Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention.

BACKGROUND: The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART. OBJECTIVES: To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. METHODS: Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. RESULTS: Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33). CONCLUSIONS: The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

Detection and molecular characterization of urinary tract HIV-1 populations.

BACKGROUND: Identification of all possible HIV reservoirs is an important aspect in HIV eradication efforts. The urinary tract has however not been well studied as a potential HIV reservoir. In this pilot study we molecularly characterized HIV-1 viruses in urine and plasma samples to investigate HIV-1 replication, compartmentalization and persistence in the urinary tract. METHODS: Prospectively collected urine and blood samples collected over 12-36 months from 20 HIV-1 infected individuals were analysed including sampling points from prior to and after ART initiation. HIV-1 pol gene RNA and DNA from urine supernatant and urine pellets respectively were analysed and compared to plasma RNA viruses from the same individual. RESULTS: HIV-1 nucleic acid was detected in urine samples from at least one time point in 8/20 (40%) treatment-naïve subjects compared to 1/13 (7.7%) individuals on antiretroviral treatment (ART) during periods of plasma viral suppression and 1/7 (14.3%) individuals with virological failure. HIV-1 RNA was undetectable in urine samples after ART initiation but HIV-1 DNA was detectable in one patient more than 6 months after treatment initiation. There was co-clustering of urine-derived pol sequences but some urine-derived sequences were interspersed among the plasma-derived sequences. CONCLUSIONS: Suppressive ART reduces HIV-1 replication in the urinary tract but HIV-1 DNA may persist in these cells despite treatment. A larger number of sequences would be required to confirm HIV compartmentalization in the urinary tract.

3HP preventive treatment among children and adolescents with HIV and child household contacts of TB patients.

INTRODUCTION: India's National TB Elimination Programme plans to roll out short-course TB preventive therapy (TPT) using 3 months of rifapentine and isoniazid (3HP). Understanding the feasibility and safety of children in programmatic settings is critical for widespread implementation. We present the findings of a targeted scale-up of 3HP among children and adolescents living with HIV (CALHIV) and child household contacts (>2 to <6 years) of pulmonary TB patients (CHHC). METHODS: Between December 2021 and July 2023, eligible CALHIV and CHHC participants were given weekly dosages of 3HP for 3 months at antiretroviral therapy (ART) and TB clinics, respectively, of a public hospital in Pune, India. RESULTS: Of 97 children screened, 91 initiated 3HP (32 CALHIV and 59 CHHC). The median age of CALHIV was 14 years; 66% were male and on dolutegravir-based ART. The median age of CHHC was 4 years; 47% were males. Thirty-one (97%) CALHIV and 56 (95%) CHHC completed 3HP without dolutegravir dose adjustment. None of the child participants discontinued 3HP due to adverse events. No child participant developed TB during 1 year of follow-up post-3HP. CONCLUSION: Our study provides evidence of the uptake and feasibility of the planned nationwide rollout of 3HP.

INTRODUCTION: Le programme national indien d'élimination de la tuberculose prévoit de mettre en place un traitement préventif de courte durée contre la tuberculose (TPT) en utilisant trois mois de rifapentine et d'isoniazide (3HP). Il est essentiel de comprendre la faisabilité et la sécurité des enfants dans le cadre des programmes pour pouvoir les mettre en œuvre à grande échelle. Nous présentons les résultats d'une extension ciblée de la 3HP parmi les enfants et les adolescents vivant avec le VIH (CALHIV, pour l'anglais « children and adolescents living with HIV ¼) et les enfants contacts familiaux (>2 à <6 ans) de patients atteints de tuberculose pulmonaire (CHHC, pour l'anglais « child household contacts ¼). MÉTHODES: Des doses hebdomadaires de 3HP ont été administrées pendant 3 mois aux participants éligibles CALHIV et CHHC dans les cliniques de thérapie antirétrovirale (ART) et de tuberculose, respectivement, d'un hôpital public de Pune, en Inde, entre décembre 2021 et juillet 2023. RÉSULTATS: Sur 97 enfants dépistés, 91 ont initié 3HP (32 CALHIV et 59 CHHC). L'âge médian des CALHIV était de 14 ans ; 66% étaient de sexe masculin et sous ART à base de dolutegravir. L'âge médian des CHHC était de 4 ans ; 47% étaient des hommes. Trente et un (97%) CALHIV et 56 (95%) CHHC ont terminé l'étude 3HP sans ajustement de la dose de dolutégravir. Aucun des enfants participants n'a interrompu le traitement 3HP en raison d'effets indésirables. Aucun enfant participant n'a développé de tuberculose au cours de l'année de suivi post-3HP. CONCLUSION: Notre étude fournit des preuves de l'adoption et de la faisabilité de la mise en œuvre prévue de 3HP à l'échelle nationale.

Three months of weekly rifapentine plus isoniazid for TB prevention among people with HIV.

BACKGROUND: Evidence on implementation of three months of weekly isoniazid (H, INH) and rifapentine (P, RPT) (3HP) as a TB preventive therapy (TPT) for at-risk groups in Indian programmatic conditions is limited. METHODS: A prospective demonstration study assessing scale-up, safety, and effectiveness of 3HP TPT among people living with HIV (PLHIV) in Indian programmatic settings was conducted. RESULTS: Of 656 screened PLHIV, 502 (77%) received 3HP. Of these, 20 (4%) discontinued TPT due to toxicity,17 (3.8%) lost to follow-up, one (0.2%) had breakthrough rifampicin-sensitive TB, and 464 (92%) completed 3 HP TPT. Of 288 (57%) overall adverse events (AEs), 46 (9%) had Grade 2 or above AEs. The median time to AE was 14 days (IQR 7-42). Serious adverse events (SAEs) were reported in 9 (2%) participants; of these, 7 (78%) were not related to 3HP. No TB episodes occurred during the 1-year follow-up period. CONCLUSION: 3HP TPT completion rate of 92%, with few adverse events leading to 3HP discontinuation, providing evidence of the scalability and safety of 3HP TPT among PLHIV in Indian health program settings.

CONTEXTE: Les données probantes sur la mise en œuvre de 3 mois de traitement hebdomadaire d'isoniazide (H, INH) et de rifapentine (P, RPT) (3HP) en tant que traitement préventif de la TB (TPT) pour les groupes à risque dans les conditions programmatiques indiennes sont limitées. MÉTHODES: Une étude de démonstration prospective évaluant la mise à l'échelle, l'innocuité et l'efficacité de la TPT 3HP chez les personnes vivant avec le VIH (PVVIH) dans des contextes programmatiques indiens a été menée. RÉSULTATS: Sur les 656 PVVIH dépistés, 502 (77%) ont reçu le traitement 3HP. Parmi eux, 20 (4%) ont interrompu le TPT en raison de toxicité, 17 (3,8%) ont été perdus de vue, un (0,2%) a développé une TB sensible à la rifampicine et 464 (92%) ont terminé le TPT 3HP. Parmi les 288 (57%) événements indésirables (AE, pour l'anglais, « adverse events ¼) en tout, 46 (9%) ont présenté des AE de Grade 2 ou supérieur. Le délai médian jusqu'à l'apparition d'un AE était de 14 jours (IQR 7­42). Des événements indésirables graves ont été rapportés chez 9 (2%) participants ; parmi eux, 7 (78%) n'étaient pas liés au traitement 3HP. Aucun épisode de TB n'a été observé pendant la période de suivi d'un an. CONCLUSION: Le taux d'achèvement du TPT 3HP est de 92%, avec peu d'événements indésirables conduisant à l'arrêt du TPT 3HP, fournissant des preuves de l'évolutivité et de l'innocuité du TPT 3HP chez les PVVIH dans le cadre de programmes de santé indiens.

Facilitators and barriers to adolescent participation in a TB clinical trial.

The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.Interviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.Investigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.Proactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

Factors associated with non-completion of TB preventive treatment in Brazil.

BACKGROUND: Among Brazilian initiatives to scale up TB preventive therapy (TPT) are the adoption of the 3HP regimen (12 weekly doses of rifapentine and isoniazid [INH]) in 2021 and the implementation in 2018 of the TPT surveillance information system. Since then, 63% of the 76,000 eligible individuals notified completed TPT. Recommended regimens in this period were 6H, 9H (6 or 9 months of INH) and 4R (4 months of rifampicin).OBJECTIVE: To analyse the factors associated with TPT non-completion.METHODS: We analysed the cohort of TPT notifications from 2018 to 2020. Robust variance Poisson regression model was used to verify the association of TPT non-completion with sociodemographic, clinical and epidemiological variables.RESULTS: Of the 39,973 TPT notified in the study period, 8,534 (21.5%) were non-completed, of which 7,858 (92.1%) were lost to follow-up. Age 15-60 years (relative risk [RR] 1.27, 95% confidence interval [95% CI] 1.20-1.35), TPT with isoniazid (RR 1.40, 95% CI 1.19-1.64) and Black/mixed race (RR 1.17, 95% CI 1.09-1.25) were associated with a higher risk of non-completion.CONCLUSION: Individuals in situations of social and financial vulnerability such as being Black/pardo race, younger and on longer TPT regimens were more likely to be associated with TPT incompletion.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.

Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

How research can help control tuberculosis.

Tuberculosis (TB) has played a central role in the history of biomedical science from Koch onwards. Research in the nineteenth and twentieth centuries yielded extremely valuable diagnostic, therapeutic and preventive tools for the control of TB. Following the development of shortcourse chemotherapy in the 1970s and 1980s, research into TB virtually evaporated. Despite the availability of an array of tools, TB control faltered, and the disease remains a major killer. The failure of the fruits of scientific research to control TB is a result of the shortcomings of the tools themselves as well the inadequate application of the tools in populations burdened by TB. A changing epidemiologic situation, with escalating rates of human immunodeficiency virus-related TB and the emergence of multidrug-resistant TB, further threatens global TB control. A robust TB research enterprise will be required to meet the global goals for controlling TB in the twentyfirst century. Basic research is needed to better understand its pathogenesis and immunology, and to identify targets for diagnostics, drugs and vaccines. Research into better biomedical tools to detect, treat and prevent TB is also a major priority, as all of the existing tools have important shortcomings. In addition, research into understanding how to apply both existing and new tools to control TB at the population level is urgently needed. Global funding for TB research, $483 million in 2007, is slowly growing but is far behind need. To meet the ambitious goals of the Global Plan to Stop TB and the Millennium Development Goals, a massive investment in research will be necessary.

Health-related quality of life of inpatients and outpatients with TB in rural Malawi.

INTRODUCTION: Patients being treated for TB may suffer reductions in health-related quality of life (HRQoL). This study aims to assess the extent of such reductions and the trajectory of HRQoL over the course of treatment in rural Malawi.METHODS: We collected patient demographic and socioeconomic status, TB-related characteristics, and HRQoL data (i.e., EQ-5D and a visual analogue scale VAS) from adults (age ≥18 years) being treated for TB in 12 primary health centers and one hospital in rural Thyolo District, Malawi, from 2014 to 2016. Associations between HRQoL and patient characteristics were estimated using multivariable linear regression.RESULTS: Inpatients (n = 197) consistently showed lower median HRQoL scores and suffered more severe health impairments during hospitalization than outpatients (n = 156) (EQ5D and VAS: 0.79, 55 vs. 0.84, 70). Longer treatment duration was associated with higher HRQoL among outpatients (EQ5D: 0.034 increase per 2 months, 95%CI 0.012-0.057). We found no substantial associations between patients´ demographic and socioeconomic characteristics and HRQoL in this setting.CONCLUSION: HRQoL scores among patients receiving treatment for TB in rural Malawi differ by clinical setting and duration of treatment, with greater impairment among inpatients and those early in their treatment course.

Subclinical tuberculosis and adverse infant outcomes in pregnant women with HIV.

BACKGROUND: Tuberculosis (TB) in pregnant women with HIV is associated with adverse maternal and infant outcomes. Previous studies have described a substantial prevalence of subclinical TB in this group, but little is known about the impact of subclinical TB on maternal and pediatric outcomes.METHODS: The Tshepiso Study recruited 235 HIV-infected pregnant women with TB (and matched HIV-positive, TB-negative pregnant controls), in Soweto, South Africa, from 2011 to 2014. During enrolment screening, some women initially recruited as controls were subsequently diagnosed with prevalent TB. We therefore assessed the prevalence of subclinical TB, associated participant characteristics and outcomes.RESULTS: Of 162 women initially recruited as TB-negative controls, seven (4.3%) were found to have TB on sputum culture. All seven had negative WHO symptom screens, and six (86%) were smear-negative. Of their seven infants, one was diagnosed with TB, and three (43%) experienced complications compared to zero infants with TB and 11% experiencing complications in the control group of TB-negative mothers (P = 0.045).CONCLUSION: We discovered an appreciable prevalence of subclinical TB in HIV-infected pregnant women in Soweto, which had not been detected by screening algorithms based solely on symptoms. Infants of HIV-infected mothers with subclinical TB appear to have a higher risk of adverse outcomes than those of TB-negative mothers.

Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.

How research can help control tuberculosis.

Tuberculosis (TB) has played a central role in the history of biomedical science from Koch onwards. Research in the nineteenth and twentieth centuries yielded extremely valuable diagnostic, therapeutic and preventive tools for the control of TB. Following the development of short-course chemotherapy in the 1970s and 1980s, research into TB virtually evaporated. Despite the availability of an array of tools, TB control faltered, and the disease remains a major killer. The failure of the fruits of scientific research to control TB is a result of the shortcomings of the tools themselves as well the inadequate application of the tools in populations burdened by TB. A changing epidemiologic situation, with escalating rates of human immunodeficiency virus-related TB and the emergence of multidrug-resistant TB, further threatens global TB control. A robust TB research enterprise will be required to meet the global goals for controlling TB in the twenty-first century. Basic research is needed to better understand its pathogenesis and immunology, and to identify targets for diagnostics, drugs and vaccines. Research into better biomedical tools to detect, treat and prevent TB is also a major priority, as all of the existing tools have important shortcomings. In addition, research into understanding how to apply both existing and new tools to control TB at the population level is urgently needed. Global funding for TB research, $483 million in 2007, is slowly growing but is far behind need. To meet the ambitious goals of the Global Plan to Stop TB and the Millennium Development Goals, a massive investment in research will be necessary.

HAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort.

SETTING: Four human immunodeficiency virus (HIV) clinics located at South African tertiary hospitals. OBJECTIVE: To assess the effectiveness of highly active antiretroviral therapy (HAART) in reducing incident tuberculosis (TB) in HIV-infected children. DESIGN: Retrospective cohort. RESULTS: A total of 1132 children's records were included in the study. At entry to the cohort, the median (interquartile range [IQR]) age, CD4%, CD4 count and viral load of all children was respectively 6.3 years (4.1-8.8), 15% (9.0-22.2), 576 cells/mm(3) (287-960) and 160 000 copies/ml (54 941.5-449 683); 75.9% were started on HAART. The male:female ratio was 1:1, and median follow-up time was 1.7 years. In children whose follow-up included both pre-HAART and on-HAART periods, the incidence of clinically diagnosed TB was respectively 21.1 per 100 person-years (py; 95%CI 18.2-24.4) and 6.4/100 py (95%CI 4.8-8.1), and when restricted to confirmed cases, respectively 3.1/100 py (95%CI 2.2-4.2) and 0.8/100 py (95%CI 0.5-1.4). Only 23% of all cases of TB were microbiologically confirmed. Multivariate analyses showed that HAART reduced incident TB by approximately 70%, both for confirmed and all TB cases. CONCLUSIONS: In this high TB burden country, the incidence of diagnosis of TB in HIV-infected children is at least as high as that of adults. HAART reduces incident TB, but further prospective TB preventive and diagnostic studies are urgently needed in children.

Tuberculosis incidence among contacts of active pulmonary tuberculosis.

BACKGROUND: Treatment of latent tuberculosis (TB) infection (LTBI) in Brazil is recommended only in the case of contacts of pulmonary smear-positive TB patients agedor=10 mm and no previous bacille Calmette-Guérin (BCG) vaccination or with a TST>or=15 mm regardless of previous BCG vaccination. OBJECTIVE: To evaluate the 2-year incidence and predictors of TB among contacts who did not meet the Brazilian criteria for LTBI treatment. DESIGN: Retrospective cohort study. Contacts aged between 12 and 15 years and those aged>or=15 years who did not meet the Brazilian criteria for LTBI treatment were enrolled in the study. RESULTS: TB incidence was 3.2% (22/667), with an estimated TB rate of 1649 per 100000 population. Risk of TB was greater among the 349 contacts with TST>or=5 mm (5.4%) compared to the 318 contacts with TST<5 mm (0.9%; RR 6.04, 95%CI 1.7-20.6). CONCLUSION: The high incidence of TB among contacts who did not meet the Brazilian criteria for LTBI treatment strongly suggests that these criteria should be reviewed. Furthermore, even among BCG-vaccinated contacts, TST induration>or=5 mm was the only variable that predicted the development of TB disease within 2years.

Tuberculosis as primary cause of death among AIDS cases in Rio de Janeiro, Brazil.

SETTING: Data from the mortality database, Rio de Janeiro City (RJC) Health Department, Rio de Janeiro, Brazil. OBJECTIVES: To determine the role played by tuberculosis (TB) in Brazil's human immunodeficiency virus (HIV) positive population, we investigated the frequency of TB as the primary cause of death among HIV-positive subjects in RJC. DESIGN: Information about acquired immune-deficiency syndrome (AIDS) deaths from 1996 to 2005 in individuals aged >12 years was obtained from the Mortality Information System (SIM), and the cause of death was classified according to the International Classification of Diseases (ICD-10), through primary causes coded in Chapter I--B20 to B24 (HIV disease). RESULTS: There were 8601 AIDS-related deaths in RJC between 1996 and 2005. TB was the primary cause of death in 9.0% of all AIDS-related deaths, while Pneumocystis carinii pneumonia (PCP) accounted for 4.7%. TB cases erroneously classified under other infectious diseases may have contributed to an underestimation of the number of TB deaths among HIV-positive patients. CONCLUSION: Our study showed that TB is the leading cause of AIDS-related deaths and is responsible for twice as many deaths as PCP, in a scenario of free access to antiretrovirals. The potential benefits of TB preventive treatment and of the availability of highly active antiretroviral treatment could not be established by this analysis.

Contribution of reinfection to recurrent tuberculosis in South African gold miners.

SETTING: A gold mine in South Africa. OBJECTIVE: To investigate incidence and risk factors for tuberculosis (TB) recurrence and the relative contribution of reinfection and relapse to recurrence. DESIGN: Prospective cohort study. METHODS: Employees cured of a first episode of culture-positive TB were followed up for recurrence, which was classified as reinfection or relapse by restriction fragment length polymorphism using an insertion sequence (IS) 6110 probe. RESULTS: Among 609 patients, 57 experienced recurrence during a median follow-up period of 1.02 years, corresponding to a recurrence rate of 7.89 per 100 person-years (py). The culture positive recurrence rate was 5.79/100 py, and was higher in human immunodeficiency virus (HIV) infected patients (8.86/100 py in HIV-infected vs. 3.35/100 py in non-HIV-infected). Among HIV-infected patients, the risk of culture-positive recurrence was higher with decreasing CD4 count (compared with CD4 < 200, hazard ratios for recurrence among individuals with CD4 200-500 and CD4 > 500 were 0.40 [95%CI 0.14-1.09] and 0.14 [95%CI 0.02-1.10], respectively, Ptrend = 0.01). IS6110 genotyping was available on both the initial and subsequent isolate for 16/42 (38%, 14 HIV-infected) patients with culture-positive recurrence, and showed reinfection in 11 (69%). CONCLUSION: HIV-infected gold miners, particularly those who are more immunosuppressed, are at higher risk of TB recurrence. TB control strategies need to take into account reinfection as an important cause of recurrent TB.