adults for acute HIV-1 infection in sub-Saharan Africa.

Sanders EJ, Wahome E, Powers KA, Werner L, Fegan G, Lavreys L, Mapanje C, McClelland RS, Garrett N, Miller WC, Graham SM. AIDS. 2015 Dec;29 Suppl 3:S221-30. doi: 10.1097/QAD.0000000000000924.

Background: Patients with acute HIV-1 infection (AHI) have elevated infectivity, but cannot be diagnosed using antibody-based testing. Approaches to screen patients for AHI are urgently needed to enable counselling and treatment to reduce onward transmission.

Methods: We pooled data from four African studies of high-risk adults that evaluated symptoms and signs compatible with acute retroviral syndrome and tested for HIV-1 at each visit. AHI was defined as detectable plasma viral load or p24 antigen in an HIV-1-antibody-negative patient who subsequently seroconverted. Using generalized estimating equation, we identified symptoms, signs, and demographic factors predictive of AHI, adjusting for study site. We assigned a predictor score to each statistically significant predictor based on its beta coefficient, summing predictor scores to calculate a risk score for each participant. We evaluated the performance of this algorithm overall and at each site.

Results: We compared 122 AHI visits with 45 961 visits by uninfected patients. Younger age (18-29 years), fever, fatigue, body pains, diarrhoea, sore throat, and genital ulcer disease were independent predictors of AHI. The overall area under the receiver operating characteristics curve (AUC) for the algorithm was 0.78, with site-specific AUCs ranging from 0.61 to 0.89. A risk score of at least 2 would indicate AHI testing for 5-50% of participants, substantially decreasing the number needing testing.

Conclusion: Our targeted risk score algorithm based on seven characteristics reduced the number of patients needing AHI testing and had good performance overall. We recommend this risk score algorithm for use by HIV programs in sub-Saharan Africa with capacity to test high-risk patients for AHI.

Abstract  Full-text [free] access

Editor’s notes: This analysis adds to the literature around the performance of risk score algorithms to guide testing for acute HIV infection (AHI). The four studies included in this analysis involved key populations in different African settings. In common with previous analyses, genital ulcer disease had by far the strongest association with AHI. The derived algorithm had modest accuracy overall and poor performance in South Africa, where symptoms and signs were particularly infrequent.

Most studies included in this analysis were cohort studies following key individuals. Whether or not algorithms based on recording of symptoms and signs during intensive follow-up for AHI can be translated for use in a real world situation of unselected people presenting for health care remains unproven. Ultimately, we really need evidence about the impact and cost-effectiveness of detecting AHI in different populations. This is in order to define the role of testing for AHI, and in particular whether rationalising testing with algorithms such as this is necessary (especially for key populations).   

Africa
Kenya, Malawi, South Africa
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Mechanism found for increased HIV risk in women using injectable progestin-only contraception

Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study.

Byrne EH, Anahtar MN, Cohen KE, Moodley A, Padavattan N, Ismail N, Bowman BA, Olson GS, Mabhula A, Leslie A, Ndung'u T, Walker BD, Ghebremichael MS, Dong KL, Kwon DS. Lancet Infect Dis. 2015 Dec 23. pii: S1473-3099(15)00429-6. doi: 10.1016/S1473-3099(15)00429-6. [Epub ahead of print]

Background: The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract.

Methods: In this prospective cohort, we enrolled HIV-negative South African women aged 18-23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods.

Findings: Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12.06 per 100 person-years, 95% CI 6.41-20.63) than women using no long-term contraception (3.71 per 100 person-years, 1.36-8.07; adjusted hazard ratio [aHR] 2.93, 95% CI 1.09-7.868, p=0.0326). HIV-negative injectable progestin-only contraceptive users had 3.92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0.0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3.25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0.0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives.

Interpretation: Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure.

Abstract access 

Editor’s notes: Several observational studies have reported increased risk of HIV acquisition in women using injectable progestin-only contraception. In this study, injectable progestin-only contraceptive use was associated with a higher frequency of activated CCR5+ CD4 T cells in the cervix. These cells are the target for HIV, and thus an increase in their number may increase the risk of HIV acquisition by accelerating viral dissemination after genital tract exposure to HIV. This study also found a significantly higher frequency of activated cervical target cells during the luteal phase of the menstrual cycle in women who were not using injectable progestin-only contraception. These findings suggest that the increased HIV acquisition risk may be mediated by both exogenous and endogenous progestin exposure. This study provides novel insights into the role of progestins, and provides a potential biological explanation for an increased risk of HIV acquisition among women using injectable progestin-only contraception. This work will hopefully inform the development of biological prophylactics to reduce HIV acquisition in women. Whether these findings will influence recommendations for contraceptive use in women living in high HIV incidence settings remains to be determined.  

Africa
South Africa
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Weighing up the risks and benefits of trial participation: understanding non-adherence in a PrEP trial

Participants' explanations for non-adherence in the FEM-PrEP clinical trial.

Corneli A, Perry B, McKenna K, Agot K, Ahmed K, Taylor J, Malamatsho F, Odhiambo J, Skhosana J, Van Damme L. J Acquir Immune Defic Syndr. 2015 Nov 3. [Epub ahead of print]

Background: FEM-PrEP - a clinical trial of daily, oral emtricitabine/tenofovir disoproxil fumarate for HIV prevention among women in sub-Saharan Africa - did not show a reduction in HIV acquisition because of low adherence to the study pill. We conducted a follow-up study to identify reasons for non-adherence.

Methods: Qualitative, semi-structured interviews (n=88) and quantitative, audio computer-assisted self-interviews (n=224) were conducted with former FEM-PrEP participants in Bondo, Kenya, and Pretoria, South Africa. Thematic analysis was used to analyze the qualitative data, and descriptive statistics were used to describe ACASI responses. Data are presented within the five categories of Ickovics' and Meisler's conceptual framework on adherence: 1) the individual, 2) trial characteristics and study pill regimen, 3) patient-provider relationship, 4) clinical setting, and 5) the disease.

Results: Participants' explanations for non-adherence were primarily situated within three of the framework's five categories: 1) the individual, 2) trial characteristics and study pill regimen, and 3) the disease. Concerns about the investigational nature of the drug being tested and side effects were the prominent reasons reported for non-adherence. Participants also described being discouraged from taking the study pill by members of the community, their sexual partners, and other participants, primarily because of these same concerns. Limited acceptability of the pill's attributes influenced non-adherence for some participants as did concerns about HIV-related stigma. Additionally, many participants reported that others continued in FEM-PrEP while not taking the study pill because of the trial's ancillary benefits and visit reimbursement - factors related to the clinical setting. Negative patient-provider relationships were infrequently reported as a factor that influenced non-adherence.

Conclusion: Despite substantial study staff engagement with participants and communities, concerns about the study pill and discouragement from others appeared to have influenced non-adherence considerably. Alternative study designs or procedures and enhanced community engagement paradigms may be needed in future studies.

Abstract access 

Editor’s notes: The authors of this important paper on a PrEP trial, end with a note of caution. They note that when interpreting the findings we should remember that the women in this study were taking a ‘study product’. The women were not taking a product of proven efficacy. Therefore, as the authors state, it would be wrong to assume that ‘African women cannot and will not be adherent if provided with PrEP outside of a clinical trial setting’. If they had been told that the product was efficacious, they may have behaved differently. This is important because a key message of the paper is that trial participants managed their participation so they felt comfortable in the trial. Many wanted to ensure they received benefits from their participation, including good health care, but they also wanted to manage risk. Risk associated with fears about the trial drug and risk from the disapproval of sexual partners about their participation. It is also very clear in these findings that the participants could manage the expectations of the trial team, by telling them what they wanted to hear during the trial. This suggests the limited value of ‘adherence questionnaires’ in some settings. The authors provide a powerful illustration of the value of mixed methods in trials of this sort. Drug concentration data told the researchers that many women were not adhering to the drug. Qualitative semi-structured interviews using this drug concentration data with the individual women helped the team to understand why. The authors also discuss the influence of community and family members in undermining participant faith in the trial. They explain the lengths that the trial team went to, to inform community members about the trial. Considerable time was given to sharing information. Doubts remained; concerns that were enough to discourage participation. This too is an important finding underlining the value of investing in community engagement in research. But it also highlights the need to find ways to enhance not just engagement, but also understanding and trust. 

Africa
Kenya, South Africa
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Condoms are highly effective at preventing HSV-2 acquisition, especially for women

Effect of condom use on per-act HSV-2 transmission risk in HIV-1, HSV-2-discordant couples.

Magaret AS, Mujugira A, Hughes JP, Lingappa J, Bukusi EA, DeBruyn G, Delany-Moretlwe S, Fife KH, Gray GE, Kapiga S, Karita E, Mugo NR, Rees H, Ronald A, Vwalika B, Were E, Celum C, Wald A, Partners in Prevention HSVHIVTST. Clin Infect Dis. 2015 Nov 17. pii: civ908. [Epub ahead of print]

Background: The efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not been previously measured on a per-act basis.

Methods: We examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts.

Results: Transmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060).

Conclusions: Condoms are recommended as an effective preventive method for heterosexual transmission of HSV-2.

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Editor’s notes: HSV-2 is extremely prevalent in sub-Saharan Africa, and an important co-factor in HIV transmission. Although condoms are recommended for preventing HSV-2 infection, there have been no previous studies of their effectiveness on a per-sex act basis. This study in HIV and HSV-2 discordant couples participating in an HIV prevention trial examined the risk of HSV-2 transmission for each sex act with and without male condoms. At enrolment, index partners were living with both HIV and HSV-2 infections; susceptible partners were negative for both infections.

The authors found that condoms provided greater protection against HSV-2 acquisition for women than for men, reducing the risk of transmission by 96% from men to women, and by 65% from women to men. However, the overall risk of HSV-2 infection was much higher for women – for each condomless sex act, women were nearly 20 times more likely than men to become infected. As a result, even when using condoms, susceptible women had only a slightly lower risk of infection than men did without condoms. Interestingly, HSV-2 suppressive therapy with acyclovir did not have any effect on HSV-2 transmission, for either sex. Although the authors were not able to confirm that the HSV-2 transmissions occurred within the partnership (e.g. by sequencing the HSV2 DNA), an analysis restricted to couples who never reported sex outside the partnership illustrated very similar results.

The difference in the protection provided by condoms between the sexes may be explained by the fact that, in men, HSV-2 viral shedding is primarily from the penile shaft whereas in women the virus is shed from the wider area of the perineum, and hence condoms are less effective for female-male transmission. These findings indicate that, in individuals who are both HIV and HSV-2 positive, male condoms are extremely effective in preventing male-to-female transmission of HSV-2, and also provide some protection against female-to-male transmission. Although condoms may not provide the same level of protection in populations who are HIV negative, their promotion remains an important public health activity for preventing HSV-2 infection.

Africa
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