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Background: Intravenous administration of zidovudine (ZDV) during labour is a key step for vertical HIV transmission (VT) prevention, but there is no evidence of benefit when maternal HIV-RNA at delivery is <50 copies/mL. The aim of this study is evaluating the appropriateness of intrapartum ZDV use in Italy., Methods: Observational study including mother-infant pairs with perinatal HIV exposure during 2002-2019, enrolled in the Italian Register for HIV Infection in Children. Univariable and multivariable logistic regression were used to evaluate factors associated with VT., Results: A total of 3,861 infants, born from 3,791 pregnancies were included. The frequency of ZDV use was 79.9%, 92.1%, 93.7% and 92.8% when HIV-RNA was not available, ≥400 copies, between 50 and 399 copies, and <50 copies/mL. Thirty-three out of 3861 (0.85%) infants were subsequently diagnosed with HIV, 25/3861 (0.6%) of them born to mothers receiving intrapartum ZDV, and 31 (93.9%) to mothers with HIV-RNA ≥50 copies/mL or not available. In women with HIV-RNA < 50 copies/mL, ART discontinuation during pregnancy was the strongest risk factor for VT (odds ratio, OR, 23.1, 95%CI 2.4-219.3), while a higher gestational age (OR 0.6, 95%CI 0.4-0.8) and PEP administration to the newborn (aOR 0.004, 95%CI <0.0001-0.4) were protective factors. Intrapartum ZDV administration did not influence the final outcome in this group., Conclusions: In ART era, more transmission events may occur in utero, limiting value of intrapartum ZDV, particularly for women with suppressed HIV-RNA load. More attention to the HIV-RNA testing of mothers before delivery may avoid unnecessary ZDV use., Competing Interests: Declaration of Competing Interest None of the authors declare conflicts of interest relevant to the present study., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2-12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children., Methods: An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018., Results: 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13-5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063-7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported., Conclusion: The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children., (© 2022. The Author(s).)

Purpose: Recommended regimens for pregnant women with HIV-1 are composed of two nucleoside reverse transcriptase inhibitors (NRTI) plus either a ritonavir-boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (ISTI), with non-nucleoside reverse transcriptase inhibitors (NNRTI) representing an alternative drug class. The study's purpose was to compare these three options in terms of pregnancy outcomes., Methods: Data from a national observational study of pregnant women with HIV-1 were used. The analysis included all pregnancies reported between 2008 and 2018, ending in live births and exposed within 32 weeks of gestation to three-drug regimens composed of a NRTI backbone plus a PI, a NNRTI or a ISTI, without class switching during pregnancy. Clinical and laboratory outcomes were evaluated in univariate and multivariable analyses., Results: Overall, 794 exposed pregnancies were analyzed (PI 78.4%, NNRTI 15.4%, ISTI 6.2%). Almost all outcomes had similar rates in the three groups. Women who received PI in pregnancy were less likely to be virologically suppressed at third trimester. PI use was associated with higher bilirubin and triglyceride levels, and ISTI use with a lower rate of low birthweight. The differences in viral suppression at third trimester and in low birthweight were not maintained in multivariable analyses that were adjusted for confounders., Discussion: We found no major differences in a wide range of outcomes relevant for pregnant women with HIV. Such results are reassuring, and this information may be helpful in a context of preconception counseling when therapeutic choices for pregnancy are discussed between women and care providers.

Introduction: Approximately 2.1 million of the estimated 36 million infected with HIV are children or adolescents. International guidelines for HIV-1 Infection suggest starting antiretrovirals (ARV) at the moment of diagnosis. Many factors limit the optimization of antiretroviral therapy in children and adolescents: lack of pediatric formulations, poor adherence, metabolic and pharmacokinetic changes associated withnormal child development and puberty. Areas covered: Three integrase inhibitors are approved by the US Food and Drug Administration and by European Medical Agency for children and adolescents with HIV-1 infection. Raltegravir is approved for children aged 4 weeks to 18 years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6 years of age. This article evaluates E/C/FTC/TAF as a treatment option. Expert opinion: E/C/FTC/TAF was well tolerated, and the antiretroviral activity and tolerability data of this combination support the use in children and adolescents. However, the studies regarding E/C/FTC/TAF in children and adolescents are scant. Consequently, additional studies investigating its safety and efficacy in children are paramount.

Background: The use of tenofovir disoproxil fumarate (TDF) has simplified the antiretroviral regimen for HIV-infected patients and improved their compliance with treatment, but it has been associated with decreased bone mineral density (BMD) in adult patients, and data in pediatric patients are debated. The aim of the current study was to assess the long-term effect of TDF on BMD in young patients., Methods: BMD was measured at the lumbar spine and in the whole skeleton in 26 HIV-infected youths (13 female and 13 male, aged 5 to 17 years at baseline). BMD was measured yearly for 10 years as part of standard care. BMD changes were compared with those calculated from 202 healthy subjects aged 3 to 24 years., Findings: All patients had good control of the infection during the 10-year study. BMD measurements changed significantly (P <0 ⋅ 0001) in HIV-infected youths. The mean annual BMD increment at the lumbar spine was 0 ⋅ 046 (0 ⋅ 006) g/cm 2 and 0 ⋅ 042 (0 ⋅ 006) g/cm 2 in males and females, respectively. The differences between the slopes of patients and healthy controls were not significant. The annual BMD increment of the whole skeleton was 0 ⋅ 030 (0 ⋅ 005) g/cm 2 in males and 0 ⋅ 019 (0 ⋅ 004) g/cm 2 in females. The slopes of BMD changes of patients and healthy controls did not differ significantly., Interpretation: These data indicate that treatment with a TDF-containing antiretroviral regimen does not impair BMD in young patients with HIV-infection. Larger studies are needed to confirm these results., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Here we describe a case of an HIV-infected young woman with extensive drug-resistant virus, who was successfully switched from a raltegravir-based regimen to a dolutegravir-based intensified antiretroviral regimen a few days before scheduled caesarean section because of the still detectable viral load. The trough concentrations of all antiretroviral drugs before and after delivery are also described. Our case underlines both the difficult management of young women, HIV-infected at young age with very limited treatment options and the great variability in the pregnancy-related physiological changes affecting the pharmacokinetics of antiretrovirals.

Background and Objectives: The introduction of highly active anti-retroviral therapy has led to a significant decline in morbidity and mortality. Although several studies in adult populations have shown that tenofovir-disoproxil-fumarate (TDF) use is associated with a significant loss of renal function, there is still uncertainty on the long-term TDF safety profile in pediatric HIV populations, mostly in vertically HIV-infected patients. The aim of this study was to evaluate the long-term TDF renal safety profile, during a ten-year follow up., Methods: Twenty-six vertically HIV-infected patients were evaluated for a total of 132 months of follow up, monitoring anthropometric parameters, renal function, viral load and CD4+ count. Generalized estimating equations were used to evaluate the changes in anthropometric and laboratory variables. Multivariable fractional polynomials were used to test for the existence of non-linear relationships of outcomes with time and other continuous covariates. In all patients, weight, height and body mass index increased linearly with time. CD4+ count and glomerular filtration rate decreased linearly with time (p < 0.01)., Results: No significant increase of serum creatinine was registered. An inverse linear relationship between time and plasma phosphate was found. Hypophosphatemia was detected in 17 patients, mostly mild. In 14 out of 17 we also genotyped single nucleotide polymorphisms rs717620 mapping in ABCC2, a gene encoding for a renal transporter., Conclusions: Our study demonstrates the relative safety of prolonged use of TDF in vertically HIV-infected children and young adults. The most relevant alteration that emerged was hypophosphatemia, appearing after 72 months of TDF therapy, mostly mild and without clinical significance.

Background: Atazanavir and lopinavir represent the main HIV protease inhibitors recommended in pregnancy, but comparative data in pregnant women are limited., Methods: Women from a national observational study, exposed in pregnancy to either atazanavir or lopinavir, were compared for glucose and lipid profiles, liver function tests, CD4 count, HIV RNA and main pregnancy outcomes. Statistical methods included univariate and multivariable analyses., Results: The study population included 428 pregnancies (lopinavir, 322; atazanavir, 106). The lopinavir group was characterized by higher rates of HIV diagnosis in pregnancy and treatment indication for maternal health, lower CD4 counts, higher HIV RNA levels, less frequent antiretroviral treatment at conception and shorter duration of drug exposure during pregnancy. No differences in pregnancy outcomes, glucose metabolism and weight gain were observed. The two groups also showed in a multivariable analysis similar odds for detectable HIV RNA in the third trimester (adjusted OR 0.85, 95% CI 0.35-2.10, P = 0.730). Total lipid levels were significantly higher in the lopinavir group (median values in the third trimester 239 versus 221 mg/dL for total cholesterol and 226 versus 181 mg/dL for triglycerides; P < 0.001 for both comparisons) and bilirubin levels were significantly higher in the atazanavir group (1.53 versus 0.46 mg/dL, P < 0.001)., Conclusions: In this observational study atazanavir and lopinavir showed similar safety and activity in pregnancy, with no differences in the main pregnancy outcomes. Atazanavir use was associated with a better lipid profile and with higher bilirubin levels. Overall, the study findings confirm that these two HIV protease inhibitors represent equally valid alternative options.

Tenofovir disoproxyl fumarate is a known cause of kidney tubular dysfunction in HIV-infected patients. Recent studies reported significant association between specific allelic variants in ABCC2, ABCC4 and/or ABCC10 genes and the development of kidney tubular dysfunction in HIV-infected adults. We describe the first 2 cases of vertically HIV-infected patients affected by kidney tubular dysfunction associated with polymorphisms in the ABCC genes.

Background: Although dual-boosted protease inhibitors regimen is not recommended in children with HIV infection, such a strategy could be useful in subjects with a complex resistance profile. This study was aimed at assessing the long term efficacy and safety of a double-boosted protease inhibitor combination, fosamprenavir (fAVP) and atazanavir/ritonavir (ATV/r) in a cohort of HIV-infected children and adolescents who had failed with nucleoside reverse transcriptase inhibitors., Methods: Seven vertically infected children and adolescents who had previously failed highly active antiretroviral therapy and were resistant to nucleoside reverse transcriptase inhibitors, received a dual protease inhibitor (PI) regimen including fAVP plus ATV/r for 42 months. The patients were assessed at baseline, every month for the first 24 weeks of therapy and every 3 months until month 32. Physical examination, CD4+ cell count, HIV-RNA viral load, lipid profile and hepatic function were assessed throughout the follow up., Results: During the study no serious adverse events were reported. CD4 absolute number increased over-time in all subjects. At baseline the median HIV-RNA was 6562 cp/mL (ranging 1048 -102772 cp/mL) and rapidly decreased below the limit of detection (50 cp/mL) after 2 months of the new treatment and remained undetectable in all cases through the entire study period. At the beginning of the study all cases showed a normal lipid profile. During the study period, 4/7 subjects showed total cholesterol, low density lipoprotein and triglyceride levels >97th cent.le for the males and 94th cent.le for the females. HDL cholesterol showed protective values. Hepatic enzymes remained stable during the entire observation, whereas total bilirubin showed toxicity II/III grade in 6/7 subjects. No change in fat redistribution and insulin resistance was observed., Conclusion: Dual-boosted protease inhibitor therapy was virologically and immunologically effective and it could be considered as a possible alternative to a rescue regimen in children and adolescents. However, hypercholesterolemia and hypertriglyceridemia need close follow-up and may limit the use of this therapeutic option.

Objective: To evaluate common carotid artery intima-media thickness (CCIMT) and cardiovascular risk factors in HIV-infected adolescents on combination antiretroviral therapy (cART)., Methods: 23 HIV-infected adolescents were matched with 19 healthy subjects by gender, age and body mass index (BMI). CCIMT was measured by Echo-Doppler ultrasound. Bootstrapped multiple linear regression was used to identify potential predictors of CCIMT including HIV status, gender, age, BMI, waist circumference, HDL-cholesterol, LDL- cholesterol, triglycerides, folate, homocysteine, insulin resistance as detected by the homeostasis model assessment, mean blood pressure, and CD36 expression., Results: In the pooled sample, age ranged from 17 to 23 years and BMI between 16.0 and 25.6 kg/m(2). Mean (SD) CCIMT was higher in HIV-infected than in healthy subjects [0.5 (0.1) vs. 0.1 (0.4) mm, p < 0.001]. Higher values of CCIMT were associated with HIV infection (p < 0.001) and male gender (p < 0.001). CCIMT was also associated with the duration of treatment in subjects with the longest cART exposure, i.e. those exposed to a PI-based and/or NNRTI-based regimen plus a single or double NRTI (p = 0.019)., Conclusion: HIV infection and longer duration of cART are associated with higher CCIMT in adolescents and young adults.

Reduced bone mass measurements are often found in HIV-infected youths. Both in vitro and human studies demonstrated a role of antiretroviral treatment in determining bone mass alteration. Nevertheless, the data regarding the responsibility of different antiretroviral drugs on bone health in children and adolescents are highly controversial. The purpose of the current study was to relate antiretroviral treatment to bone mass measurements in a large cohort of HIV-infected children and adolescents. Bone mineral content (BMC) was measured in 86 HIV-infected youths (aged 4.8-22.1 years), and in 194 healthy controls (aged 4.9-21.9 years). Fifteen patients were naive to antiretroviral treatment, 11 were receiving a dual nucleoside reverse transcriptase inhibitor (NRTIs) combination, 32 a protease inhibitor (PI)-based antiretroviral treatment, and 28 a non-nucleoside reverse transcriptase inhibitor (NNRTIs)-based regimen. Comparisons between healthy and HIV-infected children and adolescents have been performed by multiple regression analyses to correct for differences in age, sex, and anthropometric measurements. Patients receiving a PI-based treatment had lumbar spine and whole body BMC values significantly lower than healthy children (P<0.05). BMC measurements of patients on other therapeutic regimens or naive to antiretroviral treatment did not differ significantly from those of healthy children. Among patients receiving a PI-based regimen, those receiving full dose Ritonavir had significantly lower lumbar spine BMC values compared to other patients. Lumbar spine and whole body BMC measurements of patients receiving a Stavudine-containing regimen were lower compared to healthy controls, naive patients, and patients on other antiretroviral regimens. Multivariate analyses showed that patients receiving both Stavudine and full dose Ritonavir had significantly lower BMC values both at the lumbar spine (P=0.0033), and in the whole skeleton (P=0.05). In conclusion, antiretroviral treatment may have a detrimental effect on bone health of HIV-infected youths: the use of Ritonavir full dose alone or in combination with Stavudine is associated to lower bone mass measurements. The use of antiretroviral regimens including these drugs should thus be monitored closely in HIV-infected youths., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: In a previous multicentre study including 129 HIV-infected children, non-adherence to antiretroviral therapy was detected in 16% of patients and was mainly related to psychosocial rather than clinical or demographic features. The aim of this study was to explore the evolving pattern of adherence and its determinants in the same population of children., Methods: An observational, cross-sectional multicentre study was done through a structured interview to the caregivers of HIV-infected children. Adherence was quantitatively evaluated through a 4-day recall adherence instrument., Results: One hundred and twelve children were included. Nineteen (17%) omitted more than 5% of doses in the preceding 4 days and were considered non-adherent. Of these, 10 had been found non-adherent and nine adherent in the previous study. In parallel, nine of the originally non-adherent children had become adherent. Adherence rates were higher in children receiving therapy from foster parents than in children receiving therapy from biological parents. Dose number significantly correlated with adherence., Conclusions: Adherence to antiretroviral therapy is a dynamic phenomenon that changes with time. The evolving pattern shows a fairly constant distribution of adherence because a similar number of patients gain and lose adherence. Psychosocial rather than clinical features are major determinants of adherence.

An increasing prevalence of antiretroviral therapy (ART) resistance in ART-experienced and ART-naive pregnant women has been reported. Some studies suggest that antiretroviral drug-resistant viruses might have decreased replication capacity and transmissibility. However, cases of perinatal transmission of multidrug-resistant HIV type-1 (HIV-1) have been described. Here, we report the case of one child with vertically-acquired multidrug-resistant HIV-1 and the outcome of a rescue therapy with a darunavir/ritonavir- and etravirine-containing antiretroviral regimen. During the 15 months of therapy, the child showed clinical improvement, including no side effects, persistent suppression of viral replication and a great increase in CD4+ T-cell count. Paediatric HIV specialists should be prepared to manage a small, but increasing, number of babies with a 'nightmare' multidrug-resistant virus with no available treatment options. The use of experimental agents might become a compelling issue in vertically HIV-infected children born in the era of highly active ART.

Objective: An antiretroviral regimen based on lamivudine+stavudine+protease inhibitor impairs peripheral fat accrual in HIV-infected children and adolescents. We assess the effect on body composition parameters of replacing stavudine with tenofovir and protease inhibitor with efavirenz in paediatric patients., Methods: A 96-week prospective study on 24 patients, (age range: 5.0-17.9 years) with stable undetectable HIV-1 loads, who were switched from stavudine to tenofovir and from protease inhibitor to efavirenz. Patient assessment included: body composition parameters measured by dual-energy X-ray absorptiometry (DXA), viral load and CD4+ T-count and percentage. As a control group for DXA data, we studied 143 healthy controls (HCs; age range: 4.9-20.0 years)., Results: Virological suppression and unchanged CD4+ T-cell count and percentage were maintained in all patients. At baseline, patients showed decreased total, arm and leg fat masses (P < 0.01) but a similar trunk fat mass to HCs. From baseline to week 96, patient fat mass increases were comparable to those for HCs (total fat: 1.3 vs 1.2 kg; fat in arms: 0.09 vs 0.08 kg; fat in legs: 0.5 vs 0.5 kg; trunk fat: 0.6 vs 0.6 kg). However, at week 96, total and leg fat mass in patients were still significantly lower than those in HCs (P < 0.02). At baseline and at week 96, lean mass in patients was similar to that expected in HCs., Conclusions: Replacing stavudine with tenofovir and protease inhibitor with efavirenz for 96 weeks in lipoatrophic paediatrics patients led to a restoration of physiological fat accrual. Lipoatrophy did not progress but was still present, indicating the need for additional strategies.

Background: Short-term use of tenofovir (TDF) has been associated with bone mineral loss in adults and children., Objective: To assess whether the substitution of stavudine with TDF would result in decreased bone mineral content (BMC) and bone mineral density (BMD) accrual in HIV-infected children., Methods: The lumbar spine and whole-body BMC and BMD were measured by dual-energy x-ray absorptiometry in 16 HIV-infected children (age range: 6.4-17.9 years) on stable highly active antiretroviral therapy. Bone measurements were obtained 12 months before the switch, at baseline, and 12 months after switching to TDF. Expected changes in bone measurements were calculated from cross-sectional data obtained from 166 healthy children., Results: The BMC and BMD increments observed before switching therapy did not differ from expected increments. Similarly, the changes detected during treatment with TDF did not differ significantly from those calculated in healthy controls., Conclusions: Substitution to a TDF-containing antiretroviral regimen does not seem to impair bone mineral accrual in children showing a good immunologic response to antiretroviral treatment.

Objective: To assess the impact on immunological, virological and metabolic parameters of replacing protease inhibitors (PIs) with efavirenz and replacing stavudine with tenofovir in HIV-infected children., Methods: A 48-week prospective evaluation of 28 HIV-infected children, with stable undetectable HIV-1 loads, who were taking highly active antiretroviral therapy (HAART) containing lamivudine, stavudine and a PI. Individuals were randomized to switch PI to efavirenz and stavudine to tenofovir at baseline (Group 1) or at week 24 (Group 2). Patient assessment included: clinical evaluation, viral load, CD4+ T-cell count, fasting blood levels and urine samples., Results: All individuals maintained HIV RNA <50 copies/ml and unchanged CD4+ T-cell count through week 48. In Group 1 individuals, a significant decrease in cholesterol (P < 0.05), cholesterol:high-density lipoprotein (HDL) ratio (P < 0.01) and triglycerides (P < 0.05) was observed 24 and 48 weeks after the switch of HAART. The percentage of Group 1 children with increased cholesterol and triglycerides markedly decreased over the study period (from 43% to 0% and from 36% to 7%, respectively). In Group 2 individuals, unchanged lipids in the 24 weeks prior to the switch of HAART and a significant improvement on cholesterol (P < 0.05), cholesterol:HDL ratio (P < 0.01) and triglycerides (P < 0.05) were observed 24 weeks after the switch of HAART. The percentage of Group 2 children with increased cholesterol and triglycerides markedly decreased 24 weeks after the switch of HAART (from 46% to 7% and from 54% to 0%, respectively). Proteinuria and glucosuria were not detected in any individual. The mean values of serum creatinine, serum phosphorus, serum bicarbonate, estimated glomerular filtration rate, urinary microalbumin/creatinine, alpha-1-microglobulin/creatinine ratio and maximal tubular phosphate reabsorption remained unchanged in both groups., Conclusions: In HIV-infected children, switching PI to efavirenz and stavudine to tenofovir is virologically and immunologically safe, is not associated with renal impairment and provides a significant improvement in lipid profile.

Objectives: Growth hormone (GH) plays a role in thymic function, and recombinant GH may stimulate thymopoiesis in HIV-infected individuals. We performed immunologic analyses in 26 antiretroviral-treated children matched for age, pubertal status, clinical parameters, and antiretroviral exposure who did or did not show an impaired response to GH-release stimulation tests with arginine + GH-releasing hormone., Results: The following abnormalities were found in GH-deficient compared with GH-nondeficient children after >4 years of therapy: CD4 count ( P = .02) and percentage ( P = .03), CD4 as percentage of normal cells for age ( P = .003), serum interleukin-7 concentration ( P = .02), and thymic volume ( P = .01). Naive CD4 (4+62+RA+ and 4+CCR7+RA+) and CD8 (8+CCR7+RA+) lymphocytes were lower in GH-deficient children ( P = .003; P = .007; and P = .02, respectively). Postthymic pathways were also impaired in GH-deficient children. Thus, central memory (4+CCR7+RA-) CD4+ cells were reduced ( P = .006), whereas effector memory (4+CCR7-RA-) CD4+ cells ( P = .002) and late effector CD8+ lymphocytes (8+CCR7-RA+ and 8+27-28-) ( P = .009 and P = .002, respectively) were increased in these children., Conclusions: Growth hormone plays a role in thymic and postthymic pathways, and defective GH production may be associated with incomplete immunoreconstitution. Immunomodulant agents (including GH) could be useful in patients with defective GH production.

Background: Most studies of adherence to highly active antiretroviral therapy in children have been retrospective or cross-sectional. Factors relating to the caregiver, the child and the medication are all considered to be important for good adherence., Methods: Adherence with taking prescribed medication was assessed by questionnaires completed at 4, 12, 24 and 48 weeks by caregivers of previously untreated HIV-infected children participating in the PENTA 5 trial, which was designed to evaluate different dual nucleoside reverse transcriptase inhibitor therapy combinations with and without the protease inhibitor nelfinavir. The effects of several factors on adherence and the effect of adherence on virologic suppression were assessed by multivariate logistic regression., Results: Caregivers returned 266 questionnaires including at least 1 for 108 (84%) children in the trial. Nelfinavir was reported to be the most difficult drug to take (38% of questionnaires), but the difficulty decreased over time, P = 0.02. Comments on difficulties in taking and remembering drugs related to fear of disclosure and to unpleasant characteristics of the drugs. Full adherence was reported in 74% of questionnaires, did not change over time and was reported more frequently in children older than 10 years and those with symptomatic HIV disease. More children reporting full adherence achieved HIV RNA <400 copies/ml (e.g. at 48 weeks 79% vs. 50% reporting some nonadherence; overall P = 0.01)., Conclusion: Good adherence with taking prescribed medication was associated with virologic response. Social factors were important in explaining nonadherence.

Objective: To investigate the role of thymic output and viral fitness in immune reconstitution in HIV-1-infected children on antiretroviral therapy., Methods: Thymic output was studied by measuring levels of T-cell receptor rearrangement excision circles (TREC) in peripheral blood lymphocytes, using a real-time quantitative PCR assay. Recombinant viruses containing pre-therapy or post-therapy HIV-1 protease domains were evaluated for viral infectivity in a quantitative single-cycle assay., Results: Eighteen HIV-1-infected children who showed a significant increase in CD4 T-cell count after therapy were studied; HIV-1 plasma viraemia was substantially suppressed in 12 children (virological responders), but not in the other six (virological non-responders). TREC were quantified at baseline, and sequentially during the first 12 months of therapy. Both virological responders and non-responders showed an increase in TREC levels that was inversely correlated with baseline TREC and CD4 T cell counts. Changes in TREC positively correlated with CD4 T-cell count increases in virological responders, but not in non-responders; moreover, the ratios between TREC and CD4 T-cell count increases were higher in non-responders than in responders, suggesting a persistence of peripheral CD4 T-cell loss in the former. Drug-resistant viruses with reduced replicative capacity were documented in three out of six non-responders., Conclusions: These findings indicate that recovery of thymic function is a pivotal event in immune reconstitution, and suggest that CD4 T-cell increase despite persistent viraemia is sustained by a continuous thymic output that compensates peripheral CD4 T-cell depletion which might be slowed down by emerging viruses with reduced fitness.