Jennifer Fusco

Long-Term HIV/AIDS Survival Estimation in the Highly Active Antiretroviral Therapy Era

Background. Highly active antiretroviral therapy (HAART) prolongs short-term survival in patients with HIV/AIDS. HAART has only been available since 1996; thus, no longterm survival data are available. Computer simulation models extrapolating short-term survival data can provide estimates of long-term survival. These survival estimates may assist patients and clinicians in HAART treatment planning. The authors construct a computer simulation model based on observational data to estimate long-term survival in a cohort of HIV/AIDS patients undergoing treatment with HAART. Methods. The authors use data from the Collaboration in HIV Outcomes Research-US (CHORUS) observational cohort (N = 4791), the published literature, and US Life Tables to specify a computer simulation model of expected survival accounting for baseline CD4 cell count, progressive HAART treatment failure, progressive risk of HAART on treatment mortality, and age-associated mortality. Time to treatment failure for each of three rounds of HAART and risk of mortality on-treatment were estimated using parametric survival models with censoring of follow-up fit to CHORUS data. Off-treatment survival after HAART failure was estimated from the pre-HAART literature. Age-associated mortality was taken from US Life Tables. Results. Median projected survivals stratified by baseline CD4 cell count subgroups were CD4 > 200 cells/mm³, 15.4 years; CD4 ≤ 200 cells/mm³, 8.5 years; and CD4 ≤ 50 cells/mm³, 5.5 years. These values are 4 to 6 years longer than pre-HAART cohorts. The sensitivity analyses showed that the model survival predictions were most sensitive to the treatment failure rate, the on-treatment mortality rate, and the number of treatment rounds. Conclusions. Computer simulation modeling of long-term survival of patients with HIV/AIDS on HAART—accounting for differential treatment failure and death rates stratified by CD4 cell count and age-associated mortality—suggests a relatively consistent 4- to 6-year survival benefit over pre-HAAART therapies.

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.

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.

Psychiatric Symptoms in Patients Receiving Dolutegravir.

Introduction: Psychiatric symptoms (PSs) are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analyzed PSs observed with dolutegravir (DTG) and other frequently prescribed anchor drugs. Methods: Selected PSs (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during DTG treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to ViiV Healthcare were analyzed. Results: In clinical trials, PSs were reported at low and similar rates in patients receiving DTG or comparators [atazanavir, darunavir, efavirenz, or raltegravir (RAL)]. Insomnia was most commonly reported. The highest rates were observed in SINGLE (DTG 17%, efavirenz 12%), with consistently lower rates in the other trials (DTG: 3%–8% versus comparator: 3%–7%). More efavirenz-treated patients withdrew because of PSs than patients treated with other anchor drugs. In OPERA, history of PSs at baseline was lowest in efavirenz-treated patients compared with patients treated with DTG, RAL, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for PSs were lowest for DTG (0%–0.6%) and highest for RAL (0%–2.5%). Spontaneously reported events were similar in nature to clinical trial data. Conclusions: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, PSs are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.

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.