G Fusco

HIV-Associated Thrombotic Microangiopathy in the Era of Highly Active Antiretroviral Therapy: An Observational Study

The prevalence and predisposing factors of thrombotic microangiopathy (TMA) in the era of highly active antiretroviral therapy (HAART) were evaluated among patients in the Collaborations in Human Immunodeficiency Virus (HIV) Outcomes Research/US cohort. Of 6022 patients, 17 (0.3%) had TMA, with unadjusted incidences per 100 person-years of 0.079 for TMA, 0.009 for thrombotic thrombocytopenic purpura, and 0.069 for hemolytic-uremic syndrome. Compared with patients without TMA, patients with TMA had lower mean CD4(+) cell counts (197 vs. 439 cells/mm(3); P=.0009) and higher mean log(10) HIV-1 RNA levels (4.6 vs. 3.3 copies/mL; P=.0001) at last follow-up and a significantly greater incidence of acquired immune deficiency syndrome (82.4% vs. 55.3%; P=.025), Mycobacterium avium complex infection (17.6% vs. 3.3%; P=.018), hepatitis C (29.4% vs. 11.3%; P=.001), and death (41.2% vs. 7.4%; P<.0001). The prevalence of herpes and use of antiherpetics were slightly higher for patients with TMA, but unadjusted distributions were not statistically significant. TMA in a cohort surveyed after the introduction of HAART was rare and was associated with advanced HIV disease.

Effect of Persistent Moderate Viremia on Disease Progression During HIV Therapy

ObjectiveAlthough highly active antiretroviral therapy has been shown to lower plasma HIV-1 RNA in HIV infection, many patients do not reach the target goal of undetectable viremia. We evaluated whether risk of clinical progression varies by level of viral suppression achieved. DesignPatients in the Collaborations in HIV Outcomes Research/United States cohort who maintained stable HIV-1 RNA levels of either <400, 400 to 20,000, or >20,000 copies/mL during a run-in period of at least 6 months were studied. Baseline was the first day after this period. MethodsProportional hazards models were used to quantify the relation between baseline HIV-1 RNA levels and risk of a new AIDS-defining diagnosis or death after adjusting for CD4 count, age, gender, ethnicity, study site, prior AIDS-defining diagnosis, and antiretroviral therapy history. ResultsPatients (N = 3010) were followed for up to 4.3 years after the 6-month run-in period, with 343 deaths or AIDS-defining diagnoses reported. The risk of a new AIDS-defining diagnosis or death was not significantly different in the 400 to 20,000– and <400-copies/mL groups (6% vs. 7%, hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 0.7–1.4; P = 0.9) but was significantly higher in the >20,000-copies/mL group (26%, HR = 3.3, 95% CI: 2.5–4.4; P < 0.001 vs. the <400-copies/mL group). Median CD4 count changes during the first year of follow-up showed increases of 75 and 13 cells/mm3 for the <400- and 400 to 20,000–copies/mL groups, respectively, whereas the >20,000-copies/mL group had a decrease of 23 cells/mm3. ConclusionsPatients who maintained baseline HIV-1 RNA levels of 400 to 20,000 copies/mL for at least 6 months preserved immunologic status and were no more likely to die or develop a new AIDS-defining diagnosis in the time frame studied than those with baseline levels <400 copies/mL. Patients with HIV-1 RNA levels >20,000 copies/mL at baseline had greater clinical and immunologic deterioration. These data suggest that maintenance of moderate viremia may confer clinical benefit not seen when viremia exceeds 20,000 copies/mL, and this should be taken into account when considering the risks and benefits of continuing failing therapy.

Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies

BACKGROUND No large clinical end-point trials have been conducted comparing regimens among human immunodeficiency virus type 1-positive persons starting antiretroviral therapy. We examined clinical progression according to initial regimen in the Antiretroviral Therapy Cohort Collaboration, which is based on 12 European and North American cohort studies. METHODS We analyzed progression to death from any cause and to AIDS or death (AIDS/death), comparing efavirenz (EFV), nevirapine (NVP), nelfinavir, idinavir, ritonavir (RTV), RTV-boosted protease inhibitors (PIs), saquinavir, and abacavir. We also compared nucleoside reverse-transcriptase inhibitor pairs: zidovudine/lamivudine (AZT/3TC), stavudine (D4T)/3TC, D4T/didanosine (DDI), and others. RESULTS A total of 17,666 treatment-naive patients, 55,622 person-years at risk, 1,617 new AIDS events, and 895 deaths were analyzed. Compared with EFV, the adjusted hazard ratio (HR) for AIDS/death was 1.28 (95% confidence interval [CI], 1.03-1.60) for NVP, 1.31 (95% CI, 1.01-1.71) for RTV, and 1.45 (95% CI, 1.15-1.81) for RTV-boosted PIs. For death, the adjusted HR for NVP was 1.65 (95% CI, 1.16-2.36). The adjusted HR for death for D4T/3TC was 1.35 (95% CI, 1.14-1.59), compared with AZT/3TC. CONCLUSIONS Outcomes may vary across initial regimens. Results are observational and may have been affected by bias due to unmeasured or residual confounding. There is a need for large, randomized, clinical end-point trials.

Zidovudine and stavudine sequencing in HIV treatment planning: Findings from the CHORUS HIV Cohort

Background: Optimal sequencing of zidovudine and stavudine in antiretroviral therapy has not been elucidated. Objective: To examine the impact of the sequence of therapeutic regimens containing zidovudine and stavudine on HIV‐1 RNA and CD4 lymphocyte counts over 12 months. Design: Observational, multicenter, longitudinal cohort study. Setting: Four large outpatient, HIV practices participating in the community‐based Collaborations in HIV Outcomes Research—U.S. (CHORUS) cohort study. Participants: 940 HIV‐infected patients. Methods: Comparison of HIV‐1 RNA and CD4 lymphocyte responses in patients sequenced from zidovudine to stavudine or from stavudine to zidovudine using repeated measures regression models fit to outcomes by application of generalized estimating equation (GEE) methodology. Results: Patients treated with zidovudine prior to stavudine (n = 834) achieved a greater mean drop from baseline HIV‐1 RNA (p = .01) and higher proportion of undetectable HIV‐1 RNA results (p = .05) over 12 months than those sequenced from stavudine to zidovudine (n = 106). CD4+ lymphocyte increases did not differ between the groups (p = .6). Conclusions: Prior zidovudine therapy was not associated with long‐term attenuation of HIV‐1 RNA or CD4 response to subsequent stavudine‐containing regimens. Zidovudine before stavudine may have benefit in a strategic long‐term therapeutic plan.

Disease progression in HIV-infected patients treated with stavudine vs. zidovudine

BACKGROUND AND OBJECTIVES This prospective, observational study compared disease progression and death in HIV-1 patients treated with stavudine vs. zidovudine in the Collaborations in HIV Outcomes Research/U.S. (CHORUS) cohort. METHODS Patients with a first occurrence of CD4 count <500 cells/microL (n=3301) were grouped as: no nucleoside reverse transcriptase inhibitor (NRTI) use; other NRTI without stavudine or zidovudine; stavudine with no zidovudine, with or without other NRTIs; and zidovudine with no stavudine, with or without other NRTIs. The risk for death or disease progression was evaluated in unadjusted analyses and using a Cox proportional hazards model, adjusting for: study site, age, gender, race, route of HIV infection, previous AIDS-defining conditions, number of previous antiretroviral regiments, CD4 count, HIV-1 RNA, and treatment variables. Sensitivity analyses were conducted to determine the sensitivity of the results to major modeling assumptions. A landmark analysis was conducted to determine the absolute difference in time to event. RESULTS During a median follow-up of 2.4 years, there were 57 deaths and 348 AIDS-defining conditions in 405 patients. Stavudine treatment compared with zidovudine resulted in a greater percentage of patients with AIDS-defining events (14.5 vs. 10.9%; P=.013), and an increased risk of disease progression (HR=1.30; 95% CI: 1.01,1.7; P=.04). This result was not sensitive to modeling assumptions. Landmark analysis demonstrated an absolute difference in time to 95% event-free survival of 2.7 months for those with a CD4< or =200 cells/microL and 11 months for those 6 months after model entry. CONCLUSIONS In unadjusted and adjusted analyses of 3301 HIV-1 infected patients, stavudine containing combination therapy was associated with an increased risk of disease progression or death compared to therapy containing zidovudine. Most of the difference was attributable to new cases of wasting.