PubMed · 8097365
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G J Tijhuis, H G Huisman, M T Roos, R H Kauffmann. 1993. AIDS without detectable HIV: a case report.. https://doi.org/10.1016/0002-9343(93)90158-l
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BACKGROUND: Clinical trials of antiretroviral drugs can take years to complete because the outcomes measured are progression to the acquired immunodeficiency syndrome (AIDS) or death. Trials could be accelerated by the use of end points such as changes in CD4+ lymphocyte counts and plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA and beta 2-microglobulin, but there is uncertainty about whether these surrogate measures are valid predictors of disease progression. METHODS: We analyzed data from the Veterans Affairs Cooperative Study on AIDS, which compared immediate with deferred zidovudine therapy. Patients' plasma levels of HIV-1 RNA and beta 2-microglobulin were measured in stored plasma. RESULTS: Among the 129 patients in the immediate-treatment group, 34 had disease that progressed to AIDS, as compared with 57 of the 141 patients in the deferred-treatment group (P = 0.03). Progression to AIDS correlated strongly with base-line CD4+ lymphocyte counts (P = 0.001) and plasma levels of HIV-1 RNA (P < 0.001), but not with base-line levels of beta 2-microglobulin (P = 0.14). A decrease of at least 75 percent in the plasma level of HIV-1 RNA over the first six months of zidovudine therapy accounted for 59 percent of the benefit of treatment, defined as the absence of progression to AIDS (95 percent confidence interval, 13 to 112 percent). Plasma beta 2-microglobulin levels and CD4+ lymphocyte counts explained less of the effect of treatment. A 75 percent decrease in the plasma HIV-1 RNA level plus a 10 percent increase in the CD4+ lymphocyte count could explain 79 percent of the treatment effect (95 percent confidence interval, 27 to 145 percent). CONCLUSIONS: Treatment-induced changes in the plasma HIV-1 RNA level and the CD4+ lymphocyte count, taken together, are valid predictors of the clinical progression of HIV-related disease and can be used to assess the efficacy of zidovudine and possibly other antiretroviral drugs as well.
Following a 4-year controlled trial comparing early and later zidovudine treatment, we conducted an additional 3-year follow-up. Of the original 338 patients, 275 participated. Clinical outcome measures were AIDS and death. In the early therapy group (n = 170), 67 patients progressed to AIDS compared with 85 in the later therapy group (n = 168); the relative risk (RR) comparing early with later therapy was 0.72% (95% confidence interval [CI] 0.52-0.99; p = 0.044). The early therapy group had 74 deaths compared with 73 in the later therapy (RR = 0.98; 95% CI, 0.71-1.36; p = 0.91). The early group had a peak CD4+ count increase at 1-2 months and a delay of 1 year before CD4+ counts fell below baseline. For patients who received zidovudine for more than the median duration (20.3 months) before their first AIDS diagnosis, the RR for death was 2.08 (95% CI, 1.36-3.19, p = 0.001). Additional factors independently associated with poor prognosis following AIDS were a CD4+ count of < 100 cells/mm3 and increased severity of the first AIDS diagnosis, whereas use of another antiretroviral agent was associated with improved survival. We conclude that early zidovudine therapy delays progression to AIDS but does not affect survival. Patients who progress to AIDS while on prolonged zidovudine monotherapy many benefit from a change to other antiretroviral therapy(ies).
Persons with human immunodeficiency virus/AIDS are at high risk of Kaposi's sarcoma (KS), non-Hodgkin lymphoma (NHL), and possibly anal cancers. To examine whether this risk preceded the AIDS epidemic, we used pre-AIDS era data from the Surveillance, Epidemiology, and End Results program (excluding Connecticut) from 1973 to 1976, and the Connecticut Tumor Registry from 1940 to 1976. We compared risk of being single (a surrogate to identify men who might be homosexual) to those ever married, using a case control matching study with up to 10 controls per case. Overall, no excess risk was observed for KS (risk ratio for men 20-59 years old: 1.00; 95% confidence interval 0.218-3.61), but there was a suggestion of higher risk (4.00; 0.54-29.48) in 1973-1976, the period just before the AIDS epidemic. The NHL risk (0.85; 0.74-0.99) was slightly low, but for anal cancer the risk ratio of being single was significantly high both in men 20-59 years old (5.68) and older men (2.78) long before the AIDS epidemic. If the excess risk was solely due to being homosexual, the actual relative risk in the subset who were homosexual must have been much higher, given that only a fraction of the single men would have been homosexual. As comparison groups to verify the methodology, we used colon (no association with marital status) and prostatic cancer (decreased in single men), with findings as reported in other studies. Thus, single men may have been at an excess risk of KS (but a slightly low risk of NHL) just before the AIDS epidemic and have been at excess risk of anal cancer for many years before the AIDS epidemic.