Initiating Antiretroviral Treatment Early in Infancy Has Long-term Benefits on the Human Immunodeficiency Virus Reservoir in Late Childhood and Adolescence.

BACKGROUND: Early combined antiretroviral therapy (cART) limits the total HIV-DNA load in children. However, data on its impact in older children and adolescents remain scarce. This study compares HIV reservoirs in children (5-12 years) and adolescents (13-17 years) who started cART <6 months (early [E-] group) or >2 years (late [L-] group). METHODS: The ANRS-EP59-CLEAC study prospectively enrolled 76 patients perinatally infected with HIV-1 who reached HIV-RNA <400 copies/mL <24 months after cART initiation, regardless of subsequent viral suppression (E-group: 27 children, 9 adolescents; L-group: 19 children, 21 adolescents). Total and integrated HIV-DNA were quantified in blood and in CD4+ T-cell subsets. A substudy assessed HIV reservoir inducibility after ex vivo peripheral blood mononuclear cell (PBMC) stimulation. RESULTS: Total HIV-DNA levels were lower in early- versus late-treated patients (children: 2.14 vs 2.87 log copies/million PBMCs; adolescents: 2.25 vs 2.74 log; P < .0001 for both). Low reservoir was independently associated with treatment precocity, protective HLA, and low cumulative viremia since cART initiation. The 60 participants with undetectable integrated HIV-DNA started cART earlier than other patients (4 vs 54 months; P = .03). In those with sustained virological control, transitional and effector memory CD4+ T cells were less infected in the E-group than in the L-group (P = .03 and .02, respectively). Viral inducibility of reservoir cells after normalization to HIV-DNA levels was similar between groups. CONCLUSIONS: Early cART results in a smaller blood HIV reservoir until adolescence, but all tested participants had an inducible reservoir. This deserves cautious consideration for HIV remission strategies.

Does transient cART started during primary HIV infection undermine the long-term immunologic and virologic response on cART resumption?

BACKGROUND: We explored the impact of transient cART started during the primary HIV-infection (PHI) on the long-term immunologic and virologic response on cART resumption, by comparison with treatment initiation during the chronic phase of HIV infection (CHI). METHODS: We analyzed data on 1450 patients enrolled during PHI in the ANRS PRIMO cohort between 1996 and 2013. "Treatment resumption" was defined as at least 3 months of resumed treatment following interruption of at least 1 month of treatment initiated during PHI. "Treatment initiation during CHI" was defined as cART initiated ≥6 months after PHI. The virologic response to resumed treatment and to treatment initiated during CHI was analyzed with survival models. The CD4 cell count dynamics was modeled with piecewise linear mixed models. RESULTS: 136 patients who resumed cART for a median (IQR) of 32 (18-51) months were compared with 377 patients who started cART during CHI for a median of 45 (22-57) months. Most patients (97%) achieved HIV-RNA <50 cp/mL after similar times in the two groups. The CD4 cell count rose similarly in the two groups during the first 12 months. However, after 12 months, patients who started cART during CHI had a better immunological response than those who resumed cART (p = 0.01); therefore, at 36 months, the gains in √CD4 cells/mm(3) and CD4% were significantly greater in patients who started treatment during CHI. CONCLUSION: These results suggest that interruption of cART started during PHI has a significant, albeit modest negative impact on CD4 cell recovery on cART resumption.

Long-term nonprogression of HIV infection in children: evaluation of the ANRS prospective French Pediatric Cohort.

BACKGROUND: Some children who are infected with human immunodeficiency virus type 1 (HIV-1) during the perinatal period remain asymptomatic for very long periods in the absence of antiretroviral treatment, as is the case for some adults. Our objective was to estimate the proportion of children who developed neither symptoms nor major immunological perturbations to the age of > or = 10 years in a prospective cohort of infected children who had been observed since birth. METHODS: The ongoing prospective French Pediatric Cohort includes 568 HIV-1-infected children. Here, we report the follow-up data for all 348 HIV-1-infected children who were born before 1 January 1994. Children with long-term nonprogression of infection (LTNPs) were defined as HIV-1-infected children who had been observed for at least 10 years, never received antiretroviral treatment other than zidovudine monotherapy, never developed symptoms of Centers for Disease Control and Prevention clinical category C or B, and had a CD4+ cell percentage of < 25% no more than once during follow-up. Other definitions were compared. RESULTS: The Kaplan-Meier estimate of long-term nonprogression was 2.4% (95% confidence interval, 1.1%-4.6%) at 10 years of age, and 7 children were classified as LTNPs. The Kaplan-Meier estimates decreased slightly with age, to 1.8% at 12 years of age and 1.4% at 14 years of age. Plasma HIV-1 replication rates were low (< 1000 copies RNA/mL) for 2 of the 7 LTNPs at the age of 10 years (0.6% of the total denominator). None of the routinely measured maternal or perinatal markers were significantly linked to long-term nonprogression, with the exception of the mother's Centers for Disease Control and Prevention clinical category at the time of delivery. CONCLUSIONS: Approximately 2% of children who were infected during the perinatal period displayed no immunological or clinical progression by the age of 10 years. This figure is close to that reported for adults in studies that have used similar definitions.

Comparing genotoxic signatures in cord blood cells from neonates exposed in utero to zidovudine or tenofovir.

OBJECTIVES: Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero. DESIGN: We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively). METHODS: The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs. RESULTS: Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups. CONCLUSION: Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes.

Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration.

OBJECTIVE: HIV "elite controllers" (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs). METHODS: ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models. RESULTS: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63√CD4/month), followed by +0.19√CD4/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm(3), the estimated mean CD4 T-cell gain during the first 12 months was 139/mm(3) in VIRs and 80/mm(3) in ECs (p = 0.048). CONCLUSIONS: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.

High exposure to zidovudine during the first 2 weeks of life and concentration-toxicity relationships.

OBJECTIVES: The aims of the study were in a large group of neonates to identify the relative effect of bodyweight, postnatal age, and gestational age on zidovudine (ZDV) pharmacokinetics; to link concentrations with lactate and hemoglobin levels; and to find the more appropriate neonatal ZDV dose. METHODS: In 484 neonates aged 3-30 days, born to HIV-infected mothers, 767 ZDV and 417 ZDV glucuronide concentrations were collected. RESULTS: Using a population approach, ZDV clearance per kilogram increased with postnatal age but not with gestational age. High neonatal exposures were found as follows: 14,025 ng/mL·h the first week and 6528 ng/mL·h the second week in comparison to 3000 ng/mL·h in adults. At month 1, median lactate level was 2.8 mmol/L (60%, ≥2.5 mmol/L) and median hemoglobin was 10.1 g/dL (90%, <12 g/dL). ZDV trough concentrations at first sampling (days 3-7) or at last sampling (day 20 ± 10) were significantly negatively correlated to hemoglobin at months 1, 3, and 6 (P < 0.02). ZDV maximal or trough concentrations at days 3-7 and at day 20 ± 10 were significantly positively correlated to lactate levels at months 3 and 6, respectively. CONCLUSIONS: To obtain an exposure comparable to adults, which should reduce neonatal toxicity, doses should to be decreased during the first 2 weeks of life.

CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory.

BACKGROUND: There are few large published studies of HIV controllers with long-term undetectable viral load (VL). We describe the characteristics and outcomes of 81 French HIV controllers. METHODS AND RESULTS: HIV controllers were defined as asymptomatic, antiretroviral-naïve persons infected ≥10 years previously, with HIV-RNA <400 copies/mL in >90% of plasma samples. All available CD4 and VL values were collected at enrolment. Mixed-effect linear models were used to analyze CD4 cell count slopes since diagnosis. HIV controllers represented 0.31% of all patients managed in French hospitals. Patients infected through intravenous drug use were overrepresented (31%) and homosexual men were underrepresented (26% of men) relative to the ANRS SEROCO cohort of subjects diagnosed during the same period. HIV controllers whose VL values were always below the detection limit of the assays were compared with those who had rare "blips" (<50% of VL values above the detection limit) or frequent blips (>50% of VL values above the detection limit). Estimated CD4 cell counts at HIV diagnosis were similar in the three groups. CD4 cell counts remained stable after HIV diagnosis in the "no blip" group, while they fell significantly in the two other groups (-0.26√CD4 and -0.28√CD4/mm(3)/year in the rare and frequent blip groups, respectively). No clinical, immunological or virological progression was observed in the no blip group, while 3 immunological and/or virological events and 4 cancers were observed in the blip subgroups. CONCLUSIONS: Viral blips in HIV controllers are associated with a significant decline in CD4 T cells and may be associated with an increased risk of pathological events, possibly owing to chronic inflammation/immune activation.