Hind Satti

Early Outcomes of MDR-TB Treatment in a High HIV-Prevalence Setting in Southern Africa

Background Little is known about treatment of multidrug-resistant tuberculosis (MDR-TB) in high HIV-prevalence settings such as sub-Saharan Africa. Methodology/Principal Findings We did a retrospective analysis of early outcomes of the first cohort of patients registered in the Lesotho national MDR-TB program between July 21, 2007 and April 21, 2008. Seventy-six patients were included for analysis. Patient follow-up ended when an outcome was recorded, or on October 21, 2008 for those still on treatment. Fifty-six patients (74%) were infected with HIV; the median CD4 cell count was 184 cells/μl (range 5–824 cells/μl). By the end of the follow-up period, study patients had been followed for a median of 252 days (range 12–451 days). Twenty-two patients (29%) had died, and 52 patients (68%) were alive and in treatment. In patients who did not die, culture conversion was documented in 52/54 patients (96%). One patient had defaulted, and one patient had transferred out. Death occurred after a median of 66 days in treatment (range 12–374 days). Conclusions/Significance In a region where clinicians and program managers are increasingly confronted by drug-resistant tuberculosis, this report provides sobering evidence of the difficulty of MDR-TB treatment in high HIV-prevalence settings. In Lesotho, an innovative community-based treatment model that involved social and nutritional support, twice-daily directly observed treatment and early empiric use of second-line TB drugs was successful in reducing mortality of MDR-TB patients. Further research is urgently needed to improve MDR-TB treatment outcomes in high HIV-prevalence settings.

Outcomes of Multidrug-Resistant Tuberculosis Treatment with Early Initiation of Antiretroviral Therapy for HIV Co-Infected Patients in Lesotho

Background Although the importance of concurrent treatment for multidrug-resistant tuberculosis (MDR-TB) and HIV co-infection has been increasingly recognized, there have been few studies reporting outcomes of MDR-TB and HIV co-treatment. We report final outcomes of comprehensive, integrated MDR-TB and HIV treatment in Lesotho and examine factors associated with death or treatment failure. Methods We reviewed clinical charts of all adult patients who initiated MDR-TB treatment in Lesotho between January 2008 and September 2009. We calculated hazard ratios (HR) and used multivariable Cox proportional hazards regression to identify predictors of poor outcomes. Results Of 134 confirmed MDR-TB patients, 83 (62%) were cured or completed treatment, 46 (34%) died, 3 (2%) transferred, 1 (1%) defaulted, and 1 (1%) failed treatment. Treatment outcomes did not differ significantly by HIV status. Among the 94 (70%) patients with HIV co-infection, 53% were already on antiretroviral therapy (ART) before MDR-TB treatment initiation, and 43% started ART a median of 16 days after the start of the MDR-TB regimen. Among HIV co-infected patients who died, those who had not started ART before MDR-TB treatment had a shorter median time to death (80 days vs. 138 days, p = 0.065). In multivariable analysis, predictors of increased hazard of failure or death were low and severely low body mass index (HR 2.75, 95% confidence interval [CI] 1.27–5.93; HR 5.50, 95% CI 2.38–12.69), and a history of working in South Africa (HR 2.37, 95% CI 1.24–4.52). Conclusions Favorable outcomes can be achieved in co-infected patients using a community-based treatment model when both MDR-TB and HIV disease are treated concurrently and treatment is initiated promptly.

High rate of hypothyroidism among patients treated for multidrug-resistant tuberculosis in Lesotho.

BACKGROUND Hypothyroidism is a known side effect of treatment for multidrug-resistant tuberculosis (MDR-TB), but it is considered to be rare. Hypothyroidism has vague and non-specific symptoms, and can be easily missed by clinicians. OBJECTIVE To report the high rate of hypothyroidism in a cohort of MDR-TB patients in Lesotho and to describe our approach to diagnosis and management. DESIGN A retrospective study of 212 patients who initiated treatment for MDR-TB in Lesotho between 27 July 2007 and 24 March 2009 was performed. RESULTS Among 186 patients screened, 129 (69%) had hypothyroidism, defined as at least one documented thyroid-stimulating hormone (TSH) result > 10.0 mIU/l; 100 (54%) patients had a maximum TSH > 20.0 mIU/l. At 93 days after starting MDR-TB treatment, half of the patients had developed hypothyroidism. CONCLUSION Hypothyroidism may be more common during MDR-TB treatment than previously recognized. Screening all patients, even those without symptoms, for hypothyroidism within 2-3 months of starting MDR-TB treatment should be considered until prospective studies can inform screening guidelines.

Outcomes of comprehensive care for children empirically treated for multidrug-resistant tuberculosis in a setting of high HIV prevalence.

Background Few studies have examined outcomes for children treated for multidrug-resistant tuberculosis (MDR-TB), including those receiving concomitant treatment for MDR-TB and HIV co-infection. In Lesotho, where the adult HIV seroprevalence is estimated to be 24%, we sought to measure outcomes and adverse events in a cohort of children treated for MDR-TB using a community-based treatment delivery model. Methods We reviewed retrospectively the clinical charts of children ≤15 years of age treated for culture-confirmed or suspected MDR-TB between July 2007 and January 2011. Results Nineteen children, ages two to 15, received treatment. At baseline, 74% of patients were co-infected with HIV, 63% were malnourished, 84% had severe radiographic findings, and 21% had extrapulmonary disease. Five (26%) children had culture-confirmed MDR-TB, ten (53%) did not have culture results available, and four (21%) subsequently had results indicating drug-susceptible TB. All children with HIV co-infection who were not already on antiretroviral therapy (ART) were initiated on ART a median of two weeks after the start of the MDR-TB regimen. Among the 17 patients with final outcomes, 15 (88%) patients were cured or completed treatment, two (12%) patients died, and none defaulted or were lost to follow-up. The majority of patients (95%) experienced adverse events; only two required permanent discontinuation of the offending agent, and only one required suspension of MDR-TB treatment for more than one week. Conclusions Pediatric MDR-TB and MDR-TB/HIV co-infection can be successfully treated using a combination of social support, close monitoring by community health workers and clinicians, and inpatient care when needed. In this cohort, adverse events were well tolerated and treatment outcomes were comparable to those reported in children with drug-susceptible TB and no HIV infection.

Structural violence: a barrier to achieving the millennium development goals for women.

In 2000, all 191 United Nations member states agreed to work toward the achievement of a set of health and development goals by 2015. The achievement of these eight goals, the Millennium Development goals (MDGs) is highly dependent on improving the status of women, who play a key role in health and education in families and communities around the world. Yet structural violence, defined as the systematic exclusion of a group from the resources needed to develop their full human potential, remains a significant barrier against womens development and threatens the achievement of the MDGs. Although sound evidence has long existed for improving womens survival, the will to address womens health concretely and holistically is only recently gaining the advocacy needed to change policy. Concrete examples of the integration of approaches to mitigate structural violence within the delivery of health services do exist and should be incorporated into global advocacy for womens health.

Comprehensive approach to improving maternal health and achieving MDG 5: report from the mountains of Lesotho.

Background Although it is now widely recognized that reductions in maternal mortality and improvements in womens health cannot be achieved through simple, vertical strategies, few programs have provided successful models for how to integrate services into a comprehensive program for maternal health. We report our experience in rural Lesotho, where Partners In Health (PIH) in partnership with the Ministry of Health and Social Welfare implemented a program that provides comprehensive care of pregnant women from the community to the clinic level. Methods Between May and July 2009, PIH trained 100 women, many of whom were former traditional birth attendants, to serve as clinic-affiliated maternal health workers. They received performance-based incentives for accompanying pregnant women during antenatal care (ANC) visits and facility-based delivery. A nurse-midwife provided ANC and delivery care and supervised the maternal health workers. To overcome geographic barriers to delivering at the clinic, women who lived far from the clinic stayed at a maternal lying-in house prior to their expected delivery dates. We analyzed data routinely collected from delivery and ANC registers to compare service utilization before and after implementation of the program. Results After the establishment of the program, the average number first ANC visits increased from 20 to 31 per month. The clinic recorded 178 deliveries in the first year of the program and 216 in the second year, compared to 46 in the year preceding the program. During the first two years of the program, 49 women with complications were successfully transported to the district hospital, and no maternal deaths occurred among the women served by the program. Conclusions Our results demonstrate that it is possible to achieve dramatic improvements in the utilization of maternal health services and facility-based delivery by strengthening human resource capacity, implementing active follow-up in the community, and de-incentivizing home births.

Extensively Drug-Resistant Tuberculosis, Lesotho

To the Editor: Reports of extensively drug-resistant tuberculosis (XDR TB) in the Republic of South Africa have generated concern in the medical and public health literature (1,2). Given that XDR TB is spread through the air, it is not surprising that cases have been reported in multiple countries throughout the world (3). We report a documented case of XDR TB in Lesotho. This case is closely tied to transnational work in South Africa, thus raising concern about the spread of this disease across highly porous borders and the need for international attention to migrant worker health. Lesotho is a mountainous nation that is home to 2 million people and completely surrounded by South Africa. It has the third highest rate of HIV in the world; an estimated 24%–30% of the population is infected (4). Lesotho also has a high prevalence of TB with an estimated 695 cases per 100,000 population (5). Ten percent of patients with smear-positive TB are estimated to have multidrug-resistant TB (6). The US Centers for Disease Control and Prevention is undertaking a national reporting registration survey in Lesotho. In 2007, the Ministry of Health and Social Welfare began working with Partners In Health and the Foundation for Innovative and New Diagnostics, Geneva, Switzerland, to document and treat drug-resistant TB in Lesotho. Hundreds of cases of drug-resistant TB have been reported in the country, and the patient we describe in this letter was reported to have XDR TB. The patient was a 44-year-old man who had been working in the gold mines in South Africa. He had a history of receiving multiple treatments for TB while he was working in one of the mines. His condition was declared a treatment failure in July 2007. The patient was discharged from medical care in South Africa with no follow-up plan or medical records and was told, per his report, to “return home.” He traveled by road and bus to Lesotho and easily crossed the border. He was originally seen at a public TB clinic in Lesotho but, given his reports of prior TB treatment, his sputum was sent for culture and drug susceptibility testing. He was followed up at his home with a daily visit from a village health worker trained in the management of drug-resistant TB. When XDR TB was confirmed (in vitro resistance to at least isoniazid, rifampin, a fluoroquinolone, and an injectable agent [7]), he was admitted to the hospital for drug-resistant TB patients in Lesotho and placed in a negative-pressure, single isolation room. When the patient sought treatment from our program in October 2007, he exhibited severe wasting and dyspnea. An HIV test result was positive; his CD4 count was 36 cells/μL. First-line drug susceptibility testing (carried out by the Medical Research Council [MRC], Pretoria, South Africa) showed resistance to isoniazid, rifampin, and pyrazinamide. On the basis of these results, on October 26, 2007, he was empirically prescribed a regimen of second-line drugs: capreomycin, para-aminosalicylic acid, cycloserine, ethionamide, and ciprofloxacin. One month later, second-line drug susceptibility testing, sent by the medical team in Lesotho (none was ever sent during his treatment in South Africa) but carried out at MRC, showed additional resistance to amikacin (MIC 1.0 μg/mL), capreomycin (MIC 2.5 μg/mL), and ofloxacin (MIC 1.0 μg/mL) but susceptibility to ethionamide (5.0 μg/mL). The patient’s regimen was changed to kanamycin, moxifloxacin, ethionamide, para-aminosalicylic acid, and cycloserine. Unfortunately, he died of his disease in December 2007. His known contacts are being monitored closely for signs and symptoms of TB. Reports have been made to the mine in which he was working, the Ministry of Health of South Africa, and the Ministry of Health of Lesotho. As of the writing of this letter, the South African Ministry of Health has made no formal response regarding this patient. The report of this case of XDR TB in Lesotho raises many concerns. First, XDR TB was readily found (along with other forms of drug-resistant TB) in this small country that already has high prevalence of HIV. The potential for spread in the community as well as in hospital settings is substantial. The link to working in South Africa is also a major factor. Given the patient’s prior treatment while employed by a mining company and the literature reporting XDR TB in South Africa (8), XDR TB likely developed while he was working in the mines, and he brought the disease back to his home in Lesotho. Because South African mines rely heavily on migrant labor from countries such as Lesotho, Swaziland, and Mozambique, transnational spread of drug-resistant TB, including XDR TB, is quite probable and calls for a concerted international approach and institutional collaboration for management and control of this epidemic. Infection control in the mines needs to be addressed, and international efforts to communicate that migratory populations are at risk for XDR TB need to be a priority in controlling the spread of this disease.

High risk of drug-resistant tuberculosis when first-line therapy fails in a high HIV prevalence setting.

SETTING Lesotho national multidrug-resistant tuberculosis (MDR-TB) program. OBJECTIVE To determine the prevalence of drug-resistant TB (DR-TB) among patients registered for MDR-TB treatment after failure or suspected failure of the standard 6-month regimen for new TB patients (Category I). DESIGN We conducted a retrospective cohort study of patients registered for MDR-TB treatment following failure or suspected failure of Category I. RESULTS A total of 76 patients were included in the analysis, including 51 Category I treatment failures and 25 suspected Category I treatment failures. The prevalence of resistance to any drug was 92% among the treatment failures and 72% among the suspected failures. The proportion of MDR-TB was respectively 78% and 28% among the treatment failures and suspected failures. Among the subgroup of human immunodeficiency virus (HIV) positive patients, the proportion of MDR-TB was 84% among failures and 23% among suspected failures. CONCLUSION DR-TB and MDR-TB were common among patients in whom Category I failed. Early initiation of empiric second-line anti-tuberculosis treatment while awaiting culture and drug susceptibility testing (DST) results should be considered for HIV-negative and -positive patients who have failed first-line anti-tuberculosis treatment; patients suspected to be failing a first-line regimen should undergo DST at the end of the intensive phase.

Building Capacity for Multidrug-Resistant Tuberculosis Treatment: Health Systems Strengthening in Lesotho

Teboho was first diagnosed with TB in 1981 when he was 18 years old. In those days, he had just started working in the mines in South Africa, a path followed by many of his compatriots. At that time, he was treated with medications for nine months; he had no recurrent symptoms until 1998. It was in that year that he began losing weight and developed a nagging cough that would not go away. Many of his friends— who also had worked in mines for most of their lives—

Drug-Resistant Tuberculosis Treatment Complicated by Antiretroviral Resistance in HIV Coinfected Patients: A Report of Six Cases in Lesotho

Treating drug-resistant tuberculosis (DR-TB) is particularly challenging in high human immunodeficiency virus (HIV) prevalence settings. Neither antiretroviral resistance testing nor viral load monitoring is widely available in sub-Saharan Africa, and antiretroviral resistance can complicate the clinical management for DR-TB/HIV coinfected patients. We describe six cases of antiretroviral resistance in DR-TB patients with HIV coinfection in Lesotho. Two patients died before or immediately after antiretroviral resistance was detected by genotyping; the remaining four patients were switched to effective antiretroviral therapy (ART) regimens. Favorable DR-TB treatment outcomes in coinfected patients require successful management of their HIV infection, including treatment with an effective ART regimen. Coinfected patients undergoing DR-TB treatment may require closer monitoring of their response to ART, including routine viral load testing, to ensure that they receive an effective ART regimen concurrent with DR-TB treatment.