Leon Regensberg

Adherence to highly active antiretroviral therapy assessed by pharmacy claims predicts survival in HIV-infected South African adults

Summary: It is unclear how adherence to highly active antiretroviral therapy (HAART) may best be monitored in large HIV programs in sub-Saharan Africa where it is being scaled up. We aimed to evaluate the association between HAART adherence, as estimated by pharmacy claims, and survival in HIV-1-infected South African adults enrolled in a private-sector AIDS management program. Of the 6288 patients who began HAART between January 1999 and August 2004, 3805 (61%) were female and 6094 (97%) were black African. HAART adherence was ≥80% for 3298 patients (52%) and 100% for 1916 patients (30%). Women were significantly more likely to have adherence ≥80% than men (54% vs 49%, P < 0.001). The median (interquartile range) follow-up time was 1.8 (1.37-2.5) years. As of 1 September 2004, 222 patients had died-a crude mortality rate of 3.5%. In a multivariate Cox regression model, adherence <80% was associated with lower survival (relative hazard 3.23; 95% confidence interval: 2.37-4.39). When medication adherence was divided into 5 strata with a width of 20% each, each stratum had lower survival rates than the adjacent, higher-adherence stratum. Among other variables tested, only baseline CD4+ T-cell count was significantly associated with decreased survival in multivariate analysis (relative hazard 5.13; 95% confidence interval: 3.42-7.72, for CD4+ T-cell count ≤50 cells/&mgr;L vs >200 cells/&mgr;L). Pharmacy-based records may be a simple and effective population-level tool for monitoring adherence as HAART programs in Africa are scaled up.

Antiretroviral Therapy Adherence, Virologic and Immunologic Outcomes in Adolescents Compared With Adults in Southern Africa

Objective:To determine adherence to and effectiveness of antiretroviral therapy (ART) in adolescents vs. adults in southern Africa. Design:Observational cohort study. Setting:Aid for AIDS, a private sector disease management program in southern Africa. Subjects:Adolescents (age 11-19 years; n = 154) and adults (n = 7622) initiating ART between 1999 and 2006 and having a viral load measurement within 1 year after ART initiation. Main Outcome Measures:Primary: virologic suppression (HIV viral load ≤400 copies/mL), viral rebound, and CD4+ T-cell count at 6, 12, 18, and 24 months after ART initiation. Secondary: adherence assessed by pharmacy refills at 6, 12, and 24 months. Multivariate analyses: loglinear regression and Cox proportional hazards. Results:A significantly smaller proportion of adolescents achieved 100% adherence at each time point (adolescents: 20.7% at 6 months, 14.3% at 12 months, and 6.6% at 24 months; adults: 40.5%, 27.9%, and 20.6% at each time point, respectively; P < 0.01). Patients achieving 100% 12-month adherence were significantly more likely to exhibit virologic suppression at 12 months, regardless of age. However, adolescents achieving virologic suppression had significantly shorter time to viral rebound (adjusted hazard ratio 2.03; 95% confidence interval: 1.31 to 3.13; P < 0.003). Adolescents were less likely to experience long-term immunologic recovery despite initial CD4+ T-cell counts comparable to adults. Conclusions:Compared with adults, adolescents in southern Africa are less adherent to ART and have lower rates of virologic suppression and immunologic recovery and a higher rate of virologic rebound after initial suppression. Studies must determine specific barriers to adherence in this population and develop appropriate interventions.

Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy

Background World Health Organization (WHO) guidelines for monitoring HIV-infected individuals taking combination antiretroviral therapy (cART) in resource-limited settings recommend using CD4+ T cell (CD4) count changes to monitor treatment effectiveness. In practice, however, falling CD4 counts are a consequence, rather than a cause, of virologic failure. Adherence lapses precede virologic failure and, unlike CD4 counts, data on adherence are immediately available to all clinics dispensing cART. However, the accuracy of adherence assessments for predicting future or detecting current virologic failure has not been determined. The goal of this study therefore was to determine the accuracy of adherence assessments for predicting and detecting virologic failure and to compare the accuracy of adherence-based monitoring approaches with approaches monitoring CD4 count changes. Methodology and Findings We conducted an observational cohort study among 1,982 of 4,984 (40%) HIV-infected adults initiating non-nucleoside reverse transcriptase inhibitor-based cART in the Aid for AIDS Disease Management Program, which serves nine countries in southern Africa. Pharmacy refill adherence was calculated as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last refill prior to the endpoint of interest, expressed as a percentage. The main outcome measure was virologic failure defined as a viral load > 1,000 copies/ml (1) at an initial assessment either 6 or 12 mo after cART initiation and (2) after a previous undetectable (i.e., < 400 copies/ml) viral load (breakthrough viremia). Adherence levels outperformed CD4 count changes when used to detect current virologic failure in the first year after cART initiation (area under the receiver operating characteristic [ROC] curves [AUC] were 0.79 and 0.68 [difference = 0.11; 95% CI 0.06 to 0.16; χ2 = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; χ2 = 20.2] respectively at 12 mo; p < 0.001 for both comparisons). When used to detect current breakthrough viremia, adherence and CD4 counts were equally accurate (AUCs of 0.68 versus 0.67, respectively [difference = 0.01; 95% CI −0.06 to 0.07]; χ2 = 0.1, p > 0.5). In addition, adherence levels assessed 3 mo prior to viral load assessments were as accurate for virologic failure occurring approximately 3 mo later as were CD4 count changes calculated from cART initiation to the actual time of the viral load assessments, indicating the potential utility of adherence assessments for predicting future, rather than simply detecting current, virologic failure. Moreover, combinations of CD4 count and adherence data appeared useful in identifying patients at very low risk of virologic failure. Conclusions Pharmacy refill adherence assessments were as accurate as CD4 counts for detecting current virologic failure in this cohort of patients on cART and have the potential to predict virologic failure before it occurs. Approaches to cART scale-up in resource-limited settings should include an adherence-based monitoring approach.

Efavirenz versus Nevirapine-based Initial Treatment of HIV Infection: Clinical and Virological Outcomes in Southern African Adults

Objective:To determine the effectiveness of efavirenz versus nevirapine in initial antiretroviral therapy regimens for adults in sub-Saharan Africa. Design:Observational cohort study. Methods:Study participants were 2817 HIV-infected, highly active antiretroviral therapy-naive adults who began nevirapine-based or efavirenz-based highly active antiretroviral therapy between January 1998 and September 2004 via a private-sector HIV/AIDS program in nine countries of southern Africa. The primary outcome was time to virologic failure (two measurements of viral loads ≥400 copies/ml). Secondary outcomes included all-cause mortality, time to viral load less than 400 copies/ml, pharmacy-claim adherence, and discontinuation of nevirapine or efavirenz without virologic failure. Results:The median follow-up period was 2.0 years (interquartile range 1.2–2.6). Patients started on nevirapine were significantly less likely than those started on efavirenz to achieve high adherence, whether defined as 100% (30.2 versus 38.1%, P < 0.002) or more than 90% (44.8 versus 49.4%, P < 0.02) pharmacy-claim adherence. In a multivariate analysis, patients on nevirapine had greater risk of virologic failure [hazard ratio (HR 1.52; 95% confidence interval (CI) 1.24–1.86)], death (2.17; 1.31–3.60), and regimen discontinuation (1.67; 1.32–2.11). Switching from nevirapine to efavirenz had no significant virologic effect, whereas switching from efavirenz to nevirapine resulted in significantly slower time to suppression (hazard ratio 0.58, 95% confidence interval 0.35–0.93) and faster time to failure (hazard ratio 3.92; 95% confidence interval 1.61–9.55) than remaining on efavirenz. Conclusion:In initial highly active antiretroviral therapy regimens, efavirenz was associated with superior virologic and clinical outcomes than nevirapine, suggesting that efavirenz might be the preferred nonnucleoside reverse transcriptase inhibitor in resource-limited settings. However, its higher cost and potential teratogenicity are important barriers to implementation.

Association of Antiretroviral Therapy Adherence and Health Care Costs

BACKGROUND Antiretroviral therapy (ART) adherence predicts HIV disease progression and survival, but its effect on direct health care costs is unclear. OBJECTIVE To determine the effect of ART adherence on direct health care costs among adults in a resource-limited setting. DESIGN Cohort study. SETTING Aid for AIDS, a private-sector disease management program in South Africa. PATIENTS 6833 HIV-infected adults who started ART between 6 August 2000 and 30 April 2006. MEASUREMENTS Monthly direct health care costs authorized by Aid for AIDS were averaged over all months. Pharmacy claim adherence, expressed as a percentage, was categorized into quartiles, from 1 (lowest) to 4 (highest). Effects of covariates on monthly total costs were assessed with a 2-step model with logit for probability of nonzero costs and a generalized linear model (GLM). RESULTS Total mean monthly costs were

Early and Late Direct Costs in a Southern African Antiretroviral Treatment Programme: A Retrospective Cohort Analysis

370 (SD,

Improving the evidence base of Markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings.

644). Mean monthly costs of ART were

Adherence to Nonnucleoside Reverse Transcriptase Inhibitor–Based HIV Therapy and Virologic Outcomes

32 (SD,

Third-line antiretroviral therapy in Africa: effectiveness in a Southern African retrospective cohort study

18); hospitalizations,

HIV and AIDS, STI and TB in the private sector : health care delivery

151 (SD,