Keep up the fight for microbicides

via AllAfrica.com, by Julie Frederikse

Africans tracking the worldwide HIV epidemic have not found much to celebrate since Aids began ravaging the continent 30 years ago, but researchers are optimistic that they are learning as much from their failures as their successes.

Sub-Saharan Africa still carries the biggest burden of HIV worldwide, and while there has been a significant improvement in access to antiretroviral treatment in recent years, scientists searching for a gel or vaccine that can prevent HIV infection ride a rollercoaster of hope and disappointment.

Take the case of a husband and wife team from the University of KwaZulu-Natal in South Africa. Professors Salim Karim and Quarraisha Abdool Karim head up a research unit that has been at the forefront of clinical trials to find a safe and effective microbicide to protect women from HIV.

In July 2010, delegates at the last World Aids conference gave the couple a standing ovation when they announced the results of one of the most promising studies on HIV prevention to date. Their team at the Centre for the Aids Program of Research in South Africa (Caprisa), showed that a vaginal gel called tenofovir was able to reduce sexual transmission of the virus by 39 percent overall and 54 percent in women who used it consistently.

But the euphoria over this breakthrough has dissolved into disappointment, with the unexpected finding of a wider sub-Saharan African study that the microbicidal gel, when prescribed daily, does not prevent HIV infections. This has led to the suspension of tenofovir in the Vaginal and Oral Interventions to Control the Epidemic (Voice) trial.

Tenofovir is an antiretroviral drug that is taken successfully by many people living with Aids to suppress the virus. The hope had been that tenofovir could also be used to prevent HIV infection. Women are twice as likely as their male partners to acquire HIV during sex and account for 60 percent of adult HIV infections in sub-Saharan Africa. An effective microbicide would give women the option of applying the vaginal gel themselves before sex, without necessarily informing their partners.

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[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

Current State of Microbicide Research

via Cold Spring Harbor Perspectives in Medicine, by Robin J. Shattock and Zeda Rosenberg

Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral (ARV) products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. We discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape.

An effective microbicide may be one of the best ways to address a central gap in current HIV prevention strategies: lack of a discreet method that women can use to protect themselves from infection. Recently, the World Health Organization reported that AIDS is the leading cause of death among women of reproductive age globally, and particularly in sub-Saharan Africa (World Health Organization 2009). Methods available to prevent HIV include condoms, male circumcision, and behavioral interventions, but data indicate that they are insufficient to protect women. Among women in sub-Saharan Africa, one of the highest-risk factors for acquiring HIV is being in a stable long-term relationship where condom use is low (Shattock and Solomon 2004).

Condoms are impractical for women who want to conceive children or who cannot persuade their partners to use them. Next to an effective vaccine, microbicides (topical preexposure prophylaxis [PrEP]) and oral PrEP have the greatest potential to provide women with protection they can control. Both could be configured to protect men and women from transmission of HIV during unprotected anal intercourse.
Microbicides are topical PrEP products, such as gels, capsules, tablets, films, and intravaginal rings (IVR). They are designed to be applied either around the time of coitus, used on a daily basis (gels and films), or to deliver product over a prolonged period

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[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

Apparent declining efficacy in randomized trials: examples of the Thai RV144 HIV vaccine and South African CAPRISA 004 microbicide trials

via AIDS, by O’Hagan, Justin J.; Hernán, Miguel A.; Walensky, Rochelle P.; Lipsitch, Marca

Recent HIV prevention trials have given hope that a suite of interventions that effectively reduce individuals’ risk of HIV infection will soon be widely available. In two studies, the RV144 and CAPRISA 004 trials, the relative risk of infection increased toward the null value of one over time. The RV144 and CAPRISA investigators interpreted these trends as evidence that the interventions’ effects declined over the study period and suggested that their respective findings may be explained by waning vaccine efficacy and decreasing adherence. Here, we discuss these trends in the trials’ results and note that, in addition to the possible mechanisms cited by the investigators, their apparent waning efficacy may be explained in part by selection bias due to heterogeneity in infection risk, an explanation that has not been considered previously. This bias arises when study participants vary in their susceptibility to infection, for example, because of differences in immune systems or exposure to infection. This can lead to increasing differences in the composition of the study population in each trial arm over time as those at highest risk become infected, and can occur despite comparability between arms at baseline. This issue is termed ‘frailty’ in statistics and demography, in which a large body of literature addresses the matter. We also discuss several methods that can improve understanding of the effects of infectious disease interventions and risk factors by assessing the impact of frailty on results.

Variation in frailty among study participants likely creates trends in the incidence of infection over the course of a study. To understand this phenomenon, consider a theoretical placebo-controlled randomized trial, in which the risk of infection varies among participants. The highest risk individuals in such a trial are expected to become infected earlier, leaving a pool of lower risk individuals at later time points. If the intervention being tested is effective, the decline in the incidence of infection over time will be larger in the placebo arm because these individuals experience no direct protection from the intervention, and so those at high-risk will be quickly depleted, thereby lowering the infection rate over follow-up. However, high-risk individuals in the active arm may remain uninfected due to the protection conferred by the intervention, so the active arm's infection rate will be less affected. Consequently, the time-specific rate ratio for treatment vs. placebo will increase over time from a value of less than one initially to a value that may exceed one later. This phenomenon has also been termed ‘survivor bias’, ‘survivor cohort effect’, ‘crossing of hazards’ and ‘depletion of susceptibles’, and is observed in both chronic and infectious disease research.

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[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

A Defining Moment in HIV Control

via The Lancet, by Salim S Abdool Karim, Quarraisha Abdool Karim

A defining moment in the global AIDS response has been reached. The discourse is no longer about HIV prevention or HIV treatment; it is now about HIV control through the implementation of antiretrovirals as key components of combination interventions. Barely a year ago, visions of HIV control would have been considered far-fetched. The impetus for this change in mindset, which has been building since the XVIII International AIDS Conference in Vienna last year, emanates from the compelling evidence that antiretroviral drugs prevent HIV infection in the general heterosexual population, which is released this week and presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome by the Partners PrEP1 and Botswana TDF22 trials.

The Partners PrEP trial,1 involving 4758 HIV discordant couples from Kenya and Uganda, found that daily oral tenofovir disoproxil fumarate (TDF) and TDF-emtricitabine reduced HIV transmission by 62% and 73%, respectively. The Bostwana TDF2 trial,2 in 1200 heterosexual men and women from the general population, found that daily oral TDF-emtricitabine reduced HIV transmission by 63%. These findings follow close on the heels of the CAPRISA 004 trial3 of tenofovir gel, the iPrEX trial4 of oral TDF-emtricitabine in men who have sex with men, and the HPTN 052 trial5 of early antiretroviral treatment as HIV prevention. Importantly, these new findings fill a critical gap in HIV prevention with a readily available antiretroviral approach to prevent heterosexual transmission in both men and women (figure). Women benefit from a new prevention option under their control, which is particularly important for those not assured of their partner's fidelity or willingness to use a condom. The hope these studies add to HIV prevention is further bolstered by the recent step taken by the pharmaceutical company Gilead Sciences Inc to lodge TDF and emtricitabine with the UNITAID patent pool,12 thus enabling lower cost versions of the drugs to be manufactured and thereby facilitating wider access in poor countries.

 There is now no doubt that antiretroviral drugs prevent HIV infection. However, important scientific questions remain. Does the inclusion of emtricitabine in pre-exposure prophylaxis (PrEP) formulations provide sufficient additional benefit to warrant the additional costs and side-effects? Are levels of effectiveness and safety similar for daily use and use-with-sex of PrEP? Do the safety, effectiveness, cost, and acceptability profiles of oral and topical PrEP merit implementation of both formulations? Does PrEP lead to masking of HIV acquisition that is then revealed once PrEP is withdrawn? Can the new results be generalised to the type of hyper-endemic settings (HIV incidence more than 5% per annum) where the FEMPrEP trial13 was done? Since inadequate drug levels may not have been responsible for the lack of effectiveness observed in the FEMPrEP study,14 the search for an explanation for this intriguing and contrary result needs to be pursued with vigour.

There are also many practical questions about implementation: how to increase uptake of HIV testing;15 how often to monitor HIV status in people on PrEP; how to achieve high coverage in those at highest risk; how to maintain high levels of adherence; how to reduce the risk of migration away from condoms (behavioural disinhibition); and how to monitor the risk of drug resistance. While attempts are being made to obtain data to address these questions and to generate data to guide effective implementation, the development of normative guidance by WHO/UNAIDS and submissions for regulatory approvals of TDF and TDF-emtricitabine as PrEP for HIV infection are key next steps.

As antiretroviral drugs take a key role in the global effort to control the HIV epidemic, there is much to be learned from the contraceptive field where multiple technologies, approaches, formulations, and dosing options were developed to enable and maximise user choice and increase levels of uptake, coverage, and adherence and thereby improve the public health impact.

Beyond the questions of implementation, the future scientific challenge looming large for PrEP is finding a drug or class of drugs with a resistance profile that does not interfere with existing first-line and second-line AIDS treatment. Treatment of HIV-positive people for HIV prevention and PrEP and microbicides for HIV-negative people are two sides of the same coin, and cannot be viewed in isolation from each other. Although research on treatment for prevention, PrEP, and microbicides has mostly occurred in separate silos, their findings converge into a single focus in HIV prevention and necessitate guidance on how to use all three strategies synergistically for maximum benefit depending on the nature of the HIV epidemic. There is no magic bullet for the HIV epidemic. Treatment for prevention will be dependent on the extent to which couples establish their HIV status, whether the HIV-positive partner in a discordant couple adheres to therapy, and whether the HIV-negative partner maintains fidelity within the partnership. PrEP will be dependent on the extent to which people seek to establish and regularly monitor their HIV status and those on PrEP adhere to their regimen and clinical monitoring. Hyper-endemic communities, such as those in South Africa where HIV prevalence in the community is high, may require both interventions jointly and synergistically: treatment of people infected with HIV to reduce risk of transmission within the discordant couple, and PrEP to reduce the HIV-negative partner's risk of HIV acquisition from outside partners.

Therein lie the three most complex policy, implementation, fiscal, and ethical challenges generated by these new findings. First, how to scale up HIV testing, a key prerequisite in settings with stigma and discrimination. Second, how to extend antiretrovirals for both treatment and prevention when many of Africa's health systems are already struggling to cope with patients with AIDS and are not able to initiate antiretroviral therapy in everyone who currently needs it for their survival. Third, in the context of limited resources how best to ration and prioritise the limited available implementation capacity.

In this defining moment in the response to HIV, a global commitment to increased financial resources for implementation, health systems strengthening, and greater implementation efficiency is imperative. Anything less will crush the hope and promise that antiretroviral drugs can change the course of the HIV epidemic.
We were the co-Principal Investigators of the CAPRISA 004 trial of tenofovir gel. QAK is co-Principal Investigator of the HIV Prevention Trials Network, which is undertaking HPTN 052 trial of treatment for prevention. SSAK is an executive committee member of the Microbicide Trials Network, which is undertaking VOICE trial of oral and topical PrEP.


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

FACTS 001: A Quick Update

 * Original content from our Mapping Pathways blog team

Remember the FACTS 001 trial that was announced in South Africa in June 2011? (Read our blog post on it if you don’t.) We are very happy to share an exciting update about it!

On October 21, 2011, the first study participant was enrolled in this Phase III clinical trial of vaginal tenofovir gel (a microbicide, meant to protect women against HIV infection). The Desmond Tutu HIV Foundation brought the first participant on board. Five sites have begun screening women, in Cape Town, Johannesburg, Soweto, Rustenburg, and Pretoria.

To give you a quick recap, this landmark trial is a large-scale, randomized, placebo-controlled clinical study that is meant to test the safety and confirm the effectiveness of tenofovir gel used before and after sex to protect women against HIV infection, as well as HSV-2 (a virus that causes genital herpes). A total of 2,200 HIV-negative women between 18-30 years of age are going to be enrolled across nine sites in South Africa.

Essentially, the aim is to verify the CAPRISA 004 results in "larger, more diverse populations". The trial is being conducted by FACTS (Follow-on African Consortium for Tenofovir Studies) and led by Professor Helen Rees, the Executive Director of WHRI (Wits Reproductive Health and HIV Institute). FACTS 001 is sponsored by CONRAD and funded by the South African Department of Science and Technology, the U.S. Agency for International Development (USAID) and the South African Department of Health. CONRAD and Gilead Sciences, Inc. are providing the study products.

So, why is this trial such a milestone in the world of HIV prevention? If this study, along with VOICE which is testing the use of tenofovir gel and oral Truvada tablets, confirms that tenofovir gel is safe and effective, it could lead to the first licensed vaginal microbicide product. Women would then have access to and be able to control this brand-new HIV prevention method. Truly revolutionary developments!

[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]