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.

Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen.

BACKGROUND: Poor adherence to antiretroviral therapy contributes to pharmacokinetic variability and is the major determinant of virological failure. However, measuring treatment adherence is difficult, especially in children. We investigated the relationship between plasma lopinavir concentrations, pretreatment characteristics and viral load >400 copies/ml. METHODS: A total of 237 HIV-infected children aged 4-42 months on lopinavir/ritonavir oral solution were studied prospectively and followed for up to 52 weeks. Viral load and lopinavir concentration were measured at clinic visits 12, 24, 36 and 52 weeks after starting treatment. Cox multiple failure events models were used to estimate the crude and adjusted effect of lopinavir concentrations on the hazard of viral load >400 copies/ml. RESULTS: The median (IQR) pretreatment CD4(+) T-lymphocyte percentage was 18.80% (12.70-25.35) and 53% of children had a pretreatment viral load >750,000 copies/ml. The median (IQR) weight-for-age and height-for-age z-scores were -2.17 (-3.35--2.84) and -3.34 (-4.57--3.41), respectively. Median (IQR) lopinavir concentrations were 8.00 mg/l (4.11-12.42) at median (IQR) 3.50 h (2.67-4.25) after the dose. The hazard of viral load >400 copies/ml was increased with lopinavir concentrations <1 mg/l versus ≥1 mg/l (adjusted hazard ratio 2.3 [95% CI 1.63, 3.26]) and lower height-for-age z-scores. CONCLUSIONS: Low lopinavir concentrations (<1 mg/l) are associated with viraemia in children. This measure could be used as a proxy for adherence and to determine which children are more likely to fail.

Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment.

BACKGROUND: While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART. METHODS: ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005-2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata. RESULTS: A total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r. CONCLUSIONS: Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00117728.

Initiation of antiretroviral therapy before 6 months of age is associated with faster growth recovery in South African children perinatally infected with human immunodeficiency virus.

OBJECTIVE: To describe the effects of age at antiretroviral therapy (ART) initiation on growth outcomes among children infected with HIV followed for 48 months after treatment initiation. STUDY DESIGN: This secondary analysis describes anthropometric changes in children infected with HIV in Johannesburg, South Africa who initiated ritonavir-boosted lopinavir-based ART before 24 months of age and were randomized to continue ritonavir-boosted lopinavir or to receive nevirapine after achieving and maintaining virologic suppression. Weight, height, and head circumference were measured at visits over 48 months post-ART initiation. Growth patterns including weight-for-age z-scores (WAZs), height-for-age z-scores, body mass index-for-age z-scores, and head circumference for age z-score were compared between children initiating ART<6 months, 6-12 months, and 12-24 months of age. RESULTS: A total of 195 children (mean±SD age 10.7±5.9 months), including 54 (27.7%)<6 months, 69 (35.4%) 6-12 months, and 72 (36.9%) 12-24 months of age at ART initiation, were evaluated. In the first 12 months on treatment, children<6 months of age at ART initiation experienced more rapid improvement in WAZ (1.98 vs 1.44, P=.084) and head circumference for age z-score (1.24 vs 0.45, P=.004) than children who initiated ART between 12-24 months of age. By 48 months on ART, growth outcomes were similar, regardless of age at ART initiation. WAZ approached population norms by 12 months on ART. Although improving, height-for-age z-scores remained on average 1.0 z-score below population norms at 48 months of therapy. CONCLUSIONS: Initiation of ART before 6 months of age results in more rapid growth recovery in children infected with HIV. These data provide further evidence for the importance of prompt diagnosis and early initiation of ART for infants infected with HIV.

Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy.

BACKGROUND: Few studies have assessed metabolic and body composition alterations in perinatally HIV-infected African children on antiretroviral therapy (ART). We compared metabolic profiles and regional fat of children on ritonavir-boosted lopinavir (lopinavir/ritonavir), lamivudine and stavudine to those switched to nevirapine, lamivudine and stavudine. METHODS: This study evaluated metabolic and body composition outcomes in 156 HIV-infected children completing a randomised trial that assessed the continued use of lopinavir/ritonavir-based ART or switch to nevirapine-based ART in Johannesburg, South Africa (2005-2010). Fasting total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides total and regional body fat (BF) were measured. A clinical assessment for lipodystrophy (LD) was conducted. RESULTS: 156 children (mean age 5.1±0.8 years, mean duration of treatment 4.2±0.7 years, mean time since randomisation 3.4±0.7 years) were enrolled. 85 were randomised to the lopinavir/ritonavir group and 71 to the nevirapine group. The lopinavir/ritonavir group had lower mean HDL (1.3±0.4 vs 1.5±0.4 mmol/l, p<0.001) and higher mean TC (4.4±1.0 vs 4.1±0.8 mmol/l, p=0.097), LDL (2.6±0.9 vs 2.3±0.7 mmol/l, p=0.018) and triglycerides (1.1±0.4 vs 0.8±0.3 mmol/l, p<0.001). The lopinavir/ritonavir group had more total BF by mean skinfold sum (43±11.1 vs 39±10.1 mm, p=0.031) and BF% by bioelectrical impedance analysis (17.0±7.0 vs 14.1±8.0%, p=0.022). Thirteen (8.4%) met criteria for LD. CONCLUSIONS: Unfavourable alterations in lipid profile and triglycerides, and differences in fat are detectable in young HIV-infected South African children receiving lopinavir/ritonavir-based regimens versus those switched to nevirapine-based regimens. Interventions to mitigate these alterations are warranted to reduce long-term cardiovascular disease risk.

Adherence and viral suppression among infants and young children initiating protease inhibitor-based antiretroviral therapy.

BACKGROUND: High levels of adherence to antiretroviral therapy are considered necessary to achieve viral suppression. We analyzed data from a cohort of HIV-infected children who were <2 years of age receiving protease inhibitor-based antiretroviral therapy to investigate associations between viral suppression and adherence ascertained using different methods. METHODS: Data were from the prerandomization phase of a clinical trial in South Africa of HIV-infected children initiating either ritonavir-boosted lopinavir (LPV/r) or ritonavir-based antiretroviral therapy. At scheduled visits during the first 24 weeks of enrollment, study pharmacists measured quantities of medications returned to the clinic. Caregivers answered questionnaires on missed doses and adherence barriers. Associations between adherence and viral suppression (HIV-1 RNA <400 copies/mL) were investigated by regimen. RESULTS: By 24 weeks, 197 of the 269 (73%) children achieved viral suppression. There was no association between viral suppression and caregiver reported missed doses or adherence barriers. For children receiving the LPV/r-based regimen, medication return adherence to each of the 3 drugs in the regimen (LPV/r, lamivudine or stavudine) individually or together was associated with viral suppression at different adherence thresholds. For example, <85% adherence to any of the 3 medications significantly increased odds of lack of viral suppression (odds ratio: 2.30, 95% confidence interval: 1.30-4.07, P = 0.004). In contrast, for children receiving the ritonavir-based regimen, there was no consistent pattern of association between medication return and viral suppression. CONCLUSIONS: Caregiver reports of missed doses did not predict virologic response to treatment. Pharmacist medication reconciliation correlated strongly with virologic response for children taking a LPV/r-based regimen and appears to be a valid method for measuring pediatric adherence.

Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial.

BACKGROUND: Protease-inhibitor-based treatment is recommended as first-line for infants infected with HIV who have been previously exposed to nevirapine prophylaxis. However, long-term use poses adherence challenges, is associated with metabolic toxic effects, restricts second-line options, and is costly. We present the long-term outcomes of switching nevirapine-exposed children to nevirapine-based treatment after effective suppression of virus replication with a protease-inhibitor-based regimen. METHODS: We did a randomised trial to compare long-term viral suppression with nevirapine-based versus protease-inhibitor-based (ritonavir-boosted lopinavir) treatment in children who had achieved suppression with protease-inhibitor-based treatment. Randomisation (1:1) was by cohort blocks of variable size between eight and 12. Eligible children were younger than 24 months who were previously exposed to nevirapine for prevention of mother-to-child transmission, and achieved virological suppression of less than 400 copies per mL when treated with the regimen based on ritonavir-boosted lopinavir in Johannesburg, South Africa. We gave all drugs as liquids and adjusted doses at each visit in accordance with growth. We continued follow-up for a minimum of 90 weeks and maximum of 232 weeks after randomisation. We quantified HIV RNA every 3 months. Our primary endpoint was any viraemia greater than 50 copies per mL. Our analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00117728. FINDINGS: We followed up the children for a median of 156 weeks and there were three deaths in each group. Children in the switch group (Kaplan-Meier probability 0·595) were less likely to experience non-suppression greater than 50 copies per mL than in the control group (0·687; p=0·01) and had better CD4 and growth responses initially after switching (52 children in the switch group vs 66 control group met this endpoint). By 156 weeks after randomisation, more children had virological failure--which we defined as confirmed viraemia of more than 1000 copies per mL--in the switch group (22 children) than in the control group (ten children; p=0·009). We detected all 22 failures in the switch group by 52 weeks compared with five in the control group. Virological failure was related to non-adherence and pretreatment drug resistance. In children without pretreatment drug resistance, we did not identify a significant difference in virological failure between the switch (Kaplan-Meier probability 0·140) and control (0·095) groups (p=0·34; seven failures in the switch group vs five in the control group). Children in the switch group were significantly more likely to develop grade 1-3 alanine aminotransferase abnormalities over the duration of follow-up. INTERPRETATION: Viral-load testing through 52 weeks can identify all children likely to fail this protease-inhibitor-switch strategy. Switching children once suppressed to a nevirapine-based regimen might be a valuable treatment option if adequate viral-load monitoring can be done. FUNDING: National Institutes of Child Health and Human Development and Secure the Future Foundation.

Lipid profiles in young HIV-infected children initiating and changing antiretroviral therapy.

BACKGROUND: Both HIV infection and antiretroviral therapy are associated with dyslipidemias in adults, but there are fewer data on outcomes in young children. Here we examined lipid profile changes in a cohort of young children before and after suppression on an initial ritonavir-boosted lopinavir (LPV/r)-based regimen and after switch to a nevirapine (NVP)-based regimen. METHODS: One hundred ninety-five HIV-infected children who initiated LPV/r-based therapy when <24 months of age at 1 site in Johannesburg, South Africa, and who achieved viral suppression (<400 copies/mL sustained for ≥ 3 months) were randomized to either continue on the LPV/r-based regimen (n = 99) or to switch to a NVP-based regimen (n = 96). Nonfasting concentrations of total cholesterol (TC), low-density lipoprotein, high-density lipoprotein (HDL), and triglycerides (TG) were measured pretreatment, at randomization when suppressed, and at 9, 20, and 31 months postrandomization. RESULTS: Median age at treatment initiation was 9 months, and the initial regimen was maintained for an average of 9 months before randomization. TC, low-density lipoprotein, and HDL increased from pretreatment to randomization (P < 0.0001) and TC/HDL ratio and TG decreased (P < 0.0001). After switching to NVP, HDL was significantly higher (P < 0.02) and TC/HDL and TG significantly lower (P < 0.0001) through 31 months postswitch relative to remaining on the LPV/r-based regimen. CONCLUSION: Initiating antiretroviral therapy was associated with changes to a more favorable lipid profile in young children. Switching from a LPV/r-based regimen to a NVP-based regimen accentuated and continued these improvements. Investigation of safe and effective methods for managing dyslipidemias in children of different ages in resource-limited settings is warranted.

Absence seizures associated with efavirenz initiation.

Efavirenz, used in treating pediatric human immunodeficiency virus infection, has central nervous system side effects. We report on a 5-year-old girl with perinatally acquired human immunodeficiency virus infection, presenting with new onset absence seizures after starting treatment with efavirenz. Plasma efavirenz values were above therapeutic range. The child was homozygous for the CYP2B6-516T/T genotype, which is associated with poor efavirenz clearance. Seizures abated after efavirenz discontinuation.

Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial.

CONTEXT: Protease inhibitor (PI)-based therapy is recommended for infants infected with human immunodeficiency virus (HIV) who were exposed to nevirapine for prevention of mother-to-child HIV transmission. However, there are limitations of continuing PI-based therapy indefinitely and reuse of nevirapine has many advantages. OBJECTIVE: To test whether nevirapine-exposed infants who initially achieve viral suppression with PI-based therapy can maintain viral suppression when switched to nevirapine-based therapy. DESIGN, SETTING, AND PATIENTS: Randomized trial conducted between April 2005 and May 2009 at a hospital in Johannesburg, South Africa, among 195 children who achieved viral suppression less than 400 copies/mL for 3 or more months from a cohort of 323 nevirapine-exposed children who initiated PI-based therapy before 24 months of age. INTERVENTIONS: Control group children continued to receive ritonavir-boosted lopinavir, stavudine, and lamivudine (n = 99). Switch group children substituted nevirapine for ritonavir-boosted lopinavir (n = 96). MAIN OUTCOME MEASURES: Children were followed up for 52 weeks after randomization. Plasma HIV-1 RNA of greater than 50 copies/mL was the primary end point. Confirmed viremia greater than 1000 copies/mL was used as a criterion to consider regimen changes for children in either group (safety end point). RESULTS: Plasma viremia greater than 50 copies/mL occurred less frequently in the switch group (Kaplan-Meier probability, 0.438; 95% CI, 0.334-0.537) than in the control group (0.576; 95% CI, 0.470-0.668) (P = .02). Confirmed viremia greater than 1000 copies/mL occurred more frequently in the switch group (0.201; 95% CI, 0.125-0.289) than in the control group (0.022; 95% CI, 0.004-0.069) (P < .001). CD4 cell response was better in the switch group (median CD4 percentage at 52 weeks, 34.7) vs the control group (CD4 percentage, 31.3) (P = .004). Older age (relative hazard [RH], 1.71; 95% CI, 1.08-2.72) was associated with viremia greater than 50 copies/mL in the control group. Inadequate adherence (RH, 4.14; 95% CI, 1.18-14.57) and drug resistance (RH, 4.04; 95% CI, 1.40-11.65) before treatment were associated with confirmed viremia greater than 1000 copies/mL in the switch group. CONCLUSION: Among HIV-infected children previously exposed to nevirapine, switching to nevirapine-based therapy after achieving viral suppression with a ritonavir-boosted lopinavir regimen resulted in lower rates of viremia greater than 50 copies/mL than maintaining the primary ritonavir-boosted lopinavir regimen. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00117728.