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. 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. ß

BackgroundInnovative 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 FindingsParticipation 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).DiscussionPatient 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.

Abstractobjectives Further scale-up of antiretroviral therapy (ART) to those in need while supporting the growing patient cohort on ART requires continuous adaptation of healthcare delivery models. We describe several approaches to manage stable patients on ART developed by M edecins Sans Fronti eres together with Ministries of Health in four countries in sub-Saharan Africa.methods Using routine programme data, four approaches to simplify ART delivery for stable patients on ART were assessed from a patient and health system perspective: appointment spacing for clinical and drug refill visits in Malawi, peer educator-led ART refill groups in South Africa, community ART distribution points in DRC and patient-led community ART groups in Mozambique.results All four approaches lightened the burden for both patients (reduced travel and lost income) and health system (reduced clinic attendance). Retention in care is high: 94% at 36 months in Malawi, 89% at 12 months in DRC, 97% at 40 months in South Africa and 92% at 48 months in Mozambique. Where evaluable, service provider costs are reported to be lower.conclusion Separating ART delivery from clinical assessments was found to benefit patients and programmes in a range of settings. The success of community ART models depends on sufficient and reliable support and resources, including a flexible and reliable drug supply, access to quality clinical management, a reliable monitoring system and a supported lay workers cadre. Such models require ongoing evaluation and further adaptation to be able to reach out to more patients, including specific groups who may be challenged to meet the demands of frequent clinic visits and the integrated delivery of other essential chronic disease interventions.

Background Antiretroviral therapy (ART) reduces the risk of tuberculosis, but the incidence still exceeds that in HIV-uninfected people. Isoniazid preventive therapy (IPT), which decreases the risk of tuberculosis in people not on ART, may offer additional protection. Methods Pragmatic randomized double-blind placebo-controlled trial to evaluate the effect of 12 months IPT among participants established on or newly starting ART, in Khayelitsha, South Africa (NCT00463086, Lancet D-09-02885). Tuberculosis was excluded at screening by sputum culture. Incident tuberculosis was the primary endpoint. Findings 1,329 participants contributed 3,227 person-years (PY) of follow up in the modified intention-to-treat analysis; 662 on IPT and 667 on placebo. There were 95 incident tuberculosis cases: 2.3 (95%CI 1.6-3.1) versus 3.6 (95%CI 2.8-4.7) per 100 PY in the IPT and placebo arms respectively (hazard ratio 0.63, 95%CI 0.41-0.94). Study drug was discontinued due to grade 3 or 4 raised ALT in 19/662 in the IPT and 10/667 in the placebo arm, risk ratio=1.9 (95%CI 0.90-4.09). In secondary analyses, there was no evidence that the effect of IPT was restricted to those who were positive on tuberculin skin test (TST) or interferon gamma release assay (IGRA): adjusted hazard ratio for those with negative tests 0.43 (95%CI 0.21-0.86) and 0.43 (95%CI 0.20-0.96); for positive tests 0.86 (95%CI 0.37-2.00) and 0.55 (95%CI 0.26-1.24) respectively. No all cause mortality benefit of IPT was demonstrated Interpretation IPT reduced the incidence of tuberculosis in HIV-infected individuals on ART. In this high incidence setting, individuals on ART who have TST or IGRA negative results may also benefit from IPT. IPT can easily be implemented in ART clinics.

Numbers on ART have increased rapidly in South Africa, but the programme has experienced deteriorating patient retention over time, particularly due to apparent LTFU. This may represent true loss to care, but may also reflect administrative error and lack of capacity to monitor movements in and out of care. New strategies are needed for South Africa and other low-income and middle-income countries to improve monitoring of outcomes and maximize retention in care with increasing programme size.

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Rationale: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-g-secreting CD4 1 T cells. Objectives: To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS. Methods: Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-g enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART. Measurements and Main Results:In cross-sectional analysis the frequency of IFN-g-secreting T cells recognizing early secretory antigenic target (ESAT)-6, a-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P < 0.03). The biggest difference was in the recognition of a-crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4 1 and CD8 1 cells positive for activation markers HLA-DR and CD71 in both patients with TB-IRIS and non-IRIS patients. The percentage of CD4 1 cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB-IRIS, 5.3 6 4.5; non-IRIS, 2.46 6 2.46; P 5 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-g-secreting T cells in both the TB-IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB-IRIS group (P 5 0.041). Conclusions: There is an association between helper T-cell type 1 expansions and TB-IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB-IRIS remains to be fully elucidated.

Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs.