(؉)-Calanolide A is a novel, naturally occurring, nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase first isolated from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Previous studies have demonstrated that (؉)-calanolide A has specific activity against the reverse transcriptase of HIV-1 and a favorable safety profile in animals. In addition, (؉)-calanolide A exhibits a unique HIV-1 resistance profile in vitro. The safety and pharmacokinetics of (؉)-calanolide A was examined in four successive single-dose cohorts (200, 400, 600, and 800 mg) in healthy, HIV-negative volunteers. In this initial phase I study, the toxicity of (؉)-calanolide A was minimal in the 47 subjects treated. Dizziness, taste perversion, headache, eructation, and nausea were the most frequently reported adverse events. These events were not all judged to be related to study medication nor were they dose related. While 51% of subjects reported mild and transient dizziness, in many cases this appeared to be temporally related to phlebotomy. Calculation of the terminal-phase half-life (t 1/2 ) was precluded by intrasubject variability in the 200-, 400-, and 600-mg dose cohorts but was approximately 20 h for the 800-mg dose group. (؉)-Calanolide A was rapidly absorbed following administration, with time to maximum concentration of drug in plasma (T max ) values occurring between 2.4 and 5.2 h postdosing depending on the dose. Plasma levels of (؉)-calanolide A at all dosing levels were quite variable; however, both the mean concentration in plasma (C max ), and the area under the plasma concentration-time curve increased proportionately in relation to the dose. Although raw plasma drug levels were higher in women than in men, when doses were normalized for body mass, the pharmacokinetic profiles were virtually identical with those observed for males. In general, levels of (؉)-calanolide A in human plasma were higher than would have been predicted from animal studies, yet the safety profile remained benign. In conclusion, this study demonstrated the safety and favorable pharmacokinetic profile of single doses of (؉)-calanolide A in healthy, HIV-negative individuals.
To determine the incidence and natural history of Mycobacterium avium-complex infections in persons with advanced human immunodeficiency virus (HIV) infection, we studied a multicenter cohort of 1,020 persons with acquired immunodeficiency syndrome (AIDS) or the AIDS-related complex (ARC) and CD4 cell count < 0.250 x 10(9)/L initially treated with zidovudine between April 1987 and April 1988. M. avium-complex infections developed in 123 (12%) patients during follow-up, with a 2-yr actuarial risk of 19%. Patients with an initial diagnosis of Pneumocystis carinii pneumonia were more likely to develop M. avium-complex infections than patients with an initial diagnosis of another opportunistic disease or of ARC (p = 0.002). Individuals developing M. avium-complex infections had lower baseline CD4 cell counts, hematocrits, lymphocyte counts, and total white blood cell counts than those who did not develop M. avium-complex infection. During follow-up, individuals who developed M. avium-complex infections were more likely to have severe anemia, to experience zidovudine dose reductions, and to die than were patients without M. avium-complex (p < 0.001). By proportional hazards analysis, a baseline CD4 cell count < 0.100 x 10(9)/L, development of severe anemia, P. carinii pneumonia during follow-up, and zidovudine dose interruption were significantly associated with subsequently developing M. avium-complex infection. A proportional hazards analysis of survival showed that M. avium-complex infection, severe anemia, zidovudine dose interruption, occurrence of an opportunistic infection, CD4 cell count < 0.100 x 10(9)/L, baseline AIDS diagnosis, and transfusion independently predicted an increased risk of death.(ABSTRACT TRUNCATED AT 250 WORDS)
This large, single-visit, cross-sectional, US-based study shows that anemia remains highly prevalent in HIV-infected patients. Data from this analysis suggest low CD4+ count, black ethnicity, and male sex are consistently strongest correlates of overall anemia; women are significantly more likely to have marked anemia.
Compared with men, HIV-infected women in the CPCRA were at increased risk of death but not disease progression. Risks of most incident opportunistic diseases were similar for women and men; however, women were at an increased risk of bacterial pneumonia. These findings may reflect differential access to health care and standard treatments or different socioeconomic status and social support for women compared with men.
Change in HIV-1 RNA, particularly using AUCMB, and in CD4 count should be measured to aid patient management and evaluation of treatment activity in clinical trials. However, short-term changes in these markers are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show similar differences between treatments in marker changes but not similar differences in progression to AIDS/death.
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