More than 100 new medicines against AIDS and AIDS-related conditions are currently being tested in various clinical trials. These medicines promise to enhance the pipeline of more than 60 drugs already in use against the disease. Despite the progress, however, it is important to remind ourselves just how staggering this disease is in terms of its socioeconomic impact.

Each day, about 16,000 people worldwide are infected with the virus, with 95% of new cases occurring in developing countries (mostly Africa). More than 2.6 million people died of AIDS in 1999 alone¹—the highest reported toll since data gathering about the disease began in the early 1980s. With numbers such as these, AIDS has attracted vast resources from governments, universities, and industry the world over for the single purpose of controlling, preventing, and ultimately curing the disease.

There have been many descriptions and accounts regarding the discovery of the HIV virus, its variants and origins, and of the progress against the disease, which will not be covered again here. However, a reminder of its incidence and prevalence is necessary, if only to emphasize the toll it has taken. At the present time, no cure exists for AIDS. Few patients live beyond five years following initial diagnosis. On average, patients first diagnosed with AIDS have an 18- to 24-month life expectancy, although this is increasing dramatically with new treatments. However, there are many exceptions, with reports of people living with HIV for 10 years or more.

According to the American Medical Association, approximately 1 in every 100 adults worldwide between the ages of 15 and 49—about 45 million people in all—is infected with HIV. More than 75% of all adult HIV infections have resulted from heterosexual intercourse. About 43% of adults living with AIDS worldwide are women, and this proportion is growing. And of the more than 2.6 million people who died of AIDS-associated diseases last year, an estimated 550,000 were children under 15 years of age. Finally, mother-to-child transmission is responsible for more than 90% of all HIV infections around the world in infants and children¹.

As AIDS compromises the body's immune system, a wide variety of opportunistic infections and other illnesses can and often do occur. These AIDS-related complications span the gamut of diseases and include protozoal infections (Pneumocystis carinii pneumonia, toxoplasmosis, Cryptosporidium -associated enterocolitis, giardiasis), fungal infections (esophagitis candida, cryptococcal meningitis, coccidioidomycosis, histoplasmosis, aspergillosis), bacterial infections (pulmonary tuberculosis, atypical mycobacterial infection, disseminated tuberculosis, recurrent bacterial pneumonias), viral infections (herpes simplex virus, cytomegalovirus, Epstein–Barr virus, varicella-herpes zoster), malignancies (Kaposi's sarcoma, lymphoma, cervical cancer), AIDS-related dementia, and also the so-called wasting syndrome. These complications often occur at the same time, making treatment of the symptoms as well as the causes a complex balancing act. This is one of the biggest challenges facing those involved in combating the disease.

The other major challenge is combating the virus itself along different points in its life cycle. This is complicated by the fact that there is emerging drug resistance and that the very promising in vitro data simply do not transfer to human patients. Nevertheless, one way to address these challenges is to have as many approaches as possible. Table 1 lists a selection of companies and their various AIDS programs in US clinical trials, illustrating that there are indeed many efforts addressing both challenges.

What's more, despite all the progress, physician experience with managing and treating the disease is still highly variable. For example, a recent study reports on how more experienced physicians adopt new antiretroviral therapy earlier than less experienced physicians, and this may affect patient outcomes².

Finally, it is still not clear whether AIDS patients should be administered aggressive and early versus longer-term treatments. At present, early treatment aims to suppress AIDS-related viremia as aggressively as possible. However, early and aggressive therapy often leads to side effects and to the emergence of resistance. Possible alternatives include protease-sparing therapy, delayed initiation of therapy, class-sparing therapy, regular drug interruptions, frequent switches in therapy, and immunotherapy².

Future directions in AIDS research and treatment were discussed extensively at the 7th Conference on Retroviruses and Opportunistic Infections in San Francisco in February 2000. The following are some salient summary points from the conference.

Central to the management of HIV is the issue of the viral reservoir, or what remains of the viral load during and after treatment, which may lead to recurrence of viral replication. Although current and very potent therapy can decrease the viral load in plasma to undetectable levels, HIV remains in the central nervous system, the genital tract, the gastrointestinal tract, or bound by follicular dendritic cells (FDC), and virus is released from FDC at an order of magnitude higher than from infected peripheral T cells. This release may account for the two phases of HIV's decay from plasma following aggressive therapy, and points to additional avenues for therapeutic discovery and development.

In addition to what happens to the viral load, critical issues surrounding the pathogenesis of HIV itself remain and abound. For example, the actual dynamics or kinetics of the trafficking of HIV and immune cells through the lymphatic duct are under intense scrutiny. Here, macaques infected with the simian immunodeficiency virus (SIV) have proved to be an invaluable model, as they allow the quantitative tracking of both the virus and its target cells through the body, which may lead to novel types of intervention.

In terms of immunotherapy approaches against the virus, which are currently a central strategy aimed at eradicating the disease in the future, there are more than 70 vaccine candidates in animal or human clinical trials. Examples include a gag DNA vaccine alone or with interleukin-2 (IL-2), the IL-2 as an immunoglobulin (Ig) fusion protein or as an IL-2–Ig plasmid, vaccines based on the canarypox vector, and many others (see Table 1).

Immunotherapy aims to protect against the HIV infection and prevent it, but reconstituting immune function after infection remains a major goal in the fight against HIV. Here, the thymus plays a very important role. At present, there are difficulties in defining actual markers of thymic output, which is a central measure of immune system reconstitution in AIDS. There are significant efforts underway to correlate such markers with disease progression and response to various regimens, and much work remains to be done in this regard.

Finally, there are several additional targets for anti-HIV drug development, in addition to the surface glycoproteins, reverse transcriptase, and others. So-called fusion inhibitors are receiving attention, as are the HIV accessory gene products (Vpr, Vpu, Nef). Targeting these additional HIV proteins promises to open up new avenues as well as help overcome the problem of resistance.

The future will also see continued efforts to develop effective rotation and combination therapies. For example, the benefits of zidovudine treatment are reduced after several years, and a recent study reports how this effect can be countered by switching from zidovudine to stavudine or adding lamivudine to the zidovudine treatment⁴.

In addition to drug advances, the future will also see increased attention being given to the benefits of a positive mental outlook as a fundamental component of the fight against the disease. For example, a recent study found significant increases in the white blood cell count of patients who were trained in positive mental imagery methods and approaches derived from cognitive psychology, compared to control patients who did not use these approaches⁵.

Finally, the future will also see the continued elucidation of the interplay between HIV activation in vivo and host cytokines. For example, a recent study shows suggests how selective suppression of tumor necrosis factor- (TNF-) and IL-1 could slow down HIV-1 gene activation and thus slow down progression of the infection⁶. Given the critical role of cytokines in the overall functioning of the immune system, these types of studies are critically important towards the continued understanding of the virus and its effect on the host.

More is known about the HIV virus than about any other virus. There are numerous drugs that have helped slow the progress of the disease, and massive education efforts are having some impact on the overall incidence and prevalence, although with the overwhelming number of new cases, the results are hardly satisfactory. Nevertheless, no effective cross-protective vaccine is in sight. Developing a vaccine continues to be the centerpiece of research efforts, but there are numerous other targets being pursued, which will result in more effective treatments of the disease in the near future.