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1.  Changes to antiretroviral drug regimens during integrated TB-HIV treatment: Results of the SAPiT trial 
Antiviral therapy  2013;19(2):161-169.
Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and human immunodeficiency virus (HIV) therapy, as a result of treatment-limiting toxicity or virological failure, is not well established.
Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load > 1000 copies/ml on two occasions, taken at least 4 weeks apart) were assessed in these patients.
A total of 501 TB-HIV co-infected patients were followed for a mean of 16.0 (95% confidence interval (CI): 15.5 to 16.6) months after antiretroviral therapy (ART) initiation. The standard first-line ARVs used, were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate: 2.1 per 100 person-years; 95% (CI): 1.1 to 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate: 3.7 per 100 person-years; CI: 2.4 to 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4; 0.8%), elevated transaminase levels and hyperlactatemia (n= 3; 0.6%), and peripheral neuropathy (n=2; 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4+ cell count <50cells/mm3 (p<0.001) at ART initiation and body mass index greater than 25 kg/m2 (p=0.01) at entry into the study.
Both drug switches and complete regimen change were uncommon in patients co-treated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change.
PMCID: PMC3984627  PMID: 24176943
2.  The treatment journey of a patient with multidrug-resistant tuberculosis in South Africa: is it patient-centred? 
To improve the treatment of patients co-infected with multidrug-resistant tuberculosis (MDR-TB) and the human immunodeficiency virus, we measured the relationship between treatment outcomes and hospital performance at four decentralised MDR-TB sites in South Africa. We describe hospital performance from the patient’s perspective by the use of a graphic that visually represents a patient’s treatment journey. The graphic was used to report study findings to study site
PMCID: PMC3992833  PMID: 24020603
health systems; high burden of TB and HIV
3.  Association between Health Systems Performance and Treatment Outcomes in Patients Co-Infected with MDR-TB and HIV in KwaZulu-Natal, South Africa: Implications for TB Programmes 
PLoS ONE  2014;9(4):e94016.
To improve the treatment of MDR-TB and HIV co-infected patients, we investigated the relationship between health system performance and patient treatment outcomes at 4 decentralised MDR-TB sites.
In this mixed methods case study which included prospective comparative data, we measured health system performance using a framework of domains comprising key health service components. Using Pearson Product Moment Correlation coefficients we quantified the direction and magnitude of the association between health system performance and MDR-TB treatment outcomes. Qualitative data from participant observation and interviews analysed using systematic text condensation (STC) complemented our quantitative findings.
We found significant differences in treatment outcomes across the sites with successful outcomes varying from 72% at Site 1 to 52% at Site 4 (p<0.01). Health systems performance scores also varied considerably across the sites. Our findings suggest there is a correlation between treatment outcomes and overall health system performance which is significant (r = 0.99, p<0.01), with Site 1 having the highest number of successful treatment outcomes and the highest health system performance. Although the ‘integration’ domain, which measured integration of MDR-TB services into existing services appeared to have the strongest association with successful treatment outcomes (r = 0.99, p<0.01), qualitative data indicated that the ‘context’ domain influenced the other domains.
We suggest that there is an association between treatment outcomes and health system performance. The chance of treatment success is greater if decentralised MDR-TB services are integrated into existing services. To optimise successful treatment outcomes, regular monitoring and support are needed at a district, facility and individual level to ensure the local context is supportive of new programmes and implementation is according to guidelines.
PMCID: PMC3981751  PMID: 24718306
4.  Understanding the Profile of Tuberculosis and Human Immunodeficiency Virus Coinfection: Insights from Expanded HIV Surveillance at a Tuberculosis Facility in Durban, South Africa 
ISRN AIDS  2014;2014:260329.
Background. Expanded HIV surveillance in TB patients forms part of the World Health Organization framework for strategic collaborative activity. Surveillance helps understand the epidemiology of the local dual epidemic and enables design of a tailored response to these challenges. Methods. We conducted an observational, cross-sectional study of anonymous unlinked HIV testing for 741 consecutive TB suspects attending an urban TB facility during a seven-week period in 2008. Results. A total of 512 patients were found to have TB. The mean age was 35.7 years, and 63% were male. The prevalence of HIV was 72.2% (95% CI: 68.2–75.9) in all TB cases, 69.8% (95% CI: 65.3–74.2) in pulmonary tuberculosis (PTB), 81.6% (95% CI: 72.9–90.3) in extrapulmonary disease, and 66.8% (95% CI: 60.7–72.9) in those without TB disease. HIV prevalence in TB patients was higher in females than males and in younger age groups (18–29 years). The sex ratio of PTB patients correlated with the sex ratio of the prevalence of HIV in the respective age groups (P < 0.05). Conclusion. The use of a rapid HIV test performed on sputum anonymously provides an opportunity for HIV surveillance in this high-burdened setting, which has the potential to lend valuable insight into the coepidemics.
PMCID: PMC4004112  PMID: 25006526
5.  Integrating patients’ perspectives into integrated TB/HIV healthcare 
Escalating rates of TB/HIV coinfection call for improved coordination of TB and HIV healthcare services in high-burden countries such as South Africa. Patient perspectives, however, are poorly understood in the context of current integration efforts.
Under a qualitative research framework, we interviewed 40 HIV-positive adult TB patients and 8 key-informant healthcare workers across 3 clinics in KwaZulu-Natal province to explore non-clinical and non-operational aspects of TB/HIV healthcare.
Qualitative analysis highlighted critical social and ethical considerations for the concurrent delivery of TB and HIV care. Coinfected patients navigating between TB and HIV programs are exposed to missed opportunities for TB and HIV service integration, fragmented or vertical care for their dual infections, and contrasting experiences within TB and HIV clinics. These intersecting issues appear to affect patients’ health-related decisions, particularly HIV nondisclosure to non-HIV healthcare workers, and their preferences for integrated healthcare.
Our study highlights the imperative to address service fragmentation, HIV medical confidentiality and provider mistrust within the healthcare system, and the cultural differences associated with TB and HIV disease control.
PMCID: PMC3665901  PMID: 23407149
South Africa; TB/HIV coinfection; service integration; qualitative methods
6.  Social constraints to TB/HIV healthcare: accounts from coinfected patients in South Africa 
AIDS care  2012;24(12):1480-1486.
There is a growing imperative to improve the coordination and collaboration of TB and HIV healthcare services in response to escalating rates of TB/HIV coinfection. Patient-specific challenges associated with the delivery of TB/HIV care have been minimally explored in this regard. As part of a larger study conducted in South Africa, this article highlights coinfected patients’ experiences with TB and HIV healthcare in light of their broader social environments. Qualitative, in-depth interviews were conducted with 40 adult, coinfected patients (24 women, 16 men) and 8 key-informant healthcare workers at 3 urban/peri-urban, ambulatory, public health clinics in the high-burden province of KwaZulu-Natal. Transcribed interviews were analyzed under a modified grounded theory approach to capture subjective meanings of healthcare experience subsequent to patients’ co-diagnosis with TB and HIV. Emerging analytic themes highlighted critical sociomedical constraints to TB/HIV care in relation to patients’ income and employment, eligibility for social assistance and antiretroviral treatment, fears around illness disclosure, social and material support, and treatment adherence. Patients’ healthcare experiences were bound by their poor access to essential resources, multiple life responsibilities, disparate gender roles, limits within the healthcare system and the stigmatizing social symbolism of their illness. Overlapping social inequalities perpetuated coinfected patients’ experiences with stigma and collectively mediated their health decisions around disclosure, adherence and retention in medical care. The study urges a contextualized understanding of the social challenges associated with TB/HIV healthcare, and helps inform more patient-sensitive and socially-responsive interventions against the co-epidemic.
PMCID: PMC3484188  PMID: 22530855
7.  Treatment Outcomes for Extensively Drug-Resistant Tuberculosis and HIV Co-infection 
Emerging Infectious Diseases  2013;19(3):416-424.
Sputum culture conversion was poorly predictive of successful treatment.
High mortality rates have been reported for patients co-infected with extensively drug-resistant tuberculosis (XDR-TB) and HIV, but treatment outcomes have not been reported. We report treatment outcomes for adult XDR TB patients in KwaZulu-Natal Province, South Africa. Initial data were obtained retrospectively, and outcomes were obtained prospectively during 24 months of treatment. A total of 114 XDR TB patients were treated (median 6 drugs, range 3–9 drugs); 82 (73%) were HIV positive and 50 (61%) were receiving antiretroviral therapy. After receiving treatment for 24 months, 48 (42%) of 114 patients died, 25 (22%) were cured or successfully completed treatment, 19 (17%) withdrew from the study, and 22 (19%) showed treatment failure. A higher number of deaths occurred among HIV-positive patients not receiving antiretroviral therapy and among patients who did not show sputum culture conversion. Culture conversion was a major predictor of survival but was poorly predictive (51%) of successful treatment outcome.
PMCID: PMC3647656  PMID: 23622055
tuberculosis and other mycobacteria; bacteria; extensively drug-resistant tuberculosis; XDR TB; HIV; viruses; co-infection; treatment outcomes; South Africa
8.  Population Pharmacokinetics and Pharmacodynamics of Ofloxacin in South African Patients with Multidrug-Resistant Tuberculosis 
Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.
PMCID: PMC3393408  PMID: 22564839
9.  Integration of Antiretroviral Therapy with Tuberculosis Treatment 
The New England journal of medicine  2011;365(16):1492-1501.
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here.
Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006).
The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.
PMCID: PMC3233684  PMID: 22010915
10.  High Incidence of Hospital Admissions with Multidrug Resistant and Extensively Drug Resistant Tuberculosis among South African Health Care Workers 
Annals of internal medicine  2010;153(8):516-522.
Nosocomial transmission has been described in extensively drug resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about rates of drug-resistant TB among healthcare workers (HCWs) in TB and HIV endemic settings.
To estimate rates of multi-drug resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among HCWs in KwaZulu-Natal (KZN), South Africa.
Retrospective study of drug-resistant TB patients admitted for the initiation of drug-resistant TB therapy between 2003 and 2008.
A public TB referral hospital in KZN, South Africa.
HCWs admitted with MDR-TB (N=203) or XDR-TB (N=28) were compared with non-HCWs admitted with MDR-TB (N=3807) or XDR-TB (N=344).
Hospital admission rates, hospital admission incidence rate ratios.
Estimated incidence of MDR-TB hospitalization was 64.8/100,000 for HCWs versus 11.9/100,000 for non-HCWs (I.R.R. 5.56 95% C.I. 4.87–6.35). Estimated incidence of XDR-TB hospitalizations was 7.2/100,000 among HCWs versus 1.1/100,000 in non-HCWs (I.R.R. 6.69 95% C.I. 4.38–10.20). A higher percentage of HCWs than non-HCWs with MDR-TB or XDR-TB were female (78% vs. 47%, p<0.001) and fewer HCWs reported previous TB treatment (41% vs. 92%, p<0.001). Prevalence of HIV infection did not differ between HCW and non-HCW (55% vs. 57%, p=0.71), but a higher percentage of HIV infected HCWs were on antiretroviral medications (63% vs. 47%, p<0.001).
HCWs in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB compared to non-HCWs. The increased risk may be explained by occupational exposure and not by other risk factors, underlining the urgent need for TB infection control programs.
Primary Funding Source
No funding was received for this study
PMCID: PMC3074259  PMID: 20956708
11.  Extensively Drug-Resistant Tuberculosis in Women, KwaZulu-Natal, South Africa 
Emerging Infectious Diseases  2011;17(10):1942-1945.
To determine whether women in KwaZulu-Natal, South Africa, with drug-resistant tuberculosis (TB) were more likely than men to have extensively drug-resistant TB, we reviewed 4,514 adults admitted during 2003–2008 for drug-resistant TB. Female sex independently predicted extensively drug-resistant TB, even after we controlled for HIV infection. This association needs further study.
PMCID: PMC3310667  PMID: 22000378
Tuberculosis; HIV/AIDS; gender; epidemiology; extensively drug resistant tuberculosis; South Africa; tuberculosis and other mycobacteria; women; dispatch
12.  Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy 
The New England journal of medicine  2010;362(8):697-706.
Despite high mortality rates in tuberculosis patients with HIV co-infection, there is continued controversy on when to initiate antiretroviral therapy (ART) in these patients.
We conducted an open-label randomized controlled trial in Durban, South Africa to determine optimal timing of ART initiation in relation to TB treatment. Acid-fast bacilli (AFB) smear positive tuberculosis patients with HIV infection and CD4+ counts <500 cells/mm3 (n=642) were randomized to one of two integrated treatment arms (ART initiation during tuberculosis treatment) or to a sequential treatment arm (ART initiation upon tuberculosis treatment completion). Participants received standard tuberculosis therapy, cotrimoxazole prophylaxis and once daily didanosine, lamivudine and efavirenz ART regimen. The primary endpoint was all-cause mortality.
This analysis compares data from the sequential treatment arm and the combined integrated treatment arms up to 1 September 2008, when the Safety Monitoring Committee recommended halting the sequential treatment arm. Demographic, clinical and laboratory characteristics at baseline and adverse event rates during follow-up were similar in the study arms. Mortality was 56% lower (hazard ratio: 0.44; 95% Confidence Interval: 21% to 75%; p = 0.003) in the integrated arm (5.4 per 100 person-years (25 deaths; n=429)) compared to sequential arm (12.1 per 100 person-years (27 deaths; n=213)). Mortality rates were lower regardless of CD4+ count level.
Initiating ART during tuberculosis treatment in AFB positive patients with HIV co-infection and CD4+ counts <500 cells/mm3 significantly improves survival and provides further impetus for the integration of tuberculosis and AIDS services.
PMCID: PMC3076221  PMID: 20181971
13.  High Treatment Failure and Default Rates for Patients with MDR TB in KwaZulu-Natal, South Africa, 2000–2003 
Multidrug-resistant tuberculosis (MDR TB) has emerged as a significant public health threat in South Africa.
To describe treatment outcomes and determine risk factors associated with unfavorable outcomes among MDR-TB patients admitted to the provincial TB referral hospital in KwaZulu-Natal province, South Africa.
Retrospective observational study of MDR TB patients admitted from 2000–2003.
Of 1209 MDR TB patients with documented treatment outcomes, 491 (41%) were cured, 35 (3%) completed treatment, 208 (17%) failed treatment, 223 (18%) died and 252 (21%) defaulted. 52% of patients with known HIV status were HIV-infected. Treatment failure, death and default each differed in their risk factors. Greater baseline resistance (AOR 2.3–3.0), prior TB (AOR 1.7), and diagnosis in years 2001, 2002 or 2003 (AOR 1.9–2.3) were independent risk factors for treatment failure. HIV co-infection was a risk factor for death (AOR 5.6) and both HIV (AOR 2.0) and male sex (AOR 1.9) were risk factors for treatment default.
MDR TB treatment outcomes in KwaZulu-Natal were substantially worse than those published from other MDR TB cohorts. Interventions, such as individualized treatment, concurrent antiretroviral therapy and decentralized MDR TB treatment must be considered to improve MDR TB outcomes in this high HIV-prevalence setting.
PMCID: PMC3005763  PMID: 20202298
drug resistance; Mycobacterium tuberculosis; treatment outcomes; South Africa
14.  Evaluation of Time to Detection of Mycobacterium tuberculosis in Broth Culture as a Determinant for End Points in Treatment Trials▿ †  
Journal of Clinical Microbiology  2010;48(12):4370-4376.
Time to detection of Mycobacterium tuberculosis in broth culture was examined for utility as a treatment efficacy end point. Of 146 patients in a phase IIB trial, a decreased mean time to detection was found in 5 with treatment failure. Time to detection in an analysis-of-covariance model was associated with lung cavities, less intensive treatment, and differences in the bactericidal effects of treatment regimens.
PMCID: PMC3008491  PMID: 20926712
15.  HIV-Associated Tuberculosis 
The intersecting HIV and Tuberculosis epidemics in countries with a high disease burden of both infections pose many challenges and opportunities. For patients infected with HIV in high TB burden countries, the diagnosis of TB, ARV drug choices in treating HIV-TB coinfected patients, when to initiate ARV treatment in relation to TB treatment, managing immune reconstitution, minimising risk of getting infected with TB and/or managing recurrent TB, minimizing airborne transmission, and infection control are key issues. In addition, given the disproportionate burden of HIV in women in these settings, sexual reproductive health issues and particular high mortality rates associated with TB during pregnancy are important. The scaleup and resource allocation to access antiretroviral treatment in these high HIV and TB settings provide a unique opportunity to strengthen both services and impact positively in meeting Millennium Development Goal 6.
PMCID: PMC2943082  PMID: 20871843
16.  Improved Early Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South Africa 
A public tuberculosis (TB) referral hospital in KwaZulu-Natal, South Africa.
To present treatment outcomes of patients with extensively drug resistant tuberculosis (XDR-TB) patients and HIV co-infection with and without HAART.
Retrospective cohort study. Eligible patients had drug susceptibility testing that met a consensus definition for XDR-TB, and agreed to treatment. Therapy was based on drug susceptibilities, available medications, and patient tolerance.
60 XDR-TB patients initiated therapy with a median number of 5.5 drugs. Of these 43 (72%) were HIV+, and 21 (49%) were on anti-retroviral therapy. 29 HIV infected patients (67%) had available CD4 counts; median CD4 count was 200.5 (S.D. 127.4). 31/60 patients (52%) had adverse events (AEs), and 17/60 patients (28%) had severe AEs. During follow-up, 12/60 (20%) experienced sputum culture conversion, while 25/60 (42%) patients died. None of the following was significantly associated with mortality: HIV status, previous MDR diagnosis or severe AEs.
In this study it was possible to treat HIV/XDR-TB co-infected patients, and prolong survival in a resource limited setting. We highlight the challenges in treatment, including high frequencies of AEs and death. Expanded identification of cases, prompt referral for treatment, and attention to management of co-morbidities may facilitate successful treatment of in XDR-TB in HIV infected patients.
PMCID: PMC2855970  PMID: 19555535
Extensively drug resistant tuberculosis; HIV/AIDS; treatment; South Africa
17.  The whole is greater than the sum of the parts: Recognising missed opportunities for an optimal response to the rapidly maturing TB-HIV co-epidemic in South Africa 
BMC Public Health  2009;9:243.
Despite widely acknowledged WHO guidelines for the integration of TB and HIV services, heavily burdened countries have been slow to implement these and thus significant missed opportunities have arisen.
The individual-centred, rights-based paradigm of the SA National AIDS Policy, remains dissonant with the compelling public-health approach of TB control. The existence of independent and disconnected TB and HIV services results in a wastage of scarce health resources, an increased burden on patients' time and finances, and ignores evidence of patients' preference for an integrated service. The current situation translates into a web of unacceptable, ongoing missed opportunities such as failure to maximize collaborative disease surveillance, VCT, adherence support, infection control, and positive prevention. TB services present a readily identifiable cohort for HIV provider-initiated testing. Integrating HAART and DOTS will promote efficient usage of health workers' time and a more navigable experience for patients, ultimately ensuring increased TB treatment completion rates and MDR-TB prevention. As direct observation evolves into a more supportive, empowering experience for patients, adherence to both TB drugs and HAART will be bolstered. Little attention has been paid to the transmission of TB within HIV services. Low cost infection control interventions include: triaging patients, scheduling new and follow-up patients separately; well-ventilated, sheltered waiting rooms; and the use of personal respirators by patients and staff. A more patient-centred approach to TB care may be able to recruit the active participation of TB patients in positive prevention efforts, including maximizing personal infection control, limiting exposure of social contacts to TB during the intensive phase of treatment, advocating isoniazid prophylaxis within the home and patient-centred education efforts to reduce overall transmission. Several model programmes demonstrated synergy, in which the impact of the "whole" or integrated response was greater than the sum of the non-integrated parts.
The full potential of an integrated TB-HIV service has not been fully harvested. Missed opportunities discount existing efforts in both programmes, will perpetuate the burden of disease, and prevent major gains in future interventions. This paper outlines simple, readily-implementable strategies to narrow the gap and reclaim existing missed opportunities.
PMCID: PMC2716340  PMID: 19607697
18.  XDR-TB in South Africa: No Time for Denial or Complacency 
PLoS Medicine  2007;4(1):e50.
Singh and colleagues discuss the threat to regional and global public health posed by XDR-TB in KwaZulu-Natal, and propose new measures to control the outbreak.
PMCID: PMC1779818  PMID: 17253901

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