Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.

BACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.

Dyslipidaemia and insulin resistance in vertically HIV-infected children and adolescents

This cross-sectional study determined the influence of antiretroviral therapy (ART) on the lipid profile and insulin sensitivity of 119 perinatally HIV-infected Brazilian patients aged 6-19 years. Inadequate high-density lipoprotein cholesterol (HDL-c) concentrations were observed in 81.4% of patients. High concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDI.-c) and triglycerides (TG) were found in 33.9%, 9.7% and 35.6% of patients, respectively. There were statistically significant differences in mean concentrations of TC (P=0.004), HDL-c (P=0.015) and LDL-c (P=0.028) among children (< 10 years), early adolescents (10-14 years) and late adolescents (15-19 years). Children presented the highest mean concentrations of TC and LDL-c, and patients in late adolescence presented the lowest concentrations of HDL-c. Insulin sensitivity, assessed by the Homeostasis Model Assessment (HOMA) index, was diagnosed in 16.7% of patients, with a statistically higher proportion (P=0.034) of insulin-resistant children (33.3%) compared with adolescents (12.5%). There was a statistically significant association between TG concentrations and use of ART regimens containing protease inhibitors (PI) (P=0.0003). Children presented a higher prevalence of insulin resistance and dyslipidaemia compared with adolescents, suggesting that ART, especially Pls, may lead to metabolic complications. (C) 2011 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Oral lesions as predictors of highly active antiretroviral therapy failure in Brazilian HIV-infected children

OBJECTIVES: Evaluate the accuracy of HIV-related oral lesions to predict immune and virologic failure on HIV-infected children in use of highly active antiretroviral therapy (HAART). STUDY DESIGN: Data for this cross-sectional analysis come from a longitudinal study being conducted through the HIV-AIDS Outpatient Unit, ENT Division, Hospital das Clinicas, Sao Paulo University Medical School. The study began in January 1990 and is still ongoing. The cut-off point for analyses purposes was December 2004. Subjects were 471 HIV-infected consecutive children attending the outpatient unit during this period, who enrolled regardless of medical or immunological status. The children have undertaken oral cavity examination, serum CD4(+) T-lymphocyte count, and, 271 of them, viral load measurement. Sensitivity, specificity, positive predictive value, negative predictive value and relative risk were calculated. RESULTS: Oral lesions had moderate sensitivity, high specificity and positive predictive value to predict immune failure. It had low sensitivity and positive predictive value, and high specificity to predict virologic failure. DISCUSSION AND CONCLUSIONS: Oral manifestations of HIV can be important markers for immune suppression and for virologic failure, in Brazilian children undergoing HAART.

Immunogenicity of a meningococcal serogroup C conjugate vaccine in HIV-infected children, adolescents, and young adults

Children and adolescents infected with HIV typically have a lower response to immunization than do those in the general population. In most developed countries, meningococcal serogroup C conjugate vaccine is one of the recommended vaccines for such individuals. However, there have been no studies evaluating the antibody response to this vaccine in HIV-infected children, adolescents or young adults. In this study, we evaluated that response using serum bactericidal antibody (SBA) and enzyme-linked immunosorbent assay, comparing HIV-infected with non-HIV-infected patients, as well as analysing the occurrence of side effects. In non-responders, we assessed the antibody response to revaccination. This clinical trial involved 92 patients between 10 and 20 years of age: 43 HIV-infected patients (HIV+ group) and 49 non-HIV-infected patients (HIV- group). After one dose of the vaccine, 72.1% of the HIV+ group patients and 100% of the HIV- group patients were considered protected. Of the HIV+ group patients who received a second dose of the vaccine, only 40% acquired protection. Overall, 81.4% of the HIV+ group patients acquired protection (after one or two doses of the vaccine). Side effects occurred in 16.3% and 44% of the HIV+ group and HIV- group patients, respectively. Therefore, the meningococcal serogroup C conjugate vaccine proved to be safe and effective for use in HIV-infected children, adolescents, and young adults, although their antibody response was weaker than that shown by non-HIV-infected patients. This indicates the need to discuss changes to the immunization schedule for children, adolescents, and young adults infected with HIV, in order to ensure more effective protection against meningococcal disease. (c) 2012 Elsevier Ltd. All rights reserved.

Evaluation of Viral Load Thresholds for Predicting New World Health Organization Stage 3 and 4 Events in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy

Background: This study evaluated a wide range of viral load (VL) thresholds to identify a cut-point that best predicts new clinical events in children on stable highly active antiretroviral therapy (HAART). Methods: Cox proportional hazards modeling was used to assess the adjusted risk for World Health Organization stage 3 or 4 clinical events (WHO events) as a function of time-varying CD4, VL, and hemoglobin values in a cohort study of Latin American children on HAART >= 6 months. Models were fit using different VL cut-points between 400 and 50,000 copies per milliliter, with model fit evaluated on the basis of the minimum Akaike information criterion value, a standard model fit statistic. Results: Models were based on 67 subjects with WHO events out of 550 subjects on study. The VL cut-points of >2600 and >32,000 copies per milliliter corresponded to the lowest Akaike information criterion values and were associated with the highest hazard ratios (2.0, P = 0.015; and 2.1, P = 0.0058, respectively) for WHO events. Conclusions: In HIV-infected Latin American children on stable HAART, 2 distinct VL thresholds (>2600 and >32,000 copies/mL) were identified for predicting children at significantly increased risk for HIV-related clinical illness, after accounting for CD4 level, hemoglobin level, and other significant factors.

Opportunistic and Other Infections in HIV-Infected Children in Latin America Compared to a Similar Cohort in the United States

Opportunistic and other infections have declined since the introduction of highly active antiretroviral therapy (HAART) in developed countries but few studies have addressed the impact of HAART in HIV-infected children from developing countries. This study examines the prevalence and incidence of opportunistic and other infections in Latin America during the HAART era. Vertically HIV-infected children enrolled in a cohort study between 2002 and 2007 were followed for the occurrence of 29 targeted infections. Cross-sectional and longitudinal analyses were performed to calculate the prevalence of infections before enrollment and the incidence rates of opportunistic and other infections after enrollment. Comparisons were made with data from a U. S. cohort (PACTG 219C). Of the 731 vertically HIV-infected children 568 (78%) had at least one opportunistic or other infection prior to enrollment. The most prevalent infections were bacterial pneumonia, oral candidiasis, varicella, tuberculosis, herpes zoster, and Pneumocystis jiroveci pneumonia. After enrollment, the overall incidence was 23.5 per 100 person-years; the most common infections (per 100 person-years) were bacterial pneumonia (7.8), varicella (3.0), dermatophyte infections (2.9), herpes simplex (2.5), and herpes zoster (1.8). All of these incidence rates were higher than those reported in PACTG 219C. The types and relative distribution of infections among HIV-infected children in Latin America in this study are similar to those seen in the United States but the incidence rates are higher. Further research is necessary to determine the reasons for these higher rates.

Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa

Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account.

Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi

Objective  Malnutrition is common in HIV-infected children in Africa and an indication for antiretroviral treatment (ART). We examined anthropometric status and response to ART in children treated at a large public-sector clinic in Malawi. Methods  All children aged <15 years who started ART between January 2001 and December 2006 were included and followed until March 2008. Weight and height were measured at regular intervals from 1 year before to 2 years after the start of ART. Sex- and age-standardized z-scores were calculated for weight-for-age (WAZ) and height-for-age (HAZ). Predictors of growth were identified in multivariable mixed-effect models. Results  A total of 497 children started ART and were followed for 972 person-years. Median age (interquartile range; IQR) was 8 years (4–11 years). Most children were underweight (52% of children), stunted (69%), in advanced clinical stages (94% in WHO stages 3 or 4) and had severe immunodeficiency (77%). After starting ART, median (IQR) WAZ and HAZ increased from −2.1 (−2.7 to −1.3) and −2.6 (−3.6 to −1.8) to −1.4 (−2.1 to −0.8) and −1.8 (−2.4 to −1.1) at 24 months, respectively (P < 0.001). In multivariable models, baseline WAZ and HAZ scores were the most important determinants of growth trajectories on ART. Conclusions  Despite a sustained growth response to ART among children remaining on therapy, normal values were not reached. Interventions leading to earlier HIV diagnosis and initiation of treatment could improve growth response.

Measles vaccination in HIV-infected children: systematic review and meta-analysis of safety and immunogenicity

Background. Measles control may be more challenging in regions with a high prevalence of HIV infection. HIV-infected children are likely to derive particular benefit from measles vaccines because of an increased risk of severe illness. However, HIV infection can impair vaccine effectiveness and may increase the risk of serious adverse events after receipt of live vaccines. We conducted a systematic review to assess the safety and immunogenicity of measles vaccine in HIV-infected children. Methods. The authors searched 8 databases through 12 February 2009 and reference lists. Study selection and data extraction were conducted in duplicate. Meta-analysis was conducted when appropriate. Results. Thirty-nine studies published from 1987 through 2008 were included. In 19 studies with information about measles vaccine safety, more than half reported no serious adverse events. Among HIV-infected children, 59% (95% confidence intervals [CI], 46–71%) were seropositive after receiving standard-titer measles vaccine at 6 months (1 study), comparable to the proportion of seropositive HIV-infected children vaccinated at 9 (8 studies) and 12 months (10 studies). Among HIV-exposed but uninfected and HIV-unexposed children, the proportion of seropositive children increased with increasing age at vaccination. Fewer HIV-infected children were protected after vaccination at 12 months than HIV-exposed but uninfected children (relative risk, 0.61; 95% CI, .50–.73). Conclusions. Measles vaccines appear to be safe in HIV-infected children, but the evidence is limited. When the burden of measles is high, measles vaccination at 6 months of age is likely to benefit children of HIV-infected women, regardless of the child's HIV infection status.

Impaired antibody memory to varicella zoster virus in HIV-infected children: low antibody levels and avidity*

HIV-infected children have impaired antibody responses after exposure to certain antigens. Our aim was to determine whether HIV-infected children had lower varicella zoster virus (VZV) antibody levels compared with HIV-infected adults or healthy children and, if so, whether this was attributable to an impaired primary response, accelerated antibody loss, or failure to reactivate the memory VZV response.

Retention in care of HIV-infected children from HIV test to start of antiretroviral therapy: systematic review

BACKGROUND In adults it is well documented that there are substantial losses to the programme between HIV testing and start of antiretroviral therapy (ART). The magnitude and reasons for loss to follow-up and death between HIV diagnosis and start of ART in children are not well defined. METHODS We searched the PubMed and EMBASE databases for studies on children followed between HIV diagnosis and start of ART in low-income settings. We examined the proportion of children with a CD4 cell count/percentage after after being diagnosed with HIV infection, the number of treatment-eligible children starting ART and predictors of loss to programme. Data were extracted in duplicate. RESULTS Eight studies from sub-Saharan Africa and two studies from Asia with a total of 10,741 children were included. Median age ranged from 2.2 to 6.5 years. Between 78.0 and 97.0% of HIV-infected children subsequently had a CD4 cell count/percentage measured, 63.2 to 90.7% of children with an eligibility assessment met the eligibility criteria for the particular setting and time and 39.5 to 99.4% of the eligible children started ART. Three studies reported an association between low CD4 count/percentage and ART initiation while no association was reported for gender. Only two studies reported on pre-ART mortality and found rates of 13 and 6 per 100 person-years. CONCLUSION Most children who presented for HIV care met eligibility criteria for ART. There is an urgent need for strategies to improve the access to and retention to care of HIV-infected children in resource-limited settings.

Determinants of adherence to highly active antiretroviral therapy for HIV-infected children: A research synthesis

Highly active antiretroviral therapy (HAART) has taken HIV-infection from a rapidly terminal illness to one that is a slowly progressive, chronic illness. HIV-infected children can now live long, normal lives. Today, four classes of antiretroviral medications are widely used and several antiretrovirals are available in each class, but resistance and cross-resistance to these medications can occur very quickly if the patient does not adhere to strict medication dosing guidelines. One method to improve pediatric adherence to antiretrovirals is to focus on identified determinants of adherence at clinical visits, but very few studies have been conducted to identify determinants of adherence to antiretrovirals and the best methods to measure adherence in the pediatric population. This research synthesis found adherence factors related to children can be divided into child-identified factors and caregiver-identified factors. Child identified factors include medication-related, demographic-related, cognitive-related, psychosocial-related, and biological marker-related barriers to adherence. Caregiver identified factors include medication-related, cognitive-related, relationship-related, and psychosocial-related barriers to adherence. More randomized clinical trials are needed to identify determinants to adherence, identify methods to best measure adherence, and to identify the best interventions to improve adherence in HIV-infected children and adolescents. ^