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Customizing HIV Prevention in a Global Pandemic

The IAS meeting touted new preventive tools, but will the suffice to end AIDS?

Nine months ago, during an address at the US National Institutes of Health (NIH), US Secretary of State Hillary Clinton endorsed a trio of proven scientific strategies to reduce the spread of AIDS—adult male circumcision, antiretroviral drugs for pregnant HIV-infected women and earlier treatment of  all people with HIV. 


“Instead of falling behind year after year,” she ventured, “we will, for the first time, get ahead of the pandemic. We will be on the path to an AIDS-free generation. That is the real power of combination.” Clinton’s bold prediction immediately went viral. By the time the biannual meeting of the International AIDS Society (IAS) rolled around last month in Washington, D.C. top scientists, activists, global health organizations, television commentators, people with AIDS, and even President Barack Obama, in his pre-recorded message July 22 welcoming the 22,000 attendees to the six-day meeting, were saying that an AIDS-free generation was in sight.

Nor did it end there. Clinton reiterated the US commitment to ending AIDS during her plenary speech the following day, highlighting the work that US agencies have done so far to confront the epidemic. She also pledged an additional $150 million to expand adult male circumcision in South Africa, extend antiretroviral treatment of HIV positive pregnant women—an effective means of preventing transmission to the unborn—and to study the best ways to implement multiple HIV prevention strategies at once in high-risk settings. “This is a fight we can win,” said Clinton to the standing-room-only crowd. “We have already come so far—too far to stop now.”

The billion-dollar question, of course, is whether the rhetoric reflects reality. Though global HIV incidence has declined 15% between 2001 and 2011, and now stands at about 2.5% worldwide, there are still an estimated 2.7 million new infections every year. Anthony Fauci, the director of the US National Institute of Allergy and Infectious Diseases (NIAID), who has addressed all 19 IAS meetings and preceded Clinton at the AIDS 2012 session, sounded a note of caution. Major scale-ups of both treatment and prevention strategies, he noted, will be needed to significantly bend the curve of the epidemic. But he too is optimistic. “If we are fortunate to add a vaccine, this is what we hope to see,” he said, pointing to an arrow hovering tantalizingly close to zero.
 
Fauci agrees that treatment as prevention and adult male circumcision work, as does pre-exposure prophylaxis (PrEP). But he points out that their availability will not by itself suffice to end the HIV pandemic. “A lot of people, a lot of countries, a lot of regions,” he said, “have a lot to do—from country ownership to capacity building to health systems strengthening to increased coordination by current partners, and bringing in new partners. We need to get rid of what doesn’t work and concentrate on what does work. We need to remove the legal, political and stigma barriers. Only then will this occur.”

Over the past decade, the biannual IAS meeting—which often feels more like a political convention than a scientific conference—has advocated strenuously for the large-scale study of PrEP and test-and-treat. But this conference, back in the US after 22 years, was able to move past the question of whether such strategies work. Clinical trials show that they do, in some cases overwhelmingly well (see Treatment is Prevention, IAVI Report, July-Aug. 2011). Their results—along with the data from adult male circumcision trials—have convinced leaders that it’s now possible to begin closing the door on AIDS.

Aiming for zero 

Several IAS sessions offered glimpses of how some successful combination prevention programs might work. During a July 24 plenary session about the need for high-impact HIV prevention strategies, Nelly Mugo, a senior research scientist who holds dual positions at the University of Nairobi and the University of Washington—which found high PrEP efficacy in serodiscordant couples in Africa—described a demonstration project studying ways to combine antiretroviral treatment and PrEP to lower HIV risk in cohorts of high-risk serodiscordant couples in Africa. The HIV negative partners of HIV-infected participants in this study will be offered PrEP as “a bridge for six months,” until the HIV positive partners have effectively suppressed the virus.  PrEP will also be offered to the partners of those HIV-positive participants who decline or are ineligible for treatment, said Mugo.

“With ART, we know it needs to be lifelong, but for PrEP we think that you only need to use during that season of vulnerability,” said Mugo. “It shouldn’t be a lifelong intervention.”

Citing recent data from South Africa, which has an antenatal prevalence of 30% and HIV prevalence of about 17% among adults ages 15-49, Mugo stressed that countries need to test more and do a better job linking folks to care, no matter which preventive strategy they choose. Roughly 29% of the HIV positive in South Africa are eligible for treatment but 20% decline to take it. “The most common reason was that they felt well and did not see reason to commence treatment,” said Mugo.

During a session on the strategic use of antiretrovirals, Zengani Chirwa of Malawi described a pioneering effort in Africa to offer pregnant and lactating HIV-infected women triple-combination therapy for life, even if their CD4+ T-cell counts exceed 350 cells/mm3—the World Health Organization’s (WHO) recommended cutoff for treatment eligibility. The program is referred to as Option B plus. The WHO recommends two options for women with CD4+ T-cell counts above 350. Option A specifies AZT during pregnancy, single-dose nevirapine for mother and infant during delivery and for seven days afterward, and daily nevirapine for the infant until one week after breastfeeding ceases. Option B specifies triple combination therapy from the 14th week of pregnancy until the end of the breastfeeding period.

One reason Malawi opted for Option B plus was that the country lacks the resources to conduct routine immunological monitoring. Health officials said that offering lifelong triple-combination therapy to all HIV-infected pregnant women seemed more practical, given that constraint.

The US government—the leading public funder of international AIDS programs—is also studying combination prevention. The President’s Emergency Program for AIDS Relief (PEPFAR) is spending $45 million to examine the effectiveness of three different combination approaches to HIV prevention in South Africa, Botswana, Tanzania and Zambia. It will use the results to help countries pick the best strategies to prevent new infections and save lives. One of those studies is evaluating home-based testing and immediate linkage to care for the HIV positive; another is studying different combinations of mobile and home-based testing, adult male circumcision, early ARV for the HIV-infected and universal HAART during pregnancy. 

Progress in D.C.

Washington, D.C. remains the epicenter of the US AIDS epidemic. Its prevalence rate as of December 2012, among those over age 12, was 2.7%—the highest in the nation—and the heterosexual infection rate among African American women grew from 6.3% to 12.1% between 2008 and 2010. The adult HIV prevalence rate for the District has been as high as 3.3%, rivaling rates observed in some developing countries (see Why is HIV Ravaging DC?, IAVI Report, Nov.-Dec. 2010). But the district has reported progress in controlling HIV through aggressive testing and treatment. The annual number of new infections dropped slightly between 2009 and 2010—the most recent data available—and there have been no children born with HIV in the district since 2009, a point underscored by Washington, D.C., Mayor Vincent Gray during his speech on the opening night of the IAS conference.

More HIV testing and earlier treatment probably played a significant role in that decline. More than four in 10 residents of the district ages 18-64 report being tested—the highest in the US. Nearly 90% of people newly diagnosed with HIV in 2009 were linked to care within 12 months, and 76% within three months, according to the Kaiser Family Foundation. The district also instituted a needle exchange program in 2009 and stepped up efforts to link newly diagnosed men and women to care, treatment and support.

Circumcision

Researchers are studying ways of combining adult male circumcision with biomedical and behavioral strategies, and developing less invasive methods for circumcision.  For example, one community-wide program in Orange Farm, a township outside of Johannesburg, South Africa, provided free circumcisions, condoms and counseling to adult men. Its efforts boosted circumcisions from 17% to 54% between 2008 and 2011. University of Versailles researcher Bertrand Auvert said two surveys conducted before and during the rollout of that program found that HIV prevalence dropped from 12.5% to 9.3% among males between the ages of 15 and 49, and 6.2% to 4.2% among males 15-29. This is significant because South Africa, which has the highest HIV prevalence in the world, has been slow to embrace voluntary adult male circumcision, despite ample evidence that it reduces the risk of infection (see A Cut Above the Rest, IAVI Report, Nov.-Dec. 2009).

Results of a separate study conducted in Kisumu, Kenya, that was one of the first to show the benefits of adult male circumcision in lowering HIV risk appear to be holding up over time. A fresh round of data provided by University of Illinois scientist Robert Bailey showed that 5½ years after undergoing the surgical procedure, the men, who were between the ages of 18 and 24 at the time of enrollment, were still less than half as likely as uncircumcised men to become infected.

Finally, two studies, one conducted in Kenya and Zambia and the other in Rwanda, provided data on two cheaper, less invasive circumcision procedures. One called the Shang ring—which consists of two concentric plastic rings that sandwich the foreskin, allowing it to be cut away. The procedure takes less than half the time it takes to complete a traditional 20-minute adult circumcision. The other device, called PrePex, is a nonsurgical bloodless method that uses a rubber band to compress the foreskin against an inner plastic ring, causing the foreskin to die after several days due to the restricted blood flow. PrePex does not require anesthesia or sutures.

Men enrolled in the Shang Ring study found the device easy to use, and safe. PrePex was also found to be safe and effective, and Rwanda plans to incorporate it in its national HIV prevention program.
While some countries in Africa continue to shun adult male circumcision, Kenya has dramatically scaled up the service and is looking to combine it with other prevention strategies. Bailey said Kenya has worked hard to get adult men who opt for circumcision to also get tested for HIV. Previously, 40 out of every 100 men who got circumcised got tested before they were circumcised. But in the last 16 months, that number has grown from 92 out of every 100 men, he said.. “We are also screening for sexually transmitted infections,” he said. “Every man has a genital exam and is asked about his recent STI history.”

But he said circumcision programs—which do not provide ARVs or care for HIV-infected patients—need to build stronger linkages to places that do monitor and care for people with HIV. One way, said Bailey, would be to provide transportation to clinics that provide counseling, testing and treatment.

Reasons for optimism

Some leaders and organizations, citing data from ARV-based prevention strategies and adult male circumcision, have pledged to spend more money to expand such programs. PEPFAR, for one, will provide an additional $40 million to support South Africa’s plans to provide voluntary male circumcisions to almost 500,000 boys and men over the next year. Sec. Clinton said the US remains committed to a global goal of eliminating mother-to-child transmission by 2015.  She said that during the first six months of 2012, PEPFAR reached more than 370,000 women and the program is on track to reach its target of an additional 1.5 million women next year.

Scientists are also optimistic that microbicides and vaccines will eventually be added to the prevention toolkit. The most promising of these research avenues got some attention at the IAS meeting (see related story).

“Combination prevention is not a new concept,” said Mitchell Warren, the executive director of the New York-based group AVAC that advocates for the global delivery of biomedical prevention options. “We just didn’t have very good combinations.”

Yet despite significant strides in treatment and the recent progress in reducing the rate of new infections—from about 2.8 million in 2001 to 2.2 million in 2011—there are still 34 million people living with HIV today. A global goal of getting to only 1.1 million new infections by 2015, which would require a 50% drop, seems unlikely. Meanwhile, the estimated number of new infections every year continues to outpace the number of people accessing treatment in the developing world, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS).

Still, the most recent data from UNAIDS, released just before the start of the IAS meeting, suggest there have been some home runs. Between 2001 and 2011, the number of new infections dropped 22% in sub-Saharan Africa, 18% in Asia and 38% in the Caribbean. Incidence appears to have stabilized in Latin America. In 2011, more than 8 million HIV-infected people in low and middle-income countries received antiretroviral treatment—a 20% increase over 2010—putting UNAIDS within striking distance of its goal to have 15 million people on treatment by 2015. And low and middle income countries reported a steady growth of investments in the global AIDS fight, led by South Africa, Kenya, Ghana and Nigeria, according to a recent UNAIDS report.  Finally, UNAIDS data also indicate that the global rate of mother-to-child transmission of HIV dropped 24% globally between 2009 and 2011. 

In North America and Western and Central Europe, however, HIV epidemics have remained static at best for more than a decade. There are no signs that the rising incidence in Eastern and Central Europe—fueled by a surge in injection drug use—is slowing down. Worse, Uganda, an early star whose aggressive campaign to change behavior and improve treatment drove down HIV infection rates and AIDS prevalence dramatically during the 1990s, which in turn led to a drop in HIV prevalence, has witnessed an alarming uptick in new cases. A survey last year of 11,680 households that was conducted by the US and Uganda and paid for by a quintet of organizations that include the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), found HIV prevalence for ages 15-59 was 6.7%. That prevalence was slightly higher than the 6.4% reported by a 2004-2005 survey conducted by the same groups. The surveys also showed little change in circumcision rates—only about a quarter of adult Ugandan men ages 15-49 who were surveyed said they had been circumcised. 

Halting the epidemic will require significantly higher outlays of public and private dollars. A report released at the IAS meeting by AVAC and The American Foundation for AIDS Research (amFAR), estimates that at least US$18 billion will be needed in 2013, and at least $24 billion in 2015, just to begin to end the AIDS epidemic. An Action to End AIDS (available at www.avac.org) lays out a range of short-term goals. These include the expansion of treatment and the scale up of both prevention of mother to child transmission and adult male circumcision to 90% and 80%, respectively, by 2015 to more rapidly reduce new infections and deaths.

These requirements far exceed the capacity of today’s AIDS programs. A report by the Institute for Health Metrics and Evaluation in Seattle estimated that total development assistance for HIV and AIDS—which includes both private and public dollars—was just $6.4 billion in 2009. The Kaiser Family Foundation, for its part, estimates donor governments disbursed $6.9 billion to international AIDS programs in 2010, compared to $7.6 billion in 2009.

“There is some concern about this phrase [AIDS-free generation] because it implies we are close to ending the epidemic, whereas, for many millions of people, that is just not true,” said Richard Horton, executive editor of The Lancet during a July 22 press briefing that kicked off the IAS meeting.

The founder of the Bill & Melinda Gates Foundation, the largest private benefactor of AIDS research, agreed. “I think it’s a wonderful phrase,” Bill Gates told the National Journal during a recent interview. “The only way to have an AIDS-free generation is to invent a vaccine and get it out in big numbers. And although we’re making good progress, we’re almost certainly more than 10 years away from being able to deploy that vaccine.”

But Mark Dybul, who oversaw PEPFAR until 2009, believes the tools required to end the epidemic are already available. “Models,” he said, “are showing us that if we implement them, we can end the epidemic. And the notion that this is going to make people complacent I would turn on its head. We are overwhelmed with complacency these days. It’s very hard to get people focused on HIV because, to some degree, they don’t see the light at the end of the tunnel.” —Regina McEnery

 
A nod to vaccines (and microbicides) at IAS 2012  

The AIDS vaccine field has been stung more than once by off-base prognostications about when the world will see a safe and effective AIDS vaccine. So any AIDS vaccine researcher would have been forgiven for dodging that loaded question.

But Gary Nabel, the director of the US National Allergy and Infectious Disease Institute’s Vaccine Research Center (VRC), did not flinch when it was pitched at him during a session on innovations in HIV science at the International AIDS Society meeting in Washington, D.C. this past July. His reply: a safe and effective preventive AIDS vaccine might be no more than a decade away.

“Could we make it bit sooner?” wondered Francis Collins, the director of the US National Institutes of Health who was co-chairing the session.

Ten years might seem like a long way off, particularly in light of advances in other biomedical prevention strategies such as pre-exposure prophylaxis (PrEP), earlier antiviral treatment of infected individuals to block transmission of the virus, and adult male circumcision. But Nabel sees a potentially central role for a vaccine in the global campaign against HIV. Even with the array of preventive strategies now in play, he—as well as many other scientists and funders—continues to believe that nothing will do more to end the pandemic than a broadly effective HIV vaccine.

Nabel’s prediction is, in fact, testament to how far AIDS vaccine research has progressed in recent years. A mere five years ago, when the field was sifting through the unexpectedly disappointing results of the STEP trial, some leading researchers wondered whether an effective preventive vaccine was even possible.

But recent advances have provided ample reason for optimism. In the past two years, researchers have identified more than 100 broadly neutralizing antibodies (bNAbs) from the serum of HIV positive individuals and elucidated how some of these bNAbs work. Nabel and many others see these advances in particular as the beginning of a possible end game against HIV. Further, the results of the RV144 HIV vaccine trial in Thailand, which demonstrated a modest 33% efficacy (see VAX Sep. 2009 Spotlight article First Evidence of Efficacy from Large-Scale HIV Vaccine Trial), has inspired a slew of studies to unravel the immunology behind that protection and efforts to devise more effective versions of the vaccine regimen it evaluated.

Researchers are also hard at work today trying to design immunogens—the active ingredients in vaccines—that might induce bNAb production. Predictably, perhaps, that’s proving far easier said than done. During a plenary address at AIDS 2012, Barton Haynes, a Duke University professor who leads the virtual consortium known as the Center for HIV/AIDS Vaccine Immunology or CHAVI, observed that bNAbs display a number of unusual traits that complicate such efforts. Most saliently, they display a pattern of heavy mutation that reflects a long and convoluted passage to maturation. This extensive process of maturation is as essential to their efficacy as it is difficult to reproduce through vaccination. But researchers seem convinced it’s possible. Indeed, Haynes described several strategies researchers are devising to accelerate the process (see Hunting for that Ounce of Protection, IAVI Report blog; VAX June 2012 article Q & A with Barton Haynes).

During a session on the application novel genomics tools to HIV research, Collins compared the torturous maturation path that bNAbs take to climbing a mountain that becomes increasingly treacherous and circuitous the higher you go. Deep sequencing—which can trace the genetic lineage of an antibody in much the same way a family tree reveals one’s ancestry—in particular is helping to illuminate how bNAbs develop and suggesting approaches to designing vaccines that might speed up the maturation.



“We have two major scientific challenges and opportunities moving forward with an HIV vaccine,” said Carl Dieffenbach, the director of the Division of AIDS at NIAID, during an IAS session on frontiers in AIDS research. “First and foremost, we must, as a community, follow up on the RV144 results. We must either confirm or [refute] that finding, and in so doing we will be able to test a number of hypotheses. At the same time, with the isolation of the range of bNAbs, we must be able to test them in proof of concept. We must be able to demonstrate that those antibodies actually will be biologically active in preventing HIV.”

The march toward a microbicide

The IAS meeting also highlighted advances in the search for effective vaginal microbicides, including the start of a Phase III trial in Africa evaluating a monthly vaginal ring containing the antiretroviral drug dapivirine (see Prevention and Cure Steal the Show, IAVI Report blog), and progress toward the development of rectal microbicides for both men and women.

Ian McGowan, a professor of medicine at the University of Pittsburgh School of Medicine, summarized results from MTN-007, which were first presented at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle in March. A Phase 1 study of 45 HIV negative men and 20 HIV negative women in the US, that trial evaluated the safety, adherence and acceptability of the rectal application of a reduced glycerin formulation of a 1% tenofovir microbicide gel. Researchers found the gel was much better tolerated than a 1% TDF gel that was formulated for vaginal use but administered rectally in a previous trial in the US, named MTN-006 , involving 14 HIV-uninfected men and four HIV-uninfected women (see A PrEP Rally, IAVI Report, Mar.-Apr. 2011).

In MTN-007, participants were randomized to receive either the 1% tenofovir gel, a placebo gel, the spermicide nonoxynol-9 (N9) or no treatment at all. Participants were evaluated at baseline, after a single dose and after seven daily doses of the rectal microbicide, the spermacide or the placebo gel.

The microbicide candidate tested in the previous trial had a high proportion of salts to body fluid, which is thought to have triggered the diarrhea and stomach cramps reported by most of the 18 participants in the trial. That proportion was significantly lower in the reduced glycerin formulation employed in MTN-007, which could explain why 87% of participants said they would be likely to use the microbicide candidate in the future, as opposed to just 25% in the MTN-006 trial.

Rectal tissue analysis found the tenofovir gel candidate did not raise the levels of inflammatory markers, but a microarray analysis did find the gel affected more than 500 genes, primarily by decreasing their activity. The implications of these genetic effects, however, remain unclear. What is clear is that researchers have every intention of finding out. —RM