Uptake and virological outcomes of single- versus multi-tablet antiretroviral regimens among treatment-naïve youth in the HIV Research Network.

OBJECTIVES: Several single-tablet regimens (STRs) are now available and are recommended for first-line antiretroviral therapy (ART); however, STR use for youth with HIV (YHIV) has not been systematically studied. We examined the characteristics associated with initiation of STRs versus multi-tablet regimens (MTRs) and the virological outcomes for youth with nonperinatally acquired HIV (nPHIV). METHODS: A retrospective cohort study of nPHIV youth aged 13-24 years initiating ART between 2006 and 2014 at 18 US HIV clinical sites in the HIV Research Network was performed. The outcomes measured were initiation of STRs versus MTRs, virological suppression (VS) at 12 months, and time to VS. Demographic and clinical factors associated with initiation of STR versus MTR ART and VS (< 400 HIV-1 RNA copies/mL) at 12 months after initiation were assessed using multivariable logistic regression. Cox proportional hazards regression was used to assess VS within the first year. RESULTS: Of 987 youth, 67% initiated STRs. Of the 589 who had viral load data at 1 year, 84% of those on STRs versus 67% of those on MTRs achieved VS (P < 0.01). VS was associated with STR use [adjusted odds ratio (AOR) 1.61; 95% confidence interval (CI) 1.01-2.58], white (AOR 2.41; 95% CI 1.13-5.13) or Hispanic (AOR 2.38; 95% CI 1.32-4.27) race/ethnicity, and baseline CD4 count 351-500 cells/µL (AOR 1.94; 95% CI 1.18-3.19) and > 500 cells/µL (AOR 1.76; 95% CI 1.0-3.10). STR use was not associated with a shorter time to VS compared with MTR use [hazard ratio (HR) 1.07; 95% CI 0.90-1.28]. CONCLUSIONS: Use of STR was associated with a greater likelihood of sustained VS 12 months after ART initiation in YHIV.

The impact of vitamin D3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial.

OBJECTIVES: We tested the hypothesis that daily vitD3 supplementation increases neuromuscular motor skills, jump power, jump energy, muscular force, and muscular strength. METHODS: This was a secondary analysis of a randomized controlled trial of 12-months of oral 7,000 IU/day vitD3 supplementation or placebo among 56 persons living with HIV aged 9-25 years. Neuromuscular motor skills were quantified using the Bruininks-Oseretsky Test of Motor Proficiency. Power was quantified using peak jump power, and energy was quantified using peak jump height. Muscular force was quantified using isometric ankle plantar- and dorsiflexion, isokinetic knee flexion and extension. Muscular strength was quantified using isometric handgrip strength. RESULTS: After 12-months, serum 25-hydroxyvitamin D [25(OH)D] was higher with supplementation versus placebo (ß=12.1 ng/mL; P<0.001). In intention-to-treat analyses, supplementation improved neuromuscular motor skills versus placebo (ß=1.14; P=0.041). We observed no effect of supplementation on jump power, jump energy, muscular force, or muscular strength outcomes versus placebo. CONCLUSIONS: Among HIV-infected children and young adults supplementation with daily high-dose vitD3 increased concentration of serum 25(OH)D and improved neuromuscular motor skills versus placebo.

Treatment initiation factors and cognitive outcome in youth with perinatally acquired HIV infection.

OBJECTIVES: Although cognitive outcomes among perinatally infected youth have improved with highly active antiretroviral therapy (HAART), the impact of the age of initiation of treatment and the central nervous system (CNS) penetration effectiveness (CPE) of the regimen on cognitive outcomes is unknown. We aimed to describe the association between initiation age/regimen CPE score and cognitive outcomes in perinatally HIV-infected youth. METHODS: Linear regression was used to retrospectively assess the association between full-scale IQ score (FSIQ) and age of initiation of HAART, regimen CPE, and the presence/absence of an AIDS diagnosis before initiation of HAART in an urban US cohort. RESULTS: A total of 88 of 181 subjects (48.6%) had an AIDS diagnosis. In 69, AIDS preceded the start of HAART. Mean FSIQ (mean age 155.4 months) was 86.3 [standard deviation (SD) 15.6]. Neither age of initiation of HAART (P = 0.45) nor regimen CPE score (P = 0.33) was associated with FSIQ. Mean FSIQ for patients with an AIDS diagnosis before HAART initiation [82 (SD 17.0)] was significantly lower than for patients initiating HAART before an AIDS diagnosis [90 (SD 13)] (P = 0.001). Of the 129 subjects without AIDS by age 5 years, 41 (31.8%) initiated HAART before age 5 years; four of 41 later developed AIDS, compared with 32 of 88 of those who did not initiate HAART before age 5 years. The relative risk of AIDS if HAART was initiated before age 5 years was 0.19 (95% confidence interval 0.05-0.60). CONCLUSIONS: Earlier age at HAART initiation and higher CPE score of a regimen did not improve cognitive outcomes. However, initiating HAART prior to AIDS protected against AIDS and was associated with a significantly higher FSIQ.

Dendritic and natural killer cell subsets associated with stable or declining CD4+ cell counts in treated HIV-1-infected children.

BACKGROUND: Natural killer (NK) cells and plasmacytoid and myeloid dendritic cells (DCs) are depleted, and their function impaired, in advanced adult human immunodeficiency virus (HIV)-1 infection. Studies in perinatally infected children are lacking. METHODS: Percentages of NK cells and plasmacytoid and myeloid DCs were evaluated by flow cytometry. Forty children with perinatal HIV-1 infection were compared with 11 age-matched, uninfected children. Plasmacytoid and myeloid DC function was evaluated by activation-induced cytokine secretion. RESULTS: Virally suppressed children had normal levels of circulating plasmacytoid and myeloid DCs and total NK cells but had sustained depletion of a mature (CD3-/161+/56+/16+) NK cell subset and decreased interferon- alpha secretion by plasmacytoid DCs. Despite similar viral loads, percentages of myeloid and plasmacytoid DCs and mature NK cells were significantly lower in viremic children with a history of decreasing CD4+ cell percentages, compared with children with stable CD4+ cell counts. CONCLUSIONS: Children achieve partial reconstitution of myeloid and plasmacytoid DCs and NK cells during viral suppression; irrespective of viral load, a clinical history of decreasing CD4+ cell percentage is associated with greater depletion of these subsets. We hypothesize that the evaluation of selected innate-immunity effector cells may serve as a marker of CD4+ cell loss in pediatric HIV-1 infection.

Association between steatorrhea, growth, and immunologic status in children with perinatally acquired HIV infection.

OBJECTIVE: To examine the prevalence of steatorrhea and exocrine pancreatic insufficiency (EPI) and their association with growth and immune status variables in children with perinatally acquired human immunodeficiency virus (HIV) infection. DESIGN: Cross-sectional study. SETTING: Tertiary care HIV subspecialty practice. PARTICIPANTS: Children with perinatally acquired HIV infection. Exclusion criteria included being younger than 1 year and receiving mineral oil as a medication. METHODS: Weight, height, and upper arm anthropometric variables were measured. Spot stool samples were analyzed for steatorrhea using the Sudan III qualitative test and for EPI using fecal elastase-1 enzyme assay. Hormone-stimulated pancreatic function testing and 72-hour stool and dietary fat sample collection were performed when fecal elastase-1 enzyme was in the range of EPI, defined as less than 200 microgram/g. HIV RNA viral load, CD4 status, type of antiretroviral therapy, and biochemical evidence of hepatobiliary disease were measured within 3 months of stool sample collection. z Scores were computed for height, weight, triceps skinfold, and upper arm muscle area. RESULTS: We enrolled 44 patients (23 girls [52%]) with a mean +/- SD age of 7.4 +/- 3.1 years. None had hepatobiliary disease. The prevalence of steatorrhea was 39% (95% confidence interval, 23%-56%). The prevalence of EPI was 0% (95% confidence interval, 0%-9%). There were no associations between steatorrhea and EPI, growth, HIV RNA viral load, CD4 status, or type of antiretroviral therapy. Older children had decreased z scores for height (r = -0.42; P =.006). CONCLUSIONS: The clinical significance of steatorrhea in children with HIV infection is unclear. Furthermore, its evaluation should focus on nonpancreas-based conditions. Continual close monitoring of growth is essential in children with HIV infection.

Prevention of perinatal HIV infection.

In the 20 years since the first description of the clinical manifestations of HIV infection, more than 32 million people have been infected worldwide. In untreated HIV-infected pregnant women, the risk of maternal-child transmission varies from 16 to 40%. In developed countries, utilizing combinations of available medications and elective cesarean sections, it is possible to lower the transmission rates to less than 2 to 4%. Effective programs use universal screening of pregnant women, perinatal antiretroviral therapy, and, at times, delivery via elective cesarean section. In resource-poor areas, major barriers remain to the control of maternal-child transmission.

Group-specific antibody levels surrounding invasive pneumococcal illness in children infected with human immunodeficiency virus.

Pneumococcal antibody levels surrounding systemic pneumococcal illness (SPI) were measured in children infected with human immunodeficiency virus (HIV). Archived serum samples were collected from 28 HIV-infected children who had 34 cases of SPI, caused by pneumococcal groups 4, 6, 9, 14, 19, and 23. Serum samples collected within 23 weeks before and 13 weeks after the SPI were assayed by ELISA for antipneumococcal polysaccharide (PnPs) IgG antibody to 6 representative pneumococcal serotypes. There was a wide range (0. 16-30.80 microg/mL) of pre-SPI anti-PnPs antibody levels to the presumed infecting serotypes, with a geometric mean level of 0.83 microg/mL (n=34). Seventy-six percent of the antibody values were <2.0 microg/mL, and 95% were <5.0 microg/mL. Homologous seroresponses (>/=4-fold rise in anti-PnPs antibody) were detected in only 4 (27%) of 15 paired serum samples. Heterologous, noninfecting group seroresponses were detected frequently (72%) in the paired serum samples from these 4 homologous group seroresponders.

Protease inhibitor therapy in HIV-infected children.

We reviewed the short-term response to and safety of protease inhibitor (PI) therapy in HIV-infected children by performing a retrospective chart review of open-label PI containing combination therapy at two urban pediatric HIV centers. Seventy HIV-infected children received 101 PI containing antiretroviral therapy (ART) combinations. Main outcome measures were follow-up CD4 counts, viral loads, and patient or caregiver reported compliance. During follow-up, treatment with PI ART was associated with a mean maximal increase in CD4+ lymphocyte count of 454 x 10(6)/L and a mean maximal decrease in viral load of 1.76 log units. Of the 32 patients who achieved undetectable viral loads, 28 (87.5%) remained undetectable through a mean follow-up of 8.9 months. Patients who reported good compliance achieved a higher rate of response (92.6%) than those who reported poor compliance (61.5%). Of 14 changes made to a second PI because of treatment failure, 11 (78.6%) resulted in a positive response to the second regimen. Nineteen of 101 courses of PI therapy resulted in significant side effects, including renal complications in 8 of 21 patients treated with indinavir. PI ART was associated with substantial short-term improvement in immunological and virological parameters in this heavily pretreated cohort, with 40% of patients maintaining an undetectable viral load after 9 months of therapy. Patients who failed one PI regimen usually responded to a second regimen. There was a significant rate of side effects from PI treatment.

Prenatal care and HIV infection.

Recent use of zidovudine (ZDV) to reduce vertical transmission of HIV disease in newborns has demonstrated varied, but in some studies, dramatic results, with reports of reduction from approximately 8% to 25%. With this potential of efficacy in saving lives, knowledge of access to prenatal care for HIV-infected pregnant women is urgent. The current study used face-to-face and phone survey methods and employed a 77-item questionnaire to assess barriers to prenatal care in two groups of HIV-positive and HIV-negative women (n = 106). All participants had a child(ren) under 4 years of age and were currently enrolled in a primary care or family HIV clinic. Results showed that HIV-positive women had specific concerns regarding access of perinatal care that included disclosure and fear of anger from health care providers. Barriers such as transportation, insurance and child care, among others, were not predictive of the level of prenatal care received, but results may be biased by the small number of women who had not received adequate care and the general selection process from women who were currently attending clinics. A high level of prenatal care was recorded across both cohorts. Misconceptions about vertical transmission and ZDV efficacy were demonstrated, including that more than 80% of all participants stated there was a greater than 50% chance of a pregnant untreated HIV-positive woman transmitting the virus; the documented transmission rate for untreated birth mothers is 20% to 25%. In addition, HIV-negative women showed little knowledge about vertical transmission and the use of ZDV, putting this group at risk in the future. Better educational methods to more women about perinatal HIV transmission and ADV could be imperative in significantly improving reduction of vertical transmission.

Nutritional assessment for children who are HIV-infected.

Pathophysiologic, psychosocial, and economic considerations are important in nutritional assessment of infants and children who are HIV-infected. Nutritional assessment guidelines vary based on the child's circumstances. Specific assessment guidelines are proposed for (a) ongoing ambulatory care; (b) when growth decelerates or its below the fifth percentile; (c) acute illness; and (d) home and community care. The guidelines are based on data collected from a sample of 16 children who were HIV-infected and their families during a pilot study of transitional nursing care using advanced practice nurses. The guidelines were inductively derived from patient care records and from a review of the literature.

Pediatric primary care provider's knowledge of HIV/AIDS care.

To respond to the difficulties that community-based providers face in keeping abreast of the rapid changes in HIV-related care, an intensive pediatric HIV mentoring program (Pediatric HIV Miniresidency [MR]) was developed, linking a regional AIDS Education and Training Center (AETC) with an urban children's hospital HIV outpatient care site. The purpose of this study was to evaluate HIV-related knowledge and perceived skills, abilities, and willingness of community-based primary care pediatric providers and providers completing the MR. A convenience sample of community-based primary pediatric practitioners and those participants in the MR program completed a three-part mailed survey. The survey assessed practice characteristics, knowledge of pediatric HIV clinical care, and perceived skills, ability, and willingness (PSAW) to provide HIV-related care. The main outcome measures were overall knowledge and PSAW scores. One hundred nineteen community-based practitioners (NMRs), 20% of those surveyed, completed the instrument, as did 19 of 20 MR participants. NMRs exhibited low knowledge scores in key areas relating to the identification and evaluation of HIV-exposed children. Fewer than half of these respondents correctly answered questions related to HIV antibody incidence in HIV-exposed newborns and recommended diagnostic testing of such infants. Providers completing the MR scored significantly higher on the knowledge survey (15.2 vs. 8.8, p < 0.001), and had higher PSAW scores (45.8 vs. 33.9, p < 0.001). Although the generalizability of our study is limited by the low response rate, community-based physicians completing the survey demonstrated a lack of knowledge we believe necessary to provide pediatric HIV-related care (as defined by Public Health Service practice guidelines). Physicians completing the MR program had substantial HIV-related knowledge and expressed a willingness to provide care to HIV-exposed/infected children. An effective MR program provides a mechanism for developing a network of dedicated community-based physicians who are willing and capable of providing care to HIV-infected or exposed infants and children.

Protease inhibitor therapy in children with perinatally acquired HIV infection.

OBJECTIVE: To review the short-term response and safety of protease inhibitor therapy in HIV-infected children. DESIGN: Retrospective chart review of open-label protease inhibitor-containing combination therapy. SETTING: Two urban pediatric HIV centers. PATIENTS: Twenty-eight HIV-infected children were prescribed 30 protease inhibitor-containing antiretroviral therapy combinations. The median age at initiation of protease inhibitor antiretroviral therapy was 79 months. Patients had been on previous antiretroviral therapy for a mean of 45.5 months. RESULTS: Of the 28 children who completed at least 1 month of therapy, 26 experienced marked virologic and immunologic improvement (mean maximal decrease in viral load 1.90 log10 copies/ml; SD, 0.8; mean maximal rise in CD4+ lymphocytes of 279 x 10(6)/l; SD, 300 x 10(6)/l). Eleven patients achieved a viral nadir of < 400 copies/ml, and seven sustained this level of viral suppression for a mean of 6 months. Indinavir use was associated with a high incidence of renal side-effects, including two patients who developed interstitial nephritis. Two patients on ritonavir experienced a significant elevation of liver enzymes. CONCLUSIONS: Protease inhibitor therapy was associated with substantial short-term virologic and immunologic improvement in this primarily heavily pretreated cohort, with 25% maintaining a viral load of < 400 copies/ml after 6 months of therapy. There was a significant rate of adverse events. Pharmacokinetic and safety data are needed to guide aggressive antiretroviral therapy in HIV-infected children, and further treatment options are required for those failing or intolerant to the available protease inhibitors.

Imaging of pediatric central nervous system HIV infection.

With the increasing incidence of pediatric HIV infection, distinct patterns of central nervous system involvement, different from those in adults, are being recognized. This article illustrates the spectrum of neuroimaging findings seen in HIV-infected children with central nervous system involvement. Case examples include HIV encephalitis, basal ganglia calcific vasculopathy, lymphoma, and cerebrovascular complications, such as arterial ectasia and arterial fibrosing sclerosis.

Progressive multifocal leukoencephalopathy in an HIV-infected child.

A child with perinatally acquired HIV infection presented with acute neurologic deterioration. A cerebellar white matter lesion seen on CT and MRI later proved to be progressive multifocal leukoencephalopathy (PML) by histology. Although a recognized disease of HIV-infected adults, PML is certain to be seen with more frequency in HIV-infected children who are surviving longer as a result of improved medical care. Recognition of the clinical and radiographic manifestations is important because of the dismal prognosis.

Response of human immunodeficiency virus-exposed and -infected infants to Haemophilus influenzae type b conjugate vaccine.

OBJECTIVE: To evaluate the response of human immunodeficiency virus (HIV)-infected and -exposed infants to the primary series and booster dose of Haemophilus influenzae type b (Hib) conjugate vaccine. DESIGN: Retrospective study. PATIENTS AND SETTING: The HIV-exposed and -infected infants who were attending the Special Immunology Family Clinic at The Children's Hospital of Philadelphia (Pa). MAIN OUTCOME MEASURES: Geometric mean antibody titers (GMTs) to Hib polyribosyl ribitol phosphate capsular antigen were assessed after the primary series and again after the 15-month booster doses. In addition, the percentages of patients who responded with polyribosyl ribitol phosphate antibody levels greater than both 0.15 and 1.0 mg/L were compared between groups. RESULTS: After the 3-dose primary series, the GMTs were lower in the HIV-infected infants compared with those in the HIV-exposed, uninfected infants (0.86 vs 2.30, P = .02). Forty-six percent of the HIV-infected infants mounted a response ( > 1.0 mg/L) compared with that in 79% of the HIV-exposed infants (P = .05). Among the HIV-infected infants, there was no difference in the GMTs based on CD4+ cell counts or HIV-related symptoms. After the 15-month booster dose, the GMTs were not significantly different in the HIV-infected and -exposed infants. As a group, the HIV-infected infants responded to the booster dose with a 2-fold increase in the GMTs, and significantly more of these infants had antibody concentrations above 1.0 mg/L compared with their response to the primary series (62% vs 38%, P = .02). CONCLUSIONS: Most of the HIV-infected infants responded to the primary series of Hib conjugate vaccine with antibody concentrations greater than 0.15 mg/L, but the GMTs were significantly lower than those in the uninfected infants. The primary series of Hib conjugate vaccine appeared to be capable of inducing specific immunologic memory in the HIV-infected infants. The HIV-infected infants had a significant response to a booster dose of Hib conjugate vaccine, as measured by using the GMTs and the percentage of infants with antibody concentrations greater than 1.0 mg/L. The duration of protective titers will need to be followed in this population of patients who are at a high risk for serious bacterial disease.

Response to hepatitis B immunization by infants exposed to HIV.

OBJECTIVE: To assess the antibody response to hepatitis B immunization in HIV-infected and uninfected infants. DESIGN: Cohort, comparing hepatitis B surface-antibody responses of HIV-infected infants with HIV-exposed but uninfected infants. SETTING: Urban children's hospital outpatient clinic for families with HIV-infected members. INTERVENTION: All infants received hepatitis B vaccine according to the American Academy of Pediatrics and Centers for Disease Control and Prevention recommended schedule. RESULTS: Forty-one HIV-exposed or infected infants were immunized with hepatitis B vaccine in the first year of life. Twenty-two out of 24 (92%) HIV-exposed but uninfected infants demonstrated an antibody response to hepatitis B immunization, compared with six out of 17 (35%) HIV-infected infants (P < 0.0005). CD4 percentage and CD4 counts were significantly lower in the HIV-infected infants than in the uninfected infants, but there was no significant difference in CD4 count or percentage between HIV-infected responders and nonresponders. CONCLUSION: The humoral immune response to hepatitis B immunization, administered before 12 months of age, is significantly reduced in HIV-infected children and is independent of CD4 count. Given the large number of infants born each year to pregnant women coinfected with HIV and hepatitis B, further studies to assess the efficacy of increased doses of antigen and variations in the dosage schedule are urgently needed.

Responses to measles immunization in children infected with human immunodeficiency virus.

The responses to measles immunization administered between 6 and 12 months and after 12 months were compared in children with and without human immunodeficiency virus infection. No difference in response was found when primary measles immunization was administered between 6 and 12 months; however, children with human immunodeficiency virus infection had a significantly poorer response when immunization was given after 12 months. Early measles immunization should be considered in children with human immunodeficiency virus infection.