MDR-TB treatment: Six drugs better than five

A regimen containing six drugs was more likely to cure multi-drug resistant tuberculosis (MDR-TB) than a regimen containing five drugs, a nine-country observational study has shown. The study also found that each active drug in the regimen increased the likelihood of cure by 65%. The inclusion of pyrazinamide doubled the chance of curing MDR-TB. The findings were published in PLoS Medicine.

The findings suggest that physicians may need to consider using more drugs than current World Health Organization (WHO) guidelines recommend to cure TB in people with multi-drug resistant infections. Current WHO guidelines, issued in 2011, recommend the use of at least four drugs that are likely to be effective, plus pyrazinamide, for the treatment of MDR-TB.

The current guidelines recommend that in the absence of drug susceptibility testing, physicians should make a judgement about which drugs are likely to prove to be active in a treatment regimen for MDR-TB by taking into account known local patterns of drug resistance, the treatment history of the patient and their known contacts with other people diagnosed with MDR-TB. Based on the evidence available at the time, the WHO’s guidelines panel concluded that selection of drugs on the basis of the results of drug susceptibility testing resulted in a marginally greater benefit. Subsequent studies have shown that regimens chosen on the basis of drug susceptibility testing have improved outcomes, but have not quantified how many active drugs are needed to overcome MDR-TB.

Yet, the results of the nine-country study show, including drugs in the regimen on the basis of guesswork was only effective if at least three of those drugs were active against the patient’s specific strain of MDR-TB.

The prospective observational study, the Preserving Effective Tuberculosis Treatment Study (PETTS) was conducted between 2005 and 2010. The study recruited 1659 adults with culture receiving MDR-TB treatment in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand and Taiwan.

The analysis of drug response excluded patients with extensively drug-resistant TB (XDR-TB), those lacking drug sensitivity test results and those with sensitivity to either isoniazid or rifampicin. The analysis comprised 1137 eligible patients, followed for a median of 20 months after beginning MDR-TB treatment.

Participants had baseline resistance to a median of four drugs, with 13% having resistance to a second-line injectable and 6% having resistance to a fluoroquinolone. Thirteen per cent had already received one second-line regimen, 72% had received first-line treatment only and 14% had received no previous treatment.

Just over half of participants received four or fewer potentially effective drugs in their second-line regimen (55%). Thirty per cent received five. Only 15% received six or more potentially active drugs. Overall, participants received a median of three active drugs throughout their period of treatment (drugs could be substituted during treatment).

Eighty per cent of patients achieved sputum culture conversion (disappearance of TB mycobacteria from sputum) after a median of two months of treatment. After adjusting for drug exposure, in multivariable analysis the likelihood of sputum conversion was associated with:

• Receiving six or more potentially effective drugs, compared to five drugs (adjusted hazard ratio (aHR): 1.36 (95% confidence interval 1.09-1.69)
• Receiving pyrazinamide (aHR 2.00, 95% CI 1.65-2.41).

A previous course of second-line treatment reduced the likelihood of culture conversion by 28-38% in two multivariable analyses, while receiving four or three effective drugs reduced the likelihood of culture conversion by 44% and 64% respectively, when compared to treatment with five effective drugs.

A multivariable analysis controlling for the presence of pyrazinamide in the regimen found that where pyrazinamide was present, five or six effective drugs in the regimen increased the likelihood of sputum culture conversion. The authors urge caution in interpreting their finding on pyrazinamide due to the lack of baseline resistance testing, and say that assuming pyrazinamide to be an active drug when designing a regimen may “put patients at risk for poorer outcomes.”

The benefit of using untested drugs – the so-called Group 5 drugs in WHO guidelines – cycloserine, terizidone, amoxicillin/clavulanate, clarithromycin, thioacetazone, clofazimine, imipenem and linezolid – was dependent on the number of other effective drugs in the regimen, the analysis found. Where pyrazinamide was not present in the regimen, the presence of untested drugs – those newer or less frequently used drugs for which routine susceptibility testing was not carried out – increased the likelihood of culture conversion when at least three or four effective agents were included in the regimen. Each effective drug in the regimen increased the likelihood of culture conversion by 65% (aHr 1.65, 95% CI 1.48 – 1.84).

But, “without a minimum number of effective drugs present, the inclusion of an additional untested drug was not associated with any significant increase in the likelihood of sputum culture conversion,” the authors concluded. “Our results suggest that it would be preferential to use the new drugs bedaquiline and delaminid […] in place of Group 5 drugs in treatment regimens.”

More severe clinical disease, as shown by evidence of tuberculosis in both lungs by X-ray, was associated with an approximate 30% reduction in the likelihood of culture conversion when compared to TB in one lung only.

The researchers emphasise that as well as indicating that improved responses to MDR-TB may be achieved by using more than five effective drugs in the regimen, their findings also indicate the importance of having rapid access to the high-quality drug susceptibility testing results. This would allow more doctors to put together regimens composed of a larger number of effective drugs – although they acknowledge that randomised studies of individualised MDR-TB treatment informed by drug susceptibility testing are needed to determine whether regimens of more than five effective drugs result in higher cure rates than current WHO-recommended regimens.