[show abstract][hide abstract] ABSTRACT: The overlap between the epidemiology of HIV and tuberculosis and consequent rapid rise in numbers of patients with tuberculosis in many African countries has put a huge burden on health systems. The stigma of HIV has increased the existing stigma surrounding tuberculosis. There are three mechanisms by which we may reduce the number of cases of tuberculosis in a community: reducing transmission of tuberculosis, reducing reactivation of latent tuberculosis infection and reducing HIV transmission. Reinforcing the existing health service to find more cases, active case-finding in communities or enhanced case-finding in specific groups will reduce transmission of tuberculosis. However, health services that find it difficult to find cases efficiently will also find it difficult to support patients throughout treatment to achieve a cure. Partnership with traditional healers, community-based organizations and private practitioners could reduce this burden. Reactivation of tuberculosis among people living with HIV can be reduced by tuberculosis preventive therapy or by antiretroviral therapy. Programmes that identify people living with HIV can also implement enhanced tuberculosis case-finding increasing the benefits of the programme. However, the impact of widespread use of antiretroviral therapy may be to increase the number of people in a community who are mildly immunocompromised and the incidence of tuberculosis at a community level might rise. Any strategy that successfully reduces HIV transmission will benefit tuberculosis control, since around a third of all HIV-positive individuals will develop tuberculosis before they die. To control tuberculosis in high HIV prevalence settings, we must strengthen health systems to include not only expansion of the DOTS strategy but also full-blooded implementation of voluntary counselling and testing, enhanced and active tuberculosis case-finding, preventive therapy and better care for people living with HIV including antiretroviral therapy. The approach needed to control tuberculosis needs also to be integrated into broader development and poverty reduction goals.
[show abstract][hide abstract] ABSTRACT: The well-established international control strategy for tuberculosis is based upon passive case-finding of the most infectious cases followed by effective chemotherapy with sufficient support to ensure and record a successful outcome. However, no country with a severe HIV epidemic is successfully controlling tuberculosis. HIV exerts a double blow. Not only must the health service manage a greatly increased number of patients (as many as fourfold higher in many African settings) but each individual patient needs to be managed more effectively if the control programme is to have a similar impact on transmission as it did in the pre-HIV era. In this paper, we discuss some of the effects of increased burden and stigmatization. We consider the potential of preventive therapy to reduce the impact of HIV on tuberculosis control and describe a more integrated approach to both infections that is being piloted in several sites in Southern Africa.
[show abstract][hide abstract] ABSTRACT: An accurate test for Mycobacterium tuberculosis infection is urgently needed. The tuberculin skin test (TST) lacks sensitivity, particularly in HIV-infected individuals, and has poor specificity because of antigenic cross-reactivity with Bacillus Calmette-Guérin (BCG) vaccination. ESAT-6 and CFP-10 are antigens expressed in Mycobacterium tuberculosis, but not in Mycobacterium bovis BCG and most environmental mycobacteria. We investigated whether T cells specific for these antigens could serve as accurate markers of M. tuberculosis infection in an area of high tuberculosis and HIV prevalence.
Using the rapid ex-vivo enzyme-linked immunospot (ELISPOT) assay for IFN-gamma, we enumerated T cells specific for ESAT-6, CFP-10 and purified protein derivative (PPD) in blood samples from 50 Zambian tuberculosis patients, 75 healthy Zambian adults, and 40 healthy UK residents. TSTs were performed in 49 healthy Zambian adults.
All (100%; n = 11) and 90% (n = 39) of HIV-negative and HIV-positive tuberculosis patients, respectively, had detectable ESAT-6- or CFP-10-specific T cells. The ESAT-6/CFP-10-based ELISPOT assay was positive in 37 out of 54 HIV-negative healthy Zambians, suggesting a 69% prevalence of latent M. tuberculosis infection. Fewer HIV-positive Zambians possessed ESAT-6/CFP-10-specific T cells, but the impact of HIV infection was less on this assay than on the PPD-based ELISPOT or TST.
The ESAT-6/CFP-10-based ELISPOT assay detects active tuberculosis in HIV-positive individuals with high sensitivity. It is more specific, and possibly more sensitive, than PPD-based methods of detecting latent M. tuberculosis infection, and may potentially improve the targeting of isoniazid preventative therapy to HIV-positive individuals with latent tuberculosis infection.
AIDS 12/2002; 16(17):2285-93. · 6.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
The Lancet 12/2001; 358(9294):1687-93. · 39.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lusaka, Zambia.
To investigate the utility of nucleic amplification tests for the diagnosis of pulmonary tuberculosis in a resource-poor setting with a high incidence of human immunodeficiency virus (HIV).
Sputum specimens from suspects attending a referral chest clinic were examined by low-cost 'in-house' one-tube nested polymerase chain reaction (PCR), the enhanced Gen-Probe Amplified Mycobacterium Direct Test (AMTD), auramine smear and Lowenstein-Jensen culture.
PCR and AMTD detected respectively 80% and 92% of smear-positive specimens and 40% and 60% of smear-negative, culture-positive specimens. AMTD was positive for 18 culture-negative suspects; subsequent investigation indicated these to be six confirmed tuberculosis patients, nine judged from radiological data and clinical follow-up studies to have pulmonary tuberculosis, and three non-tuberculosis patients. Sensitivity for smear, culture, PCR and AMTD, when compared to a gold standard incorporating both microbiological and clinical data, was respectively 29%, 69%, 55% and 81%.
In this setting, the sensitivity of the low-cost PCR proved insufficient for its effective use as a tool for diagnosing pulmonary tuberculosis, while AMTD performed considerably better than the current laboratory methods for diagnosis of pulmonary tuberculosis. However, the high cost of this technology may limit its application in the public sector of low-income countries.
The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 05/2001; 5(4):364-9. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the long-term effect of preventive therapy (PT) for tuberculosis on the rates of tuberculosis, mortality and HIV progression.
In a randomized controlled trial, 1053 HIV-positive Zambian adults received isoniazid (H) for 6 months, rifampicin plus pyrazinamide (RZ) for 3 months, or a placebo. CD4 percentage, neopterin, absolute lymphocyte count and haemoglobin were measured from enrolment (absolute CD4 cell counts from 12 months after enrolment). Because PT reduced the incidence of tuberculosis, eligible placebo subjects were offered H. Here, tuberculosis and mortality rates are compared in the three original arms (intention to treat) using data beyond the end of the trial (average follow-up 3 years; maximum 7 years).
There were 102 cases of tuberculosis and 281 deaths (rates 3.6 and 9.0/100 person-years, respectively). There was no significant difference between the tuberculosis rates in the H and RZ groups at any time. The effect of H/RZ on tuberculosis diminished over time (P = 0.011) but the cumulative risk of tuberculosis in the first 2.5 years was significantly lower in the H/RZ group than the placebo group (rate ratio 0.55; 95% confidence interval 0.32-0.93; P = 0.028). There was no significant effect of PT on mortality or progression markers. Tuberculosis was associated with an increased mortality (adjusted rate ratio 1.96; 95% confidence interval 1.21-3.18; P = 0.006).
Both PT regimens protect against tuberculosis for at least 2.5 years but appear to have no effect on HIV progression or mortality. These results may be used in cost-effectiveness models of PT.
[show abstract][hide abstract] ABSTRACT: Three refugee camp complex clinics and an adjacent non-refugee treatment centre in North-Eastern Kenya.
To use conventional and molecular epidemiology tools to determine: 1) the prevalence of drug resistance in newly diagnosed patients with smear-positive pulmonary tuberculosis in refugee and non-refugee populations; 2) risk factors for resistance in the two populations; and 3) whether IS6110 restriction fragment length polymorphism (RFLP) and spoligotyping showed similarities in DNA fingerprinting patterns of drug-resistant isolates that could infer transmission within and between the two populations.
Of 241 isolates from the camps, 44 (18.3%) were resistant to one or more drugs, seven of which (2.9%) were multidrug-resistant TB (MDR-TB). Of 88 isolates from the non-refugees, five (5.7%) were resistant to one or more drugs without MDR-TB. Drug resistance was higher in the camps than in the non-refugee population (OR = 3.7; 95%CI 1.42-9.68; P < 0.007). Resistance was significantly higher in one camp compared with the other two, despite a comparable ethnic distribution. Unusually, females were more associated with drug resistance than their male counterparts in both populations (OR = 2.3; 95%CI 1.2-4.8; P = 0.008). There was evidence of transmission of streptomycin-resistant strains in the refugee population. DNA fingerprints of resistant strains from the non-refugee population were unique and different from those in the refugee camps.
The observed high levels of drug resistance and MDR-TB, combined with evidence of transmission of strains resistant to streptomycin in the refugee population, suggest a need for strengthened TB control programmes in settings with a high risk of developing drug-resistant strains.
The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 11/2000; 4(10):947-55. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Gold miners have very high rates of tuberculosis. The contribution of infections imported into mining communities versus transmission within them is not known and has implications for control strategies.
We did a prospective, population-based molecular and conventional epidemiological study of pulmonary tuberculosis in a group of goldminers. Clusters were defined as groups of patients with Mycobacterium tuberculosis isolates with identical IS6110 DNA fingerprints. We compared the frequency of possible risk factors in the clustered and non-clustered patients whose isolates had fingerprints with more than four bands, and re-interviewed members of 45 clusters.
Of 448 patients, ten were excluded because they had false-positive cultures. Fingerprints were made in 419 of 438, of which 371 had more than four bands. 248 of 371 were categorised into 62 clusters. At least 50% of tuberculosis cases were due to transmission within the community. Patients who had failed treatment at entry to the study were more likely to be in clusters (adjusted odds ratio 3.41 [95% CI 1.25-9.27]). Patients with multidrug-resistant isolates were more likely to have failed treatment but were less likely to be clustered than those with a sensitive strain (0.27 [0.09-0.83]). HIV infection was common (177 of 370 tested) but not associated with clustering.
Despite a control programme that cures 86% of new cases, most tuberculosis in this mining community is due to ongoing transmission. Persistently infectious individuals who have previously failed treatment may be responsible for one third of tuberculosis cases. WHO targets for cure rates are not sufficient to interrupt transmission of tuberculosis in this setting. Indicators that are more closely linked to the rate of ongoing transmission are needed.
The Lancet 10/2000; 356(9235):1066-71. · 39.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine rates of drug resistance to Mycobacterium tuberculosis and associated risk factors, including HIV infection.
Prospective cohort study of patients with pulmonary tuberculosis.
The study population comprised 28,522 men working on four goldmines in Westonaria, Gauteng. Health care is provided at a 240-bed mine hospital, Gold Fields West Hospital, and its primary health care facilities.
All 425 patients with culture-positive pulmonary tuberculosis identified in 1995.
Tuberculosis drug resistance on enrollment and after 6 months' treatment.
There were 292 cases of new tuberculosis, 77 of recurrent disease and 56 prevalent cases in treatment failure. Two hundred and seven patients (48.7%) were HIV infected. Primary resistance to one or more drugs (9%) was similar to the 11% found in a previous study done on goldminers in 1989. Primary multidrug resistance (0.3%) was also similar (0.8%). Acquired multidrug resistance was 18.1%: 6.5% for recurrent disease and 33.9% in treatment failure cases. Neither HIV infection nor the degree of immunosuppression as assessed by CD4+ lymphocyte counts was associated with drug resistance at the start or end of treatment. New patterns of drug resistance were present in 9 of 52 patients in treatment failure at 6 months, 1 of whom was HIV-infected.
Primary and acquired drug resistance rates are stable in this population and are not affected by the high prevalence of HIV infection.
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 05/2000; 90(4):381-6. · 1.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: St. Francis Hospital in Katete District, Eastern Province, Zambia.
To compare the incremental cost-effectiveness of examining serial sputum smears for screening suspects for pulmonary tuberculosis at a rural district hospital in Zambia.
An incremental cost-effectiveness analysis of serial sputum smear examinations for diagnosing pulmonary tuberculosis based on laboratory results collected during 1997 and 1998 in a rural district hospital in Zambia. The cost analysis took a health service provider perspective, and used the ingredients approach. The cost-effectiveness is expressed in terms of the incremental cost per tuberculosis case diagnosed. Relevant information was obtained from various sources, including administrative records, interviews and direct observation.
Of a total of 166 acid-fast bacilli positive suspects who had three sputum smears examined sequentially, 128 (77.1%) were found on the first smear, a further 25 (15%) on the second smear and 13 (7.9%) additional cases were identified on the third smear. The economic analysis shows that the incremental cost of performing a third test, having already done two, increases rapidly with only a small gain in terms of additional cases of tuberculosis identified.
A policy of examining two samples should be considered in resource-poor settings, if the remaining steps of the national diagnostic algorithm can be adhered to with respect to smear-negative suspects.
The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 04/2000; 4(3):246-51. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
European Respiratory Journal 03/2000; 15(2):291-6. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tuberculosis patients may have Mycobacterium tuberculosis in their sputum at the end of treatment, and may show new drug resistance, due to either inadequate treatment of the original episode or reinfection with a new strain during therapy. In a cohort study of mineworkers with tuberculosis in South Africa, 57 of 438 patients had positive sputum cultures 6 months after recruitment in 1995. Of the 31 patients who initially had fully sensitive strains, 3 developed multidrug resistance (MDR) and 3 single-drug resistance (SDR). Of the 6 who started with SDR, 3 became MDR. HIV infection was not associated with drug resistance at enrolment or 6 months later. We compared pairs of DNA fingerprints from isolates of M. tuberculosis at recruitment and 6 months later in the 48 patients for whom we had both available. In 45, the pairs were identical. In 1 patient, although both isolates were fully sensitive, the later fingerprint had 1 less band (transposition). In 2 pairs, the fingerprint patterns were completely different: one seemed to be the result of laboratory error and the other was a true reinfection with an MDR strain. Despite a high risk of infection, with a moderate proportion of background drug-resistant strains (11% SDR, 6% MDR), reinfection is not a common cause of treatment failure or drug resistance at 6 months.
Transactions of the Royal Society of Tropical Medicine and Hygiene. 01/2000;
[show abstract][hide abstract] ABSTRACT: Many studies of tuberculosis have defined clusters of patients on the basis of shared DNA fingerprint patterns of their Mycobacterium tuberculosis isolates. Clustering has been equated with recent transmission, and factors associated with clustering have been sought as a guide to population subgroups with high rates of ongoing transmission of M. tuberculosis. Considerable caution should be exercised in conducting and interpreting these studies. Groups of strains may be identical for reasons other than recent transmission, depending, for example, on the stability of the marker and the number of strains in the population over time. Cases actually due to recent transmission may not be seen as clustered if they are new immigrants to the population or if not all cases in the population are included in the study. The amount of clustering seen will depend on the duration of the study. Studies should give precise information on the study setting, the proportion of cases included, the recruitment period and the definition of clustering used. The data on clustering should be disaggregated at least by age, sex and immigration status. To be maximally informative, studies should involve a high proportion of all cases in a population, be conducted in conjunction with conventional epidemiological investigations of contacts (if possible), and should provide information on tuberculosis incidence in the population and on patients' age, sex, human immunodeficiency virus status, drug resistance and social and ethnic group.
The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 01/2000; 3(12):1055-60. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Many studies of tuberculosis have defined clusters of patients on the basis of shared DNA fingerprint patterns of their Mycobacterium tuberculosis isolates. Clustering has been equated with recent transmission, and factors associated with clustering have been sought as a guide to population subgroups with high rates of ongoing transmission of M. tuberculosis. Considerable caution should be exercised in conducting and interpreting these studies. Groups of strains may be identical for reasons other than recent transmission, depending, for example, on the stability of the marker and the number of strains in the population over time. Cases actually due to recent transmission may not be seen as clustered if they are new immigrants to the population or if not all cases in the population are included in the study. The amount of clustering seen will depend on the duration of the study.Studies should give precise information on the study setting, the proportion of cases included, the recruitment period and the definition of clustering used. The data on clustering should be disaggregated at least by age, sex and immigration status. To be maximally informative, studies should involve a high proportion of all cases in a population, be conducted in conjunction with conventional epidemiological investigations of contacts (if possible), and should provide information on tuberculosis incidence in the population and on patients' age, sex, human immunodeficiency virus status, drug resistance and social and ethnic group.
The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 11/1999; 3(12):1055-1060. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to evaluate the impact of human immunodeficiency virus (HIV) infection on treatment for tuberculosis (TB). The study population comprised 28,522 black Southern African gold miners. Patients with sputum culture-positive new or recurrent pulmonary TB diagnosed in 1995 were prospectively enrolled in the cohort. Directly observed therapy (DOT) was practiced and outcomes were assessed at 6 mo after treatment was begun. There were 376 cases of TB (incidence 1,318 per 100,000), of which 190 (50%) were HIV positive and 82 (22%) had recurrent TB. There was no association between HIV status and history of previous TB or drug resistance. Neither the treatment interruption rate (2%) nor the rate at which patients transferred out of the treatment program (1.6%) were associated with HIV status. Excluding deaths, cure rates were similar for HIV-positive and HIV-negative patients (89% versus 88%), but significantly lower in those with recurrent than in those with new TB (77% versus 92%). Mortality was 0.5% in HIV-negative patients versus 13.7% in HIV-positive patients, and in the latter group was associated with CD4(+) lymphocyte depletion. Autopsy examination showed that in HIV-positive patients, early mortality was due to TB whereas late deaths were most commonly due to cryptococcal pneumonia. The study showed that a well-run TB control program can result in acceptable cure rates even in a population with a very high incidence of TB and HIV infection. Particular vigilance is needed for concurrent infections, which may contribute significantly to mortality during treatment of TB in HIV-positive patients.
American Journal of Respiratory and Critical Care Medicine 04/1999; 159(3):733-40. · 11.04 Impact Factor