Infection with Human Immunodeficiency Virus (HIV) further complicates the management of MDR-TB. India has the third highest HIV burden in the world with an estimated 2.5 million people living with HIV/AIDS in 2006 [7]. Data from other settings suggest that mortality from MDR-TB in HIV-infected patients is extraordinarily high, particularly within the first 30 days after diagnosis [8].

Systematic reviews have shown that few studies describe MDR-TB treatment outcomes from high HIV prevalence settings and that HIV status is often inconsistently reported [9], [10]. Although the use of antiretroviral therapy (ART) with MDR-TB treatment has been shown to improve outcomes in co-infected patients [9], [10], [11], treatment of MDR-TB in HIV-infected patients remains a challenge. Patients are required to take large numbers of pills each day and there is the potential for additive side effects and drug interactions between antiretroviral agents and second-line anti-tuberculosis drugs [12].

Overall, there is a serious deficiency in reports describing treatment of MDR-TB in HIV-infected patients, especially in programmatic settings in resource-constrained countries. A recent study from Lesotho showed that starting early empirical treatment for suspected MDR-TB patients using a community-based treatment approach in mainly HIV-infected adults resulted in high culture conversion, although significant mortality remained [13].

While Mumbai has a widely accessible DOTS program in place under the Revised National Tuberculosis Control Program (RNTCP) for treatment of drug-susceptible tuberculosis, treatment for drug-resistant TB was, until recently, only available through the private sector. As a result, MDR-TB treatment has often been administered in a chaotic, unregulated manner using non-pre-qualified anti-TB drugs and at prohibitive prices for the large majority of patients. Given the large MDR-TB disease burden, there is an urgent need to scale up appropriate treatment for MDR-TB in India and in order to achieve this, a decentralized approach may be most appropriate. Special focus should be on early diagnosis and treatment initiation, particularly among HIV-infected populations.

In February 2006, Médecins Sans Frontières (MSF) started an HIV project in Mumbai, offering care and treatment to people living with HIV unable to access the public system or who could not obtain appropriate ART regimen, including second-line antiretroviral drugs. MSF has been treating MDR-TB among HIV-infected individuals in this project since May 2007. MDR-TB treatment subsequently became available in the public sector in Mumbai in late 2010.

In Mumbai, MDR-TB treatment was until recently (July 2010) only available through an unregulated, private health sector [16]. However, the private sector does not generally consider the risk of resistance amplification or the ongoing challenges of adherence to a very long and costly treatment regimen fraught with a high pill burden and significant adverse events. Private physicians rarely (if ever) use DOT as treatment strategy. The particular setting of Mumbai, a mega-metropolis where the marginalised may have inadequate nutrition, rudimentary sanitation and poor home-ventilation is particularly challenging. Difficult transportation and an extremely mobile population, further complicates the management and the follow-up of these patients. Thirty-seven percent of the patients in our cohort had already received second-line TB treatment before they were enrolled in the MSF clinic. According to their medical records and referral notes (when available), they were often on erratic regimes, under-dosed and had their treatment interrupted as they could not afford the high cost of second line anti-TB drugs for long periods of time [24], [25].

The Mumbai MSF clinic has been trying to address these MDR-TB challenges since the program started in 2007. The outcomes recorded so far in the program demonstrate the feasibility of treating HIV/MDR-TB co-infected patients in such a setting. Given the high rate of resistance to fluoroquinolones in India [4], [26] and erratic previous treatment for many of the patients the outcomes are reasonable. We suggest that the following factors contributed to these results: first, all patients received DOT thanks to a network of individual DOT providers, allowing each patient to easily access care within walking distance from his/her home. By moving treatment into the community, it was possible to overcome problems of patient access to clinics. Second, the monitoring plan for early identification of adverse events, that included systematic clinical and laboratory assessment, and the availability of ancillary drugs helped to promptly diagnose and appropriately manage adverse drug effects. Third, therapy followed internationally recommended guidelines with maximally effective drug combinations, based on DST, and at the highest recommended doses [12]; this likely reduced the risk of treatment failure and amplification of resistance. Fourth, psychosocial support was given to all patients with monthly home visits and specific support tools were developed. A multidisciplinary team (doctors, nurses, counsellors, psychologists) was essential to manage adherence challenges and psychological issues related to the disease and its treatment, stigma and isolation. Fifth, TB and HIV care were fully integrated: patients received treatment for both conditions in the same clinic as part of a “one-stop service”. This increased convenience for patients, saved time and travel expenses, and facilitated detection of drug interactions and adverse events. Moreover, the integrated approach has broadened expertise in the clinic team on the management of co-infected patients. Sixth, ambulatory treatment and follow-up may have reduced default and the risk of re-infection during hospitalization [27].

A large investment has been made in the clinic in TB infection control measures that prevent transmission of TB. A comprehensive infection control plan was designed and implemented, including environmental and administrative measures and personal protective equipment for the clinic staff. The clinic defined specific MDR-TB days, carefully organized the spacing between MDR-TB consultations, improved ventilation in consultations rooms, corridors and waiting areas and trained the staff in prevention of TB transmission. An infection control committee was established and it is now planned to expand infection control measures to the community and household level through innovative, small-scale interventions.

However, several challenges remain in this program. The high pre-treatment and early mortality rates highlight the need for intensive case finding strategies, rapid diagnosis and initiation of DR-TB treatment to reduce mortality and improve outcomes. Late referral to the clinic and advanced disease may partly explain these high rates. Studies from HIV programs have shown than even if excellent outcomes can be achieved and maintained among patients receiving antiretroviral therapy, program outcomes such as high pre-treatment mortality and pre-treatment loss-to-follow-up rates remain largely unreported [28], [29]. Similarly, failure to initiate therapy and default from treatment rates were high in this cohort, despite the provision of counselling and other psychosocial support. Our data suggests that default from treatment may be lower in more recent cohorts. While the MSF clinic reports very low loss-to-follow-up rates among non-MDR-TB patients on ART (<3%) it is disappointing that the overall rate was 26% for the co-infected patients on treatment. While there are known challenges related to the management of co-infection, several measures may have to be urgently taken to analyze and address this important issue. In our clinic, for example, we identified important gaps in patient support tools and interventions, including lack of adequate emotional and psychosocial support as well as limited access to mental health services. We have also noticed that patients referred to our clinic from the private sector have already been on various treatment regimens for long time periods and often experience treatment fatigue. Support from families is also reported to wane over time.

In this Mumbai cohort, several patients were started empirically on second-line drugs before DST results were available, based on WHO recommendations [30]. The RNTCP in India is particularly concerned with empirical treatment and strongly discourages clinicians to initiate treatment without laboratory confirmation. Considering the challenges with the unregulated private sector and the lack of trained and experienced clinicians in the management of MDR-TB in the Indian public sector, these concerns may be well justified. Ideally rather than relying on empiric treatment, efforts should be directed at introducing more rapid diagnosis that will offer both bacteriological confirmation and result in more rapid treatment initiation. The recently approved Xpert MTB/RIF (Xpert) test, has been demonstrated to be feasible in different high burden settings and has the potential to dramatically improve case detection for drug-resistant TB [31], [32]. Moreover, a recent study suggested that Xpert MTB/RIF shows good potential in the diagnosis of extrapulmonary TB and this is relevant for HIV-infected individuals [33].

In Mumbai, a community-based model of MDR-TB treatment was found to be feasible, as has been shown in other countries [13], [18], [27], [34]–[36]. DOT providers at the community level were trained to provide injections, observe pill-taking, monitor for adverse effects and support and refer patients. Adverse events occurred relatively often in this cohort, similar to a cohort from Lesotho [13]. We recorded relatively high rates of hypothyroidism and psychosis. However, with aggressive management of side effects, alterations to the TB regimen were rarely necessary.

There are some limitations to our analysis. Overall, the size of the cohort is relatively small and therefore does not allow definitive conclusions to be drawn regarding factors that may contribute to patient outcomes, particularly the high pre-treatment mortality and default from treatment. Further research aims to investigate these areas in more detail.

However, to date, there is a dearth of documented program experiences from resource-constrained settings treating co-infected patients; the global cohort of HIV/MDR-TB co-infected patients being treated is still discouragingly small.