Loss of immune function argument for early therapy

Retrovirus conference studies resistance issues

After studying AIDS patients whose CD4 levels dropped below 50 cells, government researchers have discovered that some critical cells may be irretrievably lost as the disease worsens. This finding and others presented last month at the Fourth Conference on Retroviruses and Opportunistic Infections in Washington, DC, give added weight to the benefits of early treatment, says the head of the National Institute of Allergy and Infectious Diseases.

While protease inhibitor and interleukin-2 therapies that increase CD4 counts may boost the remaining CD4 clones, they appear to have little effect on the lost cell types, says NIAID director Anthony Fauci, MD.

"These findings argue for early intervention before elements of the immune system are permanently lost," he explains.

At the other end of the disease spectrum, NIAID scientists have discovered that patients who have a wide spectrum of CD8 cells have a slower progression of disease than those who have only a single subset of CD8 cells.

"We have found a clear correlation between the patterns of CD8 cell expansion during primary infection and how well a patient did clinically during the subsequent year or 18 months," Fauci notes.

Published in the January 1997 Proceedings of the National Academy of Sciences, the study followed 21 patients with documented primary HIV infection — the phase two to four weeks after infection, in which 70% of HIV-infected people suffer flu-like symptoms.1 Those who experienced an effective primary immune response — a broad expansion of CD8 cell subsets — had low levels of virus a year later and slowly progressed to disease. Those patients who had an ineffective primary immune response — expansion of a single subset of CD8 cells — had less success in controlling the virus, and showed high levels of virus six to 12 months later, Fauci explains.

Although scientists don’t know the exact reasons for these differences, they speculate that genetic factors may play an important role.

Other data presented at the conference also underscore the importance of treatment in the early stages of HIV disease. In a clinical trial conducted at Stanford University Medical Center, 10 patients with early-stage disease and preserved lymph nodes responded to treatment with saquinavir (Invirase) from 28 to 72 weeks, compared to 0 to 28 weeks for those in later stages of disease.

"This research shows that patients’ duration of response to protease inhibitor therapy may be increased if treatment is started while the lymph nodes are still intact," says Jonathan Schapiro, MD, lead investigator of the study and researcher at the Center for AIDS Research at Stanford Medical Center.

Here are highlights of other studies presented at the conference:

• Once a person becomes infected with HIV, the immune system response results in a short-term increase in virus in the plasma. But researchers have not known where virus comes from — whether from cells already producing virus, or cells that are latently infected.

In a study by NIAID scientists, answers to this question were revealed by injecting HIV-positive patients with tetanus shots and discovering two distinct "quasispecies" of HIV in their body. One type was found in the plasma, while another type was found in peripheral blood and lymph node mononuclear cells.

"These findings suggest that the increase in viremia following activation of the immune system is a consequence of mobilization of latently infected CD4 cells in the lymph organs, not merely an increase in virus replication in cells already producing virus," Fauci says.

• The Centers for Disease Control and Prevention reports that the incidence of AIDS among people aged 13-25 rose a modest 20% between 1990 and 1995. However, the increase was greater among certain populations — 130% among heterosexuals, 70% among women, and 50% among African-Americans. The incidence of AIDS among young white gay and bisexual males declined by 30%.

CDC officials warned of the critical need for HIV prevention programs targeted to each generation of young people, particularly those at high risk.

• Researchers have debated the effectiveness of HIV prevention counseling in changing behavior, but the first randomized trial to measure both behavioral and biological outcomes shows counseling does work.

Conducted at five inner-city STD clinics, the clients were assigned to one of three kinds of face-to-face interventions urging consistent condom use: education (two didactic sessions with brief HIV/STD prevention messages); prevention counseling (four interactive, client-focused sessions based on theoretical constructs of behavior change); or enhanced prevention counseling (interactive, client-focused sessions).

Preliminary results suggest that the two prevention counseling interventions were effective in increasing condom use and preventing new STDs.

• Last year, the Food and Drug Administra tion required blood collection centers to include HIV-1 p24 antigen testing to detect HIV-contaminated blood not picked up by antibody testing alone. After five months of testing, the CDC reports that only one infectious donation among 4.5 million tested donations would not have been detected through antibody testing alone.

During this period, 39 donors were found to have false-positive test results. The CDC concludes that adoption of the new test has had little impact on the already low risk of HIV transmission by transfusion.

• What impact do antiretroviral drugs have on HIV levels in vaginal secretions of HIV-positive women? In women who had therapy with one or more drugs, the levels of HIV declined significantly in vaginal secretions, as well as in plasma. The decline may explain why using AZT reduces perinatal HIV transmission.