Voluntary medical male circumcision in selected provinces in South Africa: Outcomes from a programmatic setting.

INTRODUCTION: Voluntary medical male circumcision (VMMC) remains an effective biomedical intervention for HIV prevention in high HIV prevalence countries. In South Africa, United States Agency for International Development VMMC partners provide technical assistance to the Department of Health, at national and provincial levels in support of the establishment of VMMC sites as well as in providing direct VMMC services at site level since April 2012. We describe the outcomes of the Right to Care (RTC) VMMC program implemented in South Africa from 2012 to 2017. METHODS: This retrospective study was undertaken at RTC supported facilities across six provinces. Young males aged ≥10 years who presented at these facilities from 1 July 2012 to 31 September 2017 were included. Outcomes were VMMC uptake, HIV testing uptake and rate of adverse events (AEs). Using a de-identified observational database of these clients, summary statistics of the demographic characteristics and outcomes were calculated. RESULTS: There were a total 1,001,226 attendees of which 998,213 (99.7%) were offered VMMC and had a median age of 15 years (IQR = 12-23 years). Of those offered VMMC, 99.6% (994,293) consented, 96.7% (965,370) were circumcised and the majority (46.3%) were from Gauteng province. HIV testing uptake was 71% with a refusal rate of 15%. Of the newly diagnosed HIV positives, 64% (6,371 / 9,972) referrals were made. The rate of AEs, defined as bleeding, infection, and insufficient skin removal) declined from 3.26% in 2012 to 1.17% in 2017. There was a reduction in infection-related AEs from 2,448 of the 2,602 adverse events (94.08%) in 2012 to 129 of the 2,069 adverse events (6.23%) in 2017. CONCLUSION: There was a high VMMC uptake with a decline in AEs over time. Adolescent men contributed the most to the circumcised population, an indication that the young population accesses medical circumcision more. VMMC programs need to implement innovative demand creation strategies to encourage older males (20-34 years) at higher risk of HIV acquisition to get circumcised for immediate impact in reduction of HIV incidence. HIV prevalence in the total population increased with increasing age, notably in clients above 25 years.

Applying machine learning and predictive modeling to retention and viral suppression in South African HIV treatment cohorts.

HIV treatment programs face challenges in identifying patients at risk for loss-to-follow-up and uncontrolled viremia. We applied predictive machine learning algorithms to anonymised, patient-level HIV programmatic data from two districts in South Africa, 2016-2018. We developed patient risk scores for two outcomes: (1) visit attendance ≤ 28 days of the next scheduled clinic visit and (2) suppression of the next HIV viral load (VL). Demographic, clinical, behavioral and laboratory data were investigated in multiple models as predictor variables of attending the next scheduled visit and VL results at the next test. Three classification algorithms (logistical regression, random forest and AdaBoost) were evaluated for building predictive models. Data were randomly sampled on a 70/30 split into a training and test set. The training set included a balanced set of positive and negative examples from which the classification algorithm could learn. The predictor variable data from the unseen test set were given to the model, and each predicted outcome was scored against known outcomes. Finally, we estimated performance metrics for each model in terms of sensitivity, specificity, positive and negative predictive value and area under the curve (AUC). In total, 445,636 patients were included in the retention model and 363,977 in the VL model. The predictive metric (AUC) ranged from 0.69 for attendance at the next scheduled visit to 0.76 for VL suppression, suggesting that the model correctly classified whether a scheduled visit would be attended in 2 of 3 patients and whether the VL result at the next test would be suppressed in approximately 3 of 4 patients. Variables that were important predictors of both outcomes included prior late visits, number of prior VL tests, time since their last visit, number of visits on their current regimen, age, and treatment duration. For retention, the number of visits at the current facility and the details of the next appointment date were also predictors, while for VL suppression, other predictors included the range of the previous VL value. Machine learning can identify HIV patients at risk for disengagement and unsuppressed VL. Predictive modeling can improve the targeting of interventions through differentiated models of care before patients disengage from treatment programmes, increasing cost-effectiveness and improving patient outcomes.

Persistent Symptoms among Frontline Health Workers Post-Acute COVID-19 Infection.

Growing evidence shows that a significant number of patients with COVID-19 experience persistent symptoms, also known as long COVID-19. We sought to identify persistent symptoms of COVID-19 in frontline workers at Right to Care South Africa, who are past the acute phase of illness, using a cross-sectional survey. We analysed data from 207 eligible COVID-19 positive frontline workers who participated in a two-month post-COVID-19 online self-administered survey. The survey response rate was 30%; of the 62 respondents with a median age of 33.5 years (IQR= 30-44 years), 47 (76%) were females. The majority (n = 55; 88.7%) self-isolated and 7 (11.3%) were admitted to hospital at the time of diagnosis. The most common comorbid condition reported was hypertension, particularly among workers aged 45-55 years. The most reported persistent symptoms were characterised by fatigue, anxiety, difficulty sleeping, chest pain, muscle pain, and brain fog. Long COVID-19 is a serious phenomenon, of which much is still unknown, including its causes, how common it is especially in non-hospitalised healthcare workers, and how to treat it. Given the rise in COVID-19 cases, the prevalence of long COVID-19 is likely to be substantial; thus, the need for rehabilitation programs targeted at each persistent COVID-19 symptom is critical.

Effective public-private partnerships for sustainable antiretroviral therapy: outcomes of the Right to Care health services GP down-referral program.

BACKGROUND: The recently increased access to antiretroviral therapy (ART) in South Africa has placed additional strain on human and infrastructure resources of the public health sector. Capacity from private-sector General Practitioners (GPs) could be leveraged to ease the current burden on the public health sector. METHODS: We conducted a retrospective record review of routine electronic medical record data on a systematic sample of HIV-infected adults (≥18 years old) initiated on ART at a tertiary hospital outpatient HIV clinic in Johannesburg, South Africa and down-referred to private-GPs for continued care after stabilization on ART. We compared these patients ("GP down-referred") to a control-cohort who remained at the referring site ("Clinic A") and patients from a regional hospital outpatient HIV clinic not offering down-referral to GPs ("Clinic B"). Study outcomes assessed are viral load suppression (VL < 50 copies/ml) and attrition from care (all-cause-mortality or > 90-days late for a last-scheduled visit) by 12 months of follow-up following down-referral or eligibility. RESULTS: A total of 3685 patients, comprising 373 (10.1%) GP down-referred, 2599 (70.5%) clinic A controls, and 713 (19.4%) clinic B controls were included in the analysis. Overall, 1535 patients (53.3%) had a suppressed viral load. A higher portion of GP down-referred patients had a suppressed viral load compared to clinic A and B patients (65.7% vs 49.1% vs 58.9%). After adjusting for demographic and baseline clinical covariates, we found no difference in viral load suppression between GP down-referred and control patients (adjusted relative risk [aRR] for clinic A vs GP down-referred 1.0; 95% CI: 0.9-1.1), (aRR for clinic B vs GP down-referred 1.0; 95% CI: 0.9-1.2). Clinic B controls experienced the highest attrition compared to GP down-referred and clinic A controls (33.2% vs 11.3% vs 5.9%) and had a higher risk of attrition compared to GP down-referred patients (adjusted hazard ratio [aHR] 4.2; 95% CI: 2.8-6.5), whereas clinic B controls had a lower risk of attrition (aHR 0.5; 95% CI: 0.3-0.7). CONCLUSIONS AND RECOMMENDATIONS: Our results show that private-GPs can contribute to caring for stabilized public sector HIV patients on life-long ART. However, they require special efforts to improve retention in care.

Human immunodeficiency virus infection and older adults: A retrospective single-site cohort study from Johannesburg, South Africa.

INTRODUCTION: HIV-infected adults aged over 50 years in South Africa are increasing. This study explored differences between baseline characteristics and 12-month outcomes of younger and older HIV-infected adults initiated on antiretroviral therapy (ART). Additionally, associations with outcomes within the older group were sought. METHODS: We retrospectively reviewed treatment-naive HIV-infected adult patients at ART initiation. Patients aged 18.0-39.9 years were compared to patients aged over 50 years using log-binomial regression for baseline characteristics and 12-month outcomes. Within the older group, outcome associations were found using multivariate regression. RESULTS: The older cohort (n = 1635) compared to the younger cohort (n = 10726) comprised more males (47.2% vs. 35.4%, PR 1.52, p < 0.05), smokers (12.9% vs. 9.7%, PR 1.32, p < 0.05) and overweight patients (26.0% vs. 20.0%, PR 1.32, p < 0.05). Fewer older patients had tuberculosis (10.2% vs. 15.3%, PR 0.67, p < 0.05), other opportunistic infections (16.9% vs. 23.3%, PR 0.70, p < 0.05), World Health Organization stage 3/4 disease (39.9% vs. 43.2%, PR 0.89, p < 0.05), anaemia (22.8% vs. 28.4%, PR 0.77, p < 0.05), liver dysfunction (17.1% vs. 21.3%, PR 0.83, p < 0.05) or low CD4+ count < 100 cells/mm3 (56.3% vs. 59.9%, PR 0.71, p < 0.05).Mortality was higher in the older cohort (11.3% vs. 7.5%, PR 1.48, p < 0.05). Virological suppression was greater in the older cohort (89.5% vs. 86.5%, PR 1.28, p < 0.05) but CD4+ restitution was lower (62.8% vs. 75.0%, PR 0.61, p < 0.05). There was no difference in treatment complications between the groups.Within the older cohort, associations with death were as follows: age > 55 years (PR 1.47, p < 0.05), an AIDS-defining condition (PR 2.28, p < 0.05), raised ALT (PR 1.53, p < 0.05) and CD4+ < 100 cells/mm3 (PR 2.15, p < 0.05). Associations with favourable treatment response at 12 months were unemployment (PR 1.18, p < 0.05) and raised ALT (PR 1.19, p < 0.05). Associations with a treatment complication at 12 months were unemployment (PR 1.12, p < 0.05), smoking (PR 1.20, p < 0.05) and nevirapine use (PR 1.36, p < 0.05) but secondary education was protective (PR 0.87, p < 0.05). CONCLUSION: HIV-infected South African adults aged over 50 years differ in characteristics and outcomes compared to their younger counterparts and justify specialised management within HIV treatment facilities.

Comparison of pharmacy-based measures of adherence to antiretroviral therapy as predictors of virological failure.

We compared multiple pharmacy refill-based adherence indicators for antiretroviral therapy, as well as thresholds for defining non-adherent behavior, based on ability to predict virological failure. A total of 29,937 pharmacy visits with corresponding viral load assessments were contributed by 8,695 patients attending a large clinic in Johannesburg, South Africa. Indicators based on pill coverage and timing of refill pickup performed comparably using the strictest thresholds for adherence [100 % pill coverage: odds ratio (OR) (95 % confidence interval (CI)) : 1.26 (1.15, 1.39); prescription picked up on or before scheduled refill date: 1.27 (1.16,1.38)]. For both types of indicators, the association between non-adherence and virological failure increased as the threshold defining adherent behavior was lowered. All measures demonstrated high specificity (range 84-98 %), but low sensitivity (5-19 %). In this setting, patients identified as non-adherent using pharmacy-based indicators are likely correctly classified and in need of interventions to improve compliance. Pharmacy based measures alone, however, are inadequate for identifying most cases of nonadherence.

Incidence and predictors of herpes zoster among antiretroviral therapy-naïve patients initiating HIV treatment in Johannesburg, South Africa.

OBJECTIVES: To describe the characteristics of HIV-infected patients experiencing herpes zoster after antiretroviral therapy (ART) initiation and to describe the incidence and predictors of a herpes zoster diagnosis. METHODS: Adult patients initiating ART from April 2004 to September 2011 at the Themba Lethu Clinic in Johannesburg, South Africa were included. Patients were followed from ART initiation until the date of first herpes zoster diagnosis, or death, transfer, loss to follow-up, or dataset closure. Herpes zoster is described using incidence rates (IR) and predictors of herpes zoster are presented as subdistribution hazard ratios (sHR) and 95% confidence intervals (95% CI). RESULTS: Fifteen thousand and twenty-five patients were included; 62% were female, the median age was 36.6 years, and the median baseline CD4 count was 98 cells/mm(3). Three hundred and forty patients (2.3%) experienced herpes zoster in a median of 26.1 weeks after ART initiation. Most (71.5%) occurred within 1 year of initiation, for a 1-year IR of 18.1/1000 person-years. In an adjusted model, patients with low CD4 counts (<50 vs. ≥200 cells/mm(3); sHR: 1.71, 95% CI: 1.21-2.47) and with a prior episode of herpes zoster (sHR: 1.53, 95% CI: 0.97-2.28) were at increased risk of incident herpes zoster. CONCLUSIONS: While only 2% of patients were diagnosed with herpes zoster in this cohort, patients with low CD4 counts and those with prior episodes of herpes zoster were at higher risk for a herpes zoster diagnosis.

Incident pregnancy and time to death or AIDS among HIV-positive women receiving antiretroviral therapy.

BACKGROUND: Little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We examined the effect of incident pregnancy after HAART initiation on clinical response to HAART. METHODS: We evaluated a prospective clinical cohort of adult women initiating HAART in Johannesburg, South Africa between 1 April 2004 and 31 March 2011, and followed up until an event, transfer, drop-out, or administrative end of follow-up on 30 September 2011. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study. Main exposure was having experienced pregnancy after HAART initiation; main outcome was death and (separately) death or new AIDS event. We calculated adjusted hazard ratios (HRs) and 95% confidence limits (CL) using marginal structural Cox proportional hazards models. RESULTS: The study included 7,534 women, and 20,813 person-years of follow-up; 918 women had at least one recognized pregnancy during follow-up. For death alone, the weighted (adjusted) HR was 0.84 (95% CL 0.44, 1.60). Sensitivity analyses confirmed main results, and results were similar for analysis of death or new AIDS event. Incident pregnancy was associated with a substantially reduced hazard of drop-out (HR = 0.62, 95% CL 0.51, 0.75). CONCLUSIONS: Recognized incident pregnancy after HAART initiation was not associated with increases in hazard of clinical events, but was associated with a decreased hazard of drop-out. High rates of pregnancy after initiation of HAART may point to a need to better integrate family planning services into clinical care for HIV-infected women.

Cohort profile: the Themba Lethu Clinical Cohort, Johannesburg, South Africa.

The Themba Lethu Clinical Cohort was established in 2004 to allow large patient-level analyses from a single HIV treatment site to evaluate National Treatment Guidelines, answer questions of national and international policy relevance and to combine an economic and epidemiologic focus on HIV research. The current objectives of the Themba Lethu Clinical Cohort analyses are to: (i) provide cohort-level information on the outcomes of HIV treatment; (ii) evaluate aspects of HIV care and treatment that have policy relevance; (iii) evaluate the cost and cost-effectiveness of different approaches to HIV care and treatment; and (iv) provide a platform for studies on improving HIV care and treatment. Since 2004, Themba Lethu Clinic has enrolled approximately 30,000 HIV-positive patients into its HIV care and treatment programme, over 21,000 of whom have received anti-retroviral therapy since being enrolled. Patients on treatment are typically seen at least every 3 months with laboratory monitoring every 6 months to 1 year. The data collected include demographics, clinical visit data, laboratory data, medication history and clinical diagnoses. Requests for collaborations on analyses can be submitted to our data centre.

Incidence of pregnancy after initiation of antiretroviral therapy in South Africa: a retrospective clinical cohort analysis.

BACKGROUND: Little is known about rates of incident pregnancy among HIV-positive women initiating highly active antiretroviral therapy (HAART). METHODS: We conducted a retrospective clinical cohort study among therapy-naïve women ages 18-45 initiating HAART between 1 April 2004 and 30 September 2009 at an adult HAART clinic in Johannesburg, South Africa. We used Poisson regression to characterize rates and rate ratios of pregnancy. RESULTS: We evaluated 5,996 women who experienced 727 pregnancies during 14,095 person-years at risk. The overall rate of pregnancy was 5.2 per 100 person-years (95% confidence limits [CL] 4.8, 5.5). By six years, cumulative incidence of first pregnancy was 22.9% (95% CL 20.6%, 25.4%); among women ages 18-25 at HAART initiation, cumulative incidence was 52.2% (95% CL 35.0%, 71.8%). The strongest predictor of incidence of pregnancy was age, with women 18-25 having 13.2 times the rate of pregnancy of women ages 40-45 in adjusted analysis. CD4 counts below 100 and worse adherence to HAART were associated with lower rates of incident pregnancy. CONCLUSIONS: Women experience high rates of incident pregnancy after HAART initiation. Understanding which women are most likely to experience pregnancy will help planning and future efforts to understand the implications of pregnancy for response to HAART.

Treatment outcomes after 7 years of public-sector HIV treatment.

OBJECTIVES: To assess outcomes over the first 7 years of antiretroviral therapy (ART) at Themba Lethu Clinic, Johannesburg, South Africa. DESIGN: Observational cohort study. METHODS: Patients are managed according to South African National Treatment Guidelines. Mortality is ascertained through linkage with the national vital registration system. Loss to follow-up is defined as at least 3 months late for the last scheduled appointment. RESULTS: Between April 2004 and March 2010, 13 227 patients initiated ART, increasing from 1794 in the year 2004/2005 to 2481 in 2009/2010. Median CD4 cell count at ART initiation increased 39% between 2004 and 2009 (82 vs. 114 cells/ml). The proportion who died within 1 year on ART was below 11% at all time points, whereas the proportion lost by 1 year increased from 8.5% in 2004 to 12.1% in 2009 [risk ratio (RR) 1.42, 95% confidence interval (CI) 1.18­1.71]. We followed the 1794 patients initiated in April 2004 and March 2005 through August 2011 for 8172 person-years. We estimated 25% of patients were lost and 16% died. The overall mortality rate was 3.59 per 100 person-years (95% CI 3.20­4.02). Of the 1577 who completed at least 6 months of follow-up, 213 (13.5%) failed first-line treatment in a median (interquartile range) of 25.9 (15.8­41.4) months on treatment. Of those who failed, 141 (66.2%) switched to second-line for a rate of 48.5 per 100 person-years (95% CI 41.1­57.2). CONCLUSION: Despite some improvements over 7 years, more intervention is needed in the first year on treatment to reduce overall attrition.

Prevalent pregnancy, biological sex, and virologic response to antiretroviral therapy.

OBJECTIVE: Pregnancy is a common indication for initiation of highly active antiretroviral therapy (HAART) in sub-Saharan Africa. Our objective was to evaluate how pregnancy at treatment initiation predicts virologic response to HAART. METHODS: We evaluated an open cohort of 9173 patients who initiated HAART between April 2004 and September 2009 in the Themba Lethu Clinic in Johannesburg, South Africa. Risk ratios were estimated using log-binomial regression; hazard ratios were estimated using Cox proportional hazards models; time ratios were estimated using accelerated failure time models. We controlled for calendar date, age, ethnicity, employment status, history of smoking, tuberculosis, WHO stage, weight, body mass index, hemoglobin, CD4 count and CD4 percent, and whether clinical care was free. Extensive sensitivity and secondary analyses were performed. RESULTS: During follow-up, 822 nonpregnant women and 70 pregnant women experienced virologic failure. In adjusted analyses, pregnancy at baseline was associated with reduced risk of virologic failure by 6 months [risk ratio 0.66, 95% confidence limits (CL): 0.35 to 1.22] and with reduced hazard of virologic failure over follow-up (hazard ratio: 0.69, 95% CL: 0.50 to 0.95). The adjusted time ratio for failure was 1.44 (95% CL: 1.13 to 1.84), indicating 44% longer time to event among women pregnant at baseline. Sensitivity analyses generally confirmed main findings. CONCLUSIONS: Pregnancy at HAART initiation is not associated with increased risk of virologic failure at 6 months or during longer follow-up.

Long term outcomes of antiretroviral therapy in a large HIV/AIDS care clinic in urban South Africa: a prospective cohort study.

BACKGROUND: Clinical, immunologic and virologic outcomes at large HIV/AIDS care clinics in resource poor settings are poorly described beyond the first year of highly active antiretroviral treatment (HAART). We aimed to prospectively evaluate long-term treatment outcomes at a large scale HIV/AIDS care clinic in South Africa. METHODS: Cohort study of patients initiating HAART between April 1, 2004 and March 13, 2007, and followed up until April 1, 2008 at a public HIV/AIDS care clinic in Johannesburg, South Africa. We performed time to event analysis on key treatment outcomes and program impact parameters including mortality, retention in care, CD4 count gain, virologic success and first line regimen durability. RESULTS: 7583 HIV-infected patients initiated care and contributed to 161,000 person months follow up. Overall mortality rate was low (2.9 deaths per 100 person years, 95% CI 2.6-3.2), but high in the first three months of HAART (8.4 per 100 person years, 95% CI 7.2-9.9). Long-term on-site retention in care was relatively high (74.4% at 4 years, 95%CI 73.2-75.6). CD4 count was above 200 cells/mm(3 )after 6 months of treatment in almost all patients. By the fourth year of HAART, the majority (59.6%, 95%CI 57.8-61.4) of patients had at least one first line drug (mainly stavudine) substituted. Women were twice as likely to experience drug substitution (OR 1.97, 95% CI 1.80-2.16). By 6 months of HAART, 90.8% suppressed virus below 400 copies. Among those with initial viral suppression, 9.4% (95% CI 8.5-10.3%) had viral rebound within one year of viral suppression, 16.8% (95% CI 15.5-18.1) within 2 years, and 20.6% (95% CI 18.9-22.4) within 3 years of initial suppression. Only 10% of women and 13% of men initiated second line HAART. CONCLUSION: Despite advanced disease presentation and a very large-scale program, high quality care was achieved as indicated by good long-term clinical, immunologic and virologic outcomes and a low rate of second line HAART initiation. High rates of single drug substitution suggest that the public health approach to HAART could be further improved by the use of a more durable first line regimen.

Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy.

BACKGROUND: Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART. METHODS: We evaluated a cohort of 7066 patients who initiated HAART from April 2004 through March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation, concurrent initiation of TB treatment and HAART, and incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks. RESULTS: Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dosage. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI], 1.82-5.56) in the first 2 months of HAART, 2.51 (95% CI, 1.77-3.54) in months 3-6, and 1.19 (95% CI, 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI, 3.03-14.37) in the first 2 months, 1.88 (95% CI, 0.87-4.09) in months 3-6, and 1.07 (95% CI, 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk. CONCLUSIONS: Risk of stavudine substitution was increased among patients who received TB treatment and was especially elevated during the period soon after HAART initiation. In settings in which alternative antiretroviral drugs are available, initiation of stavudine therapy in patients receiving TB treatment may need to be reconsidered.