Search

Background: Understanding of the effects of human immunodeficiency virus (HIV) infection and antiretroviral treatment (ART) on Mycobacterium tuberculosis transmission dynamics remains limited. We undertook a cross-sectional study among household contacts of smear-positive pulmonary tuberculosis (TB) cases to assess the effect of established ART on the infectiousness of TB., Method: Prevalence of tuberculin skin test (TST) positivity was compared between contacts of index cases aged 2-10 years who were HIV-negative, HIV-positive but not on ART, on ART for <1 year and on ART for 1 year. Random-effects logistic regression was used to take into account clustering within households., Results: Prevalence of M. tuberculosis infection in contacts of HIV-negative patients, HIV-positive patients on ART 1 year and HIV-positive patients not on ART/on ART <1 year index cases was respectively 44%, 21% and 22%. Compared to contacts of HIV-positive index cases not on ART or recently started on ART, the odds of TST positivity was similar in contacts of HIV-positive index cases on ART 1 year (adjusted OR [aOR] 1.0, 95%CI 0.3-3.7). The odds were 2.9 times higher in child contacts of HIV-negative index cases (aOR 2.9, 95%CI 1.0-8.2)., Conclusions: We found no evidence that established ART increased the infectiousness of smear-positive, HIV-positive index cases.

Background: The proportion of tuberculosis attributable to transmission from close contacts is not well known. Comparison of the genome of strains from index patients and prior contacts allows transmission to be confirmed or excluded., Methods: In Karonga District, Malawi, all tuberculosis patients are asked about prior contact with others with tuberculosis. All available strains from culture-positive patients were sequenced. Up to 10 single nucleotide polymorphisms between index patients and their prior contacts were allowed for confirmation, and ≥ 100 for exclusion. The population attributable fraction was estimated from the proportion of confirmed transmissions and the proportion of patients with contacts., Results: From 1997-2010 there were 1907 new culture-confirmed tuberculosis patients, of whom 32% reported at least one family contact and an additional 11% had at least one other contact; 60% of contacts had smear-positive disease. Among case-contact pairs with sequences available, transmission was confirmed from 38% (62/163) smear-positive prior contacts and 0/17 smear-negative prior contacts. Confirmed transmission was more common in those related to the prior contact (42.4%, 56/132) than in non-relatives (19.4%, 6/31, p = 0.02), and in those with more intense contact, to younger index cases, and in more recent years. The proportion of tuberculosis attributable to known contacts was estimated to be 9.4% overall., Conclusions: In this population known contacts only explained a small proportion of tuberculosis cases. Even those with a prior family contact with smear positive tuberculosis were more likely to have acquired their infection elsewhere.

Background: Tuberculosis (TB) mortality remains high across sub-Saharan Africa despite integration of TB and HIV/ART programmes. To inform programme design and service delivery, we estimated mortality by time from starting TB treatment., Methods: Routinely collected data on TB treatment, vital status, and the timing and causes of death, were linked to cardio-respiratory autopsy data, from 1995-2008, from a cohort of male platinum miners in South Africa. Records were expanded into person-months at risk (pm)., Results: 4162 TB episodes were registered; 3170 men were treated for the first time and 833 men underwent retreatment. Overall, 509 men died, with a case fatality of 12.2% and mortality rate of 2.0/100 pm. Mortality was highest in the first month after starting TB treatment for first (2.3/100 pm) and retreatment episodes (4.8/100 pm). When stratified by HIV status, case fatality was higher in HIV positive men not on ART (first episode 14.0%; retreatment episode 26.2%) and those on ART (12.0%; 22.0%) than men of negative or unknown HIV status (2.6%; 3.6%). Mortality was also highest in the first month for each of these groups. Mortality risk factors included older age, previous TB, HIV, pulmonary TB, and diagnostic uncertainty. The proportion of deaths attributable to TB was consistently overestimated in clinical records versus cardio-respiratory autopsy., Conclusions: Programme mortality was highest in those with HIV and during the first month of TB treatment in all groups, and many deaths were not caused by TB. Resource allocation should prioritise TB prevention and accurate earlier diagnosis, recognise the role of HIV, and ensure effective clinical care in the early stages of TB treatment.

Background: Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy., Methods: For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086., Findings: 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6-3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8-4·7; hazard ratio [HR] 0·63, 95% CI 0·41-0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90-4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21-0·86] and 0·43 [0·20-0·96]; for positive tests 0·86 [0·37-2·00] and 0·55 [0·26-1·24], respectively)., Interpretation: Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status., Funding: Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We assessed the impact on measured burden and outcomes of the revised World Health Organization and Malawi guidelines reclassifying people with single (including 'scanty') positive smears as smear-positive pulmonary tuberculosis cases. In a retrospective cohort in rural Malawi, 567 (34%) of 1670 smear-positive episodes were based on single positive smears (including 176 with scanty smears). Mortality rates and the proportion starting treatment were similar in those with two positive smears or single, non-scanty smears. Those with single scanty smears had higher mortality and a lower proportion starting treatment. The reclassification will increase the reported burden substantially, but should improve treatment access.

Background: HIV infection reduces the likelihood that individuals with pulmonary tuberculosis are smear positive and that they have cavitatory disease. Antiretroviral therapy (ART) may shift the pattern of disease to be more similar to that of HIV negative patients. This would aid diagnosis--which often depends on sputum smears--but would also increase infectiousness. We assessed the effect of HIV and ART on smear positivity and cavitatory disease in laboratory-confirmed pulmonary TB patients., Methods: Three sputum samples were collected per pulmonary TB suspect and were examined using microscopy and culture. Chest radiographs were available for a subset of patients as part of another study. The effect of HIV and ART status on sputum smear positivity and lung cavitation were evaluated using multivariable logistic regression., Results: Of 1024 laboratory-confirmed pulmonary TB patients who were identified between January 2005 and December 2011, 766 had HIV and ART status available. Positive sputum smears were significantly more common among HIV negative individuals than HIV positive individuals (adjusted OR = 2.91, 95% CI 1.53-5.55). Compared to those HIV positive but not on ART, patients on ART were more likely to be smear positive (adjusted OR = 2.33, 95% CI 1.01-5.39) if they had been on ART ≤ 6 months, but only slightly more likely to be smear positive (adjusted OR = 1.43, 95% CI 0.68-2.99) if they were on ART > 6 months. HIV negative patients were more likely than HIV positive patients to have cavitatory disease (adjusted OR = 1.97, 95% CI 1.20-3.23). Patients on ART > 6 months had a slight increase in cavitatory disease compared to HIV positive patients not on ART (adjusted OR = 1.68, CI 0.78-3.63)., Conclusions: HIV infection is associated with less smear positivity and cavitation in pulmonary TB patients. Among HIV positive patients, the use of ART shifts the presentation of disease towards that seen in HIV-negative individuals, which facilitates diagnosis but which also could increase infectiousness.

Background: We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST)., Methods: Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals., Findings: 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2-6), even in IGRA-positive individuals, was 4-48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42-3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29-3·46] for IGRA vs 1·60 [0·94-2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals., Interpretation: Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone., Funding: Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To quantify the risk of infection and disease in spouses of tuberculosis patients and the extent to which intervention could reduce the risk in this highly exposed group., Methods: We compared HIV prevalence, TB prevalence and incidence and tuberculin skin test (TST) results in spouses of TB patients and community controls. HIV-positive spouses were offered isoniazid preventive therapy (IPT), and TST was repeated at 6, 12 and 24 months., Results: We recruited 148 spouses of smear-positive patients ascertained prospectively and 3% had active TB. We identified 203 spouses of previously diagnosed smear-positive patients, 11 had already had TB, and the rate of TB was 2.4 per 100 person years(py) over 2 years (95% CI 1.15-5.09). 116 were found alive and recruited. HIV prevalence was 37% and 39% in the prospective and retrospective spouse groups and 17% in controls. TST was ≥10 mm in 80% of HIV negative and in 57% of HIV-positive spouses ascertained retrospectively; 74% HIV negative and 62% HIV-positive spouses ascertained prospectively, and 48% HIV negative and 26% HIV-positive community controls. Of 54 HIV-positive spouses, 18 completed 6-month IPT. At 2 year follow-up, 87% of surviving spouses had TST ≥10 mm and the rate of TB was 1.1 per 100 py (95% CI 0.34-3.29)., Conclusions: Spouses are a high-risk group who should be screened for HIV and active TB. TST prevalence was already high by the time the spouses were approached but further infections were seen to occur. Uptake and adherence to IPT was disappointing, lessening the impact of short-duration therapy., (© 2011 Blackwell Publishing Ltd.)

Intensified case finding is the regular screening for evidence of tuberculosis in people infected with HIV, at high risk of HIV, or living in congregate settings. We systematically reviewed studies of intensified case finding published between January, 1994, and April, 2009. In 78 eligible studies, the number of people with tuberculosis detected during intensified case finding varied substantially between countries and target groups of patients. Median prevalence of newly diagnosed tuberculosis was 0.7% in population-based surveys, 2.2% in contact-tracing studies, 2.3% in mines, 2.3% in programmes preventing mother-to-child transmission of HIV, 2.5% in prisons, 8.2% in medical and antiretroviral treatment clinics, and 8.5% in voluntary counselling and testing services. Metaregression analysis of studies that included only people with HIV showed that for each increment in national prevalence of tuberculosis of 100 cases per 100 000 population, intensified case finding identified an additional one case per 100 screened individuals (p=0.03). Microbiological sputum examination of all individuals without prior selection by symptom screening yielded an additional four cases per 100 individuals screened (p=0.05). Data on the use of serial screening, treatment outcomes in actively identified cases of tuberculosis, and cost-effectiveness, however, were lacking. Concerted action is needed to develop intensified case finding as an important method for control of tuberculosis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

This paper summarises tuberculosis (TB) research over almost 30 years in Karonga District, northern Malawi, an area typical of much of rural Africa. The dominant factor has been the human immunodeficiency virus (HIV), which arrived in the district about 1980, leading to an increase in TB incidence to a peak of approximately 65 smear-positive pulmonary cases per 100000 population in 2000. Tuberculin surveys indicate annual risks of Mycobacterium tuberculosis infection of approximately 1%; thus, most of the population is uninfected and at risk of primary infection and disease. Molecular epidemiological studies demonstrate that about two thirds of TB arises from recent infection, but recognisable recent contact is responsible for only about 10% of disease. By 2001, 57% of TB was directly attributable to HIV, implying that it would have declined were it not for HIV. HIV infection increases the risk of TB most among young adults, and greatly increases the risk of recurrence from new infection after treatment. Mortality rates in the HIV-infected are high, but there is no association of HIV with drug resistance. Other risk factors with relatively smaller effects include age and sex, contact, several genetic polymorphisms and area. Neither one nor two doses of the bacille Calmette-Guérin (BCG) vaccine provides protection against adult pulmonary TB, despite protecting against leprosy. Skin test surveys, cohort studies and comparative immunological studies with the UK suggest that exposure to environmental mycobacteria provides some protection against TB and that BCG's failure is attributable partly to this widespread heterologous exposure masking effects of the vaccine. Drug resistance has remained constant (<10%) over more than 20 years. Immunotherapy with M. vaccae provided no benefits, but treatment of HIV-positive patients with cotrimoxazole reduced mortality. The Karonga programme illustrates the value of long-term population-based studies to investigate the natural history of TB and to influence TB control policy. Current studies focus on immunological markers of infection, disease and protection, and on elucidating the impact of antiretroviral treatment on TB incidence at population level.

Background: HIV increases the risk of tuberculosis directly, through immunosuppression, and indirectly, through onward transmission of Mycobacterium tuberculosis from the increased caseload. We assess the contribution of these two mechanisms by time since seroconversion to HIV., Methods: The incidence of new pulmonary tuberculosis was estimated in a retrospective cohort study of South African gold miners over 14 years. HIV tests were done in random surveys in 1992-1993, and in clinics. One thousand nine hundred fifty HIV positive men with seroconversion intervals of less than 3 years were identified and linked to medical, demographic and occupational records. They were compared with men who were HIV-negative in a survey, with no later evidence of HIV. Analyses were censored when men were diagnosed with tuberculosis, died or left the mine., Results: Tuberculosis incidence rose soon after HIV infection, reaching 1.4/100 person-years (95% confidence interval 1.1-1.9) within 2 years, and 10.0/100 person-years (95% confidence interval 6.5-15.5) at 10 or more years. By 11 years from seroconversion, nearly half the men had had tuberculosis. Among 5702 HIV-negative men, tuberculosis incidence was 0.48/100 person-years (95% confidence interval 0.33-0.70) in 1991-1993 and doubled over the period of the study (after adjusting for age). Age-adjusted model estimates suggest that half the increase in tuberculosis incidence by time since HIV infection was attributable to increasing incidence over calendar period--the indirect effect., Conclusion: For the first time, we have shown that the increase in tuberculosis risk by time since seroconversion reflects both direct effects of HIV increasing susceptibility, and indirect effects due to onward transmission. Innovative and sustained public health measures are needed to reduce Mycobacterium tuberculosis transmission.

Objectives: To describe causes of death and respiratory infections in HIV-infected miners in the pre-antiretroviral era, by duration of HIV infection., Design: A retrospective cohort of 1950 gold miners with known dates of HIV seroconversion and 6164 HIV-negative miners was followed from the early 1990s to 2002., Methods: Causes of death were available from multiple sources: personnel records, clinical records, death certificates and autopsies of cardiorespiratory organs performed for compensation purposes., Results: Causes of death were known for 279 of 308 HIV-positive (91%) and 234 of 254 HIV-negative (92%) men who died while employed or within 6 months of leaving employment. The mortality rate from unnatural causes was similar in HIV-positive and HIV-negative miners and by duration of HIV infection. Among deaths from natural causes, 87% in HIV-positive and 41% in HIV-negative individuals were caused by infection (P < 0.001); 47% of HIV-positive and 26% of HIV-negative individuals had tuberculosis. The proportion of deaths from natural causes with any infection, or with specific infections (tuberculosis, cryptococcus, pneumocystis), did not vary with the duration of HIV infection. Autopsies were performed on 29% of men who died from natural causes: 83% of HIV-positive and 37% of HIV-negative men had respiratory infections (P < 0.001), half of which were clinically undiagnosed., Conclusion: Tuberculosis was the leading cause of death in HIV-positive and negative men who died from natural causes. Although the mortality rate from natural causes increased greatly with the duration of HIV infection, the pattern of disease hardly changed, suggesting that slow and fast progressors succumb to the same range of diseases.

Setting: Randomised controlled clinical trial of Mycobacterium vaccae vaccination as an adjunct to anti-tuberculosis treatment in human immunodeficiency virus (HIV) positive patients with smear-positive tuberculosis (TB) in Lusaka, Zambia, and Karonga, Malawi., Objective: To explain the difference in mortality between the two trial sites and to identify risk factors for death among HIV-positive patients with TB., Design: Information on demographic, clinical, laboratory and radiographic characteristics was collected. Patients in Lusaka (667) and in Karonga (84) were followed up for an average of 1.56 years. Cox proportional hazard analyses were used to assess differences in survival between the two sites and to determine risk factors associated with mortality during and after anti-tuberculosis treatment., Results: The case fatality rate was 14.7% in Lusaka and 21.4% in Karonga. The hazard ratio for death comparing Karonga to Lusaka was 1.47 (95% confidence interval [CI] 0.9-2.4) during treatment and 1.76 (95%CI 1.0-3.0) after treatment. This difference could be almost entirely explained by age and more advanced HIV disease among patients in Karonga., Conclusion: It is important to understand the reasons for population differences in mortality among patients with TB and HIV and to maximise efforts to reduce mortality.

Background: Infection with human immunodeficiency virus (HIV) increases the risk of tuberculosis (TB), but no study has assessed how this risk changes with time since HIV seroconversion., Methods: The incidence of pulmonary TB was estimated in miners with and those without HIV infection in a retrospective cohort study. HIV test results were linked to routinely collected TB, demographic, and occupational data. The rate ratio (RR) for the association between HIV status and TB was estimated by time since HIV seroconversion, calendar period, and age., Results: Of the 23,874 miners in the cohort, 17,766 were HIV negative on entry, 3371 were HIV positive on entry, and 2737 seroconverted during follow-up (1962 had a seroconversion interval of < or =2 years). A total of 740 cases of TB were analyzed. The incidence of TB increased with time since seroconversion, calendar period, and age. TB incidence was 2.90 cases/100 person-years at risk (pyar) in HIV-positive miners and was 0.80 cases/100 pyar in HIV-negative miners (adjusted RR, 2.9 [95% confidence interval {CI}, 2.5-3.4]). TB incidence doubled within the first year of HIV infection (adjusted RR, 2.1 [95% CI, 1.4-3.1]), with a further slight increase in HIV-positive miners for longer periods, up to 7 years., Conclusion: The increase in the risk of TB so soon after infection with HIV was unexpected. Current predictive models of TB incidence underestimate the effect of HIV infection in areas where TB is endemic.

In a 7-year population-based study in Malawi, we showed that Beijing genotype tuberculosis (TB) increased as a proportion of TB cases. All the Beijing genotype strains were fully drug sensitive. Contact histories, TB type, and case-fatality rates were similar for Beijing and non-Beijing genotype TB.

Drug-resistant tuberculosis can be transmitted (primary) or develop during the course of treatment (secondary). We investigated risk factors for each type of resistance. We compared all patients in England and Wales with isoniazid- and multidrug-resistant tuberculosis in two time-periods (1993-1994 and 1998-2000) with patients with fully sensitive tuberculosis, examining separately patients without and with previous tuberculosis (a proxy for primary and secondary drug-resistant tuberculosis). Patients with previous tuberculosis smear positivity and arrival in the United Kingdom <5 years were strongly associated with multidrug resistance and isoniazid resistance. In patients with no previous tuberculosis HIV infection, residence in London and foreign birth were risk factors for multidrug resistance, and non-white ethnicity, residence in London and HIV infection for isoniazid resistance. Risk factors for each type of resistance differ. Elevated risks associated with London residence, HIV positivity, and ethnicity were mainly seen in those without previous tuberculosis (presumed transmission).

Background: HIV infection increases the risk of tuberculosis. The HIV epidemic is also likely to have an indirect effect on the incidence of tuberculosis because of the increased number of infectious individuals in the population. This should be apparent as an increase in tuberculosis among HIV-negative individuals, but this has not previously been demonstrated directly., Methods: A retrospective cohort study was conducted in four gold mines in South Africa, including all miners who had HIV tests in 1991-1997. Tuberculosis was detected by annual screening, contact tracing and self-presentation of symptomatic patients., Results: The annual incidence of new pulmonary tuberculosis in the mines rose from 0.53% in 1991 to 1.0% in 1997. The HIV status was known for 23 874 miners, of whom 3371 were HIV positive on entry and 2737 seroconverted during follow-up. The incidence of tuberculosis was higher among HIV-positive miners than HIV-negative miners from 1992 onwards, and the proportion of tuberculosis attributable to HIV increased from 0% in 1991 to over 40%. The incidence of tuberculosis increased in HIV-negative miners from 1995 onwards; incidence in the late 1990s was double that in the early 1990s., Conclusion: HIV infection has dramatically increased the incidence of tuberculosis. There was a direct increase in those who were HIV infected, but also a doubling in tuberculosis incidence in those remaining HIV negative, implying considerable ongoing Mycobacterium tuberculosis transmission. This has occurred despite active case finding and directly observed therapy, which exceeds WHO targets for cure rates. Further interventions targeted at both HIV and tuberculosis are needed.

Background: The proportion of recurrent tuberculosis cases attributable to relapse or reinfection and the risk factors associated with these different mechanisms are poorly understood. We followed up a cohort of 326 South African mineworkers, who had successfully completed treatment for pulmonary tuberculosis in 1995, to determine the rate and mechanisms of recurrence., Methods: Patients were examined 3 and 6 months after cure, and then were monitored by the routine tuberculosis surveillance system until December, 1998. IS6110 DNA fingerprints from initial and subsequent episodes of tuberculosis were compared to determine whether recurrence was due to relapse or reinfection All patients gave consent for HIV-1 testing., Findings: During follow-up (median 25.1 months, IQR 13.2-33.4), 65 patients (20%) had a recurrent episode of tuberculosis, a recurrence rate of 10.3 episodes per 100 person-years at risk (PYAR)-16.0 per 100 pyar in HIV-1-positive patients and 6.4 per 100 pyar in HIV-1-negative patients. Paired DNA fingerprints were available in 39 of 65 recurrences: 25 pairs were identical (relapse) and 14 were different (reinfection). 93% (13/14) of recurrences within the first 6 months were attributable to relapse compared with 48% (12/25) of later recurrences. HIV-1 infection was a risk factor for recurrence (hazard ratio 2.4, 95% CI 1.5-4.0), due to its strong association with disease caused by reinfection (18.7 2.4-143), but not relapse (0.58; 0.24-1.4). Residual cavitation and increasing years of employment at the mine were risk factors for relapse., Interpretation: In a setting with a high risk of tuberculous infection, HIV-1 increases the risk of recurrent tuberculosis because of an increased risk of reinfection. Interventions to prevent recurrent disease, such as lifelong chemoprophylaxis in HIV-1-positive tuberculosis patients, should be further assessed.

Setting: Karonga district, northern Malawi., Objective: To compare the sensitivity and specificity of two versus three smears for the diagnosis of pulmonary tuberculosis in a setting with high HIV prevalence., Design: A total of 1992 pulmonary tuberculosis suspects with three sputum smears taken over a 2-7 day period and at least one culture result were studied. Smears were auramine stained and examined using fluorescence microscopy, and positives were confirmed with Ziehl-Neelsen staining and light microscopy. Cultures were set up on Löwenstein-Jensen media. True negative and positive status was defined on the basis of culture. The sensitivity, specificity, and positive and negative predictive values of two and three smears were compared., Results: Compared to culture, the sensitivity, specificity, and positive and negative predictive values of three smears were 70%, 98%, 92%, and 92%, respectively. Restriction to the first two smears gave similar results. Of those detected as smear-positive using three smears, at least 97% would have been detected by two. Among those with HIV serology results available, the sensitivity of two smears for detecting culture-positive tuberculosis was identical to that using three., Conclusion: In this setting, using fluorescence and light microscopy, collecting two smears rather than three would only marginally reduce sensitivity and would slightly improve the specificity of diagnosis of tuberculosis; this is unaffected by HIV status. The potential for improving specificity is important because of the costs of misdiagnosis. In practice, both sensitivity and specificity may be increased due to the time saved by examining two rather than three smears.

The aim of this study was to determine risk factors for disease due to nontuberculous mycobacteria (NTM) compared to those due to Mycobacterium tuberculosis in South African gold miners with pulmonary mycobacterial disease. A case/control study comparing tuberculosis and NTM cases amongst all patients with a positive sputum mycobacterial culture in 1995 was carried out. The 51 cases of disease due to NTM and 425 tuberculosis cases were similar with regard to age, education, home region, smoking habits and percentage of CD4 cells. After adjustment for confounders, those with NTM were more likely to have had previous tuberculosis treatment (odds ratio (OR) 3.61; 95% confidence interval (CI) 1.9-6.9), have worked longer underground (p-value for trend=0.05) or have evidence of silicosis (OR 12.6; 95% CI 2.2-71) and were less likely to drink regularly (OR 0.12; 95% CI 0.02-0.93) than patients with tuberculosis. In patients with disease due to NTM, 35.3% were human immunodeficiency virus-positive compared with 48.8% of tuberculosis patients (p=0.2) and an estimated 21% overall in the mines at the time of the study. Previous tuberculosis treatment, silicosis and duration of underground work are even more strongly associated with disease due to nontuberculous mycobacteria than with tuberculosis. Attempts to reduce the incidence of all pulmonary mycobacterial disease in this community should address recognized risk factors and ensure that those with tuberculosis are diagnosed, treated and cured.

Setting: Queen Elizabeth Central Hospital, Blantyre, and Zomba Central Hospital, Zomba, Malawi., Objective: To evaluate treatment outcome of unsupervised ambulatory treatment (2R3H3Z3/2TH[EH]/4H) in Blantyre and 'standard' treatment (1STH[SEH]/11TH[EH]) in Zomba in human immunodeficiency virus (HIV) seropositive and seronegative patients with smear-negative pulmonary tuberculosis (PTB) and pleural TB., Design: All patients with smear-negative and pleural TB registered between 1 April and 31 December 1995 were assessed for enrolment in the study. Study patients were followed up and 12-month treatment outcomes were recorded., Results: A total of 434 patients, 296 with smear-negative PTB and 138 with pleural TB, were enrolled: 366 (84%) of patients were HIV-positive; 220 (51%) completed treatment, and 144 (33%) died by 12 months. In patients from Blantyre and Zomba, baseline characteristics were similar, apart from older age in those from Zomba, and the proportion of patients who completed treatment and who died were similar. In both sites, significantly higher case fatality rates were found in older patients, HIV-positive patients and patients with pulmonary parenchymal lung disease., Conclusion: Unsupervised ambulatory treatment evaluated in this study had an efficacy similar to that of 'standard' treatment. For operational reasons, however, it will not be recommended for widespread use in Malawi's National Tuberculosis Control Programme.

The availability of DNA fingerprinting techniques for Mycobacterium tuberculosis has led to attempts to estimate the extent of recent transmission in populations, using the assumption that groups of tuberculosis patients with identical isolates ("clusters") are likely to reflect recently acquired infections. It is never possible to include all cases of tuberculosis in a given population in a study, and the proportion of isolates found to be clustered will depend on the completeness of the sampling. Using stochastic simulation models based on real and hypothetical populations, the authors demonstrate the influence of incomplete sampling on the estimates of clustering obtained. The results show that as the sampling fraction increases, the proportion of isolates identified as clustered also increases and the variance of the estimated proportion clustered decreases. Cluster size is also important: the underestimation of clustering for any given sampling fraction is greater, and the variability in the results obtained is larger, for populations with small clusters than for those with the same number of individuals arranged in large clusters. A considerable amount of caution should be used in interpreting the results of studies on clustering of M. tuberculosis isolates, particularly when sampling fractions are small.

Previous studies have found Mycobacterium leprae in nasal swabs from leprosy patients, their contacts, and persons living in endemic areas. It might be expected that M. tuberculosis would be present on nasal mucosa of pulmonary tuberculosis patients, but whether they can be detected in patients or contacts is unknown. We used the polymerase chain reaction (PCR) technique on nasal swabs from tuberculosis patients, contacts of tuberculosis patients, leprosy patients, and London controls to look for both M. tuberculosis and M. leprae. Swabs dipped in sputum specimens from smear-positive patients were used as positive controls. The PCRs were conducted in two independent laboratories. M. tuberculosis was detected in nasal swabs from 6/16 smear-positive tuberculosis patients and from 1/10 household contacts by one of the laboratories. All of the sputum swabs were positive for M. tuberculosis, and all of the London controls were negative. M. leprae were found in nasal swabs from 2/5 leprosy patients, but one laboratory also reported M. leprae in swabs from 4/21 tuberculosis patients and from one sputum specimen. The results show that M. tuberculosis can be found in the noses of some tuberculosis patients, and suggest that the bacilli also may be detected in some household contacts. The comparisons with M. leprae and between the two laboratories give further insights into the sensitivity and specificity of the technique.

There is concern that drug-resistant tuberculosis is increasing and may be concentrated among HIV-positive patients. Little information is available from developing countries, where surveillance studies are often unable to distinguish resistance in previously untreated patients (initial resistance) from resistance acquired following drug therapy, and where information on the HIV status of the patients is rare. Initial resistance patterns reflect the strains being transmitted in the community. We have studied patterns of resistance in northern Malawi, where the Lepra Evaluation Project has been collecting data on drug resistance since 1986. Initial drug sensitivity results were available for 373 new cases of tuberculosis. Initial resistance to at least one drug was found in 44 of these patients (11.8%, 95% CI 8.5-15.1): 13 were resistant to streptomycin alone, 13 to isoniazid alone, and 17 to more than one drug. Only 3 patients showed initial rifampicin resistance-1 in isolation, 1 in combination with streptomycin, and 1 with triple resistance. Drug resistance was not related to age, sex, or HIV status of the patient and there was no evidence of any increase over the period studied. There was no evidence of geographic clustering of the resistant strains, or of any increased risk of resistant strains in households with previous tuberculosis cases. Acquired resistance during follow-up was found in 5 of 329 patients with documented initially fully sensitive strains. 5 patients with initial resistance seemed to show reversion to sensitivity. The absence of an increase in drug resistance, despite an increase in tuberculosis cases over the period, is encouraging for the control programme. It emphasises the need to collect information from many areas before assuming that increases in antituberculosis drug resistance are occurring worldwide.