By Regina McEnery
Microbicide Candidate Fails in Phase III Trial
The field of microbicide research was dealt another blow this month when a candidate known as PRO 2000, which had shown some promise in an earlier study, failed to have any effect in preventing HIV infection in a Phase III efficacy trial involving 9,385 women in the UK, Tanzania, South Africa, Zambia, and Uganda.
All women received condoms and regular HIV prevention counseling. At the conclusion of the MDP 301 trial—a randomized, double-blind, placebo-controlled study launched four years ago—130 HIV infections had occurred among women who received PRO 2000, compared to 123 infections among those who received a placebo gel. This analysis excluded HIV-infected women who became pregnant during the trial, as well as women whose HIV infection was detected a year after their first study visit.
Another analysis that included all HIV infections, regardless of pregnancy or time of infection, was equally disappointing: 145 HIV infections among women in the PRO 2000 group, compared to 143 in the placebo group. There was also no significant difference in efficacy between women who used the gel more consistently prior to sexual activity. A woman was determined to be a consistent gel user if she attended at least seven of the 13 scheduled visits over 12 months, reported using the gel prior to her most recent sex act at at least half of her site visits, and returned at least one used applicator at all visits when gel use was reported.
PRO 2000 is a water-based topical gel composed of 0.5% of a synthetic polyanionic polymer that was intended to bind nonspecifically to viruses and bacteria, thus preventing the pathogens from binding to and infecting cells. MDP 301 was originally designed to test two doses of the PRO 2000 gel, but investigators discontinued the higher 2% dose in February 2008, when the study’s Independent Data Monitoring Committee concluded that the higher dose was unlikely to show any increased benefit in preventing acquisition of HIV compared to the 0.5% gel.
A year ago, researchers reported results from a Phase IIb test-of-concept trial involving 3,099 women in South Africa, Malawi, Zambia, Zimbabwe, and the US, which showed that women who received PRO 2000 gel along with condoms had 30% fewer HIV infections than those who received the placebo gel and condoms (seeCanvassing CROI, IAVI Report, Jan.-Feb. 2009). The finding, though promising, was not statistically significant.
Salim Abdool Karim, a clinical infectious disease specialist who led the Phase IIb trial of PRO 2000 known as HPTN 035, said he was surprised by the MDP 301 findings and had no explanation for why the trials produced such different results. “It points to the complexity of human trials,” says Karim. “Was HPTN 035 the result of a pure fluke, a pure chance finding for a product that has no benefit? I can’t answer that.”
PRO 2000 is the latest in a string of microbicide candidates that have been found ineffective in preventing HIV infection. Some candidates tested previously have even been associated with an increased susceptibility to HIV infection (see Vaccine Briefs, IAVI Report, March-April 2008).
The MDP 301 trial was conducted by the Microbicide Development Programme, a partnership of 16 African and European research institutions, and was primarily funded by the UK’s Medical Research Council.
AIDS advocates responded to the results with disappointment, but said the field should continue to press forward in exploring microbicides that are gel formulations of existing antiretrovirals (ARVs). Topical forms of the ARV tenofovir, and a combination of tenofovir and emtricitabine known as Truvada, are currently being tested for efficacy in Southern Africa (see PrEP Work, IAVI Report, Nov.-Dec. 2008).
Sheena McCormack, principal investigator of MDP 301, said the results were disheartening, but she remains optimistic about the future. Karim says the future for microbicides is bright, singling out three areas of research. One is, of course, the development of ARV-based microbicides. But Karim also said there is research looking at how best to formulate the products, such as delivering the gels through a vaginal ring. Additionally, researchers are looking at new ways to address adherence. “The need for a microbicide is as great as ever,” says Karim. “This should not be a time for despondency, we need to move on.”
Update on Pandemic Shows New HIV Infections Steadily Declining
In its annual update on the status of the global epidemic, the Joint United Nations Programme on HIV/AIDS (UNAIDS) reported a 17% drop in the number of new HIV infections over the past eight years and suggested that the spread of HIV appears to have peaked in 1996, when 3.5 million new infections occurred (see Figure 2, below).
According to the report, which was released in November in advance of World AIDS Day, an estimated 2.7 million new HIV infections occurred in 2008. This brings the estimated number of people living with HIV to 33.4 million, slightly higher than in 2007 when 33 million were estimated to be living with the virus (see Figure 3, below). This is largely due to the life-prolonging effect of antiretrovirals (ARVs). UNAIDS estimates that there are now about four million people in low- and middle-income countries receiving ARVs—a 10-fold increase over the past five years. AIDS-related mortality peaked in 2004, when there were 2.2 million deaths. Last year, it is estimated that there were two million AIDS-related deaths.
The 2008 data reflect advances in software that have enabled epidemiologists to more reliably estimate HIV incidence using updated mathematical models. The more accurate accounting is expected to help countries more precisely define the scope of the epidemic in high-risk regions and populations. A dozen countries have used a model to analyze HIV incidence by the mode of transmission. This enables epidemiologists to predict where new infections are likely to occur, both generally and within pre-identified subgroups. This approach enabled Uganda to identify an estimated number of new infections that may occur among heterosexual couples considered at low risk of HIV infection.
The latest data also found dramatic variations in HIV prevalence within countries, a sign that prevention strategies need to be tailored to local needs and that national responses to the AIDS epidemic should be decentralized, according to UNAIDS. “The common failure to prioritize focused HIV prevention programs for key populations is especially apparent,” according to the report. “Even though injecting drug users, men who have sex with men, sex workers, prisoners, and mobile workers are at higher risk of HIV infection, the level of resources directed toward focused prevention programs for these groups is typically quite low, even in concentrated epidemics.”
For instance, although serodiscordant couples account for a substantial percentage of new infections in some African countries, HIV testing and counseling programs are seldom geared specifically toward this risk group, the report said. Similarly, many programs that have targeted adolescents fail to grasp some of the key determinants of their vulnerability to HIV, such as the high prevalence of intergenerational partnerships in many countries.
Timed to coincide with the release of its annual report, UNAIDS also rolled out a glossy, more reader-friendly magazine-style publication of its UNAIDS Outlook. A link to both the UNAIDS annual report and its new publication can be found at www.unaids.org.
Progress and Promise
On World AIDS Day, scientists marked a promising year on both research and policy fronts
As it does every year, the global AIDS community marked World AIDS Day, December 1, with programs intended to raise awareness about the pandemic. Countries entered the year stuck in a global recession that has cast a shadow on funding for AIDS programs. But despite the economic uncertainty, 2009 turned out to be a promising year on both the research and policy fronts, with many of these developments highlighted, if not announced, on or around World AIDS Day.
The biggest burst of news in HIV prevention this year emerged from the AIDS vaccine field in September. RV144, a 16,000-person trial conducted in Thailand, provided the first evidence of vaccine-induced protection against HIV. This finding, along with other scientific developments, helped energize the field. “This has been a banner year in the AIDS vaccine effort,” said Wayne Koff, senior vice president of research and development at IAVI, during a World AIDS Day seminar in New York City about recent progress and future directions in AIDS vaccine research and development. The event was co-sponsored by IAVI, the AIDS Vaccine Advocacy Coalition (AVAC), and the Global HIV Vaccine Enterprise.
Magda Sobieszczyk, a Columbia University AIDS researcher who spoke at the seminar about recently completed and ongoing HIV prevention trials, said RV144 “piqued people’s interest” and mobilized the field. The results of RV144 also took center stage at a World AIDS Day event in Washington, D.C., sponsored by more than a dozen organizations, including AVAC, IAVI, and the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases.
Other AIDS vaccine-related events included a two-day rally, seminar, and workshop at the Global Science Academy in Basti, India, and a presentation in Maryland by the Walter Reed Army Institute of Research and the US Military HIV Research Program, major collaborators on the RV144 trial. Elsewhere around the world, organizations pledged solidarity to the search for an AIDS vaccine by holding rallies, debates, lectures, sports events, and plays. The Desmond Tutu HIV Research Center in South Africa sponsored a soccer tournament for young people and used the event as a way to spread information about the importance of HIV testing and counseling and to encourage adolescents to inform their peers about how to reduce the spread of HIV. An event in Amsterdam sponsored by IAVI, AIDS Fonds, and Stop AIDS Now!, centered on new prevention technologies, while vaccine trial sites in the Dominican Republic held a video forum on vaccine research and sponsored a frank discussion about the commercial sex trade in Santo Domingo.
World AIDS Day also provided a stage for the announcement of several policy shifts. In South Africa, the epicenter of the AIDS pandemic, President Jacob Zuma announced that antiretrovirals (ARVs) would be made available to all HIV-infected pregnant women and infants, that HIV testing would be expanded, and that he was planning to get tested for HIV. Treatment will also be expanded to those with tuberculosis, the leading cause of death among South Africans infected with HIV.
Reflecting a change in treatment guidelines unveiled by the World Health Organization (WHO) the day before, Zuma said his country would also offer treatment sooner to all HIV-infected individuals. The WHO’s previous recommendations called for treatment to be initiated when a person develops AIDS (as defined by having fewer than 200 CD4+ T cells in a microliter of blood) or an AIDS-related illness. But on November 30, the WHO announced that it was raising the minimum threshold for initiation of treatment to 350 CD4+ T cells. The WHO’s updated guidelines are now in line with those of leading government health agencies in the US and Europe.
The new WHO guidelines also recommend the prolonged use of ARVs to reduce the risk of mother-to-child transmission of HIV. For the first time, the WHO recommends that HIV-infected mothers or their infants take ARVs while breastfeeding to prevent HIV transmission.
Zuma’s policies stand in sharp contrast to those of his predecessor, Thabo Mbeki, whose administration was heavily criticized for its HIV/AIDS policies. Glenda Gray, executive director of the Perinatal HIV Research Unit at the University of the Witwatersrand in Soweto, South Africa, described the government’s commitment to expanding access to treatment as “incredibly ambitious and incredibly right.”
Gray says there are 1.4 million people in South Africa who need to be on ARVs. “So we basically need to double the amount of people on treatment by 2011,” she says. “How to get there will be another challenge.”
This will be a global challenge. There are an estimated four million HIV-infected individuals worldwide who are currently receiving ARVs. However, approximately five million HIV-infected individuals who were eligible for treatment based on the old WHO guidelines still do not have access to therapy. With the updated guidelines in place, the number of people eligible for therapy could potentially double, substantially increasing the demand for ARVs.
After announcing that it planned to lift a controversial policy that prevented HIV-infected individuals from entering the US beginning next year, the Obama administration announced on World AIDS Day that Washington, D.C., the nation’s capital, would host the XIX International AIDS Conference in 2012. The International AIDS Society (IAS), which sponsors the biannual conference, had opposed the travel ban, which was instituted in 1987, and made it clear it would not hold the conference in the US until the ban was lifted.
“Everybody recognized that the US travel ban had no scientific merit and no public health merit,” says IAS President Julio Montaner, noting that 14 other countries still have similar travel bans in place. “It was based on ignorance and discrimination, and persisted on the books for historical reasons. It was a serious infringement on the rights of people with HIV.”
Montaner says the fact that the US capital—which has the highest HIV/AIDS prevalence in the country—will be hosting the 2012 AIDS conference is significant. “We hope the conference will serve as a catalytic event in trying to rally the necessary forces around addressing the epidemic, not just in the inner city of D.C., but elsewhere,” says Montaner. The last time the AIDS conference was held in the US was in 1990 in San Francisco.
The US government also unveiled a new five-year strategy for the US President’s Emergency Plan for AIDS Relief (PEPFAR) on World AIDS Day. Notably, this new strategy signals a transition for PEPFAR from an emergency response to HIV/AIDS to the promotion of sustainable programs in individual countries. Prevention, care, and treatment services provided through PEPFAR will still be expanded, but efforts will also be made to integrate HIV/AIDS initiatives into broader global health and development programs to maximize the impact on health systems in developing countries. PEPFAR will now focus on strengthening capacity in its target countries to enable them to take the lead on their responses to AIDS and other health demands and improve service delivery. US Global AIDS Coordinator Eric Goosby said the current economic realities are forcing changes in the way the government is approaching the program. The Obama administration is seeking to make PEPFAR part of a US$63 billion Global Health Initiative that will also focus on other major public health challenges such as nutrition and maternal health (see Despite Recession, New Funding Stimulates Research, IAVI Report, May-June 2009).
PEPFAR-funded programs are at work in more than 30 countries. In 2009, the program provided antiretroviral drugs to more than 2.4 million HIV-infected people and plans are to provide treatment to four million people by 2014. But AIDS advocates fear that the global recession and a shift in political priorities in the US could hinder the success of PEPFAR. Michel Kazatchkine, executive director of the Global Fund to Fight AIDS, Tuberculosis and Malaria, stressed the importance of remaining committed to the goals of universal access to treatment when he spoke at a World AIDS Day discussion about food security, HIV/AIDS, and maternal and child health sponsored by the World Bank and held in Washington, D.C.
PrEP Trial Unable to Meet Efficacy Endpoints
A Phase III trial originally designed to test the safety and efficacy of Truvada—a combination of the antiretroviral (ARV) drugs tenofovir and emtricitabine—in reducing the risk of HIV infection among 1,200 HIV-uninfected heterosexual men and women in Botswana will not be able to determine the efficacy of this drug combination because the HIV incidence rate among volunteers was lower than anticipated. To meet the pre-specified efficacy endpoint for this trial, investigators would have had to double enrollment. However, the clinical research centers participating in the trial had also encountered unanticipated problems in retaining volunteers, so instead trial investigators have decided to modify the protocol and collect only safety and behavioral data.
The study, known as TDF2, is among several large clinical trials investigating whether the delivery of ARVs prior to HIV exposure, an idea known as pre-exposure prophylaxis (PrEP), can prevent HIV transmission among individuals at risk of HIV infection. The trial began in 2005, testing tenofovir alone, but then switched to testing Truvada in early 2007. TDF2 is being conducted by BOTUSA, a partnership between the Botswana Ministry of Health and the US Centers for Disease Control and Prevention (CDC) in Atlanta. The amended trial protocol will be submitted for approval to the scientific and ethical review boards in Botswana and the US in January.
Lynn Paxton, team leader for the PrEP and Microbicides Team for the CDC’s Division of HIV/AIDS Prevention, says initially the incidence data for men and women ages 18-29 in Botswana was estimated at around 10%. “We were conservative and halved that number but we subsequently found, over the course of the study, that the incidence was likely much lower than that.” Paxton said researchers are still analyzing data collected from the trial and are unable to say what the observed HIV incidence rate was during the three-year study.
Paxton attributes the lower-than-anticipated HIV incidence to a number of factors, including government-sponsored education and prevention programs that target younger men and women. She says the availability of ARVs among HIV-infected people in Botswana may also play a role in driving down HIV incidence rates in the country.
The low retention rates in TDF2 were also due to many factors. Some enrollees moved out of the area or became pregnant, which made them ineligible to continue in the trial, while others found the time requirements for participation too great. Paxton said BOTUSA took steps to overcome these challenges, including expanding weekend clinic hours, increasing participant reimbursements, and strengthening participant education and retention procedures. While these improvements have made a difference, the trial organizers still weren’t sure a valid efficacy endpoint could be determined.
Paxton says Botswana is known for having a very mobile population. “Also, our study population was young and working. That made it more difficult,” she says.
The original TDF2 trial protocol called for volunteer participation for 12 months after the study was fully enrolled. The CDC says it may now be possible to shorten the follow-up time, while still securing the necessary data to address safety and adherence questions. Proposed plans are being discussed and finalized with the Botswana Ministry of Health, as well as with the trial’s community advisory boards.