HIV This Week

Turning the tide against HIV

Shattock RJ, Warren M, McCormack S, Hankins CA. Science. 2011;333(6038):42-3.

Study of the interactions among, and combinations of, novel HIV biomedical intervention tools represents the next imperative for HIV prevention science—offering hope, at last, for a tangible impact on halting and reversing the HIV pandemic. Shattock and colleagues predict that combining implementation of new biomedical prevention tools to create additive or synergistic effects will stimulate incremental reductions in HIV incidence. This, in turn, will raise the bar of evidence required for evaluation of new approaches, as reduced incidence will necessitate larger, and therefore more costly, trials and place an intrinsic research value on higher-incidence cohorts. For PrEP, this will mean increasing emphasis on surrogate markers of activity, including pharmacokinetics and pharmacodynamics, to demonstrate potential superiority over approaches with proven efficacy in randomized controlled trials. For vaccines, it will require proof of efficacy in non-human primate (NHP) studies, definition of correlates of immune protection, and demonstration of their induction in early phase I/II clinical trials. New biomedical tools with proven effectiveness should be added to individual-level behavioural and population-level structural components, with national policies guided by cost-effectiveness and population impact assessed in randomized controlled trials. Sequential implementation of each new biomedical intervention is an inevitable process for unlicensed products. However, the authors recommend accelerated assessment of potentially beneficial combinations through innovative randomized controlled trials that assess more than one biomedical tool against a common control.

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Editor’s note: This policy forum reviews the positive results of biomedical HIV prevention trials that have been reported since 2005—medical male circumcision in 3 sub-Saharan African countries, RV144 HIV vaccine in Thailand, 1% tenofovir gel in KwaZulu Natal, pre-exposure prophylaxis (PrEP) in men who have sex with men in 6 countries, and early antiretroviral treatment for the HIV-positive partners in serodiscordant couples in 9 countries (see Cohen, this issue). To these, we can add two more trials that reported positive results in July 2011: the Partners PrEP trial among serodiscordant couples in Kenya and Uganda (the negative partner took the PrEP) and the TDF-2 trial among heterosexual men and women in Botswana. With all these exciting results, the standard prevention package used in all arms of a biomedical HIV prevention trial will evolve as new international guidelines for HIV prevention in countries are developed and published. Trial design and conduct will have to evolve too to remain both affordable and ethical. There are exciting possibilities for biological synergies when two partially protective biomedical prevention approaches, such as PrEP and vaccines, are combined. When added to the structural and behavioural components of combination prevention, these new biomedical approaches will help turn the tide.

Combinations of 3-hydroxyphthalic anhydride-modified ovalbumin with antiretroviral drug-based microbicide candidates display synergistic and complementary effects against HIV-1 infection

Li L, Tan S, Lu H, Lu L, Yang J, Jin H, Liu S, Jiang S. J Acquir Immune Defic Syndr. 2011 Jan 13

The development of a safe, effective, and affordable combination microbicide to prevent the sexual transmission of HIV is urgently needed. Li and colleagues’ previous studies demonstrated that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) exhibited potent antiviral activity against a broad spectrum of HIV, simian immunodeficiency virus (SIV), and herpes simplex virus (HSV), making it a promising candidate as a component of a combination microbicide. Here the authors evaluate potential synergistic anti-HIV-1 effect of HP-OVA in combinations with antiretroviral drug-based microbicide candidates. The antiviral activity of HP-OVA and the antiretroviral drugs, including HIV-1 entry inhibitors (T20, C52L, NB64, NBD556, AMD3100 and Maraviroc) and reverse transcriptase inhibitors (Tenofovir, UC781 and TMC120), tested alone or in combination, against HIV-1 X4 and R5 viruses, including some drug-resistant strains, was determined in MT-2 and peripheral blood mononuclear cells using p24 assay. The immune responses induced by HP-OVA applied in the vaginas of rats were detected by ELISA. When each of these antiretroviral-based microbicide candidates was combined with HP-OVA, synergistic activity was observed against infection by both X4 and R5 strains, and the degree of synergy differed in each case. HP-OVA was highly effective against several antiretroviral-resistant HIV-1 strains, suggesting that combining HP-OVA with these antiretroviral-based microbicide candidates might work cooperatively against both drug-sensitive and resistant HIV-1 strains. Human body fluids and human proteins had little or no effects on HP-OVA-mediated inhibitory activity against HIV-1 infection. HP-OVA formulated in the universal gel maintained its antiviral activity for at least one month and only induced weak immune responses after its multiple applications in the vaginas of rats. Synergistic and complementary effects against infection by a broad spectrum of HIV-1 strains were observed by combining HP-OVA with the antiretroviral-based microbicide candidates. These findings provide a sound scientific platform for the development of a safe, effective and affordable combination microbicide to prevent the sexual transmission of HIV and other sexually transmissible viruses.

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Editors’ note: While work proceeds on delivery vehicles for microbicides, such as gels, rings, and films, combination microbicides that have both specific and non-specific components are the next frontier. Surprisingly, chicken ovalbumin, which is widely available and inexpensive, has potent antiviral activity against HIV-1 including against viruses that are resistant to various antiretroviral drugs. This laboratory study found that combining chicken ovalbumin with HIV fusion/entry inhibitors, particularly the CCR5 antagonist Maraviroc, resulted in potent synergistic anti-HIV-1 activity. Synergistic effects were also seen when chicken ovalbumin was combined with reverse transcriptase inhibitors (NRTI and NNRTI) that target the construction of viral DNA from RNA. Studies in rats did not reveal harmful immune responses with multiple vaginal applications of this chicken foreign protein, the product was stable at room temperature for 1 week, and the presence of human proteins or body fluids did not reduce antiviral activity. An important advantage of this combination chicken ovalbumin/antiretroviral drug microbicide is its effectiveness against antiretroviral resistant HIV. These combination microbicide candidates constitute a very promising concept for the microbicide pipeline.

Exploring the condom gap: is supply or demand the limiting factor? – Condom access and use in an urban and a rural setting in Kilifi district, Kenya

Papo JK, Bauni EK, Sanders EJ, Brocklehurst P, Jaffe HW. AIDS. 2011 Jan 14;25(2):247-55

The objective of this study was to explore the extent of the condom gap, investigating the relative roles of supply-side and demand-side factors in determining condom use through GPS mapping of condom outlets, and a population-based survey. An urban and a rural site were selected within the Epidemiological and Demographic Surveillance Site in Kilifi district, Kenya. Potential condom outlets (n = 281) were mapped and surveyed, and questionnaires on condom access and use (n = 630) were administered to a random sample of men and women aged 15-49. Multivariate logistic regression was performed to assess the relative roles of supply-side and demand-side barriers on condom use. The median straight-line distance to free condoms was 18-fold higher in the rural versus the urban site. Among sexually active respondents, 42% had ever used a condom, and 23% had used a condom over the past 12 months, with lower levels among rural versus urban respondents (P < 0.05). The mean number of condoms used was 2.2/person per year among all sexually active individuals (condom users and nonusers), amounting to 8.2% protected sex acts/person per year. The adjusted odds of condom use (past 12 months) were 8.1 times greater among individuals experiencing no supply-side or demand-side barriers, compared with individuals experiencing both types of barriers. Despite low levels of usage and the presence of supply-side and demand-side barriers, reported unmet need for condoms was low. There is an urgent need for renewed condom promotion efforts aimed at building demand, in addition to improving physical access, in resource-limited settings with generalized HIV epidemics in sub-Saharan Africa.

Abstract

Editors’ note: If HIV prevalence where you lived was 5%, how far would you walk to buy a condom (0.15 USD for a 3-pack)? How far would you walk for a free condom? Two-thirds of the people in this study were living on less than a dollar a day so you might think cost would be the major deterrent to accessing and using condoms. The picture is more complex. There were gaps in the physical availability of condoms – the shortest route to the nearest free condom outlet for rural respondents was almost 5 kilometres and less than 1 % of all condom outlets (none rural) had female condoms. But the biggest barriers to condom use were on the demand side: 81% of people had one or more demand side barriers whereas 30% had supply side barriers. People with neither were 8 times more likely to have used condoms in the previous 12 months. The most striking finding of this study regards unmet need: only 7% of people reported having ever wanted to access or use a condom and been unable to do so. There is an imperative here, as in many parts for the world, to increase demand and perceived need for condoms. After all, condoms remain the single, most efficient available technology to reduce sexual transmission of HIV—6000 adults become infected daily, the majority through unprotected sex.

The challenge of defining standards of prevention in HIV prevention trials

Philpott S, Heise L, McGrory E, Paxton L, Hankins C; the participants in the 2009 GCM/CDC/UNAIDS Consultation on Standards of Prevention in HIV Prevention Trials. J Med Ethics. 2010 Dec 24

As new HIV prevention tools are developed, researchers face a number of ethical and logistic questions about how and when to include novel HIV prevention strategies and tools in the standard prevention package of ongoing and future HIV prevention trials. Current Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO) guidance recommends that participants in prevention trials receive 'access to all state of the art HIV risk reduction methods', and that decisions about adding new tools to the prevention package be made in consultation with 'all relevant stakeholders'. The guidance, however, leaves open questions of both process and implementation. In March 2009, the Global Campaign for Microbicides, UNAIDS, and the Centers for Disease Control and Prevention convened a consultation to develop practical answers to these questions. Fifty-nine diverse participants, including researchers, ethicists, advocates, and policymakers, worked to develop consensus criteria on when to include new HIV prevention tools in future trials. Participants developed a set of questions to guide decision-making, including: whether the method has been recommended by international bodies or adopted at a national level; the size of the effect and weight of the evidence; relevance to the trial population; whether the tool has been approved or introduced in the trial country; whether adding the tool might lead to trial futility; outstanding safety issues and status of the trial. Further work is needed to develop, implement and evaluate approaches to facilitate meaningful stakeholder participation in this deliberative process.

Abstract

Editors’ note: Biomedical HIV prevention is an evolving field with 3 African trials of male circumcision, the Thai RV144 vaccine trial, the CAPRISA 004 tenofovir gel trial, and the iPrEx trial of pre-exposure prophylaxis among men who have sex with men—all having reported encouraging results. Offering male circumcision to heterosexual men participating in HIV prevention trials in high HIV prevalence settings is now considered standard of prevention. What of the other trials that provided proof-of-concept that a vaccine could work, that gel use could protect, and that antiretroviral pill-taking prevents HIV acquisition? This article highlights the thorny issues that researchers, sponsors, funders, communities, ethicists, advocates, and government decision makers must face in deciding together what prevention services should be offered to all trial participants. We can expect an even more complicated situation over the coming 3 years as more trials of topical and oral pre-exposure prophylaxis report findings in diverse populations.