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1.  The timing of tuberculosis after isoniazid preventive therapy among gold miners in South Africa: a prospective cohort study 
BMC Medicine  2016;14:45.
Background
The durability of isoniazid preventive therapy (IPT) in preventing tuberculosis (TB) is limited in high-prevalence settings. The underlying mechanism (reactivation of persistent latent TB or reinfection) is not known. We aimed to investigate the timing of TB incidence during and after IPT and associated risk factors in a very high TB and HIV-prevalence setting, and to compare the observed rate with a modelled estimate of TB incidence rate after IPT due to reinfection.
Methods
In a post-hoc analysis of a cluster-randomized trial of community-wide IPT among South African gold miners, all intervention arm participants that were dispensed IPT for at least one of the intended 9 months were included. An incident TB case was defined as any participant with a positive sputum smear or culture, or with a clinical TB diagnosis assigned by a senior study clinician. Crude TB incidence rates were calculated during and after IPT, overall and by follow-up time. HIV status was not available. Multivariable Cox regression was used to analyse risk factors by follow-up time after IPT. Estimates from a published mathematical model of trial data were used to calculate the average reinfection TB incidence in the first year after IPT.
Results
Among 18,520 participants (96 % male, mean age 41 years, median follow-up 2.1 years), 708 developed TB. The TB incidence rate during the intended IPT period was 1.3/100 person-years (pyrs; 95 % confidence interval (CI), 1.0–1.6) and afterwards 2.3/100 pyrs (95 % CI, 1.9–2.7). TB incidence increased within 6 months followed by a stable rate over time. There was no evidence for changing risk factors for TB disease over time after miners stopped IPT. The average TB incidence rate attributable to reinfection in the first year was estimated at 1.3/100 pyrs, compared to an observed rate of 2.2/100 pyrs (95 % CI, 1.8–2.7).
Conclusions
The durability of protection by IPT was lost within 6–12 months in this setting with a high HIV prevalence and a high annual risk of M. tuberculosis infection. The observed rate was higher than the modelled rate, suggesting that reactivation of persistent latent infection played a role in the rapid return to baseline TB incidence.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0589-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0589-3
PMCID: PMC4804575  PMID: 27004413
Isoniazid preventive therapy; Latent infection; Reactivation; Reinfection; Tuberculosis
2.  Individualised motivational counselling to enhance adherence to antiretroviral therapy is not superior to didactic counselling in South African patients: Findings of the CAPRISA 058 randomised controlled trial 
AIDS and behavior  2015;19(1):145-156.
Concerns that standard didactic adherence counselling may be inadequate to maximise antiretroviral therapy (ART) adherence led us to evaluate more intensive individualised motivational adherence counselling. We randomised 297 HIV-positive ART-naïve patients in Durban, South Africa, to receive either didactic counselling, prior to ART initiation (n=150), or an intensive motivational adherence intervention after initiating ART (n=147). Study arms were similar for age (mean 35.8 years), sex (43.1% male), CD4+ cell count (median 121.5 cells/μl) and viral load (median 119 000 copies/ml). Virologic suppression at nine months was achieved in 89.8% of didactic and 87.9% of motivational counselling participants (risk ratio [RR] 0.98, 95% confidence interval [CI] 0.90-1.07, p=0.62). 82.9% of didactic and 79.5% of motivational counselling participants achieved >95% adherence by pill count at six months (RR 0.96, 95%CI 0.85-1.09, p=0.51). Participants receiving intensive motivational counselling did not achieve higher treatment adherence or virological suppression than those receiving routinely provided didactic adherence counselling. These data are reassuring that less resource intensive didactic counselling was adequate for excellent treatment outcomes in this setting.
doi:10.1007/s10461-014-0763-6
PMCID: PMC4185011  PMID: 24696226
antiretroviral therapy adherence; IMB; motivational interviewing; HIV
3.  Missed Opportunities for TB Investigation in Primary Care Clinics in South Africa: Experience from the XTEND Trial 
PLoS ONE  2015;10(9):e0138149.
Setting
40 primary health clinics (PHCs) in four provinces in South Africa, June 2012 –February 2013.
Objective
To determine whether health care worker (HCW) practice in investigating people with TB symptoms was altered when the initial test for TB was changed from smear microscopy to Xpert MTB/RIF.
Design
Cross-sectional substudy at clinics participating in a pragmatic cluster randomised trial, Xpert for TB: Evaluating a New Diagnostic "XTEND", which evaluated the effect of Xpert MTB/RIF implementation in South Africa.
Methods
Consecutive adults exiting PHCs reporting at least one TB symptom (defined as any of cough, weight loss, night sweats and fever) were enrolled. The main outcome was the proportion who self-reported having sputum requested by HCW during the clinic encounter just completed.
Results
3604 adults exiting PHCs (1676 in Xpert arm, 1928 in microscopy arm) were enrolled (median age 38 years, 71.4% female, 38.8% reported being HIV-positive, 70% reported cough). For 1267 participants (35.2%) the main reason for attending the clinic was TB symptom(s).
Overall 2130/3604 (59.1%) said they reported their symptom(s) to HCW. 22.7% (818/3604) reported having been asked to give sputum for TB investigation. Though participants in the Xpert vs. microscopy arm were more likely to have sputum requested by HCW, this was not significantly different: overall (26.0% [436/1676] vs 19.8% [382/1928]; adjusted prevalence ratio [aPR] 1.31, [95% CI 0.78–2.20]) and when restricted to those presenting at clinics due to symptoms (49.1% [260/530] vs 29.9% [220/737]; aPR 1.38 [0.89–2.13]) and those reporting being HIV-positive (29.4% [190/647] vs 20.8% [156/749]; aPR 1.38[0.88–2.16]).
Those attending clinic due to TB symptoms, were more likely to have sputum requested if they had increasing number of symptoms; longer duration of cough, unintentional weight loss and night sweats and if they reported symptoms to HCW.
Conclusions
A large proportion of people exiting PHCs reporting TB symptoms did not get tested. Implementation of Xpert MTB/RIF did not substantially change the probability of testing for TB. Better systems are needed to ensure that opportunities to identify active TB among PHC attendees are not missed.
doi:10.1371/journal.pone.0138149
PMCID: PMC4575203  PMID: 26383102
4.  Attitudes to directly observed antiretroviral treatment in a workplace HIV care programme in South Africa 
Sexually Transmitted Infections  2007;83(5):383-386.
Objective
To investigate attitudes to directly observed antiretroviral therapy (DOT ART) among HIV infected adults attending a workplace HIV care programme in South Africa.
Methods
Clients attending workplace HIV clinics in two regions were interviewed using a semi‐structured questionnaire.
Results
100 individuals (99% male, mean age 40.2 years) participated, 61% were already taking ART by self administration. 71% had previous tuberculosis (TB) with the majority having received DOT for TB. 65% of individuals indicated that they would not like to receive ART by DOT—the main reason given was a desire to take responsibility for their own treatment. This contrasted with 79% who thought TB treatment by DOT a good idea. On questioning about disclosure, 70% reported disclosure to their sexual partners and 21% to fellow workers. 78% of individuals indicated willingness to support someone else taking ART.
Conclusion
ART by DOT was not an immediately popular concept with our patients, primarily because of a desire to retain responsibility for their own treatment. More work is needed to understand what key elements of treatment support are needed to promote adherence.
doi:10.1136/sti.2007.025585
PMCID: PMC2659034  PMID: 17567686
antiretroviral treatment; directly observed therapy; South Africa
5.  Molecular Epidemiology of Mycobacterium tuberculosis among South African Gold Miners 
Rationale: HIV-associated tuberculosis remains a major health problem among the gold-mining workforce in South Africa. We postulate that high levels of recent transmission, indicated by strain clustering, are fueling the tuberculosis epidemic among gold miners.
Objectives: To combine molecular and epidemiologic data to describe Mycobacterium tuberculosis genetic diversity, estimate levels of transmission, and examine risk factors for clustering.
Methods: We conducted a cross-sectional study of culture-positive M. tuberculosis isolates in 15 gold mine shafts across three provinces in South Africa. All isolates were subject IS6110-based restriction fragment length polymorphisms, and we performed spoligotyping analysis and combined it with basic demographic and clinical information.
Measurements and Main Results: Of the 1,602 M. tuberculosis patient isolates, 1,240 (78%) had genotyping data available for analysis. A highly diverse bacillary population was identified, comprising a total of 730 discrete genotypes. Four genotypic families (Latin American Mediterranean spoligotype family; W-Beijing; AH or X; and T1–T4) accounted for over 50% of all strains. Overall, 45% (560/1,240) of strains were genotypically clustered. The minimum estimate for recent transmission (n − 1 method) was 32% (range, 27–34%). There were no individual-level risk factors for clustering, apart from borderline evidence for being non–South African and having self-reported HIV infection.
Conclusions: The high M. tuberculosis genetic diversity and lack of risk factors for clustering are indicative of a universal risk for disease among gold miners and likely mixing with nonmining populations. Our results underscore the urgent need to intensify interventions to interrupt transmission across the entire gold-mining workforce in South Africa.
doi:10.1513/AnnalsATS.201404-150OC
PMCID: PMC4342800  PMID: 25419914
gold mines; molecular epidemiology; South Africa; tuberculosis
6.  Clinical Relevance of Nontuberculous Mycobacteria Isolated from Sputum in a Gold Mining Workforce in South Africa: An Observational, Clinical Study 
BioMed Research International  2015;2015:959107.
Background. The clinical relevance of nontuberculous mycobacteria (NTM), detected by liquid more than solid culture in sputum specimens from a South African mining workforce, is uncertain. We aimed to describe the current spectrum and relevance of NTM in this population. Methods. An observational study including individuals with sputum NTM isolates, recruited at workforce tuberculosis screening and routine clinics. Symptom questionnaires were administered at the time of sputum collection and clinical records and chest radiographs reviewed retrospectively. Results. Of 232 individuals included (228 (98%) male, median age 44 years), M. gordonae (60 individuals), M. kansasii (50), and M. avium complex (MAC: 38) were the commonest species. Of 38 MAC isolates, only 2 (5.3%) were from smear-positive sputum specimens and 30/38 grew in liquid but not solid culture. MAC was especially prevalent among symptomatic, HIV-positive individuals. HIV prevalence was high: 57/74 (77%) among those tested. No differences were found in probability of death or medical separation by NTM species. Conclusions. M. gordonae, M. kansasii, and MAC were the commonest NTM among miners with suspected tuberculosis, with most MAC from smear-negative specimens in liquid culture only. HIV testing and identification of key pathogenic NTM in this setting are essential to ensure optimal treatment.
doi:10.1155/2015/959107
PMCID: PMC4477445  PMID: 26180817
7.  The Diagnostic Accuracy of Urine Lipoarabinomannan Test for Tuberculosis Screening in a South African Correctional Facility 
PLoS ONE  2015;10(5):e0127956.
Background
We evaluated the diagnostic accuracy of the urine lipoarabinomannan (LAM) antigen detection assay (Clearview TB-ELISA) to screen for tuberculosis in a South African correctional facility.
Methods
Between September 2009 and October 2010, male offenders were screened for tuberculosis (symptoms, chest radiograph, two spot sputum specimens for microscopy and culture), and urine tested for LAM. Sensitivity, specificity and predictive values of LAM were calculated using definite and probable tuberculosis combined as our gold standard.
Findings
33/871 (3.8%) participants (26% HIV-positive) had tuberculosis. Amongst HIV-positive vs. HIV-negative offenders the sensitivity and specificity of LAM was 7.1% vs. 0% and 98.5% vs. 99.8% respectively.
Conclusion
Urine LAM ELISA has inadequate sensitivity for TB screening in this population.
doi:10.1371/journal.pone.0127956
PMCID: PMC4444353  PMID: 26010840
8.  A Qualitative Study of Patient Motivation to Adhere to Combination Antiretroviral Therapy in South Africa 
AIDS Patient Care and STDs  2015;29(5):299-306.
Abstract
Taken as prescribed, that is, with high adherence, combination antiretroviral therapy (ART) has changed HIV infection and disease from being a sure predictor of death to a manageable chronic illness. Adherence, however, is difficult to achieve and maintain. The CAPRISA 058 study was conducted between 2007 and 2009 to test the efficacy of individualized motivational counselling to enhance ART adherence in South Africa. As part of the overall trial, a qualitative sub-study was conducted, including 30 individual interviews and four focus group discussions with patients in the first 9 months of ART initiation. Data were inductively analyzed, using thematic analysis, to identify themes central to ART adherence in this context. Four themes emerged that characterize the participants' experiences and high motivation to adhere to ART. Participants in this study were highly motivated to adhere, as they acknowledged that ART was ‘life-giving’, in the face of a large amount of morbidity and mortality. They were further supported by techniques of routine remembering, and highlighted the importance of good social support and access to supportive healthcare workers, to their continued success in negotiating their treatment. Participants in the current study told us that their adherence motivation is enhanced by free accessible care, approachable and supportive healthcare workers, broad social acceptance of ART, and past first-hand experiences with AIDS-related co-morbidity and mortality. Programs that include specific attention to these aspects of care will likely be successful in the long term.
doi:10.1089/apc.2014.0293
PMCID: PMC4410570  PMID: 25692575
9.  Tuberculosis Prevention in South Africa 
PLoS ONE  2015;10(4):e0122514.
Background
South Africa has one of the highest per capita rates of tuberculosis (TB) incidence in the world. In 2012, the South African government produced a National Strategic Plan (NSP) to control the spread of TB with the ambitious aim of zero new TB infections and deaths by 2032, and a halving of the 2012 rates by 2016.
Methods
We used a transmission model to investigate whether the NSP targets could be reached if immediate scale up of control methods had happened in 2014. We explored the potential impact of four intervention portfolios; 1) “NSP” represents the NSP strategy, 2) “WHO” investigates increasing antiretroviral therapy eligibility, 3) “Novel Strategies” considers new isoniazid preventive therapy strategies and HIV “Universal Test and Treat” and 4) “Optimised” contains the most effective interventions.
Findings
We find that even with this scale-up, the NSP targets are unlikely to be achieved. The portfolio that achieved the greatest impact was “Optimised”, followed closely by “NSP”. The “WHO” and “Novel Strategies” had little impact on TB incidence by 2050. Of the individual interventions explored, the most effective were active case finding and reductions in pre-treatment loss to follow up which would have a large impact on TB burden.
Conclusion
Use of existing control strategies has the potential to have a large impact on TB disease burden in South Africa. However, our results suggest that the South African TB targets are unlikely to be reached without new technologies. Despite this, TB incidence could be dramatically reduced by finding and starting more TB cases on treatment.
doi:10.1371/journal.pone.0122514
PMCID: PMC4388715  PMID: 25849558
10.  Evaluation of a point-of-care tuberculosis test-and-treat algorithm on early mortality in people with HIV accessing antiretroviral therapy (TB Fast Track study): study protocol for a cluster randomised controlled trial 
Trials  2015;16:125.
Background
Early mortality for HIV-positive people starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis the most important cause. Existing rapid diagnostic tests for tuberculosis lack sensitivity among HIV-positive people, and consequently, tuberculosis treatment is either delayed or started empirically (without bacteriological confirmation). We developed a management algorithm for ambulatory HIV-positive people, based on body mass index and point-of-care tests for haemoglobin and urine lipoarabinomannan (LAM), to identify those at high risk of tuberculosis and mortality. We designed a clinical trial to test whether implementation of this algorithm reduces six-month mortality among HIV-positive people with advanced immunosuppression.
Methods/design
The TB Fast Track study is an open, pragmatic, cluster randomised superiority trial, with 24 primary health clinics randomised to implement the intervention or standard of care. Adults (aged ≥18 years) with a CD4 count of 150 cells/μL or less, who have not received any tuberculosis treatment in the last three months, or ART in the last six months, are eligible. In intervention clinics, the study algorithm is used to classify individuals as at high, medium or low probability of tuberculosis. Those classified as high probability start tuberculosis treatment immediately, followed by ART after two weeks. Medium-probability patients follow the South African guidelines for test-negative tuberculosis and are reviewed within a week, to be re-categorised as low or high probability. Low-probability patients start ART as soon as possible. The primary outcome is all-cause mortality at six months. Secondary outcomes include severe morbidity, time to ART start and cost-effectiveness.
Discussion
This trial will test whether a primary care-friendly management algorithm will enable nurses to identify HIV-positive patients at the highest risk of tuberculosis, to facilitate prompt treatment and reduce early mortality. There remains an urgent need for better diagnostic tests for tuberculosis, especially for people with advanced HIV disease, which may render empirical treatment unnecessary.
Trial registration
This trial was registered with Current Controlled Trials (identifier: ISRCTN35344604) on 12 September 2012.
doi:10.1186/s13063-015-0650-0
PMCID: PMC4394596  PMID: 25872501
Tuberculosis; HIV infections; Pragmatic clinic trials; Mortality; Treatment
11.  Isoniazid Preventive Therapy and Risk for Resistant Tuberculosis 
Emerging Infectious Diseases  2006;12(5):744-751.
Preventive therapy may increase risk for drug resistance.
In the context of tuberculosis (TB) resurgence, isoniazid preventive therapy (IPT) is increasingly promoted, but concerns about the risk for development of isoniazid-resistant tuberculosis may hinder its widespread implementation. We conducted a systematic review of data published since 1951 to assess the effect of primary IPT on the risk for isoniazid-resistant TB. Different definitions of isoniazid resistance were used, which affected summary effect estimates; we report the most consistent results. When all 13 studies (N = 18,095 persons in isoniazid groups and N = 17,985 persons in control groups) were combined, the summary relative risk for resistance was 1.45 (95% confidence interval 0.85–2.47). Results were similar when studies of HIV-uninfected and HIV-infected persons were considered separately. Analyses were limited by small numbers and incomplete testing of isolates, but findings do not exclude an increased risk for isoniazid-resistant TB after IPT. The diagnosis of active TB should be excluded before IPT. Continued surveillance for isoniazid resistance is essential.
doi:10.3201/eid1205.050681
PMCID: PMC3374455  PMID: 16704830
tuberculosis; review; isoniazid; chemoprevention; prophylaxis; drug resistance; research
12.  Tuberculosis Control in South African Gold Mines: Mathematical Modeling of a Trial of Community-Wide Isoniazid Preventive Therapy 
American Journal of Epidemiology  2015;181(8):619-632.
A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006–2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial (“optimized intervention”), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus–positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus–positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens.
doi:10.1093/aje/kwu320
PMCID: PMC4388015  PMID: 25792607
mass community-wide isoniazid preventive therapy; mathematical model; tuberculosis
13.  The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(11):e112017.
Objective
To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment.
Design
We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis.
Subjects
The study population included individuals receiving ART before or during TB treatment.
Main Outcome Measures
Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status.
Results
Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29–0.56).
Conclusion
Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic.
doi:10.1371/journal.pone.0112017
PMCID: PMC4229142  PMID: 25391135
14.  Resistance to tenofovir-based regimens during treatment failure of subtype C HIV-1 in South Africa 
Antiviral therapy  2013;18(7):915-920.
Background
Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principle TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV.
Methods
Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virologic failure (defined as an HIV RNA >1000 c/mL) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors.
Results
Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major NNRTI mutations in 24 (57%), and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA log10 3.3 versus 4.2 c/mL) and prior stavudine exposure. An additional 5 patients had minority K65R populations identified by allele-specific PCR.
Conclusions
These data suggest that the K65R prevalence at virologic failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype C infected patients with up to 6 months of failure of a TDF-containing regimen.
doi:10.3851/IMP2652
PMCID: PMC4046272  PMID: 23751421
15.  Changing predictors of mortality over time from cART start: implications for care 
Objective
To determine predictors of mortality and changes in those predictors over time on combination antiretroviral therapy (cART) in South Africa.
Design
A cohort study.
Methods
Using routine clinic data with up to 4 years follow-up after ART initiation and with death ascertainment from a national vital statistics register, we used proportional hazards modeling to assess baseline and time-updated predictors of mortality, and changes in strength of those predictors over time on cART. Furthermore, we compared CD4 count among individuals who died by duration on cART.
Results
15,060 subjects (64% men, median CD4 count 127 cells/mm3) started antiretroviral therapy between January 2003 and January 2008. Over a median follow-up of 1.8 years, 2,658 subjects died. The baseline characteristics of WHO stage, haemoglobin, CD4 count, HIV RNA level, and symptoms were all associated with mortality during the first 12 months of cART but lost association thereafter. However time updated factors of CD4 count, body mass index, symptoms, anemia, and HIV RNA suppression remained strong predictors of death. Most recent CD4 count prior to death rose from 71 during the first 3 months of cART to 175 cells/mm3 after >3 years of cART.
Conclusion
Over 4 years of cART, risk of death declined and associations with mortality changed. An increase in CD4 count at death and changing associations with mortality may suggest a shift in causes of death, possibly from opportunistic infections to other infections and chronic illnesses.
doi:10.1097/QAI.0b013e31823219d1
PMCID: PMC4009722  PMID: 21876447
mortality; HIV; resource limited setting; Africa; antiretroviral therapy; proportional hazards
16.  Mortality associated with delays between clinic entry and ART initiation in resource-limited-settings: results of a transition-state model 
Objective
Estimate the mortality impact of delay in antiretroviral therapy (ART) initiation from the time of entry-into-care.
Design
A state-transition Markov process model. This technique allows for assessing mortality before and after ART initiation associated with delays in ART initiation among a general population of ART eligible patients without conducting a randomized trial.
Methods
We used patient-level data from three South African cohorts to determine transition probabilities for pre-ART CD4 count changes and pre-ART and on-ART mortality. For each parameter we generated probabilities and distributions for Monte Carlo simulations with one week cycles to estimate mortality 52 weeks from clinic entry.
Results
We estimated an increase in mortality from 11.0% to 14.7% (relative increase of 34%) with a 10 week delay in ART for patients entering care with our pre-ART cohort CD4 distribution. When we examined low CD4 ranges, the relative increase in mortality delays remained similar; however, the absolute increase in mortality rose. For example, among patients entering with CD4 count 50–99 cells/mm3, 12 month mortality increased from 13.3% with no delay compared to 17.0% with a 10 week delay and 22.9% with a 6 month delay.
Conclusions
Delays in ART initiation, common in routine HIV programs, can lead to important increases in mortality. Prompt ART initiation for patients entering clinical care and eligible for ART, especially those with lower CD4 counts, could be a relatively low cost approach with a potential marked impact on mortality.
doi:10.1097/QAI.0b013e3182893fb4
PMCID: PMC3647455  PMID: 23392457
ART delay; Africa; CD4 count; mortality; state-transition model
17.  Linking Women Who Test HIV-Positive in Pregnancy-Related Services to HIV Care and Treatment Services in Kenya: A Mixed Methods Prospective Cohort Study 
PLoS ONE  2014;9(3):e89764.
Introduction
There has been insufficient attention to long-term care and treatment for pregnant women diagnosed with HIV.
Objective and Methods
This prospective cohort study of 100 HIV-positive women recruited within pregnancy-related services in a district hospital in Kenya employed quantitative methods to assess attrition between women testing HIV-positive in pregnancy-related services and accessing long-term HIV care and treatment services. Qualitative methods were used to explore barriers and facilitators to navigating these services.
Structured questionnaires were administered to cohort participants at enrolment and 90+ days later. Participants’ medical records were monitored prospectively. Semi-structured qualitative interviews were carried out with a sub-set of 19 participants.
Findings
Only 53/100 (53%) women registered at an HIV clinic within 90 days of HIV diagnosis, of whom 27/53 (51%) had a CD4 count result in their file. 11/27 (41%) women were eligible for immediate antiretroviral therapy (ART); only 6/11 (55%) started ART during study follow-up. In multivariable logistic regression analysis, factors associated with registration at the HIV clinic within 90 days of HIV diagnosis were: having cared for someone with HIV (aOR:3.67(95%CI:1.22, 11.09)), not having to pay for transport to the hospital (aOR:2.73(95%CI:1.09, 6.84)), and having received enough information to decide to have an HIV test (aOR:3.61(95%CI:0.83, 15.71)). Qualitative data revealed multiple factors underlying high patient drop-out related to women’s social support networks (e.g. partner’s attitude to HIV status), interactions with health workers (e.g. being given unclear/incorrect HIV-related information) and health services characteristics (e.g. restricted opening hours, long waiting times).
Conclusion
HIV testing within pregnancy-related services is an important entry point to HIV care and treatment services, but few women successfully completed the steps needed for assessment of their treatment needs within three months of diagnosis. Programmatic recommendations include simplified pathways to care, better-tailored counselling, integration of ART into antenatal services, and facilitation of social support.
doi:10.1371/journal.pone.0089764
PMCID: PMC3960101  PMID: 24646492
18.  High Tuberculosis Prevalence in a South African Prison: The Need for Routine Tuberculosis Screening 
PLoS ONE  2014;9(1):e87262.
Background
Tuberculosis is a major health concern in prisons, particularly where HIV prevalence is high. Our objective was to determine the undiagnosed pulmonary tuberculosis (“undiagnosed tuberculosis”) prevalence in a representative sample of prisoners in a South African prison. In addition we investigated risk factors for undiagnosed tuberculosis, to explore if screening strategies could be targeted to high risk groups, and, the performance of screening tools for tuberculosis.
Methods and Findings
In this cross-sectional survey, male prisoners were screened for tuberculosis using symptoms, chest radiograph (CXR) and two spot sputum specimens for microscopy and culture. Anonymised HIV antibody testing was performed on urine specimens. The sensitivity, specificity and predictive values of symptoms and investigations were calculated, using Mycobacterium tuberculosis isolated on sputum culture as the gold standard.
From September 2009 to October 2010, 1046 male prisoners were offered enrolment to the study. A total of 981 (93.8%) consented (median age was 32 years; interquartile range [IQR] 27–37 years) and were screened for tuberculosis. Among 968 not taking tuberculosis treatment and with sputum culture results, 34 (3.5%; 95% confidence interval [CI] 2.4–4.9%) were culture positive for Mycobacterium tuberculosis. HIV prevalence was 25.3% (242/957; 95% CI 22.6–28.2%). Positive HIV status (adjusted odds ratio [aOR] 2.0; 95% CI 1.0–4.2) and being an ex-smoker (aOR 2.6; 95% CI 1.2–5.9) were independently associated with undiagnosed tuberculosis. Compared to the gold standard of positive sputum culture, cough of any duration had a sensitivity of 35.3% and specificity of 79.6%. CXR was the most sensitive single screening modality (sensitivity 70.6%, specificity 92.2%). Adding CXR to cough of any duration gave a tool with sensitivity of 79.4% and specificity of 73.8%.
Conclusions
Undiagnosed tuberculosis and HIV prevalence was high in this prison, justifying routine screening for tuberculosis at entry into the prison, and intensified case finding among existing prisoners.
doi:10.1371/journal.pone.0087262
PMCID: PMC3907552  PMID: 24498059
19.  Outcomes Following Virological Failure and Predictors of Switching to Second-line Antiretroviral Therapy in a South African Treatment Programme 
Journal of acquired immune deficiency syndromes (1999)  2012;61(3):10.1097/QAI.0b013e318266ee3f.
Objectives
Without resistance tests, deciding which patients with virological failure should switch to second-line antiretroviral therapy (ART) is difficult. The factors influencing this decision are poorly understood. We assess predictors of switching regimens following virological failure.
Design
Retrospective cohort study using clinical data from a South African ART programme with 6-monthly viral load (VL) monitoring
Methods
We constructed a dataset of patient visits occurring following first-line virological failure, and used random effects logistic regression (accounting for individual- and clinic-level clustering) to assess predictors of switching at each visit.
Results
1668 patients with virological failure (73% male, mean age 41yrs, median CD4 184 cells/mm3, mean log10VL 4.3) contributed 1922 person-years of viraemia. 12 months following failure, the cumulative incidence of switching regimen, viral re-suppression or death was 16.9%, 13.2% and 4.6% respectively. In adjusted analysis, switching was more likely at the third or subsequent visit following failure; in visits occurring in 2008 vs.2003-2007; and in patients with ART-experience pre-programme, current high VL or low CD4 count. Switching was less likely in patients with no clinic contact for 4 months, or declining VL. Switching rates varied between clinics with clinic-level clustering evident in the final model (p<0.001).
Conclusion
Despite 6-monthly virological monitoring and recommendations to switch following adherence interventions and confirmed viraemia, patients experienced delayed switching. Individual-level covariates influenced switching but did not account for variable switching rates between clinics, suggesting differences in guideline implementation. In certain circumstances delays may be warranted; however understanding barriers to guideline implementation will limit unnecessary delays.
doi:10.1097/QAI.0b013e318266ee3f
PMCID: PMC3840925  PMID: 22820803
Virological failure; switching; second-line antiretroviral therapy; South Africa; predictors
20.  Eligibility for Isoniazid Preventive Therapy in South African Gold Mines 
PLoS ONE  2013;8(11):e81376.
Setting
The “Thibela TB” cluster randomised trial of community-wide isoniazid preventive therapy (IPT) to reduce tuberculosis incidence in the South African gold mines.
Objectives
To determine the proportion of participants eligible for IPT and the reasons and risk factors for ineligibility, to inform the scale-up of IPT.
Design
Cross-sectional survey of participants in intervention clusters (mine shafts) consenting to tuberculosis screening and assessment for eligibility to start IPT.
Results
Among 27,126 consenting participants, 94.7% were male, the median age was 41 years, 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently taking antiretroviral therapy. There were 24,430 (90.1%) assessed as eligible to start IPT, of whom 23,659 started IPT. The most common reasons for ineligibility were having suspected tuberculosis that was subsequently confirmed by a positive smear and/or culture (n=705), excessive alcohol consumption (n=427) and being on tuberculosis treatment at time of initial screen (n=241). Ineligibility was associated with factors including older age, female gender, prior history of tuberculosis and being in “HIV care”. However, at least 78% were eligible for IPT in all of these sub-groups.
Conclusions
The vast majority of participants in this community-wide intervention were eligible for IPT.
doi:10.1371/journal.pone.0081376
PMCID: PMC3828258  PMID: 24244741
21.  Viral Suppression Following Switch to Second-line Antiretroviral Therapy: Associations With Nucleoside Reverse Transcriptase Inhibitor Resistance and Subtherapeutic Drug Concentrations Prior to Switch 
The Journal of Infectious Diseases  2013;209(5):711-720.
Background. High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification.
Methods. Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression.
Results. One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77–263) and 4.3 log10 copies/mL (IQR, 3.8–4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL.
Conclusions. Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.
doi:10.1093/infdis/jit411
PMCID: PMC3923537  PMID: 23943851
second-line antiretroviral therapy; adherence; resistance; virological failure
22.  A novel HIV treatment model using private practitioners in South Africa 
Sexually transmitted infections  2012;88(2):136-140.
Objectives
The extent of the HIV epidemic in South Africa may render the public sector capacity inadequate to manage all patients requiring antiretroviral therapy (ART). Private practitioners are an underutilised resource that could be utilized to ease this challenge.
Methods
We developed a model of care using 72 private practitioners in five provinces in urban and rural areas of South Africa with centralised clinical support, training, pharmacy control and data management. We describe the programme, its quality control measures and patient outcomes using a cohort analysis.
Results
Between January 2005 and December 2008, 9,102 individuals were started on ART, 63% female, mean age 35 years, median viral load 50,655 copies/ml and median baseline CD4 count 123 cells/μl. Retention (alive and in care) in those who started on ART after 12 months was 63% (5,743/9,102) in the 2005 cohort and did not change by calendar year. After 36 months, retention was 50% and 59%, for those enrolled in 2005 and 2006 respectively. The percentage virally suppressed remained similar over the cohorts at 6 months, 82% vs. 84%, 84% and 85% from 2005 - 2008, p=0.66; but improved slightly at 12 months, 78% vs. 83%, 83% and 84% from 2005 - 2008, p=0.05.
Conclusions
The results show that a well-managed private practitioner-based model can achieve comparable results to public service programmes, although long-term retention needs further evaluation. This model of ART delivery can be used to expand access to ART in areas where the public sector is unable to meet the demand.
doi:10.1136/sextrans-2011-050194
PMCID: PMC3724420  PMID: 22345028
23.  Antiretroviral therapy using zidovudine, lamivudine, and efavirenz in South Africa: tolerability and clinical events 
AIDS (London, England)  2008;22(1):67-74.
Objective
To describe the safety and tolerability of zidovudine, lamivudine, and efavirenz in a low-income setting.
Design
We conducted a prospective cohort study in a workplace HAART programme in South Africa, which uses a first-line regimen of efavirenz, zidovudine, and lamivudine and provides routine clinical and laboratory monitoring 6-monthly pre-HAART and at 2, 6, 12, 24, 36, 48 weeks during HAART.
Methods
We assessed the incidence of specified clinical and laboratory events (AIDS Clinical Trials Group grade 3 or higher) and associated regimen changes, hospitalizations, and deaths one year before HAART initiation and one year on-HAART using person-year analysis.
Results
Between November 2002 and October 2005, 853 subjects (98% male, median age 40 years, and median CD4 cell count at HAART initiation 186 cells/μl) met enrollment criteria. The incidence of events on-HAART was higher than pre-HAART for neutropenia and nausea/vomiting. Dizziness was common early after HAART initiation (not evaluated pre-HAART). Of those with neutropenia, 88% had no apparent clinical consequences. The incidence of anemia, hepatotoxicity, peripheral neuropathy, and rash was similar or higher pre-HAART than on-HAART. Mean hemoglobin rose during the time on-HAART and was higher at 24 and 48 weeks than at baseline (P < 0.001).
Discussion
This regimen was well tolerated with a short-term increase in neutropenia, nausea, and probably neurocerebellar events. Most significantly, in contrast to reports from high-income countries, we observed a long-term improvement in the hemoglobin concentration.
doi:10.1097/QAD.0b013e3282f2306e
PMCID: PMC3724474  PMID: 18090393
24.  Is Forced Migration a Barrier to Treatment Success? Similar HIV Treatment Outcomes Among Refugees and a Surrounding Host Community in Kuala Lumpur, Malaysia 
AIDS and Behavior  2013;18(2):323-334.
In response to an absence of studies among refugees and host communities accessing highly active antiretroviral therapy (HAART) in urban settings, our objective was to compare adherence and virological outcomes among clients attending a public clinic in Kuala Lumpur, Malaysia. A cross-sectional survey was conducted among adult clients (≥18 years). Data sources included a structured questionnaire that measured self-reported adherence, a pharmacy-based measure of HAART prescription refills over the previous 24 months, and HIV viral loads. The primary outcome was unsuppressed viral load (≥40 copies/mL). Among a sample of 153 refugees and 148 host community clients, refugees were younger (median age 35 [interquartile range, IQR 31, 39] vs 40 years [IQR 35, 48], p < 0.001), more likely to be female (36 vs 21 %, p = 0.004), and to have been on HAART for less time (61 [IQR 35, 108] vs 153 weeks [IQR 63, 298]; p < 0.001). Among all clients, similar proportions of refugee and host clients were <95 % adherent to pharmacy refills (26 vs 34 %, p = 0.15). When restricting to clients on treatment for ≥25 weeks, similar proportions from each group were not virologically suppressed (19 % of refugees vs 16 % of host clients, p = 0.54). Refugee status was not independently associated with the outcome (adjusted odds ratio, aOR = 1.28, 95 % CI 0.52, 3.14). Overall, the proportions of refugee and host community clients with unsuppressed viral loads and sub-optimal adherence were similar, supporting the idea that refugees in protracted asylum situations are able to sustain good treatment outcomes and should explicitly be included in the HIV strategic plans of host countries with a view to expanding access in accordance with national guidelines for HAART.
Electronic supplementary material
The online version of this article (doi:10.1007/s10461-013-0494-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s10461-013-0494-0
PMCID: PMC3905173  PMID: 23748862
Refugees; Forced migration; HIV; Antiretrovirals; Outcomes; Adherence
25.  Comparison of Tenofovir, Zidovudine, or Stavudine as Part of First-Line Antiretroviral Therapy in a Resource-Limited-Setting: A Cohort Study 
PLoS ONE  2013;8(5):e64459.
Background
Tenofovir (TDF) is part of the WHO recommended first-line antiretroviral therapy (ART); however, there are limited data comparing TDF to other nucleoside reverse transcriptase inhibitors in resource-limited-settings. Using a routine workplace and community-based ART cohort in South Africa, we assessed single drug substitution, HIV RNA suppression, CD4 count increase, loss-from-care, and mortality between TDF, stavudine (d4T) 30 mg dose, and zidovudine (AZT).
Methods
In a prospective cohort study we included ART naïve patients aged ≥17 years-old who initiated ART containing TDF, d4T, or AZT between 2007 and 2009. For analysis of single drug substitutions we used a competing-risks time-to-event analysis; for loss-from-care, mixed-effect Poisson modeling; for HIV RNA suppression, competing-risks logistic regression; for CD4 count slope, mixed-effects linear regression; and for mortality, proportional hazards modeling.
Results
Of 6,196 patients, the initial drug was TDF for 665 (11%), d4T for 4,179 (68%), and AZT for 1,352 (22%). During the first 6 months of ART, the adjusted hazard ratio for a single drug substitution was 2.3 for d4T (95% confidence interval [CI]: 0.27, 19) and 5.2 for AZT (95% CI: 1.1, 23), compared to TDF; whereas, after 6 months, it was 10 (95% CI: 5.8, 18) and 4.4 (95% CI: 2.5, 7.8) for d4T and AZT, respectively. Virologic suppression was similar by agent; however, CD4 count rise was lowest for AZT. The adjusted hazard ratio for loss-from-care, when compared to TDF, was 1.5 (95% CI: 1.1, 1.9) for d4T and 1.2 (95% CI: 1.1, 1.4) for AZT. The adjusted hazard ratio for mortality, when compared to TDF, was 2.7 (95% CI: 2.0, 3.5) and 1.4 (95% CI: 1.3, 1.5) and for d4T and AZT, respectively.
Discussion
In routine care, TDF appeared to perform better than either d4T or AZT, most notably with less drug substitution and mortality than for either other agent.
doi:10.1371/journal.pone.0064459
PMCID: PMC3653880  PMID: 23691224

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