We conducted a questionnaire-based, case-control study among adult persons ≥ 18 years old enrolled in treatment under DOTS at public health facilities in South Africa between January 1 and December 31, 2002. Eligible cases were defined as any new and re-treatment TB patient (with pulmonary or extrapulmonary TB) who were on treatment for at least 4 weeks, then defaulted from a six-month (new) or eight-month (re-treatment) TB regimen. New patients received a fixed dose combination Rifafour® (isoniazid, rifampin, pyrazinamide, ethambutol), retreatment cases received Rifafour® plus streptomycin injection.
We defined default as interrupting TB treatment for two or more consecutive months during treatment. Eligible controls were those persons diagnosed with TB who began therapy and were cured, completed or failed treatment. Persons were excluded if they were recorded to have died or transferred, were younger than 18 years, were known to have multidrug-resistant TB or were prisoners or wards of the state.
Interviewers were trained to review medical records available at the health facilities, and to trace and interview TB patients with written informed consent. Interviewers made every effort to locate patients using information available from the health center records or staff who knew the patients; they telephoned patients, located their homes if possible and made multiple visits if necessary. In the event a patient no longer lived at a specific address, they asked local neighbors and guides to help them trace the patients. To minimize bias, the interviewers did not know the patients and were not associated with the local health services. Data collected from the health facilities included demographic information, patient's address, treatment information including dates of TB registration, treatment initiation and completion and treatment outcome.
A structured questionnaire was adapted from a questionnaire previously used in South Africa to study MDR TB adherence, with additional questions concerning the role of food and nutrition during TB treatment [6
]. Questions covered five domains commonly cited regarding adherence to long-term therapies (Figure ) [11
]. The questionnaire was pre-tested and translated from English into 10 South African home languages (Xitsonga, Tshivenda, Siswati, Setswana, Sesotho, IsiZulu, IsiXhosa, IsiNdebele, Afrikaans) and back-translated into English to ensure the quality of translation. The questionnaire was a combination of multiple-choice, yes/no and open-ended questions on demographic, social, health service and treatment characteristics. We inquired about the provision of nutritional support and the role of enablers and incentives. Information on the HIV status of persons with TB was not included as HIV services were not integrated in the TB program in 2002.
Questionnaires were administered in the TB patient's home language using face-to-face interviews. Interviewers were trained to encourage defaulters to return to the health clinic to be evaluated for TB treatment. For patients who were found to have died, the outcome of death, date of death and cause, if available, was recorded. Patients were given a standard food parcel equivalent to approximately US$15 for participating in the study, offered after the informed consent and interview so as to not bias study participation or responses.
The sample was selected from facility-based national TB registers in 8 provinces and matched by quarter of enrolment and health facility at a ratio of 1 case: 2 controls. TB registers from Limpopo province were not available and thus excluded. Sample selection for each province was conducted by multi-stage sampling made up of urban and rural sub-samples that reflected the estimated demographic population proportions reported for 2001. For each province, we compiled a list of all urban and rural public clinics including number of new patients enrolled and number of defaulters in 2002. The health facility sub-samples were chosen by systematic sampling proportional to clinic enrolment size. TB registers were requested from selected health facilities and the pre-calculated number of cases and matched controls were selected randomly from the TB registers.
Based on historic program data on the proportion of patients from each province classified as re-treatment patients (8-27% depending on the province), we calculated a sample size large enough to show at least a 25% difference between cases and controls that would result in a statistically significant odds ratio (OR) of > 2.9 with a 95% confidence interval (CI) and a power of 80%, for each province. In anticipation of difficulties associated with finding defaulters, the overall sample size was increased by 75%. Based on these calculations, the targeted sample size for the 8 provinces was 1055 cases and 2110 controls.
Data were entered into an EpiData v.3.1 database and analyzed with STATA 8 [12
]. Data were validated by checking consistency values, evaluating range values, and performing uniqueness checks. We analyzed differences in proportions using the Mantel-Haenszel chi-square statistic (χ2
) or Fisher's exact test where appropriate. For data not normally distributed, we compared differences in medians using the Wilcoxon rank-sum test. We performed multivariable logistic regression analysis with forward selection. We evaluated all variables in the bivariate analysis that were significant at P
< 0.20 in the multivariable analysis using logistic regression for the final models. For all statistical tests, we considered a P
value of < 0.05 as statistically significant. All pair wise interactions of the explanatory variables that were epidemiologically relevant in the model were considered.
This study was approved by the Ethics Committee of the South African Medical Research Council and the respective provincial research committees. This study was also approved as human subjects' research by the Institutional Review Board at the US Centers for Disease Control and Prevention in Atlanta, GA, USA. Voluntary written informed consent was obtained from all participants included in the study.