Rory Dunbar

Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial.

BACKGROUND Southern Africa has had an unprecedented increase in the burden of tuberculosis, driven by the HIV epidemic. The Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial examined two public health interventions that aimed to reduce the burden of tuberculosis by facilitating either rapid sputum diagnosis or integrating tuberculosis and HIV services within the community. METHODS ZAMSTAR was a community-randomised trial done in Zambia and the Western Cape province of South Africa. Two interventions, community-level enhanced tuberculosis case-finding (ECF) and household level tuberculosis-HIV care, were implemented between Aug 1, 2006, and July 31, 2009, and assessed in a 2×2 factorial design between Jan 9, 2010, and Dec 6, 2010. All communities had a strengthened tuberculosis-HIV programme implemented in participating health-care centres. 24 communities, selected according to population size and tuberculosis notification rate, were randomly allocated to one of four study groups using a randomisation schedule stratified by country and baseline prevalence of tuberculous infection: group 1 strengthened tuberculosis-HIV programme at the clinic alone; group 2, clinic plus ECF; group 3, clinic plus household intervention; and group 4, clinic plus ECF and household interventions. The primary outcome was the prevalence of culture-confirmed pulmonary tuberculosis in adults (≥18 years), defined as Mycobacterium tuberculosis isolated from one respiratory sample, measured 4 years after the start of interventions in a survey of 4000 randomly selected adults in each community in 2010. The secondary outcome was the incidence of tuberculous infection, measured using tuberculin skin testing in a cohort of schoolchildren, a median of 4 years after a baseline survey done before the start of interventions. This trial is registered, number ISRCTN36729271. FINDINGS Prevalence of tuberculosis was evaluated in 64,463 individuals randomly selected from the 24 communities; 894 individuals had active tuberculosis. Averaging over the 24 communities, the geometric mean of tuberculosis prevalence was 832 per 100,000 population. The adjusted prevalence ratio for the comparison of ECF versus non-ECF intervention groups was 1·09 (95% CI 0·86-1·40) and of household versus non-household intervention groups was 0·82 (0·64-1·04). The incidence of tuberculous infection was measured in a cohort of 8809 children, followed up for a median of 4 years; the adjusted rate ratio for ECF versus non-ECF groups was 1·36 (95% CI 0·59-3·14) and for household versus non-household groups was 0·45 (0·20-1·05). INTERPRETATION Although neither intervention led to a statistically significant reduction in tuberculosis, two independent indicators of burden provide some evidence of a reduction in tuberculosis among communities receiving the household intervention. By contrast the ECF intervention had no effect on either outcome. FUNDING Bill & Melinda Gates Foundation.

Changing Mycobacterium tuberculosis population highlights clade-specific pathogenic characteristics.

Mycobacterium tuberculosis strains can be classified into a number of major clades according to defined evolutionary markers. It is hypothesised that strains comprising these clades have evolved different properties which may influence a local strain population structure. To investigate this, we analysed the incidence of tuberculosis caused by the predominant clades (Beijing, Haarlem, LAM, Quebec and the Low-Copy Clade) found in a community within the Cape Town metropole in South Africa over a 12-year period. We found that while the incidence of cases infected with strains of the Haarlem, LAM, Quebec and the Low-Copy Clades remained relatively stable, that of cases of the Beijing clade increased exponentially over time, with a doubling time of 4.86 years (P=0.018). This growth was exclusively attributable to drug-susceptible strains. Although drug-resistant Beijing cases remained constant in number, non-Beijing drug-resistant cases declined over time (P=0.007). Drug-susceptible Beijing-infected cases had a greater proportion of smear-positive sputa than their non-Beijing counterparts (P=0.013) and were less likely to be successfully treated (retreatment cases) (P=0.026). Recent evidence suggests that these differences likely reflect enhanced pathogenicity rather than transmissibility. The rapid emergence of Beijing strains demonstrates adaptation to conditions within the study community and poses a grave challenge to future TB control.

The Temporal Dynamics of Relapse and Reinfection Tuberculosis After Successful Treatment: A Retrospective Cohort Study

BACKGROUND There is increasing evidence from tuberculosis high-burden settings that exogenous reinfection contributes considerably to recurrent disease. However, large longitudinal studies of endogenous reactivation (relapse) and reinfection tuberculosis are lacking. We hypothesize a relationship between relapse vs reinfection and the time between treatment completion and recurrent disease. METHODS Population-based retrospective cohort study on all smear-positive tuberculosis cases successfully treated between 1996 and 2008 in a suburban setting in Cape Town, South Africa. Inverse gaussian distributions were fitted to observed annual rates of relapse and reinfection, distinguished by DNA fingerprinting of Mycobacterium tuberculosis strains recultured from diagnostic samples. RESULTS Paired DNA fingerprint data were available for 130 (64%) of 203 recurrent smear-positive tuberculosis cases in the 13-year study period. Reinfection accounted for 66 (51%) of 130 recurrent cases overall, 9 (20%) of 44 recurrent cases within the first year, and 57 (66%) of 86 thereafter (P < .001). The relapse rate peaked at 3.93% (95% confidence interval [CI], 2.35%-5.96%) per annum 0.35 (95% CI, .15-.45) years after treatment completion. The reinfection tuberculosis rate peaked at 1.58% (95% CI, .94%-2.46%) per annum 1.20 (95% CI, .55-1.70) years after completion. CONCLUSIONS To our knowledge, this is the first study of sufficient size and duration using DNA fingerprinting to investigate tuberculosis relapse and reinfection over a lengthy period. Relapse occurred early after treatment completion, whereas reinfection dominated after 1 year and accounted for at least half of recurrent disease. This temporal relationship may explain the high variability in reinfection observed across smaller studies. We speculate that follow-up time in antituberculosis drug trials should take reinfection into account.

A comparison of multidrug-resistant tuberculosis treatment commencement times in MDRTBPlus line probe assay and Xpert® MTB/RIF-based algorithms in a routine operational setting in Cape Town.

Background Xpert MTB/RIF was introduced as a screening test for all presumptive tuberculosis cases in primary health services in Cape Town, South Africa. Study Aim To compare multidrug-resistant tuberculosis (MDR-TB) treatment commencement times in MDRTBPlus Line Probe Assay and Xpert MTB/RIF-based algorithms in a routine operational setting. Methods The study was undertaken in 10 of 29 high tuberculosis burden primary health facilities, selected through stratified random sampling. An observational study was undertaken as facilities transitioned to the Xpert MTB/RIF-based algorithm. MDR-TB diagnostic data were collected from electronic laboratory records and treatment data from clinical records and registers. Kaplan Meier time-to-event analysis was used to compare treatment commencement time, laboratory turnaround time and action delay between algorithms. A facility-level paired analysis was done: the median time-to-event was estimated per facility in each algorithm and mean differences between algorithms compared using a paired t-test. Cox proportional hazards regression was used to assess the effect of patient-level variables on treatment commencement time. The difference between algorithms was compared using the hazard ratio. Results The median treatment commencement time in the Xpert MTB/RIF-based algorithm was 17 days (95% CI 13 to 22 days), with a median laboratory turnaround time (to result available in the laboratory) of <1 day (95% CI<1 to 1 day). There was a decrease of 25 days (95% CI 17 to 32 days, p<0.001) in median MDR-TB treatment commencement time in the Xpert MTB/RIF-based algorithm. We found no significant effect on treatment commencement times for the patient-level variables assessed. Conclusion MDR-TB treatment commencement time was significantly reduced in the Xpert MTB/RIF-based algorithm. Changes in the health system may have contributed. However, an unacceptable level of delay remains. Health system and patient factors contributing to delay need to be evaluated and addressed to optimise test benefits.

High prevalence of Tuberculosis and insufficient case detection in two communities in the Western Cape, South Africa

Background In South Africa the estimated incidence of all forms of tuberculosis (TB) for 2008 was 960/100000. It was reported that all South Africans lived in districts with Directly Observed Therapy, Short-course. However, the 2011 WHO report indicated South Africa as the only country in the world where the TB incidence is still rising. Aims To report the results of a TB prevalence survey and to determine the speed of TB case detection in the study communities. Methods In 2005 a TB prevalence survey was done to inform the sample size calculation for the ZAMSTAR (Zambia South Africa TB and AIDS Reduction) trial. It was a cluster survey with clustering by enumeration area; all households were visited within enumeration areas and informed consent obtained from eligible adults. A questionnaire was completed and a sputum sample collected from each adult. Samples were inoculated on both liquid mycobacterium growth indicator tube (MGIT) and Löwenstein-Jensen media. A follow-up HIV prevalence survey was done in 2007. Results In Community A, the adjusted prevalence of culture positive TB was 32/1000 (95%CI 25–41/1000) and of smear positive TB 8/1000 (95%CI 5–13/1000). In Community B, the adjusted prevalence of culture positive TB was 24/1000 (95%CI 17–32/1000) and of smear positive TB 9/1000 (95%CI 6–15/1000). In Community A the patient diagnostic rate was 0.38/person-year while in community B it was 0.30/person-year. In both communities the adjusted HIV prevalence was 25% (19–30%). Discussion In both communities a higher TB prevalence than national estimates and a low patient diagnostic rate was calculated, suggesting that cases are not detected at a sufficient rate to interrupt transmission. These findings may contribute to the rising TB incidence in South Africa. The TB epidemic should therefore be addressed rapidly and effectively, especially in the presence of the concurrently high HIV prevalence.

Tuberculosis Patients In Primary Care Do Not Start Treatment. What Role Do Health System Delays Play

SETTING Primary health care facilities in five provinces of South Africa. OBJECTIVE To investigate the association between the proportion of sputum results with a prolonged smear turnaround time and the proportion of smear-positive tuberculosis (TB) cases initially lost to follow-up. DESIGN The unit of investigation was a primary health care facility and the outcome was the initial loss to follow-up rate per facility, which was calculated by comparing the sputum register with the TB treatment register. A prolonged turnaround time was defined as more than 48 h from when the sputum sample was documented in the sputum register to receipt of the result at the facility. RESULTS The mean initial loss to follow-up rate was 25% (95%CI 22-28). Smear turnaround time overall was inversely associated with initial loss to follow-up (P = 0.008), when comparing Category 2 (33-66% turnaround time within 48 h) with Category 1 (0-32%) (OR 0.73, 95%CI 0.48-1.13, P = 0.163) and when comparing Category 3 (67-100%) with Category 1 (OR 0.62, 95%CI 0.39-0.99, P = 0.045). The population preventable fraction of initial loss to follow-up (when turnaround time was <48 h in ≥67% of smear results) was 21%. CONCLUSION Initial loss to follow-up should be reported as part of the TB programme to ensure that patients are initiated on treatment to prevent transmission within communities.

Tuberculosis cases missed in primary health care facilities: should we redefine case finding?

SETTING This study was conducted in Cape Town in two primary health care facilities in a sub-district with a high prevalence of bacteriologically confirmed pulmonary tuberculosis (TB). OBJECTIVE To determine the proportion of adults with respiratory symptoms who attend health care facilities but are not examined for nor diagnosed with TB in facilities where routine TB diagnosis depends on passive case finding. DESIGN A total of 423 adults with respiratory symptoms exiting primary health care services were consecutively enrolled during April-July 2011. RESULTS Twenty-one (5%) participants were diagnosed with culture-positive TB. None had sought care at the facility for their respiratory symptoms, none were asked about respiratory symptoms during their visit and none were asked to produce a sputum sample. Nine cases had attended the facility for reasons regarding their own health, while 12 cases were accompanying someone else attending the facility, or for another reason. CONCLUSION Patients with infectious TB attend primary health care facilities, but are not recognised and diagnosed as cases. Health care staff should search actively within facilities for cases who attend the health care services to ensure that cases are not missed. Intensified case finding should start within the facility, and should not be limited to patients who report respiratory symptoms or who are human immunodeficiency virus positive.

The rate of sputum smear-positive tuberculosis after treatment default in a high-burden setting: a retrospective cohort study.

Rationale High rates of recurrent tuberculosis after successful treatment have been reported from different high burden settings in Sub-Saharan Africa. However, little is known about the rate of smear-positive tuberculosis after treatment default. In particular, it is not known whether or not treatment defaulters continue to be or become again smear-positive and thus pose a potential for transmission of infection to others. Objective To investigate, in a high tuberculosis burden setting, the rate of re-treatment for smear-positive tuberculosis among cases defaulting from standardized treatment compared to successfully treated cases. Methods Retrospective cohort study among smear-positive tuberculosis cases treated between 1996 and 2008 in two urban communities in Cape Town, South Africa. Episodes of re-treatment for smear-positive tuberculosis were ascertained via probabilistic record linkage. Survival analysis and Poisson regression were used to compare the rate of smear-positive tuberculosis after treatment default to that after successful treatment. Results A total of 2,136 smear-positive tuberculosis cases were included in the study. After treatment default, the rate of re-treatment for smear-positive tuberculosis was 6.86 (95% confidence interval [CI]: 5.59–8.41) per 100 person-years compared to 2.09 (95% CI: 1.81–2.41) after cure (adjusted Hazard Ratio [aHR]: 3.97; 95% CI: 3.00–5.26). Among defaulters, the rate was inversely associated with treatment duration and sputum conversion prior to defaulting. Smear grade at start of the index treatment episode (Smear3+: aHR 1.61; 95%CI 1.11–2.33) was independently associated with smear-positive tuberculosis re-treatment, regardless of treatment outcome. Conclusions In this high-burden setting, there is a high rate of subsequent smear-positive tuberculosis after treatment default. Treatment defaulters are therefore likely to contribute to the pool of infectious source cases in the community. Our findings underscore the importance of preventing treatment default, as a means of successful tuberculosis control in high-burden settings.

Increased risk of default among previously treated tuberculosis cases in the Western Cape Province, South Africa

OBJECTIVE To investigate, in two urban communities with high tuberculosis (TB) incidence and high rates of TB recurrence, whether a history of previous TB treatment is associated with treatment default. METHODS Retrospective cohort study of TB cases with an episode of treatment recorded in the clinic-based treatment registers between 2002 and 2007. Probabilistic record linkage was used to ascertain treatment history of TB cases back to 1996. Based on the outcome of their most recent previous treatment episode, previously treated cases were compared to new cases regarding their risk of treatment default. RESULTS Previous treatment success (adjusted odds ratio [aOR] 1.79; 95%CI 1.17-2.73), previous default (aOR 6.18, 95%CI 3.68-10.36) and previous failure (aOR 9.72, 95%CI 3.07-30.78) were each independently associated with treatment default (P < 0.001). Other factors independently associated with default were male sex (P = 0.003) and age 19-39 years (P < 0.001). CONCLUSIONS Previously treated TB cases are at increased risk of treatment default, even after previous successful treatment. This finding is of particular importance in a setting where recurrent TB is very common. Adherence to treatment should be ensured in new and retreatment cases to increase cure rates and reduce transmission of TB in the community.

Missed Opportunities for Retention in Pre-ART Care in Cape Town, South Africa

Background Few studies have evaluated access to and retention in pre-ART care. Objectives To evaluate the proportion of People Living With HIV (PLWH) in pre-ART and ART care and factors associated with retention in pre-ART and ART care from a community cohort. Methods A cross sectional survey was conducted from February – April 2011. Self reported HIV positive, negative or participants of unknown status completed a questionnaire on their HIV testing history, access to pre-ART and retention in pre-ART and ART care. Results 872 randomly selected adults who reported being HIV positive in the ZAMSTAR 2010 prevalence survey were included and revisited. 579 (66%) reconfirmed their positive status and were included in this analysis. 380 (66%) had initiated ART with 357 of these (94%) retained in ART care. 199 (34%) had never initiated ART of whom 186 (93%) accessed pre-ART care, and 86 (43%) were retained in pre-ART care. In a univariable analysis none of the factors analysed were significantly associated with retention in care in the pre-ART group. Due to the high retention in ART care, factors associated with retention in ART care, were not analysed further. Conclusion Retention in ART care was high; however it was low in pre-ART care. The opportunity exists, if care is better integrated, to engage with clients in primary health care facilities to bring them back to, and retain them in, pre-ART care.