To the Editors:
Tuberculosis (TB) remains a serious public health problem in many low- and middle-income countries in Africa, Asia and the former Soviet Union . Mozambique is one of them. Despite the fact that in this country, detection of patients with TB has drastically increased during the past decade due to improved notification (from nearly 20,000 new TB cases notified in 1998 to nearly 40,000 in 2008), less than half of the cases of TB estimated to emerge annually are currently being detected. As in other southern African countries, the HIV epidemic is fuelling the TB epidemic in Mozambique, with 60% of patients with TB being co-infected with HIV . Drug-resistant TB is thought to be a major problem, although the latest information available on the magnitude of resistance to anti-TB drugs is from 1998, when the first national drug resistance survey (DRS) was conducted. At that time, multidrug-resistant (MDR)-TB (defined as TB resistant to at least isoniazid and rifampicin, the two main first-line drugs in the treatment of TB) was found among 3.5 and 3.3% of new and previously treated TB cases, respectively . Since then, there has been no further investigation of the magnitude of drug resistance in the country. Based on the latest available data, >3,500 MDR-TB cases are estimated to have emerged in Mozambique in 2008 . Detecting and treating patients with MDR-TB is feasible but substantially more complex and costly than treating patients with fully susceptible Mycobacterium tuberculosis strains. Knowing the levels of anti-TB drug resistance in the country is essential for any national TB programme (NTP) to evaluate the efficacy of TB control measures and treatment practices in the community, as well as to design effective treatment regimens for all patients with TB [4, 5].
For this reason, after nearly 10 yrs from the first survey, a new DRS on a national representative sample of TB patients has been conducted, with the objectives to investigate levels and patterns of resistance to first- and second-line anti-TB drugs among new and previously treated TB cases, compare the new findings with the existing data, and explore the association between the HIV epidemic and anti-TB drug resistance. The findings will be used by the NTP to develop treatment and management policies for TB and MDR-TB patients. .
The survey was designed according to the guidelines of the World Health Organization (WHO) , and conducted between February 2007 and May 2008 in 40 diagnostic centres sampled from all centres distributed in all 11 provinces of the country. The sampling was probability proportional to size, based on the number of new sputum smear-positive cases in 2006. Each cluster was required to enroll 30 new sputum smear-positive TB patients. During the enrolment period, all previously treated TB patients presenting to the 40 diagnostic centers were also included. Sputum smear-negative and extrapulmonary TB patients were excluded from the survey. Patients were classified as newly diagnosed or previously treated according to WHO definitions . The following variables were collected through a questionnaire administered during sputum collection: sex, age, treatment history (new/previously treated) and HIV status. Medical records were reviewed to confirm the reliability of the information gathered through the questionnaire. Sputum samples were sent to the National Reference Laboratory in Maputo for culture and first-line drug susceptibility testing (DST), performed on Löwenstein–Jensen medium. All MDR-TB strains and 10% of randomly selected susceptible strains were sent to the Supranational Reference Laboratory in Milan, Italy for re-checking and second-line DST. The study was approved by the National Ethical Review Board of Ministry of Health of Mozambique. Informed consent was obtained before enrolment. Summary analyses were performed using Stata (version 10.0; StataCorp, College Station, TX, USA).
A total of 1,398 sputum smear-positive pulmonary TB patients were diagnosed during the study period. Due to failure of TB culture growth, 198 of them were excluded from the analysis (159 were culture-negative and 39 were culture-contaminated). Of the 1,200 cases with culture-positive specimens, DST results were available for 1,127 patients (in 21 cases, DST was contaminated and in 52 cases, the secondary culture did not grow). The overall total culture and DST recovery rate was 80.6%, which was consistent with national expectations and WHO recommendations .
Of the 1,127 patients with final results, the vast majority were new cases of TB, as only 25 previously treated cases could be included in the survey (2.2% of the total, consistent with national notification data). As expected, males were more frequent than females (61.8%). The mean±sd age of the study population was 35±13 yrs. Information on HIV status was available for 937 patients (83.1% of those with final DST results), and 36.9% of them (346 out of 937 cases) had HIV co-infection.
Overall proportions of MDR-TB were 3.5% (38 out of 1,102, 95% CI 2.2– 4.8%) among newly diagnosed TB cases and 11.2% (three out of 25, 95% CI 0.0–25.2%) among those previously treated for TB. Levels of resistance to isoniazid (H), rifampicin (R), ethambutol (E) and streptomycin (S), as well as frequencies of any resistance, monoresistance and resistance to other patterns are shown by treatment history in table 1. All 41 MDR-TB strains were tested for second-line drug resistance and no cases of extensively drug-resistant (XDR)-TB (defined as MDR-TB plus resistance to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin)) were observed.
Among the 917 new TB cases with known HIV status, proportions of MDR-TB were 2.1% (12 out of 583, 95% CI 0.9–3.4%) and 4.5% (15 out of 334, 95% CI 2.2–6.7%) among those with negative and positive HIV status, respectively. MDR-TB frequencies were higher in people living with HIV, with risk ratio 2.4 (95% CI 1.2–4.8; p = 0.007). The association between resistance to any first-line anti-TB drug and HIV was not found to be statistically significant (table 2).
Compared with a study conducted recently in neighbouring Tanzania, where MDR-TB was found in only 1.1% of the new TB cases tested , and surveys conducted in several African countries in the last decade , the proportion of MDR-TB detected in Mozambique is quite high. Fortunately, no significant difference could be detected between the levels of MDR-TB found in new TB cases in 1998 (3.5%, 95% CI 2.5–4.8%) and in 2007 (3.5%, 95% CI 2.2–4.8%). This very important finding confirms that MDR-TB is not rapidly spreading in the community and that the NTP has been effective in preventing the development and transmission of drug resistance by improving detection of TB cases and provision of proper treatment. Due to the low number of previously treated cases enrolled in the study, it is not possible to conclude whether the proportion of MDR-TB is increasing in this group (four out of 122 in 1998 versus three out of 25 in 2007).
People living with HIV were found to have a statistically significant greater risk of being infected with MDR-TB strains compared with HIV-negative patients (RR 2.4, 95% CI 1.2–4.8; p = 0.007). As shown by reports from the neighboring South African province of Kwazulu Natal [9, 10], patients with MDR/XDR-TB have very high case fatality if they are not rapidly diagnosed and treated with second-line anti-TB drugs and antiretroviral therapy.
In Mozambique, second-line treatment for MDR-TB is available to the entire country free of charge through the NTP, though the majority of patients accessing treatment live in Maputo. More efforts are needed to ensure rapid diagnosis of MDR-TB and access to treatment with second-line drugs, as well as antiretroviral therapy for all those in need.
Statement of Interest
- ©ERS 2011