Challenges in recruiting children to a multidrug-resistant TB prevention trial.

BACKGROUND: Recruitment to randomised clinical trials can be challenging and slow recruitment has serious consequences. This study aimed to summarise and reflect on the challenges in enrolling young children to a multidrug-resistant TB (MDR-TB) prevention trial in South Africa.METHODS: Recruitment to the Tuberculosis Child Multidrug-resistant Preventive Therapy Trial (TB-CHAMP) was tracked using an electronic recruiting platform, which was used to generate a recruiting flow diagram. Structured personnel questionnaires, meeting minutes and workshop notes were thematically analysed to elucidate barriers and solutions.RESULT: Of 3,682 (85.3%) adult rifampicin (RIF) resistant index cases with pre-screening outcomes, 1597 (43.4%) reported having no children under 5 years in the household and 562 (15.3%) were RIF-monoresistant. More than nine index cases were pre-screened for each child enrolled. Numerous barriers to recruitment were identified. Thorough recruitment planning, customised tracking data systems, a dedicated recruiting team with strong leadership, adequate resources to recruit across large geographic areas, and excellent relationships with routine TB services emerged as key factors to ensure successful recruitment.CONCLUSION: Recruitment of children into MDR-TB prevention trials can be difficult. Several MDR-TB prevention trials are underway, and lessons learnt from TB-CHAMP will be relevant to these and other TB prevention studies.

Lamivudine monotherapy in children and adolescents: The devil is in the detail.

Although expanded access to antiretroviral therapy (ART), and starting lifelong ART as soon as possible after diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother-to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential accumulation of resistance mutations, limited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF.

Cutting the cost of South African antiretroviral therapy using newer, safer drugs.

Antiretrovirals are a significant cost driver for HIV programmes. Current first-line regimens have performed well in real-life programmes, but have a low barrier to virological resistance and still carry toxicity that limits adherence. New drug developments may mean that we have access to safer, more robust and cheaper regimens, but only if the appropriate clinical trials are conducted. We briefly discuss these trials, and demonstrate the large cost savings to the South African HIV programme if these are successful.

Microbiological investigation for tuberculosis among HIV-infected children in Soweto, South Africa.

SETTING: A paediatric human immunodeficiency virus (HIV) clinic in an academic hospital in Soweto, South Africa. OBJECTIVES: 1) To describe and compare the clinical, immunological and virological characteristics of HIV-infected children co-treated for tuberculosis (TB), and 2) to compare those investigated microbiologically with those who were not, with a description of the results of the microbiological TB investigation. DESIGN: Retrospective analysis of TB-HIV-infected children aged <15 years treated for TB between 1 October 2007 and 15 March 2009. RESULTS: Anti-tuberculosis treatment was initiated in 616/3358 (18%) children during the study period. Microbiological TB investigation results were available for 399/616 (65%), among whom culture-confirmed TB was diagnosed in 49 (12%). Drug susceptibility testing was performed in 29/49 (59%) children: 5/29 (17%) were isoniazid-resistant, and 3 had multidrug-resistant TB. Children aged >8 years and those between 3 and 8 years were more likely to have culture-confirmed TB than those aged <3 years (aOR 9.4, 95%CI 2.26-39.08 vs. aOR 6.7, 95%CI 1.60-27.69), as were those with CD4 count <200 cells/mm(3) compared to those with >500 cells/mm(3) (aOR 3.95, 95%CI 1.23-12.72). CONCLUSION: Our study in HIV-infected children showed a high TB case rate, a low rate of definite TB and a high rate of drug-resistant TB based on World Health Organization case definitions. Increased uptake of available TB tests and availability of new diagnostic tests remains a priority in high TB-HIV burden settings.