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Over 25 years into the AIDS pandemic, it’s shocking that we have so few methods of preventing the transmission of HIV.
The ABC approach—abstinence, be faithful, use condoms—does not a full prevention toolbox make. Abstinence is a time-limited option for most of us, and one which vulnerable populations, such as women, gay men, and males who have sex with males, don’t always have the choice to make. Being faithful is actually a risk factor for many women around the world who are in fact infected by their husbands or significant others. Being faithful takes two. And condoms, while the gold standard of prevention with an efficacy rate around 98% when used consistently and correctly, are not utilized regularly by many of us due to a whole host of factors, ranging from lack of access to the inability to negotiate their use to the simple human desire to have natural sex without a latex barrier. It’s how we make babies, after all.
How is it that we have been satisfied with these extraordinarily limited options for something so important? Why do we think condoms are somehow enough? Would you be satisfied having only to choose between caf or decaf at the local Cari-bucks?
Of course, we also have voluntary counseling and testing, HIV care and treatment for people living with HIV/AIDS, as well as genital STD testing, diagnosis, and treatment. However, while these prevention strategies are effective, they have not been sufficiently resourced or ramped up to slow the rate of infection.
According to the 2006 UNAIDS Global Report, 4.1 million new HIV infections occurred worldwide in 2005 with around 8,000 deaths a day attributed to the disease. In the United States, we see between 40,000–60,000 new HIV infections annually. We have been at this plateau for years, since the advent of highly active antiretroviral therapy (HAART). Clearly, there is an urgent need to provide more options for people to protect themselves.
So, while the hype on new prevention strategies dominating the XVI International AIDS Conference held in Toronto this past August was arguably a bit overblown and perhaps too focused on biomedical, technological solutions, the enormous attention paid to exploring novel methods to supplement our prevention toolbox was welcome. Many of us working in the field are more accustomed to prevention being treated like the dirty stepsister who never gets to the ball rather than the star of the show, so it was admittedly thrilling to be front and center even as we attempted to diffuse the “magic bullet” reporting.
Microbicides, pre-exposure prophylaxis (also known as “PrEP” but re-coined “oral prevention”), and male circumcision each received significant attention throughout the conference at plenaries and numerous sessions, and transfixed the media. Sound bites provided by heavy hitters like Bill and Melinda Gates and former president Bill Clinton catapulted the discussion of new prevention technologies beyond the fringe into the front pages of your local daily and were featured in the health segments of television and radio programming from Albuquerque to Auckland.
In an important plenary session held August 15th titled “Prevention: Proven Approaches and New Technologies,” Dr. Gita Ramjee, director of the South African Medical Research Council’s HIV Prevention Research Unit, laid out the potential, the promise, and the challenges associated with the research and development of microbicides, oral prevention, and the proof, as well as the polemic, around the preventive effect of male circumcision.
Super Lubes
Microbicides are products currently being researched that would provide protection against HIV in the absence of condoms. A microbicide might kill or inactivate the virus, form a barrier between the body and the virus, create an environment that is inhospitable to the virus, or otherwise disrupt the virus in ways that make it unable to take hold and replicate in the host body. Some may have contraceptive qualities while others may allow conception. Microbicides are currently being formulated as lubricants, gels, or creams and would need to be inserted vaginally or rectally prior to intercourse. In the future, delivery systems for a microbicide may include things like sponges, vaginal rings, douches, or enemas that may not be coitally dependent.
One of the most important qualities of a microbicide is that it will be controlled by the receptive partner. For women—who must negotiate all current prevention methods with their partner, and often do not have the ability to decide when they will have sex, let alone negotiate condom use with a male partner—having a tool in their control will be a major breakthrough.
There are currently four “first generation” products in Phase III, large-scale efficacy clinical trials. Most of these studies are being conducted in high-prevalence populations in Africa, though Philadelphia is a location as well. All products are vaginal formulations; three would form a barrier between the body and the virus (Carraguard, Pro 2000, Cellulose Sulfate) and the other (BufferGel) boosts the vagina’s natural defenses as a deterrent to HIV. We expect to start seeing results from some of these trials in December 2007.
Determining a vaginal microbicide’s efficacy is challenging and the results of Phase III trials difficult to determine when confounded by pregnancy, other risk factors (such as anal intercourse and injection drug use), and the very fact that participants in the trial receive superior HIV prevention information, ready access to condoms, and STD testing, diagnosis, and treatment. Cellegy Pharmaceuticals closed the USAID-funded trial of the microbicide called Savvy at the end of August because the data the trial was generating was deemed to not be statistically significant. The data monitoring committee observed a “lower-than-expected” HIV transmission rate in the trial, “which was less than half of the expected rate,” according to the company. Essentially, it was not clear if the microbicide was working, or if the condoms made available to the participants were working. The trial’s disappointing demise means the vulnerable microbicide development pipeline went from five promising candidates in Phase III trials down to the current four.
Rectal microbicide research is under-funded and has mostly focused on pre-clinical work in the lab and on acceptability and behavioral studies. However, there is great news for advocates and the large numbers of men and women who engage in anal intercourse globally. This fall, the University of California at Los Angeles will launch the first Phase 1 safety trial of a rectal microbicide called UC-781, meaning the first human study testing an actual product. It is a topical application of an antiretroviral therapy that was formulated for vaginal use but will be tested among men and women for rectal safety.
This is historic and a huge advance for the young and struggling rectal side of the microbicide field. Even though we know there is a demand for rectal microbicides among women, gay men, and males who have sex with males—all vulnerable populations—and that a large amount of HIV incidence is due to unprotected anal intercourse (10–100 times more likely to transmit HIV compared to unprotected vaginal intercourse), the stigma, homophobia, denial and other political and sociocultural barriers to the topic of anal intercourse have hindered research and created a strong disincentive for scientists.
Daily Dosing
Oral prevention, commonly referred to as pre-exposure prophylaxis (PrEP), was another hot topic in Toronto. The idea here is that high-risk negative individuals would take an anti-HIV drug once a day to prevent the acquisition of HIV. We already have proof of concept with the practice of delivering a dose of AZT prior to delivery to avoid mother-to-child transmission and in the case of preventive medicines for malaria.
Tenofovir (Viread) and Truvada (which contains Viread and Emtriva), both nucleoside reverse transcriptase inhibitors, are being studied in a number of safety and efficacy trials—among male and female injection drug users in Thailand; among males who have sex with males in the U.S. and Peru; and among heterosexuals in Botswana. Three studies have ended prematurely. Ethical questions, and controversy, regarding community involvement in trial design and access to HIV treatment health care post-trial, halted studies in Cameroon, Malawi, Nigeria, and Cambodia—some before they even started.
The trials—data from which may start coming as early as this year through 2009—will not only try to prove efficacy, but will also obtain information about safety, including assessments of renal function, liver health, bone mineral density, drug resistance, viral load, and CD4 T-cell counts after seroconversion, antiviral immune responses, adherence patterns, drug levels, and interactions with hepatitis B viruses (Viread is effective against hep B). A key issue will be the implications of breakthrough infections with resistant virus for future therapy options.
Other issues of concern include the acceptability of long-term medication regimens for otherwise healthy people and for the potential of “abuse” among those who will not or cannot use condoms. Will oral prevention give people reason to increase high risk behaviors? This is an important question, and the research is supposed to be assessing risk behavior and the incidence of sexually transmitted infections to determine whether risk behavior increases or decreases during the study period. While risky behavior has been observed to decrease after post-exposure prophylaxis, likely reflecting the counseling and condoms provided to all recipients, further research will be warranted to best convey the recommendations and counseling necessary for oral prevention to be both effective and safe.
Cost and access to oral prevention will also be a huge issue if we indeed determine safety and efficacy. As we all know, HIV drugs are not cheap, so just who will be able to choose oral prevention and who simply won’t have the cash? Will insurance cover oral prevention? And will governments and foundations pay to roll this expensive option out in the developing world (where, let’s be honest, we have done horribly providing cheap, scientifically proven condoms)?
While we must ensure microbicides are cheap and over the counter, we also need to be busily planning for their access and distribution. Like condoms, just being cheap and effective won’t mean they will magically get into the hands of women and men who will need them to save their lives, and the lives of those they love. The real work will begin once we have a product available.
Snip, Snip
Finally, the last big “new” prevention technology that burned up the airwaves out of Toronto, and caused not a few men to wince, was male circumcision. Male circumcision refers to the removal of the foreskin from the penis. The inner mucosa of the foreskin is more susceptible to HIV and other sexually transmitted infections, and has a higher density of Langerhans cells that HIV targets compared to the dry external skin surface. Lack of foreskin is correlated to lower risk of HIV.
Three randomized, controlled clinical trials are currently in process or have recently been concluded in Africa to determine whether circumcision of adult males will reduce their risk for HIV infection. One of these studies, in South Africa, was actually terminated in 2005 because an interim analysis showed a strong protective effect of circumcision. Men who had been randomly assigned to the circumcision group had a 76% lower HIV incidence compared with men who had been assigned to a wait-list group to be circumcised at the completion of the study.
Two other studies—in Kenya and Uganda—finished enrollment in 2005 and are scheduled to be completed in 2007. Epidemiological evidence points to lower HIV prevalence in men who are circumcised and a meta-analysis conducted in 2000 in 38 (mainly African) studies indicated a lower risk of HIV acquisition among circumcised men.
So, that’s a pretty strong case for the “snip, snip.” However, a number of safety and ethical challenges, as well as cultural and religious acceptability issues, variable from country to country, will need to be addressed before we can move a proposed intervention like this from science-based evidence to a massive public health undertaking.
In a relatively low prevalence country like the U.S., where most men are already circumcised, it seems unlikely that this item on the prevention buffet will ever be offered in a large, systematic way. Besides, the studies on male circumcision have been conducted in countries where the majority of HIV transmission occurs in a penile/vaginal context (though this is debatable, as the prevalence of anal intercourse is unappreciated.)
In the U.S., the majority of HIV transmission occurs due to unprotected penile/anal contact among males who have sex with males. For these reasons, the U.S. Centers for Disease Control and Prevention (CDC) currently have no recommendations around male circumcision as a means of preventing the transmission of HIV.
In Sub-Saharan Africa, widespread implementation of male circumcision could avert two million HIV infections over the next 10 years. That’s a lot of fathers left to help care for their families, a lot of human suffering averted. While there are concerns about over-confidence in the protective benefit of circumcision, this option should certainly be considered where appropriate if the other clinical trials also point to strong efficacy.
And it is this point that sums up the importance of all these new biomedical prevention technologies. None will be the “answer” or act as the so-called “magic bullet.” All have their drawbacks. What microbicides, oral prevention, and male circumcision will offer are new, much-needed tools to our sparse prevention armamentarium. They will complement, rather than replace, the tools we already have at our disposal. Of course, none of these “techno-fixes” will solve the issues of women’s lack of power and social status, or the fact that poverty, racism, homophobia, and stigma are the real drivers behind this epidemic, but they will allow us time—if we are up to this mammoth task—to ramp up the political, sociocultural, and financial resources to fight HIV honestly… and have someone left to be fighting for. |
