Neonatal and infant diagnostic HIV-PCR uptake and associations during three sequential policy periods in Cape Town, South Africa: a longitudinal analysis.

INTRODUCTION: To strengthen the early infant diagnosis (EID) programmes and timeously identify and treat HIV-infected infants, birth HIV-PCR for some/all infants has been recommended in the Western Cape, South Africa since 2014. Operational data on the implementation of such programmes in low- and middle-income countries are limited. METHODS: Utilizing the electronic records platform at primary care facilities, we developed an electronic register which consolidated obstetric and HIV-related data, allowing us to track a cohort of HIV-infected/exposed mother/infant dyads longitudinally from antenatal care through delivery to infant HIV-PCR. We assessed guideline implementation and impact on EID of three sequential EID policies in a referral chain of facilities in Cape Town (primary-tertiary care). Birth HIV-PCR was indicated in period 1 if symptomatic; period 2 if meeting high-risk criteria for transmission; and period 3 for all HIV-exposed neonates. RESULTS: We enrolled 2012 HIV-exposed infants; 89.2% had at least one HIV-PCR at any point. The majority of birth tests were performed in hospital versus primary care regardless of policy period. Almost half of all infants (47.9%) had at least one high-risk criterion for vertical infection; of these, 39.7% had a birth test. Infants with more risk factors were more likely to have birth EID. Receipt of a birth HIV-PCR significantly reduced the likelihood of receiving a follow-up test at six to ten weeks, even after adjusting for potential confounders (aOR 0.18 (0.12 to 0.26)). The proportion of infants tested at six to ten weeks old dropped from 92.9% (period 1) to 80.2% in period 3 and those receiving birth HIV-PCR increased, peaking at 67.4% during period 3. The proportion of positive birth tests was highest (2.9%) when birth tests were restricted to infants meeting high-risk criteria, with a low proportion positive for the first time at six to ten weeks. During period 3, the proportion positive at six to ten weeks was high (2.4%), highlighting the importance of follow-up to detect intrapartum and early postpartum infections. CONCLUSIONS: Over all policy periods, EID guidelines were incompletely implemented across all levels of care but especially in primary care. Birth HIV-PCR reduced return for follow-up testing, such follow-up testing is critical for the effectiveness of the programme.

Medication Side Effects and Retention in HIV Treatment: A Regression Discontinuity Study of Tenofovir Implementation in South Africa and Zambia.

Tenofovir is less toxic than other nucleoside reverse-transcriptase inhibitors used in antiretroviral therapy (ART) and may improve retention of human immunodeficiency virus (HIV)-infected patients on ART. We assessed the impact of national guideline changes in South Africa (2010) and Zambia (2007) recommending tenofovir for first-line ART. We applied regression discontinuity in a prospective cohort study of 52,294 HIV-infected adults initiating first-line ART within 12 months (±12 months) of each guideline change. We compared outcomes in patients presenting just before and after the guideline changes using local linear regression and estimated intention-to-treat effects on initiation of tenofovir, retention in care, and other treatment outcomes at 24 months. We assessed complier causal effects among patients starting tenofovir. The new guidelines increased the percentages of patients initiating tenofovir in South Africa (risk difference (RD) = 81 percentage points, 95% confidence interval (CI): 73, 89) and Zambia (RD = 42 percentage points, 95% CI: 38, 45). With the guideline change, the percentage of single-drug substitutions decreased substantially in South Africa (RD = -15 percentage points, 95% CI: -18, -12). Starting tenofovir also reduced attrition in Zambia (intent-to-treat RD = -1.8% (95% CI: -3.5, -0.1); complier relative risk = 0.74) but not in South Africa (RD = -0.9% (95% CI: -5.9, 4.1); complier relative risk = 0.94). These results highlight the importance of reducing side effects for increasing retention in care, as well as the differences in population impact of policies with heterogeneous treatment effects implemented in different contexts.

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.

Optimal right heart filling pressure in acute respiratory distress syndrome determined by strain echocardiography.

INTRODUCTION: Right ventricular (RV) systolic dysfunction is common in acute respiratory distress syndrome (ARDS). While preload optimization is crucial in its management, dynamic fluid responsiveness indices lack reliability, and there is no consensus on target central venous pressure (CVP). We analyzed the utility of RV free wall longitudinal strain (RVFWS) in the estimation of optimal RV filling pressure in ARDS. METHODS: A retrospective cross-sectional analysis of clinical data and echocardiograms of patients with ARDS was performed. Tricuspid annular plane systolic excursion (TAPSE), tricuspid peak systolic velocity (S'), RV fractional area change (RVFAC), RVFWS, CVP, systolic pulmonary artery pressure (SPAP), and left ventricular ejection fraction (LVEF) were measured. RESULTS: Fifty-one patients with moderate-severe ARDS were included. There were inverse correlations between CVP and TAPSE, S', RVFAC, RVFWS, and LVEF. The most significant was with RVFWS (r:.74, R2 :.55, P:.00001). Direct correlations with creatinine and lactate were noted. Receiver operating characteristic analysis showed that RVFWS -21% (normal reference value) was associated with CVP: 13 mm Hg (AUC: 0.92, 95% CI: 0.83-1.00). Regression model analysis of CVP, and RVFWS interactions established an RVFWS range from -18% to -24%. RVFWS -24% corresponded to CVP: 11 mm Hg and RVFWS -18% to CVP: 15 mm Hg. Beyond a CVP of 15 mm Hg, biventricular systolic dysfunction rapidly ensues. CONCLUSIONS: Our data are the first to show that an RV filling pressure of 13±2 mm Hg-as by CVP-correlates with optimal RV mechanics as evaluated by strain echocardiography in patients with moderate-severe ARDS.

Changes in estimated glomerular filtration rate over time in South African HIV-1-infected patients receiving tenofovir: a retrospective cohort study.

INTRODUCTION: Tenofovir has been associated with decline in kidney function, but in patients with low baseline kidney function, improvements over time have been reported. Additionally, the magnitude and trajectory of estimated glomerular filtration rate (eGFR) changes may differ according to how eGFR is calculated. We described changes in eGFR over time, and the incidence of, and risk factors for, kidney toxicity, in a South African cohort. METHODS: We included antiretroviral-naïve patients ≥16 years old who started tenofovir-containing antiretroviral therapy (ART) between 2002 and 2013. We calculated eGFR using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockcroft-Gault equations. We described changes in eGFR from ART initiation using linear mixed effects regression. We described the incidence of eGFR <30 mL/min on treatment, and identified associations with low eGFR using Cox regression. RESULTS: We included 15156 patients with median age of 35.4 years (IQR 29.9-42.0), median CD4 cell count of 168 cells/µL (IQR 83-243), and median eGFR (MDRD) of 98.6 mL/min (IQR 84.4-115.6). Median duration of follow up on tenofovir was 12.9 months (IQR 5.1-23.3). Amongst those with a baseline and subsequent eGFR  available, mean eGFR change from baseline at 12 months was -4.4 mL/min (95% CI -4.9 to -4.0), -2.3 (-2.5 to -2.1), and 0.6 (0.04 to 1.2) in those with baseline eGFR ≥90 mL/min; and 11.9 mL/min (11.0 to 12.7), 14.6 (13.5 to 15.7), and 11.0 (10.3 to 11.7), in those with baseline eGFR <90 mL/min, according to the MDRD, CKD-EPI (n = 11 112), and Cockcroft-Gault (n = 9 283) equations, respectively. Overall, 292 (1.9%) patients developed eGFR <30 mL/min. Significant associations with low eGFR included older age, baseline eGFR <60 mL/min, CD4 count <200 cells/µL, body weight <60 kg, and concomitant protease inhibitor use. CONCLUSION: Patients on tenofovir with baseline eGFR ≥90 mL/min experienced small but significant declines in eGFR over time when eGFR was estimated using the MDRD or CKD-EPI equations. However, eGFR increased in patients with eGFR <90 mL/min, regardless of which estimating equation was used. Decreases to below 30 mL/min were uncommon. In settings with limited access to laboratory testing, monitoring guidelines should consider focusing on higher risk patients.

First-line antiretroviral drug discontinuations in children.

INTRODUCTION: There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010. METHODS: We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity. RESULTS: We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively. CONCLUSIONS: While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

Treatment and outcome of AIDS-related Kaposi sarcoma in South Africa, Malawi and Zambia: an international comparison.

HIV-related Kaposi sarcoma (KS) is common in sub-Saharan Africa, but optimal treatment strategies in resource-limited settings remain unclear. We did a retrospective cohort study of adults diagnosed with KS before initiating antiretroviral therapy (ART) at three ART programs in South Africa, Malawi and Zambia. We extracted data from medical charts at HIV clinics and oncological referral centers and used electronic data from the International epidemiology Databases to Evaluate AIDS Southern Africa. We used descriptive statistics to assess tumor (T) and systemic illness (S) stage and treatment of AIDS-KS patients. Kaplan-Meier analyses were used to assess survival after KS diagnosis. We analyzed data from 57 patients in total (20 from South Africa, 20 from Zambia, 17 from Malawi). Median age at KS diagnosis was 35 years and similar across sites. The percentage of patients with poor risk AIDS-KS (T1S1) was similar in South Africa (25%) and Malawi (24%) and higher in Zambia (45%). All AIDS-KS patients initiated ART at the HIV clinic. For KS care, in South Africa 18 patients (90%) were referred to an oncology department; in Malawi and Zambia most patients were managed by the HIV clinics. In Malawi and South Africa, most AIDS-KS patients received systemic chemotherapy, in Zambia one patient received chemotherapy at the HIV clinic. A year after KS diagnosis, 15 patients (75%) in South Africa, 10 patients (50%) in Zambia, and 8 patients (47%) in Malawi were still alive; another 3 patients (15%) in South Africa, 8 patients (40%) in Zambia and 4 patients (24%) in Malawi were lost to follow-up. Management of AIDS-KS patients varied considerably across sites in Malawi, South Africa and Zambia. We need more reliable survival data for AIDS-KS patients in sub-Saharan Africa before we can assess which treatments and clinical pathways should be adopted in a specific setting.

Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa?

OBJECTIVE: We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single-drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa. DESIGN: Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART. METHODS: We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART. RESULTS: In all, 33 441 (8.9%; 95% confience interval 8.7-8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine. CONCLUSION: The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine.

'I Know that I Do Have HIV but Nobody Saw Me': Oral HIV Self-Testing in an Informal Settlement in South Africa.

Reaching universal HIV-status awareness is crucial to ensure all HIV-infected patients access antiretroviral treatment (ART) and achieve virological suppression. Opportunities for HIV testing could be enhanced by offering self-testing in populations that fear stigma and discrimination when accessing conventional HIV Counselling and Testing (HCT) in health care facilities. This qualitative research aims to examine the feasibility and acceptability of unsupervised oral self-testing for home use in an informal settlement of South Africa. Eleven in-depth interviews, two couple interviews, and two focus group discussions were conducted with seven healthcare workers and thirteen community members. Thematic analysis was done concurrently with data collection. Acceptability to offer home self-testing was demonstrated in this research. Home self-testing might help this population overcome barriers to accepting HCT; this was particularly expressed in the male and youth groups. Nevertheless, pilot interventions must provide evidence of potential harm related to home self-testing, intensify efforts to offer quality counselling, and ensure linkage to HIV/ART-care following a positive self-test result.

Clinician compliance with laboratory monitoring and prescribing guidelines in HIV-1-infected patients receiving tenofovir.

BACKGROUND: Tenofovir is part of the preferred first-line regimen for HIV-infected patients in South Africa (SA), but is associated with kidney toxicity. SA antiretroviral therapy (ART) guidelines recommend creatinine monitoring at baseline (ART start) and at 3, 6 and 12 months, and substituting tenofovir with zidovudine, stavudine or abacavir should creatinine clearance (CrCl) decrease to <50 mL/min. OBJECTIVE: To assess clinician compliance with tenofovir monitoring and prescribing guidelines. METHODS: We described the proportion of adult patients on tenofovir-based first-line ART who were screened for baseline renal impairment, were monitored according to the SA antiretroviral treatment guidelines, and were switched from tenofovir if renal function declined. RESULTS: We included 13 168 patients who started ART from 2010 to 2012. Creatinine concentrations were recorded in 11 712 (88.9%) patients on tenofovir at baseline, 9 135/11 657 (78.4%) at 3 months, 5 426/10 554 (51.4%) at 6 months, and 5 949/ 8 421 (70.6%) at 12 months. At baseline, 227 (1.9%) started tenofovir despite a CrCl <50 mL/min. While on tenofovir, 525 patients had at least one CrCl of <50 mL/min. Of 382 patients with ≥3 months' follow-up after a CrCl <50 mL/min, 114 (29.8%) stopped tenofovir within 3 months. Clinicians were more likely to stop tenofovir in patients with lower CrCl and CD4 count. Of 226 patients who continued to receive tenofovir and had further CrCls available, 156 (69.0%) had a CrCl ≥50 mL/min at their next visit. CONCLUSIONS: Creatinine monitoring is feasible where access to laboratory services is good. Kidney function recovered in most patients who continued to receive tenofovir despite a CrCl <50 mL/min. Further research is needed to determine how best to monitor renal function with tenofovir in resource-limited settings.

CD4 count at antiretroviral therapy initiation and the risk of loss to follow-up: results from a multicentre cohort study.

BACKGROUND: Antiretroviral therapy (ART) initiation is now recommended irrespective of CD4 count. However data on the relationship between CD4 count at ART initiation and loss to follow-up (LTFU) are limited and conflicting. METHODS: We conducted a cohort analysis including all adults initiating ART (2008-2012) at three public sector sites in South Africa. LTFU was defined as no visit in the 6 months before database closure. The Kaplan-Meier estimator and Cox's proportional hazards models examined the relationship between CD4 count at ART initiation and 24-month LTFU. Final models were adjusted for demographics, year of ART initiation, programme expansion and corrected for unascertained mortality. RESULTS: Among 17 038 patients, the median CD4 at initiation increased from 119 (IQR 54-180) in 2008 to 257 (IQR 175-318) in 2012. In unadjusted models, observed LTFU was associated with both CD4 counts <100 cells/µL and CD4 counts ≥300 cells/µL. After adjustment, patients with CD4 counts ≥300 cells/µL were 1.35 (95% CI 1.12 to 1.63) times as likely to be LTFU after 24 months compared to those with a CD4 150-199 cells/µL. This increased risk for patients with CD4 counts ≥300 cells/µL was largest in the first 3 months on treatment. Correction for unascertained deaths attenuated the association between CD4 counts <100 cells/µL and LTFU while the association between CD4 counts ≥300 cells/µL and LTFU persisted. CONCLUSIONS: Patients initiating ART at higher CD4 counts may be at increased risk for LTFU. With programmes initiating patients at higher CD4 counts, models of ART delivery need to be reoriented to support long-term retention.

Implementation and Operational Research: Risk Charts to Guide Targeted HIV-1 Viral Load Monitoring of ART: Development and Validation in Patients From Resource-Limited Settings.

BACKGROUND: HIV-1 RNA viral load (VL) testing is recommended to monitor antiretroviral therapy (ART) but not available in many resource-limited settings. We developed and validated CD4-based risk charts to guide targeted VL testing. METHODS: We modeled the probability of virologic failure up to 5 years of ART based on current and baseline CD4 counts, developed decision rules for targeted VL testing of 10%, 20%, or 40% of patients in 7 cohorts of patients starting ART in South Africa, and plotted cutoffs for VL testing on colour-coded risk charts. We assessed the accuracy of risk chart-guided VL testing to detect virologic failure in validation cohorts from South Africa, Zambia, and the Asia-Pacific. RESULTS: In total, 31,450 adult patients were included in the derivation and 25,294 patients in the validation cohorts. Positive predictive values increased with the percentage of patients tested: from 79% (10% tested) to 98% (40% tested) in the South African cohort, from 64% to 93% in the Zambian cohort, and from 73% to 96% in the Asia-Pacific cohort. Corresponding increases in sensitivity were from 35% to 68% in South Africa, from 55% to 82% in Zambia, and from 37% to 71% in Asia-Pacific. The area under the receiver operating curve increased from 0.75 to 0.91 in South Africa, from 0.76 to 0.91 in Zambia, and from 0.77 to 0.92 in Asia-Pacific. CONCLUSIONS: CD4-based risk charts with optimal cutoffs for targeted VL testing maybe useful to monitor ART in settings where VL capacity is limited.

Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study.

BACKGROUND: As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the effect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the effect of age on mortality of patients on ART in South Africa and whether this effect is mediated by baseline immunological status. METHODS: In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the first time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDS-Southern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age. FINDINGS: Between Jan 1, 2004, and Dec 31, 2013, 84,078 eligible adults started ART. Of these, we followed up 83,566 patients for 174,640 patient-years. 8% (1817 of 23,258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2·52 (95% CI 2·01-3·17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per µL, the adjusted mortality hazard ratio was 2·52 (2·04-3·11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per µL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44,909 patients still alive and in care were aged 50 years or older. INTERPRETATION: Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV. FUNDING: National Institutes of Health (National Institute of Allergy and Infectious Diseases), US Agency for International Development, and South African Centre for Epidemiological Modelling and Analysis.

Reducing CD4 Monitoring in Children on Antiretroviral Therapy With Virologic Suppression.

BACKGROUND: Ongoing CD4 monitoring in patients on antiretroviral therapy (ART) with viral suppression has been questioned. We evaluated the probability of CD4 decline in children with viral suppression and CD4 recovery after 1 year on ART. METHODS: We included children from 8 South African cohorts with routine HIV-RNA monitoring if (1) they were "responders" [HIV-RNA < 400 copies/mL and no severe immunosuppression after ≥1 year on ART (time 0)] and (2) ≥1 HIV-RNA and CD4 measurement within 15 months of time 0. We determined the probability of CD4 decline to World Health Organization-defined severe immunosuppression for 3 years after time 0 if viral suppression was maintained. Follow-up was censored at the earliest of the following dates: the day before first HIV-RNA measurement >400 copies/mL; day before a >15-month gap in testing and date of death, loss to follow-up, transfer out or database closure. RESULTS: Among 5984 children [median age at time 0: 5.8 years (interquartile range: 3.1-9.0)], 270 children experienced a single CD4 decline to severe immunosuppression within 3 years of time 0 with probability of 6.6% (95% CI: 5.8-7.4). A subsequent CD4 measurement within 15 months of the first low measurement was available for 63% of children with CD4 decline and 86% showed CD4 recovery. The probability of CD4 decline was lowest (2.8%) in children aged 2 years or older with no or mild immunosuppression and on ART for <18 months at time 0. This group comprised 40% of children. CONCLUSIONS: This finding suggests that it may be safe to stop routine CD4 monitoring in children older than 2 years and rely on virologic monitoring alone.

CD4 changes among virologically suppressed patients on antiretroviral therapy: a systematic review and meta-analysis.

INTRODUCTION: The effectiveness of antiretroviral therapy (ART) is assessed by measuring CD4 cell counts and viral load. Recent studies have questioned the added value of routine CD4 cell count measures in patients who are virologically suppressed. METHODS: We systematically searched three databases and two conference sites up to 31 October 2014 for studies reporting CD4 changes among patients who were on ART and virologically suppressed. No geographic, language or age restrictions were applied. RESULTS AND DISCUSSION: We identified 12 published and 1 unpublished study reporting CD4 changes among 20,297 virologically suppressed patients. The pooled proportion of patients who experienced an unexplained, confirmed CD4 decline was 0.4% (95% CI 0.2-0.6%). Results were not influenced by duration of follow-up, age, study design or region of economic development. No studies described clinical adverse events among virologically suppressed patients who experienced CD4 declines. CONCLUSIONS: The findings of this review support reducing or stopping routine CD4 monitoring for patients who are immunologically stable on ART in settings where routine viral load monitoring is provided.

Perceptions of Community Members and Healthcare Workers on Male Involvement in Prevention of Mother-To-Child Transmission Services in Khayelitsha, Cape Town, South Africa.

Involving male partners of pregnant women accessing PMTCT programs has the potential to improve health outcomes for women and children. This study explored community members' (men and women) and healthcare workers' perceptions of male involvement in the prevention of mother-to-child transmission of HIV in Khayelitsha, South Africa. Two focus group discussions were held with 25 men of unknown HIV status and one focus group discussion held with 12 HIV-positive women in the community. In depth interviews were conducted with four HIV-positive couples and five service providers purposely sampled from the community and a health facility, respectively. Both men and women interviewed in this study were receptive towards male involvement in PMTCT. However, men were reluctant to engage with health services due to stigma and negative attitudes from nurses. This study also found HIV testing, disclosure and direct health worker engagement with men increases male involvement in PMTCT. Using men in the media and community to reach out to fellow men with prevention messages tailored to suit specific audiences may reduce perceptions of antenatal care as being a woman`s domain.

Outcomes of Infants Starting Antiretroviral Therapy in Southern Africa, 2004-2012.

BACKGROUND: There are limited published data on the outcomes of infants starting antiretroviral therapy (ART) in routine care in Southern Africa. This study aimed to examine the baseline characteristics and outcomes of infants initiating ART. METHODS: We analyzed prospectively collected cohort data from routine ART initiation in infants from 11 cohorts contributing to the International Epidemiologic Database to Evaluate AIDS in Southern Africa. We included ART-naive HIV-infected infants aged <12 months initiating ≥3 antiretroviral drugs between 2004 and 2012. Kaplan-Meier estimates were calculated for mortality, loss to follow-up (LTFU), transfer out, and virological suppression. We used Cox proportional hazard models stratified by cohort to determine baseline characteristics associated with outcomes mortality and virological suppression. RESULTS: The median (interquartile range) age at ART initiation of 4945 infants was 5.9 months (3.7-8.7) with follow-up of 11.2 months (2.8-20.0). At ART initiation, 77% had WHO clinical stage 3 or 4 disease and 87% were severely immunosuppressed. Three-year mortality probability was 16% and LTFU 29%. Severe immunosuppression, WHO stage 3 or 4, anemia, being severely underweight, and initiation of treatment before 2010 were associated with higher mortality. At 12 months after ART initiation, 17% of infants were severely immunosuppressed and the probability of attaining virological suppression was 56%. CONCLUSIONS: Most infants initiating ART in Southern Africa had severe disease with high probability of LTFU and mortality on ART. Although the majority of infants remaining in care showed immune recovery and virological suppression, these responses were suboptimal.

Implementation and Operational Research: Reconstructing the PMTCT Cascade Using Cross-sectional Household Survey Data: The PEARL Study.

BACKGROUND: Given the ambitious targets to reduce pediatric AIDS worldwide, ongoing assessment of programs to prevent mother-to-child HIV transmission (PMTCT) is critical. The concept of a "PMTCT cascade" has been used widely to identify bottlenecks in program implementation; however, most efforts to reconstruct the cascade have relied on facility-based approaches that may limit external validity. METHODS: We analyzed data from the PEARL household survey, which measured PMTCT effectiveness in 26 communities across Zambia, South Africa, Cote d'Ivoire, and Cameroon. We recruited women who reported a delivery in the past 2 years. Among mothers confirmed to be HIV infected at the time of survey, we reconstructed the PMTCT cascade with self-reported participant information. We also analyzed data about the child's vital status; for those still alive, HIV testing was performed by DNA polymerase chain reaction testing. RESULTS: Of the 976 eligible women, only 355 (36%) completed every step of the PMTCT cascade. Among the 621 mother-child pairs who did not, 22 (4%) reported never seeking antenatal care, 103 (17%) were not tested for HIV during pregnancy, 395 (64%) reported testing but never received their HIV-positive result, 48 (8%) did not receive maternal antiretroviral prophylaxis, and 53 (9%) did not receive infant antiretroviral prophylaxis. The lowest prevalence of infant HIV infection or death was observed in those completing the cascade (10%, 95% confidence interval: 7% to 12%). CONCLUSIONS: Future efforts to measure population PMTCT impact should incorporate dimensions explored in the PEARL study-including HIV testing of HIV-exposed children in household surveys-to better understand program effectiveness.

The Contribution of Ebola Viral Load at Admission and Other Patient Characteristics to Mortality in a Médecins Sans Frontières Ebola Case Management Centre, Kailahun, Sierra Leone, June-October 2014.

This paper describes patient characteristics, including Ebola viral load, associated with mortality in a Médecins Sans Frontières Ebola case management centre (CMC).Out of 780 admissions between June and October 2014, 525 (67%) were positive for Ebola with a known outcome. The crude mortality rate was 51% (270/525). Ebola viral load (whole-blood sample) data were available on 76% (397/525) of patients. Univariate analysis indicated viral load at admission, age, symptom duration prior to admission, and distance traveled to the CMC were associated with mortality (P < .05). The multivariable model predicted mortality in those with a viral load at admission greater than 10 million copies per milliliter (P < .05, odds ratio >10), aged ≥ 50 years (P = .08, odds ratio = 2) and symptom duration prior to admission less than 5 days (P = .14). The presence of confusion, diarrhea, and conjunctivitis were significantly higher (P < .05) in Ebola patients who died.These findings highlight the importance viral load at admission has on mortality outcomes and could be used to cohort cases with viral loads greater than 10 million copies into dedicated wards with more intensive medical support to further reduce mortality.