AIDS Agenda Still Daunting
Fifteen years ago, the research agenda delineated in these pages regarding the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) stressed the importance of a diverse and robust scientific portfolio. It included basic studies of the molecular biology, natural history, epidemiology, and pathogenesis of HIV, as well as applied research to develop therapies for HIV-infected individuals and effective ways of preventing transmission of the virus.
Today we can look back with some satisfaction on the many advances in HIV/AIDS research that have emanated from these areas. Of particular importance have been the rapid development of antiretroviral drugs that can limit HIV replication and immune system damage, and the formulation of strategies and clinical guidelines for the use of these medications. Combination therapy with potent antiretroviral drugs–commonly called highly active antiretroviral therapy, or HAART–has helped to dramatically reduce AIDS-related morbidity and mortality in developed countries. In the United States, for example, the estimated annual number of AIDS-related deaths fell approximately 70 percent from 1995 to 2001, largely because of the widespread use of HAART among patients with advanced HIV disease.
In addition to their role in the treatment of HIV-infected individuals, certain antiretroviral drug regimens also have been shown in both developed and developing countries to dramatically reduce the risk of HIV transmission from mother to child. The risk factors associated with HIV transmission have been well defined, and tools of prevention deployed to some extent in most nations of the world. In virtually all developed nations and in certain developing countries, such as Uganda, Brazil, and Thailand, HIV prevention has proven effective in slowing the spread of the virus. Interventions employed successfully have included mass media campaigns; voluntary HIV testing and counseling; education and outreach to at-risk populations; drug abuse treatment; behavioral modification programs, such as the promotion of abstinence; abbreviated courses of antiretroviral drugs to prevent mother-to-child transmission of HIV; and condom promotion and distribution.
Progress, but work remains
Despite significant progress in HIV treatment and prevention, however, HIV and AIDS continue to exact an enormous toll throughout the world. Indeed, the pandemic is accelerating in some countries and regions, including China, India, and parts of Eastern Europe and central Asia. As of the end of 2002, an estimated 42 million people worldwide were living with HIV/AIDS, and more than 20 million people with HIV/AIDS had died, according to the Joint United Nations Programme on AIDS. In 2002 alone, HIV/AIDS-associated illnesses caused the deaths of approximately 3.1 million people, including more than 600,000 children aged 14 years or younger. More than 95 percent of these infections and deaths occurred in developing countries, many of which also are burdened by other significant health challenges, including famine and endemic diseases such as malaria and tuberculosis. In these nations, HIV/AIDS threatens not only human welfare, but social, political, and economic stability as well.
Even in countries that have managed to slow the spread of the virus, rates of new HIV infections continue at an unacceptably high level. In the United States, the Centers for Disease Control and Prevention estimates that HIV incidence has leveled off, but at an unacceptable plateau: 40,000 new infections annually, with minority communities disproportionately affected.
Clearly, much remains to be accomplished in the global fight against HIV, both in terms of the scientific and medical challenges of HIV and the logistical and operational challenges of making HIV therapies and other interventions available to poor countries. A vaccine that prevents HIV infection or at least slows the progression of disease is badly needed, but still lacking. The reasons for this relate to formidable obstacles faced by vaccine developers, including the virus’s genetic diversity and the lack of a clear understanding of the correlates of protective immunity in HIV infection. Nonetheless, government, academia, industry, and philanthropies are mounting significant efforts, including projects involving cross-sector partnerships and collaborations. Numerous promising HIV vaccine candidates are in various stages of preclinical and clinical development. Several novel vaccine candidates, including recombinant viral vectors that express HIV proteins and DNA vaccines, have shown considerable promise in nonhuman primate models of HIV and are rapidly being moved into human clinical trials around the world.
Concurrently, researchers are testing a diverse range of novel HIV prevention strategies, including new barrier methods and topically applied microbicides that individuals could use to protect themselves from HIV and other sexually transmitted pathogens. Basic research continues apace, as investigators home in on the host and viral factors in HIV that will help inform vaccine and therapeutics development.
The development of a next generation of therapies also remains a priority. Unfortunately, many HIV-infected individuals have not responded adequately to current medications, cannot tolerate their toxicities, or harbor virus that has developed resistance to them. Currently, all but 1 of the 20 antiretroviral medications licensed in the United States target one of two HIV enzymes: reverse transcriptase or protease. However, many new drug targets and novel treatment strategies are now being pursued. Among them are inhibitors of the viral integrase that block viral genes from entering the host cell nucleus, and agents that keep the virus from attaching to or entering the cell in the first place. In the latter category, a drug known as Fuzeon (enfuvirtide), which blocks the fusion of HIV to the host cell membrane, was recently approved and holds considerable promise for treatment-experienced patients who have run out of treatment options because of drug resistance.
Benefits lag in developing world
Although HAART has dramatically changed the prognosis for HIV-infected patients in developed countries, little of this benefit has been realized in the developing world, largely because of the high price of HIV medications and the lack of a sufficient health care infrastructure to deliver them. Fortunately, this situation is beginning to change. In the past several years, many scientists, policymakers, public health officials, and activists have articulated the compelling social and moral imperative for treating HIV-infected individuals who need therapy, regardless of their socioeconomic status. International organizations, governments, philanthropies, academic researchers, activist groups, and pharmaceutical companies have mobilized significant resources and have shown that HIV care and prevention services can successfully be delivered, even in resource-poor settings.
In addition, there is an increased recognition that the acceptability and effectiveness of HIV prevention programs depend on the availability of treatment. In the past, attempts at pursuing prevention efforts in resource-poor settings, such as sub-Saharan Africa, have been hampered by the fact that little could be offered to the people who participated in such efforts. Now, with dramatic reductions in the price of HAART and greatly increased funding for the health infrastructure needed to reach HIV-infected patients with HAART, it has become feasible to pursue a comprehensive approach to the AIDS pandemic in poor countries, linking the provision of anti-HIV therapy to efforts in prevention and care.
A truly comprehensive approach to HIV disease will require not only developing and implementing better treatment and prevention efforts, but also overcoming the stigma and discrimination frequently associated with HIV infection. Unlike many individuals afflicted with other chronic diseases, people with HIV frequently face prejudice and even physical violence. In certain communities in the United States, as well as abroad (especially in developing nations), HIV-infected individuals are shunned by their friends and co-workers and even their own families. For a person living with HIV, institutional discrimination also can be harrowing, as they may be denied housing, employment, or insurance.
The medical consequences of stigma and discrimination are serious as well, because people may avoid lifesaving treatment and suffer needlessly because of fear. In addition, the psychic toll of isolation and ostracism can be profound. From a public health perspective, stigma and discrimination are particularly problematic, because at-risk people may avoid HIV testing altogether. Not only will untested, infected people miss the opportunity for needed treatment, but they also will be less apt to access prevention programs that could help them avoid infecting others with HIV.
We are at a pivotal point in the HIV/AIDS pandemic. We know that HIV treatment and prevention, when appropriately applied, can be enormously effective, and that the next generation of therapies and prevention tools is within reach. Now we must overcome the financial and logistical challenges, as well as those posed by stigma and discrimination, to make the availability of HIV treatment and prevention the rule, not the exception, for all the citizens of the world, rich and poor alike.
Gregory K. Folkers ([email protected]) is a researcher and Anthony S. Fauci is director at the National Institute of Allergy and Infectious Diseases.