Antiretroviral treatment for children with peripartum nevirapine exposure.

BACKGROUND: Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS: We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. RESULTS: A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS: Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).

Socioemotional and behavioural difficulties in children with chronic physical conditions: analysis of the Longitudinal Study of Australian Children.

OBJECTIVES: To examine the prevalence of socioemotional and behavioural difficulties (SEBDs) in children with chronic physical conditions (CPCs) and to analyse how this prevalence varied with the type and number of CPCs and the age of the child. DESIGN: Cross-sectional study of a secondary data analysis of the Longitudinal Study of Australian Children. SETTING: An Australian nationally representative sample of general population of children. PARTICIPANTS: 15 610 children-waves aged 6-14 years. INTERVENTION/EXPOSURE: Children reported to have at least 1 of the 21 CPCs by their parents. MAIN OUTCOME MEASURES: Clinically relevant SEBDs were defined using standardised cut-offs of the parent-administered Strengths and Difficulties Questionnaire. RESULTS: Children with a CPC have significantly increased odds of total, internalising and externalising SEBDs than those without (total SEBDs, adjusted odds rartio or OR 3.13, 95% CI 2.52 to 3.89), controlling for sex, age, socioeconomic status and parental mental health status. The highest prevalence of total SEBDs was found in children with chronic fatigue (43.8%), epilepsy (33.8%) and day wetting (31.6%). An increasing number of comorbid CPCs was associated with a rising prevalence of SEBDs. On average, 24.2% of children with at least four CPCs had SEBDs. These children had 8.83-fold increased odds (95% CI 6.9 to 11.31) of total SEBDs compared with children without a CPC. Age was positively related to the odds of SEBDs. CONCLUSION: Children with a CPC have a significantly increased risk of having SEBDs than those without. These findings highlight the need for routine assessment and integrated intervention for SEBDs among children with CPCs.

Neurodevelopmental delay among HIV-infected preschool children receiving antiretroviral therapy and healthy preschool children in Soweto, South Africa.

Neurodevelopmental delay has been documented in up to 97.5% of HIV-infected children in Soweto who were not yet on antiretroviral treatment (ART). With growing numbers of children in South Africa being successfully treated with ART, the effects of ART on neurocognitive functioning in children require investigation. The objective of this study was to determine the extent of neurodevelopmental delay in stable HIV-infected preschool children (aged five to six years) receiving ART and compare it to an apparently healthy (unconfirmed HIV-status) group of preschool children. Thirty HIV-infected preschool children (virologically and immunologically stable on ART for more than one year) were conveniently sampled from 350 eligible children on ART at the Harriet Shezi Children's Clinic in Soweto, Johannesburg. The comparison group comprised 30 well-nourished preschool children attending the Lilian Ngoyi Primary Health Care Clinic in Soweto for routine immunizations. Each child was assessed using the Griffiths Mental Development Scales-Extended Revised Version (GMDS-ER), at a single point in time. The overall developmental z-scores on GMDS-ER were <-2 (indicating severe delay) in 27 (90%) children in the HIV-infected group compared to 23 (76%) in the comparison group (p = 0.166). Mental handicap (overall GQ < 70) was evident in 46.7% of children in the HIV-infected group compared to 10% in the comparison group (p = 0.002). There was a 7.88-fold increased likelihood of severe delay in the HIV infected group. The HIV-infected group and comparison group had significantly different (p = 0.001) mean overall GQ scores of 70 (95% CI: 66.0-74.0) and 78 (95% CI: 75.6-80.5), respectively, with lower mean scores in the HIV-infected group in all individual domains. Early initiation of ART in HIV-infected infants may improve cognitive functioning among this group; however, intervention strategies which optimize early cognitive development for all children in the area need to be urgently considered.

Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children.

BACKGROUND: Nevirapine resistance after failed prophylaxis to prevent mother-to-child human immunodeficiency virus (HIV) transmission can compromise subsequent nevirapine-based highly active antiretroviral therapy (HAART). METHODS: Nevirapine-exposed children who achieved virologic suppression with lopinavir/ritonavir-based induction HAART before switch to nevirapine-based HAART or who continued the lopinavir/ritonavir regimen were studied. Nevirapine-resistant HIV was quantified (≥ 1% frequency) in plasma before therapy and archived in peripheral blood mononuclear cells after induction HAART with ultradeep pyrosequencing. The primary endpoint was virologic failure (confirmed viremia ≥ 1000 copies/mL by 52 weeks) on nevirapine-based HAART, and Receiver operating characteristic analysis identified threshold levels of resistance associated with failure. RESULTS: Nevirapine resistance mutations were detected in plasma at a median frequency of 25.6% in 41 (33%) of 124 children starting HAART at median 9 months of age. After a median nine months of induction HAART, nevirapine-resistant HIV remained archived in cells in 59 (61%) of 96 children (median 13.6% of cells). The threshold frequency of nevirapine resistance in plasma most predictive of virologic failure on nevirapine-based HAART was 25%. Children maintaining resistance before therapy at or above this threshold frequency had a 3.5 fold higher risk of failure (95% confidence interval, 1.1-10.8) than children without detectable plasma resistance. In contrast, virologic failure was not independently associated with age, resistance in plasma below 25% frequencies, or archived in cells. CONCLUSIONS: Virologic suppression with lopinavir/ritonavir-based HAART in nevirapine-exposed children raises the threshold level of resistance at which reuse of nevirapine-based therapy is compromised. Standard genotyping may allow identification of children likely to benefit from an induction-switch approach.

Initial response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age in South Africa: effect of cotreatment for tuberculosis.

BACKGROUND: South African guidelines recommend protease-inhibitor-based antiretroviral therapy (ART) with lopinavir-ritonavir for human immunodeficiency virus (HIV)-infected children <36 months of age. We investigated factors associated with viral suppression and mortality among young children initiating ART. METHODS: Treatment-naive, ART-eligible, HIV-infected children (aged 6-104 weeks) were enrolled in an ART strategies trial in South Africa and initiated protease-inhibitor-based ART. Mortality and the probability of viral suppression (defined as HIV RNA load of <400 copies/mL) by 39 weeks after ART initiation were investigated. RESULTS: Of 254 children who initiated ART, 99 (39%) were cotreated for tuberculosis during follow-up. The mortality rate was 14%. Factors predicting mortality were lower pre-ART weight-for-age z score and higher HIV RNA load. By 39 weeks, 84% of surviving children achieved viral suppression. Children who were not cotreated for tuberculosis were more likely to achieve viral suppression (94.8%) than were children who were receiving cotreatment at ART initiation (74.2%) or who started tuberculosis cotreatment after ART initiation (51.6%; P < .001). Other factors predicting lower probability of viral suppression were lower pre-ART weight- and length-for-age z score, higher HIV RNA load, and World Health Organization disease stage. CONCLUSION: High rates of viral suppression can be achieved among infants and young children who initiate protease-inhibitor-based ART. Cotreatment for tuberculosis reduced viral suppression. How best to treat HIV-infected children who require tuberculosis treatment warrants urgent investigation.

Pharmacokinetics and Safety of a Raltegravir-Containing Regimen in Children Aged 4 Weeks to 2 Years Living With Human Immunodeficiency Virus and Receiving Rifampin for Tuberculosis.

Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to <2 years receiving concurrent rifampin to treat TB. CLINICAL TRIALS REGISTRATION: NCT01751568.

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.

Persistent minority K103N mutations among women exposed to single-dose nevirapine and virologic response to nonnucleoside reverse-transcriptase inhibitor-based therapy.

OBJECTIVE: We investigated whether there are long-lasting effects of exposure to single-dose nevirapine (sdNVP) treatment on virologic response to nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy among human immunodeficiency virus (HIV)-infected women. METHODS: An observational epidemiologic study was conducted in Johannesburg, South Africa. Initial and sustained virologic response to NNRTI-based therapy was compared between 94 HIV-infected women who had received sdNVP 18-36 months earlier and 60 unexposed, HIV-infected women who had been pregnant 12-36 months earlier. Viral load was measured every 4 weeks up to week 24 and then every 12 weeks up to week 78. Time to viral suppression (viral load, <50 copies/mL) and confirmed rebound in the viral load (viral load, >400 copies/mL) were compared. Drug resistance was assessed using K103N allele-specific real-time polymerase chain reaction assay and population sequencing. RESULTS: Almost all women (97.5% of sdNVP-exposed women and 91.3% of sdNVP-unexposed women; P = .21) achieved viral suppression by week 24, and similar percentages of sdNVP-exposed and -unexposed women (19.4% and 15.1%, respectively) experienced viral rebound within 78 weeks after treatment (P = .57). K103N was detected with the K103N allele-specific real-time polymerase chain reaction assay among sdNVP-exposed and -unexposed women before treatment; detection was strongly predictive of inadequate viral response: 60.9% of women for whom K103N was detected in either viral RNA or DNA did not experience viral suppression or experienced viral rebound, compared with 15.1% of women for whom K103N was not detected (P < .001). After treatment, the M184V mutation occurred less frequently among sdNVP-exposed women than among sdNVP-unexposed women, but the frequency of NNRTI-associated mutations was similar between these groups of women with inadequate virologic response. CONCLUSIONS: Exposure to sdNVP in the prior 18-36 months was not associated with a reduced likelihood of achieving and sustaining viral suppression while receiving NNRTI-based therapy. However, women with minority K103N mutations before treatment had a reduced durability of virologic suppression.

4E10-resistant variants in a human immunodeficiency virus type 1 subtype C-infected individual with an anti-membrane-proximal external region-neutralizing antibody response.

The broadly neutralizing monoclonal antibody (MAb) 4E10 recognizes a linear epitope in the C terminus of the membrane-proximal external region (MPER) of gp41. This epitope is particularly attractive for vaccine design because it is highly conserved among human immunodeficiency virus type 1 (HIV-1) strains and neutralization escape in vivo has not been observed. Multiple env genes were cloned from an HIV-1 subtype C virus isolated from a 7-year-old perinatally infected child who had anti-MPER neutralizing antibodies. One clone (TM20.13) was resistant to 4E10 neutralization as a result of an F673L substitution in the MPER. Frequency analysis showed that F673L was present in 33% of the viral variants and in all cases was linked to the presence of an intact 2F5 epitope. Two other envelope clones were sensitive to 4E10 neutralization, but TM20.5 was 10-fold less sensitive than TM20.6. Substitutions at positions 674 and 677 within the MPER rendered TM20.5 more sensitive to 4E10 but had no effect on TM20.6. Using chimeric and mutant constructs of these two variants, we further demonstrated that the lentivirus lytic peptide-2 domain in the cytoplasmic tail affected the accessibility of the 4E10 epitope, as well as virus infectivity. Collectively, these genetic changes in the face of a neutralizing antibody response to the MPER strongly suggested immune escape from antibody responses targeting this region.

Pharmacokinetics and safety of a raltegravir-containing regimen in HIV-infected children aged 2-12 years on rifampicin for tuberculosis.

OBJECTIVES: Drug-drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose of RAL when administered with RIF to HIV and TB co-infected children. DESIGN: P1101 is a phase I/II open-label dose-finding study of RAL with RIF for children 2 to less than 12 years of age beginning treatment for HIV and active TB. SETTING: Four sites in South Africa. METHODS: Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after antiretroviral therapy was initiated; a fourth antiretroviral agent was then added. RESULTS: Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old) and cohort 2 (6 to <12 years old). Pharmacological targets [geometric mean (GM) AUC12 h of 14-45 µmol/l h and GM C12 h ≥75 nmol/l) were reached in both cohort 1 (28.8 µmol/l h and 229 nmol/l) and cohort 2 (38.8 µmol/l h and 228 nmol/l). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment because of grade 4 hepatitis that was possibly treatment-related. At week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml; 19 of 24 (79%) were below 50 copies/ml. CONCLUSION: Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.

Hepatitis C virus infection in children and adolescents.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated morbidity and mortality worldwide. Short-course, oral, curative, direct-acting antiviral regimens have transformed treatment for HCV infection. Since the 2016 launch of the first global strategy towards elimination of viral hepatitis as a public health threat by 2030, the predominant focus of the global response has been on the treatment of adults, who bear the greatest burden of morbidity and mortality of HCV-related chronic liver disease. Compared with adults, there has been little attention paid to addressing the response to HCV in children and adolescents, in part because of the scarcity of data to inform specific paediatric management practices and policy. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HCV infection in adolescents and children, and we highlight key differences from infection acquired in adulthood. The estimated global prevalence and burden of HCV infection in children aged 1-19 years is 0·15%, corresponding to 3·5 million people (95% CI 3·1-3·9 million). HCV infection is usually asymptomatic during childhood, and cirrhosis and hepatocellular carcinoma are rare. Sofosbuvir with ledipasvir and sofosbuvir with ribavirin have received regulatory approval and guidelines recommend their use in adolescents aged 12 years and older with HCV infection. In April, 2019, glecaprevir with pibrentasvir also received regulatory approval for adolescents aged 12-17 years. Key actions to address the current policy gaps and achieve treatment scale-up that is comparable to that in adults include: establishment of a campaign on access to testing and treatment that is targeted at children and adolescents; fast-track evaluation of pan-genotypic regimens; and accelerated approval of paediatric formulations. Research gaps that need to be addressed include: age-specific prevalence studies of HCV viraemia in priority countries; further validation of non-invasive tests for staging of liver disease in children; and establishment of paediatric treatment registries and international consortia to promote collaborative research agendas.

Hepatitis B virus infection in children and adolescents.

Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease and associated morbidity and mortality worldwide. Vertical (mother-to-child) and horizontal early childhood transmission are the main routes of HBV transmission and are responsible for most chronic infections, including among adults who bear the greatest burden of morbidity and mortality. Universal hepatitis B immunisation at birth and in infancy is the key strategy for global elimination of HBV infection, and has been highly effective in reducing new vertical infections. However, global progress in scale-up of HBV testing and treatment has been slow in adults and children. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HBV infection in adolescents and children, and we highlight key differences from HBV infection in adults. The estimated global prevalence of HBV infection in children aged 5 years or younger is 1·3%. Most children are in the high-replication, low-inflammation phase of infection, with normal or only slightly raised aminotransferases; cirrhosis and hepatocellular carcinoma are rare. Although entecavir is approved and recommended for children aged 2-17 years, and tenofovir for those aged 12-18 years, a conservative approach to treatment initiation in children is recommended. Key actions to address current policy gaps include: validation of non-invasive tests for liver disease staging; additional immunopathogenesis studies in children with HBV infection; long-term follow-up of children on nucleoside or nucleotide analogue regimens to inform guidance on when to start treatment; evaluation of different treatment strategies for children with high rates of HBV replication; and establishment of paediatric treatment registries and international consortia to promote collaborative research.

Polymorphisms in Nef associated with different clinical outcomes in HIV type 1 subtype C-infected children.

The human immunodeficiency virus type 1 (HIV-1) negative factor, or Nef, has a variety of functions that are important in viral pathogenesis. Sequence analysis has identified nef mutations that are linked to the rate of disease progression in adults and children infected with HIV-1 subtype B. Here we have sequenced and analyzed HIV-1 subtype C nef sequences from 34 children with rapid (RP) or slow progressing (SP) disease and identified polymorphisms associated with disease stage including motifs involved in specific pathogenic functions. Unlike subtype B, insertions and deletions in the N-terminal variable region were observed exclusively in SP children (8 out of 25). Strong positive selection pressures were found in sites of known functional importance among SP sequences, whereas RP had strong negative selection across the gene. A lineage analysis of selection pressures indicated weaker pressure across the nef gene in SP sequences bearing a deletion in region 8-12, suggesting this deletion has functional importance in vivo. Together these results suggest a differential adaptation of certain Nef functions related to disease progression, some of which may be attributable to immune-imposed pressures. These data broadly reflect previous studies on subtype B, corroborate the decreased cytopathicity of SP viruses, but also highlight potential subtype differences that require further investigation.

Insensitivity of paediatric HIV-1 subtype C viruses to broadly neutralising monoclonal antibodies raised against subtype B.

BACKGROUND: A Phase I clinical trial has been proposed that uses neutralising monoclonal antibodies (MAbs) as passive immunoprophylaxis to prevent mother-to-child transmission of HIV-1 in South Africa. To assess the suitability of such an approach, we determined the sensitivity of paediatric HIV-1 subtype C viruses to the broadly neutralising MAbs IgG1b12, 2G12, 2F5, and 4E10. METHODS AND FINDINGS: The gp160 envelope genes from seven children with HIV-1 subtype C infection were cloned and used to construct Env-pseudotyped viruses that were tested in a single-cycle neutralisation assay. The epitopes defining three of these MAbs were determined from sequence analysis of the envelope genes. None of the seven HIV-1 subtype C pseudovirions was sensitive to 2G12 or 2F5, which correlated with the absence of crucial N-linked glycans that define the 2G12 epitope and substitutions of residues integral to the 2F5 epitope. Four viruses were sensitive to IgG1b12, and all seven viruses were sensitive to 4E10. CONCLUSIONS: Only 4E10 showed significant activity against HIV-1 subtype C isolates, while 2G12 and 2F5 MAbs were ineffective and IgG1b12 was partly effective. It is therefore recommended that 2G12 and 2F5 MAbs not be used for passive immunization experiments in southern Africa and other regions where HIV-1 subtype C viruses predominate.

Genotypic and phenotypic characterization of viral isolates from HIV-1 subtype C-infected children with slow and rapid disease progression.

The genotypes and biological phenotypes of HIV-1 isolates obtained from 40 perinatally infected children in South Africa were analyzed. This included 15 infants who had HIV-related symptoms, most of whom died within 2 years of birth (rapid progressors), and 25 children who survived between 4 and 9 years with varying signs of disease (slow progressors). Heteroduplex mobility assays and sequence analysis confirmed that within the env and gag regions, all isolates were HIV-1 subtype C. Viral isolates from 14 of the 15 rapid progressors used the CCR5 coreceptor, whereas 1 (02ZARP1) used both the CXCR4 and CCR5 coreceptors. Among the 25 slow progressors, 22 isolates used CCR5 only, 2 used CXCR4 only, and 1 used both CCR5 and CXCR4. Two of the slow-progressing children who harbored CXCR4-using viruses had AIDS. All four CXCR4-using viruses had genotypic changes in the V3 region previously shown to be associated with CXCR4 usage. This cross-sectional study shows that HIV-1 subtype C viruses from both rapid- and slow-progressing perinatally infected children used predominantly CCR5. Similar to adults, CXCR4 usage was uncommon among HIV-1 subtype C isolates from pediatric infections.

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.

Age-specific and sex-specific weight gain norms to monitor antiretroviral therapy in children in low-income and middle-income countries.

BACKGROUND: Viral load and CD4% are often not available in resource-limited settings for monitoring children's responses to antiretroviral therapy (ART). We aimed to construct normative curves for weight gain at 6, 12, 18, and 24 months following initiation of ART in children, and to assess the association between poor weight gain and subsequent responses to ART. DESIGN: Analysis of data from HIV-infected children younger than 10 years old from African and Asian clinics participating in the International epidemiologic Databases to Evaluate AIDS. METHODS: The generalized additive model for location, scale, and shape was used to construct normative percentile curves for weight gain at 6, 12, 18, and 24 months following ART initiation. Cox proportional models were used to assess the association between lower percentiles (< 50th) of weight gain distribution at the different time points and subsequent death, virological suppression, and virological failure. RESULTS: Among 7173 children from five regions of the world, 45% were underweight at baseline. Weight gain below the 50th percentile at 6, 12, 18, and 24 months of ART was associated with increased risk of death, independent of baseline characteristics. Poor weight gain was not associated with increased hazards of virological suppression or virological failure. CONCLUSION: Monitoring weight gain on ART using age-specific and sex-specific normative curves specifically developed for HIV-infected children on ART is a simple, rapid, sustainable tool that can aid in the identification of children who are at increased risk of death in the first year of ART.

Positive association between dietary iron intake and iron status in HIV-infected children in Johannesburg, South Africa.

Anemia is a common complication of pediatric HIV infection and is associated with suboptimal cognitive performance and growth failure. Routine iron supplementation is not provided to South African HIV-infected children. We hypothesized that dietary iron intake without supplementation is sufficient to protect against iron deficiency (ID) in HIV-infected children receiving highly active antiretroviral therapy. In this prospective study, the difference between dietary intakes of iron-deficient children (soluble transferrin receptor >9.4 mg/L) and iron-sufficient children after 18 months on highly active antiretroviral therapy was examined. The association between iron intake and hemoglobin (Hb) concentration was also assessed. Longitudinal data collected for 18 months from 58 HIV-infected African children were assessed by generalized estimation equations, with adjustment for demographic information, dietary intakes, growth parameters, and CD4%. After adjustment for covariates, the longitudinal association between dietary iron intake and Hb concentration remained significant. This association shows that for every 1-mg increase in iron intake per day, Hb increases by 1.1 g/L (P < .001). Mean Hb increased significantly after 18 months of follow-up (106 ± 14 to 129 ± 14 g/L, P < .01), but soluble transferrin receptor also increased (7.7 ± 2.7 to 8.9 ± 3.0 mg/L, P < .01). The incidence of ID increased from 15.2% at baseline to 37.2% after 18 months. Children with animal protein intakes greater than >20 g/d had significantly lower odds for ID at 18 months than did children with lower intakes (odds ratio, 0.40; 95% confidence interval, 0.21-0.77). Dietary iron intake was insufficient to protect against ID, pointing to a need for low-dose iron supplementation for iron-deficient HIV-infected children and interventions to increase the consumption of animal protein.