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1.  Adverse events in an integrated, home-based treatment program for MDR-TB and HIV in KwaZulu-Natal, South Africa 
Most patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are HIV-infected, but the safety and tolerability of co-treatment is unknown. We reviewed all adverse events (AEs) for MDR-TB patients in a home-based treatment program in rural KwaZulu-Natal. Of 91 MDR-TB patients, 74 (81%) were HIV-positive and receiving antiretroviral therapy (ART). AEs were common but most were mild and did not require therapy modification. The most common severe AEs were hypothyroidism (36%) and psychosis (5%). Patients receiving concurrent ART did not experience AEs more frequently than those on MDR-TB therapy alone. Concurrent treatment for MDR-TB/HIV can be safely administered in a home-based care setting.
doi:10.1097/QAI.0b013e31828175ed
PMCID: PMC3641171  PMID: 23254152
HIV; multidrug-resistant tuberculosis; side effects; adverse events; resource-limited settings
2.  Minimal Diversity of Drug-Resistant Mycobacterium tuberculosis Strains, South Africa1 
Emerging Infectious Diseases  2014;20(3):426-437.
Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005–2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type.
doi:10.3201/eid2003.131083
PMCID: PMC3944869
Mycobacterium tuberculosis; drug resistance; transmission; genotype; South Africa; HIV; bacteria; tuberculosis; tuberculosis and other mycobacteria; antimicrobial resistance
3.  Intensified specimen collection to improve tuberculosis diagnosis in children from Rural South Africa, an observational study 
Background
In drug-resistant TB settings, specimen collection is critical for drug-susceptibility testing (DST). This observational study included multiple specimen types collected from pediatric TB suspects with the aim to determine diagnostic yield and inform clinical practice in children with drug-resistant and drug-susceptible TB.
Methods
From 03/2009-07/2010, TB suspects aged ≥6 months and ≤12 years were recruited among outpatient and inpatient settings. Subjects were new TB suspects or had persistent symptoms despite ≥2 months of TB treatment. The protocol included collection of a single blood and urine specimen, a single sputum induction and, if inpatients and <5 years of age, collection of 3 gastric aspirates (GA). Samples were cultured on solid and/or liquid media. DST was by 1% proportion method.
Results
Among 118 children with possible, probable or confirmed TB, the mean age was 4.9 years [SD 3.2] and 64 (62%) of those tested were HIV-positive. Eight (7%) subjects were culture-positive from at least one specimen; yield did not differ by HIV status or TB treatment history. Among those with positive cultures, 7/8 (88%) were from induced sputum, 5/6 (83%) from GA, 3/8 (38%) from blood, and 3/7 (43%) from urine. In subjects with both induced sputum and GA collection, sputum provided one additional case compared to GA. Multidrug resistant (MDR)-TB was detected by urine culture alone in one child >5 years old. Pan-resistant extensively drug resistant (XDR)-TB was identified by cultures from all sites in one subject.
Conclusions
TB was cultured from HIV-positive and -negative children, and allowed for identification of MDR and XDR-TB cases. Urine and induced sputum each provided an additional TB diagnosis and, when compared to GA, may be considered a less invasive, same-day method of specimen collection for childhood TB suspects. This study illustrates the continued challenges and limitations of available strategies for pediatric TB diagnostics.
doi:10.1186/1471-2334-14-11
PMCID: PMC3890632  PMID: 24400822
Tuberculosis; Diagnosis; Childhood; Drug resistance; South Africa
4.  Nosocomial Transmission of Extensively Drug-Resistant Tuberculosis in a Rural Hospital in South Africa 
Background. Extensively drug-resistant tuberculosis (XDR-tuberculosis) is a global public health threat, but few data exist elucidating factors driving this epidemic. The initial XDR-tuberculosis report from South Africa suggested transmission is an important factor, but detailed epidemiologic and molecular analyses were not available for further characterization.
Methods. We performed a retrospective, observational study among XDR-tuberculosis patients to identify hospital-associated epidemiologic links. We used spoligotyping, IS6110-based restriction fragment–length polymorphism analysis, and sequencing of resistance-determining regions to identify clusters. Social network analysis was used to construct transmission networks among genotypically clustered patients.
Results. Among 148 XDR-tuberculosis patients, 98% were infected with human immunodeficiency virus (HIV), and 59% had smear-positive tuberculosis. Nearly all (93%) were hospitalized while infectious with XDR-tuberculosis (median duration, 15 days; interquartile range: 10–25 days). Genotyping identified a predominant cluster comprising 96% of isolates. Epidemiologic links were identified for 82% of patients; social network analysis demonstrated multiple generations of transmission across a highly interconnected network.
Conclusions. The XDR-tuberculosis epidemic in Tugela Ferry, South Africa, has been highly clonal. However, the epidemic is not the result of a point-source outbreak; rather, a high degree of interconnectedness allowed multiple generations of nosocomial transmission. Similar to the outbreaks of multidrug-resistant tuberculosis in the 1990s, poor infection control, delayed diagnosis, and a high HIV prevalence facilitated transmission. Important lessons from those outbreaks must be applied to stem further expansion of this epidemic.
doi:10.1093/infdis/jis631
PMCID: PMC3523793  PMID: 23166374
tuberculosis; HIV; drug resistance; transmission; genotyping
5.  Transmission of Tuberculosis in Resource-Limited Settings 
Current HIV/AIDS reports  2013;10(3):10.1007/s11904-013-0164-x.
Unrecognized transmission is a major contributor to ongoing TB epidemics in high-burden, resource-constrained settings. Limitations in diagnosis, treatment, and infection control in health-care and community settings allow for continued transmission of drug-sensitive and drug-resistant TB, particularly in regions of high HIV prevalence. Health-care facilities are common sites of TB transmission. Improved implementation of infection control practices appropriate for the local setting and in combination, has been associated with reduced transmission. Community settings account for the majority of TB transmission and deserve increased focus. Strengthening and intensifying existing high-yield strategies, including household contact tracing, can reduce onward TB transmission. Recent studies documenting high transmission risk community sites and strategies for community-based intensive case finding hold promise for feasible, effective transmission reduction. Infection control in community settings has been neglected and requires urgent attention. Developing and implementing improved strategies for decreasing transmission to children, within prisons and of drug-resistant TB are needed.
doi:10.1007/s11904-013-0164-x
PMCID: PMC3809054  PMID: 23824469
Tuberculosis; Transmission; Resource-limited setting; South Africa; Infection control; Nosocomial; MDR/XDRTB; Ventilation; UV light; Household contact investigation; Health care workers; Intensive case finding; Community; HIV/TB co-infection
6.  Chest Radiograph Findings and Time to Culture Conversion in Patients with Multidrug-Resistant Tuberculosis and HIV in Tugela Ferry, South Africa 
PLoS ONE  2013;8(9):e73975.
Background
The majority of patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are co-infected with HIV, but the radiographic features of MDR-TB and their relationship with time to sputum culture conversion in the antiretroviral therapy era have not been described.
Methods
We reviewed baseline chest radiographs for 56 patients with MDR-TB from a rural area of South Africa. We analyzed the association of cavities, consolidation, pleural effusion and hilar lymphadenopathy with time to sputum culture conversion, adjusting for HIV status, baseline sputum smear and CD4 count.
Results
Of the 56 subjects, 49 (88%) were HIV-positive, with a median CD4 count of 136 cells/mm3 (IQR 65-249). Thirty-two (57%) patients were sputum smear positive. Twenty-two (39%) patients had a cavity and 37 (66%) patients had consolidations. Cavitary disease and consolidations were each associated with longer time to culture conversion on bivariate analysis but not after adjusting for sputum smear status (aORs 1.79 [0.94-3.42] and 1.09 [0.67-1.78], respectively). Positive baseline sputum smear remained independently associated with longer time to conversion (aOR 3.45 [1.39-8.59]). We found no association between pleural effusion or hilar lymphadenopathy and time to conversion. Seventy-nine percent of patients were cured at the end of treatment.
Conclusions
Despite high rates of HIV co-infection and advanced immunodeficiency, the majority of patients had severe pathology on baseline chest radiograph. Nevertheless, culture conversion rates were high and treatment outcomes were favorable. Cavitation and consolidation do not appear to have an independent association with time to culture conversion beyond that of baseline sputum smear status.
doi:10.1371/journal.pone.0073975
PMCID: PMC3765317  PMID: 24040132
7.  Immune Reconstitution Inflammatory Syndrome following Antiretroviral Therapy Initiation in Tuberculosis Patients: Findings from the SAPiT Trial 
Annals of internal medicine  2012;157(5):313-324.
Background
Concerns about immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during anti-tuberculosis treatment in co-infected patients.
Objective
We assessed IRIS incidence, severity, and outcomes relative to timing of ART initiation in patients with HIV-related tuberculosis (HIV-TB).
Setting
An outpatient clinic in Durban, South Africa
Patients
642 HIV-TB co-infected patients
Design
In a secondary analysis of the SAPiT trial, IRIS was assessed in patients randomized to initiate ART either within four weeks of tuberculosis treatment initiation (early integrated-treatment arm), within four weeks of completion of the intensive phase of tuberculosis treatment (late integrated-treatment arm) or within four weeks after tuberculosis therapy completion (sequential-treatment arm). IRIS was defined as new onset or worsening symptoms, signs or radiographic manifestations temporally related to treatment initiation accompanied by a treatment response. IRIS severity, hospitalization and time to resolution were monitored.
Results
IRIS incidence was 19.5 (n=43), 7.5 (n=18) and 8.1 (n=19) per 100 person-years in the early integrated-, late integrated-, and sequential-treatment arms, respectively; P < 0.001, and 45.5, 9.7 and 19.7 per 100 person-years in patients with baseline CD4+ counts <50 cells/mm3, P = 0.004. IRIS incidence was higher in the early integrated- compared to the late integrated- (incidence rate ratio (IRR) = 2.6, 95%confidence interval (CI): 1.5 to 4.8; P < 0.001) or sequential-treatment arm (IRR=2.4, 95%CI: 1.4 to 4.4; P < 0.001). IRIS cases in the early integrated-treatment arm were more severe (34.9% vs. 18.9%, P = 0.18); had significantly higher hospitalization rates (18/43 vs. 5/37; P = 0.01), and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) compared to IRIS cases in the other two arms.
Limitation
IRIS could not be assessed, due to LTFU, withdrawal or death within 6 months of scheduled ART initiation, in more patients from the sequential treatment arm (n=74) than in the late integrated treatment arm (n=50) and in the early integrated treatment arm (n=32). This study did not assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis.
Conclusion
Initiation of ART early during tuberculosis treatment resulted in significantly higher IRIS rates, with longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings, particularly relevant to patients initiating ART with CD4+ counts < 50 cells/mm3, need to be considered together with the increased survival benefit of early ART initiation in this group. Clintrials.gov: NCT00398996
doi:10.7326/0003-4819-157-5-201209040-00004
PMCID: PMC3534856  PMID: 22944873
8.  The Epidemic-level Impact of Preventing Nosocomial Transmission of Extensively Drug-Resistant (XDR) Tuberculosis in Rural South African District Hospitals 
Lancet  2007;370(9597):1500-1507.
Background
Extensively drug-resistant (XDR) tuberculosis has spread among hospitalized patients in South Africa, but the epidemic-level impact of hospital-based infection control strategies remains unknown.
Methods
We investigated the effect of administrative, environmental, and personal infection control measures on the epidemic trajectory of XDR tuberculosis in a rural South African community. Assessments were performed with a mathematical model, which incorporated inpatient airborne tuberculosis transmission and community tuberculosis and HIV transmission.
Results
If no new interventions are introduced, 1,300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012. Over half of these cases are likely to be nosocomially transmitted. Mask use would avert less than 10% of overall cases, due to long inpatient exposure times and real-world face-seal leakage rates, but could reduce a significant proportion of hospital staff XDR tuberculosis cases. Combining mask use with reduced hospitalization time and a shift to outpatient therapy, however, could prevent nearly one-third of XDR tuberculosis cases. Supplementing this approach with improved ventilation, rapid drug resistance testing, HIV treatment, and tuberculosis isolation facilities could avert 48% of XDR tuberculosis cases (range 34-50%) by the end of 2012. Involuntary detention, however, could result in an unexpected rise in incidence, given limited isolation capacity.
Conclusions
In the face of rising XDR tuberculosis incidence, prevalence and burden on the health care system, a synergistic combination of available nosocomial infection control strategies may prevent nearly half of XDR tuberculosis cases, even in a resource-limited setting. XDR tuberculosis transmission will continue in the community in spite of such efforts, however, indicating the need to develop parallel community-based programs.
doi:10.1016/S0140-6736(07)61636-5
PMCID: PMC3711808  PMID: 17964351
Tuberculosis, Drug-Resistant; Tuberculosis, Multidrug-Resistant; Tuberculosis, Extensively Drug-Resistant; Tuberculosis, MDR; Tuberculosis, XDR; Mathematical Model; Nosocomial Infections; Hospital Infections; South Africa; Infection Control
9.  Natural ventilation reduces high TB transmission risk in traditional homes in rural KwaZulu-Natal, South Africa 
BMC Infectious Diseases  2013;13:300.
Background
Transmission of drug susceptible and drug resistant TB occurs in health care facilities, and community and households settings, particularly in highly prevalent TB and HIV areas. There is a paucity of data regarding factors that may affect TB transmission risk in household settings. We evaluated air exchange and the impact of natural ventilation on estimated TB transmission risk in traditional Zulu homes in rural South Africa.
Methods
We utilized a carbon dioxide decay technique to measure ventilation in air changes per hour (ACH). We evaluated predominant home types to determine factors affecting ACH and used the Wells-Riley equation to estimate TB transmission risk.
Results
Two hundred eighteen ventilation measurements were taken in 24 traditional homes. All had low ventilation at baseline when windows were closed (mean ACH = 3, SD = 3.0), with estimated TB transmission risk of 55.4% over a ten hour period of exposure to an infectious TB patient. There was significant improvement with opening windows and door, reaching a mean ACH of 20 (SD = 13.1, p < 0.0001) resulting in significant decrease in estimated TB transmission risk to 9.6% (p < 0.0001). Multivariate analysis identified factors predicting ACH, including ventilation conditions (windows/doors open) and window to volume ratio. Expanding ventilation increased the odds of achieving ≥12 ACH by 60-fold.
Conclusions
There is high estimated risk of TB transmission in traditional homes of infectious TB patients in rural South Africa. Improving natural ventilation may decrease household TB transmission risk and, combined with other strategies, may enhance TB control efforts.
doi:10.1186/1471-2334-13-300
PMCID: PMC3716713  PMID: 23815441
Tuberculosis transmission; MDR/XDR TB; Household; South Africa; Infection control; Ventilation
10.  A randomized controlled trial of HAART versus HAART and chemotherapy in therapy-naïve patients with HIV-associated Kaposi sarcoma in South Africa 
Background
The optimal approach to HIV-associated KS (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes.
Methods
We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naïve patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine and nevirapine (Triomune®); CXT arm received Triomune® plus bleomycin, doxorubicin, and vincristine (ABV) every 3 weeks. When ABV was not available, oral etoposide (50-100 mg days 1-21 of a 28 day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included: time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence and quality-of-life.
Results
59 subjects were randomized to HAART, 53 to CXT. 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference 27%; 95% CI 9%-43%, p=0.005). At 12 months, 77% were alive (no survival difference between arms, p=0.49), 82% had HIV viral load <50 copies/mL without difference between arms, (p=0.47); CD4 counts and QOL measures improved in all patients.
Conclusions
HAART with chemotherapy produced higher overall KS response over 12 months, while HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and HHV-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.
doi:10.1097/QAI.0b013e318251aedd
PMCID: PMC3360837  PMID: 22395672
Kaposi sarcoma; acquired immunodeficiency syndrome; human immunodeficiency virus; highly active antiretroviral therapy; South Africa
11.  A Pilot Study of an mHealth Application for Healthcare Workers: Poor Uptake Despite High Reported Acceptability at a Rural South African Community-Based MDR-TB Treatment Program 
PLoS ONE  2013;8(5):e64662.
Introduction
As the South African province of KwaZulu-Natal addresses a growing multidrug-resistant tuberculosis (MDR-TB) epidemic by shifting care and treatment from trained specialty centers to community hospitals, delivering and monitoring MDR-TB therapy has presented new challenges. In particular, tracking and reporting adverse clinical events have been difficult for mobile healthcare workers (HCWs), trained health professionals who travel daily to patient homes to administer and monitor therapy. We designed and piloted a mobile phone application (Mobilize) for mobile HCWs that electronically standardized the recording and tracking of MDR-TB patients on low-cost, functional phones.
Objective
We assess the acceptability and feasibility of using Mobilize to record and submit adverse events forms weekly during the intensive phase of MDR-TB therapy and evaluate mobile HCW perceptions throughout the pilot period.
Methods
All five mobile HCWs at one site were trained and provided with phones. Utilizing a mixed-methods evaluation, mobile HCWs’ usage patterns were tracked electronically for seven months and analyzed. Qualitative focus groups and questionnaires were designed to understand the impact of mobile phone technology on the work environment.
Results
Mobile HCWs submitted nine of 33 (27%) expected adverse events forms, conflicting with qualitative results in which mobile HCWs stated that Mobilize improved adverse events communication, helped their daily workflow, and could be successfully expanded to other health interventions. When presented with the conflict between their expressed views and actual practice, mobile HCWs cited forgetfulness and believed patients should take more responsibility for their own care.
Discussion
This pilot experience demonstrated poor uptake by HCWs despite positive responses to using mHealth. Though our results should be interpreted cautiously because of the small number of mobile HCWs and MDR-TB patients in this study, we recommend carefully exploring the motivations of HCWs and technologic enhancements prior to scaling new mHealth initiatives in resource poor settings.
doi:10.1371/journal.pone.0064662
PMCID: PMC3665589  PMID: 23724075
12.  Prevalence of methicillin-resistant Staphylococcus aureus nasal carriage among hospitalised patients with tuberculosis in rural KwaZulu-Natal 
Background
There is little information regarding the presence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA), an important nosocomial pathogen, in rural African hospitals.
Objectives
To determine the prevalence of MRSA colonisation in patients admitted to a rural hospital with tuberculosis (TB) in an endemic HIV area and to describe transmission dynamics and resistance patterns among MRSA isolates.
Methods
A prospective prevalence survey in the adult TB wards of the Church of Scotland Hospital, a provincial government district hospital in Tugela Ferry, KwaZulu-Natal. Patients were eligible if over the age of 15 and admitted to the TB wards between 15 November and 15 December 2008. Nasal swabs were cultured within 24 hours of admission and repeated at hospital-day 14 or upon discharge. Susceptibility testing was performed with standard disk diffusion. Demographic and clinical information was extracted from medical charts.
Results
Of 52 patients with an admission nasal swab, 11 (21%) were positive for MRSA. An additional 4 (10%) of patients with negative admission swabs were positive for MRSA on repeat testing. MRSA carriage on admission was more common among patients with previous hospitalisation, and among HIV-infected patients was significantly associated with lower CD4 counts (p=0.03). All MRSA isolates were resistant to cotrimoxazole, and 74% were resistant to ≥5 classes of antibiotics; all retained susceptibility to vancomycin.
Conclusions
A high prevalence of multidrug-resistant MRSA nasal carriage was found. Studies are needed to validate nosocomial acquisition and to evaluate the impact of MRSA on morbidity and mortality among TB patients in similar settings.
PMCID: PMC3628595  PMID: 21837877
13.  Integrated, Home-based Treatment for MDR-TB and HIV in Rural South Africa: An Alternate Model of Care 
SUMMARY
Treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) in South Africa have suffered as centralized, inpatient treatment programs struggle to cope with rising prevalence and HIV co-infection rates. A new treatment model is needed to expand treatment capacity and improve MDR-TB and HIV outcomes. We describe the design and preliminary results of an integrated, home-based MDR-TB/HIV treatment program created in rural KwaZulu-Natal. In 2008, a decentralized center was established to provide outpatient MDR-TB and HIV treatment. Nurses, community health workers, and family supporters have been trained to administer injections, provide adherence support, and monitor adverse reactions in patients’ homes. Physicians assess clinical response, adherence, and adverse reaction severity to MDR-TB and HIV therapy at monthly follow-up visits. Treatment outcomes are assessed by monthly cultures and CD4 and viral load every 6 months. Eighty patients initiated MDR-TB therapy from 2/2008–4/2010; 66 were HIV co-infected. Retention has been high (only 5% defaults, 93% of visits attended) and preliminary outcomes have been favorable (77% cured/still on treatment, 82% undetectable viral load). Few patients have required escalation of care (9%), had severe adverse events (8%), or died (6%). Integrated, home-based treatment for MDR-TB and HIV is a promising treatment model to expand capacity and achieve improved outcomes in rural, resource-poor, and high-HIV prevalent settings.
doi:10.5588/ijtld.11.0713
PMCID: PMC3390442  PMID: 22668560
HIV/AIDS; Multidrug-resistant tuberculosis; Community-based treatment; Program development; AIDS
14.  Rifampin, but not Rifabutin, May Produce Opiate Withdrawal in Buprenorphine-Maintained Patients* 
Drug and Alcohol Dependence  2011;118(2-3):326-334.
Background
This series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication.
Methods
Opioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-hour blood sampling studies: 1. for buprenorphine pharmacokinetics and 2. following 15 days of rifampin 600 mg daily or rifabutin 300 mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics.
Results
Rifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p=<0·001) and onset of opiate withdrawal symptoms in 50% of participants (p=0·02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p<0·001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p=0·009), although rifabutin and its active metabolite concentrations remained in the therapeutic range.
Conclusions
Rifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed.
doi:10.1016/j.drugalcdep.2011.04.013
PMCID: PMC3272858  PMID: 21596492
buprenorphine/naloxone; rifampin; rifabutin; tuberculosis; opioid addiction; drug interactions
15.  Integration of Antiretroviral Therapy with Tuberculosis Treatment 
The New England journal of medicine  2011;365(16):1492-1501.
Background
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1056/NEJMoa1014181
PMCID: PMC3233684  PMID: 22010915
16.  Survival from XDR-TB Is Associated with Modifiable Clinical Characteristics in Rural South Africa 
PLoS ONE  2012;7(3):e31786.
Background
Drug-resistant tuberculosis (TB) is a major threat to global public health. Patients with extensively drug-resistant TB (XDR-TB), particularly those with HIV-coinfection, experience high and accelerated mortality with limited available interventions. To determine modifiable factors associated with survival, we evaluated XDR-TB patients from a community-based hospital in rural South Africa where a large number of XDR-TB cases were first detected.
Methodology/Principal Findings
A retrospective case control study was conducted of XDR-TB patients diagnosed from 2005–2008. Survivors, those alive at 180 days from diagnostic sputum collection date, were compared with controls who died within 180 days. Clinical, laboratory and microbiological correlates of survival were assessed in 69 survivors (median survival 565 days [IQR 384–774] and 73 non-survivors (median survival 34 days [IQR 18–90]). Among 129 HIV+ patients, multivariate analyses of modifiable factors demonstrated that negative AFB smear (AOR 8.4, CI 1.84–38.21), a lower laboratory index of routine laboratory findings (AOR 0.48, CI 0.22–1.02), CD4>200 cells/mm3 (AOR 11.53, 1.1–119.32), and receipt of antiretroviral therapy (AOR 20.9, CI 1.16–376.83) were independently associated with survival from XDR-TB.
Conclusions/Significance
Survival from XDR-TB with HIV-coinfection is associated with less advanced stages of both diseases at time of diagnosis, absence of laboratory markers indicative of multiorgan dysfunction, and provision of antiretroviral therapy. Survival can be increased by addressing these modifiable risk factors through policy changes and improved clinical management. Health planners and clinicians should develop programmes focusing on earlier case finding and integration of HIV and drug-resistant TB diagnostic, therapeutic, and preventive activities.
doi:10.1371/journal.pone.0031786
PMCID: PMC3295798  PMID: 22412840
17.  Interaction Between Buprenorphine and Atazanavir or Atazanavir/Ritonavir 
Drug and Alcohol Dependence  2007;91(2-3):269-278.
Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
doi:10.1016/j.drugalcdep.2007.06.007
PMCID: PMC3272856  PMID: 17643869
buprenorphine/naloxone; atazanavir; ritonavir; drug interactions
18.  Spread of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal Province, South Africa 
PLoS ONE  2011;6(5):e17513.
Background
In 2005 a cluster of 53 HIV-infected patients with extensively drug-resistant tuberculosis (XDR-TB) was detected in the Msinga sub-district, the catchment area for the Church of Scotland Hospital (CoSH) in Tugela Ferry, in KwaZulu-Natal province (KZN), South Africa. KZN is divided into 11 healthcare districts. We sought to determine the distribution of XDR TB cases in the province in relation to population density.
Methods
In this cross-sectional study, the KZN tuberculosis laboratory database was analysed. Results of all patients with a sputum culture positive for Mycobacterium tuberculosis from January 2006 to June 2007 were included. Drug-susceptibility test results for isoniazid, rifampicin, ethambutol, streptomycin, kanamycin and ofloxacin were available for all patients as well as the location of the hospital where their clinical diagnosis was made.
Findings
In total, 20858 patients attending one of 73 hospitals or their adjacent clinics had cultures positive for M. tuberculosis. Of these, 4170 (20%) were MDR-TB cases. Four hundred and forty three (11%) of the MDR tuberculosis cases displayed the XDR tuberculosis susceptibility profile. Only 1429 (34%) of the MDR-TB patients were seen at the provincial referral hospital for treatment. The proportion of XDR-TB amongst culture-confirmed cases was highest in the Msinga sub-district (19.6%), followed by the remaining part of the Umzinyati district (5.9%) and the other 10 districts (1.1%). The number of hospitals with at least one XDR-TB case increased from 18 (25%) to 58 (80%) during the study period.
Interpretation
XDR-TB is present throughout KZN. More than 65% of all diagnosed MDR-TB cases, including XDR-TB patients, were left untreated and likely remained in the community as a source of infection.
doi:10.1371/journal.pone.0017513
PMCID: PMC3104985  PMID: 21655324
19.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1056/NEJMoa0905848
PMCID: PMC3076221  PMID: 20181971
20.  Increasing Drug Resistance in Extensively Drug-Resistant Tuberculosis, South Africa 
Emerging Infectious Diseases  2011;17(3):510-513.
We expanded second-line tuberculosis (TB) drug susceptibility testing for extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa. Of 19 patients with extensively drug-resistant TB identified during February 2008–April 2009, 13 (68%) had isolates resistant to all 8 drugs tested. This resistance leaves no effective treatment with available drugs in South Africa.
doi:10.3201/eid1703.101363
PMCID: PMC3166021  PMID: 21392446
Extensively drug-resistant tuberculosis; tuberculosis and other mycobacteria; HIV; drug resistance; second-line drugs; South Africa; dispatch
21.  Antiretroviral Medication Adherence and Class-Specific Resistance in a Large Prospective Clinical Trial 
AIDS (London, England)  2010;24(3):395-403.
Objective
To assess the association between adherence to antiretroviral therapy and the presence of class-specific antiretroviral medication resistance.
Design
Secondary analysis of prospective clinical trial data
Methods
Participants randomized to the protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) strategies of the Community Programs for Clinical Research on AIDS (CPCRA) Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study were included. Adherence was measured by 7-day self-report. Virological failure was defined as an HIV-RNA > 1000 at or after 4 months. The association between cumulative adherence and the development of class-specific genotypic resistance was assessed by Cox regression analysis.
Results
Included were 457 and 446 antiretroviral naïve participants on the PI and NNRTI strategies respectively. The median time to initial virological failure in the PI strategy was 1.2 years; 135 (30%) individuals failed with resistance. The median time to initial virological failure in the NNRTI strategy was 3.0 years; 127 (28%) failed with resistance. No association was found between cumulative adherence and PI resistance (HR 1.1, 95% CI 0.9 – 1.4 per 10% lower adherence). However, lower cumulative adherence was associated with an increased risk of NNRTI resistance at initial virological failure (HR 1.2, 95% CI 1.1 – 1.3 per 10% lower adherence). In both strategies lower cumulative adherence was associated with an increased risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance at initial virological failure.
Conclusions
Adherence-resistance relationships are class-specific. For NRTIs and NNRTIs, initial virological failure with resistance is more likely at lower levels of cumulative adherence.
PMCID: PMC2886717  PMID: 20099399
adherence; antiretroviral therapy; HIV; virological failure; antiretroviral resistance
22.  Transmission of Drug-Susceptible and Drug-Resistant Tuberculosis and the Critical Importance of Airborne Infection Control in the Era of HIV Infection and Highly Active Antiretroviral Therapy Rollouts 
Comprehensive and successful tuberculosis (TB) care and treatment must incorporate effective airborne infection-control strategies. This is particularly and critically important for health care workers and all persons with or at risk of human immunodeficiency virus (HIV) infection. Past and current outbreaks and epidemics of drug-susceptible, multidrug-resistant, and extensively drug-resistant TB have been fueled by HIV infection, with high rates of morbidity and mortality and linked to the absence or limited application of airborne infection-control strategies in both resource-rich and resource-limited settings. Airborne infection-control strategies are available—grouped into administrative, environmental, and personal protection categories—and have been shown to be associated with decreases in nosocomial transmission of TB; their efficacy has not been fully demonstrated, and their implementation is extremely limited, particularly in resource-limited settings. New research and resources are required to fully realize the potential benefits of infection control in the era of TB and HIV epidemics.
doi:10.1086/651496
PMCID: PMC3029014  PMID: 20397953
23.  Culture Conversion Among HIV Co-Infected Multidrug-Resistant Tuberculosis Patients in Tugela Ferry, South Africa 
PLoS ONE  2011;6(1):e15841.
Background
Little is known about the time to sputum culture conversion in MDR-TB patients co-infected with HIV, although such patients have, historically, had poor outcomes. We describe culture conversion rates among MDR-TB patients with and without HIV-co-infection in a TB-endemic, high-HIV prevalent, resource-limited setting.
Methods
Patients with culture-proven MDR-TB were treated with a standardized second-line regimen. Sputum cultures were taken monthly and conversion was defined as two negative cultures taken at least one month apart. Time-to-conversion was measured from the day of initiation of MDR-TB therapy. Subjects with HIV received antiretroviral therapy (ART) regardless of CD4 count.
Results
Among 45 MDR-TB patients, 36 (80%) were HIV-co-infected. Overall, 40 (89%) of the 45 patients culture-converted within the first six months and there was no difference in the proportion who converted based on HIV status. Median time-to-conversion was 62 days (IQR 48-111). Among the five patients who did not culture convert, three died, one was transferred to another facility, and one refused further treatment before completing 6 months of therapy. Thus, no patients remained persistently culture-positive at 6 months of therapy.
Conclusions
With concurrent second-line TB and ART medications, MDR-TB/HIV co-infected patients can achieve culture conversion rates and times similar to those reported from HIV-negative patients worldwide. Future studies are needed to examine whether similar cure rates are achieved at the end of MDR-TB treatment and to determine the optimal use and timing of ART in the setting of MDR-TB treatment.
doi:10.1371/journal.pone.0015841
PMCID: PMC3017058  PMID: 21253585
24.  Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen 
Annual review of medicine  2009;60:307-320.
The presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control.
doi:10.1146/annurev.med.60.053107.103955
PMCID: PMC3013225  PMID: 19630575
XDR TB; multiple-drug-resistant tuberculosis (MDR TB); TB/HIV coinfection; Tugela Ferry; South Africa
25.  Multidrug-resistant and extensively drug-resistant tuberculosis: consequences for the global HIV community 
Purpose of review
Physicians, researchers and policy makers must understand the myriad consequences of multidrug and extensively drug-resistant tuberculosis (TB) within the HIV community in order to guide clinical care, research and resource allocation.
Recent findings
Extensively drug-resistant TB can no longer be considered as occurring in isolated outbreaks as it has been reported in 45 countries from all regions of the world. HIV has been associated as an independent risk factor for infection with drug-resistant TB. HIV patients appear more likely to suffer from primary, transmitted resistance as opposed to developing acquired resistance during the course of treatment for TB. New rapid diagnostics offer promise of providing clinically useful first-line drug susceptibility information but require validation in HIV patients and smear negative individuals. Demonstration projects of community-based treatment of drug-resistant TB and integration of TB and HIV care provide opportunities to decentralize management of drug-resistant TB.
Summary
Multidrug-resistant and extensively drug-resistant TB disproportionately affect HIV patients and result in increased morbidity and mortality. In this study, we address these challenging issues and offer some short-term and longer term strategies for their alleviation.
doi:10.1097/QCO.0b013e3283210020
PMCID: PMC3013226  PMID: 19532076
drug-resistant tuberculosis; extensively drug-resistant tuberculosis; multidrug-resistant tuberculosis; South Africa; tuberculosis/HIV coinfection

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