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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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;18:323-334.
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
13.  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
14.  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
15.  “Proof-Of-Concept” Evaluation of an Automated Sputum Smear Microscopy System for Tuberculosis Diagnosis 
PLoS ONE  2012;7(11):e50173.
Background
“TBDx” is an innovative smear microscopy system that automatically loads slides onto a microscope, focuses and digitally captures images and then classifies smears as positive or negative using computerised algorithms.
Objectives
To determine the diagnostic accuracy of TBDx, using culture as the gold standard, and compare this to a microscopist's diagnostic performance.
Methods
This study is nested within a cross-sectional study of tuberculosis suspects from South African gold mines. All tuberculosis suspects had one sputum sample collected, which was decontaminated prior to smear microscopy, liquid culture and organism identification. All slides were auramine-stained and then read by both a research microscopist and by TBDx using fluorescence microscopes, classifying slides based on the WHO classification standard of 100 fields of view (FoV) at 400× magnification.
Results
Of 981 specimens, 269 were culture positive for Mycobacterium tuberculosis (27.4%). TBDx had higher sensitivity than the microscopist (75.8% versus 52.8%, respectively), but markedly lower specificity (43.5% versus 98.6%, respectively). TBDx classified 520/981 smears (53.0%) as scanty positive. Hence, a proposed hybrid software/human approach that combined TBDx examination of all smears with microscopist re-examination of TBDx scanty smears was explored by replacing the “positive” result of slides with 1–9 AFB detected on TBDx with the microscopist's original reading. Compared to using the microscopist's original results for all 981 slides, this hybrid approach resulted in equivalent specificity, a slight reduction in sensitivity from 52.8% to 49.4% (difference of 3.3%; 95% confidence interval: 0.2%, 6.5%), and a reduction in the number of slides to be read by the microscopist by 47.0%.
Discussion
Compared to a research microscopist, the hybrid software/human approach had similar specificity and positive predictive value, but sensitivity requires further improvement. Automated microscopy has the potential to substantially reduce the number of slides read by microscopists.
doi:10.1371/journal.pone.0050173
PMCID: PMC3510232  PMID: 23209666
16.  Genotype MTBDRplus for Direct Detection of Mycobacterium tuberculosis and Drug Resistance in Strains from Gold Miners in South Africa 
Journal of Clinical Microbiology  2012;50(4):1189-1194.
GenoType MTBDRplus is a molecular assay for detection of Mycobacterium tuberculosis and drug resistance. Assay performance as applied directly to consecutive unselected sputum samples has not been established. The objective of this study was to determine the accuracy of the MTBDRplus test for direct detection of M. tuberculosis (in sputum) and for drug resistance in consecutively submitted sputum samples. In this cross-sectional study in South Africa, one sputum specimen from each person suspected of having pulmonary tuberculosis was tested by smear microscopy, direct MTBDRplus, and Mycobacterial Growth Indicator Tube (MGIT) culture with MGIT drug susceptibility testing. MGIT results were the reference standard. We tested 2,510 sputum samples, and 529 (21.1%) were positive for M. tuberculosis by MGIT. Direct MTBDRplus identified M. tuberculosis in 256 of 529 specimens (sensitivity, 48.4%; 95% confidence interval [CI], 44.1, 52.7). The sensitivity of MTBDRplus for M. tuberculosis detection by sputum smear status was as follows: smear negative, 13.7% (95% CI, 9.8, 18.4); smear scanty, 46.2% (95% CI, 19.2, 74.9); smear 1+, 69.1% (95% CI, 55.2, 80.9); smear 2+, 86.3% (95% CI, 73.7, 94.3); smear 3+, 89.8% (95% CI, 83.7, 94.2). Direct MTBDRplus testing was negative for 1,594/1,612 sputum samples that were culture negative for M. tuberculosis (specificity, 98.9%; 95% CI, 98.2, 99.3). For specimens positive for M. tuberculosis by MTBDRplus, this assay's sensitivity and specificity for rifampin resistance were 85.7% (95% CI, 57.2, 98.2) and 96.6% (95% CI, 93.2, 98.6) and for isoniazid resistance they were 62.1% (95% CI, 42.3, 79.3) and 97.9% (95% CI, 94.8, 99.4). For sputum testing, the sensitivity of MTBDRplus is directly related to the specimen's bacillary burden. Our results support recommendations that the MTBDRplus test not be used for direct testing of smear-negative or paucibacillary sputum samples.
doi:10.1128/JCM.05723-11
PMCID: PMC3318561  PMID: 22238443
17.  Performance Characteristics of the Cepheid Xpert MTB/RIF Test in a Tuberculosis Prevalence Survey 
PLoS ONE  2012;7(8):e43307.
Background
Xpert MTB/RIF (“Xpert”) is a molecular test for detection of Mycobacterium tuberculosis (MTB) in sputum. Performance characteristics have been established for its use during passive tuberculosis (TB) case detection in symptomatic TB suspects, but Xpert performance has not been assessed in other settings. Objectives were to determine Xpert performance and costs in the context of a TB prevalence survey.
Methodology/Principal Findings
This was a diagnostic sub-study of a TB prevalence survey conducted in gold mining companies in South Africa. Sputa (one per participant) were tested using smear microscopy, liquid culture (reference comparator), and Xpert. Costs were collected using an ingredients approach and analyzed using a public health program perspective. 6893 participants provided a sputum specimen. 187/6893 (2.7%) were positive for MTB in culture, 144/6893 (2.1%) were positive for MTB by Xpert, and 91/6893 (1.3%) were positive for acid fast bacilli by microsocopy. Sensitivity, specificity, positive predictive value, and negative predictive value for detection of MTB by Xpert were 62.6% (95% confidence interval [CI] 55.2, 69.5), 99.6% (99.4, 99.7), 81.3% (73.9, 87.3), and 98.9 (98.6, 98.8); agreement between Xpert and culture was 98.5% (98.2, 98.8). Sensitivity of microscopy was 17.6% (12.5, 23.9). When individuals with a history of TB treatment were excluded from the analysis, Xpert specificity was 99.8 (99.7, 99.9) and PPV was 90.6 (83.3, 95.4) for detection of MTB. For the testing scenario of 7000 specimens with 2.7% of specimens culture positive for MTB, costs were $165,690 for Xpert and $115,360 for the package of microscopy plus culture.
Conclusion
In the context of a TB prevalence survey, the Xpert diagnostic yield was substantially higher than that of microscopy yet lower than that of liquid culture. Xpert may be useful as a sole test for TB case detection in prevalence surveys, particularly in settings lacking capacity for liquid culture.
doi:10.1371/journal.pone.0043307
PMCID: PMC3419700  PMID: 22905254
18.  Second-Line Antiretroviral Therapy in a Workplace and Community-Based Treatment Programme in South Africa: Determinants of Virological Outcome 
PLoS ONE  2012;7(5):e36997.
Background: As antiretroviral treatment (ART) programmes in resource-limited settings mature, more patients are experiencing virological failure. Without resistance testing, deciding who should switch to second-line ART can be difficult. The consequences for second-line outcomes are unclear. In a workplace- and community-based multi-site programme, with 6-monthly virological monitoring, we describe outcomes and predictors of viral suppression on second-line, protease inhibitor-based ART.
Methods: We used prospectively collected clinic data from patients commencing first-line ART between 1/1/03 and 31/12/08 to construct a study cohort of patients switched to second-line ART in the presence of a viral load (VL) ≥400 copies/ml. Predictors of VL<400 copies/ml within 15 months of switch were assessed using modified Poisson regression to estimate risk ratios.
Results: 205 workplace patients (91.7% male; median age 43 yrs) and 212 community patients (38.7% male; median age 36 yrs) switched regimens. At switch compared to community patients, workplace patients had a longer duration of viraemia, higher VL, lower CD4 count, and higher reported non-adherence on first-line ART. Non-adherence was the reported reason for switching in a higher proportion of workplace patients. Following switch, 48.3% (workplace) and 72.0% (community) achieved VL<400, with non-adherence (17.9% vs. 1.4%) and virological rebound (35.6% vs. 13.2% with available measures) reported more commonly in the workplace programme. In adjusted analysis of the workplace programme, lower switch VL and younger age were associated with VL<400. In the community programme, shorter duration of viraemia, higher CD4 count and transfers into programme on ART were associated with VL<400.
Conclusion: High levels of viral suppression on second-line ART can be, but are not always, achieved in multi-site treatment programmes with both individual- and programme-level factors influencing outcomes. Strategies to support both healthcare workers and patients during this switch period need to be evaluated; sub-optimal adherence, particularly in the workplace programme must be addressed.
doi:10.1371/journal.pone.0036997
PMCID: PMC3362581  PMID: 22666338
19.  Contrasting Reasons for Discontinuation of Antiretroviral Therapy in Workplace and Public-Sector HIV Programs in South Africa 
AIDS Patient Care and STDs  2011;25(1):53-59.
Abstract
We investigated reasons for clinical follow-up and treatment discontinuation among HIV-infected individuals receiving antiretroviral therapy (ART) in a public-sector clinic and in a workplace clinic in South Africa. Participants in a larger cohort study who had discontinued clinical care by the seventh month of treatment were traced using previously provided locator information. Those located were administered a semistructured questionnaire regarding reasons for discontinuing clinical follow-up. Participants who had discontinued antiretroviral therapy were invited to participate in further in-depth qualitative interviews. Fifty-one of 144 (35.4%) in the workplace cohort had discontinued clinical follow-up by the seventh month of treatment. The median age of those who discontinued follow-up was 46 years and median educational level was five years. By contrast, only 16.5% (44/267) of the public-sector cohort had discontinued follow-up. Among them the median age was 37.5 years and median education was 11 years. Qualitative interviews were conducted with 17 workplace participants and 10 public-sector participants. The main reasons for attrition in the workplace were uncertainty about own HIV status and above the value of ART, poor patient–provider relationships and workplace discrimination. In the public sector, these were moving away and having no money for clinic transport. In the workplace, efforts to minimize the time between testing and treatment initiation should be balanced with the need to provide adequate baseline counseling taking into account existing concepts about HIV and ART. In the public sector, earlier diagnosis and ART initiation may help to reduce early mortality, while links to government grants may reduce attrition.
doi:10.1089/apc.2010.0140
PMCID: PMC3030909  PMID: 21214378
20.  Cytomegalovirus Viremia as a Risk Factor for Mortality Prior to Antiretroviral Therapy among HIV-Infected Gold Miners in South Africa 
PLoS ONE  2011;6(10):e25571.
Background
Cytomegalovirus (CMV) viremia has been shown to be an independent risk factor for increased mortality among HIV-infected individuals in the developing world. While CMV infection is nearly ubiquitous in resource-poor settings, few data are available on the role of subclinical CMV reactivation on HIV.
Methods
Using a cohort of mineworkers with stored plasma samples, we investigated the association between CMV DNA concentration and mortality prior to antiretroviral therapy availability.
Results
Among 1341 individuals (median CD4 count 345 cells/µl, 70% WHO stage 1 or 2, median follow-up 0.9 years), 70 (5.2%) had CMV viremia at baseline; 71 deaths occurred. In univariable analysis CMV viremia at baseline was associated with a three-fold increase in mortality (hazard ratio [HR] 3.37; 95% confidence intervals [CI] 1.60, 7.10). After adjustment for CD4 count, WHO stage and HIV viral load (N = 429 with complete data), the association was attenuated (HR 2.27; 95%CI 0.88, 5.83). Mortality increased with higher CMV viremia (≥1,000 copies/ml vs. no viremia, adjusted HR 3.65, 95%CI: 1.29, 10.41). Results were similar using time-updated CMV viremia.
Conclusions
High copy number, subclinical CMV viremia was an independent risk factor for mortality among male HIV-infected adults in South Africa with relatively early HIV disease. Studies to determine whether anti-CMV therapy to mitigate high copy number viremia would increase lifespan are warranted.
doi:10.1371/journal.pone.0025571
PMCID: PMC3192109  PMID: 22022413
21.  Development of a Standardized Screening Rule for Tuberculosis in People Living with HIV in Resource-Constrained Settings: Individual Participant Data Meta-analysis of Observational Studies 
PLoS Medicine  2011;8(1):e1000391.
Haileyesus Getahun and colleagues report the development of a simple, standardized tuberculosis (TB) screening rule for resource-constrained settings, to identify people living with HIV who need further investigation for TB disease.
Background
The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule.
Methods and Findings
We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%–90.9%) and specificity was 49.6% (95% CI 29.2%–70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%–96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%–94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%–98.0%) and 90.0% (95% CI 88.6%–91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%).
Conclusions
Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2009, 1.7 million people died from tuberculosis (TB)—equating to 4,700 deaths a day—including 380,000 people living with HIV. TB remains the most common cause of death in people living with HIV and compared to people without HIV, people living with HIV are more than 20 times more likely to develop TB. Furthermore, TB infection may occur at any stage of HIV disease and is often the initial presentation of underlying HIV infection. Without antiretroviral treatment, up to 50% of people living with HIV who are diagnosed with TB die during the 6–8 months of TB treatment.
Although antiretroviral treatment can reduce the incidence of TB both at the individual and population level, people living with HIV on antiretroviral treatment still have higher TB incidence rates and a higher risk of dying from TB. Therefore, the World Health Organization recommends regular screening for active TB disease in all people living with HIV, so those identified as having active TB disease can be provided with appropriate treatment, and isoniazid preventive therapy (to help mitigate TB morbidity, mortality, and transmission) can be given to vulnerable individuals who do not yet have active TB.
Why Was This Study Done?
There is currently no internationally accepted evidence-based tool to screen for TB in people living with HIV—a serious gap given that the presenting signs and symptoms of TB in people living with HIV are different from those in people without HIV. Therefore, the researchers aimed to develop a simple, standardized TB screening rule for resource-constrained settings, on the basis of the best available evidence that would adequately distinguish between people living with HIV who are very unlikely to have TB from those who require further investigation for TB disease.
What Did the Researchers Do and Find?
The researchers selected 12 studies that met their strict criteria, then asked the authors of these studies for primary data so that they could map individual-level data to identify five symptoms common to most studies. Using a statistical model, the researchers devised 23 screening rules derived from these five symptoms and used meta-analysis methods (bivariate random-effects meta-analysis) and the association of study-level and individual-level correlates (hierarchical summary relative operating characteristic curves) to evaluate the sensitivity and specificity of each tool used in each individual study.
The authors of the selected studies were able to provide data for 29,523 participants, of whom 10,057 were people living with HIV. The dataset included 9,626 people living with HIV who had TB screening and sputum culture performed, of which 8,148 individuals could be evaluated on the five symptoms of interest from nine of 12 studies. TB disease was diagnosed in 5.8% of people living with HIV and the best performing rule was the presence of any one of the following: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of the rule was 78.9% and the specificity was 49.6%. However, the sensitivity of the rule increased to 90.1% among participants selected from clinical settings and to 88.0% among those who were not previously screened for TB.
What Do These Findings Mean?
The results of this study suggest that in resource-constrained settings, the absence of current cough, fever, night sweats, and weight loss (all inclusive) can identify those people living with HIV who have a low probability of having TB disease. Furthermore, any one of these symptoms can be used in resource-constrained settings to identify people living with HIV who are in need of further diagnostic assessment for TB.
Despite the limitations of the methodology used in this study, until there are evidence-based and internationally recommended guidelines for the diagnosis and treatment of TB in people living with HIV, use of the algorithm developed and presented in this study could result in earlier TB diagnosis and treatment for people living with HIV and could help to substantially scale-up isoniazid preventive therapy.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000391.
The World Health Organization has information about TB in people living with HIV
The US Centers for Disease Control and Prevention also provide information about TB and HIV coinfection
The World Health Organization also has information about isoniazid preventative therapy
The Stop TB Partnership's TB/HIV Working Group provide information about TB and HIV co-infection
doi:10.1371/journal.pmed.1000391
PMCID: PMC3022524  PMID: 21267059
23.  Low haemoglobin predicts early mortality among adults starting antiretroviral therapy in an HIV care programme in South Africa: a cohort study 
BMC Public Health  2010;10:433.
Background
Antiretroviral therapy (ART) has dramatically reduced morbidity and mortality among people with HIV infection; however, mortality after the start of ART is high in resource-limited settings. We investigated risk factors for mortality among adults starting ART in a multi-clinic community programme in South Africa.
Methods
Cohort of adults starting ART at 27 clinics between February 2005 and June 2006, followed to 31st March 2007. Kaplan-Meier survival estimates were used to describe overall mortality. Shared frailty Cox regression was used to identify baseline risk factors for early mortality.
Results
Among 1350 participants (median age 35.5 years, 60% female, median CD4 count 83/μL [interquartile range (27 - 147)], median follow-up 13.4 months), there were 185 deaths, overall mortality rate 13/100 pyrs; for 0-3, 3-9 and >9 months from ART start mortality rates were 24, 13 and 6/100 pyrs respectively. 43% of the deaths were in the first 3 months of treatment. Risk factors for mortality in univariable analysis were baseline CD4 count, viral load, haemoglobin and body mass index, in multivariable analysis adjusting for age and gender, only CD4 count and haemoglobin remained independently associated with proportional hazards not being satisfied for haemoglobin. Adjusted hazard ratios (aHR) for participants with haemoglobin <8, 8.1-9.9, >11.9(f)/12.9 (m) g/mL were 4.99, 3.05 and 0.12 respectively comparing to 10-11.9 (f)/12.9 (m)g/mL in the first 3 months of ART. aHRs for CD4 counts were 0.40, 0.38 and 0.34 for 50-99, 100-200 and >200/μL comparing to <50/μL.
Conclusions
The high mortality rate in the first 3 months underlines the need for earlier HIV diagnosis so that ART can be initiated earlier. Low haemoglobin and low CD4 count are both strong predictors of mortality, and could be used to identify individuals at high risk who might benefit from intensive case management.
doi:10.1186/1471-2458-10-433
PMCID: PMC2919476  PMID: 20653940
24.  Contrasting predictors of poor antiretroviral therapy outcomes in two South African HIV programmes: a cohort study 
BMC Public Health  2010;10:430.
Background
Many national antiretroviral therapy (ART) programmes encourage providers to identify and address baseline factors associated with poor treatment outcomes, including modifiable adherence-related behaviours, before initiating ART. However, evidence on such predictors is scarce, and providers judgement may often be inaccurate. To help address this evidence gap, this observational cohort study examined baseline factors potentially predictive of poor treatment outcomes in two ART programmes in South Africa, with a particular focus on determinants of adherence.
Methods
Treatment-naïve patients starting ART were enrolled from a community and a workplace ART programme. Potential baseline predictors associated with poor treatment outcomes (defined as viral load > 400 copies/ml or having discontinued treatment by six months) were assessed using logistic regression. Exposure variables were organised for regression analysis using a hierarchical framework.
Results
38/227 (17%) of participants in the community had poor treatment outcomes compared to 47/117 (40%) in the workplace. In the community, predictors of worse outcomes included: drinking more than 20 units of alcohol per week, having no prior experience of chronic medications, and consulting a traditional healer in the past year (adjusted odds ratio [aOR] 15.36, 95% CI 3.22-73.27; aOR 2.30, 95%CI 1.00-5.30; aOR 2.27, 95% CI 1.00-5.19 respectively). Being male and knowing someone on ART were associated with better outcomes (aOR 0.25, 95%CI 0.09-0.74; aOR 0.44, 95%CI 0.19-1.01 respectively). In the workplace, predictors of poor treatment outcomes included being uncertain about the health effects of ART and a traditional healer's ability to treat HIV (aOR 7.53, 95%CI 2.02-27.98; aOR 4.40, 95%CI 1.41-13.75 respectively). Longer pre-ART waiting time (2-12 weeks compared to <2 weeks) predicted better treatment outcomes (aOR 0.13, 95% CI 0.03-0.56).
Conclusion
Baseline predictors of poor treatment outcomes were largely unique to each programme, likely reflecting different populations and pathways to HIV care. In the workplace, active promotion of HIV testing may have extended ART to individuals who, without provider initiation, would not have spontaneously sought care. As provider-initiated testing makes ART available to individuals less motivated to seek care, patients may need additional adherence support, especially addressing uncertainty about the health benefits of ART.
doi:10.1186/1471-2458-10-430
PMCID: PMC2920888  PMID: 20649946
25.  HIV Infection Does Not Affect Active Case Finding of Tuberculosis in South African Gold Miners 
Rationale: Gold miners in South Africa undergo annual radiological screening for tuberculosis in an occupational health center of a gold mining company, but the optimal screening algorithm is unclear.
Objectives: To evaluate methods for active case detection of tuberculosis.
Methods: A sequential sample of miners attending annual medical examination was screened for tuberculosis using a symptom questionnaire, chest radiograph, and two sputum specimens for microscopy and culture.
Measurements and Main Results: There were 1,955 miners included in this study; all were male with a median age of 41 years (range, 20–61 yr). Presence of at least one of a trio of symptoms (new or worsening cough, night sweats, or weight loss) had similar sensitivity (29.4%) to either chest radiograph (25.5%) or sputum smear (25.5%). These sensitivities did not differ by HIV status. Presence of one or more elements of the symptom trio and/or new radiological abnormality substantially increased sensitivity to 49.0%. Specificity of the symptom trio was higher in HIV-uninfected (91.8%) than in HIV-infected persons (88.2%; P = 0.018). Specificity of chest radiography and smear were similar (98.7% and 99.0%, respectively) and did not differ by HIV status (both P values > 0.8).
Conclusions: In a population of gold miners who undergo regular radiological screening, the addition of chest radiography to symptom screening substantially improved the sensitivity and positive predictive value. HIV infection did not alter the sensitivity of the screening tool.
doi:10.1164/rccm.200806-846OC
PMCID: PMC2796737  PMID: 19745207
tuberculosis; HIV infection; case finding

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