Severe acute malnutrition and antiretroviral treatment in children with HIV.
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Background: Childhood malnutrition remains a common problem in many parts of the world and is a contributing factor in 45% of the 5.9 million annual deaths in children under 5 years. HIV-infected children have a disproportionately higher prevalence of malnutrition and higher mortality associated with malnutrition as compared to non-infected children. Physiological changes associated with malnutrition and re-nutrition complicate antiretroviral treatment in these children. This thesis explores aspects related to antiretroviral treatment (ART) in severely malnourished HIV-infected children, including the timing of ART initiation, pharmacokinetics of antiretroviral drugs, co-infections with bacterial and mycobacterial infections and the effect of microbial translocation on immune restoration. Methods: Eight-two patients were enrolled in this randomized controlled trial, where HIV-infected children admitted with severe acute malnutrition (SAM) were initiated on ART either early (within 14 days of admission) or delayed (after 14 days with evidence of nutritional recovery). Clinical and laboratory parameters were collected during the admission and patients were followed up at 4, 8, 12, 24 and 48 weeks post admission. A pharmacokinetic evaluation of lopinavir (LPV) was conducted on Day1 and 14 of ART initiation. Samples for evaluation of microbial translocation and immune restoration were collected in 32 study patients and 75 additional patients in 3 control groups. Results/Discussion: There were no significant differences in immunologic, virologic or anthropometric responses at 48 weeks between the early and delayed arms. However, significantly improved rates in the changes in viral load, WAZ (weight-for-age Z score) and HAZ (height-for-age Z score) favoured the delayed arm. Pharmacokinetic (pk) evaluation of the LPV, displayed significant pk variability, reduced bioavailability and consequently greater apparent clearance (CL/F) estimates in comparison to other pk studies of LPV in non-malnourished children. Fat-free Mass (FFM) was shown to affect LPV variability; however delay in ART initiation and “super-boosted” LPV/rtv did not affect LPV variability. Bacterial pathogens were identified in 51% of patients. Of the hospital acquired infections (HAI), 41% were extended spectrum beta-lactamase (ESBL)-producing gram-negative infections. Tuberculosis (TB) co-infection was common (25.6%), with bacteriological confirmation in 38% of treated cases. Malnutrition was associated with increased microbial translocation, immune activation and immune exhaustion, with a negative impact on immune recovery in HIV-infected children on ART. Conclusions: Delaying ART initiation to at least 14 days after starting nutritional support is associated with improved rates of clinical (changes in WAZ and HAZ) and virologic outcomes. However this delay did not improve LPV exposures and dose adjustment of LPV during nutritional recovery needs to be further evaluated. These results can be used to inform changes in clinical practice and national and international guidelines for the management of severely malnourished HIV-infected children.