A case control study with equal number of cases and controls was conducted by recruiting a total of 268 study participants to determine factors associated with developing MDR-TB after taking first line anti-TB treatment. Factors which were associated with MDR-TB: the first site of TB infection being pulmonary, encountering drug side effects during the first course of treatment, having more than one TB episode, undergoing the Category II regimen, and taking anti-TB treatment for less than 7 months.
The study also found that being male was a risk factor for MDR-TB development. A study in Nigeria showed that being male was a risk factor for defaulting from anti-TB medication . Similarly, this study showed that among MDR-TB cases who were defaulters in their first-line TB treatment, 62.5% were males. The association between being male and having MDR-TB could be due to the fact that males have a higher tendency not to adhere to anti-TB treatment than females, thus increasing their risk of developing MDR-TB. Another study showed that individuals who do not take anti-TB medication regularly have increased risk for MDR-TB . Our study also showed that individuals who did not take first-line anti-TB drugs regularly had increased risk for development of MDR-TB.
Evidence from a previous study has shown that poor treatment adherence was a risk factor for MDR-TB . The current study also showed that individuals who took first-line anti-TB treatment for duration of 2 to 7 months had increased risk of developing MDR-TB. In Ethiopia, the previous guideline for first-line anti-TB treatment was 8 months’ duration, but the standard has been changed to 6 months. TB therapy requires more than 90% adherence to facilitate cure , and 2 to 7 months (25%–87.5% of the prescribed duration) is less than the required duration to result in cure.
Additionally, individuals who were not under strict DOTS per national guidelines during their first anti-TB treatment had an 11.7 times increased risk for MDR-TB. An analysis that used empirical data to determine the impact of the expansion of the DOTS strategy on TB case finding and treatment success found that countries with full DOTS coverage had at least an 18% increase in the treatment success rate . An individual who is supervised by a health worker is more likely to take the appropriate dose of medicine and less likely to miss a treatment. Furthermore, individuals who come for DOTS have frequent contact with health workers and thus have increased opportunities to get advice and counseling, which might help them to adhere to medication protocol.
As expected, individuals who encountered drug side effects during the first course of TB treatment had a 4.5 times increased risk of developing MDR-TB. Studies done in three districts of Arsi Zone, Ethiopia, found that anti-TB drug side effects were significantly associated with a high rate of defaulting . When patients develop side effects, they tend to stop treatment, which favors the development of MDR-TB. If the DOTS strategy of the nation were followed in all cases, there would be a chance to counsel patients and even treat adverse drug reactions before treatment interruption. In our study, the first-line anti-TB treatment of 48.5% of the MDR-TB cases was not directly observed. A systematic review of 29 published reports on risk factors associated with MDR-TB in Europe revealed that previous treatment was the strongest determinant of MDR-TB and that the pooled risk of MDR-TB was 10.23 times higher in previously treated than in never-treated cases . A study in Uganda also showed that multiple TB episodes and treatment failure were significantly associated with MDR-TB . Similarly, in Ethiopia, according to a nationwide anti-TB drug resistance survey conducted in 2005, 1.6% of newly diagnosed TB cases were infected with MDR-TB, while 11.8% of the MDR-TB cases were previously treated TB cases .
One can see how MDR-TB is prevalent in individuals who have a history of treatment compared to new patients. Similarly, the current study showed that having more than one TB episode also increased risk for MDR-TB. This may be related to the previous treatment outcome, default, treatment failure, or relapse, or the patient may have had MDR-TB initially.
Having pulmonary TB during first anti-TB treatment was associated with increased risk for MDR-TB. This may also be associated with the fact that smear-positive pulmonary TB individuals have a high bacterial load and may not respond to the treatment within a short period of time, as do those with a low bacterial load . For this reason, smear-positive pulmonary TB patients might be more prone to develop MDR-TB. The other explanation might be associated with diagnostic difficulties. In case of extra pulmonary MDR- TB the bacterial load is lower and difficult for definite diagnosis comparing to pulmonary MDR-TB. Limited capacity of the existing laboratory facilities especially for the diagnosis of extra pulmonary MDR-TB might explain the association of being Pulmonary TB and having MDR-TB.
This study showed that individuals who were treated by the Category II regimen had increased risk for MDR-TB. More than one explanation may be given for the association of Category II treatment and MDR-TB. These individuals might have had a previous TB treatment history and registered for the treatment as treatment failures, defaulters, or relapse cases, or they might have already had MDR-TB at the initiation of the Category II regimen. Another explanation is that adding one drug in the failing regimen could change susceptible strains and lead to multidrug resistance. “Michael Iseman, the US-based MDR-TB specialist, had 10 commandments for the physicians not to change fully drug susceptible organisms to MDR-TB; the first one was never to add a single drug to a failing regimen and the other nine were to repeat the first commandment to make sure it was well understood” . WHO recommends that DST should be done for all previously treated patients before they are treated with the Category II drug regimen, and in conditions where DST is not available, the Category II regimen can be used for relapse, default, and treatment failure for low- or medium-MDR-TB-burden countries . A cross-sectional study in South Africa showed that retreatment patients had increased risk for any drug resistance and MDR-TB . Having a DST before embarking on the Category II regimen is very important. In Ethiopia, because of low laboratory capacity, performing DST for all previously treated patients is difficult even though the country is one of the high-MDR-TB- burden countries. An individual’s treatment may fail because they have already had MDR-TB or because drug resistance was caused by the retreatment regimen . This is because the patient has already taken all the drugs in the Category II regimen in the previous treatment, except streptomycin, which is the oldest drug.
In the current study, HIV status had no significant association with MDR-TB. A study in Thailand showed also that HIV status was not significantly associated with MDR-TB . In France, being HIV positive was associated with primary MDR-TB but it was not associated with secondary MDR-TB . A cross-sectional study in South Africa showed that in retreated patients, HIV had no significant association with MDR-TB . The study participants in the current study were patients who had a history of first-line anti-TB treatment. It is possible that the result could have been different if all study participants were primary MDR-TB cases rather than MDR-TB cases who had a history of previous treatment. A study in Ukraine showed that HIV-positive individuals had a 50% higher risk of developing MDR-TB at their first TB infection . This is because being HIV positive is one risk factor for drug-susceptible TB, which is related to immune system suppression. Being HIV positive might carry the same risk of infection with MDR-TB but may not contribute to the change of a drug-susceptible strain of TB to MDR-TB.
The strengths of the current study are that study participants in the control group finished first-line anti-TB treatment two years before the study period, which reduced the chance of relapse. They were selected from the five health facilities in Addis Ababa that reported the most MDR-TB cases to St. Peter Hospital, so that cases and controls would have a better likelihood of coming from similar backgrounds and be most likely to receive the same service. Regarding the case group, all cases that fulfilled the eligibility criteria that were available during the study period and willing to respond were included in the study. This was helpful to decrease sampling error.
The current study is not without limitations, however. Recall bias could be considered one potential challenge, since some of the information was based on the recall of the study participants. Furthermore, it was not clear whether all cases had MDR-TB before or after undergoing first-line TB treatment, since DST was not done before they took first-line TB treatment or Category II regimens.