The Continuing Burden of Advanced HIV Disease Over 10 Years of Increasing Antiretroviral Therapy Coverage in South Africa.

Background: Antiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)-related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa. Methods: Annual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/µL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care. Results: Patients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/µL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/µL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/µL in 2016 were men, compared to approximately one-third of all patients on ART in the same year. Conclusions: Ongoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response.

Contemporary disengagement from antiretroviral therapy in Khayelitsha, South Africa: A cohort study.

BACKGROUND: Retention in care is an essential component of meeting the UNAIDS "90-90-90" HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from care remains an important challenge. We sought to determine the incidence of and risk factors associated with disengagement from care during 2013-2014 and outcomes for those who disengaged. METHODS AND FINDINGS: We conducted a retrospective cohort study of all patients ≥10 years of age who visited 1 of the 13 Khayelitsha ART clinics from 2013-2014 regardless of the date they initiated ART. We described the cumulative incidence of first disengagement (>180 days not attending clinic) between 1 January 2013 and 31 December 2014 using competing risks methods, enabling us to estimate disengagement incidence up to 10 years after ART initiation. We also described risk factors for disengagement based on a Cox proportional hazards model, using multiple imputation for missing data. We ascertained outcomes (death, return to care, hospital admission, other hospital contact, alive but not in care, no information) after disengagement until 30 June 2015 using province-wide health databases and the National Death Registry. Of 39,884 patients meeting our eligibility criteria, the median time on ART to 31 December 2014 was 33.6 months (IQR 12.4-63.2). Of the total study cohort, 592 (1.5%) died in the study period, 1,231 (3.1%) formally transferred out, 987 (2.5%) were silent transfers and visited another Western Cape province clinic within 180 days, 9,005 (22.6%) disengaged, and 28,069 (70.4%) remained in care. Cumulative incidence of disengagement from care was estimated to be 25.1% by 2 years and 50.3% by 5 years on ART. Key factors associated with disengagement (age, male sex, pregnancy at ART start [HR 1.58, 95% CI 1.47-1.69], most recent CD4 count) and retention (ART club membership, baseline CD4) after adjustment were similar to those found in previous studies; however, notably, the higher hazard of disengagement soon after starting ART was no longer present after adjusting for these risk factors. Of the 9,005 who disengaged, the 2 most common initial outcomes were return to ART care after 180 days (33%; n = 2,976) and being alive but not in care in the Western Cape (25%; n = 2,255). After disengagement, a total of 1,459 (16%) patients were hospitalized and 237 (3%) died. The median follow-up from date of disengagement to 30 June 2015 was 16.7 months (IQR 11-22.4). As we included only patient follow-up from 2013-2014 by design in order to maximize the generalizability of our findings to current programs, this limited our ability to more fully describe temporal trends in first disengagement. CONCLUSIONS: Twenty-three percent of ART patients in the large cohort of Khayelitsha, one of the oldest public-sector ART programs in South Africa, disengaged from care at least once in a contemporary 2-year period. Fifty-eight percent of these patients either subsequently returned to care (some "silently") or remained alive without hospitalization, suggesting that many who are considered "lost" actually return to care, and that misclassification of "lost" patients is likely common in similar urban populations. A challenge to meeting ART retention targets is developing, testing, and implementing program designs to target mobile populations and retain them in lifelong care. This should be guided by risk factors for disengagement and improving interlinkage of routine information systems to better support patient care across complex care platforms.

Population-wide differentials in HIV service access and outcomes in the Western Cape for men as compared to women, South Africa: 2008 to 2018: a cohort analysis.

INTRODUCTION: Few studies have systematically described population-level differences comparing men and women across the continuum of routine HIV care. This study quantifies differentials in HIV care, treatment and mortality outcomes for men and women over time in South Africa. METHODS: We analysed population-wide linked anonymized data, including vital registration linkage, for the Western Cape Province, from the time of first CD4 count. Three antiretroviral therapy guideline eligibility periods were defined: 1 January 2008 to 31 July 2011 (CD4 cell count <200 cells/µL), 1 August 2011 to 31 December 2014 (<350 cells/µL), 1 January 2015 to 31 August 2016 (<500 cells/µL). We estimated care uptake based on service attendance, and modelled associations for men and women with ART initiation and overall, pre-ART and ART mortality. Separate Cox proportional hazard models were built for each outcome and eligibility period, adjusted for tuberculosis, pregnancy, CD4 count and age. RESULTS: Adult men made up 49% of the population and constituted 37% of those living with HIV. In 2009, 46% of men living with HIV attended health services, rising to 67% by 2015 compared to 54% and 77% of women respectively. Men contributed <35% of all CD4 cell counts over 10 years and presented with more advanced disease (39% of all first presentation CD4 cell counts from men were <200 cells/µL compared to 25% in women). ART access was lower in men compared to women (AHR 0.79 (0.77 to 0.80) summarized for Period 2) over the entire study). Mortality was greater in men irrespective of ART (AHR 1.08 (1.01 to 1.16) Period 3) and after ART start (AHR 1.15 (1.05 to 1.20) Period 3) with mortality differences decreasing over time. CONCLUSIONS: Compared to women, men presented with more advanced disease, were less likely to attend health care services annually, were less likely to initiate ART and had higher mortality overall and while receiving ART care. People living with HIV were more likely to initiate ART if they had acute reasons to access healthcare beyond HIV, such as being pregnant or being co-infected with tuberculosis. Our findings point to missed opportunities for improving access to and outcomes from interventions for men along the entire HIV cascade.

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.

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.

Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort.

INTRODUCTION: The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. METHODS: Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. RESULTS: Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/microl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyperlactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART > or =6 months, weighing > or =75 kg at baseline. DISCUSSION: A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk.

Superior virologic and treatment outcomes when viral load is measured at 3 months compared to 6 months on antiretroviral therapy.

INTRODUCTION: Routine viral load (VL) monitoring is utilized to assess antiretroviral therapy (ART) adherence and virologic failure, and it is currently scaled-up in many resource-constrained settings. The first routine VL is recommended as late as six months after ART initiation for early detection of sub-optimal adherence. We aimed to assess the optimal timing of first VL measurement after initiation of ART. METHODS: This was a retrospective, cohort analysis of routine monitoring data of adults enrolled at three primary care clinics in Khayelitsha, Cape Town, between January 2002 and March 2009. Primary outcomes were virologic failure and switch to second-line ART comparing patients in whom first VL done was at three months (VL3M) and six months (VL6M) after ART initiation. Adjusted hazard ratios (aHR) were estimated using Cox proportional hazard models. RESULTS: In total, 6264 patients were included for the time to virologic failure and 6269 for the time to switch to second-line ART analysis. Patients in the VL3M group had a 22% risk reduction of virologic failure (aHR 0.78, 95% CI 0.64-0.95; p=0.016) and a 27% risk reduction of switch to second-line ART (aHR 0.73, 95% CI 0.58-0.92; p=0.008) when compared to patients in the VL6M group. For each additional month of delay of the first VL measurement (up to nine months), the risk of virologic failure increased by 9% (aHR 1.09, 95% CI 1.02-1.15; p=0.008) and switch to second-line ART by 13% (aHR 1.13, 95% CI 1.05-1.21; p<0.001). CONCLUSIONS: A first VL at three months rather than six months with targeted adherence interventions for patients with high VL may improve long-term virologic suppression and reduce switches to costly second-line ART. ART programmes should consider the first VL measurement at three months after ART initiation.

[Street food among children: a study in north Tunisia]. / L'alimentation de rue chez l'écolier dans une région du nord de la Tunisie.

As urbanization increases in Tunisia, eating meals outside the home is becoming more frequent. Children are prime consumers for the fast food sold in the streets. Neither their nor their parents' attitude towards street food is well documented as yet. This study was conducted in the city of Bizerte in February 1998. Its aim was to gather information about street food and parents' and children's attitudes towards it to help organize educational sessions with the children, parents, teachers, and vendors. The study interviewed 421 primary school children, ranging in age from 6 to 15 years (mean age: 10 years), from 24 schools. Half received pocket money, a percentage that did not differ by sex. Three quarters of the children used more than 75% of their pocket money to buy street food. The items bought most frequently were candy (27.2%), sandwiches (23.9%), pastries (23.9%), sunflower seeds and peanuts (21%), and either pizza, chocolate, or cheese (20.3%); the largest proportion of money was spent on sandwiches. In more than half the cases (55.7% of the children), the main motivation for buying street food was either to replace or fill out a meal at home, with sandwiches or pastries. The parents' monthly income did not influence the children's purchasing behavior, but the rhythm of receiving pocket money did. Most children were satisfied with the nutritional and hygienic quality of the food available, but their opinion of this quality as well as the reasons for buying the food and the prices spent on it differed considerably from that of their parents. This study highlights the important role of street foods in the daily diet of schoolchildren and the need for appropriate nutrition education in primary schools.

A three-tier framework for monitoring antiretroviral therapy in high HIV burden settings.

The provision of antiretroviral therapy (ART) in low and middle-income countries is a chronic disease intervention of unprecedented magnitude and is the dominant health systems challenge for high-burden countries, many of which rank among the poorest in the world. Substantial external investment, together with the requirement for service evolution to adapt to changing needs, including the constant shift to earlier ART initiation, makes outcome monitoring and reporting particularly important. However, there is growing concern at the inability of many high-burden countries to report on the outcomes of patients who have been in care for various durations, or even the number of patients in care at a particular point in time. In many instances, countries can only report on the number of patients ever started on ART. Despite paper register systems coming under increasing strain, the evolution from paper directly to complex electronic medical record solutions is not viable in many contexts. Implementing a bridging solution, such as a simple offline electronic version of the paper register, can be a pragmatic alternative. This paper describes and recommends a three-tiered monitoring approach in low- and middle-income countries based on the experience implementing such a system in the Western Cape province of South Africa. A three-tier approach allows Ministries of Health to strategically implement one of the tiers in each facility offering ART services. Each tier produces the same nationally required monthly enrolment and quarterly cohort reports so that outputs from the three tiers can be aggregated into a single database at any level of the health system. The choice of tier is based on context and resources at the time of implementation. As resources and infrastructure improve, more facilities will transition to the next highest and more technologically sophisticated tier. Implementing a three-tier monitoring system at country level for pre-antiretroviral wellness, ART, tuberculosis and mother and child health services can be an efficient approach to ensuring system-wide harmonization and accurate monitoring of services, including long term retention in care, during the scale-up of electronic monitoring solutions.

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.

The effect of complete integration of HIV and TB services on time to initiation of antiretroviral therapy: a before-after study.

BACKGROUND: Studies have shown that early ART initiation in TB/HIV co-infected patients lowers mortality. One way to implement earlier ART commencement could be through integration of TB and HIV services, a more efficient model of care than separate, vertical programs. We present a model of full TB/HIV integration and estimate its effect on time to initiation of ART. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively reviewed TB registers and clinical notes of 209 TB/HIV co-infected adults with a CD4 count <250 cells/µl and registered for TB treatment at one primary care clinic in a South African township between June 2008 and May 2009. Using Kaplan-Meier and Cox proportional hazard analysis, we compared time between initiation of TB treatment and ART for the periods before and after full, "one-stop shop" integration of TB and HIV services (in December 2009). Potential confounders were determined a priori through directed acyclic graphs. Robustness of assumptions was investigated by sensitivity analyses. The analysis included 188 patients (100 pre- and 88 post-integration), yielding 56 person-years of observation. Baseline characteristics of the two groups were similar. Median time to ART initiation decreased from 147 days (95% confidence interval [CI] 85-188) before integration of services to 75 days (95% CI 52-119) post-integration. In adjusted analyses, patients attending the clinic post-integration were 1.60 times (95% CI 1.11-2.29) more likely to have started ART relative to the pre-integration period. Sensitivity analyses supported these findings. CONCLUSIONS/SIGNIFICANCE: Full TB/HIV care integration is feasible and led to a 60% increased chance of co-infected patients starting ART, while reducing time to ART initiation by an average of 72 days. Although these estimates should be confirmed through larger studies, they suggest that scale-up of full TB/HIV service integration in high TB/HIV prevalence settings may shorten time to ART initiation, which might reduce excess mortality and morbidity.

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.

Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource-limited setting in rural Lesotho.

BACKGROUND: Latest World Health Organization guidelines recommend shifting away from Stavudine (d4T)-based regimens due to severe side effects. However, widespread replacement of d4T by Tenofovir (TDF) or Zidovudine (AZT) is hampered by cost concerns. METHODS: We established the cost-effectiveness of alternative first-line regimens using primary utilization, cost, and outcome data from a program in a rural district in Lesotho. We calculated cost per patient-year, incremental costs, and incremental cost-effectiveness ratios per life year, and per Quality Adjusted Life Year gained. Uncertainty was assessed using multiway and probabilistic sensitivity analyses. RESULTS: Our study included 1260 patients representing 1635 patient-years on antiretroviral therapy (ART). Six hundred eight patients were on TDF, 290 were on AZT, and 362 were on d4T. Patients on d4T experienced more toxicities; toxicities with the biggest impact on quality of life were moderate neuropathy and severe lipodystrophy. The cost per patient-year ranged from US $266 on d4T to US $353 on TDF. Inpatient care and essential drug costs were higher for patients on d4T than on AZT or TDF. Incremental cost-effectiveness ratio results suggest that AZT-based ART is weakly dominated by a combination of d4T- and TDF-based ART. DISCUSSION: This is one of the first analyses to investigate the cost-effectiveness of TDF using primary data in a resource-poor setting. Although TDF-based first-line ART is more costly than d4T, it is also more effective. Political pressure should be exerted to encourage further price reductions and additional generic manufacturing for TDF and partner drugs such as Efavirenz. This should be met by a commitment from donors and implementers to ensure that supply is met by a clear demand.

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.

Trends in loss to follow-up among migrant workers on antiretroviral therapy in a community cohort in Lesotho.

BACKGROUND: The provision of antiretroviral therapy (ART) to migrant populations raises particular challenges with respect to ensuring adequate treatment support, adherence, and retention in care. We assessed rates of loss to follow-up for migrant workers compared with non-migrant workers in a routine treatment programme in Morjia, Lesotho. DESIGN: All adult patients (≥18 years) initiating ART between January 1, 2008, and December 31, 2008, and followed up until the end of 2009, were included in the study. We described rates of loss to follow-up according to migrant status by Kaplan-Meier estimates, and used Poisson regression to model associations between migrant status and loss to follow-up controlling for potential confounders identified a priori. RESULTS: Our cohort comprised 1185 people, among whom 12% (148) were migrant workers. Among the migrant workers, median age was 36.1 (29.6-45.9) and the majority (55%) were male. We found no statistically significant differences between baseline characteristics and migrant status. Rates of lost to follow up were similar between migrants and non-migrants in the first 3 months but differences increased thereafter. Between 3 and 6 months after initiating antiretroviral therapy, migrants had a 2.78-fold increased rate of defaulting (95%CI 1.15-6.73); between 6 and 12 months the rate was 2.36 times greater (95%CI 1.18-4.73), whereas after 1 year the rate was 6.69 times greater (95%CI 3.18-14.09). CONCLUSIONS: Our study highlights the need for programme implementers to take into account the specific challenges that may influence continuity of antiretroviral treatment and care for migrant populations.

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/microl in 2001 to 131 cells/microl in 2006). Patients who remained virologically suppressed continued to gain CD4 cells at 5 years (median 22 cells/microl 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.

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

INTRODUCTION: Lesotho 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 APPROACH: We 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 EVALUATION: Overall, 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. CONCLUSION: Despite 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.

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.