Antiretroviral Therapy In HIV-infected Children Research Articles

Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children

The use of antiretroviral therapy in HIV-infected children has been a widely discussed issue. The aim of this study was to compare the effectiveness of dual nucleoside analogue reverse transcriptase inhibitor (NRTI) regimens and three-drug regimens [2NRTI+ non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI)] in a cohort of HIV-infected children. The study was carried out in a referral center for the management of infected children, which is affiliated with the School of Medicine of Universidade Federal de Minas Gerais (UFMG). Those children whose antiretroviral therapy was implemented between January 1998 and December 2000 and who were followed until December 2001 were included in the study. Therapeutic failure or death was regarded as the endpoint in our analysis. A total of 101 patients were assessed, 58 (57.4%) on dual therapy and 43 (42.6%) on triple therapy. No statistically significant difference was observed between the groups in terms of gender, age, CD4+ count and baseline viral load. The average duration of dual therapy was 26.3 months (95%CI 21.3-31.3) and that of triple therapy was 34.3 months (95%CI 29.2-39.5%). There was therapeutic failure in 33 (56.9%) patients on dual therapy and in 11 (25.6%) patients on triple therapy (log rank = 5.03; p = 0.025). The relative risk of therapeutic failure of the dual therapy was 2.2 times higher (95%CI 1.3-3.9). The percentage of initial CD4+ T cells was a predictor of risk for therapeutic failure (p = 0.001). Patients on triple therapy showed a more remarkable reduction in their viral load (p = 0.001). Triple therapy was efficient for a longer time period and showed better virologic response than dual therapy in this cohort of HIV-infected children. Therefore, triple therapy should be the treatment of choice.

Use of total lymphocyte count for informing when to start antiretroviral therapy in HIV-infected children: a meta-analysis of longitudinal data

Total lymphocyte count has been proposed as an alternative to the percentage of CD4+ T-cells to indicate when antiretroviral therapy should be started in children with HIV in resource-poor settings. We aimed to assess thresholds of total lymphocyte count at which antiretroviral therapy should be considered, and compared monitoring of total lymphocyte count with monitoring of CD4-cell percentage. Longitudinal data on 3917 children with HIV infection were pooled from observational and randomised studies in Europe and the USA. The 12-month risks of death and AIDS by most recent total lymphocyte count and age were estimated by parametric survival models, based on measurements before antiretroviral therapy or during zidovudine monotherapy. Risks were derived and compared at thresholds of total lymphocyte count and CD4-cell percentage for starting antiretroviral therapy recommended in WHO 2003 guidelines. Total lymphocyte count was a powerful predictor of the risk of disease progression despite a weak correlation with CD4-cell percentage (r=0.08-0.19 dependent on age). For children older than 2 years, the 12-month risk of death and AIDS increased sharply at values less than 1500-2000 cells per muL, with little trend at higher values. Younger children had higher risks and total lymphocyte count was less prognostic. Mortality risk was substantially higher at thresholds of total lymphocyte count recommended by WHO than at corresponding thresholds of CD4-cell percentage. When the markers were compared at the threshold values at which mortality risks were about equal, total lymphocyte count was as effective as CD4-cell percentage for identifying children before death, but resulted in an earlier start of antiretroviral therapy. In this population, total lymphocyte count was a strong predictor of short-term disease progression, being only marginally less predictive than CD4-cell percentage. Confirmatory studies in resource-poor settings are needed to identify the most cost-effective markers to guide initiation of antiretroviral therapy.

Trends in Pediatric HIV Treatment, 1987–2003

Guidelines for the use of combination antiretroviral therapy in HIV-infected children were first published in 1998. To evaluate how pediatric HIV

Efficacy of Highly Active Antiretroviral Therapy in HIV-Infected Children Participating in Thailand's National Access to Antiretroviral Program

Programs for access to antiretroviral treatment were only recently implemented in developing countries. This study aimed to describe the effect of highly active antiretroviral therapy (HAART) in treating human immunodeficiency virus (HIV)-infected children in Thailand's National Access to Antiretroviral Program for People Living with HIV/AIDS. From August 2002 to July 2003, a total of 107 children were enrolled in the study. They received HAART consisting of either nevirapine or efavirenz, together with lamivudine and stavudine. Generic drugs and/or adult formulations were used. CD4 lymphocyte count, plasma HIV RNA level, and weight-for-age and height-for-age z scores were measured before, 2 months after, and every 6 months after initiation of HAART. A genotypic resistance assay was performed for patients with poor virological response. The mean age of the patients was 7.7 years (range, 2.1-13.8 years). At baseline, the median CD4 cell percentage was 3%, and the plasma HIV RNA level was 5.4 log10 copies/mL. Four patients died from HIV-related illness. After 72 weeks of HAART, the median CD4 cell percentage was 21%, and 76% of patients had HIV RNA levels of < 50 copies/mL. The mean weight-for-age and height-for-age z scores increased from -1.9 to -1.3 (P < .0001) and from -2.3 to -2.0 (P < .0001), respectively. The percentage of patients who took > or = 95% of prescribed medications during the interval between every follow-up visit was 86% For patients with suboptimal virological response, the most common resistance mutations among HIV isolates were associated with lamivudine and with nonnucleoside reverse-transcriptase inhibitors. In this resource-limited setting, HAART is safe and effective for HIV-infected children despite initiation of treatment during the advanced stage of disease. The use of generic and nonpediatric drug formulations is feasible.

Recomendaciones para el tratamiento antirretroviral de inicio de la infección por el VIH en niños. Actualización 2003

Highly active antiretroviral therapy in HIV-infected children has been associated with a dramatic decrease in progression to AIDS and HIV-related deaths, and infected children currently have an excellent quality of life. Antiretroviral drugs cannot eradicate the virus, although they can achieve a situation of latent infection. However, chronic use of these drugs has multiple adverse effects, the most important of which are metabolic complications. The large number of drugs required and patient characteristics such as age, tolerance to drugs, adherence, and social problems make unifying the criteria for initial therapy in HIV-infected children difficult. A balance should be sought between not delaying the start of treatment, to avoid immunologic deterioration, and minimizing the long-term adverse effects of the therapy. The present treatment recommendations are adapted from international guidelines and are based on a literature review and on our own experience. Our group previously published recommendations on the treatment of HIV-infected children and the aim of the present article is to provide an update.

Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children.

To assess body composition changes in HIV-infected children receiving highly active antiretroviral therapy (HAART). Thirty-seven HIV-positive children were enrolled. Dual-energy X-ray absorptiometry (DXA) scans were performed in all HIV-infected children at baseline and after an additional 12 months of HAART and in 54 matched (for sex, age, body mass index [BMI], and pubertal stage) healthy controls. Abdominal MRI was performed in 14 of 37 HIV-positive children at baseline and in 28 of 37 HIV-positive children after additional 12 months of HAART. During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI, CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change. DXA scans showed an increase in lean mass, peripheral fat loss, and central fat accumulation in all HIV-infected children. As compared with controls, 70% and 84% of HIV-infected children showed DXA-detectable LD at baseline and at 12 months of follow-up, respectively. Mixed LD and central fat accumulation were the most common LD phenotype. At baseline and at 12 months of follow-up, intra-abdominal adipose tissue (IAT) was greater than in controls in 33% and 35% of HIV-infected children, and it was greater in those with LD than in those without. Peripheral fat loss and IAT content were associated with duration of HAART and were independent of immunologic stage of disease and immunologic response. Changes in body composition related to LD in HAART-treated children are frequent, precocious, and progressive. Duration of HAART negatively influences visceral adiposity and peripheral fat loss.

When to start antiretroviral therapy in HIV-infected children

No abstract available.

PENTA guidelines for the use of antiretroviral therapy in paediatric HIV infection

To produce European Guidelines for the use of antiretroviral therapy (ART) in HIV-infected children. Systematic literature review using Medline, the major antiretroviral conference reports, and IDSA recommendations on guideline production. Pediatric European Network for Treatment of AIDS (PENTA) Steering Committee. Guidelines have been produced for the use of antiretroviral therapy in HIV-infected children in Europe. Recommendations on when to start ART and which ART to start, with dosages and a summary of the relevant literature, have been produced. These guidelines are aimed at assisting paediatricians in Europe with ART prescribing, and provide a more cautious approach to starting therapy than current paediatric USA guidelines.

Adherence to Combination Antiretroviral Treatment in Children

Purpose: To assess the level of nonadherence to combination antiretroviral therapy of HIV-infected children and to identify the main problems faced by caregivers when giving medicines to children. Method: A questionnaire was administered to the caregivers of HIV-infected children who were under combination antiretroviral treatment and were followed at our institution. Results: We evaluated 44 children (mean age, 9.4 years); 13 were treated with a two-drug regimen, 30 with a three-drug regimen, and 1 with a four-drug regimen. Each child received a mean of 8.1 pills and/or syrup doses. In 54.5% of treatments, food restrictions were necessary. The mother was the main person giving medicines to the child (56.8%). A complete written schedule of the child’s treatment was present in 50% of families. About 20.5% and 31.8% of children had missed at least one dose of antiretroviral drugs in the last 3 days before assessment and since last visit (1-2 months earlier), respectively. Main problems reported by caregivers were: (a) too many medicines/ pills (34%); (b) difficulty in swallowing pills (29.5%); (c) taking medicines at school or out of home (27.3%); (d) child resisting/refusing therapy/spitting out (25%); and (e) food interactions (22.7%). Conclusion: The observed high level of nonadherence was similar to what was reported by other pediatric studies. Specific interventions aimed at improving compliance in pediatric patients were identified: improvement of anti-HIV drug formulations, better counselling for children and their families, and tailoring of antiretroviral treatment. However, caution is necessary in generalizing our results due to the small sample size and to the heterogeneity of the cohort.

Patterns of CD8 T cell clonal dominance in response to change in antiretroviral therapy in HIV-infected children.

To examine the influence of change in antiretroviral therapy (ART) on patterns of CD8 T cell clonal dominance in HIV-infected children. Seventeen HIV-infected children with plasma virus loads between 3.1 and 5.7 log10 were investigated before and after changes in ART. CDR3 spectratyping was performed in 22 T cell receptor (TCR) Vbeta subfamilies by multiplex polymerase chain reaction (PCR) in purified peripheral blood CD8 T cells in conjunction with CD4 cell counts, plasma HIV-RNA copies and lymphoproliferative assays (LPA). CD8 T cell clonal dominance in two or more Vbeta families was present in eight out of 17 children. After a change in therapy, 13 patients (76%) acquired new clones whereas three patients (17.6%) showed a loss in CD8 cell clones. An increase in the numbers of dominant clones correlated with an increase in percentage CD4 cell counts (P < 0.001) and with improved LPA responses to tetanus (P < 0.05) and alloantigens (P < 0.01). CD4 cell increase was associated with an initial mean gain of 3.1+/-2.1 CD8 cell clones, independent of a virological response. A loss of CD8 cell clones or failure to achieve CD4 T cell increase was associated with failure to achieve virological suppression. Children with chronic HIV infection manifest CD8 T cell clonal dominance, which appears to be dependent upon the adequacy of the CD4 cells. With optimization of therapy, a gain in clonal dominance is the predominant response, except in situations of failure to contain viral replication.

Treatment-resistant expansion of CD8+CD28-cells in pediatric HIV infection.

There is a disease stage-dependent loss of CD28 expression on T cells in HIV-infected children. In this study, T cell recovery, in particular CD28 expression on T cells, was analyzed after initiation of highly active antiretroviral therapy in a group of eight mostly treatment-naive HIV-infected children. Plasma HIV-RNA levels were recorded, and numbers of CD4, CD8, CD4+CD28+, and CD8+CD28+ cells were determined by two-color flow cytometry. Values after 12 mo of therapy were compared with age-matched, seronegative control subjects. CD4 recovery to subnormal values was observed in all children. CD8+CD28+ cells recovered and were within the normal range after 12 mo of therapy (patients, 703 +/- 250 cells/microL; controls, 789 +/- 269 cells/microL), whereas CD8+CD28- cells (546 +/- 269 cells/microL) remained significantly expanded compared with age-matched controls (140 +/- 35 cells/microL). Expansions of CD8+CD28- cells persisted even in cases with long-term suppression of viral replication. Highly active antiretroviral therapy in HIV-infected children induces substantial but incomplete T cell recovery.

Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume.

Despite significant rises in total CD4 T cells, the process of immune reconstitution in adults with HIV infection treated with potent antiretroviral treatment results in a rather slow increase in phenotypically naive lymphocytes. In children more than in adults, thymic function may be at least partly restored when disease-induced immunosuppression is attenuated by pharmacological means. Twenty-five vertically infected and antiretroviral-experienced [zidovudine (ZDV)/ZDV plus didanosine (ddl)] children were prospectively followed during 12 months of treatment with lamivudine (3TC), stavudine (d4T) and indinavir (IDV). The plasma HIV viral load and phenotypic and functional cellular immunity-defining parameters were examined. The relationship between the degree of immune reconstitution and thymus volume assessed by nuclear magnetic resonance was also examined. An early and steep increase in CD45RA+62L+ T cells was observed in parallel with a sustained decrease in plasma HIV RNA levels and a significant rise in total CD4 T cells. This increase was significantly greater than that observed in CD4+CD45RO+ T cells. Analysis of the CD4 T cell receptor (TCR) beta repertoire and T helper function showed the ability to reconstitute families almost completely absent at baseline, and a substantial improvement of antigen-specific responses by peripheral blood lymphocytes. The rise in CD4 cells and in CD4+CD45RA+62L+ T cells was statistically associated with changes in thymus size observed over time. These data suggest a relevant contribution of the thymus to reconstitution of the peripheral pool of T cells in vertically HIV-infected children treated with potent antiretroviral regimens.

Adherence to antiretroviral therapy in HIV-infected children in Italy

Adherence to antiretroviral therapy is a major problem in children with HIV infection, who depend on parents or foster parents for receiving drugs. During an ongoing investigation on intestinal function in children with symptomatic HIV infection who were treated with zidovudine, blood samples were obtained six hours after the administration of zidovudine as reported by the parents and, again, one and six hours after its administration in the hospital, and drug concentration was measured by radioimmunoassay. Both peak and steady state zidovudine levels were within the expected concentration ranges after administration in the hospital. In contrast, they were below the effective concentration in five of the 10 children that reportedly had received the drug at home by the parents. These data directly show poor compliance with antiretroviral therapy in children. Compliance with antiretroviral therapy should be carefully checked in children and strategies are needed to increase full and permanent adherence with antiretroviral therapy by people in charge to administer drugs to HIV-infected children.

Anti-retroviral therapy for HIV-infected children--toward maximal effectiveness.

Viral suppression may be more difficult to achieve in children compared to adults. However, appropriate regimens at adequate dosages combined with monitoring of adherence and virologic response should allow children with HIV infection to realize a sustained benefit from combination anti-retroviral therapy.

Effect of changing antiretroviral therapy on human immunodeficiency virus viral load: experience with fifty-four perinatally infected children.

Experience in adults has shown that combination therapy including HIV protease inhibitors (PI) can profoundly affect viral replication and slow progression of HIV-associated disease. Trials defining the influence of PI and combination therapies on long term outcome of HIV infection in children have not yet been completed. Experience with infants and children who were receiving routine care in an HIV specialty clinic was reviewed to characterize the effect of changes involving one, two or three antiretrovirals. Clinical and laboratory findings of children in whom antiretroviral therapy was changed were retrospectively reviewed. Successful response was defined as a reduction of viral load of at least 0.7 log10 RNA copies/ml lasting for at least 3 months. Differences in characteristics and the character of the response associated with successful and unsuccessful changes were analyzed. Of the 72 changes in therapy that were made in 54 children, 29 resulted in a successful response. A change involving 3 antiretrovirals was more likely to produce a successful response than a change involving 1 agent (6 of 9 vs. 6 of 24; P < 0.04). Reduction of viral load by > 100-fold or to undetectable amounts occurred more frequently in children who responded to a regimen containing a PI than in children who responded to reverse transcriptase inhibitors (11 of 21 vs. 1 of 8; P=0.05). Furthermore successful responses associated with addition of a PI were associated with a greater reduction in viral load than those that involved reverse transcriptase inhibitors (1.63+/-0.60 vs. 0.99+/-0.12 log10; P=0.003). This experience suggests that changing antiretroviral therapy in HIV-infected children to regimens containing three drugs is more likely to result in a successful virologic outcome than changes in therapy involving one drug. This experience further supports the conclusion that including a PI as part of an antiretroviral regimen is more likely to result in a greater reduction in viral load in children.