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

BACKGROUND: An increasing number of patients in Africa are experiencing virologic failure on second-line antiretroviral therapy (ART) and those who develop resistance to protease inhibitors (PI) will require third-line ART, but no data on the outcomes of third-line are available from the region. We assessed the virologic outcomes and survival of patients started on salvage ART in a Southern African private sector disease management programme. METHODS: Retrospective observational cohort study with linkage to the national death register. Adults (≥18 years) who started salvage ART between July 2007 and December 2011 were included. Salvage ART was defined by inclusion of darunavir or tipranavir in an ART regimen after having failed another PI. For Kaplan-Meier (KM) analysis, patients were followed up until event, or censored at death (only for virologic outcomes), leaving the programme, or April 2014. RESULTS: 152 patients were included. Subtype was known for 113 patients: 111 (98 %) were infected with subtype C. All 152 had a genotype resistance test demonstrating major PI resistance mutations. Salvage drugs included were: darunavir/ritonavir (n = 149), tipranavir/ritonavir (n = 3), raltegravir (n = 58), and etravirine (n = 8). Median follow-up was 2.5 years (IQR = 1.5-3.3). 82.9 % achieved a viral load ≤400 copies/ml and 71.1 % ≤50 copies/ml. By the end of the study 17 (11.2 %) of the patients had died. The KM estimate of cumulative survival was 87.2 % at 2000 days. CONCLUSIONS: Virologic suppression was comparable to that demonstrated in clinical trials and observational studies of salvage ART drugs conducted in other regions. Few deaths occurred during short term follow-up. Third-line regimens for patients with multidrug resistant subtype C HIV in Africa are virologically and clinically effective.

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

BACKGROUND: Despite concerns about affordability and sustainability, many models of the lifetime costs of antiretroviral therapy (ART) used in resource limited settings are based on data from small research cohorts, together with pragmatic assumptions about life-expectancy. This paper revisits these modelling assumptions in order to provide input to future attempts to model the lifetime costs and the costs of scaling up ART. METHODS: We analysed the determinants of costs and outcomes in patients receiving ART in line with standard World Health Organization (WHO) guidelines for resource poor settings in a private sector managed ART programme in South Africa. The cohort included over 5,000 patients with up to 4 years (median 19 months) on ART. Generalized linear and Cox proportional hazards regression models were used to establish cost and outcome determinants respectively. RESULTS: The key variables associated with changes in mean monthly costs were: being on the second line regimen; receiving ART from 4 months prior to 4 months post treatment initiation; having a recent or current CD4 count <50 cells/microL or 50-199 cells/microl; having mean ART adherence <75% as determined by monthly pharmacy refill data; and having a current or recent viral load >100,000 copies/mL. In terms of the likelihood of dying, the key variables were: baseline CD4 count<50 cells/microl (particularly during the first 4 months on treatment); current CD4 count <50 cells/microl and 50-199 cells/microl (particularly during later periods on treatment); and being on the second line regimen. Being poorly adherent and having an unsuppressed viral load was also associated with a higher likelihood of dying. CONCLUSIONS: While there are many unknowns associated with modelling the resources needed to scale-up ART, our analysis has suggested a number of key variables which can be used to improve the state of the art of modelling ART. While the magnitude of the effects associated with these variables would be likely to differ in other settings, the variables influencing costs and survival are likely to be generalizable. This is of direct relevance to those concerned about assessing the long-term costs and sustainability of expanded access to ART.

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 $370 (SD, $644). Mean monthly costs of ART were $32 (SD, $18); hospitalizations, $151 (SD, $436); consultations, $76 (SD, $66); investigations, $37 (SD, $50); and non-ART medications, $53 (SD, $180). Total mean monthly costs ranged from $313 (SD, $598) for quartile 4 to $376 (SD, $657) for quartile 1. Hospitalization costs increased from 29% to 51% of total costs as adherence decreased. In the GLM 2-step model, moving from adherence quartile 1 to quartile 2, 3, or 4 increased the probability of having nonzero total monthly costs by 0.078, 0.15, and 0.21 percentage point, respectively (P < 0.001). For patients with nonzero costs, increasing adherence from quartile 1 to quartile 2, 3, or 4 decreased total monthly costs by $70, $133, and $192, respectively (P < 0.001). Moving from adherence quartiles 1 to 4 had the highest decrease in net overall median monthly health care costs (-$85 [interquartile range, -$116 to -$41]). LIMITATIONS: Indirect health care costs were not included. Experience may not reflect that of public HIV/AIDS programs. CONCLUSION: High ART adherence was associated with lower mean monthly direct health care costs, particularly reduced hospitalization costs, in this South African HIV cohort.

Early and late direct costs in a Southern African antiretroviral treatment programme: a retrospective cohort analysis.

BACKGROUND: There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa. METHODS/FINDINGS: We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/microl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/microl and 5.16 log(10) copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age. CONCLUSIONS: Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART. Please see later in the article for the Editors' Summary.

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 < or = 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.

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 >or=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.

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; chi(2) = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; chi(2) = 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]; chi(2) = 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.

Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes.

BACKGROUND: Adherence of 95% or more to unboosted protease regimens is required for optimal virologic suppression in HIV-1-infected patients. Whether the same is true for nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy is unclear. OBJECTIVE: To assess the relationship between adherence to NNRTI-based therapy and viral load in treatment-naive patients. DESIGN: Observational cohort study. SETTING: Private-sector HIV and AIDS disease management program in South Africa. PATIENTS: 2821 adults infected with HIV who began NNRTI-based therapy between January 1998 and March 2003 (2764 patients [98%] were enrolled after December 2000). MEASUREMENTS: Adherence was assessed by monthly pharmacy claims. The primary end point was sustained viral load suppression (<400 copies/mL) in 100% of recorded viral load measurements throughout follow-up. Secondary end points included time to initial viral load suppression and time to subsequent virologic failure (>400 copies/mL). RESULTS: The median follow-up period was 2.2 years (interquartile range, 1.7 to 2.7 years). The proportion of patients with sustained viral load suppression ranged from 13% (41 of 325 patients) in patients who filled less than 50% of antiretroviral drug prescriptions to 73% (725 of 997 patients) in those who filled 100% of antiretroviral drug prescriptions. Each 10% increase in pharmacy claim adherence greater than 50% was associated with a mean absolute increase of 0.10 in the proportion of patients with sustained virologic suppression (P < 0.001). Predictors for shorter time to virologic failure after initial suppression in multivariable Cox regression included CD4+ T-cell counts of 0.50 x 10(9) cells/L or less (hazard ratio, 1.60 [95% CI, 1.22 to 2.10] vs. CD4+ T-cell counts >0.20 x 10(9) cells/L), baseline viral load greater than 10(5) copies/mL (hazard ratio, 1.39 [CI, 1.14 to 1.70]), nevirapine-based regimen (hazard ratio, 1.43 [CI, 1.16 to 1.75]), and low pharmacy claim adherence (hazard ratio, 1.58 [CI, 1.48 to 1.69], per 10% decrease in adherence to 50%). LIMITATIONS: Observational study with adherence stratification at study end and lack of standardized timing for outcome measurement. CONCLUSION: Virologic outcomes improve in a linear dose-response manner as adherence to NNRTI-based regimens increases beyond 50%.

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

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 >or=80% for 3298 patients (52%) and 100% for 1916 patients (30%). Women were significantly more likely to have adherence>or=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 count200 cells/microL). Pharmacy-based records may be a simple and effective population-level tool for monitoring adherence as HAART programs in Africa are scaled up.