Microbicides Finally Gel, Securing Spotlight at the International AIDS Conference
The efficacy of a microbicide candidate was the definitive bright spot at this year’s conference, while the lingering economic slowdown and its impact on HIV/AIDS funding were dark clouds on the horizon
By Kristen Jill Kresge
2010 was to be a landmark year in the global response to HIV/AIDS. Following the endorsement by the member states of the United Nations (UN) at the 2005 UN Millennium Summit, this year was when the international community was to achieve universal access to HIV treatment, prevention, and care. But it came as no surprise to the more than 19,000 delegates from 193 countries who gathered in Vienna from July 18-23 for the XVIII International AIDS Conference (IAC) that this goal is far from being met, despite substantial progress in delivering antiretroviral therapy (ART) to those in need.
“We are nowhere near delivering on the promise of universal access,” said Julio Montaner, outgoing president of the International AIDS Society, which hosts the biannual IAC.
Some researchers even speculated that the hardest battles in delivering treatment are yet to be fought. “It is possible we’ve done the easiest part of the job,” said Yves Souteyrand, coordinator of the strategic information unit in the HIV/AIDS department at the World Health Organization (WHO). Reports of the escalating HIV/AIDS epidemic in Eastern Europe and Central Asia, where HIV continues to spread within marginalized populations, such as injection drug users, migrants, and sex workers, were a harbinger of how difficult it may be to achieve universal access. “In the past five years, the coverage of HIV treatment in low- and middle-income countries has increased ten-fold,” said Brigitte Schmied, president of the Austrian AIDS Society at the conference’s opening ceremony. Yet, only 23% of people in need of ART in Eastern Europe and Central Asia have access, according to Schmied.
These regions are now home to a “volatile and increasing” number of new HIV infections, according to the WHO. Although the number of new HIV infections in 2008 was relatively stable in many parts of the world, Europe now has the fastest growing HIV epidemic due to the growing number of new infections in Eastern Europe, primarily in the Ukraine and the Russian Federation.
The hopes of achieving universal access any time soon were also dampened by the lingering economic slowdown that has gripped many of the nations that are the biggest funders of HIV/AIDS treatment and prevention. Concerns about future financing of the HIV/AIDS response dominated this year’s IAC, with many keynote speakers, including former US President Bill Clinton and Bill Gates, co-chair of the Bill & Melinda Gates Foundation, calling on organizations to be more efficient in their use of donor money.
But amidst the clouds of economic uncertainty, a bright spot emerged in HIV prevention efforts with the results of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial, which showed that a microbicide candidate consisting of a 1% tenofovir gel was able to reduce the HIV incidence in a group of South African women by 39% (1). “The implications of this are really enormous,” said Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases. Even with this level of efficacy, one of the trial’s principal investigators, Salim Abdool Karim, said that mathematical models indicate “this gel could prevent 1.3 million new HIV infections and over 800,000 deaths in South Africa alone.”
Updates on other prevention strategies, including adult male circumcision, HIV vaccines, and the use of antiretrovirals (ARVs) for prevention were also provided.
A victory in South Africa
After successfully hosting this year’s World Cup, South Africa, or at least HIV prevention researchers in that country, had another reason to celebrate. “Today we celebrate the proof-of-concept of microbicides,” said Gita Ramjee, director of the HIV prevention research unit at the South African Medical Research Council, who spoke at the session in which the CAPRISA 004 results were presented.
Delegates and researchers were unabashedly gleeful about the first efficacy trial of any microbicide candidate to show a statistically significant reduction in risk of HIV infection. The audience at the standing room only session, which occurred the day after the news dominated the headlines, greeted the data and the trial’s co-principal investigators, the husband and wife duo Quarraisha and Salim Abdool Karim, with multiple standing ovations. Researchers also expressed their excitement. “These groundbreaking results mean a lot to me personally,” said Ramjee.
The proof-of-concept, double-blinded, placebo-controlled trial tested the safety and efficacy of a coitally dependent, vaginal application of a 1% gel formulation of the ARV tenofovir in 889 women at high risk of HIV infection.
Women in the trial received regular HIV prevention counseling and were instructed to apply the gel up to 12 hours before sex and as soon as possible following intercourse, but within 12 hours—a regimen referred to as BAT24. The overall retention rate was 95%, with 422 women who received the microbicide candidate and 421 women who received the placebo gel completing the trial.
The pre-determined endpoint for the trial was the accumulation of 92 HIV infections. After 30 months, there were 60 HIV infections among placebo recipients and only 38 among the women who received the tenofovir gel, corresponding to a statistically significant 39% lower HIV incidence in the microbicide group (p-value of 0.017, confidence interval of 6%-60%).
However, when researchers looked at earlier time points in the trial, they found that the HIV incidence rate in the microbicide group was as much as 50% lower than in the placebo group after just 12 months. The effectiveness of the tenofovir gel seemed to slowly decline over the subsequent year and a half of the study (see Table 1, below). “Whichever way you analyze this data, we have a range of protection with a statistically significant result,” said Quarraisha Abdool Karim.
*Effectiveness of microbicide candidate as compared to placebo
This was a relief to some researchers who were familiar with the results released last year from RV144, the efficacy trial of a prime-boost HIV vaccine candidate that provided the first evidence of vaccine-induced protection against HIV. The results stirred some skepticism within the AIDS vaccine field because only one analysis of the data yielded a statistically significant result (see Raft of Results Energizes Researchers, IAVI Report, Sep.-Oct. 2009). “There was a certain feeling of ease and pleasure in looking at data that no matter how you slice it are statistically significant,” said Fauci.
Researchers analyzed how the effectiveness of the microbicide candidate correlated with adherence to the prescribed BAT24 dosing regimen. To evaluate adherence, they asked women to return their used plastic applicators to the clinics. Each month, study participants returned an average of six used applicators and reported on average having five sex acts.
Researchers classified women who used the gel more than 80% of the time as “high adherers.” Among this group, the efficacy of the tenofovir gel was a statistically significant 54%, as compared to placebo, higher than the overall efficacy of 39%. The efficacy was markedly lower, only 28%, among the group of “low adherers,” who used the gel less than 50% of the time.
Over the course of the study, researchers found that the number of returned applicators declined among the women who eventually became HIV infected, suggesting that gel use over time tapered off. This could be a cause for concern, as adherence will obviously impact the real-world efficacy of any behaviorally dependent intervention. And adherence rates outside of the setting of a clinical trial might differ. “I think we will see very different gel use outside of a trial setting,” says Salim Abdool Karim. He thinks gel use may actually be higher in a real-world setting because women would be receiving more positive messages. In a clinical trial, Salim Abdool Karim said women are repeatedly told that they might be getting placebo or that the gel might not have any effect.
Applicator used to dispense either the microbicide candidate or placebo gel. Photo courtesy of Centre for the Programme of Research in South Africa.
In addition to its ability to protect against HIV infection, researchers also determined that the tenofovir microbicide gel reduced the incidence of herpes simplex virus (HSV)-2 by 51% (p-value 0.003, confidence interval 22%-70%) in a subset of women who weren’t already infected with HSV-2 at the start of the study. Previous studies have shown that individuals infected with HSV-2 have twice the probability of acquiring HIV (see HIV Prevention in a Pill?, IAVI Report, Sep.-Oct. 2005). But the ability of the tenofovir gel to block HSV-2 transmission is not responsible for the protection against HIV seen in this trial, according to investigators. “HSV-2 does not account for the effect on HIV,” said Salim Abdool Karim. Tenofovir, which was developed by the biopharmaceutical company Gilead, comes from the same precursor compound as a sister drug that has been shown to have potency against HSV-2.
Gilead still holds licensing rights for the use of tenofovir for HIV treatment, but provided the drug for use in CAPRISA 004 and has granted CONRAD—which collaborated with Family Health International and CAPRISA to carry out this trial—and the International Partnership for Microbicides co-exclusive rights to develop a tenofovir-based vaginal microbicide. About 90% of the funding for the trial came from the United States Agency for International Development, with the remainder contributed by the South African Department of Science and Technology.
CONRAD has given the rights to manufacture tenofovir gel to the South African government, which means that if a tenofovir gel microbicide is eventually licensed, it can be manufactured and distributed directly in South Africa. However, as Salim Abdool Karim explained, the CAPRISA 004 results are really just the “first step and additional studies are needed to confirm findings from this trial.”
Luckily, one of those trials is already underway. The Vaginal and Oral Interventions to Control the Epidemic (VOICE) study is comparing daily application of a tenofovir gel to oral administration of either tenofovir or Truvada (a single pill combination of tenofovir and another antiretroviral emtricitabine) in 5,000 women in southern Africa. Results from this trial are expected in 2013. “We’re going to get data that will hopefully confirm this and push the field further ahead,” said Fauci.
In the meantime, researchers are studying the drug levels in both blood and cervicovaginal fluid among CAPRISA 004 volunteers, and looking for possible explanations for why some women who used the gel still became infected. Angela Kashuba, an associate professor of pharmacotherapy and experimental therapeutics at the University of North Carolina, reported that tenofovir concentrations in blood plasma were <1 ng/ml in women using the microbicide gel. This may be in part why researchers did not detect any tenofovir-associated resistance mutations in women who received the tenofovir gel and eventually became HIV infected. “I was very struck by the lack of any degree of resistance,” said Fauci. “That was really quite encouraging.”
In contrast, tenofovir concentrations in the cervicovaginal fluids in the first few days following dosing were above 1,000 ng/ml. “The concentrations in the vagina compared to blood showed you could get a whopping concentration at the portal of entry,” said Fauci, who called this “the best of all possible worlds.” Kashuba also showed that the tenofovir concentrations in the cervicovaginal fluid correlated with HIV and HSV-2 infection status. She said that it would be difficult to achieve such high drug concentrations if tenofovir were taken orally rather than topically, raising questions about how effective oral pre-exposure prophylaxis (PrEP) will be in blocking HIV transmission.
Update on other prevention strategies
While the field eagerly awaits the first efficacy results from oral PrEP trials, which are expected as early as this year, researchers in Vienna reported some interim results from smaller safety studies. Data from a placebo-controlled Phase II trial in the US indicate that there were no significant safety issues associated with administration of once-daily tenofovir to HIV-uninfected men who have sex with men (MSM). The overall number of adverse events that occurred in men receiving tenofovir was similar to that in the placebo group.
Although tenofovir is generally safe and well tolerated in HIV-infected individuals, use of the drug has been associated with some more serious side effects, including compromised kidney function and a reduction in bone mineral density. However, in this study, there was no significant difference in bone density between the tenofovir and placebo groups, and none of the individuals had elevated creatinine levels, which are an indication of compromised kidney function.
The study, conducted by the US Centers for Disease Control and Prevention, enrolled 400 MSM in Atlanta, San Francisco, and Boston. The men were randomized to receive a once-daily dose of 300 mg of tenofovir or placebo either at the start of the trial, or after a nine-month delay. This allowed researchers to compare the risk behaviors between the two groups during the nine months when only half of the volunteers were taking a daily dose of either tenofovir or placebo. In the analyses conducted so far, researchers reported that there was no significant difference in risk behaviors between the two groups of men during that nine-month period.
Data on the safety of intermittent dosing of Truvada in five female sex workers and 67 MSM in Kenya, as well as 36 serodiscordant couples (where one partner is HIV infected and the other is not) in Uganda were also presented in a poster at the conference. In this study, researchers compared daily dosing of Truvada or placebo with an intermittent dosing schedule consisting of a fixed dose on Mondays and Fridays and a dose following each sex act, without exceeding one pill per day. At the conclusion of the four-month study, researchers found that the safety profiles of the daily and intermittently scheduled dosing of Truvada were similar.
Researchers also compared the adherence rates for volunteers in the daily and intermittent groups. Adherence to Truvada or placebo was primarily assessed using the medication event monitoring system (MEMS), an electronic pill bottle cap that records each date and time that the bottle is opened. Investigators also calculated adherence based on self-reported behavior, collected either through questionnaires or though an interactive short message service (SMS). The overall adherence rate to the daily dose was high—83% among the MSM and female sex workers at two sites in Kenya, and 96% among discordant couples in Uganda. Adherence in the intermittent-dosing group was lower with an overall adherence rate of 68% in Kenya and 80% in Uganda. In both groups, adherence rates among discordant couples were significantly higher than in MSM or female sex workers.
When researchers analyzed the adherence rates to the fixed versus post-coital doses in the intermittent group, they found the adherence rates to the post-coital dose were much lower—26% in Kenya and 45% in Uganda for the post-coital dose, compared to 55%, and 91% respectively for the fixed doses. The self-reported behavior differed drastically—volunteers reported taking the post-coital doses 105% of the time in Kenya and 103% of the time in Uganda. Although the investigators acknowledge that it was difficult to accurately measure adherence to the post-coital dosing, they suggest this may be a challenge in these settings and that fixed-dosing schedules may be preferable.
This study, conducted by IAVI in collaboration with the Kenya AIDS Vaccine Initiative, the Kenya Medical Research Institute, the Medical Research Council in Uganda, and the Uganda Virus Research Institute, was the first to compare the safety of and adherence to an intermittent PrEP regimen with daily use.
|Therapeutic Vaccine Candidate Shows Promise|
Results from a Phase II trial show that multiple intramuscular injections of a DNA-based vaccine candidate, developed by the biotechnology company FIT Biotech, reduced average HIV viral load by 0.5 log compared to placebo in 60 clade C HIV-infected, treatment-naive volunteers. The viral load reduction was statistically significant and was sustained for at least two years.
The trial was conducted at a single clinical trial center in Soweto, South Africa, and was the first therapeutic vaccine trial to be conducted in the country. All volunteers were HIV-infected for at least three years, had HIV viral loads greater than 38,000 copies per ml of blood plasma, and CD4+ T-cell counts above 500 cells per µl, making them ineligible to receive treatment based on South Africa’s guidelines.
The vaccine candidate, referred to as FIT-06, utilizes a proprietary gene transfer unit (GTU) technology that allows for more long-term gene expression, and therefore requires lower doses of DNA. “So far, DNA vaccines haven’t been so successful, so the technology makes a difference,” says Joep Lange, head of the Amsterdam Institute for Global Health and Development.
Researchers speculate that the CD4+ and CD8+ T-cell responses induced by the candidate helped control viral replication. In this trial, an increase in antigen-specific CD4+ and CD8+ T-cell responses was detected in 55% of volunteers.
FIT Biotech plans to initiate a Phase I trial in the US to test this vaccine candidate as a preventive approach.—KJK
One month, 36,000 circumcisions
While several trials of microbicides and PrEP are underway, Bill Gates reminded the delegates in Vienna that several proven HIV prevention strategies, including adult male circumcision, the prevention of mother-to-child transmission, and syringe exchange still need to be implemented more widely. He said these strategies were “so cheap and effective it’s more expensive not to pursue them,” and he emphasized the need to scale up strategies as soon as they’re proven to work. “Male circumcision is an amazing advance in prevention,” said Gates.
Efforts to scale up adult male circumcision, which was found to be about 60% effective in reducing HIV infection risk among heterosexual men in three large trials, have been underway in several African countries. But perhaps nowhere has there been more progress than in Kenya, where between November and December 2009, the country launched a campaign in 11 districts of Nyanza province to perform voluntarily circumcisions on 30,000 men in 30 days.
After one month, researchers actually exceeded this target—36,077 voluntary medical male circumcisions were performed. On average, the team performed 10 male circumcisions per day, which reduced the overall cost of the intervention because the staff achieved optimal efficiency, according to Elijah Odoyo June, of the Nyanza Reproductive Health Society, who presented on the success of this circumcision campaign.
“I was doubtful a large number of men would sign up for it, [but] I was wrong,” said Gates. June said the demand for male circumcision by parents of boys younger than 12 was higher than expected. Of the 36,077 males who were circumcised, nearly half (45%) were under 15 years of age.
In advance of the campaign, the team accelerated public education efforts on male circumcision and strengthened referral services in the target districts. Yet uptake was still slow at the start of the campaign. “Despite a lot of preparation, it took two weeks to attain optimal client flow,” said June. Given the overall success of the campaign, June said the team recommends using this approach to scale up male circumcision in other areas.
Less enthusiasm for test and treat
The use of universal testing and immediate antiretroviral treatment for those infected, what is referred to as the test and treat strategy, has received growing attention in the past year. However, in Vienna, questions were raised about this approach, much to the chagrin of Montaner, who said he hoped it would be the emerging issue of the conference. “We have abundant evidence that ARV treatment is prevention,” he said.
But others were more circumspect about the potential benefits of test and treat. Myron Cohen, director of the Institute for Global Health at the University of North Carolina, speaking at a session on ARV-based prevention, declared himself a big advocate of treatment and prevention, but said “the details really matter.”
A study, presented by Jing Luo of the University of Illinois Chicago College of Medicine, found ARV therapy had no effect on HIV transmission rates during a three-year study in nearly 2,000 serodisordant couples in Henan province, China. However, one limitation was that researchers did not collect adherence or viral load data, which could have elucidated whether the HIV-infected partners had stopped therapy or were on sub-optimal therapy due to development of drug resistance. “Most likely the patients were intermittently taking therapy,” suggested Cohen. Luo acknowledged the study’s limitations, but still concluded that “antiretroviral treatment alone may not be sufficient to reduce HIV transmission among serodiscordant couples in real-world, resource-poor settings.”
“We need to deal with these issues and flesh this out going forward,” said Cohen. He also said more long-term studies are needed to see if the prevention benefits of ARV therapy, which have been seen in other studies, are durable. Cohen is heading up a study of nearly 1,800 serodiscordant couples to see if there is a prevention benefit over five to seven years if the HIV-infected partners are taking ARVs.
Studies have indicated that during acute or early HIV infection, a person is at least 26 times more infectious, and other studies have estimated that between 9% and 90% of infections are the result of HIV transmission from someone who is acutely infected. Cohen called this an “inconvenient truth,” and said this may mean that initiating treatment immediately regardless of CD4+ T cell count may not have as great of an effect on preventing the spread of HIV as treating people either very early or late in the course of HIV infections when people are most infectious.
|A Summary of Progress in the HIV Vaccine Field|
“We need a big game changer and that can only be a vaccine,” said Peter Piot, a professor at Imperial College London and chairman of the board of the Global HIV Vaccine Enterprise, speaking at the satellite session “The Search for an HIV Vaccine: Where are we, where are we going, and how can we get there faster,” which was held on the opening day of the XVIII International AIDS Conference in Vienna.
During the session, almost everyone commented on the significant progress in the field, and in particular the results of the RV144 efficacy trial, which, when released last September, marked the first evidence of vaccine-induced protection against HIV to emerge from clinical trials (see Raft of Results Energizes Researchers, IAVI Report, Sep.-Oct., 2009). According to Piot, these results “put HIV vaccine development back on the world stage.”
Another area of progress in the HIV vaccine field was the recent identification of several new broadly neutralizing antibodies (bNAbs) against HIV (see Adding to the Armamentarium of Broadly Neutralizing Antibodies, IAVI Report, Jan.-Feb. 2010). Seth Berkley, president and chief executive officer of IAVI, which isolated two of the new more potent bNAbs (dubbed PG9 and PG16) last year in collaboration with The Scripps Research Institute, said these discoveries have contributed to what he called a renaissance in AIDS vaccine research and development.
The discovery of three other new bNAbs, identified by researchers at the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases, was officially reported just before the start of the conference in Vienna (2). Berkley said there are also “more than a dozen new antibodies that are in the process of discovery,” and are now being characterized.
Robin Shattock, a professor of cellular and molecular infection at St. George’s, University of London, said these new antibodies “open up a real hope for identification of novel immunogens.” But Shattock also pointed out that these bNAbs only develop in HIV-infected individuals after several years of infection, suggesting that the maturation of antibody responses may contribute to their potency and ability to neutralize so broadly (see Vaccines to Antibodies: Grow Up!). Shattock said that researchers may have the challenge of developing “vaccine approaches that could mimic that maturation without multiple injections.”
This work is now underway as researchers try to reverse engineer vaccine immunogens based on this new crop of bNAbs. A proof of principle for this reverse vaccinology approach was recently demonstrated by scientists at Merck Research Laboratories (3). The researchers identified an engineered peptide that mimics the N-terminal heptad repeat (NHR) region of the pre-hairpin intermediate that is transiently exposed during the binding of HIV’s gp41 protein to cell membranes. X-ray crystallographic studies showed that this peptide could bind to a monoclonal antibody referred to as D5 that can neutralize various HIV isolates in vitro.
Vaccination of guinea pigs with two of the most promising immunogens developed based on this peptide elicited neutralizing antibody responses against some tier 1 viral isolates, but not against any tier 2 viruses, which are generally more difficult to neutralize. The neutralization potency and quantity of the D5-like antibodies induced in rabbits were much lower than in guinea pigs, leading the study’s authors to conclude that this “may point to increased difficulty in eliciting protective neutralizing antibody titers in higher species, including primates.”
While there are still many obstacles to eliciting broadly neutralizing antibodies against HIV through vaccination, many researchers believe this is still an important goal. “If we could achieve broadly neutralizing antibodies or broad cellular immunity, those would undoubtedly add to the efficacy we observed [in RV144],” said Merlin Robb, HIV program director for the US Military HIV Research Program.
In his special plenary session during the conference, Bill Gates spoke about the need to speed up the HIV vaccine development process, citing the fact that only three vaccine candidates have undergone efficacy testing so far. “The ultimate prevention tool is a vaccine,” said Gates, and “it is possible.” —KJK
The funding forecast
Looming over nearly all the discussions at the IAC this year were dark clouds of economic uncertainty. In 2008, the global investment in HIV/AIDS reached a record high of US$15.6 billion, a 39% increase in funding from the previous year, according to a recent report issued by the Joint United Nations Programme on HIV/AIDS (UNAIDS).
But following the recent economic crisis, many countries are freezing their investments in global health. “The idea that we should cut back now is ridiculous,” said Michel Sidibé, executive director of UNAIDS. An analysis by UNAIDS and the Kaiser Family Foundation, which was released in Vienna, found that contributions from the Group of Eight Nations, the European Commission, and other governments provided $7.6 billion for AIDS in developing countries in 2009, nearly level with their $7.7 billion contribution in 2008. This was the first year of flat funding, following a substantial increase in donor support for AIDS since 2002 when the total contribution was only $1.2 billion.
Funding for HIV vaccine research was also flat in 2009. According to the HIV Vaccines and Microbicides Resource Tracking Working Group, the total global investment in HIV vaccine research and development held steady last year at $868 million. And according to Seth Berkley, president and chief executive officer of IAVI, the only reason it stayed flat rather than dipping was because of the economic stimulus funding the US government provided, some of which went to preventive HIV vaccine research projects funded by the US National Institutes of Health.
“We’re not seeing the increases we’ve seen in the past,” said Gates. “Today, skeptics say we can’t beat AIDS because of these financial limitations,” he added. But while acknowledging that these are tough economic times, Gates said he is still an optimist and emphasized the need to “push for efficiency in both treatment and prevention.”
For treatment, Gates said organizations should share best practices and strive to lower the cost of delivering ARVs. “If we could limit the delivery costs to $300 per person per year we could treat twice as many people [with existing funding],” Gates said.
Peter Mugyeni, director and founder of the HIV/AIDS Joint Clinical Research Centre in Uganda, said that by doing fewer CD4+ T-cell tests in developing countries, researchers could save money that could be used to provide treatment to more people. “We’re not arguing for second-rate HIV monitoring but we could treat more people by eliminating non-essential tests,” he said.
Former president Clinton also called for more efficiency in HIV/AIDS programs. “We cannot get to the end of this epidemic without more money and changes in the way we spend it.” Clinton said more of the money spent on AIDS needs to go directly to helping people rather than on the apparatus or establishment that provides the services. “Every dollar we waste today puts a life at risk,” he said. Clinton also suggested that programs should shift tasks from doctors to nurses wherever possible to cut costs, and that donors should only support organizations that do things better, faster, and at a lower cost.
“We’re at a turning point. We can push ourselves to make the most out of every dollar of funding,” said Gates, who also spoke about his foundation’s commitment. “We give more to AIDS than any other disease and we’ll be here until this thing gets finished and keep it as our top priority.”