STD Quarterly-Experts say current drugs won't kill virus
The pendulum will swing back toward later treatment of HIV-infected patients, and the definition of failure of clinical trials will be revisited, predicted Mauro Schechter, MD, PhD, professor of infectious diseases at the Hospital Universitario Clementino Fraga Filho at Federal University of Rio de Janeiro in Rio de Janeiro, Brazil.
Speaking at the 13th International AIDS Conference in Durban, South Africa, Schechter offered predictions about what would happen by the time the international conference reconvenes in 2002 in Barcelona. He foresaw a greater emphasis on "delta viral load," the renaissance of CD4 count as a guide to therapy, and the availability of simpler drug regimens. He also addressed a renewal of interest in the prevention of opportunistic infections, which in turn will take into consideration local epidemiological conditions.
Schechter's address re-emphasized the point made by Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, MD, that eradication of the virus with currently available drugs is unlikely.
Since the Geneva conference two years ago, data indicate that virologic failures are more common in practice than in trials and that opportunistic infections occur at similar CD4 cell counts in patients on therapy and patients who are not, Schechter said. Although many patients did not achieve full immune recovery in those studies, a large proportion did achieve a "safe" level of immune competence, he added. On a more cautionary note, he said antiretroviral therapy was associated with potentially serious side effects, some of which might be time-dependent.
The treatment timing debate
These newly acquired data have led to renewed debate on the optimum time to treat, the choice of initial drug regimens, when to change and how to sequence them, and how to simplify existing regimens, Schechter said. Emphasis has shifted to the role of new drugs, pharmacological enhancement in extending treatment benefits, and management and prevention of opportunistic infections.
Schechter reviewed recent data on a wide range of issues related to HIV/AIDS treatment, making reference, among others, to the contested debate about what is considered to be the optimal time to initiate therapy, particularly in connection with threshold values of viral load and CD4 cells.
With regard to viral load, two recently published reports demonstrated a direct association between the slope of the increase of plasma viral load in the first few years after seroconversion and the probability of progressing to AIDS, said Schechter.1,2
"It was also shown that for those who progressed to AIDS, the slope of viral load increase in the three years preceding progression to AIDS was similar, regardless of prior AIDS-free time," he noted.
Those observations argue against a blanket concept of a fixed set point, he observed. They also suggest that it may be more appropriate to measure viral load in a serial fashion, rather than rely on one or two measurements to make therapeutic decisions. Schechter referred to a report presented at the conference by Julio Montaner, MD, national co-director of the Canadian HIV Trials Network in Ottawa, Ontario, on a population based cohort analysis of antiretroviral naive patients in British Columbia who started highly-active antiretroviral therapy between August 1996 and September 1999.
Results from the study, which involved 1,200 eligible participants, showed that effectiveness of therapy is dependent on baseline CD4 count, not on age, gender, viral load, prior AIDS diagnosis, or protease inhibitor use.
"Furthermore, few patients with baseline CD4 > 200 cells/mm3 experienced clinical progression, and progression rates were similar for patients with CD4 counts of 200-350 or 350-500 cells/mm3," Schechter noted.
The study also showed that it is probably correct to postpone treatment initiation provided therapy is started while immune recovery to "safe" levels is still possible. However, the question of how to define that moment precisely remains unanswered, he said.
More progress needed
While progress has been made in the past two years, Schechter emphasized that many earlier conclusions have yet to be revisited. The future will see a re-evaluation of "less potent" regimens, particularly of their cost effectiveness in resource-limited settings, he predicted.
Structured treatment interruptions will be discussed as a means of making treatment less toxic and more affordable, and pressure on industry and governments will increase to ensure equal and universal access to antiretroviral therapy, Schechter forecasted. That approach is still not available to the majority of those infected with HIV in the developing world, he observed.
References
1. Lyles RH, Munoz A, Yamashita TE, et al. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis 2000; 181:872-880.
2. Lyles RH, Xu J. Classifying individuals based on predictors of random effects. Multicenter AIDS Cohort Study. Stat Med 1999; 18:35-52.
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