Factors associated with the development of drug resistance mutations in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy in South Africa

OBJECTIVE Limited data are available from the developing world on antiretroviral drug resistance in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy, especially in the context of a high tuberculosis burden. We describe the proportion of children with drug resistance mutations after failed protease inhibitor-based antiretroviral therapy as well as associated factors. METHODS Data from children initiated on protease inhibitor-based antiretroviral therapy with subsequent virological failure referred for genotypic drug resistance testing between 2008 and 2012 were retrospectively analysed. Frequencies of drug resistance mutations were determined and associations with these mutations identified through logistic regression analysis. RESULTS The study included 65 young children (median age 16.8 months [IQR 7.8; 23.3]) with mostly advanced clinical disease (88.5% WHO stage 3 or 4 disease), severe malnutrition (median weight-for-age Z-score -2.4 [IQR -3.7;-1.5]; median height-for-age Z-score -3.1 [IQR -4.3;- 2.4]), high baseline HIV viral load (median 6.04 log10, IQR 5.34;6.47) and frequent tuberculosis co-infection (66%) at antiretroviral therapy initiation. Major protease inhibitor mutations were found in 49% of children and associated with low weight-for-age and height-for-age (p = 0.039; p = 0.05); longer duration of protease inhibitor regimens and virological failure (p = 0.001; p = 0.005); unsuppressed HIV viral load at 12 months of antiretroviral therapy (p = 0.001); tuberculosis treatment at antiretroviral therapy initiation (p = 0.048) and use of ritonavir as single protease inhibitor (p = 0.038). On multivariate analysis, cumulative months on protease inhibitor regimens and use of ritonavir as single protease inhibitor remained significant (p = 0.008; p = 0.033). CONCLUSION Major protease inhibitor resistance mutations were common in this study of HIV-1-infected children, with the timing of tuberculosis treatment and subsequent protease inhibitor dosing strategy proving to be important associated factors. There is an urgent need for safe, effective, and practicable HIV/tuberculosis co-treatment in young children and the optimal timing of treatment, optimal dosing of antiretroviral therapy, and alternative tuberculosis treatment strategies should be urgently addressed.All files are available from the GenBank database under accession numbers KT031999-KT032063.Ms LAW Hahne for the development of the electronic database for the Kalafong clinic. Mr T Moto for the assistance with data collection. Drs G Malherbe and P Mahasha for assisting with the development of the genotyping assay and the staff at the HIV clinics for their dedicated service to patients and their assistance with data collection.Conceived and designed the experiments: TR UF. Performed the experiments: GVD. Analyzed the data: GM. Contributed reagents/materials/analysis tools: TR GM. Wrote the paper: TR UF GM GVD WT NDP TA.This research and selected researchers (TR and GVD) were partially funded by a grant from the Delegation of the European Union to South Africa: "Drug Resistance Surveillance and Treatment Monitoring Network for the Public Sector HIV Antiretroviral Treatment Programme in the Free State” - Sante 2007/147-790 - and National Research Council of South Africa, Unlocking the Future 61509.http://www.plosone.orgam201

Patronage and the Idea of an Urban Bourgeoisie

From the reports of travelers and historians, people learn of the crafting of beautiful rock crystal and metalwork objects in the Cairo bazaar and, during the later Mamluk period, of beautiful gilded and enameled glass being produced in commercial areas of Aleppo and Damascus. Given the diverse subject matter of the manuscripts, people may speak of a patronage base allying the intelligentsia to the merchant class within a more broadly conceived bourgeoisie, one whose interests and aesthetic preferences, as compared with those of the court, might be productively investigated through such illustrated manuscripts. One of the frontispieces of a wonderful illustrated manuscript contains clearly Christian iconographical elements, and among the Christian community of Iraq and Syria, people encounter ample evidence for the patronage and production of metalwork, ceramics, and gilded and enameled glass as well as manuscripts

Relation of vitamin A and carotenoid status to growth failure and mortality among ugandan infants with human immunodeficiency virus

Although growth failure is common during pediatric infection with human immunodeficiency virus (HIV) and associated with increased mortality, the relation of specific nutrition factors with growth and mortality has not been well characterized. A longitudinal study was conducted with 194 HIV-infected infants in Kampala, Uganda. Plasma vitamin A, carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin), and vitamin E were measured at age 14 wk, and weight and height were followed up to age 12 mo. Vitamin A and low plasma carotenoid concentrations were predictive of decreased weight and height velocity. Between ages 14 wk and 12 mo, 32% of infants died. Underweight, stunting, and low concentrations of plasma carotenoids were associated with increased risk of death in univariate analyses. Plasma vitamin A concentrations were not associated with risk of death. In a final multivariate model adjusting for weight-for-age, plasma β-carotene was significantly associated with increased mortality (odds ratio: 3.16, 95% confidence interval: 1.38 to 7.21, P \u3c 0.006). These data suggest that low concentrations of plasma carotenoids are associated with increased risk of death during HIV infection among infants in Uganda. Copyright © 2001 Elsevier Science Inc

Factors Associated with the Development of Drug Resistance Mutations in HIV-1 Infected Children Failing Protease Inhibitor-Based Antiretroviral Therapy in South Africa.

Limited data are available from the developing world on antiretroviral drug resistance in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy, especially in the context of a high tuberculosis burden. We describe the proportion of children with drug resistance mutations after failed protease inhibitor-based antiretroviral therapy as well as associated factors.Data from children initiated on protease inhibitor-based antiretroviral therapy with subsequent virological failure referred for genotypic drug resistance testing between 2008 and 2012 were retrospectively analysed. Frequencies of drug resistance mutations were determined and associations with these mutations identified through logistic regression analysis.The study included 65 young children (median age 16.8 months [IQR 7.8; 23.3]) with mostly advanced clinical disease (88.5% WHO stage 3 or 4 disease), severe malnutrition (median weight-for-age Z-score -2.4 [IQR -3.7;-1.5]; median height-for-age Z-score -3.1 [IQR -4.3;-2.4]), high baseline HIV viral load (median 6.04 log10, IQR 5.34;6.47) and frequent tuberculosis co-infection (66%) at antiretroviral therapy initiation. Major protease inhibitor mutations were found in 49% of children and associated with low weight-for-age and height-for-age (p = 0.039; p = 0.05); longer duration of protease inhibitor regimens and virological failure (p = 0.001; p = 0.005); unsuppressed HIV viral load at 12 months of antiretroviral therapy (p = 0.001); tuberculosis treatment at antiretroviral therapy initiation (p = 0.048) and use of ritonavir as single protease inhibitor (p = 0.038). On multivariate analysis, cumulative months on protease inhibitor regimens and use of ritonavir as single protease inhibitor remained significant (p = 0.008; p = 0.033).Major protease inhibitor resistance mutations were common in this study of HIV-1-infected children, with the timing of tuberculosis treatment and subsequent protease inhibitor dosing strategy proving to be important associated factors. There is an urgent need for safe, effective, and practicable HIV/tuberculosis co-treatment in young children and the optimal timing of treatment, optimal dosing of antiretroviral therapy, and alternative tuberculosis treatment strategies should be urgently addressed

Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: A controlled clinical trial

We investigated whether vitamin A supplementation would decrease mortality and morbidity rates in children infected with the human immunodeficiency virus (HIV). We conducted a randomized, double-blind, placebo-controlled clinical trial at Mulago Hospital, a large hospital that serves the urban and semiurban populations of Kampala, Uganda. One hundred eighty-one HIV-infected children were enrolled at 6 mo and randomized to receive vitamin A supplementation, 60 mg retinol equivalent, or placebo every 3 mo from ages 15 to 36 mo. Morbidity was assessed through a 7-d morbidity history every 3 mo, and vital events were measured. Children received daily trimethoprim-sulfamethoxazole prophylactic therapy. After age 15 mo, children were followed for a median of 17.8 mo (interquartile range = 11.1 to 21.0 mo). The trial was stopped when there was a new policy to implement a program of mass supplementation of vitamin A in the country. Mortality rates among 87 children in the vitamin A group and 94 children in the control group were 20.6% and 32.9%, respectively, yielding a relative risk of 0.54 (95% confidence interval, 0.30 to 0.98; P = 0.044) after adjusting for baseline weight-for-height Z score. Children who received vitamin A had lower modified point prevalences of persistent cough (odds ratio, 0.47; 95% confidence interval, 0.23 to 0.96; P = 0.038) and chronic diarrhea (odds ratio, 0.48; 95% confidence interval, 0.19 to 1.18; P = 0.11) and a shorter duration of ear discharge (P = 0.03). Vitamin A supplementation had no significant effect on modified point prevalences of fever, ear discharge, bloody stools, or hospitalizations. Vitamin A supplementation decreases mortality rate in HIV-infected children and should be considered in the care for these children in developing countries. © 2005 Elsevier Inc. All rights reserved

Prototypical Recombinant Multi-Protease Inhibitor Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type-1

The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI-resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel\u27s viruses in the context of a correlation network of PI-resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI-resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activity of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most, if not all clinically relevant PI-resistant viruses

Comparison of projected susceptibility to antiretroviral medication in children with and without major protease inhibitor (PI) drug resistance mutations.

<p>Data collected from 65¹ and 64² patients respectively</p><p>Predicted drug susceptibility categories were determined through the Stanford HIVdb Algorithm</p><p><b>Abbreviations:</b> PI = protease inhibitors; LPV/r = ritonavir-boosted lopinavir; DRV/r = ritonavir-boosted darunavir; TPV/r = ritonavir-boosted tipranavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; EFV = efavirenz; ETR = etravirine; NRTI = nucleoside reverse transcriptase inhibitor; ABC = abacavir; AZT = zidovudine; d4T = stavudine; TDF = tenofovir; 3TC = lamivudine</p><p>Comparison of projected susceptibility to antiretroviral medication in children with and without major protease inhibitor (PI) drug resistance mutations.</p

Clinical and laboratory findings of the cohort.

<p>Data collected from 65¹, 61², 60³, 59⁴ and 47⁵ patients respectively</p><p><b>Abbreviations:</b> ART = antiretroviral therapy; PI = protease inhibitor; IQR = interquartile range; BMI = Body mass index; CD4 = CD4+ T-cell count in cells/mm³; CD4% = CD4 percentage; VL = HIV viral load in log₁₀ copies/ml; Nr = number; WHO stage = HIV disease staging according to World Health Organization; d4T = stavudine; 3TC = lamivudine; LPV/r = boosted lopinavir; RTV-sPI = ritonavir as full-dose single protease inhibitor; LPV/R⁺ = super-boosted lopinavir; ABC = abacavir; AZT = zidovudine; TB = tuberculosis.</p><p>*From first failure time point (using LDL cut-off & >6 months on ART) to date of genotype</p><p>**Age- and sex-adjusted anthropometry according to WHO growth standards [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133452#pone.0133452.ref022" target="_blank">22</a>]</p><p>Clinical and laboratory findings of the cohort.</p