Themba Lethu Clinic Research Articles

Factors associated with patients defaulting on HIV treatment at Helen Joseph Hospital, Gauteng province, South Africa

Background: South Africa’s government has made significant improvements in expanding access to antiretroviral (ARV) treatment. A rate of adherence of 95% to 100% is necessary to achieve the intended outcomes of antiretroviral treatment. However, antiretroviral treatment adherence remains a significant challenge at Helen Joseph Hospital, where an adherence rate of 51% to 59% has been reported. Objective: The goal of this study was to examine the factors associated with ARV therapy non-adherence among HIV patients at Helen Joseph Hospital. Method: The study used a case-control design. There were 32 570 eligible patients for this study and 322 were selected from the overall population. Epi Info™ 7.2 was used to calculate the sample size. A total of 322 questionnaires were administered to participants during their clinic visits. The Aids Clinical Trial Group (ACTG) Questionnaire was used to measure and describe factors associated with ART treatment defaulting. Epi Info™ 7.2 was used to calculate crude odds ratios and SPSS version 26 was used to conduct multivariate logistic regression to compute adjusted odds ratios at 95% confidence intervals and p-values. Results: In total, there were 322 (100%) study participants, of which 51% (n = 165) were non-adherent to ARV therapy and 49% (n = 157) were adherent. Participants’ ranged between 19 and 58 years old, with a mean age of 34 years old and a standard deviation of 8.03 years. Treatment non-adherence was associated with long waiting times at Helen Joseph’s Themba Lethu Clinic after adjusting for gender, age, educational level and employment status. The adjusted odds ratio was 4.78, 95% CI 1.12–20.42, and p = 0.04. Conclusion: The study explored factors associated with ARV treatment defaults at Helen Joseph hospital. The long waiting times at the hospital were strongly associated with non-adherence to ARV treatment. A reduction in clinic waiting times will result in improved adherence to ARV treatment. To reduce long waiting times, the study recommends a multi-month medication dispensing programme and differentiation of HIV care. We recommend that future research include patients and clinic managers (as well as other key players) in the development of solutions to reduce waiting times. Contribution: Helen Joseph Hospital did not view long waiting times as a factor that would cause a patient to default on their ARV treatment in the past. Helen Joseph Hospital’s management team was influenced by the study results. To achieve an adherence rate of 95% to 100%, the hospital is reducing waiting times.

Assessment of facility-level antiretroviral treatment patient status utilizing a national-level laboratory cohort: Toward an understanding of system-level tracking and clinic switching in South Africa.

Most estimates of HIV retention are derived at the clinic level through antiretroviral (ART) patient management systems, which capture ART clinic visit data, yet these cannot account for silent transfers across HIV treatment sites. Patient laboratory monitoring visits may also be observed in routinely collected laboratory data, which include ART monitoring tests such as CD4 count and HIV viral load, key to our work here. In this analysis, we utilized the NHLS National HIV Cohort (a system-wide viewpoint) to investigate the accuracy of facility-level estimates of retention in care for adult patients accessing care (defined using clinic visit data on patients under ART recorded in an electronic patient management system) at Themba Lethu Clinic (TLC). Furthermore, we describe patterns of facility switching among all patients and those patients classified as lost to follow-up (LTFU) at the facility level. Of the 43,538 unique patients in the TLC dataset, we included 20,093 of 25,514 possible patient records (78.8%) in our analysis that were linked with the NHLS National Cohort, and we restricted the analytic sample to patients initiating ART between 1 January 2007 and 31 December 2017. Most (60%) patients were female, and the median age (IQR) at ART initiation was 37 (31-45) years. We found the laboratory records augmented retention estimates by a median of 860 additional active records (about 8% of all median active records across all years) from the facility viewpoint; this augmentation was more noticeable from the system-wide viewpoint, which added evidence of activity of about one-third of total active records in 2017. In 2017, we found 7.0% misclassification at the facility-level viewpoint, a gap which is potentially solvable through data integration/triangulation. We observed 1,134/20,093 (5.6%) silent transfers; these were noticeably more female and younger than the entire dataset. We also report the most common locations for clinic switching at a provincial level. Integration of multiple data sources has the potential to reduce the misclassification of patients as being lost to care and help understand situations where clinic switching is common. This may help in prioritizing interventions that would assist patients moving between clinics and hopefully contribute to services that normalize formal transfers and fewer silent transfers.

An investigation of maternal anaemia among HIV infected pregnant women on antiretroviral treatment in Johannesburg, South Africa.

Introductionmaternal anaemia is a major public health problem in developing countries. Data suggests that anaemia contributes to the progression of Human Immunodeficiency Virus (HIV)-infection. The aim of this study was to investigate if pregnancy was an aggravating factor for anaemia among HIV-positive women on anti-retroviral treatment (ART).Methodswe analyzed data of all HIV-positive women aged 18-49 years receiving ART at Themba Lethu Clinic, Helen Joseph Hospital, Johannesburg, South Africa, from 1st April 2004- 30t hApril 2011. HIV-positive pregnant women were matched with non-pregnant women using the year of initiation of treatment. The outcome of interest ´anaemia´ was defined as “no anaemia”, “anaemia” and “moderate/severe anaemia”. We fitted an ordered logistic regression model to predict the likelihood of having severe/moderate anaemia versus no anaemia. We included pregnancy status as a predictor of the outcome and controlled the effect of other covariates in the analysis.Resultsthe study included 236 HIV positive patients, of which half (n=118, 50%) were pregnant. At baseline, about (n=143, 60%) of patients were anaemic. The proportion of pregnant women classified as anaemic (anaemia, moderate/severe) differed significantly (p=0.02) from that of non-pregnant women. The following characteristics were significantly associated with anaemia at baseline: Body mass index (BMI) category (p=0.01); World Health Organization (WHO) stage (p=0.001) and CD4 count (p=0.001). Seven months after initiation of treatment, the proportion of HIV positive women with anaemia decreased significantly.Conclusionanaemia is a significant risk factor for untoward health outcomes, especially among HIV-positive pregnant women. Early ART access might result in a significant decrease in anaemia in pregnancy.

Clinical predictor score to identify patients at risk of poor viral load suppression at six months on antiretroviral therapy: results from a prospective cohort study in Johannesburg, South Africa.

Purpose: As countries work toward 90:90:90 targets, early identification of patients with inadequate response to antiretroviral therapy (ART) is critical for achieving optimal HIV treatment outcomes. We developed and evaluated a clinical prediction score (CPS) to identify HIV-positive patients at risk of poor viral load suppression at 6 months on ART.Patients and methods: We conducted a prospective cohort study of HIV-positive ART naïve adults (≥18 years) initiating standard first-line ART between February 2012 and April 2014 at Themba Lethu Clinic in Johannesburg, South Africa. We used Modified Poisson regression to estimate the association between patient characteristics and poor viral load suppression, defined as a viral load ≥400 copies/mL at 6 months on ART. We developed a CPS following the Spiegel Halter and Knill-Jones approach and determined the diagnostic accuracy compared to viral load as the “gold standard”. We identified the optimal cutoff at which the CPS would identify those at risk of poor viral load suppression.Results: Among 353 patients, 67.7% had a viral load measurement at 6 months on ART and 30.1% of these were viremic (≥400 copies/mL). Male gender, platelet count <150 cells/mm3, ≥7 days late for ≥2 ARV visits, visual analog scale (VAS) <90% and <14.5 fL increase in mean cell volume from baseline to 6 months were included in the CPS. The optimal cutoff was 5 (≥5 vs <5; sensitivity [Se] 65.3%, specificity [Sp] 46.7%) and the CPS performed better than standard measures of adherence (eg, VAS Se 24.5%; Simplified Medication Adherence Questionnaire Se 26.5%).Conclusion: Our findings suggest a 6-month CPS may have the potential to identify patients at risk of poor viral load suppression. The CPS may be used to target patients who need intensive adherence support, with the caveat that there may be a three- to four-fold increase in the pool of patients identified for adherence counseling.

Predictors of switch to and early outcomes on third-line antiretroviral therapy at a large public-sector clinic in Johannesburg, South Africa

BackgroundWhile efficacy data exist, there are limited data on the outcomes of patients on third-line antiretroviral therapy (ART) in sub-Saharan Africa in actual practice. Being able to identify predictors of switch to third-line ART will be essential for planning for future need. We identify predictors of switch to third-line ART among patients with significant viraemia on a protease inhibitor (PI)-based second-line ART regimen. Additionally, we describe characteristics of all patients on third-line at a large public sector HIV clinic and present their early outcomes.MethodsRetrospective analysis of adults (≥ 18 years) on a PI-based second-line ART regimen at Themba Lethu Clinic, Johannesburg, South Africa as of 01 August 2012, when third-line treatment became available in South Africa, with significant viraemia on second-line ART (defined as at least one viral load ≥ 1000 copies/mL on second-line ART after 01 August 2012) to identify predictors of switch to third-line (determined by genotype resistance testing). Third-line ART was defined as a regimen containing etravirine, raltegravir or ritonavir boosted darunavir, between August 2012 and January 2016. To assess predictors of switch to third-line ART we used Cox proportional hazards regression among those with significant viraemia on second-line ART after 01 August 2012. Then among all patients on third-line ART we describe viral load suppression, defined as a viral load < 400 copies/mL, after starting third-line ART.ResultsAmong 719 patients in care and on second-line ART as of August 2012 (with at least one viral load ≥ 1000 copies/mL after 01 August 2012), 36 (5.0% over a median time of 54 months) switched to third-line. Time on second-line therapy (≥ 96 vs. < 96 weeks) (adjusted Hazard Ratio (aHR): 2.53 95% CI 1.03–6.22) and never reaching virologic suppression while on second-line ART (aHR: 3.37 95% CI 1.47–7.73) were identified as predictors of switch. In a separate cohort of patients on third-line ART, 78.3% (47/60) and 83.3% (35/42) of those in care and with a viral load suppressed their viral load at 6 and 12 months, respectively.ConclusionsOur results show that the need for third-line is low (5%), but that patients’ who switch to third-line ART have good early treatment outcomes and are able to suppress their viral load. Adherence counselling and resistance testing should be prioritized for patients that are at risk of failure, in particular those who never suppress on second-line and those who have been on PI-based regimen for extended periods.

Social and behavioral factors associated with failing second-line ART – results from a cohort study at the Themba Lethu Clinic, Johannesburg, South Africa

ABSTRACTPoor adherence is a main challenge to successful second-line ART in South Africa. Studies have shown that patients can re-suppress their viral load following intensive adherence counselling. We identify factors associated with failure to re-suppress on second-line ART.The study was a retrospective cohort study which included HIV-positive adults who experienced an elevated viral load ≥400 copies/ml on second-line ART between January 2013–July 2014, had completed an adherence counselling questionnaire and had a repeat viral load result recorded within 6 months of intensive adherence counselling. Log-binomial regression was used to evaluate the association between patient characteristics and social, behavioral or occupational factors and failure to suppress viral load (≥400 copies/ml).A total of 128 patients were included in the analysis, and of these 39% (n = 50) failed to re-suppress their viral load. Compared to those who suppressed, far more patients who failed to suppress reported living with family (44.2% vs. 23.7%), missing a dose in the past week (53.3% vs. 30.0%), using traditional/herbal medications (63.2% vs. 34.3%) or had symptoms suggestive of depression (57.7% vs. 34.3%).These patient-related factors could be targeted for interventions to reduce the risk for treatment failure and prevent switching to expensive third-line ART.

The right combination - treatment outcomes among HIV-positive patients initiating first-line fixed-dose antiretroviral therapy in a public sector HIV clinic in Johannesburg, South Africa.

BackgroundLong-term antiretroviral therapy (ART) adherence is critical for achieving optimal HIV treatment outcomes. Fixed-dose combination (FDC) single-pill regimens, introduced in South Africa in April 2013, has simplified pill taking. We evaluated treatment outcomes among patients initiated on a FDC compared to a similar multi-pill ART regimen in Johannesburg, South Africa.MethodsWe conducted a retrospective cohort study of ART-naïve HIV-positive non-pregnant adult (≥18 years) patients without tuberculosis who initiated first-line ART on tenofovir and emtricitabine or lamivudine with efavirenz at Themba Lethu Clinic in Johannesburg, South Africa. We compared those initiated on a multi-pill ART regimen (3–5 pills/day; September 1, 2011–August 31, 2012) to those initiated on a FDC ART regimen (one pill/day; September 1, 2013–August 31, 2014). Treatment outcomes included attrition (combination of lost to follow-up and mortality), missed medical visits, and virologic suppression (viral load <400 copies/mL) by 12 months post-ART initiation. Cox proportional hazards models and Poisson regression were used to estimate the association between FDCs vs multiple pills and treatment outcomes.ResultsWe included 3151 patients in our analysis; 2230 (70.8%) patients initiated multi-pill ART and 921 (29.2%) patients initiated on a FDC. By 12 months post-initiation, attrition (adjusted hazard ratio: 0.98; 95% CI: 0.77–1.24) was similar across regimen types (FDC vs multi-pill). Although not significant, patients on a FDC were marginally more likely to achieve viral suppression by 6 (adjusted relative rate [aRR]: 1.10; 95% CI: 0.99–1.23) and 12 months (aRR: 1.12; 95% CI: 0.92–1.36) on ART. Patients initiated on a FDC were significantly less likely to miss medical visits during the first 12 months of treatment (aRR: 0.66; 95% CI: 0.52–0.83).ConclusionOur results suggest FDCs may have a role to play in supporting patient adherence and medical monitoring through improved medical visit attendance. This may potentially improve treatment outcomes later on in treatment.

Cervical cancer risk and impact of Pap‐based screening in HIV‐positive women on antiretroviral therapy in Johannesburg, South Africa

Data on invasive cervical cancer (ICC) incidence in HIV-positive women and the effect of cervical cancer screening in sub-Saharan Africa are scarce. We estimated i) ICC incidence rates in women (≥18 years) who initiated antiretroviral therapy (ART) at the Themba Lethu Clinic (TLC) in Johannesburg, South Africa, between 2004 and 2011 and ii) the effect of a Pap-based screening program. We included 10,640 women; median age at ART initiation: 35 years [interquartile range (IQR) 30-42], median CD4 count at ART initiation: 113 cells/µL (IQR 46-184). During 27,257 person-years (pys), 138 women were diagnosed with ICC; overall incidence rate: 506/100,000 pys [95% confidence interval (CI) 428-598]. The ICC incidence rate was highest (615/100,000 pys) in women who initiated ART before cervical cancer screening became available in 04/2005 and was lowest (260/100,000 pys) in women who initiated ART from 01/2009 onward when the cervical cancer screening program and access to treatment of cervical lesions was expanded [adjusted hazard ratio (aHR) 0.42, 95% CI 0.20-0.87]. Advanced HIV/AIDS stage (4 versus 1, aHR 1.95, 95% CI 1.17-3.24) and middle age at ART initiation (36-45 versus 18-25 years, aHR 2.51, 95% CI 1.07-5.88) were risk factors for ICC. The ICC incidence rate substantially decreased with the implementation of a Pap-based screening program and improved access to treatment of cervical lesions. However, the risk of developing ICC after ART initiation remained high. To inform and improve ICC prevention and care for HIV-positive women in sub-Saharan Africa, implementation and monitoring of cervical cancer screening programs are essential.

Markers of poor adherence among adults with HIV attending Themba Lethu HIV Clinic, Helen Joseph Hospital, Johannesburg, South Africa.

BackgroundTo date, there is no consensus on ideal ways to measure antiretroviral treatment (ART) adherence in resource limited settings. This study aimed to identify markers of poor adherence to ART.MethodsRetrospective data of HIV-positive ART-naïve adults initiating standard first-line ART at Themba Lethu Clinic, Helen Joseph Hospital, Johannesburg, South Africa from April 2004 to December 2011 were analysed. Poisson regression models with robust error variance were used to assessed the following potential markers of poor adherence ‘last self-reported adherence, missed clinic visits, mean corpuscular volume (MCV), CD4 count against definition of adherence, suppressed HIV viral load using traditional test metrics’.ResultsA total of 11 724 patients were eligible; 1712 (14.6%) had unsuppressed viral load within 6 months after initiating ART. The main marker of poor adherence was a combination of change in CD4 count and MCV; change in CD4 ≥expected and change in MCV <14.5 fL (RR 2.82, 95% CI 2.16–3.67), change in CD4 <expected and change in MCV <14.5 fL (RR 5.49, 95% CI 4.13–7.30) compared to change in CD4 ≥expected and change in MCV ≥14.5 fL.ConclusionsA combination of less than expected increase in CD4 and MCV at 6 months after treatment initation was found to be a marker of poor adherence. This could help identify and monitor poor treatment adherence in the absence of viral load testing.

Awareness, perceived risk and practices related to cervical cancer and Pap smear screening: A cross-sectional study among HIV-positive women attending an urban HIV clinic in Johannesburg, South Africa.

Cervical cancer is a major cause of cancer-related deaths, especially in the context of the HIV epidemic. To examine awareness, perceived risk and practices related to cervical cancer screening among HIV-positive women. Interviewer-administered structured questionnaires were administered to HIV-positive women (aged ≥18 years) enrolled in a cervical cancer screening study at the Themba Lethu Clinic, Johannesburg, South Africa, from November 2009 to December 2011. Modified Poisson regression with robust standard errors was used to identify factors at enrolment associated with awareness, perceived risk and adequate practice related to cervical screening. Adjusted relative risks (aRRs) with 95% confidence intervals (CIs) are presented. Of the 1 202 women enrolled, 71.3% and 18.2% were aware of the Pap smear and HPV, respectively. Of the 1 192 participants with data evaluated, 76.5% were worried and 23.5% were not worried about cervical cancer; 28.6% of the women had adequate screening practice. Older age (40 - 49 years or ≥50 years v. 18 - 29 years) (aRR 1.63, 95% CI 1.12 - 2.37; aRR 2.22, 95% CI 1.44 - 3.41), higher education (tertiary v. less than grade 10) (aRR 1.39, 95% CI 1.00 - 1.93), initiation on combination antiretroviral therapy (aRR 1.36, 95% CI 1.00 - 1.85) and awareness of Pap smear screening (aRR 16.18, 95% CI 7.69 - 34.01) were associated with adequate screening practice. High levels of Pap smear awareness and low levels of Pap smear screening uptake were observed. However, Pap smear awareness was associated with adequate screening practice. More research into effective health education programmes to address these gaps is needed.

Low-Cost Method to Monitor Patient Adherence to HIV Antiretroviral Therapy Using Multiplex Cathepsin Zymography

Monitoring patient adherence to HIV antiretroviral therapy (ART) by patient survey is inherently error prone, justifying a need for objective, biological measures affordable in low-resource settings where HIV/AIDS epidemic is highest. In preliminary studies conducted in Ethiopia and South Africa, we observed loss of cysteine cathepsin activity in peripheral blood mononuclear cells of HIV-positive patients on ART. We optimized a rapid protocol for multiplex cathepsin zymography to quantify cysteine cathepsins, and prospectively enrolled 350 HIV-positive, ART-naïve adults attending the Themba Lethu Clinic, Johannesburg, South Africa, to test if suppressed cathepsin activity could be a biomarker of ART adherence (103 patients were included in final analysis). Poor adherence was defined as detectable viral load (>400 copies/ml) or simplified medication adherence questionnaire, 4-6months after ART initiation. 86% of patients with undetectable viral loads after 6months were cathepsin negative, and cathepsin-positive patients were twice as likely to have detectable viral loads (RR 2.32 95% CI 1.26-4.29). Together, this demonstrates proof of concept that multiplex cathepsin zymography may be an inexpensive, objective method to monitor patient adherence to ART. Low cost of this electrophoresis-based assay makes it a prime candidate for implementation in resource-limited settings.

CD4+ gain percentile curves for monitoring response to antiretroviral therapy in HIV-infected adults.

We constructed CD4 cell count gain percentile distributions standardized by baseline CD4 cell count and assessed the association between poor CD4 cell count gain and subsequent death and virological failure on antiretroviral therapy (ART). Secondary analysis of 10 years of clinical data from a cohort of adults initiated on ART at the Themba Lethu clinic in Johannesburg, South Africa. The generalized additive model for location, scale and shape was used to construct percentile curves for CD4 cell count gain standardized by baseline CD4 cell count in the first 28 months of ART. Cox proportional models were used to assess the association between lower percentiles (<50th) of CD4 cell count gain, and subsequent death and virological failure. Among 9640 nonpregnant adults 7406, with available CD4 cell count results for CD4 gain calculation at 4 months of ART, 843 (8.7%) died subsequently and 1101 (11.4%) experienced virologic failure, respectively. For CD4 gains below the third percentile, the adjusted hazard ratios at different time points ranged between 2.72 and 5.73 for death, and between 1.48 and 6.93 for virologic failure. The CD4 percentile curves revealed a gradient of increasing risk of subsequent death and virological failure, with lower CD4 gain percentiles and increasing time on ART, and were more informative than the WHO criteria for immunological failure or current CD4 cell count. Percentile curves of CD4 cell count gain provide a simple tool for healthcare workers in low-resource settings to monitor response to ART with improved information regarding risk of death and virological failure compared to current WHO criteria for immunological failure.

An investigation of fingerstick blood collection for point-of-care HIV-1 viral load monitoring in South Africa.

Viral load (VL) quantification is an important tool in determining newly developed drug resistance or problems with adherence to antiretroviral therapy (ART) in HIV-positive patients. VL monitoring is becoming the standard of care in many resource-limited settings. Testing in resource-limited settings may require sampling by fingerstick because of general shortages of skilled phlebotomists and the expense of venepuncture supplies and problems with their distribution. To assess the feasibility and ease of collecting 150 µL capillary blood needed for the use of a novel collection device following a classic fingerstick puncture. Patients were recruited by the study nurse upon arrival for routine ART monitoring at the Themba Lethu Clinic in Johannesburg, South Africa. Each step of the fingerstick and blood collection protocol was observed, and their completion or omission was recorded. One hundred and three patients consented to the study, of whom three were excluded owing to the presence of callouses. From a total of 100 patients who consented and were enrolled, 98% of collection attempts were successful and 86% of participants required only one fingerstick to successfully collect 150 µL capillary blood. Study nurse adherence to the fingerstick protocol revealed omissions in several steps that may lower the success rate of capillary blood collection and reduce the performance of a subsequent VL assay. The findings of this study support the feasibility of collecting 150 µL of capillary blood via fingerstick for point-of-care HIV-1 VL testing in a resource-limited setting.

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

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. 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). 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. 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.

Leveraging rapid implementation of an HIV treatment policy to reduce confounding in observational analysis of antiretroviral outcomes

Since their inception, HIV treatment programmes in Sub-Saharan Africa (SSA) have implemented a number of changes in the initiation, mode of delivery, and monitoring of antiretroviral therapy (ART). The initial scale-up was facilitated by the availability of inexpensive, effective fixed-dose combination drug regimens. Stavudine (d4T), in combination with lamivudine and efavirenz or nevirapine, was an important component of the initial regimens (Wester et al. 2005; Stringer et al. 2006; Assefa & Kloos 2008). However, the short- and long-term toxicities of d4T constrained its continued use. In 2006, the World Health Organization (WHO) recommended the use of newer generation, less toxic, but more expensive antiretroviral drugs (WHO 2006). Following this recommendation, tenofovir disoproxil fumarate (TDF), which has a favourable toxicity profile and activity against hepatitis B virus, an important co-infection in SSA, has gradually replaced d4T. While randomised trials comparing patient outcomes with d4T vs. TDF have been undertaken (Gallant et al. 2004), there have been limited observational cohort data on this comparison in SSA. Using data from a single large HIV clinic in Johannesburg, South Africa, Brennan and colleagues compared 24-month outcomes between the two drugs (Brennan et al. 2014). Comparing ART outcomes between two or more drug regimens using observational data is susceptible to various forms of confounding, including that of secular trends. Secular trends confound observational analysis when changes in patient and programme characteristics are paralleled by changes in the probability that a patient receives one treatment vs. another (i.e. as a new policy is implemented). In their paper, Brennan and colleagues leveraged the rapid implementation of South Africa's 2010 switch from d4T to TDF to reduce the impact of secular trends. In Themba Lethu Clinic, implementation of this policy change was very rapid with the proportion of patients initiating d4T-containing regimens decreasing from approximately 90% to 20% within 3 months. This allowed Brennan and colleagues to utilise a before and after study design, making the assumption that patient characteristics before and after implementation were similar (i.e. that secular trends were minimal). In the primary analysis, the authors compared those starting d4T in the 12 months before with TDF in the 12 months after implementation. The authors excluded from analysis patients who received TDF before the guideline change, an action that could have biased their results, as that group of patients may have been sicker and their exclusion could have altered average outcomes in the TDF group. Patients in the TDF group had higher CD4+ T-cell counts and lower WHO disease stages than their d4T counterparts, reflecting the substantial secular changes in patient and HIV programme characteristics that have been described in SSA (Geng et al. 2011). To account for these secular trends, Brennan and colleagues adjusted multivariable models for available patient characteristics. Another approach could have been to adjust models for calendar month. Importantly, the authors conducted a sensitivity analysis on the cohort that initiated ART within 3 months of implementation and reported similar outcomes. This lent evidence that secular trends were not influencing their results. So, what were their results? The two regimens were similar; however, there was a trend towards lower mortality rates, fewer losses to follow-up and better viral suppression in the TDF group. Whether the magnitude of the difference was clinically significant and/or generalisable is a subject for further studies in different settings. These results provide important evidence that the policy change did not adversely affect patient outcomes. Further analysis of cost-effectiveness and quality-adjusted life years would be required to fully understand the benefits of policy implementation to the South African HIV programme. In conclusion, Brennan and colleagues' paper demonstrates how the rapid implementation of a treatment policy can be leveraged to reduce bias in observational data. By selecting a short interval around the guideline change, the impact of secular trends was reduced. Similar approaches could be employed to answer other important clinical and implementation questions.

The Impact of Choice of NNRTI on Short-Term Treatment Outcomes among HIV-Infected Patients Prescribed Tenofovir and Lamivudine in Johannesburg, South Africa

IntroductionRecent WHO guidelines for resource-limited settings recommend tenofovir in first-line antiretroviral therapy (ART) yet there are suggestions that patients receiving nevirapine with tenofovir have worse outcomes than those receiving efavirenz. We sought to compare outcomes among those taking nevirapine vs. efavirenz with tenofovir and lamivudine.MethodsWe analyzed data on ART naïve, non-pregnant patients, ≥18 years old without tuberculosis co-infection, initiating tenofovir with lamivudine and either nevirapine or efavirenz between April 1, 2010 and July 31, 2011 (when South Africa’s public-sector use of tenofovir began) at Themba Lethu Clinic in South Africa. We measured virologic suppression (viral load <400 copies/ml), virologic failure (2 consecutive viral loads >1000 copies/ml), and attrition (death/loss to follow-up) all at 12 months after ART initiation. Modified Poisson regression with robust error estimation was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for predictors of each outcome.Results2,254 patients were prescribed efavirenz, 131 nevirapine. Patients were followed a median (range) of 12.0 (0.1–12.0) person-months. 62.2% were female and median (IQR) age was 37.7 years (31.5–44.1). Patients prescribed efavirenz had similar initiating CD4 counts (median 132 for both regimens) but were somewhat more likely to be WHO Stage III or IV (39.6% vs. 33.6%) than those prescribed nevirapine. No difference in attrition was found (aRR: 0.83; 95% CI: 0.49–1.41). Among patients with ≥1 viral load within 1 year on ART, those prescribed nevirapine were as likely to reach virologic suppression (aRR: 0.97; 95% CI: 0.88–1.07) but more likely to experience virologic failure (aRR: 1.84; 95% CI: 1.02–3.31) than those prescribed efavirenz.ConclusionsOur results support the notion that, among patients prescribed tenofovir and lamivudine, virologic failure is more common among those taking nevirapine than among those taking efavirenz. Longer-term follow up and larger studies will be needed to confirm this finding.

High predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIV/AIDS patients

Efavirenz is primarily metabolized by CYP2B6, with a minor contribution from CYP1A2, CYP2A6, CYP3A4 and CYP3A5. Genetic variability in these genes contributes towards differences in plasma efavirenz concentration, which ultimately leads to either development of adverse drug events or emergence of virus resistance. However, the clinical utility or validity of introducing genotype-assisted dosing is not known. The aim of this study was therefore to evaluate the effects of 14 single-nucleotide polymorphisms (SNPs) in five drug-metabolizing enzyme genes on steady-state plasma efavirenz levels in South African HIV/AIDS patients as well as their clinical validity. HIV/AIDS patients were recruited from Themba Lethu Clinic, at Helen Joseph Hospital, Johannesburg. Blood samples for plasma drug levels and DNA extraction were obtained from each participant. PCR/RFLP and SNaPshot genotyping were used for SNPs in CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 among 464 Bantu-speaking South Africans. Plasma efavirenz concentrations were measured using LC/MS/MS. Genotypes and plasma efavirenz levels were used to calculate predictive values. Multivariate analysis was used to select the minimal set of SNPs with significant clinical validity. Qualitative and quantitative differences in allele frequencies were observed when comparing South Africans with African, Caucasian and Asian populations. CYP2B6 516T and 785G (*6) and CYP2B6 983C (*18) alleles were significantly associated with high plasma efavirenz levels. CYP2B6 A-G-A-C-C and A-T-G-T-C haplotypes (with respect to CYP2B6 136A>G; CYP2B6 516G>T; CYP2B6 785A>G; CYP2B6 983T>C; and CYP2B6 1459C>T) were associated with higher levels of efavirenz, whereas G-G-A-T-C and A-G-A-T-C haplotypes showed significantly lower levels of efavirenz. The CYP2B6*1/*6 genotype was significantly associated with an increased risk of loss to follow-up. The sensitivity, specificity and positive predictive values for the CYP2B6*6/*6 genotype in predicting efavirenz levels above 4 µg/ml were 46, 97 and 88%, respectively. However, these values improved to 49, 100 and 100%, respectively, when either the CYP1A2 -163A (*1F) allele or the NR1I3 8784C/C genotype was present. Screening for CYP2B6 516G>T SNP has a high specificity and positive predictive value for efavirenz levels above 4 µg/ml and could be used in deciding on efavirenz dosage among individuals homozygous for this variant, which could lead to better precision medication.

HIV-associated lipodystrophy in South Africa: The impact on the patient and the impact on the plastic surgeon

With 67% of the world's human immunodeficiency virus (HIV)-infected population existing in sub-Saharan Africa and recent access to highly active antiretroviral therapy (HAART), the demand for plastic surgical intervention in addressing lipodystrophy has expanded dramatically. We assessed the rate of lipodystrophy in a random clinic cohort, the demand for surgical correction and risk of treatment non-compliance. Questionnaire and database cross-sectional review of 554 patients over a 3-month period at the Themba Lethu Clinic, Johannesburg, South Africa. A total of 479 patients completed the questionnaire, 83% were female. Nearly 90% of patients were on, or had been on, stavudine (d4T). The prevalence of lipodystrophy was 11.7%. Nearly 5.9% of patients had considered stopping treatment due to the development of lipodystrophy; 47% would consider surgery to correct unwanted physical changes. Male patients were satisfied by the changes they noted in their physical features following treatment (pre-treatment satisfaction 38% vs. post-treatment satisfaction of 94%). Female patients had6.5 times more breast hypertrophy-related symptoms than in their pre-treatment state. We identify a prevalence of 11.7% of patients with HIV-associated lipodystrophy, of whom 5.9% would consider non-compliance on the basis of this side effect alone. The demand for surgical correction is significant and needs to be addressed.

Gender differences in mortality and CD4 count response among virally suppressed HIV-positive patients.

Treatment outcomes for antiretroviral therapy (ART) patients may vary by gender, but estimates from current evidence may be confounded by disease stage and adherence. We investigated the gender differences in treatment response among HIV-positive patients virally suppressed within 6 months of treatment initiation. We analyzed data from 7,354 patients initiating ART between April 2004 and April 2010 at Themba Lethu Clinic, a large urban public sector treatment facility in South Africa. We estimated the relations among gender, mortality, and mean CD4 response in HIV-infected adults virally suppressed within 6 months of treatment initiation and used inverse probability of treatment weights to correct estimates for loss to follow-up. Male patients had a 20% greater risk of death at both 24 months and 36 months of follow-up compared to females. Older patients and those with a low hemoglobin level or low body mass index (BMI) were at increased risk of mortality throughout follow-up. Men gained fewer CD4 cells after treatment initiation than did women. The mean differences in CD4 count gains made by women and men between baseline and 12, 24, and 36 months were 28.2 cells/mm(3) (95% confidence interval [CI] 22.2-34.3), 60.8 cells/mm(3) (95% CI 71.1-50.5 cells/mm(3)), and 83.0 cells/mm(3) (95% CI 97.1-68.8 cells/mm(3)), respectively. Additionally, patients with a current detectable viral load (>400 copies/mL) and older patients had a lower mean CD4 increase at the same time points. In this initially virally suppressed population, women showed consistently better immune response to treatment than did men. Promoting earlier uptake of HIV treatment among men may improve their immunologic outcomes.

Same-Day CD4 Testing to Improve Uptake of HIV Care and Treatment in South Africa: Point-of-Care Is Not Enough

Background. We evaluated whether a pilot program providing point-of-care (POC), but not rapid, CD4 testing (BD FACSCount) immediately after testing HIV-positive improved retention in care. Methods. We conducted a retrospective record review at the Themba Lethu Clinic in Johannesburg, South Africa. We compared all walk-in patients testing HIV-positive during February, July 2010 (pilot POC period) to patients testing positive during January 2008–February 2009 (baseline period). The outcome for those with a ≤250 cells/mm3 when testing HIV-positive was initiating ART <16 weeks after HIV testing. Results. 771 patients had CD4 results from the day of HIV testing (421 pilots, 350 baselines). ART initiation within 16 weeks was 49% in the pilot period and 46% in the baseline period. While all 421 patients during the pilot period should have been offered the POC test, patient records indicate that only 73% of them were actually offered it, and among these patients only 63% accepted the offer. Conclusions. Offering CD4 testing using a point-of-care, but not rapid, technology and without other health system changes had minor impacts on the uptake of HIV care and treatment. Point-of-care technologies alone may not be enough to improve linkage to care and treatment after HIV testing.