Person:

Meloni, Seema

Background: Mortality among Human Immunodeficiency Virus-1 (HIV-1) infected children initiated on Antiretroviral Therapy (ART) though on a decline still remains high in resource-limited countries. Identifying baseline factors that predict mortality could allow their possible modification in order to improve pediatric HIV care and reduce mortality. Methods: We conducted a retrospective cohort study analyzing data on 691 children, aged 2 months-15 years, diagnosed with HIV-1 infection and initiated on ART between July 2005 and March 2013 at the pediatric HIV clinic of Jos University Teaching Hospital. Lost to follow-up children were excluded from the analyses. A multivariate Cox proportional hazards model was fitted to identify predictors of mortality. Results: Median follow-up time for the 691 children initiated on ART was 4.4 years (interquartile range (IQR), 1.8-5.9) and at the end of 2752 person-years of follow-up, 32 (4.6%) had died and 659 (95.4%) survived. The mortality rate was 1.0 per 100 child-years of follow-up period. The median age of those who died was about two times lower than that of survivors [1.7 years (IQR, 0.6-3.6) versus 3.9 years (IQR, 3.9 - 10.3), p<0.001]. On unadjusted Cox regression, the risk of dying was about three and half times more in children <5 years of age compared to those >5 years (p=0.02) Multivariate modeling identified age as the main predictor of death with mortality decreasing by 24% for every 1 year increase in age (Adjusted Hazard Ratio (AHR)=0.76 [0.62-0.94], p=0.013. Conclusion: The lower mortality rate for our study suggests that even in RLCs, mortality rates could be reduced given a good standard of care. Early initiation of ART in younger children with close monitoring during follow-up could further reduce mortality.

Abstract Background: Although there are a number of studies comparing the currently recommended preferred and alternative first-line (1L) antiretroviral therapy (ART) regimens on clinical outcomes, there are limited data examining the impact of 1L regimen choice and duration of virologic failure (VF) on accumulation of drug resistance mutations (DRM). The patterns of DRM from patients failing zidovudine (AZT)-containing versus tenofovir (TDF)-containing ART were assessed to evaluate the predicted susceptibility to second-line (2L) nucleoside reverse-transcriptase inhibitor (NRTI) backbone options in the context of an ongoing programmatic setting that uses viral load (VL) monitoring. Methods: Paired samples from Nigerian ART patients who experienced VF and switched to 2L ART were retrospectively identified. For each sample, the human immunodeficiency virus (HIV)-1 polymerase gene was sequenced at 2 time points, and DRM was analyzed using Stanford University’s HIVdb program. Results: Sequences were generated for 191 patients. At time of 2L switch, 28.2% of patients on AZT-containing regimens developed resistance to TDF, whereas only 6.8% of patients on TDF-containing 1L had mutations compromising susceptibility to AZT. In a stratified evaluation, patients with 0–6 months between tested VL samples had no difference in proportion compromised to 2L, whereas those with >6 months between samples had a statistically significant difference in proportion with compromised 2L NRTI. In multivariate analyses, patients on 1L AZT had 9.90 times higher odds of having a compromised 2L NRTI option than patients on 1L TDF. Conclusions: In the context of constrained resources, where VL monitoring is limited, we present further evidence to support use of TDF as the preferred 1L NRTI because it allows for preservation of the recommended 2L NRTI option.

Background: For patients on antiretroviral therapy (ART), treatment interruptions can impact patient outcomes and result in the accumulation of drug resistance mutations leading to virologic failure. There are minimal published data on the impact of an ART stock shortage on development of drug resistance mutations (DRMs). In this report, we evaluate data from patients enrolled in the Government of Nigeria National ART Program that were receiving treatment at the time of a national drug shortage in late 2003. Methods: We conducted a cross-sectional evaluation of samples collected between December 2004 and August 2005 from ART patients in virologic failure that either had a treatment interruption or did not during the late 2003 drug shortage period at the Jos University Teaching Hospital (JUTH). Plasma virus was genotyped, sequence data were edited and analyzed, and mutation profiles were categorized to evaluate predicted drug susceptibility. Data were analyzed to examine factors associated with development of resistance mutations. A genotypic sensitivity score to the alternate recommended regimen was computed to assess drug susceptibility if regimens were changed. Results: A total of 56 patients were included in this evaluation (28 interrupted, 28 uninterrupted). Patients in the interrupted group had more DRMs than those in the uninterrupted group (p < 0.001); interrupted patients were more likely than uninterrupted patients to have one or more TAM-2 mutations (57.1% interrupted vs. 21.3% uninterrupted; p = 0.04). There was a statistically significant difference in resistance to both d4T (53.7% interrupted vs. 17.9 uninterrupted; p = 0.011) and AZT (64.3% interrupted vs. 25.0% uninterrupted; p = 0.003) by drug interruption status. Examining genotypic sensitivity scores, we found that 67.9% of the interrupted patients, as compared to 25.0% of the uninterrupted patients, did not have full susceptibility to one drug in the regimen to which guidelines recommended they be switched (p = 0.001). Discussion In this small observational study, we found evidence of a difference in resistance profiles and ART susceptibility between those that were stocked-out of drug versus those that were not. We believe that these data are relevant for many other low- and middle-income countries (LMIC) that also experienced similar ART shortages as they rapidly scaled up their national programs.