Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Role of efavirenz plasma concentrations on long-term HIV suppression and immune restoration in HIV-infected children.

BackgroundTo access the long term relationship between efavirenz plasma concentrations and evolution of HIV RNA loads and CD4 cell counts in children.MethodsRetrospective analysis of data from HIV-infected children on first line efavirenz-containing regimen. A population pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the evolution of HIV RNA load and CD4 cell count (efficacy outcomes) in relation to efavirenz plasma concentration. Individual CYP2B6 516 G>T genotype data were not available for this analysis. A score (ISEFV) quantifying the effect of efavirenz concentrations on the long-term HIV replication was calculated from efavirenz concentrations and PD parameters and, a value of ISEFV below which HIV replication is likely not suppressed was determined. Cox proportional hazards regression models were used to assess the association of the risk of viral replication with ISEFV, and with efavirenz mid-dose concentration(C12).ResultsAt treatment initiation, median (interquartile range, IQR) age was 8 years (5 to 10), body weight 17 kg (14 to 23), HIV RNA load 5.1 log10 copies/mL (4.6 to 5.4), and CD4 cell count 71 cells/mm3. A model of PK-PD viral dynamics assuming that efavirenz decreases the rate of infected host cells adequately described the relationship of interest. After adjusting for age, baseline HIV RNA load and CD4 cell counts an ISEFV ConclusionThe ISEFV score was a good predictor of viral replication in children on efavirenz-based treatment

Incidence and risk factors of loss to follow-up among HIV-infected children in an antiretroviral treatment program

International audienceIntroductio: The success of antiretroviral treatment (ART) programs can be compromised by high rates of patient loss to follow-up (LTFU). We assessed the incidence and risk factors of LTFU in a large cohort of HIV-infected children receiving ART in Thailand.Methods: All children participating in a multicenter cohort (NCT00433030) between 1999 and 2014 were included. The date of LTFU was 9 months after the last contact date. ART interruption was defined as ART discontinuation for more than 7 days followed by resumption of treatment. Baseline and time-dependent risk factors associated with LTFU were identified using Fine and Gray competing risk regression models with death or referral to another hospital as competing events.Results: Of 873 children who were followed during a median of 8.6 years (interquartile range 4.5–10.6), 196 were LTFU, 73 died, and 195 referred. The cumulative incidence of LTFU was 2.9% at 1 year, 7.3% at 5 years and 22.2% at 10 years. Children aged 13 years and more had a 3-fold higher risk (95% confidence interval 2.06–4.78) of LTFU than those younger. Children who had interrupted ART within the previous year had a 2.5-fold higher risk (1.12–5.91) than those who had not. The risk of LTFU was lower in children stunted (height-for-age Z-scores <-2 SD) (0.42–0.96) or underweight (weight-for-age Z-scores <-2 SD) (0.24–0.97).Conclusion: Adolescence, ART interruption and absence of growth deficit were associated with LTFU. These may be warnings that should draw clinicians’ attention and possibly trigger specific interventions. Children with no significant growth retardation may also be at risk of LTFU

Incidence of Tuberculosis and Associated Mortality in a Cohort of Human Immunodeficiency Virus-Infected Children Initiating Antiretroviral Therapy

Background.: We assessed the incidence of tuberculosis, risk factors for tuberculosis, and the contribution of tuberculosis on mortality in a large cohort of human immunodeficiency virus (HIV)-infected children 30 days after ART initiation, divided by the total person-years of follow-up (PYFU). Risk factors for incident tuberculosis were identified using Fine and Gray's competing risks models, with death from other causes treated as a competing event, and risk factors for death were identified using Cox models. Results.: At ART initiation, 670 children (55% female) had a median age of 6.4 years (interquartile range, 2.0-9.6), body mass index-for-age z-score -0.8 (-1.9 to 0.0), HIV ribonucleic acid viral load 5.1 log10 copies/mL (4.6-5.6), and CD4 9% (3-17). Median duration of follow-up was 7.7 years. Tuberculosis incidence was 7 per 1000 PYFU (95% confidence interval [CI], 5-11) and decreased with ART duration. Lower age-adjusted hemoglobin, hematocrit, and CD4 at ART initiation were associated with a higher risk of incident tuberculosis. Of the 30 incident tuberculosis cases, 9 died. Diagnosis of incident tuberculosis was associated with mortality (unadjusted hazard ratio = 10.2, 95% CI = 4.8-21.5, P < .001 and adjusted hazard ratio = 5.4, 95% CI = 2.5-11.7, P < .001). Conclusions.: Incident tuberculosis was strongly associated with mortality. CD4 counts or hemoglobin or hematocrit levels may prompt clinicians to consider a possible tuberculosis infection

Incidence of Tuberculosis and Associated Mortality in a Cohort of Human Immunodeficiency Virus-Infected Children Initiating Antiretroviral Therapy

Abstract Background. We assessed the incidence of tuberculosis, risk factors for tuberculosis, and the contribution of tuberculosis on mortality in a large cohort of human immunodeficiency virus (HIV)-infected children 30 days after ART initiation, divided by the total person-years of follow-up (PYFU). Risk factors for incident tuberculosis were identified using Fine and Gray’s competing risks models, with death from other causes treated as a competing event, and risk factors for death were identified using Cox models. Results. At ART initiation, 670 children (55% female) had a median age of 6.4 years (interquartile range, 2.0–9.6), body mass index-for-age z-score −0.8 (−1.9 to 0.0), HIV ribonucleic acid viral load 5.1 log10 copies/mL (4.6–5.6), and CD4 9% (3–17). Median duration of follow-up was 7.7 years. Tuberculosis incidence was 7 per 1000 PYFU (95% confidence interval [CI], 5–11) and decreased with ART duration. Lower age-adjusted hemoglobin, hematocrit, and CD4 at ART initiation were associated with a higher risk of incident tuberculosis. Of the 30 incident tuberculosis cases, 9 died. Diagnosis of incident tuberculosis was associated with mortality (unadjusted hazard ratio = 10.2, 95% CI = 4.8–21.5, P < .001 and adjusted hazard ratio = 5.4, 95% CI = 2.5–11.7, P < .001). Conclusions. Incident tuberculosis was strongly associated with mortality. CD4 counts or hemoglobin or hematocrit levels may prompt clinicians to consider a possible tuberculosis infection

Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy

BACKGROUND: Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV (PMTCT) have evolved overtime. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV-RNA viral load (VL) during pregnancy. METHODS: A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either (1) zidovudine (ZDV) monotherapy, (2) ZDV+lopinavir/ritonavir (LPV/r) or (3) ZDV+lamivudine (3TC)+LPV/r. VL time-course during pregnancy was described as a function of pre-treatment VL and treatment duration using an Emax non-linear mixed effect model. VL reduction and median time to achieve a VL<50 copies/mL were estimated for each regimen. RESULTS: Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r, ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/mL with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/mL. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/mL and the higher the pre-treatment VL, the larger the impact 3TC had on reducing the time to VL<50 copies/mL. CONCLUSIONS: The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/mL was shorter. This beneficial effect of 3TC is critical for PMTCT in women who receive ARVs late and with high pre-treatment VL

Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy

BACKGROUND: Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV (PMTCT) have evolved overtime. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV-RNA viral load (VL) during pregnancy. METHODS: A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either (1) zidovudine (ZDV) monotherapy, (2) ZDV+lopinavir/ritonavir (LPV/r) or (3) ZDV+lamivudine (3TC)+LPV/r. VL time-course during pregnancy was described as a function of pre-treatment VL and treatment duration using an Emax non-linear mixed effect model. VL reduction and median time to achieve a VL<50 copies/mL were estimated for each regimen. RESULTS: Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r, ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/mL with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/mL. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/mL and the higher the pre-treatment VL, the larger the impact 3TC had on reducing the time to VL<50 copies/mL. CONCLUSIONS: The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/mL was shorter. This beneficial effect of 3TC is critical for PMTCT in women who receive ARVs late and with high pre-treatment VL

Maternal and Infant Bone Mineral Density 1 Year After Delivery in a Randomized, Controlled Trial of Maternal Tenofovir Disoproxil Fumarate to Prevent Mother-to-child Transmission of Hepatitis B Virus.

In a randomized, double-blind, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) use from 28 weeks gestational age to 2 months postpartum to prevent mother-to-child transmission of hepatitis B virus, there was no significant effect of maternal TDF use on maternal or infant bone mineral density 1 year after delivery/birth. Clinical Trials Registration. NCT01745822

Prevalence and Clinical Outcomes of Poor Immune Response Despite Virologically Suppressive Antiretroviral Therapy Among Children and Adolescents With Human Immunodeficiency Virus in Europe and Thailand: Cohort Study

International audienceIn human immunodeficiency virus (HIV)-positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART