Extensively drug-resistant tuberculosis (XDR-TB) is curable with intensive and specialized care conclude two recent studies published in the New England Journal of Medicine (NEJM) and The Lancet. Both studies were conducted by researchers from the Department of Global Health and Social Medicine at Harvard Medical School, the Division of Global Health Equity at Brigham and Women's Hospital, Socios En Salud (PIH’s partner organization in Peru) and PIH, in cooperation with other organizations.

When XDR-TB burst into the headlines in 2006, it was widely portrayed as a new and virtually incurable disease. An outbreak of XDR-TB in South Africa in 2006, in which 52 out of the 53 patients infected died, lent credence to fears that being diagnosed with XDR-TB was an effective death sentence. 

Multidrug-resistant or MDR-TB strains are those with resistance to at least the two main first-line drugs, isoniazid and rifampin. XDR-TB strains are resistant not only to isoniazid and rifampin but also to at least three of the six classes of second-line drugs. 

 Directly Observed Therapy in Tomsk
 
MDR-TB patient in Peru

In Peru, between 1999 and 2002, patients with MDR-TB (some of whom also met the definition of XDR-TB) were treated with an aggressive treatment protocol.  The authors of the NEJM study demonstrated that XDR-TB had appeared well before 2006 and that it can be treated using this protocol. Of 651 patients entering the treatment program, 48 already suffered from what would now be classified as XDR-TB. The other 603 patients had MDR-TB that was not also XDR-TB. Fully 60 percent of the patients with XDR-TB were successfully treated and cured, a cure rate only slightly lower than the 66 percent achieved with the other MDR-TB patients.

The study adds urgency and hope to the debate about drug-resistant strains of tuberculosis, said Carole Mitnick, the study’s lead author and a PIH research associate. She added that she hoped this report would help doctors move away from using the treatment protocol that has been used for 15 years to treat MDR-TB unsuccessfully.

That protocol calls for a standard six-month regimen, known as DOTS (Directly Observed Treatment, Short Course), of first-line TB drugs. If this regimen is unsuccessful the first time, then it is repeated. The regimen is highly effective when used on TB strains that are susceptible to the drugs included. But in those patients who already have drug-resistant TB, the first-line drugs are ineffective from the start, and can only make the problem worse.

When asked what needed to change in order to see more widespread success in treating drug-resistant TB globally, Mitnick said, “The mentality needs to change. A one-size-fits-all method doesn’t work for some groups of TB patients. Specialized interventions need to be adopted.”

Mitnick suggests that in places where drug-resistant strains of TB are widespread, at the first diagnosis of TB, patient strains should be tested to determine whether they are susceptible or resistant to the most important drugs. Policies mandating such an approach could make it possible to start effective treatment with second-line drugs immediately.  This would increase the chance of curing patients and reduce both fatalities and transmission of resistant strains, including XDR-TB.

Mitnick also pointed out that, when necessary, patients in the study received nutritional and financial support, psychosocial counseling and surgery. Community health workers were instrumental in providing daily supervision of patients’ doses. She said that the study indicated that comprehensive, community-based treatment of this sort may amplify the benefits of the drug regimens.

Same treatment, similar results in Russia

 Directly Observed Therapy in Tomsk
 
Doctor and MDR-TB patient
in a Russian prison

The same treatment protocol was applied by PIH and collaborators in a rather different setting, in the Siberian province of Tomsk in the Russian Federation. The study published in the Lancet looked at 608 patients with MDR-TB who received treatment in civilian or prison health services between 2000 and 2004. Of these patients,  29 had XDR-TB. Treatment programmes were designed for each patient based on the results of drug-sensitivity testing and previous treatments they had received, with the aim of providing at least five drugs to which that particular patient’s strain of TB was susceptible. If five effective drugs were not available, doctors considered using drugs to which resistance was known, especially if patients had no previous exposure to them.

The researchers found that using this aggressive regimen, 48% of the patients diagnosed with XDR-TB were cured (compared to 67% of non-XDR TB patients).  Interestingly, adverse events due to medications were similar in both sets of patients.
Although this program was implemented in a setting with a high level of alcoholism, the study reported outcomes similar to those achieved in Peru. 

"Our study is novel because it shows that XDRTB can be treated under regular
program conditions as part of an integrated TB program,"  said Salmaan Keshavjee, the report’s lead author. "Although the Russian system has a hospital-based component during the intensive phase of treatment (generally the first 6 months), the remainder of the treatment occurred on an ambulatory basis.  This is very important, in the setting of some countries wanting to keep patients with MDR-TB and XDR-TB under quarantine….

"The fact that our findings are similar to Mitnick and colleagues’ contribution in the NEJM supports the fact that aggressive treatment regimens, aggressive adverse-events management, and community-based delivery of care are part of a package that works for MDR-TB and XDR-TB.  This doesn't mean that we don't need new drugs as soon as possible -- instead it means that with the existing drug regimens, delivered appropriately, we can save many more lives now."

From Peru and Russia to Lesotho, raising the bar

Although the Peru and Russia reports showed that XDR-TB can be treated, they also highlighted one additional factor that contributed to the lethal outbreak in Kwazulu-Natal – co-infection with HIV. None of the XDR-TB patients treated in Peru or Russia tested positive for HIV. All of the South African victims of XDR-TB were also infected with HIV.

"The new twist is one that we predicted, and many others did as well," PIH co-founder Paul Farmer said last year at the launch of a PIH program to tackle the epidemic of drug-resistant TB in Lesotho, just across the border from Kwazulu-Natal. "When HIV and drug-resistant tuberculosis collide, there is going to be an even more urgent need to intervene effectively because HIV really speeds up the process and makes these epidemics faster and more lethal."

In Lesotho, where as many as three quarters of XDR-TB patients are co-infected with HIV, PIH has taken a groundbreaking treatment approach modeled on what proved so successful in Peru. Patients are not quarantined, as they have been in other countries like South Africa, but are visited twice a day by community health workers at their homes or at rented houses near the hospital, allowing them to remain with their families during treatment. Up to 300 patients are expected to be enrolled in PIH’s XDR-TB program in Lesotho by the end of this year.

As in Peru and Russia, the Lesotho program follows the same treatment protocol proposed by PIH in a 2004 Lancet report led by Joia Mukherjee, PIH’s Medical Director.  XDR-TB patients in Lesotho are enrolled in a two-year treatment program using drugs selected after sensitivity testing to determine resistance for their particular strain of TB. Although none of the patients have yet completed the course of treatment, indications suggest that unlike in Kwazulu-Natal, a significant proportion of these patients can be treated successfully. 

Keshavjee, who has worked with both the Russia and Lesotho programs and is the chair of the WHO’s Green Light Committee on MDR-TB treatment, notes that “part of the challenge is to diagnose patients early, get them on appropriate MDR-TB and HIV treatment, address their often profound malnutrition, and deliver care to them for the two years that it will take for them to be cured. It isn’t an easy task, but it’s something that, given appropriate human and financial resources, we know we are able to do.”

Unfortunately, many XDR-TB cases are discovered and treated too late, especially for those with HIV. To see better outcomes in the treatment of XDR-TB, Paul Farmer, Carole Mitnick, Salmaan Keshavjee, and Hind Satti (PIH Lesotho’s MDR-TB program director), all agree on the need to expand resources for both research and treatment, as called for at a recent Workshop on Clinical Trials for DR-TB of which Mitnick and Keshavjee were principal organizers. In Satti’s words, “increased investment in research that will give rise to evidence-based policies and procedures is key to fighting the epidemic.”

[published August 2008]

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