New approaches and resolve may define the future of the global HIV pandemic.

More than 25 years since the first cases of AIDS were described, there continue to be grim reports of the growing global pandemic. These include an estimated 40 million HIV-infected people, with approximately 4 to 5 million new infections per year and little evidence of a decline in the rate of infection. In addition, despite ongoing research to define the immunopathogenesis of HIV disease, there remains little hope in the near future for the development of an effective preventative vaccine. On a more positive note, the year 2006 represented the 11th year in which potent combination antiretroviral therapy has been routinely used in the richest countries. Even more importantly, this past year may be remembered for pivotal events in research related to both treatment and prevention that may define the future of the HIV/AIDS epidemic for both rich and resource-limited parts of the world.

For the wealthy countries, antiretroviral therapy has continued to become increasingly well tolerated by patients, relatively easy to administer, and associated with virologic suppression in the overwhelming majority of individuals starting treatment for the first time. (1) From a psychological and emotional perspective, the pinnacle of this success was the availability of a single pill: once-daily therapy given as the fixed-dose combination of tenofovir DF/emtricitabine/efavirenz. Despite this progress, there are still those who experience virologic failure and others who have been on treatment for many years with the emergence of highly drug-resistant HIV that limits their ability to achieve viral suppression. For these individuals, other new drugs have offered hope, particularly with regimens that include the fusion inhibitor enfuvirtide, which is the first available agent in a novel class since the development of protease inhibitors. (2-4) Nevertheless, there remain many who cannot tolerate available treatments or have viruses so resistant that even these new advances are insufficient to allow for long-term virologic suppression.

The past year will likely be remembered as one that ushered in an extraordinary array of novel therapeutics, including several in new classes.5 In fact, by the end of 2006 in the United States, there were 2 new drugs available in expanded access that offered options for treatment-experienced individuals, one of which was etravirine, a "second generation" non-nucleoside reverse transcriptase inhibitor, and the other MK0518, an integrase inhibitor. Integrase inhibitors are a new class of drugs that are expected to have activity against the virus of even the most treatment-experienced individuals. In addition, another agent in a new class, maraviroc, the chemokine receptor (CCR5) inhibitor, will be available through expanded access during the early part of 2007. There are also other drugs in the integrase and CCR5 inhibitor classes that are in development, and additional promising new classes, such as maturation inhibitors, are being actively evaluated in clinical trials. Assuming results from studies underway prove to be as promising as hoped, these advances may offer extraordinary opportunities for those in need of new treatment options. In fact, these drugs could make the goal of achieving full virologic suppression in previously difficult-to-treat individuals the norm, as it has become in those starting therapy for the first time.

Another milestone during the last year was the unprecedented expansion of programs to roll out potent antiretroviral therapy to resource-limited settings. This advance has in part been made possible by dramatic reductions in the cost of treatment, as well as increased training of local health care providers. Furthermore, preliminary studies have demonstrated high levels of adherence amongst those who were first to access treatment in resource-limited countries, in addition to an associated decline in mortality mimicking that seen with the introduction of protease inhibitor-based regimens in the developed world. (6,7) Only time will tell whether the world's resolve will be sufficient to address the many challenges associated with treating millions of people in resource-limited settings, particularly in meeting the recently established goal of universal access to HIV care by 2010 as proposed at the 2006 G8 summit.

The alarming rate of new infections throughout the world remains an enormous problem that has been inconsistently addressed with current prevention programs such as voluntary counseling and testing and ABC (abstinence, be faithful, and condoms). Moreover, it is increasingly clear that a preventative vaccine is not on the immediate horizon. In 2006, the scientific community took major steps towards establishing novel prevention strategies that do not rely on changing behaviors or the development of a vaccine. Instead, the prevention field has re-evaluated the potential impact of pharmacologic and biologic strategies. After all, one of the greatest advances in the history of the epidemic is the ability to use antiretroviral therapy to prevent mother-to-child transmission. It has been suggested that the benefit associated with reducing maternal viral load and prophylaxing the baby with antiretroviral therapy to prevent maternal-fetal transmission could be used to prevent sexual transmission. This is supported by the observation that increased plasma HIV RNA is associated with the enhanced risk of transmission amongst serodiscordant couples. (8) Together, these observations have led to studies assessing the impact antiretroviral therapy might have on sexual transmission. This includes studies of pre-exposure prophylaxis, a controversial yet innovative means of avoiding transmission by administering antiretroviral drugs to uninfected individuals prior to potential exposure. Even more intriguing is the possibility that sexual transmission of HIV might be reduced by increasing the number of individuals on treatment, a potential public health benefit of the global rollout of antiretroviral therapy. (9) Needless to say, the benefits of such strategies might be countered by changes in risk-taking behavior, increased transmission of drug-resistant virus, and drug-related toxicity.

Since the stakes are high and outcomes unpredictable with all prevention strategies, it is exciting to note that the field is not resting its hopes on any one modality. Instead, several pharmacologic and biologic interventions are simultaneously being pursued with the hope that any one or several could impact the growing epidemic. Novel prevention strategies are attempting to exploit new technologies, as well as what we have learned about cofactors for transmission. For example, studies are evaluating the safety and efficacy of microbicides, perhaps more aptly referred to as agents that can prevent infection at the mucosal level during vaginal intercourse. If initial studies show promise, women would be empowered to protect themselves. Moreover, this modality could be extended to protect against transmission during anal intercourse. Other interventions focus on the relationship between HIV transmission and the presence of sexually transmitted diseases. In this case, studies can be designed to assess the benefit of more aggressive treatment and/or suppression of these infections.

Finally, the past year may forever be remembered as a time when epidemiologic observations of the biologically plausible relationship between male circumcision and reduced risk of acquiring HIV infection were confirmed by randomized controlled trials. One study was published and 2 others recently closed because of a marked reduction in heterosexual HIV acquisition by circumcised men compared to uncircumcised controls. (10) Further study is still needed to determine whether male circumcision of an infected individual will reduce transmission to others, as well as whether such strategies can be safely implemented in resource-limited areas. Regardless, the outcomes of these studies represent a major advance towards curbing the spread of HIV around the world.

While major breakthroughs in our understanding of HIV immunopathogenesis and the development of treatments occurred during the first 25 years of the HIV epidemic, it also became clear that there were major obstacles towards achieving curative treatment and the development of a preventative vaccine. As we look to the future, it is satisfying to note that the field has moved forward with improved treatment modalities that are better tolerated and increasingly available at relatively low cost to many resource-limited countries. Moreover, prevention efforts have expanded to consider the potential impact that universal access to antiretroviral treatment might have on the global pandemic. In addition, novel pharmacologic and biologic prevention strategies are moving forward, some of which have already demonstrated great promise. For these reasons, there remains great hope that the next 10 years will redefine the global HIV pandemic.

References

(1.) Gallant JE, DeJesus E, Arribas JR, et al. N Engl J Med. 2006;354:251-260.

(2.) Lalezari JP, Henry K, O'Hearn M, et al. NEngl J Med. 2003;348:2175-2185.

(3.) Hicks CB, Cahn P, Cooper DA, et al. Lancet. 2006;368:466-475.

(4.) Pozniak A, Saag M, Bellos N, et al. 12th Annual Conference of British HIV Association. Brighton, UK, March 29-April 1, 2006.

(5.) Reed C, Daar ES. Curr Infect Dis Rep. 2006;8:489-496.

(6.) Mills EJ, Nachega JB, Buchan I, et al. JAMA. 2006;296:679-690.

(7.) Goldie S J, Yazdanpanah Y, Losina E, et al. NEngl J Med. 2006;355:1141-1153.

(8.) Quinn TC, Wawer MJ, Sewankambo N, et al. N Engl J Med. 2000;342:921-929.

(9.) Montaner JSG, Hogg R, Wood E, et al. Lancet. 2006;368:531-536.

(10.) Auvert B, Taljaard D, Lagarde, E, Sobngwi-Tambekou J, Sitta R, Puren A. PLoS Med. 2005;2:e298.

Eric S. Daar is Chief of the Division of HIV Medicine at Harbor-UCLA Medical Center and Professor of Medicine at the David Geffen School of Medicine at UCLA in Los Angeles.