In order to evaluate strategies to reduce HIV transmission through breast milk and optimize both maternal and infant health among HIV-infected women and their infants, we designed and implemented a large, randomized clinical trial in Lilongwe, Malawi. The development of protocols for large, randomized clinical trials is a complicated and lengthy process often requiring alterations to the original research design. Many factors lead to delays and changes, including study site-specific priorities, new scientific information becoming available, the involvement of national and international human subject committees and monitoring boards, and alterations in medical practice and guidance at local, national, and international levels. When planning and implementing a clinical study in a resource-limited setting, additional factors must be taken into account, including local customs and program needs, language and socio-cultural barriers, high background rates of malnutrition and endemic diseases, extreme poverty, lack of personnel, and limited infrastructure. Investigators must be prepared to modify the protocol as necessary in order to ensure participant safety and successful implementation of study procedures. This paper describes the process of designing, implementing, and subsequently modifying the Breastfeeding, Antiretrovirals, and Nutrition, (BAN) study, a large, ongoing, randomized breastfeeding intervention trial of HIVinfected women and their infants conducted at a single site in Lilongwe, Malawi. We highlight some of the successes, challenges, and lessons learned at different stages during the conduct of the trial.
SummaryA 35-year old man with lupus erythematosus of the skin is demonstrated, who also shows signs of systemic L. E.: sometimes slightly increased ESR, varying thrombocytopenia, slightly prolonged coagulation and prothrombin time, positive cepnalin-cholesterol flocculation test, biologically false positive syphilis reactions and signs of a slightly increased haemolysis. Electrophoretic examination of the serum proteins presents practically normal values, certainly no hypergammaglobulinaemia. Analytical examination of coagulation reveals hypoprothrombinaemia and an anticoagulant most probably directed against thrombocyte factor 3, intrinsic thromboplastin and tissue thromboplastin. The anticoagulant seems to be only active in the presence of prothrombin. Prothrombin therefore, is considered a co-factor of the anticoagulant. The inactive anticoagulant is localized in the gamma globulins. The possible cause of the hypoprothrombinaemia (immune reaction?) and the data in the literature are discussed.
The M184V mutation in the HIV-1 reverse transcriptase gene is primarily associated with rapid, high-level lamivudine (3TC) resistance. It has also been observed to arise under selective pressure by abacavir, to which it confers low-level resistance. Although the development of viral drug resistance remains a major concern in antiretroviral therapy, it is known that some immunological and clinical benefit can still be derived from highly active antiretroviral therapy (HAART) regimens despite resistance-associated virological failure. This residual benefit on a failing regimen is commonly attributed to the preservation of fitness-reducing protease inhibitor (PI) resistance mutations under continued drug pressure. However, fitness-reducing nucleoside reverse transcriptase inhibitor (NRTI) mutations may also contribute to the effect. M184V is both common in the treated population and fitness-reducing. A number of studies, both of dual nucleoside therapy and HAART, have noted a residual treatment effect for 3TC despite the assumed or observed presence of M184V and high-level phenotypic resistance. The speed and consistency with which this mutation is selected by 3TC under suboptimal viral suppression therefore makes M184V a particularly interesting model for further clinical studies on the association of drug resistance with ongoing treatment benefit. While fitness considerations are likely to be a major contributor to the clinical observations noted, there are a number of other potential mechanisms that may contribute to a continuing response to 3TC in the presence of M184V. These include the delay and reversal of zidovudine (ZDV) resistance, hypersensitization to other NRTIs, reduced reverse transcriptase (RT) processivity and a possible reduction in RT pyrophosphorolysis. The full impact of M184V on therapeutic prospects will require further elucidation; ideally, the risk/benefit of preserving this substitution would be investigated in randomized trials. However, existing data suggest that the presence of this mutation may preserve some benefit in spite of the loss of 3TC susceptibility which, with further study, may prove valuable.
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