AIDSWEEKLY Plus, Monday, 14 July 1997
Daniel J. DeNoon, Senior Editor
Potent new therapies attack HIV in the blood and lymph nodes, but it remains unclear whether the virus lurks in other nooks of the body.
Evaluating virus levels in such areas remains a challenge for the design of clinical trials.
"It would be a Pyrrhic victory to successfully treat HIV in the blood and not reach it in the CNS [central nervous system] and testes," said Robert W. Coombs of the University of Washington, Seattle.
Coombs discussed the compartmentalization of HIV between the blood and the genital tract in an address to "New Opportunities for HIV Therapy - From Discovery to Clinical Proof-of-Concept," the 2nd Joint Conference of the National Institute of Allergy and Infectious Diseases (NIAID) Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) and the National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV), held June 22-26, 1997, in Vienna, Virginia.
Coombs and colleagues performed two separate longitudinal analyses of proviral DNA, viral RNA, and infectious viral load. The first examined peripheral blood samples from 44 HIV infected people with CD4 counts of >400 cells/(micro)L; the second examined paired semen and blood samples from 128 HIV infected men with CD4 counts of <400 cells/(micro)L.
"We showed that the within-person variability was significantly less than the person-to-person variability for all virologic measures assessed," Coombs et al. reported in their presentation abstract. "The within-subject variation (SD) was smallest for plasma viral RNA (0.26 log[10] for the first group and 0.24 log[10] for the second group, compared to cell-associated infectious virus (0.79 log[10]) and proviral DNA (1.03 log[10])."
For the 84 men in the second group for whom three RNA tests were available, the 95th percentile of natural variability was 0.38 log[10] of viral RNA per milliliter of blood plasma and 1.15 log[10] of viral RNA per milliliter of seminal plasma.
This high between-sample variability in RNA levels of semen compared to blood suggested that blood and semen may indeed represent separate viral compartments.
Weak correlations could be detected between blood and seminal plasma HIV RNA levels and between CD4 counts and seminal plasma HIV RNA levels.
"Those individuals who were culture positive in semen tended to have higher plasma viremia," Coombs said. "But some patients with very high plasma viremia had no culturable virus in semen. Large individual variations were seen."
While the study underscores the importance of measuring virus in each compartment, the statistical implications create logistical problems for clinical trials.
For example, if a clinical trial measured only one sample at each time point, it would need 52 subjects in order to measure with 80 percent power a five-fold change in viral RNA in semen. Only 10 subjects would be needed if blood alone were studied. Even if four samples were measured, meaningful semen measures would require 40 subjects.
Coombs listed several major implications from the studies:
* Used alone, HIV RNA levels in blood plasma cannot be used to predict viral load in the semen.
* Factors other than RNA level determine whether HIV can be cultured from semen.
* Variability in RNA levels between men may partially explain the variable detection rates of culturable virus.
* Multiple measures of seminal RNA may improve estimates of HIV copy number.
* Five times more subjects are needed to detect changes in seminal viral load compared to blood viral load.
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