This retrospective cohort study of 662 patients from two provinces of Vietnam found an overall treatment success rate of 65.5% and identified several important barriers to successful MDR-TB treatment. While treatment outcomes were influenced by a variety of demographic, financial, and clinical factors, a patient’s gender, HIV status, the extent of antibiotic resistance at diagnosis, and whether bacteriological conversion was achieved within 4 months of commencing treatment were most strongly associated with treatment success.
The reduced odds of treatment success among patients living with HIV in this study was comparable to other Vietnamese [8, 9] and global [10] estimates. Although the HIV burden in Vietnam is relatively low (compared with other high MDR-TB burden counties [1]), and affordable antiretroviral therapy is readily available [11,12,13], patients receiving concomitant treatment for HIV/TB may be at a greater risk of experiencing drug-related side effects compared with patients who are not being treated for HIV [7]. Patient discomfort resulting from severe side effects or pill burden can increase the chance of voluntary withdrawal from treatment, and this may be reflected in the considerable risk of loss to follow-up associated with patients also under treatment for HIV in this study (see Additional file 1: Table S3). The stigma associated with being under treatment for both infections can also result in social alienation and discrimination, further increasing the risk of voluntary withdrawal from treatment [6, 14]. Additional care for patients living with HIV, including psychosocial support, is thus essential to ensuring that side effects are effectively managed and treatment adherence is optimal [15].
Patients with RR-/MDR-TB in this study were more likely to achieve treatment success in comparison to those with pre-XDR-TB and XDR-TB. This is consistent with global treatment success rates estimates of just 56% and 30% for MDR-TB and XDR-TB patients, respectively [12, 16]. As such, in cases where treatment failure results in additional acquired antibiotic resistance, a prolonged and more complicated retreatment may be required, further reducing the odds of a successful outcome. This is particularly problematic for patients with already substantial resistance as it limits future treatment options to less effective and potentially more toxic regimens. In addition, treatment failure may prolong the period in which the patient is infectious, thus potentially contributing to ongoing community transmission. Although acquired resistance was not specifically recorded in this study, 12% of patients reported considerable antibiotic resistance (pre-XDR-/XDR-TB) at diagnosis. Due to the poor treatment success rate and risks associated with higher levels of resistance, treatment of these patients represents a major clinical and public health challenge for Vietnam’s healthcare system.
Patients in this study who attained culture conversion by the end of 4 months were considerably more likely to ultimately achieve treatment success compared to those whose sputum remained positive after 4 months. This highlights both the utility of routine and accurate testing, and the importance of bacteriological conversion early in treatment. While conversion after 2 months of treatment has been suggested as a possible means for predicting treatment success [17], the results of this study are consistent with evidence showing conversion results after 4 months to be a more useful indicator [18]. While both sputum smear and culture results were acceptable predictors of treatment success, we found culture results to be a more suitable option when adjusted for all variables included in the multivariable model.
The reduced odds of treatment success for males, compared to females, was consistent with studies showing poorer treatment outcomes amongst male patients treated for MDR-TB [19, 20]. This may be a reflection of the higher risk of loss to follow-up among male patients, which in turn may be related to the financial burden associated with MDR-TB treatment. Catastrophic treatment-related costs borne by the household have been shown to be a significant barrier to treatment success [5, 21, 22]. In cases where male patients are the primary breadwinner, loss of employment or time away from work during treatment can result in considerable income reduction, placing financial strain on a patient’s household. This in turn may prompt voluntary withdrawal from treatment in order to return to work, resulting in poorer treatment adherence amongst male patients. As such, financial support through the social health insurance (SHI) program may be an important protective measure against poor treatment outcomes. Although not significantly associated with treatment success, our study showed that patients receiving subsidies through the public social health insurance scheme experienced lower rates of loss to follow-up (see Additional file 1: Table S3), which is consistent with research in other settings [5, 6, 23]. This highlights the importance of financial support for patients during treatment, especially if the patient is the primary breadwinner for their household. As such, this support should include not only direct costs (e.g., medication and transportation), but also indirect costs, such as loss of wages, to compensate for the reduction of household income. This could have an effect on the overall treatment success rate by offering an incentive with which to complete treatment, thus improving patient retention.
This study has a number of limitations. As we relied upon routinely collected programmatic data, a proportion of cases lacked complete data, particularly for comorbidities and treatment toxicity results. Furthermore, screening for treatment toxicity was not standardised. This may have resulted in ascertainment bias, and an underestimation of the frequency of adverse events and their effect upon treatment outcomes. In addition, missing outcome data may have resulted in either an underestimation or overestimation of the overall treatment success rate. Although the characteristics of patients for whom a treatment outcome was unavailable were otherwise similar to that of patients with a reported treatment outcome (see Additional file 1: Tables S6 and S7), it is unclear as to how many of these patients may have achieved treatment success. A lack of complete case data also presented challenges in performing the multivariable analysis. As multiple imputation was used to complete the dataset used in the multivariable analysis, a level of uncertainty with the parameter estimates was unavoidable. However, while 20 imputations are considered sufficient to produce accurate estimates [24], 50 imputations were used in this study to ensure accuracy and preserve statistical testing power. Finally, the findings of this study are applicable to patients treated with regimens that accorded with WHO guidelines at the time. These results are not generalisable to patients treated with newer all-oral regimens.
This study has important policy implications for the treatment of MDR-TB patients in Vietnam. We found that a high proportion (34.5%) of patients did not achieve a successful treatment outcome. This indicates a significant gap between treatment policy and implementation. Unfortunately, the proportion of patients with successful treatment was lower than for the first cohort of patients with MDR-TB treated in Vietnam a decade ago. This may reflect the challenges in scaling-up care for MDR-TB, as well as regional differences in care. Additional interventions are required to retain patients in care, improve reporting of treatment toxicity, and optimize management of co-morbidities. A comprehensive standardized evaluation of co-morbidities at the time of enrolment in treatment may enable clinicians to provide holistic medical care and improve treatment outcomes. In addition, this study provides evidence to expand access to subsidised treatment for all patients, suggesting that further research is required to assess the effects of social health insurance coverage upon loss to follow-up during treatment. Financial support provided through insurance may have an important role in minimizing loss to follow-up, and including as many facets of the treatment process as possible in this scheme may have a beneficial impact on overall treatment adherence.
As advanced drug resistance significantly reduces the odd of success treatment outcome, pre-XDR-/XDR-TB patients should be carefully monitored to ensure treatment adherence, particularly during outpatient care. Drug susceptibility testing for second-line antibiotics should be used to individualise treatment in order to ensure optimal treatment outcomes and avoid acquired antibiotic resistance.