Els Dobbels

Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial

BACKGROUND Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. METHODS CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir-ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960. FINDINGS 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16-25). Time to restarting of ART after interruption was 33 weeks (26-45) in ART-40W and 70 weeks (35-109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38-0·93, p=0·02) for ART-40W and 0·47 (0·27-0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. INTERPRETATION Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. FUNDING US National Institutes of Health.

Immunogenicity following the first and second doses of 7-valent pneumococcal conjugate vaccine in HIV-infected and -uninfected infants.

BACKGROUND The immunogenicity of pneumococcal conjugate vaccine (PCV) has not been evaluated in HIV-infected infants following the first and second PCV-doses. We studied antibody kinetics of serotypes included in 7-valent PCV in HIV-infected and HIV-uninfected infants prior to and following each of three PCV-doses. METHODS HIV-uninfected infants born to HIV-uninfected (HUU) and HIV-infected mothers (HEU); and perinatal HIV-infected children with CD(4+)<25% randomized to initiate antiretroviral treatment (ART) when clinically and/or immunologically indicated (ART-) or immediately (ART+) were enrolled. Vaccination occurred at approximately 7.4, 11.5 and 15.5 weeks of age. Serotype-specific antibody was measured by ELISA following each PCV-dose and opsonophagocytic activity (OPA) to three serotypes following the second and third doses. RESULTS Pre-vaccination, antibody geometric mean concentrations (GMCs) were higher in HUU compared to HIV-exposed groups for most serotypes. GMCs and proportion of infants with antibody ≥0.35 μg/ml were similar in HUU compared to other groups following the second PCV-dose. In all groups, GMCs were greater following the third compared to post-second dose; and a higher proportion within each group had antibody ≥0.35 μg/ml to 6B and 23F. OPA GMTs increased after the third compared to post-second dose for studied-serotypes; as did the proportion with OPA ≥8 to 23F. CONCLUSION A two-dose primary-series of PCV probably confers similar protection against invasive pneumococcal disease in HIV-infected compared to HUU children. The inferior response to serotypes 6B and 23F, and lower GMCs and OPA GMTs, following two compared to after three PCV-doses may have implications in the prevention of pneumococcal disease in high-burden countries.

White matter signal abnormalities in children with suspected HIV-related neurologic disease on early combination antiretroviral therapy.

Background: The natural history and manifestation of HIV-related neurologic disease have been ameliorated by combination antiretroviral therapy (ART). We describe the characteristics of white matter signal abnormalities (WMSA) on magnetic resonance imaging in children with HIV-related neurologic disease. Methods: We reviewed magnetic resonance imaging scans of children with suspected HIV-related neurologic disease despite early ART and correlated with clinical, neurodevelopmental data, virologic markers and time on ART. These children were also on the Children with HIV Early Antiretroviral (CHER) trial. Results: Magnetic resonance imaging scans were performed at a mean age 31.9 months (range 8–54) on 44 children: 10 on deferred and 34 on early treatment arms, commencing ART at mean age of 18.5 and 8 weeks, respectively. Multiple high signal intensity lesions on T2/fluid attenuated inversion recovery were documented in 22 patients (50%), predominantly in frontal (91%) and parietal (82%) white matter. No differences in neurodevelopmental scores comparing children with and without WMSA were found. Neither lesion load nor distribution showed significant correlation with neurodevelopmental scores or neurologic examination. Normal head growth was more common in the WMSA group (P = 0.01). There was a trend for association of WMSA and longer time on ART (P = 0.13) and nadir CD4% (P = 0.08). Conclusions: Half of children referred with HIV-related brain disease had WMSA on T2/fluid attenuated inversion recovery. Our findings of the association with normal head growth and duration of ART require further study. We suspect that WMSA can occur early and that initiating ART by 8 weeks of life may be too late to prevent HIV from entering the central nervous system.

HIV-associated CD4+/CD8+ depletion in infancy is associated with neurometabolic reductions in the basal ganglia at age 5 years despite early antiretroviral therapy.

Objective:Investigating consequences of early or late antiretroviral therapy (ART) initiation in infancy on young brain development using magnetic resonance spectroscopy. Design:Most pediatric HIV/ART-related neurological studies are from neuropsychological/clinical perspectives. Magnetic resonance spectroscopy can elucidate the mechanisms underpinning neurocognitive outcomes by quantifying the brains chemical condition through localized metabolism to provide insights into health and development. Methods:Basal ganglia metabolite concentrations were assessed in thirty-eight 5-year-old HIV-infected children previously participating in a randomized trial comparing early limited ART to deferred continuous ART, as well as 15 uninfected controls (12 HIV exposed). Metabolite levels were compared between 26 infected children who initiated ART at/before 12 weeks and 12 who initiated afterward, and were correlated with clinical HIV and treatment-related measures. Results:HIV-infected children initiating ART after 12 weeks had lower creatine, choline and glutamate (P < 0.05) than those initiating ART at/before 12 weeks. The CD4+/CD8+ ratio at baseline correlated with N-acetyl-aspartate (r = 0.56, P = 0.003) and choline (r = 0.36, P = 0.03) at 5 years, irrespective of treatment regimen and ART interruption. In comparison with uninfected controls, 80% of whom were HIV-exposed in utero, children on early treatment had higher N-acetyl-aspartate (P = 0.006) and choline (P = 0.03). Conclusions:Despite early ART (<12 weeks), low baseline CD4+/CD8+ predicts brain metabolite levels in later childhood. Also, HIV exposure and antiretroviral exposure for preventing vertical HIV transmission may hinder metabolite health, but needs further investigation.

Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

Abstract: The WHO recommends protease inhibitor (PI)–based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited.

Utility of clinical parameters to identify HIV infection in infants below ten weeks of age in South Africa: a prospective cohort study

BackgroundAs HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa.HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fishers exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings.Results417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50th centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression.ConclusionsA combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere.

Five year neurodevelopment outcomes of perinatally HIV-infected children on early limited or deferred continuous antiretroviral therapy

Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV‐infected (HIV‐positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long‐term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV‐infected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART‐Def); immediate time‐limited ART for 40 weeks (ART‐40W) or 96 weeks (ART‐96W). ART was restarted in the time‐limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants.

Functional Connectivity Alterations between Networks and Associations with Infant Immune Health within Networks in HIV Infected Children on Early Treatment: A Study at 7 Years

Although HIV has been shown to impact brain connectivity in adults and youth, it is not yet known to what extent long-term early antiretroviral therapy (ART) may alter these effects, especially during rapid brain development in early childhood. Using both independent component analysis (ICA) and seed-based correlation analysis (SCA), we examine the effects of HIV infection in conjunction with early ART on resting state functional connectivity (FC) in 7 year old children. HIV infected (HIV+) children were from the Children with HIV Early Antiretroviral Therapy (CHER) trial and all initiated ART before 18 months; uninfected children were recruited from an interlinking vaccine trial. To better understand the effects of current and early immune health on the developing brain, we also investigated among HIV+ children the association of FC at 7 years with CD4 count and CD4%, both in infancy (6–8 weeks) and at scan. Although we found no differences within any ICA-generated resting state networks (RSNs) between HIV+ and uninfected children (27 HIV+, 18 uninfected), whole brain connectivity to seeds located at RSN connectivity peaks revealed several loci of FC differences, predominantly from seeds in midline regions (posterior cingulate cortex, paracentral lobule, cuneus, and anterior cingulate). Reduced long-range connectivity and increased short-range connectivity suggest developmental delay. Within the HIV+ children, clinical measures at age 7 years were not associated with FC values in any of the RSNs; however, poor immune health during infancy was associated with localized FC increases in the somatosensory, salience and basal ganglia networks. Together these findings suggest that HIV may affect brain development from its earliest stages and persist into childhood, despite early ART.

Late-Onset Hiv Encephalopathy In Children With Long-Standing Virologic Suppression Followed By Slow Spontaneous Recovery Despite no Change In Antiretroviral Therapy: 4 Case Reports

We describe 4 Children with HIV Early Antiretroviral Therapy trial participants with late-onset HIV encephalopathy despite long-standing viral suppression in blood and undetectable HIV DNA and RNA polymerase chain reaction in cerebrospinal fluid. Extensive investigations revealed no alternative etiology. Reassuringly, all 4 experienced slow spontaneous recovery despite no change in antiretroviral therapy. Virally suppressed HIV-infected children remain at risk for fluctuating neurologic signs and symptoms.