Substituting Abacavir for Stavudine in Children Who Are Virally Suppressed Without Lipodystrophy: Randomized Clinical Trial in Johannesburg, South Africa.

OBJECTIVES: Abacavir has replaced stavudine in antiretroviral therapy (ART) regimens because it has largely been phased out as a result of toxicity concerns; this loss has reduced further the already-limited drug options for children. Few data regarding virologic and metabolic outcomes among children who undergo substitution of stavudine exist. We evaluated the effects of preemptive substitution of abacavir for stavudine in children initially without lipodystrophy and virally suppressed on a stavudine-containing regimen. METHODS: At Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa, virally suppressed human immunodeficiency virus (HIV)-infected children ≥36 months of age without lipodystrophy were randomly assigned to continue taking stavudine as part of their ART regimen (n = 106) or to have abacavir substituted for stavudine (n = 107). The children were followed for 56 weeks after randomization in the context of a larger trial of treatment options for ART-experienced children. RESULTS: The mean age of the children was 4.3 years, and the mean duration of ART before random assignment was 3.5 years. No differences in virological outcomes, CD4 response, growth, or dyslipidemia were noted between the stavudine and abacavir groups. By 56 weeks, children in the abacavir group had less clinically detected lipodystrophy (4.7% vs 16%, respectively), a higher proportion of leg fat relative to total fat (0.243 vs 0.230, respectively; P = .006), and a lower trunk/leg-skinfold ratio (0.547 vs 0.569, respectively; P = .003) than the children in the stavudine group. CONCLUSION: Substituting abacavir for stavudine did not compromise virological response to treatment and was associated with significantly less lipodystrophy. These results support recommendations that favor abacavir in this population.

Patterns of Growth, Body Composition, and Lipid Profiles in a South African Cohort of Human Immunodeficiency Virus-Infected and Uninfected Children: A Cross-Sectional Study.

BACKGROUND: Prior research in sub-Saharan Africa reports dyslipidemia in perinatally human immunodeficiency virus (HIV)-infected children receiving ritonavir-boosted lopinavir (LPV/r) compared with efavirenz; however, interpretation of findings is limited by lack of comparison data from HIV-uninfected children. METHODS: We conducted a cross-sectional analysis of lipid profiles and growth within a larger longitudinal cohort study of perinatally HIV-infected and HIV-uninfected children aged 4-9 years in Johannesburg, South Africa. At enrollment, anthropometrics, viral load, CD4, total cholesterol (TC), high-density lipoprotein, low-density lipoprotein (LDL), and triglycerides were measured. Weight-for-age Z-score (WAZ), height-for-age Z-score (HAZ), and body mass index-for-age Z-score (BAZ) were calculated. United States pediatric thresholds for dyslipidemia were used. RESULTS: Five hundred fifty-three HIV-infected and 300 HIV-uninfected children (median age 6.9 years) of similar demographic characteristics were enrolled. Of the HIV-infected children, 94.8% were on combination antiretroviral therapy (cART) (65.4% on LPV/r- and 28.6% on efavirenz-based regimens). Among the treated, 94.3% had a viral load <200 copies/mL. Median CD4% was 34.4. The HIV-infected children had lower mean WAZ (-0.7 vs -0.3, P < .01) and HAZ (-1.1 vs -0.7, P < .01) compared with HIV-uninfected children. A lower proportion of HIV-infected children were overweight (BAZ >1) compared with HIV-uninfected children (14.4% vs 21.7%, P = .04). Whether on LPV/r or efavirenz, a higher proportion of HIV-infected children had borderline/elevated TC or abnormal triglycerides than HIV-uninfected children, although a higher proportion of those on LPV/r had borderline/elevated TC, borderline/elevated LDL, or abnormal triglycerides than those on efavirenz. CONCLUSIONS: In a South African cohort of HIV-infected children and population-appropriate HIV-uninfected children, unfavorable alterations in lipid profiles were detected in HIV-infected children regardless of treatment regimen compared with HIV-uninfected children. The HIV-infected children were of smaller size than HIV-uninfected children, but there was a high prevalence of overweight in both groups. Strategies for optimizing growth and early life management of lipid alterations may be warranted.

Extent of disclosure: what perinatally HIV-infected children have been told about their own HIV status.

How and when to disclose a positive HIV diagnosis to an infected child is a complex challenge for caregivers and healthcare workers. With the introduction of antiretroviral therapy, pediatric HIV infection has transitioned from a fatal disease to a lifelong chronic illness, thus increasing the need to address the disclosure process. As HIV-infected children mature, begin to take part in management of their own health care, and potentially initiate HIV-risk behaviors, understanding the nature of their infection becomes essential. Guidelines recommend developmentally appropriate incremental disclosure, and emphasize full disclosure to school-age children. However, studies from Sub-Saharan Africa report that disclosure to HIV-infected children is often delayed. Between 2013 and 2014, 553 perinatally HIV-infected children aged 4-9 years were enrolled into a cohort study in Johannesburg, South Africa. We assessed the extent of disclosure among these children and evaluated characteristics associated with disclosure. No children aged 4 years had been told their status, while 4% of those aged 5 years, and 8%, 13%, 16%, and 15% of those aged 6, 7, 8, and 9 years, respectively, had been told their status. Age was the strongest predictor of full disclosure (odds ratio 1.6 per year, p = .001). An adult living in the household who was unaware of the child's status was associated with a reduced probability of disclosure, and knowing that someone at the child's school was aware of child's status was associated with an increased probability of disclosure. Among caregivers who had not disclosed, 42% reported ever discussing illness in general with the child, and 17% reported ongoing conversations about illness or HIV. In conclusion, a small minority of school-age children had received full disclosure. Caregivers and healthcare workers require additional support to address disclosure. A broader public health strategy integrating the disclosure process into pediatric HIV treatment programs is recommended.

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children.

BACKGROUND: Adequate exposure to antiretroviral drugs is necessary to achieve and sustain viral suppression. However, the target antiretroviral concentrations associated with long-term viral suppression have not been adequately defined in children. We assessed the relationship between plasma lopinavir or nevirapine concentrations and the risk of subsequent viremia in children initially suppressed on antiretroviral therapy. METHODS: After an induction phase of antiretroviral treatment, 195 children with viral suppression (viral load ≤400 copies/mL) were randomized to continue a lopinavir/ritonavir-based regimen or to switch to a nevirapine-based regimen (together with lamivudine and stavudine). Viral load and lopinavir or nevirapine concentrations were measured at clinic visits 4, 8, 12, 16, 20, 24, 36, 52, 64 and 76 weeks post randomization. Cox multiple failure event models were used to estimate the effects of drug concentrations on the hazard of viremia (viral load >50 copies/mL) RESULTS:: At randomization, the median (interquartile range) age, CD4 T-Lymphocyte percentage, weight-for-age and weight-for-height z scores were 19 (16-24) months, 29% (23-37), -0.6 (-1.3 to 0.2) and -3.2 (-4.1 to -2.1), respectively. The proportion of children with viral load 51-400 copies/mL at randomization was 43%. The hazard of subsequent viremia during follow-up was increased for lopinavir concentrations <1 versus ≥1 mg/L [adjusted hazard ratio 0.62 (95% confidence interval, 0.40-0.94)] and for children with viral loads 51-400 copies/mL at randomization. Nevirapine concentrations were not significantly associated with subsequent viremia. CONCLUSIONS: Plasma lopinavir concentrations predicted viral outcomes in children receiving lopinavir-based antiretroviral therapy. Our findings support a minimum target concentration of ≥1 mg/L of lopinavir to ensure sustained viral suppression.

Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation.

BACKGROUND: Efavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children. CASE PRESENTATION: Four black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5-15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation. CONCLUSION: Efavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.

Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial.

IMPORTANCE: Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission. OBJECTIVE: To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization. INTERVENTIONS: Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148). MAIN OUTCOMES AND MEASURES: Risk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points. RESULTS: The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to ∞) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to ∞). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group. CONCLUSIONS AND RELEVANCE: Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01146873.

Young age at start of antiretroviral therapy and negative HIV antibody results in HIV-infected children when suppressed.

BACKGROUND: Negative results on standard HIV antibody tests have been described among HIV-infected children suppressed on antiretroviral therapy (ART) started early in life. Here, we describe the frequency and predictors of this phenomenon in a well characterized cohort of treated children. METHODS: We selected samples from 103 HIV-infected children who started ART 14 months of age or less and from 122 children who started 6 months of age or less followed as part of two sequential clinical trials in Johannesburg, South Africa. Children had attained viral suppression on ART and had received ART for between 3 and 6.4 years (mean 4.3 years) when tested for HIV antibody using a standard ELISA (Genescreen HIV1/2 version 2; Bio-rad). RESULTS: Only children 6 months of age or less when ART was started had negative antibody results when tested after suppression on ART several years later. Negative or low-positive antibody results were observed in 40.0, 37.0 and 27.8% of children starting ART less than 2 months of age, or starting during month 2 or 3, respectively. This dropped to 5.9, 3.5 and 5.3% if ART was started during month 4, 5 and 6, respectively. Higher CD4 percentage prior to ART initiation and no recorded intermittent viremia also predicted negative antibody results. CONCLUSION: Testing negative on standard HIV antibody tests occurs fairly commonly among HIV-infected children who started ART 3 months of age or less and are virally suppressed. It would be prudent in clinical practice to avoid HIV antibody tests among virally suppressed, early-treated children to prevent unnecessary confusion.

Virologic failure among children taking lopinavir/ritonavir-containing first-line antiretroviral therapy in South Africa.

OBJECTIVE: To report the outcomes, clinical management decisions and results of resistance testing among a group of children who developed virologic failure on first-line lopinavir/ritonavir (LPV/r)-based therapy from a large cohort of antiretroviral therapy-treated children in Soweto. DESIGN: Historical cohort study. METHODS: Children with virologic failure were identified from a group of 1692 children <3 years who had initiated first-line LPV/r-containing therapy since 2000 up to the end November 2011. Genotyping was conducted in some children, and outcomes, management decisions and resistance results were described. RESULTS: A total of 152 children with virologic failure on first-line LPV/r-containing antiretroviral therapy were included. Resistance testing was performed in 75/152 (49%), and apart from a younger age (11.1 vs. 15.1 months, P = 0.04), the children with versus those without resistance testing were similar for baseline characteristics (weight, CD4, viral load and time to failure). Genotyping revealed that 8/75 (10.7%) had significant LPV/r-associated resistance mutations, including 2 with intermediate darunavir resistance. Among 63/75 (84%) children remaining on LPV/r-based therapy, 32/63 (51%) achieved virologic suppression, and 2 of these children with significant LPV mutations. In accordance with the local guidelines at the time, 12/152 (8%) children were switched to non-nucleoside reverse-transcriptase inhibitors-based therapy. Of these, 4/12 (33%) resuppressed, and the rest did not achieve virologic suppression including the 2 with lopinavir mutations. CONCLUSIONS: Virologic failure of LPV/r-containing first-line regimens is associated with accumulation of LPV/r mutations in children. The implications are unclear, and surveillance at selected sites is warranted for long-term virologic outcomes and development of resistance.