March 24, 2003
The project's DOTS-Plus project -- which entailed the addition of second-line drugs, monitoring by sputum culture, drug-susceptibility testing, and directly observed individualized therapy to the well-established Peruvian DOTS program -- treated a cohort of 75 outpatients with chronic MDR-TB. Researchers retrospectively reviewed the charts of all patients enrolled in the program between August 1, 1996 and February 1, 1999, and identified predictors of poor outcomes.
While susceptibility tests were pending, most patients were treated empirically under direct observation with regimens containing at least five drugs their strains were deemed as likely to be sensitive on the basis of previous regimens used. Definitive regimens, containing a minimum of five drugs and lasting at least 18 months, were determined by susceptibility tests, available a mean (+SD) of 62.6+32.9 days after sputum collection. First-line drugs were used preferentially even when repeated tests were inconsistent, provided susceptibility was documented at least once. A parenteral agent was administered for at least six months after culture conversion. Treatment terminated after 12 or more consecutive negative cultures.
A single intervening positive culture with fewer than 10 colonies was allowed. Treatment failure was defined by the presence of a positive culture after six months of treatment. Withdrawal from therapy was defined by one or more months of missed therapy during the first year, and two or more months of missed therapy during the second year.
Patients were young; most were single; with nearly equal numbers of men and women. Four had concurrent extrapulmonary TB. One of 65 patients tested had HIV. A low hematocrit was recorded in 12 patients (18 percent). Nearly half the patients had an elevated resting respiratory rate, a low body-mass index, or both. Bilateral cavitary parenchymal disease was evident in 47 baseline chest radiographs (63 percent). Patients previously received a median of three prior TB regimens (range, 0-10) during the nearly four years between diagnosis and DOTS-plus, and a median of seven TB drugs (range, 0-10) for at least one month each. The TB strains were resistant to a median of six drugs.
The 75 patients received treatment with 58 different regimens, containing a median of six drugs (range, 5-9), lasting a median of 23 months (range, .4-35.9). The records of 60 patients were reviewed for adverse events; 44 patients (73 percent) had such events, all managed without physician-directed discontinuation of therapy. Among the 66 patients who completed four or more months of therapy, 55 (83 percent) were probably cured at the completion of treatment. Five of these 66 patients (8 percent) withdrew from therapy, therapy failed in one patient, and five (8 percent) died while receiving therapy.
Patients were followed for a median of 40 months (range, 7-66) after therapy. During therapy and follow-up, 18 poor clinical outcomes occurred: 17 deaths and one failure of therapy.
All patients in whom treatment failed or who died had extensive bilateral pulmonary disease. In a multiple Cox proportional-hazards regression model, the predictors of the time to treatment failure or death were a low hematocrit, resistance to pyrazinamide or ethambutol, and a low body-mass index. Inclusion of pyrazinamide and ethambutol in the regimen (when susceptibility was confirmed) was associated with a favorable outcome. Study authors concluded that community-based outpatient treatment of MDR-TB can yield high cure rates outside referral centers in a resource-poor country. In settings with high cure rates with first-line treatment, however, patients in whom DOTS regimens have failed and patients thought to have primary MRTB are unlikely to benefit from standardized treatment regimens recommended for resource-poor settings. Early initiation of appropriate therapy can preserve susceptibility to first-line drugs and improve treatment outcomes.
New England Journal of Medicine
01.09.03; Vol. 348, No. 2, P. 119-128; Carole Mitnick, Sc.D.; Jaime Bayona, M.D., M.P.H.; Eda Palacios, R.N.; Sonya Shin, M.D.; Jennifer Furin, M.D., Ph.D.; Felix Alcántara, M.D.; Epifanio Sánchez, M.D.; Madeleny Sarria, R.N.; Mercedes Becerra, Sc.D.; Mary C. Smith Fawzi, Sc.D.; Saidi Kapiga, M.D., Sc.D.; Donna Neuberg, Sc.D.; James H. Maguire, M.D.; Jim Yong Kim, M.D., Ph.D.; and Paul Farmer, M.D., Ph.D.