October-December 2011, Volume 4, Number 4

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Contents:

AVAC's Take
At a Glance

PrEP: New directions amidst mixed data
Next steps for PrEP demonstration projects

Data Dispatch

AIDS Vaccine 2011: New Signals
What's next for the Thai prime-boost regimen?

Recently Released
Not to be Missed

AVAC's Take

Over the past 18 months, advocates and activists working in the biomedical prevention research field have plunged into the arena of implementation and post-trial access. What happens after a trial has an initial positive finding? How does the field expand on and confirm positive results, while acknowledging that trials can—and do—yield mixed data as recently seen in Partners PrEP and VOICE studies? (For details, see our write-up of VOICE updates in At a Glance.) How do stakeholders keep a broad pipeline of next-generation products moving through development while also advocating for prevention and treatment delivery—especially in the context of constrained resources for the global AIDS response?

Px Wire can’t answer all these questions, but in our centerfold timeline and trials table, we’ve added new categories and types of trials with the goal of helping us all keep track of the constantly evolving landscape.

At a Glance

PrEP: New directions amidst mixed data

In September, as Px Wire went to press, the Microbicide Trials Network announced that VOICE, its five-arm HIV prevention trial in women, would be modified: The arm of the trial in which women were taking oral tenofovir (TDF) would be stopped and the women would exit the trial. The announcement came after an interim independent data review showed that there was no possibility that daily oral TDF would reduce risk of HIV in the context of the VOICE trial. There were no safety concerns in the trial, and the daily oral TDF/FTC and daily 1% tenofovir gel arms of the trial, along with two placebo arms, will continue. The trial is scheduled to conclude in 2012 with data available early in 2013.

Thus far, the data related to oral PrEP in women are mixed. The Partners PrEP trial found that both oral TDF and oral TDF/FTC reduced risk of HIV infection among HIV-negative men and women in heterosexual HIV-serodiscordant couples. The TDF2 trial, an expanded safety trial, also found evidence of efficacy for daily oral TDF/FTC in both men and women, though the numbers were too small to draw definitive conclusions by gender. In contrast, there was no evidence of benefit from daily oral TDF/FTC in the FEM-PrEP trial—and, as noted above, the oral TDF arm is stopping in VOICE. The 1% tenofovir gel was found effective in the CAPRISA 004 study. Data analysis is ongoing and will hopefully shed light on why PrEP worked for women in some contexts and not others.

Previously, the iPrEx trial studied daily TDF/FTC as PrEP in gay men, men who have sex with men (MSM) and transgender women. It found that TDF/FTC reduced HIV risk by 42 percent, and additional data will come from a follow-on open-label trial. In January 2011, two months after the iPrEx result, the US CDC released interim guidance for TDF/FTC as PrEP for gay men and transgender women. It is now developing US Public Health Service guidelines scheduled to be ready for public comment early in 2012. These guidelines may only address TDF/FTC as PrEP for MSM. When trial results for heterosexual women and men and IDUs are published and full review of the data is possible, CDC will consider including these populations in the guidelines.

At the same time, Gilead Sciences Inc., the manufacturer of oral TDF and TDF/FTC, plans to submit an application to the US FDA for approval of TDF/FTC for HIV prevention. Currently, TDF/FTC is only approved for HIV/AIDS treatment. Gilead plans to submit all available data from PrEP studies in early 2012. Once the application is submitted, the FDA review process, including a public hearing, will take approximately six to ten months.

If the FDA determines that a prevention indication is warranted, this could increase the likelihood of financing the costs of PrEP. Right now, clinicians who want to prescribe TDF/FTC for patients have to do so as “off-label” use. A prevention label might also give providers more confidence in discussing PrEP with potential users. Internationally, a prevention indication might facilitate public financing for TDF/FTC for PrEP demonstration projects.

Next steps for PrEP demonstration projects

The University of California, San Francisco, in conjunction with the San Francisco Department of Public Health, was awarded an NIH grant to implement pilot PrEP studies using daily TDF/FTC in gay men and other MSM in San Francisco, set to launch early next year. The two-site demonstration project is a pilot study that would enroll a total of 300 HIV-negative MSM, initiated to help determine optimal programming and monitoring for PrEP in the “real world”. San Francisco is expected to partner with counterparts in Miami, enrolling an additional 200 men. The project plans to look at community demand, social equity to ensure low-income and men of color have access, behavior (adherence and risk compensation) and additional effectiveness data. In addition, the CDC is discussing the evaluation of program cost and financing with select Medicaid programs and private insurers.

PrEP: Roadmap to the Real World, a document issued by a coalition of advocates, including AVAC and Project Inform, urges the US Department of HHS to develop a plan addressing the number and geographic location of PrEP pilot projects that will be needed to assess the relevance, feasibility and potential efficacy of PrEP for different communities of MSM and transgender women; the questions to be addressed through these projects; and the human and financial resources necessary to implement the projects.

Data Dispatch

AIDS Vaccine 2011: New signals

In September, for a few nights in Bangkok, the AIDS vaccine field enjoyed the fruits of hard work and exhaustive research.

First and foremost was the announcement that the search for immune correlates from the Thai prime-boost vaccine trial known as RV144 had yielded unexpected success. Analysis of blood samples from volunteers generated two hypotheses about immune responses and their role in vaccine-induced protection. This research was an unprecedented international collaboration led by Barton Haynes of Duke University. With this big news, the field has its first clues about specific immune responses in people who received a moderately effective vaccine.

What’s next for the Thai prime-boost regimen?

The short answer is that scientists take these findings and use them in a process that will take several years, the end result of which aims to develop what is hoped to be a more effective vaccine.

“When you come to a crossroads, take it,” said US NIH Division of AIDS Director Carl Dieffenbach at the Bangkok meeting. For RV144, there are actually three paths to be pursued simultaneously as next steps. First, the correlates analysis work will continue. Additional secondary analyses include studies of the types of viruses that infected vaccine recipients to see whether there was a “sieve effect”. This occurs when vaccine-induced immune responses block some of the HIV strains, but not all.

Looking at the blood samples from trial participants who received the vaccine strategy, the RV144 correlates analysis found one immune response that was linked to lower risk of HIV infection and one immune response that seemed to interfere with vaccine-induced protection.

The second step is to understand why binding antibodies were linked to protection, as it is a surprise. The apparently protective response was antibodies against epitopes (protein fragments) found in the V1/V2 region of the HIV envelope protein (the outer coat of HIV). The antibodies induced by the RV144 regimen are binding antibodies, not neutralizing antibodies. Neutralizing antibodies are thought to be an essential immune response for highly effective vaccines. They bind to foreign invaders and directly block their activity in the body. Binding antibodies also bind to antigens, but they don’t neutralize, or stop their activity. Instead they may tag the antigen, sending up a red flag to other arms of the immune system, or have other effects on the course of infection.

Researchers have already developed monoclonal antibodies like the ones seen in Thai volunteers, and they will use them in laboratory and animal experiments to learn about how they interact with HIV.

Finally, work is ongoing to try to improve upon and establish the generalizabilty of the immune protection seen in the vaccine trial. In RV144 the regimen appeared to reduce HIV risk by about 60 percent at 12 months (after the immunization series was complete), and then wane over time.

Other key questions center on whether a similar vaccine would work in other parts of the world or in populations with other risk profiles. Answers to these questions could come from planned follow-on research with an RV144-like regimen in South Africa and in Thailand, among higher-risk volunteers.

Recently Released

An Exploratory Analysis of HIV Treatment Research and Development Investments in 2009. This report issued by TAG and AVAC tracks global investment in research and development of new, or enhancing existing, HIV therapeutic regimens. It establishes an investment baseline, starting with 2009 investments. The report will be published annually. (www.avac.org/resourcetracking)

Multipurpose Prevention Technologies (MPT) for Reproductive Health: Advancing the Scientific and Product Development Agenda. This report from a May 5 think tank convened by AVAC, CAMI and USAID lays out a scientific rationale and research agenda for development of new strategies that could provide combined HIV, STI and pregnancy prevention. (www.avac.org/multipurposetech)

Not to be Missed