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 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

Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study

Background Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle-and high-income countries, including some in Western and Central Europe (W&amp;CE), Eastern Europe (Russia and Ukraine), and Thailand. Methods and findings Children with perinatal HIV aged &lt; 18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (&lt;=/&gt; 6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&amp;CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged &lt; 5 years had a CD4 lymphocyte percentage &lt; 15% in 1997-2003, which fell to 15% of children in 2011 onwards (p &lt; 0.001). Similarly, 53% and 18% of children &gt;= 5 years had a CD4 count &lt; 200 cells/mm(3) in 1997-2003 and in 2011 onwards, respectively (p &lt; 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load &gt; 400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time. Conclusions In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred &lt;= 6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&amp;CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at &gt; 6 months after initiation of cART

Characteristics of children overall, and by timing of death, for those who died.

<p>Characteristics of children overall, and by timing of death, for those who died.</p

Rates of AIDS-defining events among children with no previous AIDS diagnosis at initiation of cART, <i>N</i> = 2,863.

<p>Rates of AIDS-defining events among children with no previous AIDS diagnosis at initiation of cART, <i>N</i> = 2,863.</p

Causes of death for children who died, overall, and by timing of death.

<p>Causes of death for children who died, overall, and by timing of death.</p

CD4% (left panel) and count (right panel) at initiation of cART, by age group and calendar period.

<p>cART, combination antiretroviral therapy; CD4%, CD4 lymphocyte percentage.</p

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