We estimated the proportion of household contacts whose drug-susceptibility test results matched those of the purported source patient with multidrug-resistant tuberculosis. Ninety-nine (88.4%) contacts had isolates resistant to isoniazid and rifampin, and 41 (36.6%) contacts had isolates with results that also matched the purported source for ethambutol, streptomycin, and pyrazinamide.

Rationale A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.

BACKGROUND:Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy.METHODS:We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis.RESULTS:Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2-53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17-0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17-50.60]; P = .004).CONCLUSIONS:Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease.

Two cases of multidrug-resistant tuberculosis (MDR TB) in a household are assumed to reflect within-household transmission. However, in high-incidence areas of MDR TB, secondary cases may arise through exposure to MDR TB in the community. To estimate the frequency of multiple introductions of MDR TB into households, we used spoligotyping and 24-loci mycobacterial interspersed repetitive unit- variable number tandem repeats to classify isolates from 101 households in Lima, Peru, in which >1 MDR TB patient received treatment during 1996-2004. We found different MDR TB strains in >10% of households. Alternate approaches for classifying matching strains produced estimates of multiple introductions in <38% of households. At least 4% of MDR TB patients were reinfected by a second strain of MDR Mycobacterium tuberculosis. These findings suggest that community exposure to MDR TB in Lima occurs frequently. Rapid drug sensitivity testing of strains from household contacts of known MDR TB patients is needed to identify optimal treatment regimens.

BACKGROUND:Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have emerged as major global health threats. WHO recommends contact investigation in close contacts of patients with MDR and XDR tuberculosis. We aimed to assess the burden of tuberculosis disease in household contacts of such patients. METHODS:We undertook a retrospective cohort study of household contacts of patients treated for MDR or XDR tuberculosis in Lima, Peru, in 1996-2003. The primary outcome was active tuberculosis in household contacts at the time the index patient began MDR tuberculosis treatment and during the 4-year follow-up. We examined whether the occurrence of active tuberculosis in the household contacts differed by resistance pattern of the index patient: either MDR or XDR tuberculosis. FINDINGS:693 households of index patients with MDR tuberculosis were enrolled in the study. In 48 households, the Mycobacterium tuberculosis isolate from the index patient was XDR. Of the 4503 household contacts, 117 (2·60%) had active tuberculosis at the time the index patient began MDR tuberculosis treatment-there was no difference in prevalence between XDR and MDR tuberculosis households. During the 4-year follow-up, 242 contacts developed active tuberculosis-the frequency of active tuberculosis was nearly two times higher in contacts of patients with XDR tuberculosis than it was in contacts of patients with MDR tuberculosis (hazard ratio 1·88, 95% CI 1·10-3·21). In the 359 contacts with active tuberculosis, 142 (40%) had had isolates tested for resistance against first-line drugs, of whom 129 (90·9%, 95% CI 85·0-94·6) had MDR tuberculosis. INTERPRETATION:In view of the high risk of disease recorded in household contacts of patients with MDR or XDR tuberculosis, tuberculosis programmes should implement systematic household contact investigations for all patients identified as having MDR or XDR tuberculosis. If shown to have active tuberculosis, these household contacts should be suspected as having MDR tuberculosis until proven otherwise. FUNDING:The Charles H Hood Foundation, the David Rockefeller Center for Latin American Studies at Harvard University, and the Bill & Melinda Gates Foundation.

We estimated the proportion of recurrence within 2 years among adults cured by individualized multidrug-resistant tuberculosis regimens in Peru. Among 310 individuals with at least 24 months of follow-up, 16 experienced an episode of recurrent tuberculosis. If we assume the worst for treatment effectiveness-that all 16 episodes were caused by the original tuberculosis strain-then 5.2% (95% confidence interval, 3.0%-8.2%) experienced true relapse. This is an upper-bound estimate of relapse on which new regimens must improve.

BACKGROUND:Multidrug-resistant tuberculosis (MDR-TB) disproportionately affects young adults, including women of childbearing age; however, treatment of MDR-TB during pregnancy is still controversial. This study looks at the treatment and pregnancy outcomes in a cohort of women who were treated for MDR-TB during pregnancy during a period of 10 years.METHODS:A retrospective case study was performed using a standardized data collection form and data from 3 ranked sources of patient records. All 38 participants were treated during pregnancy with individualized regimens that included second-line TB medications. We examined the frequency of favorable and adverse outcomes with regard to disease and pregnancy.RESULTS:After completion of MDR-TB treatment, 61% of the women were cured, 13% had died, 13% had defaulted, 5% remained in treatment, and 5% had experienced treatment failure. Four of the women experienced clinical deterioration of TB during pregnancy. Five of the pregnancies terminated in spontaneous abortions, and 1 child was stillborn. Among the living newborns, 3 were born with low birth weight, 1 was born prematurely, and 1 had fetal distress.CONCLUSIONS:The rates of success in treating MDR-TB in our cohort are comparable to those of other MDR-TB treatment programs in Peru. The birth outcomes of our cohort are similar to those among the general Peru population. Therefore, we advocate that a woman should be given the option to continue treatment of MDR-TB rather than terminating pregnancy or discontinuing MDR-TB treatment.

Background: Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru.Methods: A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant.Results: Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [+/-SD] number of regimens, 4.2+/-1.9 vs. 3.2+/-1.6; P<0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4+/-1.1 vs. 5.3+/-1.5; P<0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3+/-1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36).Conclusions: Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis.

Many countries with financial support for HIV treatment experience delays in scale-up because of bureaucratic, operational, and technical obstacles. The authors describe the Peruvian National HIV Program's response to such challenges. A team of consultants experienced in the scale-up of the Peruvian national program to treat multidrug-resistant tuberculosis worked with the national HIV program to identify and address key factors contributing to slow enrollment of HIV patients into the antiretroviral treatment program. The rate of enrollment into the antiretroviral treatment program increased from 124 patients/month in the first 9 months of the program to 226 patients/month in the last 7 months, an increase of 83%. This strategy achieved 38.5% coverage of the population in need. Effective programmatic expansion of the Peruvian National HIV Program was facilitated by a multidisciplinary collaboration in a systematized effort to overcome barriers to scale-up.

Socios En Salud uses directly observed therapy to treat a majority of the multidrug-resistant tuberculosis in Peru. The nurses play an important role in this community-based model as the patients' primary care givers. Since nurses, rather than physicians, are involved in patients' daily care, we developed a nurse-order entry system to test whether such a system would improve the accuracy and quality of medication data. We compared regimen information from patient electronic medical records, paper charts and pharmacy records. After a two-month training period on the new system, we conducted the trial for 52 days in two of Lima's six geographic treatment areas, and re-reviewed the three sources of medication data. We measured the error rates after the trial period and found there was no significant difference in the control group's (Lima Este), error rate (8.6% vs. 6.9%, P=0.66) after the trial. The intervention group (Lima Callao), however, showed a significant drop in the error rate (17.4% vs. 3.1%, P=0.0074) after the same time interval. Additionally, the nurse expressed satisfaction with the order entry system and its ease of use. The decrease in error rates and user satisfaction regarding the system are promising measures of our order entry system's success.