Objective-To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication.Design-A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62,760 HIV-infected, therapy-naïve individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Conclusions-We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up. Results

These data suggest substantial increases in the number of individuals who require treatment and call for early HIV testing.

BackgroundDespite the success of combination antiretroviral therapy (cART) in reducing the incidence of Kaposi sarcoma, HIV-infected individuals who have responded to treatment continue to be diagnosed with Kaposi sarcoma. We examine factors associated with the incidence of Kaposi sarcoma among cART-treated HIV-infected homosexual men and changes in their survival after its diagnosis over calendar time.MethodsData were from HIV-infected homosexual men with well-estimated dates of HIV seroconversion (ie, change in status from being HIV negative to having HIV antibodies detected). Incidence of Kaposi sarcoma was calculated. We used Kaplan–Meier methods to determine survival after Kaposi sarcoma diagnosis in three calendar periods: before 1996, 1996–2000, and 2001–2006. Poisson models were used to examine the effect of risk factors such as current and nadir CD4 cell count (ie, the lowest CD4 cell count ever recorded for a person), duration of infection, and age at diagnosis for Kaposi sarcoma incidence in cART-treated men. All statistical tests were two-sided.ResultsAmong the 9473 men, 555 were diagnosed with Kaposi sarcoma in the period 1986–2006, of whom 319 died. The percentage surviving 24 months after Kaposi sarcoma diagnosis rose statistically significantly during the study period from 35% (95% confidence interval [CI] = 29% to 42%) before 1996 to 84% (95% CI = 76% to 90%) in 1996–2000 and to 81% (95% CI = 70% to 88%) in 2001–2006 (P < .001). Seventy men were diagnosed with Kaposi sarcoma after starting cART. Current (ie, within 6 months) CD4 cell count was associated with incidence of Kaposi sarcoma among cART-treated men (rate ratios [RRs] = 18.91, 95% CI = 8.50 to 42.09, for CD4 level category <200 cells per cubic millimeter; RR = 3.55, 95% CI = 1.40 to 9.00, for 200–349 cells per cubic millimeter; and RR = 4.11, 95% CI = 1.74 to 9.70, for 350–499 cells per cubic millimeter; all compared with ≥500 cells per cubic millimeter). After adjustment for current CD4 cell count, HIV infection duration, age, or nadir CD4 cell count was not associated with Kaposi sarcoma incidence.ConclusionsAmong cART-treated HIV-infected homosexual men, current CD4 cell count was the factor most strongly associated with the incidence of Kaposi sarcoma. Survival estimates after Kaposi sarcoma diagnosis have improved over time.

Background Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 109 cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. Objective To identify the optimal CD4 cell count at which cART should be initiated. Design Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 109 cells/L. Setting HIV clinics in Europe and the Veterans Health Administration system in the United States. Patients 20 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 109 cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 109 cells/L and were included in the analysis. Measurements Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. Results Compared with initiating cART at the CD4 cell count threshold of 0.500 × 109 cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations CD4 cell count at cART initiation was not randomized. Residual confounding may exist. Conclusion Initiation of cART at a threshold CD4 count of 0.500 × 109 cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 ×109 cells/L. Primary Funding Source National Institutes of Health.

IMPORTANCE Although hospitalizations for injection drug use-associated infective endocarditis (IDU-IE) have increased during the opioid crisis, utilization of and mortality associated with receipt of medication for opioid use disorder (MOUD) after discharge from the hospital among patients with IDU-IE are unknown. OBJECTIVE To assess the proportion of patients receiving MOUD after hospitalization for IDU-IE and the association of MOUD receipt with mortality. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used a population registry with person-level medical claims, prescription monitoring program, mortality, and substance use

Most patients experience virologic rebound soon after cART interruption; however, although PTCs are rare, the results of this study confirm their existence.

Effect estimates from randomized trials and observational studies might not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a 3-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocols (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate our approach, we compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive for the human immunodeficiency virus from the Strategic Timing of Antiretroviral Therapy (START) randomized trial and the observational HIV-CAUSAL Collaboration.

Summary Background Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (cART). We compared effectiveness of three strategies for initiation of cART in high-income countries for HIV-positive individuals who do not have AIDS: immediate universal cART initiation, cART initiation at a CD4 cell count below 500, and cART initiation at a CD4 cell count below 350 cells/mm3. Methods We used data from the HIV-CAUSAL collaboration of cohorts in Europe and the United States. We included 55,826 individuals diagnosed with HIV between 2000-2013, ART naïve, AIDS-free, aged≥18 years and within 6 months of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders to estimate the following quantities as would have been observed under each cART initiation strategy after 7 years of HIV diagnosis: relative risks of both death and of death or AIDS-defining illness, mean survival time, proportion in need of cART, and proportion with HIV RNA<50 copies/mL. Findings Median [interquantile range] CD4 at HIV diagnosis was 376 [222,551] cells/mm3. Compared with immediate initiation, the mortality risk ratio estimate (95% CI) was 1.02 (1.01,1.02) under initiation at CD4<500 cells/mm3, and 1.06 (1.04,1.08) under initiation at CD4<350 cells/mm3. The corresponding estimates were 1.06 (1.06,1.07) and 1.20 (1.17,1.23) for the combined endpoint. Compared with immediate initiation, the mean survival time at 7 years under initiation at CD4<500 cells/mm3 and at CD4<350 cells/mm3 was 2 (1,2) and 5 (4,6) days shorter. Seven years after HIV diagnosis, 100%, 99%, and 93% of individuals would have been in need of cART, and 87%, 87% and 84% would have HIV-RNA<50 copies/mL, under immediate initiation, initiation at CD4<500 and <350 cells/mm3, respectively. Interpretation The benefits of immediate initiation of cART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of cART.