Six Months In…. Highlights from the dynamic world of HIV-prevention and the Mapping Pathways project

Original content from the Mapping Pathways blog team

As the year 2012 passes its halfway mark, it is time to take stock of some of the key events this year in the field of HIV treatment and prevention as well as some of the highlights of the Mapping Pathways project.

The year opened on a slippery note with the January 2012 issue of Sexually Transmitted Diseases – Journal of the American Transmitted Diseases Association publishing data from a rectal health and behavior study whose findings “suggest some lubricant products may increase vulnerability to STIs.”

The paper fueled a tremendous amount of discussion in HIV treatment and prevention communities around the world, including the membership listserv run by IRMA (International Rectal Microbicide Advocates).

“We need to be clear – there are only associations between lube use for anal intercourse and STDs. There is no proof that lube use causes increased risk. We simply don’t know that. Because we don't know, IRMA has long been advocating for a lube safety research agenda to fill in our gaps in the science and the evidence base,” says Jim Pickett, Director of Prevention Advocacy and Gay Men’s Health at the AIDS Foundation of Chicago, chair of IRMA, and a member of the Mapping Pathways team. Click here for more info on lube safety.

In March, important new data, specifically from the FEM-PrEP, iPrEX and 

Partners PrEP trials, was revealed at the 19^th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington. All the webcasts and sessions from the conference can be viewed online here.

The FEM-PrEP trial’s independent data and safety monitoring board (DSMB) recommended that the trial be halted due to “futility” in April 2011 as the study could not answer the question of whether daily Truvada worked, or not, in terms of preventing HIV among the trial population. New information presented by investigators at CROI suggested that the lack of efficacy was related to low levels of adherence to medication.

While participants in the study stated that they took their pills 95% of the time, drug levels found in the blood of women assigned to the Truvada study wing indicated that less than 50% of the women had actually taken the drug in the last 12 days.

In contrast, the Partners PrEP study indicated adherence to medication at almost 97%. Early results reported in Rome last July showed high levels of effectiveness in both men and women. These findings were reviewed at CROI, with no major changes to the estimated effectiveness of the drug.

At CROI, the Partners PrEP team presented analyses of plasma tenofovir levels in trial participants who became HIV-positive and a group of 1,000 participants who did not.

Two key findings were that individuals who remained HIV-negative had detectable blood levels of tenofovir at 82% of their study visits and that having detectable tenofovir in your blood at any given study visit was highly predictive of being HIV-negative at that visit.

The trial had a tenofovir arm, a Truvada arm and a placebo arm. According to the Partners PrEP team, “TDF (tenofovir) and FTC/TDF (Truvada) PrEP definitely provided 67% and 75% protection, respectively, against HIV-1 acquisition in African men and women at risk for HIV-1 infection, when provided in the context of other HIV-1 prevention services.” In short, women and men who took daily tenofovir-based PrEP had a significant reduction in HIV risk.

The results of the iPrEX trial indicated that gay/MSM participants who took Truvada daily had a 44% reduction in HIV incidence over the course of 1.2 years of follow-up compared with placebo. For individuals who did take the drug, and had detectable levels of drug in their bodies, the efficacy of Truvada as PrEP was approximately 90%.

At CROI, researchers presented new results of a case-control analysis on drug levels of the iPrEx trial participants that indicated that the blood-drug level observed with a dosing frequency of four doses per week was associated with a 95% reduction in HIV risk.

Mapping Pathways presented an oral abstract at the Microbicides 2012 (M2012) conference in Sydney in April. Pickett says the abstract and presentation were well received and generated a lot of interest in work Mapping Pathways has been doing and is planning to do in the coming year.

The importance of adherence was further highlighted at M2012. Says Jim “Adherence, the A-word, was a very big topic throughout the entire conference. We realized that we have to make HIV-prevention or treatment products people like and will want to adhere to. We have to figure out how tools like PrEP and microbicides fit in people’s lives, and funding should be put in place to better understand what people want, how they have sex, and the role of pleasure, love and intimacy, among many other ‘real world’ realities.” (Read our entire interview with Jim here.)

In May, an important landmark was achieved when a panel of experts at the U.S. Food and Development Administration (FDA) recommended approval of Truvada for use in PrEP in HIV-uninfected gay men and MSM, HIV-uninfected partners in serodiscordant relationships and other individuals “at risk” of acquiring HIV through sexual activity.

The webcast can be seen here and copies of all the slide presentations are here. The final FDA decision is expected by mid September.

June saw Mapping Pathways team members disseminating findings at the International Association of Physicians in AIDS care (IAPAC) evidence summit on TasP and PrEP in London. Click here to see Jim’s slides and here to read more analyses of the meeting via aidsmap. .

In light of the FDA panel’s approval of Truvada for PrEP in May, Mapping Pathways U.S. partners, AIDS United and AIDS Foundation of Chicago, presented a webinar June 19 focusing on PrEP. Key U.S.-focused findings of the Mapping Pathways online survey and stakeholder interviews were presented at the webinar helping illuminate diverse perspectives of advocates, clinicians, policy makers and people living with HIV.

In a few weeks, Mapping Pathways team members will be presenting data collected in 2011 from India, South Africa and the U.S. at the International AIDS Conference (AIDS 2012) in Washington D.C. The data presented will include findings related to community stakeholder perspective on ARV-based prevention – “grassroots” and “grasstops” – as well as an extensive literature review conducted by RAND, a Mapping Pathways partner.

Please click here to see the complete list of Mapping Pathways activities at AIDS 2012. And join us! All posters and presentations from AIDS 2012 will be made available on the blog, and archived here.

[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position. Please look for us on Facebook here www.facebook.com/MappingPathways and you can follow us on Twitter @mappingpathways as well.]

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.]

Epidemiological impact of tenofovir gel on the HIV epidemic in South Africa

via pubmed.gov, by Williams BG, Abdool Karim SS, Karim QA, Gouws E.

Background

Tenofovir gel, an antiretroviral-based vaginal microbicide, reduced HIV acquisition by 39% in women in a recent randomized controlled clinical trial in South Africa.

Methods

To inform policy, we used a dynamical model of HIV transmission, calibrated to the epidemic in South Africa, to determine the population-level impact of this microbicide on HIV incidence, prevalence, and deaths and to evaluate its cost-effectiveness.

Results

If women use tenofovir gel in 80% or more of sexual encounters (high coverage), it could avert 2.33 (0.12 to 4.63) million new infections and save 1.30 (0.07 to 2.42) million lives and if used in 25% of sexual encounters (low coverage), it could avert 0.50 (0.04 to 0.77) million new infections and save 0.29 (0.02 to 0.44) million deaths, over the next 20 years. At US $0.50 per application, the cost per infection averted at low coverage is US $2392 (US $562 to US $4222) and the cost per disability-adjusted life year saved is US $104 (US $27 to US $181); at high coverage the costs are about 30% less.

Conclusions

Over 20 years, the use of tenofovir gel in South Africa could avert up to 2 million new infections and 1 million AIDS deaths. Even with low rates of gel use, it is highly cost-effective and compares favorably with other control methods. This female-controlled prevention method could have a significant impact on the epidemic of HIV in South Africa. Programs should aim to achieve gel use in more than 25% of sexual encounters to significantly alter the course of the epidemic.

Read the rest.


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

MTN Statement on Decision to Discontinue Use of Oral Tenofovir Tablets in VOICE, a Major HIV Prevention Study in Women

via Microbicide Trials Network

VOICE, an HIV prevention trial evaluating two antiretroviral (ARV)-based approaches for preventing the sexual transmission of HIV in women – daily use of one of two different ARV tablets or of a vaginal gel – will be dropping one of the oral tablets from the study. The decision to discontinue use of tenofovir tablets in VOICE comes after a routine review of study data concluded that the trial will not be able to demonstrate that tenofovir tablets are effective in preventing HIV in the women enrolled in the trial. VOICE will continue to test the safety and effectiveness of the other oral tablet, Truvada®, a combination of tenofovir and emtricitabine, and of the vaginal gel formulation of tenofovir.

Importantly, the review, which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID)’s independent Prevention Trials Data and Safety Monitoring Board (DSMB), identified no safety concerns with any of the products being studied in VOICE.

VOICE – Vaginal and Oral Interventions to Control the Epidemic – involves 5,029 women at 15 trial sites in Uganda, South Africa and Zimbabwe. The trial is being conducted by the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network funded by the National Institute for Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver Institute for Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health.

The study was designed with five study groups: tenofovir gel, an inactive placebo gel, oral tenofovir, oral Truvada and an inactive placebo tablet. The women in each group (about 1,000) are asked to take their assigned study product daily. VOICE is the only trial evaluating the daily use of an ARV tablet – an approach called oral pre-exposure prophylaxis, or PrEP – and a vaginal gel in the same study. This design is important for determining how each product works compared to its control (placebo gel or placebo tablet) and which approach women prefer.

On September 16, 2011, the NIAID Prevention Trials DSMB reviewed VOICE study data for the period between Sept. 9, 2009, when the study began, and July 1, 2011. Based on this interim review, the DSMB determined that it was not possible to show whether oral tenofovir tablets were any better than a placebo for preventing HIV in the women assigned to that study group. The DSMB therefore recommended that the women randomized to the oral tenofovir tablet group discontinue their use of the study product. This recommendation does not apply to the women in the groups using either the tenofovir gel or oral Truvada tablets, or the corresponding placebos; the DSMB recommended that these four study groups continue in VOICE.

Read the rest.


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

Tricky Terminology in HIV Prevention – Part 2: “Microbicides” and “Oral PrEP”

“I think elegance must take second seat to being clear and helping people absorb vast amounts of new information.”

We recently blogged about the terms “abstinence” and “being faithful” – words that have caused a great deal of controversy in the HIV prevention arena. In this post, we discuss another instance of tricky terminology – the need to maintain the distinction between “oral PrEP” and “microbicides,” a difference that is extremely important in the context of the rapidly changing face of HIV prevention.

Lori Heise of the London School of Hygiene and Tropical Medicine has some thoughts on this matter. “In the next few years, as policymakers, providers, and potential users are trying to get their minds around all this new research and the expanding array of prevention options” she says, “it is absolutely essential that we stick to the language of ‘oral PrEP’ and ‘microbicides’ (for instance: ‘oral tenofovir’ or ‘tenofovir gel’).”

There has been a move within scientific circles to shift the language toward PrEP and ARVs, just making distinctions between mode of delivery (topical, oral, systemic), and there are supporters of this formulation. “However, as we shift from clinical trials into introduction and use,” she says, “we need every means at our disposal to help people make appropriate distinctions among methods.”(See this Mapping Pathways blog post for a snapshot of the various ways in which antiretrovirals can be used to prevent new HIV infections.)

Clear and accurate terminology help policymakers, advocates, and other stakeholders engage in rational discussions about which methods might best suit the needs of different individuals at different moments in time and with which types of partners or sexual settings. Substituting words or using umbrella terms tends to cloud clarity and cause confusion. “Over the last several months, I have sat through a number of presentations that combine information about oral PrEP and microbicides, but use the language of PrEP to describe both.” Lori recounts. “Even among groups of experts, I have noticed people getting confused – misapplying data, conclusions, or assumptions that mostly apply to microbicides or to oral PrEP, to both.There is a tendency to talk about PrEP and topical PrEP – but people don't register the ‘topical’ and so important nuances are lost.”

Indeed, these different products have critical distinctions to keep in mind. For instance, oral PrEP may potentially protect a wider range of users than microbicides, such as in the case of injection drug users (IDUs) whose primary risk of HIV infection is from tainted syringes, not unprotected sexual intercourse (though we are still waiting on data on the efficacy of PrEP among IDUs. Then, the license to develop tenofovir gel as a microbicide is held by the public sector, while the licenses for oral tenofovir and Truvada – both of which are already available for treatment – are controlled by Gilead. This dual-use issue where ARVs taken orally can be used for either treatment or prevention doesn't exist for any microbicide.

“These distinctions are important, and I think we need to use terminology that helps people keep them in the forefront of their minds – at least for the next few years, as we broaden the circle of discussion to add groups that as yet know very little about PrEP or microbicides....In this case,” says Lori, “I think elegance must take second seat to being clear and helping people absorb vast amounts of new information.”


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