Pre-exposure prophylaxis

Stop stalling and make PrEP for HIV available now

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Further delay to pre-exposure prophylaxis risks the NHS appearing discriminatory of populations at risk

Compelling evidence of the effectiveness of pre-exposure prophylaxis (PrEP) for HIV has been available for over five years. But we are still waiting for the NHS to embrace this potentially revolutionary intervention.

Truvada, a combination of emtricitabine and tenofovir usually used to treat HIV, can also prevent HIV infection. PrEP could at last mean real headway in reducing the transmission of HIV, with the number of newly diagnosed people unchanged in the UK for the past decade.1

In November 2010, the iPrEX (pre-exposure prophylaxis initiative) trial found efficacy of 92% among those who took PrEP as prescribed.2 Subsequent studies have confirmed its efficacy and its effectiveness. One of the most recent is the UK’s PROUD (pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection) study, which looked at the real world effect among men who have sex with men.3 The reduction in incidence among men in the PrEP arm was 86%. Additionally, those who did get HIV while participating in the study were not likely to be taking PrEP when infected.

The US Food and Drug Administration licensed Truvada for use as PrEP in 2012, and in 2014 the Centers for Disease Control and Prevention recommended PrEP for those at high risk of acquiring HIV. Other countries such as France are now following suit. In England, however, progress is painfully slow.

Strong equalities argument

Men who have sex with men and people from black African communities are at highest risk of HIV infection.1 So there is a strong equalities argument for PrEP to be made available now. And, conversely, any further delay may appear to reflect a lack of value placed on the health of these most affected communities. The stigma that still surrounds HIV and its sexual route of transmission cannot be allowed to trump evidence.

We know that PrEP works and that it is cost effective when provided to people at high risk of HIV infection. Yet NHS England’s vacillating has thrown into stark relief a health system that is not designed to come to timely and confident decisions about nationally important preventive interventions, for all the talk we hear of prevention being the new health priority.

PrEP highlights the lack of system-wide accountability. Even if the drug were commissioned by NHS England, the sexual health clinic service to prescribe and monitor PrEP would have to be separately commissioned by each local authority. So even if we eventually get a positive decision from NHS England on the drug, that won’t be the end of the story. Does it make sense for the prevention of infectious disease to be delegated to 150 local bodies, without any national strategic direction?

In September 2014 NHS England began the process to decide whether to commission the drug used in PrEP. In March 2016, after 18 months of work and just before its final decision was due, NHS England announced that this specialised commissioning process was inappropriate because PrEP is a preventive intervention.

Despite a legal argument by the National AIDS Trust (NAT), NHS England reconfirmed this decision in late May 2016. Faced with this impasse, NAT has no choice but to take the matter before a court for judicial review. The public interest in resolving this is too great to ignore it.

Fractured decision making

This is a health system failing to look at the bigger picture, with decision making dangerously fractured and with no one providing clear direction and leadership. The provision of PrEP for those at high risk, who need it and want it, could reduce the human and financial costs of this preventable condition. While we delay, 17 people a day are being diagnosed with HIV.1

Antiretroviral PrEP for Injection-Drug Users?

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In a randomized, controlled trial involving injection-drug users in Thailand, tenofovir reduced the risk for HIV infection.

 

Antiretroviral pre-exposure prophylaxis (PrEP) is effective in preventing sexually acquired HIV infection among men who have sex with men as well as heterosexual men and women. Might it also help to prevent HIV infection among injection-drug users? To find out, investigators from the CDC and the Thailand Ministry of Health conducted a study involving HIV-uninfected injection-drug users recruited at drug-treatment clinics in Bangkok.

A total of 2413 individuals were randomized to oral tenofovir or placebo, either administered daily via directly observed therapy (DOT) or provided at monthly visits. The decision to use DOT was up to the participants, who could switch at monthly visits. Each month during follow-up (mean duration, 4 years), participants received HIV testing and risk-reduction and adherence counseling. Drug levels were also measured at some of the clinics, and at the time of the first positive HIV test in all individuals who seroconverted.

The median age of participants was 31; 80% were men, and 48% had 

≤6 years of education. Twenty-two percent were enrolled in a methadone program. Baseline characteristics were similar between groups, except that sexual intercourse with casual partners and having sex with men during the 12 weeks preceding enrollment were more common in the placebo group.

HIV infection was confirmed in 50 participants — 17 in the tenofovir group and 33 in the placebo group — for an overall 48.9% reduction in HIV incidence with tenofovir in intent-to-treat analysis. Efficacy was higher — 73.5% — among individuals with detectable tenofovir levels in their plasma.

Comment: This study is the first to demonstrate the efficacy of tenofovir in preventing HIV infection among injection-drug users. Almost concomitantly, the CDC published interim guidance for pre-exposure prophylaxis in this population. Interestingly, the CDC recommended using tenofovir/FTC (not tenofovir alone, as studied in Thailand), arguing that tenofovir/FTC and not tenofovir alone is approved by the FDA for prophylaxis. The CDC also suggested that prevention services targeting injection and sexual risk behaviors be provided for injection-drug users.

I must emphasize that this study used directly observed therapy as one strategy, and that efficacy of antiretrovirals for prevention depends on adherence. Thus, any PrEP program should incorporate strong adherence counseling.

 

Source: Journal Watch HIV/AIDS Clinical Care

HIV pre-exposure prophylaxis in injecting drug users.

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Globally, there are an estimated 15·9 million injecting drug users, 3 million of whom have HIV.1 The illicit nature of injection drug use and associated social stigma have created substantial challenges for HIV prevention in this group. Despite these obstacles, several programmes have shown that HIV transmission in injecting drug users can be prevented, stabilised, and even reversed with needle exchange programmes.2 However, the HIV epidemic continues to grow in this high-risk population in some regions, particularly in eastern Europe, central Asia, and, since 2007, sub-Saharan Africa.3 Much more needs to be done to reduce the continuing high rates of HIV transmission in injecting drug users.

Findings from a series of randomised placebo-controlled trials, viewed cumulatively, provide compelling evidence (figure) that antiretroviral pre-exposure prophylaxis (PrEP), when taken, is effective in preventing mother-to-child transmission of HIV,4 sexual transmission in men who have sex with men, and sexual transmission between men and women.5 In women, both oral and topical antiretrovirals have been shown to prevent sexual transmission. However, there is no rigorous evidence on whether PrEP is effective in preventing parenteral HIV transmission. In 2005, the US Centers for Disease Control and Prevention initiated the Bangkok Tenofovir Study to address this major gap and assess the efficacy of daily oral tenofovir disoproxyl fumarate (tenofovir) in preventing parenteral transmission of HIV.

In The Lancet, Kachit Choopanya and colleagues report the results of this important study.6 They enrolled 2413 participants who reported injecting drugs within the previous 12 months and followed them up for a mean of 4·0 years. During follow-up, 50 participants acquired HIV: 17 were in the tenofovir group (HIV incidence=0·35 per 100 person-years) and 33 were in the placebo group (0·68 per 100 person-years), which translates into 49% effectiveness of tenofovir (95% CI 9·6—72·2). Additional per-protocol and drug level analyses drew attention to the importance of adherence to achieve high levels of protection from PrEP.

Although findings from this study provide the evidence to show that PrEP is effective in preventing HIV infection in people who inject drugs, it is less clear as to whether the findings show that PrEP prevents parenteral transmission of HIV. People who inject drugs can acquire HIV through either unprotected sexual intercourse or sharing of needles and syringes. These two routes of HIV transmission are often linked epidemiologically. Not only do injecting drug users engage in unprotected sex, they might also engage in commercial sex to get money for drugs.

Because no biological marker exists to distinguish between HIV transmission that occurs through sex and that which occurs parenterally, all HIV infections during follow-up in this trial contribute to the overall efficacy measure. Tenofovir is known to be effective in preventing sexual transmission of HIV, so some fraction of the recorded 49% protection is probably due to prevention of sexual transmission, in view of the fact that the number of reports of multiple sexual partners decreased during follow-up. The extent of the remaining protection attributable to parenteral transmission is not known. However, although the participants in this trial were confirmed injecting drug users at enrolment, there were substantial reductions in reported levels of injecting drug use from enrolment to month 12 (from 63% to 23%) and needle-sharing (from 18% to 2%). These reductions continued—by 72 months, 18% reported injecting drugs and 1% reported needle-sharing. Furthermore, the investigators noted that the protective benefits of PrEP were evident only after the first 3 years of follow-up, by which time reported levels of injecting drug use and needle-sharing were low. Hence, it is not possible to make definitive conclusions about the efficacy of daily tenofovir for the prevention of parenteral transmission of HIV from these data. As a result, PrEP is not a replacement for politically sensitive needle exchange programmes to prevent parenteral transmission.

Even though questions remain about the extent to which PrEP can be effective in preventing either of the routes of transmission in this group, the overall result is that daily tenofovir does reduce HIV transmission in injecting drug users. The introduction of PrEP for HIV prevention in injecting drug users should be considered as an additional component to accompany other proven prevention strategies like needle exchange programmes, methadone programmes, promotion of safer sex and injecting practices, condoms, and HIV counselling and testing. PrEP as part of combination prevention in injecting drug users could make a useful contribution to the quest for an AIDS-free generation.

Source: Lancet

 

Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial.

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Summary

Background

Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users.

Methods

In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20—60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered withClinicalTrials.gov, number NCT00119106.

Findings

Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0·35 per 100 person-years) and 33 in the placebo group (0·68 per 100 person-years), indicating a 48·9% reduction in HIV incidence (95% CI 9·6—72·2; p=0·01). The occurrence of serious adverse events was much the same between the two groups (p=0·35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0·002).

Interpretation

In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs.

Discussion

Once-daily oral tenofovir decreased the risk of HIV infection by 48·9% in injecting drug users when provided with other HIV prevention services at drug-treatment clinics in Bangkok. Findings from other pre-exposure prophylaxis trials showed that adherence had an important effect on efficacy.11, 12 In this study, efficacy increased from 46% to 56% in the per-protocol analysis based on observed adherence and to 74% when limited to participants with detectable tenofovir concentrations. Although the trial was not powered to assess efficacy in subgroups, we saw higher efficacy in women (79%) and in participants aged 40 years or older (89%)—two subgroups with high levels of adherence. The modified intention-to-treat efficacy result did not rule out tenofovir efficacy at less than 10% as specified in the protocol.

We do not know why HIV incidence in the two groups did not differ consistently until after 36 months (figure 2). Low levels of adherence or low risk behaviour during the first 36 months could have masked the effect of tenofovir, but adherence did not change by time on study and risk behaviour decreased during follow-up. The low HIV incidence and slow accrual of infections might be why no between-group difference was seen before 36 months. At 36 months, there were 27 infections and, assuming 49% efficacy, the distribution should have been nine with tenofovir and 18 with placebo. However, there were 13 with tenofovir and 14 with placebo, a difference of only four events.

As has been reported in other trials,11, 12 participants in the tenofovir group reported more nausea and vomiting in the first couple of months of follow-up than did those in the placebo group. When used for treatment of HIV, tenofovir is associated with small decreases in renal function.26, 27 We did not find higher rates of increased creatinine or renal disease in participants randomly allocated to tenofovir.

Other pre-exposure prophylaxis trials have described antiretroviral-resistance mutations in HIV-positive participants, especially in those with unrecognised HIV infection at enrolment.11—13 We did not detect tenofovir resistance in HIV-positive participants in this study. The two participants with unrecognised HIV infection at enrolment were randomly allocated to placebo, limiting the possibility that acquired resistance would occur.

Participant reports of injecting drugs and sharing needles decreased during follow-up, consistent with previous trials in people who inject drugs in Bangkok.28, 29 The HIV incidence in placebo recipients in our study was 0·68 per 100 person-years. This incidence compares with an incidence of 5·8 per 100 person-years in a preparatory trial done in the same clinics in 1995—99 and of 3·4 per 100 person-years during the 1999—2003 AIDSVAX B/E HIV vaccine trial.22, 28 This decrease over time is probably due to many factors, including monthly HIV risk-reduction counselling, decreased needle sharing, and monthly HIV testing speeding up the diagnosis of HIV and limiting the number of people with unrecognised acute HIV infection able to transmit HIV to others.

Our study had several limitations. Participants could have under-reported stigmatised and illegal behaviours such as injecting drugs.30 However, the illegality and stigma attached to these activities did not change during the trial, meaning that rates of under-reporting should have remained constant. The study aimed to establish whether tenofovir would reduce parenteral HIV transmission, but participants might have become infected sexually. Previous studies in people who inject drugs in the same clinics in Bangkok have shown strong associations between injecting drugs and HIV infection, but no association between sexual activity and HIV infection.28, 29 In this study, although reports of injecting drug use decreased, 1018 (45%) participants reported injecting drugs during follow-up, including 35 (70%) of those who contracted HIV during the course of the study. Furthermore, similar to the previous studies in the drug-treatment clinics, drug overdose, traffic accidents, and sepsis were the most common causes of death, and participants were frequently incarcerated. Together these data suggest that participants were actively injecting drugs and that parenteral HIV transmission, not sex, was the primary route of HIV infection. Additional risk behaviour analyses are underway. The study was done in drug-treatment clinics offering a package of HIV prevention interventions and DOT; tenofovir effectiveness might differ in other settings.

Findings from three randomised, placebo-controlled trials have shown that a daily dose of tenofovir or tenofovir-emtricitabine can reduce sexual HIV transmission.11—13 Findings from two other studies showed that tenofovir and tenofovir-emtricitabine did not reduce sexual HIV transmission.31, 32 Adherence seems to be the key factor determining efficacy.33These trials draw attention to the need for methods to help people using pre-exposure prophylaxis achieve effective levels of adherence.

To our knowledge, this study is the first to show that daily oral pre-exposure prophylaxis with tenofovir, when used in combination with other HIV prevention strategies, reduces the risk of HIV infection among people who inject drugs (panel). The US Food and Drug Administration has approved the use of tenofovir-emtricitabine to prevent sexual acquisition of HIV in high-risk individuals.34 On the basis of the results of this study, regulatory and public health authorities can now consider whether pre-exposure prophylaxis with tenofovir should be part of an HIV prevention package to reduce the risk of HIV infection in people who inject drugs.

Panel

Research in context

Systematic review

We searched PubMed for phase 1, 2, and 3 randomised clinical trials in human beings assessing tenofovir for the treatment of HIV infection and animal trials using tenofovir to prevent HIV infection. We used the search terms “HIV”, “tenofovir”, “treatment”, “prevention”, and “clinical trials”, restricting our search to studies published in English through December, 2004. The study was launched in 2005 and, at the time, no phase 3 clinical trials using tenofovir in human beings for HIV pre-exposure prophylaxis had published results.

Interpretation

To our knowledge, this is the first study to show that daily oral pre-exposure prophylaxis with tenofovir, when used in combination with other HIV prevention strategies, reduces the risk of HIV infection in people who inject drugs. Much like findings from other pre-exposure prophylaxis trials, our findings showed that adherence had an important effect on efficacy. On the basis of these findings regulatory and public health authorities can now consider whether pre-exposure prophylaxis with tenofovir should be part of an HIV prevention package to reduce the risk of HIV infection in people who inject drugs.

Source: http://www.thelancet.com

Extra-couple HIV transmission in sub-Saharan Africa: a mathematical modelling study of survey data.

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Background

The proportion of heterosexual HIV transmission in sub-Saharan Africa that occurs within cohabiting partnerships, compared with that in single people or extra-couple relationships, is widely debated. We estimated the proportional contribution of different routes of transmission to new HIV infections. As plans to use antiretroviral drugs as a strategy for population-level prevention progress, understanding the importance of different transmission routes is crucial to target intervention efforts.

Methods

We built a mechanistic model of HIV transmission with data from Demographic and Health Surveys (DHS) for 2003—2011, of 27 201 cohabiting couples (men aged 15—59 years and women aged 15—49 years) from 18 sub-Saharan African countries with information about relationship duration, age at sexual debut, and HIV serostatus. We combined this model with estimates of HIV survival times and country-specific estimates of HIV prevalence and coverage of antiretroviral therapy (ART). We then estimated the proportion of recorded infections in surveyed cohabiting couples that occurred before couple formation, between couple members, and because of extra-couple intercourse.

Findings

In surveyed couples, we estimated that extra-couple transmission accounted for 27—61% of all HIV infections in men and 21—51% of all those in women, with ranges showing intercountry variation. We estimated that in 2011, extra-couple transmission accounted for 32—65% of new incident HIV infections in men in cohabiting couples, and 10—47% of new infections in women in such couples. Our findings suggest that transmission within couples occurs largely from men to women; however, the latter sex have a very high-risk period before couple formation.

Interpretation

Because of the large contribution of extra-couple transmission to new HIV infections, interventions for HIV prevention should target the general sexually active population and not only serodiscordant couples.

Funding

US National Institutes of Health, US National Science Foundation, and J S McDonnell Foundation.

Introduction

In the past 2 years, major research advances have been made in anti-HIV interventions. Antiretroviral drugs can help prevent HIV transmission, either by reducing infectiousness when given as antiretroviral therapy (ART) to HIV-positive individuals (treatment as prevention [TasP]),1, 2 or by reducing the susceptibility of HIV-negative individuals when given as oral or topical pre-exposure prophylaxis (PrEP).3, 4 These advances have led to debate about how best to use ART to further reduce HIV incidence.5 An approach that combines several biomedical and behavioural interventions will be needed,6 and policy makers are debating the criteria used to target interventions, including TasP and PrEP.

A serodiscordant couple, defined as an HIV-positive and HIV-negative individual in an ongoing sexual relationship, is a clear example of a susceptible individual being at risk of HIV infection from an infectious individual.7, 8 Targeting of well defined, high-risk groups such as seronegative individuals in serodiscordant partnerships is expected to be resource-efficient. Thus, research of HIV transmission and intervention efficacy has tended to focus on cohorts of serodiscordant couples7 such that seronegative individuals in these partnerships are often the first group in which a new intervention is shown to work. For example, in response to the proven effectiveness of TasP in prevention of transmission in a cohort of serodiscordant couples,1 WHO has recommended this strategy to HIV-positive partners in serodiscordant couples, irrespective of immune status.9 However, not all transmission is within serodiscordant couples; routes also include infection of individuals who are single, and of those in couples by sexual partners outside their relationship (extra-couple relationships). Granich and colleagues10 propose a test-and-treat policy that would target all heterosexual routes of transmission. This approach consists of annual voluntary testing of the entire sexually active population, with immediate and sustained provision of ART to those who test HIV positive. This approach is more expensive and logistically difficult than are targeted approaches, and its value is strongly dependent on the proportion of new transmission events that occur between partners in serodiscordant couples versus those occurring by other routes.

We constructed a mathematical model to estimate rates of HIV transmission before couple formation, rates attributable to extra-couple intercourse, and rates within serodiscordant couples, to assess the proportional contribution of different routes of transmission to new HIV infections. Because the probability that an individual acquires HIV during any period is a function of the period’s duration,11 we disentangled routes of transmission by relating couple serostatus to information about couple duration, duration of sexual activity before couple formation, the population prevalence of HIV, and age-specific estimates of HIV survival.

Discussion

Our findings show three major conclusions. First, extra-couple transmission has played and still plays a major part in driving HIV incidence for both sexes, but particularly for men; second, within couples, HIV seems to be propagated more from men to women than vice versa; third, women have a period of high infection risk before entering a cohabiting partnership. We emphasise that the fitted transmission coefficients aggregate several behavioural and physiological processes and thus should be interpreted cautiously. Because the hazard of infection is the product of transmission coefficients and prevalence in the opposite sex, comparisons between male and female transmission coefficients should be made with consideration of the differing HIV prevalences for each sex. For example, although we estimate that more men than women are infected through extra-couple transmission, the estimated transmission coefficients are roughly similar because female infectious HIV prevalence is greater than that of the opposite sex. The transmission coefficients will also partially absorb unmodelled mixing patterns. For example, young women tend to mix with older men, who have a greater probability of being seropositive than do younger men. This effect would tend to increase female incidence before partnership formation, thus needing greater fitted female before-partnership transmission coefficients to fit the recorded data, but not necessarily biasing the estimate of incidence through this route.

Investigators of previous studies17—23 using DHS and similar cross-sectional couple data have come to diverse conclusions (panel). Analyses of DHS couples data have noted that slightly less than half of serodiscordant couples had seropositive women rather than men;17, 20 others used mathematical models to estimate the proportion of transmission that took place outside serodiscordant partnerships versus between partners.21, 22 These studies all conclude that the high prevalence of female-positive and male-positive serodiscordant partnerships suggests that, contrary to mainstream beliefs,20 both women and men often have risky extra-couple intercourse, with the modelling studies estimating that much of the transmission to both sexes is from outside rather than within the couple. These studies have largely overlooked that routes of infection cannot be directly inferred from cross-sectional data, such as DHS. Estimations of transmission from outside a couple combine infections occurring from extra-couple intercourse with those acquired before that couple’s formation when the individual was either single or in another couple. Thus, the existence of serodiscordant couples does not necessarily suggest extra-couple transmission, and estimates of the proportion of transmission from outside existing partnerships do not measure extra-couple transmission.

A second important factor largely overlooked in analyses of cross-sectional couple data is survival bias—ie, only couples in which both partners survive to be sampled are recorded. Median survival time after seroconversion is about 6—13 years, dependent on the age at seroconversion.12 Many couples in which one or both partners become infected are thus removed from the population before the sample is taken. This effect will be different for serodiscordant and seroconcordant couples. Studies analysing cross-sectional couple data while ignoring mortality17,20—22,28 could therefore yield biased conclusions for the proportional contribution of extra-couple intercourse to incidence.

Our findings show that extra-couple and within-couple transmission are both important routes of HIV infection and both account for many recorded infections in men and women; however, results vary substantially by country. We obtained this result despite finding that fitted extra-couple transmission coefficients were by far the smallest of the three routes of infection. This result is consistent with Chemaitelly and colleagues’28 finding that most infections in serodiscordant couples are due to within-couple transmission. The large contribution of extra-couple transmission at the population level is because most cohabiting couples are concordant negative and, on average, the surveyed individuals had spent most time in a couple since their sexual debut. Thus, the large amount of person-time spent at risk from extra-couple transmission more than compensates for its small transmission coefficients. Results from our analysis, which was only of couples, greatly contrast those of Dunkle and colleagues,19 who concluded that within-couple transmission accounts for most of the HIV incidence in sexually active urban populations (ie, in single individuals and those in couples) in Zambia and Rwanda. This contrast is probably because of the reliance of Dunkle and colleagues on downwards-biased self-reported rates of intercourse with non-cohabiting partners, which could lead to substantial underestimation of the contribution of extra-couple intercourse.29

When available, molecular evidence shows the importance of extra-couple transmission. In several cohort studies of serodiscordant couples,1,2,25—27 13—32% of incident infections were from virus not linked to that isolated from the seroconverter’s partner and were presumably due to extra-couple intercourse. Compared with cohort studies, we attributed a smaller proportion of transmission within serodiscordant couples to extra-couple intercourse, which might be because individuals enrolled in cohort studies differ systematically from the general population, which is more representatively sampled by DHS. Furthermore, seronegative individuals in cohort studies might engage in more extra-couple and less within-couple intercourse upon finding that their partner is seropositive.27 This behavioural effect could explain why our estimated rates of within-couple transmission are generally greater than those from cohort studies (table 2).1, 2, 25

Our finding that, within couples, the directionality of HIV propagation is more from men to women than vice versa is because of the greater average duration of sexual activity in men before couple formation and additionally, for some countries, because of their greater hazard rate for extra-couple infection. Although the average duration of sexual activity before partnership formation is much shorter for women than for men, we noted that, as reported elsewhere,11 this difference is partly compensated by the greater risk of infection per unit time in women before partnership formation.

With use of relationship and serostatus data, country-specific trends for the prevalence of HIV, and estimates of HIV survival times to explicitly estimate the probability that infections were because of pre-couple, within-couple, or extra-couple transmission, our model addresses several limitations of previous studies, and advances estimations of transmission breakdown by behavioural routes from cross-sectional data. However, our model retains certain assumptions. We assumed homogeneous mixing between age groups for sexual partners chosen before couple formation or during extra-couple intercourse. Although this assumption might bias our results, to the extent that patterns of age mixing cause a consistent bias for overestimates or underestimates in the estimated prevalence that individuals are exposed to, this bias will be counteracted by underestimates or overestimates in transmission coefficients, with no effect on estimates of total hazard and per-route contributions to transmission.

We also assumed that the probability of infection via a particular transmission route is dependent on only the duration an individual is at risk by that route, the time-varying HIV prevalence in the population of the opposite sex (or partner seropositivity for within-partner transmission), and a transmission coefficient for each gender-route combination. In reality, the frequency of intercourse and the number and riskiness of partners also affect transmission. Other causes of heterogeneity not considered here include genetic and immunological factors, type of sexual exposure, sexually transmitted infections, viral loads, viral characteristics, tendency to seek care, male circumcision, and protected sex; many of these factors vary both between individuals and through time within individuals.7, 16 Although we assumed that individuals were homogeneous, our results were robust to this assumption. Our sensitivity analysis shows that even with a large individual-level heterogeneity in hazard rates, the association between relationship histories and serostatuses was substantial enough for the model to accurately infer the proportional breakdown of infections by transmission routes.

Hazards can vary over time for reasons other than changing prevalence. Declines in HIV prevalence in several countries have been attributed to behavioural changes in response to interventions or overall HIV awareness.30 Such changes would lead to decreasing transmission coefficients during the epidemic, but how this decrease might be divided among the routes of transmission we considered is unclear; therefore, we were unable to assess this possibility. We did not include effects of ART on HIV survival times or within-couple transmission in our main analysis because DHS surveys do not provide the drug status of individuals, and because we believe that the within-couple effects of therapy were small. On the basis of policies created before WHO’s 2012 TasP recommendations, most treated individuals would have already exposed their partners to infection for a long time before they become ill, get tested, have CD4 counts decrease to less than 200 counts per μL, and start ART. Furthermore, coverage of ART in the countries analysed was negligible for most of the period covered by the couples in our survey.13 This factor explains why our results were robust in sensitivity analyses allowing for ART to affect within-couple transmission or relaxing the assumption that all individuals on ART are non-infectious.

Finally, in view of the range of the DHS and the relatively narrow scope of our study, we necessarily excluded many couples because of missing or inconsistent data. However, these exclusions are unlikely to cause major selection bias and our results are roughly generalisable to the couples in the population as sampled by DHS. In particular, our results are likely to be more representative of the general population than are those from virological linkage cohort studies, which have more specific selection criteria and alter the behaviour of participants.27

We have shown that substantial HIV transmission occurs through all transmission routes: within serodiscordant couples and before couple formation and from extra-couple intercourse. We make no assumptions about the morality31 or potential for mitigation32 of extra-couple sex. Extra-couple sex does not necessarily constitute a choice and could be motivated by basic needs or indicate large social support structures.33 However, policy choices should be made in view of our finding that extra-couple transmission by both sexes has a major role in the HIV epidemic in sub-Saharan Africa.

Offering of TasP to only HIV-positive individuals in stable, serodiscordant couples is tempting because the partner is identifiable, and clearly at risk. However, the aggregate risk to partners not in stable relationships with positive individuals is also high. This finding does not mean that TasP and PrEP programmes have no place in targeted treatment of serodiscordant couples. These programmes have been effective and represent major advances in HIV prevention strategy. PrEP, in particular, could change the gender power dynamics in serodiscordant couples by empowering women to prevent HIV transmission. In view of this fairly small proportion of populations constituted by serodiscordant couples, these approaches could be a good starting point for HIV control efforts, especially in the context of resource limitations. However, our results do imply that behavioural and biomedical interventions focused on serodiscordant couples will not be sufficient to cause major reductions in HIV incidence at the population level. Interventions should address all transmission routes to fight the HIV epidemic. Despite its expense and logistical demands, the universal test-and-treat strategy could reduce all forms of heterosexual transmission.

Source: Lancet

CDC Issues Guidance on Pre-Exposure Prophylaxis for HIV in Heterosexual Adults.

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The CDC has released interim recommendations on providing pre-exposure prophylaxis (PrEP) to prevent HIV in very-high-risk heterosexual adults — for example, those whose partners are infected.

Among the recommendations, published in MMWR:

  • Before prescribing PrEP, clinicians should screen patients for sexually transmitted infections and hepatitis B.
  • Clinicians should explain to women that the effect of the drugs on the developing fetus is not fully known, but no harms have been reported so far. Breast-feeding mothers should not receive PrEP.
  • When pregnant women take PrEP, clinicians can anonymously submit data on the pregnancy to the Antiretroviral Pregnancy Registry.
  • Tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine (FTC) 200 mg (i.e., one Truvada tablet) should be taken daily, and patients should be given no more than a 90-day supply.
  • HIV tests should be administered every 2 to 3 months.
  • Women should take a pregnancy test at each follow-up visit.

Source: MMWR

 

Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals.

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More than 30 years into the global HIV/AIDS epidemic, infection rates remain alarmingly high, with over 2.7 million people becoming infected every year. There is a need for HIV prevention strategies that are more effective. Oral antiretroviral pre-exposure prophylaxis (PrEP) in high-risk individuals may be a reliable tool in preventing the transmission of HIV.

Objectives

To evaluate the effects of oral antiretroviral chemoprophylaxis in preventing HIV infection in HIV-uninfected high-risk individuals.

Search methods

We revised the search strategy from the previous version of the review and conducted an updated search of MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in April 2012. We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing trials.

Selection criteria

Randomised controlled trials that evaluated the effects of any antiretroviral agent or combination of antiretroviral agents in preventing HIV infection in high-risk individuals

Data collection and analysis

Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors using a standardized data extraction form. Relative risk with a 95% confidence interval (CI) was used as the measure of effect.

Main results

We identified 12 randomised controlled trials that meet the criteria for the review. Six were ongoing trials, four had been completed and two had been terminated early. Six studies with a total of 9849 participants provided data for this review. The trials evaluated the following: daily oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms: TDF, TDF-FTC and placebo arm. The studies were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, serodiscordant couples and other high risk men and women.

Overall results from the four trials that compared TDF-FTC versus placebo showed a reduction in the risk of acquiring HIV infection (RR 0.51; 95% CI 0.30 to 0.86; 8918 participants). Similarly, the overall results of the studies that compared TDF only versus placebo showed a significant reduction in the risk of acquiring HIV infection (RR 0.38; 95% CI 0.23 to 0.63, 4027 participants). There were no significant differences in the risk of adverse events across all the studies that reported on adverse events. Also, adherence and sexual behaviours were similar in both the intervention and control groups.

Authors’ conclusions

Finding from this review suggests that pre-exposure prophylaxis with TDF alone or TDF-FTC reduces the risk of acquiring HIV in high-risk individuals including people in serodiscordant relationships, men who have sex with men and other high risk men and women.

 

Plain language summary

Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals

This review evaluated the effects of giving people at high risk for HIV infection drugs to prevent infection (called antiretroviral pre-exposure prophylaxis, or PrEP). We found six randomised controlled trials that assessed the effects of oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo, and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms (TDF, TDF-FTC and placebo arm). The trials were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, people in serodiscordant sexual relationships where one partner is infected and the other is not, and other high risk men and women. The findings suggests that the use of TDF alone or TDF+FTC reduces the risk of becoming infected with HIV. However, further studies are need to evaluate the method of administration (daily versus intermittent dosing), long-term safety and cost effectiveness of PrEP in different risk groups and settings.

Source: Cochrane Library.