The study aimed at ascertaining the clinical characteristics and outcomes of MDR-TB in HIV co-infected patients based on timing of ART initiation, as well as determining the predictors of mortality, and treatment failure. This study revealed a higher proportion of new MDR-TB cases and the presence of other non-TB opportunistic infections among patients who initiated ART after commencing MDR-TB. These findings point to the importance of early initiation of ARVs and its protective benefits for HIV positive patients. On the whole, outcomes of MDR-TB did not differ significantly between patients who started ART before or after initiation of MDR-TB except for mortality which was higher among patients who commenced ART before initiating MDR-TB treatment. Risk factors for mortality were the use of ART before the commencement of MDR-TB, being severely underweight and underweight, cavitary lesions on baseline chest x-ray, the presence of other opportunistic infections and other co-morbidities. Severe anaemia at baseline, and the presence of other co-morbidities were associated with higher rates of treatment failure.
Predictors of mortality
Antiretroviral therapy use prior to MDR-TB treatment initiation was significantly associated with higher odds of mortality compared with ART initiation after commencement of MDR-TB treatment. This finding is surprising and has not been reported before by other studies. It should be assumed that patients should have benefited from being on ARVs before MDR-TB treatment. Based on this data, a greater percentage of patients who commenced ART before MDR-TB treatment initiation were severely underweight. They also had more extra-pulmonary TB, adverse events, and modified regimen based on patients’ history at baseline compared with patients who started ART after initiation of MDR-TB treatment at baseline. A lack of effect of ART from poor adherence, and treatment failure may have been responsible for this trend. The availability of viral load data at baseline would have further buttressed this fact, but this was not done routinely during the study period.
Prior to 2010, MDR-TB patients were initiated on ARTs if their CD4 cell count was <350 cell/mm3 based on the WHO guidelines [13]. Thereafter, ART was encouraged to be initiated within 6–8 weeks of starting MDR-TB treatment irrespective of CD4 count [15]; hence prior to 2010, patients with higher CD4 cell count were monitored until their CD4 counts dropped to <350 cells/mm3. This trend also explains the presence of more EPTB and the slightly lower baseline weight and the mortality seen in this group. Following prior initiation of ART, their CD4 cell counts may have improved such that they appeared similar CD4 cell count as with patients who started on ART after initiating MDR-TB treatment at baseline, as noted in our study.
This result poses questions on the issue of adherence to ART for patients who were already on ART prior to MDR-TB treatment in a country like South Africa with majority of HIV positive patients on ARVs. Additionally, drug-drug interactions between the MDR-TB and ARVs pills may have resulted in the high mortality in this study. IRIS was considered as the most potential explanation for this finding simply due to the fact that when analysis was restricted to patients who were on ART within six months as opposed to 3 months prior to commencement of MDR-TB treatment compared with those who started on ART after initiating MDR-TB treatment, no statistically significant relationship was observed with prior ART initiation and mortality. This further affirms the rigorous monitoring and management of IRIS by attending clinicians. Clinicians should not undervalue the role of adherence to ART treatment in patients who are already on ART before starting MDR-TB treatment. Appropriate management of already existing adverse events, opportunistic infections and co-morbidities in these patients are important to maximise the protective benefits of being on ART before initiating MDR-TB treatment, and on the whole achieve better treatment outcomes.
This study found that being severely underweight and underweight were risk factors of mortality. These findings are similar to previous studies [9, 12, 17–19]. HIV and TB are linked to malnutrition [18]; and wasting syndrome is a hallmark of severity of TB and HIV infection, therefore its strong association as a predictor of mortality irrespective of patients’ ART status is not surprising. A Cavitary lesion seen on chest x-ray at baseline was a risk factor of mortality. There have been conflicting studies on the role of cavitation on chest x-ray as a risk factor of poor outcomes. Some studies have linked the presence of cavitation on chest x-rays with longer culture conversion time; a surrogate marker for poor outcomes [20–22]. Others have found no statistically significant relationship between cavitation and poor outcomes [17, 23]. In a recent study done by Brust JC et al. in South Africa, its failure of finding a significant relationship between cavitation and longer time to sputum conversion may have been due to the limited sample size of 56 patients [23].
The presence of other non-TB opportunistic infections was a significant predictor of mortality. This finding has not been reported before by other studies beyond the descriptive level [9]. There is a higher risk of mortality and development of other opportunistic infections in HIV-TB co-infected patients [24, 25]. The role of other non-TB opportunistic infections is important in the clinical and prognostic staging of HIV positive patients. Serious opportunistic infections like Kaposi sarcoma, cervical cancer, Cytomegalovirus (CMV) infections, HIV-associated nephropathy (HIVAN), etc. are already indicators of the depressed immunity with an increase likelihood of mortality masking the importance of timing of ART initiation in these patients.
In this study the presence of co-morbidities was a significant risk factor of mortality. This result was reported in a recent study in the United Kingdom and Peru [26, 27]. However, the proportion of co-morbidities like diabetes, chronic kidney disease, and chronic liver disease was higher than that reported in the United Kingdom. There is an established “bidirectional synergistic” relationship between TB-HIV co-infection and the development of co-morbidities like DM [28–30]. Treatment of HIV with ART especially with the protease inhibitors is associated with hyperglycaemia, insulin resistance, dyslipidaemia [31]; not only leading to the development and complication of DM, but cardio-vascular, cerebro-vascular, hepatic and renal problems. Most studies done on the role of certain co-morbidities on TB mortality focus on single disease entity like DM; with positive [32], and negative [17] results. This study is the first in South Africa to incorporate the presence of other non-communicable co-morbidities apart from DM to assess its impact on mortality in MDR-TB HIV co-infected patients, especially with the emerging link of infectious and non-communicable diseases.
Predictors of treatment failure
Severe anaemia (haemoglobin <7.0 mg/dl) at baseline predicted treatment failure. The causes of anaemia in MDR-TB HIV co-infected patients are multi-factorial; resulting from the HIV/mycobacterial infection and treatment with both anti-TB and ARV medications. This finding is consistent with that of Mitnick C, et al. where low haematocrit was associated with about 4 times increase in the hazard of failure or death compared with normal haematocrit [18].
This study found that the presence of other co-morbidities was associated with a higher rate of treatment failure. The co-existence of other communicable and chronic non-communicable medical conditions such as DM, heart failure, cerebrovascular diseases, renal diseases, etc. increases the pill burden, adverse events and drug-drug interactions for HIV co-infected MDR-TB treatment. These patients require regimen modifications based on their clinical state, and hence may affect adherence to both ART and MDR-TB treatment, and lead to treatment failure. DM has been associated with MDR-TB [33] and PTB [34] treatment failure; however these studies did not consider the effect of other co-morbidities.
Modified individualised regimen at baseline for patients based on co-morbidities and adverse-events was significantly associated with treatment failure. The treatment of MDR-TB utilizes at least five medications at baseline and the WHO advocates the use of DST results to guide treatment regimen. In the practical clinical setting the presence of severe adverse-events, co-morbidities, and pre-XDR strains guide the clinicians on what regimen to use in initiating MDR-TB treatment regimen not just the DST result. Therefore for some of these patients certain drugs were delayed or added (in cases of pre-XDR strains) at baseline pending improvement in clinical condition. For example, Kanamycin/Amikacin were omitted and substituted with other drugs when there was renal toxicity. Terizidone was substituted if there was a serious psychiatric side effect. In cases of pre-XDR TB, the deviation was solely based on available antibiogram showing resistance to the injectable or Fluroquinolone. These patients termed as those on “modified individualized regimen” in this study to reflect the challenges clinicians face when initiating MDR-TB treatment using DST results bearing in mind patient centred care. This finding supports the result by Leimane V et al. which noticed that patients on ≤ 5 drugs for 3 months or more were more likely to fail or die [19].
Limitations and strengths
This study depended on already collected data from medical records, hence may not have measured all the possible confounders. Viral load for patients would have been a true test of adherence especially for patients on ART prior to initiating MDR-TB treatment, thereby helping in the explanation of the relevant findings. However, viral load could not be used as the definition of virological suppression varied over the years according to the NHLS definitions. Additionally only few data were collected for this variable because during this period viral load was expensive and could not be afforded for all patients at baseline except where patients were suspected to have had immunological or clinical failure.
In this study, timing of ART was stratified as before or after commencement of MDR-TB treatment and this may not have allowed proper assessment of the true effect of duration of ART on the outcomes. Information on baseline ART regimen were not collected, which would have been a pointer to drug resistance and virological failure and may have possibly helped in explaining the role of timing of ART on mortality in terms of adverse-events and toxicity of individual drugs. Coding co-morbidities as a yes or no variable instead of looking at individual diseases may have overestimated the effect of such variable on the outcomes in patients who had one or two co-morbidities compared to those who had a combination of highly fatal co-morbidities. Findings of this study may not be generalizable to regions with low ART coverage.
This is one of the largest cohorts of MDR-TB HIV co-infected patients, allowing reasonable power to detect a difference between the two exposure groups in relation to the major outcomes and other risk factors for mortality, and failure. The objective measurements of the outcomes minimised misclassification bias as majority of patients were confirmed as cured or failed treatment based on TB culture results from NHLS and extensive follow-up. Mortality was also confirmed in the hospital and for patients who died at home, regular tracing and reminders for visits helped in ascertaining home-related mortality. Certain variables like weight, height, CD4 count, haemoglobin, and chest x-rays were collected within specified periods to prevent disparate exposure duration hence, preventing over or under-estimation of the effect size. Information on certain exposures like other opportunistic infections, co-morbidity and adverse events were collected and this may have helped explain the predictors of mortality, and failure. The standard practice of ascertaining patients’ ART status at baseline and documentation of definite start dates by physicians at Sizwe Hospital reduced the likelihood of misclassification bias based on ART status.