Brazil's Model Approach
Recent international conference highlighted the need to partner prevention and treatment in the response to the epidemic
By Kristen Jill Kresge
The 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment was recently held in Rio de Janeiro. But Brazil’s opportunity to host this large international meeting was not only due to the impressive landscape of this seaside city. The country has become a leader among developing countries for its progressive and comprehensive response to the epidemic. And long before thousands of delegates arrived, Brazil was stealing headlines with its defiant attitude towards drug pricing (see box, below).
Lauded as one of the first to adopt a national treatment program, Brazil is also a leader in HIV prevention and simultaneously working on both fronts is what Pedro Chequer, director of the National AIDS Program, calls the cornerstone of their success. In addition to universal access to life-saving antiretrovirals (ARVs), the government also acted quickly to implement a needle-exchange program for intravenous drug users (IDUs) and to create outreach programs that collaborated with highly-affected communities like commercial sex workers and men who have sex with men. "Treatment, prevention, and care are all part of the same package and each is equally important," says Chequer.
The significance of linking HIV prevention efforts with access to treatment emerged throughout several sessions at the conference. Mauro Schechter of the Rio de Janeiro Federal University and a conference co-chair associated the renewed emphasis on prevention with advancements in the scale up of ARV programs. Discussing prevention had been difficult because of its obvious link with HIV testing, which is a hard sell when there was nothing to offer people who were infected. But since 2000, when the world AIDS conference was held in Durban, there has been a sustained international interest in making treatment programs available in developing countries. Schechter emphasizes that now that progress is finally occurring on this front—thanks to a collection of global initiatives including the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the World Health Organization’s (WHO) ‘3 by 5’ initiative—reinforcing prevention messages has become a necessity.
Several talks throughout the four-day meeting also underscored the inability of treatment alone to control the epidemic. Researchers repeatedly acknowledged that even as the availability of ARVs improves, countries must remain vigilant in providing prevention services. Treatment programs and ARV trials provide an opportunity for healthcare workers to discuss risk-reduction strategies and offer a variety of prevention services, including voluntary counseling and testing (VCT), according to Marie Laga from the Institute of Tropical Medicine in Antwerp, Belgium, who spoke about the synergy of prevention and care in Africa. A recent report from the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) illustrated the positive effect treatment has on the uptake of VCT—people are more likely to get tested if they known they will have access to therapy. One district in Uganda witnessed a 27-fold increase in VCT services after the introduction of ARVs. Laga also credits the provision of drug therapy with helping to reduce the stigma associated with HIV and therefore increasing disclosure within communities. In his speech at the conference, Stephen Lewis, UN special envoy to Africa, heaped praise on the ‘3 by 5’ initiative for making such a difference not only for treatment but also for prevention efforts (For more on Stephen Lewis, see interview).
Among the prominent prevention strategies discussed during the meeting were the increased importance of tailoring risk reduction efforts for IDUs, exploring novel strategies like male circumcision, the diaphragm, and ARV prophylaxis, as well as the importance of long-term options like vaccines.
| Brazil battles over drug pricing
The recent IAS meeting also furthered the debate about the pricing and availability of antiretrovirals (ARVs) and several representatives from Brazil seized the opportunity of hosting the meeting to further the very public debate between the Ministry of Health and three US-based pharmaceutical companies on securing reduced drug prices for the country's national treatment program. The most heated negotiations have occurred between the ministry and Abbott over the pricing of its patented drug lopinavir/ritonavir (Kaletra), which eats up almost a third of Brazil's annual treatment budget. In response, the government threatened Abbot that if they didn't lower the price, Brazil would begin manufacturing the drug domestically. This tactic, known as compulsory licensing, is permitted within the international regulations of the World Trade Organization for member countries that are acting in the public interest. Pharmaceutical lobbying groups in the US heavily criticized Brazil’s stance, arguing that compulsory licensing would limit future investment into novel therapies. However within Brazil this move was viewed as a necessary step to sustain the universal treatment policy in the face of escalating expenses. Manufacturing capacity for lopinavir/ritonavir could be up and running by next year and would cost approximately US$0.40 per pill, according to Chequer.
Negotiations seemed to reach resolution before the start of the conference but within days of announcing an agreement Brazil's health minister resigned, throwing a wrench into the works. At the conference the new minister, Jose Saraiva Felipe, defended Brazil's right to manufacture the drug generically and was dismissive of any arrangement reached prior to his accepting the post. Chequer used his speaking engagements at the conference to emphasize his opinion that the Brazilian government should move forward with compulsory licensing to ensure the best care for its citizens. He argued that the details of the deal with Abbott required the country to spend $70 million on Kaletra regardless of the number of people who need the drug as part of their regimen. Chequer accused Abbott of overestimating the future demand in order to overestimate potential savings.
Many of the nation's prominent activists agreed with Chequer. "The agreement with Abbott is a step backwards for Brazil," said community activist Octavio Valente Jr. at the opening session of the conference. The ministry is also negotiating with Merck on pricing of the drug efavirenz (Sustiva) and Gilead Sciences on tenofovir (Viread).
Risk among IDUs soars
In a plenary talk on emerging HIV epidemics, Chris Beyrer of Johns Hopkins University offered a sobering description of the dire conditions facing IDUs in several countries in Eurasia (Eastern Europe and Central Asia), where the number of new HIV infections is exploding but access to treatment and prevention remains minimal. Official statistics estimate that currently 1.4 million people in the former countries of the Soviet Union are HIV infected, along with 1.1 million in China and Eastern Asia.
Beyrer pinpointed 11 countries where explosive HIV epidemics—defined as a 30-40% prevalence—are in progress. The majority of these new infections are occurring among IDUs and the spread of the epidemic is facilitated by close proximity to known heroin trading routes, the continued criminalization of risk behaviors, and the limited access to prevention programs that discourage IDUs from sharing syringes or injection equipment.
Tajikistan, the poorest country of the former Soviet bloc, is struggling to cope with a growing epidemic among IDUs. The gross domestic product per capita was only US$179 in 2000, making it poorer than many African countries, and around a third to a half of all economic activity there is linked to drug revenue. Yet there are currently no programs offering free access to ARVs and only a single non-governmental organization (The Open Society) is working on HIV prevention. "While we are responding globally with access to treatment, HIV is spreading in new regions," says Beyrer. "A very rapid HIV epidemic is now unfolding in a context where very little prevention is happening."
Prevention programs like needle exchange or drug substitution, which use methadone or buprenorphine to wean people from heroin addiction, are effective in reducing the transmission of HIV among IDUs but remain limited in number and reach. Despite the expansion of harm reduction efforts in some countries, including China where the government just recently loosened restrictions on methadone programs, only an estimated 10% of IDUs worldwide have access to needle-exchange programs (NEPs). Access is also limited by funding restrictions like those in the US President’s Emergency Plan for AIDS Relief (PEPFAR) that restrict grant money from being used to fund syringe exchange. "We need to implement programs that we already know work. Unfortunately they have been very hard to initiate, despite mounds of scientific evidence that show they are effective," according to Beyrer.
What is even more disconcerting to Beyrer is the exclusion of IDUs from many of the global treatment programs. He points out that throughout Eurasia IDUs were the first groups to become HIV infected and therefore should be overrepresented in the populations receiving ARV treatment, but according to Beyrer this is not the case. "Even where policy allows, the de facto reality is that people don’t get into treatment programs," he says. "It’s a terrible way to approach public health because you are isolating the people at highest risk."
The spread of hepatitis C virus (HCV) in IDUs is a useful marker for emerging HIV epidemics because it indicates that risk behaviors like needle sharing are occurring. Epidemics of HCV tend to precede HIV in some populations because of the infectiousness of the virus during blood-to-blood contact—sexual transmission of HCV is rare—and therefore an HCV epidemic could be an important signal that aggressive prevention efforts are needed.
Some countries, such as Canada, are exploring innovative options to make injection drug use safer. Vancouver opened the first supervised injection facility in the Americas to address risk behaviors among the city’s large IDU population and Mark Tyndall of the BC Center for Excellence in HIV/AIDS provided an update on the center’s first 18 months. The site is modeled after similar locations in Europe and Australia and offers needle exchange, provides visitors with information on safe injection practices, and has nurses on hand to supervise injections. Counselors are also available and they can provide referrals to detoxification centers in the city.
Tyndall reported that there were 15,000 different visitors to the site, and while transmission rates among frequent visitors at safe injections sites in Europe have declined, the rates in Vancouver continue to be high at around 30%. More impressively however, visitors were one third less likely to share needles. The idea of expanding the number and reach of these sites throughout the country is resting on Vancouver’s site, said Tyndall, who argues that the best results can only be achieved when there are multiple sites in each city.
A short cut on the road to prevention
One of the biggest news stories at the conference came when a group of French researchers presented results from the first prospective study on the effect of male circumcision on female-to-male transmission of HIV. Bertran Auvert of INSERM, the French National Institute for Medical Research, presented data from study ANRS 1265 sponsored by the French National Agency for AIDS Research that showed that adult male circumcision offered a 65% rate of protection from HIV infection.
Researchers have long thought that circumcision could be protective because it reduces the surface area available for transmission and encourages a keratinization of the surrounding skin. The foreskin is also home to a high density of dendritic cells that could facilitate transmission of HIV. This cross-sectional study confirmed the results of more than 30 previous observational studies on the benefits of circumcision, but few had expected such a profound effect. A previous meta-analysis of the numerous observational studies found a 42% reduction in the risk of HIV infection.
This study enrolled over 3,000 men between the ages of 18 and 24 in an urban area on the outskirts of Johannesburg, known as Orange Farm, who were randomized to be circumcised immediately or to defer circumcision until after 21 months. Both groups received intensive counseling on risk reduction at each study visit (planned for 3 months, 12 months, and 21 months following their initial visit) and were treated for sexually-transmitted infections (STIs). Of 69 new HIV infections during the trial, 51 occurred in the control group and only 18 in the circumcised men.
While many in the prevention field were excited by this result, the researchers as well as officials from the WHO and UNAIDS stressed the need for caution by urging governments to await the results of other ongoing prospective studies before making recommendations on circumcision. "More research is needed to confirm the reproducibility of these results in differing social and cultural contexts," says Catherine Hankins of UNAIDS.
Three similar studies to the ANRS trial are currently in progress, two in Uganda and one in Kenya. The US National Institutes of Health is sponsoring one in each country and the Bill & Melinda Gates Foundation is sponsoring another in Uganda that is enrolling 800 HIV discordant couples to monitor the effects of circumcision on male-to-female transmission. The NIH trial in Uganda, the largest to date, has already enrolled 5,000 men, but the earliest results of these trials are not expected until 2007. No trials have yet looked at the effect of circumcision on transmission in men who have sex with men.
A recently-published cross-sectional study (J. Acquir. Immune Defic. Syndr. 39, 576, 2005) conducted by the Centers for Disease Control and Prevention (CDC) provides additional support to the protective effect of circumcision. This study found that men in HIV-infected male/female concordant couples were 11 times more likely than men in discordant couples to be uncircumcised. This study included 126 discordant couples and 40 sero-concordant couples in Kampala, Uganda.
Although Auvert emphasized the simplicity of the procedure in the context of the study—"You just pull it, clamp it, and cut it"—offering this intervention on a large scale would be difficult. Many public health experts fear that the high rate of protection offered in the South African study could encourage men to have circumcisions outside of a supervised medical facility, putting them at greater risk of HIV infection. WHO is currently formulating guidelines on safe circumcision practices to avoid this situation.
Researchers are also concerned that circumcised men will feel a false sense of protection and increase their risk behaviors—discontinuing use of condoms or increasing their number of sexual partners—referred to as disinhibition. There are also many lingering questions about how acceptable circumcision will be in cultures and religions that typically discourage the practice. "If this trial is confirmed by others, then it would be an important advance for prevention," says Helene Gayle, president of the IAS. "But it should not be implemented until we have further information. There is no one thing that is going to make all the difference in prevention."
More prevention alternatives
Of equal importance is reducing male-to-female transmission, and for this scientists are testing an old mainstay in the field of reproductive health: the diaphragm. A Gates Foundation-funded study to evaluate the diaphragm’s ability to protect women from becoming HIV infected is being led by Nancy Padian of the University of California, San Francisco and is approaching full enrollment at sites in South Africa and Zimbabwe. A total of 4,500 women will be randomized to either the diaphragm or the control group and followed for four years. Both arms of the trial will receive risk-reduction counseling and be encouraged to use condoms.
This study is sparking enthusiasm among prevention researchers because of the simplicity of using the diaphragm, which is already approved and available. It is much more discreet than male or female condoms, can be inserted without a partner’s knowledge, and can be used repeatedly.
Researchers also hope that this study will answer critical questions about the role the cervix plays in HIV transmission. Diaphragms have proven effective at preventing other STIs like chlamydia and trichomoniasis because the rubber disc acts as a physical barrier that protects the cervix, which is also considered a focal point for HIV infection. The epithelium of the cervix has a much thinner surface than the vagina, making it more susceptible to infection. It is also packed with dendritic cells that can enhance HIV transmission. Padian hopes that shielding the fragile surface of the cervix and stopping viral particles in semen from reaching the upper genital tract will offer some protection against HIV.
Another innovative approach to prevent HIV transmission is using oral prophylaxis with ARVs, a strategy that is referred to as pre-exposure prophylaxis (PREP). The idea of taking ARVs to prevent infection is well established and short-term use after exposure to HIV—such as during childbirth or after accidental contact with HIV-infected blood from a needle stick injury—is a common and effective way to avert HIV infection. PREP extends this approach by offering people ARVs even before exposure.
This concept received great attention at the Rio meeting, despite a dearth of data in human trials. Most of the discussion about PREP concerned the recent closure of two trial sites because of concerns among activists and participants about the ethics of the study. These trials were evaluating the efficacy of the drug tenofovir, manufactured by Gilead Sciences, to prevent individuals at high risk (men who have sex with men, commercial sex workers, and IDUs) from contracting HIV. One study being run by US-based Family Health International (FHI) involving sex workers in Cameroon was recently closed after a 5-month suspension, but both FHI and the CDC are sponsoring other Phase II studies with tenofovir.
Joep Lange of the University of Amsterdam explained the scientific rationale for PREP at a special session. The initial Gilead studies in 1995 showed prevention of infection in long-tailed macaques that received a daily subcutaneous injection of tenofovir (then called PMPA) for four weeks and were challenged with a single intravenous dose (10 ID50) of SIV. Lange also highlighted the most recent animal data, which was presented earlier this year at the 12th Conference on Retroviruses and Opportunistic Infections. In this study Chinese rhesus macaques received an oral dose of tenofovir either once daily, once weekly, or not at all, and were then challenged weekly by rectal exposure to SHIV SF162P3. All animals eventually became infected, but the onset of infection was delayed in monkeys given tenofovir. Infection required at least six SHIV inoculations for monkeys receiving tenofovir, whereas only a single viral challenge was sufficient to infect the controls.
Lange refers to this recent data as "somewhat less rosy" and warns that "PREP is not a universal panacea" for HIV prevention. Still, many in the public health field eagerly await the results of human trials. And the idea of PREP should extend beyond tenofovir, advises Kenneth Mayer of Brown University, who predicts that the future of PREP may rest in combination therapy. "Using a single drug to prevent infection may not work any better than using one drug for treatment."
Understanding immune responses
Despite the lack of critical breakthroughs in the search for an effective AIDS vaccine, some studies presented in Rio did provide some insight into the nature of the immune responses that could be protective against HIV infection.
Sarah Rowland-Jones of Oxford University presented a study of post-natal HIV transmission through breast feeding to gain insight into whether a vaccine that induces cell-mediated immune responses might be able to prevent HIV infection. This collaborative trial with Julie Overbaugh’s lab at the University of Washington enrolled 510 mother/infant pairs in East Africa. The women were all HIV-infected and received ARV prophylaxis during labor and delivery to prevent transmission to their children. Any women that chose not to breast feed in this study were offered a milk-substitution free.
The majority of infants that acquired HIV did so during the first month, making it difficult to determine if the infection was a result of exposure during childbirth or from breast milk. But of the children that remained uninfected at a month, Rowland-Jones and her colleagues found a direct correlation between their T cell responses and the likelihood of acquiring HIV through their first year of life, suggesting that the immune responses in the infants are able to protect them from HIV infection even during continual exposure to the virus. Rowland Jones is optimistic about this study. "It shows that young children can mount a cellular immune response and that it can be protective," she says. "It’s simply a correlation, but it’s encouraging."