Minimal diversity of drug-resistant Mycobacterium tuberculosis strains, South Africa.

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.

Investigation of the interactions between methadone and elvitegravir-cobicistat in subjects receiving chronic methadone maintenance.

Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

Natural ventilation reduces high TB transmission risk in traditional homes in rural KwaZulu-Natal, South Africa.

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.

Pharmacokinetic interactions between buprenorphine/naloxone and raltegravir in subjects receiving chronic buprenorphine/naloxone treatment.

BACKGROUND: Interactions between human immuno-deficiency virus (HIV) and opioid-dependence therapies can occur. OBJECTIVES: We sought to determine whether such interactions occurred between buprenorphine/naloxone and raltegravir. METHODS: We performed a within-subject open-labeled pharmacokinetic and pharmacodynamic study in 12 HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone therapy. Subjects underwent baseline and steady-state evaluation of the effect of raltegravir 400 mg BID on buprenorphine/naloxone parameters. RESULTS: Compared with baseline values, buprenorphine AUC(0-24 h) (58.2 vs. 56.0 hr*ng/mL) and C(max) (7.37 vs. 6.60 ng/mL) did not differ significantly after achieving steady-state raltegravir. Similar analyses of norbuprenorphine, the primary metabolite of buprenorphine, demonstrated no significant difference after raltegravir administration. Naloxone concentrations were unchanged for AUC(0-24 h) (.595 vs. .581 hr*ng/mL), C(max) (.251 vs. .243 ng/mL) and T(max) (.75 vs.1.08 h). Objective opioid withdrawal was not observed. The AUC(0-12 h) and C(max) of raltegravir did not significantly differ from historical controls (5543 vs. 4428 h*ng/mL and 1070 vs. 1266 ng/mL), respectively. CONCLUSION: The addition of raltegravir to stabilized patients receiving buprenorphine/naloxone does not significantly affect buprenorphine/naloxone or raltegravir pharmacokinetic or pharmacodynamic parameters.

Averting epidemics of extensively drug-resistant tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has been detected in most provinces of South Africa, particularly in the KwaZulu-Natal province where several hundred cases have been reported since 2004. We analyzed the transmission dynamics of XDR TB in the region using mathematical models, and observed that nosocomial transmission clusters of XDR TB may emerge into community-based epidemics under the public health conditions of many South African communities. The effective reproductive number of XDR TB in KwaZulu-Natal may be around 2. Intensified community-based case finding and therapy appears critical to curtailing transmission. In the setting of delayed disease presentation and high system demand, improved diagnostic approaches may need to be employed in community-based programs rather than exclusively at tertiary hospitals. Using branching process mathematics, we observed that early, community-based drug-susceptibility testing and effective XDR therapy could help curtail ongoing transmission and reduce the probability of XDR TB epidemics in neighboring territories.

Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs.

HIV-infected drug users have increased age-matched morbidity and mortality compared with HIV-infected people who do not use drugs. Substance-use disorders negatively affect the health of HIV-infected drug users, who also have frequent medical and psychiatric comorbidities that complicate HIV treatment and prevention. Evidence-based treatments are available for the management of substance-use disorders, mental illness, HIV and other infectious complications such as viral hepatitis and tuberculosis, and many non-HIV-associated comorbidities. Tuberculosis co-infection in HIV-infected drug users, including disease caused by drug-resistant strains, is acquired and transmitted as a consequence of inadequate prescription of antiretroviral therapy, poor adherence, and repeated interfaces with congregate settings such as prisons. Medication-assisted therapies provide the strongest evidence for HIV treatment and prevention efforts, yet are often not available where they are needed most. Antiretroviral therapy, when prescribed and adherence is at an optimum, improves health-related outcomes for HIV infection and many of its comorbidities, including tuberculosis, viral hepatitis, and renal and cardiovascular disease. Simultaneous clinical management of multiple comorbidities in HIV-infected drug users might result in complex pharmacokinetic drug interactions that must be adequately addressed. Moreover, interventions to improve adherence to treatment, including integration of health services delivery, are needed. Multifaceted, interdisciplinary approaches are urgently needed to achieve parity in health outcomes in HIV-infected drug users.

HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality.

RATIONALE: The multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) epidemics are rapidly expanding in South Africa. Our initial report of HIV-associated XDR TB in South Africa revealed rapid and near complete mortality. Lower mortality has been described in the literature, but few of these patients have been HIV coinfected. OBJECTIVES: To characterize mortality from MDR and XDR TB in a setting with high HIV-coinfection rates. METHODS: We conducted a retrospective observational study among 654 MDR and XDR TB cases diagnosed in Tugela Ferry, South Africa, from 2005 to 2007. Demographics and HIV status were abstracted from available medical records. MEASUREMENTS AND MAIN RESULTS: Survival was determined from the date of sputum collection until October 2008 and correlated with year of diagnosis and drug-susceptibility test results. From 2005 to 2007, 272 MDR TB and 382 XDR TB cases were diagnosed; HIV-coinfection rates were 90 and 98%, respectively. One-year mortality was 71% for MDR and 83% for XDR TB patients; 40% of MDR TB and 51% of XDR TB cases died within 30 days of sputum collection. One-year mortality among both MDR and XDR TB patients improved from 2005 to 2007; however, the majority of deaths still occurred within the first 30 days. One-year and 30-day mortality rates were worse with greater degree of drug resistance (P < 0.001). CONCLUSIONS: Mortality from MDR and XDR TB in this high HIV-prevalence region is extraordinarily high, particularly within the first 30 days. Efforts to reduce mortality must focus on earlier diagnosis and early initiation of second-line TB and antiretroviral therapy.

Tipranavir/ritonavir induction of buprenorphine glucuronide metabolism in HIV-negative subjects chronically receiving buprenorphine/naloxone.

BACKGROUND: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/ naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP. METHODS: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500?mg coadministered with ritonavir 200?mg (TPV/r). RESULTS: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The C(max) of BUP-3G was 8.78???5.23?ng/mL without TPV/r and increased to 12.7???11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1???19.4?(ng/mL)?(h) without TPV/r and increased to 58. 6???49.5 after steady state of TPV/r was achieved (p?=?.0966). In contrast, steady-state norBUP-3G AUC(0?24?h) (p?=?.0216) and C(max) (p?=?.0088) were significantly decreased in the presence of steady-state TPV/r. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G.

Preparing for highly active antiretroviral therapy rollout in rural South Africa: an assessment using the information, motivation, and behavioral skills model.

Following a controversial history and before South Africa started the world's largest highly active antiretroviral therapy (HAART) rollout, little was known about community-level information, motivation, and behavioral skills (IMB) regarding HAART in high-HIV-prevalence rural communities. The IMB model has been shown to predict behaviors that are associated with desirable HAART outcomes. We conducted an anonymous, cross-sectional "HAART-Felt Prospects" survey among HIV-serostatus-unknown young adults in Tugela Ferry, KwaZulu-Natal. We aimed to identify behavioral aspects of HAART preparedness that could be targeted by local interventions to enhance HAART outcomes. Data analysis included: percent correct, thematic means based on a four-point Likert-scale, and composite quotients. Subjects (N=176) were Zulu (99%), young (mean 19 years), and severely impoverished (55%). Relatively high levels of information were reported: overall correct score was 46%, secondary-transmission-of-resistance information was highest (81%), and only 15% reported traditional or government-advocated folk remedies cure or treat HIV/AIDS. Motivation quotient was "consistent" with favorable HAART behaviors; attitudes toward medication-taking behaviors (3.48) and condom use during HAART (3.43) ranked the highest. Desire for HIV testing (71%) was associated with HIV treatment optimism [adjusted odds ratio (AOR)=4.0, p=0.0004] and previous experience with good treatment outcome [AOR=3.2, p=0.01]. Acceptance of HAART (93%) was associated with HIV optimism [AOR=18.0, p=0.001] and not believing government-advocated folk remedies cure or treat HIV/AIDS [AOR=10.0, p=0.04]. Behavioral skills quotient was "neutral" for favorable HAART behaviors; side effects self-efficacy was the highest (3.16); and medication-taking self-efficacy the lowest (2.51). Only 47% believed disclosing HIV-serostatus would be easy. Despite controversy surrounding HAART initiation, these results suggest that local South African at-risk youth were relatively well-poised for HAART rollout. This conclusion is supported by subsequent successful HAART rollout locally. Community-based assessments are urgently needed as HAART rollouts continue. Adaptation of this IMB-based survey may better inform efforts to enhance HAART-program implementation in resource-limited settings globally.

Opportunities for community health workers to contribute to global efforts to end tuberculosis.

Tuberculosis (TB) has emerged as the leading infectious cause of death globally. New paradigms are needed to reduce TB rates and mortality. Programs harnessing the potential of community health workers (CHWs) to enhance TB prevention and care have shown great promise. In this perspective article, we review the history of CHW-based efforts to prevent and treat TB, present evidence illustrating the effectiveness of CHWs across the entire cascade of TB care, and outline additional opportunities for CHWs to address challenges particular to the TB pandemic. Despite many promising studies, knowledge gaps persist and we suggest an agenda for future research on the role of CHWs in TB prevention and care.

Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis.

Multidrug-resistant (MDR) tuberculosis is a growing clinical and public-health concern. To evaluate existing evidence regarding treatment regimens for MDR tuberculosis, we used a Bayesian random-effects meta-analysis of the available therapeutic studies to assess how the reported proportion of patients treated successfully is influenced by differences in treatment regimen design, study methodology, and patient population. Successful treatment outcome was defined as cure or treatment completion. 34 clinical reports with a mean of 250 patients per report met the inclusion criteria. Our analysis shows that the proportion of patients treated successfully improved when treatment duration was at least 18 months, and if patients received directly observed therapy throughout treatment. Studies that combined both factors had significantly higher pooled success proportions (69%, 95% credible interval [CI] 64-73%) than other studies of treatment outcomes (58%, 95% CI 52-64%). Individualised treatment regimens had higher treatment success (64%, 95% CI 59-68%) than standardised regimens (54%, 95% CI 43-68%), although the difference was not significant. Treatment approaches and study methodologies were heterogeneous across studies. Many important variables, including patients' HIV status, were inconsistently reported between studies. These results underscore the importance of strong patient support and treatment follow-up systems to develop successful MDR tuberculosis treatment programmes.

Top stories of 2008. Antiretroviral rollout--successes and challenges.

The continued success of ART rollout programs will depend on efforts to prevent resistance and ensure adequate follow-up.

Low expression Macrophage Migration Inhibitory Factor (MIF) alleles and tuberculosis in HIV infected South Africans.

Host immunity is crucial for controlling M. tuberculosis infection. Functional polymorphisms in the cytokine macrophage migration inhibitory factor (MIF) show global population stratification, with the highest prevalence of low expression MIF alleles found in sub-Saharan Africans, which is a population with the greatest confluence of both TB and HIV infection and disease. We investigated the association between MIF alleles and tuberculosis (TB) and HIV in South Africa. We acquired clinical information and determined the frequency of two MIF promoter variants: a functional -794 CATT5-8 microsatellite and an associated -173 G/C SNP in two HIV-positive cohorts of patients with active laboratory-confirmed TB and in controls without active TB who were all HIV positive. We found a greater frequency of low expression MIF promoter variants (-794 CATT5,6) among TB disease cases compared to controls (OR = 2.03, p = 0.023), supporting a contribution of genetic low MIF expression to the high prevalence of TB in South Africa. Among those with HIV, circulating MIF levels also were associated with lower CD4 cell counts irrespective of TB status (p = 0.016), suggesting an influence of HIV immunosuppression on MIF expression.

Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study.

BACKGROUND: Extensively drug-resistant (XDR) tuberculosis has spread among hospitalised patients in South Africa, but the epidemic-level effect of hospital-based infection control strategies remains unknown. We modelled the plausible effect of rapidly available infection control strategies on the overall course of the XDR tuberculosis epidemic in a rural area of South Africa. METHODS: We investigated the effect of administrative, environmental, and personal infection control measures on the epidemic trajectory of XDR tuberculosis in the rural community of Tugela Ferry. Assessments were done with a mathematical model incorporating over 2 years of longitudinal inpatient and community-based data. The model simulated inpatient airborne tuberculosis transmission, community tuberculosis transmission, and the effect of HIV and antiretroviral therapy. FINDINGS: If no new interventions are introduced, about 1300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012, more than half of which are likely to be nosocomially transmitted. Mask use alone would avert fewer than 10% of cases in the overall epidemic, but could prevent a large proportion of cases of XDR tuberculosis in hospital staff. The combination of mask use with reduced hospitalisation time and a shift to outpatient therapy could prevent nearly a 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. However, involuntary detention could result in an unexpected rise in incidence due to restricted isolation capacity. INTERPRETATION: A synergistic combination of available nosocomial infection control strategies could prevent nearly half of XDR tuberculosis cases, even in a resource-limited setting. XDR tuberculosis transmission will probably continue in the community, indicating the need to develop and implement parallel community-based programmes.

Superiority of directly administered antiretroviral therapy over self-administered therapy among HIV-infected drug users: a prospective, randomized, controlled trial.

BACKGROUND: Directly administered antiretroviral therapy (DAART) is one approach to improve treatment adherence among human immunodeficiency virus (HIV)-infected drug users. METHODS: In this randomized, controlled trial (ClinicalTrials.gov identifier, NCT00367172), the biological outcomes of a 6-month community intervention of DAART were compared with those of self-administered therapy among HIV-infected drug users. Patients randomized to receive DAART received supervised therapy 5 days per week from workers in a mobile health care van. The primary outcome, using an intention-to-treat approach, was the proportion of patients achieving either a reduction in HIV-1 RNA level of > or = 1.0 log10 copies/mL or an HIV-1 RNA level < or = 400 copies/mL at 6 months. Secondary outcomes included the mean change from baseline in HIV-1 RNA level and CD4+ T lymphocyte count. RESULTS: Of the 141 patients who met the entry criteria, 88 were randomized to receive DAART, and 53 were randomized to receive self-administered therapy; 74 (84%) of 88 of the patients randomized to receive DAART accepted the intervention. Of the 74 patients who initiated DAART, 51 (69%) completed the full 6-month intervention. At the end of 6 months, a significantly greater proportion of the DAART group achieved the primary outcome (70.5% vs. 54.7; P=.02). Additionally, compared with patients receiving self-administered therapy, patients receiving DAART demonstrated a significantly greater mean reduction in HIV-1 RNA level (-1.16 log10 copies/mL vs. -0.29 log10 copies/mL; P=.03) and mean increase in CD4+ T lymphocyte count (+58.8 cells/microL vs. -24.0 cells/microL; P=.002). CONCLUSIONS: This randomized, controlled trial was, to our knowledge, the first to demonstrate the effectiveness of DAART at improving 6-month virologic outcomes among drug users. These results suggest that DAART should be more widely available in HIV treatment programs that target drug users who have poor adherence to treatment.

Antiretroviral treatment regimen outcomes among HIV-infected prisoners.

BACKGROUND: Despite the high prevalence of HIV in correctional settings, the duration of therapy and response to various highly active antiretroviral therapy (HAART) regimens in this setting is unknown. METHOD: Using a retrospective cohort study (1997-2002) of HIV-infected prisoners in Connecticut that linked demographic, pharmacy, and laboratory data, we compared HIV-1 RNA (VL) and CD4 lymphocyte responses to four treatment strategies at baseline and at the end of incarceration. RESULTS: Using an analysis of 1,044 incarceration periods or 1,099 subjects for whom 6 months of continuous data were available, HAART regimens that included a triple NRTI, two NRTIs + either a PI or NNRTI, or a three-class (NRTI+NNRTI+PI) strategy demonstrated no difference in virological and immunological outcomes. The proportion of subjects who were initiated with NRTI, NNRTI, PI, or three-class regimens were 14%, 32%, 46%, and 8%, respectively. For all study groups, the mean change from baseline in CD4 and VL was +74 cells/muL and -0.93 log(10) copies/mL (p < .0001), respectively. Overall, 59% of subjects had an HIV-1 RNA level below the level of detection (<400 copies/mL) by the end of their incarceration. Using Kaplan-Meier curves to examine the time to change in the initial HAART strategy over the incarceration period, the three-class strategy was significantly more likely to be changed earlier than all others (p < .05). CONCLUSION: Although the three-class strategy was less durable, initiating HAART with any strategy resulted in similar and impressive virological and immunological outcomes by the end of incarceration, further supporting prison as an important site for the initiation and provision of effective antiretroviral therapy.

Sexual risk behaviour among HIV-positive individuals in clinical care in urban KwaZulu-Natal, South Africa.

We assessed the incidence and predictors of unprotected sex among 152 HIV-positive patients in clinical care in KwaZulu-Natal, South Africa. Nearly 50% were sexually active; 30% of those reported unprotected sex. Alcohol use during sex, reporting forced sex, sex with a perceived HIV-positive partner, and sex with a casual partner predicted more unprotected sex, whereas HIV status disclosure was related to less unprotected sex. These findings highlight the need for linking HIV prevention and care in Africa.

Opioid dependence: rationale for and efficacy of existing and new treatments.

Opioid dependence is a chronic and relapsing medical disorder with a well-established neurobiological basis. Opioid agonist treatments, such as methadone and the recently approved buprenorphine, stabilize opioid receptors and the intracellular processes that lead to opioid withdrawal and craving. Both methadone and buprenorphine have been proven effective for the treatment of opioid dependence and can contribute to a decreased risk of human immunodeficiency virus (HIV) transmission. In addition, a buprenorphine/naloxone combination appears to have a decreased potential for abuse or diversion, compared with that associated with methadone. Largely because of these properties, recent legislation now affords an unprecedented opportunity for general physicians to offer opioid agonist treatment through their offices. This review focuses on the neurobiological basis of opioid dependence, the rationale for methadone and buprenorphine treatments, and issues in prescribing these medications to patients with HIV infection.