HIV Prevention Research: The Relay Race Continues

Researchers gathered at the International AIDS Conference focused on long-term efforts to control the spread of HIV

By Regina McEnery

If there is one thing researchers have come to realize in their search for a safe and effective vaccine, it’s that HIV doesn’t allow its victims—or science—much time to mount a successful defense.

Within six days after exposure to HIV—about the length of time the approximately 25,000 researchers, healthcare workers, and activists gathered at the XVII International AIDS Conference in Mexico City from August 3-8—the virus overcomes the body’s initial defenses and infects enough target cells to cause a ramping up of viremia that essentially turns HIV into the biological equivalent of a runaway train. This early, yet crucial, chapter in the life cycle of the virus was referenced in a number of key talks at the sprawling conference, reminding attendees at the biennial event why vaccines and other biomedical methods of preventing HIV represent enormous and thus far unmet challenges for scientists.

“We refer to [those six days] as a window of vulnerability,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). “But [those days] can also become a window of opportunity,” he added. “Our success or failure with vaccines, as well as with our ability to ultimately control [and] perhaps even cure HIV, will rest in that very short time frame.”

Fauci’s remarks opened a session on new directions in AIDS research that could have served well as the back-up theme for the conference’s main mantra of “Universal Action Now.” Following the recent setbacks in the development of microbicides and vaccines, the field of HIV prevention was at the forefront of many discussions. The failure of Merck’s cell-mediated adenovirus serotype 5 (Ad5) vector-based vaccine candidate (MRKAd5) to show any efficacy in a large Phase IIb test-of-concept trial has steered researchers back to basic research, and the conference unexpectedly became a forum to showcase these shifting priorities.

The Mexico City conference, the first to be held in Latin America, squeezed in presentations on a disparate list of topics ranging from the study of better animal models for HIV pathogenesis, to the status of multiple approaches to HIV prevention, including vaccines, microbicides, oral pre-exposure prophylaxis (PrEP), and implementing safe male circumcision programs.

A shifting pipeline

The most vibrant example of shifting priorities in the AIDS vaccine field occurred last month when Fauci decided not to move forward with a Phase IIb test-of-concept trial known as PAVE 100A of a prime-boost vaccine regimen developed by researchers at the Vaccine Research Center, part of NIAID (see PAVEing the way to a smaller trial). Although Fauci is considering a smaller trial in place of PAVE 100A, the pipeline of vaccine candidates could still shrink in the coming months. In its biennial 2008 AIDS Vaccine Blueprint, IAVI recommended that less promising vaccine candidates get weeded from the product development pipeline and that the freed-up resources be funneled instead to basic discovery research (see Vaccine Briefs).

A number of sessions at the conference also focused on ways to attract a new generation of researchers into AIDS vaccine research, an issue that has become in vogue ever since NIAID held a summit on HIV vaccine research and development earlier this year (see Balancing AIDS Vaccine Research, IAVI Report, March-April 2008). “Everywhere you go it is the same faces, all of us in our mid-50s,” said Mauro Schechter, chief of AIDS research at the Universidad de Federal do Rio de Janeiro in Brazil. “Where is the next generation? We are not giving the right message if we do not tell all the researchers that this is a relay race,” he said.

Though major strides have been made in the past decade in both the development of new antiretrovirals (ARVs) and in providing ARV treatment to more people living with HIV/AIDS, countries have been less successful in controlling the spread of new infections, particularly in high-risk populations. The US Centers for Disease Control and Prevention (CDC) released updated HIV incidence estimates at the conference showing that the annual number of new infections has been more than 16,000 higher in the US than the estimated 40,000 infections that had been continuously reported since the mid-1990s (see A Static Epidemic, IAVI Report, May-June, 2008).

The most recent estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS), which were released just prior to the start of the conference, indicate that 33 million people are currently living with HIV/AIDS and that 2.7 million new HIV infections occurred globally last year. Though the rate of new HIV infections has fallen in some countries, including in some of the hardest-hit regions of sub-Saharan Africa, this has been offset by increases in new infections in other countries, according to the UNAIDS report.

Moreover, the cost of treatment has grown astronomically since the advent of highly active antiretroviral therapy (HAART). To meet the goal of universal access, UNAIDS estimates it will cost approximately US$54 billion each year to provide ARVs to those in need in low- and middle-income countries by 2015. In Brazil, for instance, the cost of providing ARVs in 2008 is estimated to be $525 million—double the costs in 2004, according to the UNAIDS report.

UNAIDS Director Peter Piot said there are also some worrisome trends in the modes of transmission, creating even greater challenges for government-funded prevention programs. In Thailand, for instance, the highest rate of new infections is now among married women, said Piot. He also cited concern about increasing rates of HIV among injection-drug users (IDUs) and men who have sex with men (MSM) in some African countries.

“We have absolutely no choice but to continue to develop the science required for an HIV vaccine no matter how long it takes,” said Myron Cohen, associate director of the University of North Carolina’s Center for AIDS Research during his plenary talk on preventing the sexual transmission of HIV.

Back to basics?

Lack of efficacy prompted Merck to halt immunizations in the STEP trial 11 months ago. Unfortunately, the disappointing news didn’t stop there. Subsequent observations by researchers involved in the study suggested that the modified cold virus used to ferry the HIV antigens may have actually increased the risk of HIV acquisition in certain sub-groups of trial volunteers—mainly uncircumcised MSM who had pre-existing immunity to the Ad5 vector.

While the results of the STEP trial may have slowed interest in the development of cell-mediated vaccines, clinical investigators attending the conference say there is still much to be learned from the trial volunteers. Susan Buchbinder, of the San Francisco Department of Public Health and a principal investigator in the STEP trial, said researchers are still awaiting data on human leukocyte antigen (HLA)-typing and herpes simplex-2 (HSV-2) status from trial volunteers who subsequently became HIV infected. They are also collecting behavioral data that could elucidate any possible sexual networks among uncircumcised men at certain trial sites, which are associated with an increased risk of HIV infection. Buchbinder noted that the retention rate in the STEP study, even after unblinding the volunteers, is still about 95%. “We explained to the study volunteers that this is a pivotal trial and that we need their continued participation and our retention rates have been very, very high,” said Buchbinder, adding that this was “a testament to the incredible dedication of our study volunteers.”

In a separate session focused solely on AIDS vaccine research, Buchbinder went into greater detail about the potential connection between susceptibility to HIV infection and circumcision status in MSM. Research suggests that the foreskin harbors an abundance of Langerhans cells, which can aid HIV transmission, but the protective effects of circumcision have only been established in heterosexual men. In the STEP trial, researchers observed a high number of HIV infections among uncircumcised MSM who reported having unprotected, insertive anal intercourse. Buchbinder said one hypothesis is that HIV may have targeted activated Langerhans cells in these uncircumcised MSM, making the “less risky practice” of insertive anal sex much riskier.

Clues from nonhuman primates

A number of other talks at the conference focused on developing better animal models for studying HIV infection and searching for clues about virus control from different species of nonhuman primates.

Although nonhuman primates are the best animal model available, they are still an imperfect approximate for studying HIV infection in humans. This has led researchers to explore other options for preclinical evaluation of AIDS vaccine candidates, including mice that are genetically altered to express human immune cells, so-called humanized mice. Victor Garcia-Martinez, a virologist at the University of Texas Southwestern Medical Center, presented on a humanized mouse model that he has been using to study the transmission and pathogenesis of HIV.

Garcia-Martinez said the humanized mice developed human T cells at a furious pace after being injected with the bacterial toxin that causes toxic shock syndrome or Toxic 1—one measure of proof that their immune systems were reacting in a similar fashion to a human’s. They also measured the amount of time it took the mice to produce cytokines and found that it correlated with the time it takes to induce human inflammatory responses. As a final test of concept, they challenged the mice with Epstein-Barr virus and found that the responses closely resembled those seen in humans. Garcia-Martinez said his laboratory is now using the humanized mice to study HIV pathogenesis in the gut, a central battleground for virus replication and CD4+ T-cell depletion early on in the course of HIV infection in humans.

While the humanized mouse model is being further developed, primates are still the best model available for studying HIV infection. Guido Silvestri, director of the clinical laboratory at the University of Pennsylvania, whose focus is the pathogenesis of HIV in different species of nonhuman primates, presented on the role the immune system plays in aggravating progression of HIV infection in humans.

In experiments with sooty mangabeys, natural hosts of SIV that can be infected with the virus without any deleterious consequences, Silvestri’s laboratory has observed an apparent lack of immune activation during infection, despite levels of virus replication comparable to those in other nonhuman primate species that do develop the monkey equivalent of AIDS. He compared sooty mangabeys to long-term nonprogressors—a rare subset of humans who are infected with HIV but do not progress to AIDS in the typical time frame, even without the aid of antiretroviral therapy. The difference between the two, said Silvestri, is that viral replication continued unabated in the primates, while it remains suppressed in long-term nonprogressors.

Silvestri believes his observations in sooty mangabeys have implications for vaccine development. “When it comes to vaccines, the main problem is that every time we try to mount an immune response against the virus, we are also creating new targets for the virus itself,” he said.

A pill to prevent HIV?

With no AIDS vaccine looming on the horizon, there is increasing attention being placed on the growing array of clinical trials evaluating oral PrEP—the use of ARVs to prevent HIV infection. Nowhere was this more evident than at the conference, where the status of PrEP trials and future concerns about its effectiveness and implementation were discussed at a broad range of sessions and received considerable media coverage. An industry liaison forum sponsored by the International AIDS Society, which hosted the conference, included a discussion of PrEP, which was also the topic of a report released at the conference by the AIDS Vaccine Advocacy Coalition (AVAC).

There is no evidence yet from trials evaluating whether daily administration of the ARV tenofovir, or a combination pill of two ARVs known as truvada, will be effective at preventing HIV transmission, but the research and advocacy communities are gearing up for the results. Seven trials are currently underway or in the planning stages. The furthest along of these is a US trial funded by the CDC that is testing oral administration of tenofovir in 400 HIV-uninfected MSM. Results are expected next year on this study, according to Timothy Mastro, senior director of research at Family Health International, a sexual and reproductive health organization that is also funding a PrEP trial that will begin enrolling volunteers in Africa this year.

Mastro, who gave an overview talk on PrEP, said the primary purpose of the current batch of studies is to determine whether the ARV-based intervention prevents HIV infection and whether it is safe. Only then will researchers tackle some of the thornier issues involved with this prevention strategy. “Then we will evaluate risk behaviors, adherence, alteration of disease progression, and whether or not [HIV] resistance develops in those that become infected [during the] trial,” he said.

Four other trials are now enrolling volunteers, including a study of 2,400 IDUs in Thailand, a study of 1,200 heterosexual men and women from Botswana, and a study of 3,000 MSM in Brazil, Ecuador, Peru, and the US, with additional sites to be added later. Another trial involving 4,200 women in southern Africa will evaluate a topical application of a gel-based microbicide containing tenofovir to determine its ability to block HIV infection.

In total, the seven PrEP studies will involve close to 18,000 volunteers and that number is likely to get even higher because study investigators in at least two of the trials have decided to expand enrollment in order to strengthen the statistical power of their trials. Mastro said the decision was made to expand enrollment in trials in both Thailand and Botswana after investigators observed a lower HIV incidence rate than what had been previously estimated in the study populations.

Mastro said studies have shown that oral PrEP can prevent transmission of SIV in repeat challenge studies in rhesus macaques, which is why advocates have high hopes for its efficacy in humans. If effective, though, there will be many obstacles to successful implementation of PrEP programs. “We may have an answer in 2-3 years and we have to make sure we are ready for the data,” said Mitchell Warren, executive director of AVAC.

An underutilized strategy

While the HIV prevention field awaits answers on PrEP, questions are mounting about why the implementation of male circumcision programs is lagging. Three years ago, researchers halted two large randomized trials after data showed that male circumcision reduced HIV transmission by as much as 65% in heterosexual men. Despite the plethora of favorable data, researchers and AIDS advocates at the conference reported that the intervention is underutilized, particularly in hard-hit regions in sub-Saharan Africa where heterosexual sex is the primary mode of HIV transmission.

New data was also released at the conference showing that adult male circumcision was not associated with increased promiscuity. Robert Bailey, an epidemiologist at the University of Illinois, reported that male circumcision did not appear to increase HIV risk behavior in a randomized control trial of 1,319 men in Kenya (PLoS ONE, 3(6):e2443, 2008).

Bailey, who has been studying circumcision for more than a decade, also presented data based on surveys of men in a Kenyan cohort suggesting that circumcision actually increases penile sensitivity and results in an enhanced ease of reaching orgasm among newly circumcised men as compared to men in an uncircumcised control group. He also observed a significant reduction in sexual risk behavior among both circumcised and uncircumcised men 6-12 months after enrollment in the circumcision study.

Population Services International (PSI), a nonprofit organization focused on alleviating major health problems in the developing world, is pushing for a scale-up of male circumcision in Africa, where efforts to provide the procedure to men have faced a number of cultural, religious, and even political barriers, despite solid evidence for its protective effects against HIV infection. And there is now some evidence that the tide may be turning.

Shortly after the close of the Mexico City Conference, President Yoweri Museveni of Uganda, who previously had opposed mass circumcision because he thought it would encourage the spread of HIV/AIDS, announced plans to circumcise more than 3,000 local youths between the ages of 12 and 18, according to Reuters news service.

Dvora Joseph, acting director of PSI, said there is still much stigma surrounding circumcision in some countries, while in others there are long lines of men waiting for the procedure due to shortages of trained healthcare workers. Warren acknowledged that circumcision is not a magic bullet, but in the absence of a vaccine, he said interventions like circumcision have become an important component in reducing the spread of HIV. PSI said widespread circumcision in sub-Saharan Africa—particularly in southern Africa, where the current circumcision rates are low—could prevent an estimated two million new HIV infections over the next 10 years and save as many as four million lives over the next 20.

Next-generation microbicides

The development of topical microbicides that women can apply before intercourse to prevent HIV transmission was a hot topic at the 2006 AIDS conference in Toronto, particularly after Bill and Melinda Gates specifically called for increased research efforts to develop microbicides and other new HIV prevention tools. But the announcement earlier this year that the microbicide gel Carraguard had no effect on HIV infection rates in women enrolled in a Phase III clinical trial made it just the latest in a string of candidates that have failed to provide protection against HIV (see Vaccine Briefs, IAVI Report, March-April, 2008).

Zeda Rosenberg, chief executive officer of the International Partnership for Microbicides (IPM), spoke at a number of sessions about the development of a new cadre of microbicides, which are comprised of existing antiretroviral drugs and therefore have a more precise mechanism of action against the virus. These ARV-based microbicides include gel formulations of tenofovir; dapirivine, a non-nucleoside reverse transcriptase inhibitor; and maraviroc, a CCR5 inhibitor.

The first results from efficacy trials of these second-generation candidates are not expected until 2010, when a Phase IIb test-of-concept trial testing a tenofovir gel will be completed in South Africa. However, a study released at the conference is cause for optimism. In a late-breaker abstract by CDC researcher Walid Heneine, he showed that a microbicide candidate consisting of truvada provided almost complete protection against repeated vaginal SHIV challenge in rhesus macaques. This supports other encouraging animal data on the topical use of ARVs in preventing HIV transmission.