Katherine Hilderbrand

Seven-year experience of a primary care antiretroviral treatment programme in Khayelitsha, South Africa

Objectives:We report on outcomes after 7 years of a community-based antiretroviral therapy (ART) programme in Khayelitsha, South Africa, with death registry linkages to correct for mortality under-ascertainment. Design:This is an observational cohort study. Methods:Since inception, patient-level clinical data have been prospectively captured on-site into an electronic patient information system. Patients with available civil identification numbers who were lost to follow-up were matched with the national death registry to ascertain their vital status. Corrected mortality estimates weighted these patients to represent all patients lost to follow-up. CD4 cell count outcomes were reported conditioned on continuous virological suppression. Results:Seven thousand, three hundred and twenty-three treatment-naive adults (68% women) started ART between 2001 and 2007, with annual enrolment increasing from 80 in 2001 to 2087 in 2006. Of 9.8% of patients lost to follow-up for at least 6 months, 32.8% had died. Corrected mortality was 20.9% at 5 years (95% confidence interval 17.9–24.3). Mortality fell over time as patients accessed care earlier (median CD4 cell count at enrolment increased from 43 cells/μl in 2001 to 131 cells/μl in 2006). Patients who remained virologically suppressed continued to gain CD4 cells at 5 years (median 22 cells/μl per 6 months). By 5 years, 14.0% of patients had failed virologically and 12.2% had been switched to second-line therapy. Conclusion:At a time of considerable debate about future global funding of ART programmes in resource-poor settings, this study has demonstrated substantial and durable clinical benefits for those able to access ART throughout this period, in spite of increasing loss to follow-up.

Implementing Antiretroviral Therapy in Rural Communities: The Lusikisiki Model of Decentralized HIV/AIDS Care

Health worker shortages are a major bottleneck to scaling up antiretroviral therapy (ART), particularly in rural areas. In Lusikisiki, a rural area of South Africa with a population of 150,000 serviced by 1 hospital and 12 clinics, Médecins Sans Frontières has been supporting a program to deliver human immunodeficiency virus (HIV) services through decentralization to primary health care clinics, task shifting (including nurse-initiated as opposed to physician-initiated treatment), and community support. This approach has allowed for a rapid scale-up of treatment with satisfactory outcomes. Although the general approach in South Africa is to provide ART through hospitals-which seriously limits access for many people, if not the majority of people-1-year outcomes in Lusikisiki are comparable in the clinics and hospital. The greater proximity and acceptability of services at the clinic level has led to a faster enrollment of people into treatment and better retention of patients in treatment (2% vs. 19% lost to follow-up). In all, 2200 people were receiving ART in Lusikisiki in 2006, which represents 95% coverage. Maintaining quality and coverage will require increased resource input from the public sector and full acceptance of creative approaches to implementation, including task shifting and community involvement.

Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy.

CONTEXT Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described. OBJECTIVE To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy. DESIGN, SETTING, AND PARTICIPANTS Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006. INTERVENTIONS Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine. MAIN OUTCOME MEASURES Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed. RESULTS The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7). CONCLUSION In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.

Antiretroviral therapy and early mortality in South Africa

OBJECTIVE To describe province-wide outcomes and temporal trends of the Western Cape Province antiretroviral treatment (ART) programme 5 years since inception, and to demonstrate the utility of the WHO monitoring system for ART. METHODS The treatment programme started in 2001 through innovator sites. Rapid scaling-up of ART provision began early in 2004, located predominantly in primary-care facilities. Data on patients starting ART were prospectively captured into facility-based registers, from which monthly cross-sectional activity and quarterly cohort reports were aggregated. Retention in care, mortality, loss to follow-up and laboratory outcomes were calculated at 6-monthly durations on ART. FINDINGS By the end of March 2006, 16 234 patients were in care. The cohort analysis included 12 587 adults and 1709 children. Women accounted for 70% of adults enrolled. After 4 and 3 years on ART respectively, 72.0% of adults (95% confidence interval, CI: 68.0-75.6) and 81.5% (95% CI: 75.7-86.1) of children remained in care. The percentage of adults starting ART with CD4 counts less than 50 cells/microl fell from 51.3% in 2001 to 21.5% in 2005, while mortality at 6 months fell from 12.7% to 6.6%, offset in part by an increase in loss to follow-up (reaching 4.7% at 6 months in 2005). Over 85% of adults tested had viral loads below 400 copies/ml at 6-monthly durations until 4 years on ART. CONCLUSION The location of care in primary-care sites in this programme was associated with good retention in care, while the scaling-up of ART provision was associated with reduced early mortality.

Antiretroviral treatment outcomes from a nurse-driven, community-supported HIV/AIDS treatment programme in rural Lesotho: observational cohort assessment at two years

IntroductionLesotho has the third highest HIV prevalence in the world (an adult prevalence of 23.2%). Despite a lack of resources for health, the country has implemented state-of-the-art antiretroviral treatment guidelines, including early initiation of treatment (<350 cells/mm3), tenofovir in first line, and nurse-initiated and managed HIV care, including antiretroviral therapy (ART), at primary health care level.Programme approachWe describe two-year outcomes of a decentralized HIV/AIDS care programme run by Doctors Without Borders/Médecins Sans Frontières, the Ministry of Health and Social Welfare, and the Christian Health Association of Lesotho in Scott catchment area, a rural health zone covering 14 clinics and one district hospital. Outcome data are described through a retrospective cohort analysis of adults and children initiated on ART between 2006 and 2008.Discussion and EvaluationOverall, 13,243 people have been enrolled in HIV care (5% children), and 5376 initiated on ART (6.5% children), 80% at primary care level. Between 2006 and 2008, annual enrolment more than doubled for adults and children, with no major external increase in human resources. The proportion of adults arriving sick (CD4 <50 cells/mm3) decreased from 22.2% in 2006 to 11.9% in 2008. Twelve-month outcomes are satisfactory in terms of mortality (11% for adults; 9% for children) and loss to follow up (8.8%). At 12 months, 80% of adults and 89% of children were alive and in care, meaning they were still taking their treatment; at 24 months, 77% of adults remained in care.ConclusionDespite major resource constraints, Lesotho is comparing favourably with its better resourced neighbour, using the latest international ART recommendations. The successful two-year outcomes are further evidence that HIV/AIDS care and treatment can be provided effectively at the primary care level. The programme highlights how improving HIV care strengthened the primary health care system, and validates several critical areas for task shifting that are being considered by other countries in the region, including nurse-driven ART for adults and children, and lay counsellor-supported testing and counselling, adherence and case management.

Effectiveness of the first district-wide programme for the prevention of mother-to-child transmission of HIV in South Africa

OBJECTIVE The aim of this study was to estimate the field efficacy of the first routine programme for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) initiated in South Africa, in the subdistrict of Khayelitsha. METHODS A consecutive sample of 658 mother-infant pairs, identified from the PMTCT register from 1 March to 30 November 2003, were identified for enrolment in this study. Details of the regimen received were established and HIV status of the infants at between 6 and 10 weeks of age was determined by qualitative DNA polymerase chain reaction. Zidovudine (AZT) was provided antenatally from week 34 of gestation and during labour. Infant formula milk was-offered to mothers who chose not to breastfeed. The protocol was amended in July 2003 such that women who had received < 2 weeks of treatment with AZT were given a single dose of nevirapine (NVP) at the onset of labour, and the infant received a weight-adjusted dose of NVP within 72 h of delivery. RESULTS Of the 535 mother-infant pairs (81%) eventually included in the study, 410 (77%) received an effective PMTCT intervention according to the protocol. The rate of transmission of HIV from mother to child was 8.8% (95% confidence interval (CI), 6.2-10.9). A maternal age of > 25 years was the only significant independent risk factor for transmission (odds ratio, 2.12; 95% CI, 1.14-4.07). CONCLUSION The results of this study demonstrate the feasibility and effectiveness of a large-scale PMTCT programme in an urban public-sector setting.

Effectiveness of Patient Adherence Groups as a Model of Care for Stable Patients on Antiretroviral Therapy in Khayelitsha, Cape Town, South Africa

Background Innovative models of care are required to cope with the ever-increasing number of patients on antiretroviral therapy in the most affected countries. This study, in Khayelitsha, South Africa, evaluates the effectiveness of a group-based model of care run predominantly by non-clinical staff in retaining patients in care and maintaining adherence. Methods and Findings Participation in “adherence clubs” was offered to adults who had been on ART for at least 18 months, had a current CD4 count >200 cells/ml and were virologically suppressed. Embedded in an ongoing cohort study, we compared loss to care and virologic rebound in patients receiving the intervention with patients attending routine nurse-led care from November 2007 to February 2011. We used inverse probability weighting to estimate the intention-to-treat effect of adherence club participation, adjusted for measured baseline and time-varying confounders. The principal outcome was the combination of death or loss to follow-up. The secondary outcome was virologic rebound in patients who were virologically suppressed at study entry. Of 2829 patients on ART for >18 months with a CD4 count above 200 cells/µl, 502 accepted club participation. At the end of the study, 97% of club patients remained in care compared with 85% of other patients. In adjusted analyses club participation reduced loss-to-care by 57% (hazard ratio [HR] 0.43, 95% CI = 0.21–0.91) and virologic rebound in patients who were initially suppressed by 67% (HR 0.33, 95% CI = 0.16–0.67). Discussion Patient adherence groups were found to be an effective model for improving retention and documented virologic suppression for stable patients in long term ART care. Out-of-clinic group-based models facilitated by non-clinical staff are a promising approach to assist in the long-term management of people on ART in high burden low or middle-income settings.

Early initiation of antiretroviral therapy and associated reduction in mortality, morbidity and defaulting in a nurse-managed, community cohort in Lesotho

Introduction:The latest WHO guidelines recommend initiating antiretroviral therapy (ART) at CD4 cell counts less than 350 cells/μl. However, donors and national governments are reluctant to support implementation owing to uncertainty regarding feasibility and relative benefit. Lesotho has supported earlier initiation since 2008. We assessed outcomes comparing early (CD4 cell counts >200 cells/μl) and late (CD4 cell counts ≤200 cells/μl) initiation. Methods:We describe survival probability among patients initiating ART at CD4 cell counts 200 or less and more than 200 cells/μl and assess associations between baseline CD4 cell counts and mortality, morbidity, loss to follow-up and hospitalization using Cox regression adjusting for confounders identified a priori. Results:Our analysis included 1177 patients; median age was 38 years and the majority (67%) were women. Median time on ART for the overall cohort was 506 days (interquartile range 396–608). Five hundred and thirty eight patients initiated ART at a CD4 cell count 200 cells/μl or less (interquartile range 54–160) and 639 patients initiated at CD4 cell count more than 200 cells/μl (interquartile range 238–321). In multivariate analysis, we found that patients initiating at CD4 cell count more than 200 cells/μl were 68% less likely to die (adjusted hazard ratio 0.32, 95% confidence interval 0.20–0.50), and 39% less likely to be lost to follow-up (adjusted hazard ratio 0.61, 95% confidence interval 0.43–0.87). Initiating ART at CD4 cell count more than 200 cells/μl was also associated with a 27% reduction in the rate of incident morbidity (adjusted hazard ratio 0.73, 95% confidence interval 0.65–0.82) and a 63% decreased rate of hospitalization (adjusted hazard ratio 0.37, 95% confidence interval 0.19–0.73). Conclusion:Earlier initiation is feasible in a low resource, high HIV prevalence setting, and provides important benefits in terms of reduced mortality, morbidity, retention and hospitalization. Donors should fully support the implementation of the latest WHO recommendations.

Renal Safety of a Tenofovir-Containing First Line Regimen: Experience from an Antiretroviral Cohort in Rural Lesotho

Introduction Current guidelines contraindicate TDF use when creatinine clearance (CrCl) falls below 50 ml/min. We report prevalence of abnormal renal function at baseline and factors associated with abnormal renal function from a community cohort in Lesotho. Methods We calculated changes in CrCl from baseline for patients initiated on TDF at 6 and 12 months and the proportion of patients initiated on TDF who developed renal impairment. Screening algorithms were developed using risk factors determined by multivariate analysis. Results Among 933 adults for whom baseline creatinine was available, 176 (18.9%) presented with a baseline CrCl <50 ml/min. Renal function improved during follow-up. 19 patients who developed renal toxicity during follow up remained on TDF; renal function improved (CrCl≥50 ml/min) in all but 3 of these patients. Among 15 patients with a baseline CrCl <50 ml/min were started in error, none developed severe renal impairment. Conclusion In this setting TDF-associated renal toxicity is rare and mainly transient. Further studies to assess TDF safety at lower CrCl thresholds are warranted.

Implementing a Tenofovir-Based First-Line Regimen in Rural Lesotho: Clinical Outcomes and Toxicities After Two Years

Background: The latest World Health Organization guidelines recommend replacing stavudine with tenofovir or zidovudine in first-line antiretroviral therapy in resource-limited settings. We report on outcomes and toxicities among patients on these different regimens in a routine treatment cohort in Lesotho. Methods: All adult patients initiating antiretroviral therapy from January 1, 2008, to December 31, 2008, were included in the analysis and followed until December 31, 2009. Choice of regimen was determined by clinical criteria. Results: Of 1124 patient records analyzed, median age was 39 years, and the majority (67.7%) were women. Five hundred eighty-seven patients were started on tenofovir, 255 on zidovudine, and 282 on stavudine. Patients on zidovudine were more than twice as likely to experience a toxicity-driven regimen substitution compared with tenofovir (adjusted hazard ratio: 2.32, 95% confidence interval: 1.23 to 4.40); for patients on stavudine, the risk of a toxicity-driven regimen switch was almost 6 times higher than tenofovir (adjusted hazard ratio: 5.43, 95% confidence interval: 3.31 to 8.91). Conclusions: Our findings support the latest World Health Organization Guidelines, in particular the adoption of tenofovir in first line, given the advantages in terms of tolerability and availability as a once-daily formulation.