Stephen M. Arpadi

lipodystrophy in Hiv-infected Children Is Associated With High Viral Load and Low Cd4+-lymphocyte Count and Cd4+-lymphocyte Percentage at Baseline and Use of Protease Inhibitors and Stavudine

Summary: Alterations in regional fat, often associated with abnormalities in lipid and insulin metabolism, have been reported in HIV‐infected adults. To determine whether similar abnormalities occur in children with HIV, patterns of change in regional body fat distribution were determined by dual energy x‐ray absorptiometry in 28 prepubertal HIV‐infected children. Eight (29%) children experienced lipodystrophy (LD), defined as extremity lipoatrophy together with trunk fat accumulation. Despite a mean body weight increase of 2.9 ± 2.4 kg, children with LD experienced a mean loss of total fat in contrast to children without LD who increased total fat (‐0.151 ± 0.324 versus 0.981 ± 1.041 kg; p < .01). Children with LD had significantly higher levels of HIV RNA and lower CD4 count and percentage at baseline. LD was associated with use of protease inhibitors or stavudine, (odds ratio [OR], 7.0, 95% confidence interval [CI], 1.1‐45.2, p = .04; OR, 9.0, 95% CI, 1.4‐59.8, p = .03, respectively). This observational study suggests that during a time in childhood when accumulation of extremity and trunk fat is expected, some HIV‐infected children experience changes in fat distribution that are similar to HIV‐associated LD reported in adults. Studies to determine whether HIV‐infected children with changes in regional fat also experience increases in “atherogenic” lipids and insulin resistance as described in adults with HIV‐associated LD are warranted.

Growth faltering due to breastfeeding cessation in uninfected children born to HIV-infected mothers in Zambia

BACKGROUND The effect of breastfeeding on growth in HIV-exposed infants is not well described. OBJECTIVE The objective was to evaluate the effect of early breastfeeding cessation on growth. DESIGN In a trial conducted in Lusaka, Zambia, HIV-infected mothers were randomly assigned to exclusive breastfeeding for 4 mo followed by rapid weaning to replacement foods or exclusive breastfeeding for 6 mo followed by introduction of complementary foods and continued breastfeeding for a duration of the mothers choice. Weight-for-age z score (WAZ), length-for-age z score (LAZ), and weight-for-length z score (WLZ) and the self-reported breastfeeding practices of 593 HIV-uninfected singletons were analyzed. Generalized estimating equations were used to adjust for confounders. RESULTS WAZ scores declined precipitously between 4.5 and 15 mo. The decline was slower in the breastfed infants. At 9, 12, and 15 mo, mean WAZs were, respectively, -0.74, -0.92, and -1.06 in infants who were reportedly breastfed and were -1.07, -1.20, and -1.31 in the weaned infants (P = 0.003, 0.007, and 0.02, respectively). No differences were observed past 15 mo. Breastfeeding practice was not associated with LAZ, which declined from -0.98 to -2.24 from 1 to 24 mo. After adjustment for birth weight, maternal viral load, body mass index, education, season, and marital and socioeconomic status, not breastfeeding was associated with a 0.28 decline in WAZ between 4.5 and 15 mo (P < 0.0001). During the rainy season, not breastfeeding was associated with a larger WAZ decline (0.33) than during the dry season (0.22; P for interaction = 0.02). CONCLUSIONS Early growth is compromised in uninfected children born to HIV-infected Zambian mothers. Continued breastfeeding partially mitigates this effect through 15 mo. Nutritional interventions to complement breastfeeding after 6 mo are urgently needed. This trial was registered at clinicaltrials.gov as NCT00310726.

Effect of Bimonthly Supplementation With Oral Cholecalciferol on Serum 25-Hydroxyvitamin D Concentrations in HIV-Infected Children and Adolescents

OBJECTIVE. Vitamin D insufficiency occurs commonly in HIV-infected youth in the United States. In light of the importance of vitamin D for skeletal and nonskeletal health, including innate immunity, developing methods for improving vitamin D status in HIV-infected children and adolescents is an important area of clinical research. The objective of this study was to evaluate the effect of administration of oral cholecalciferol, 100000 IU every 2 months, and 1 g/day calcium on serum 25-hydroxyvitamin D concentrations, serum and urine calcium, and HIV disease progression during a 12-month period. METHODS. HIV-infected children and adolescents who were aged 6 to 16 years were randomly assigned to receive vitamin D (100000 IU bimonthly) and calcium (1 g/day; n = 29) or double placebo (n = 27). Serum 25-hydroxyvitamin D concentrations as measured by radioimmunoassay, albumin-corrected calcium concentrations, and spot urinary calcium-creatinine ratios were determined monthly. RESULTS. No abnormalities in serum calcium concentration were observed. One participant who received placebo developed hypercalciuria. No group differences were seen in the change in CD4 count or CD4% or viral load during 12 months. The overall mean monthly serum 25-hydroxyvitamin D concentrations were higher in the group that received vitamin D and calcium than in the placebo group, as was the monthly serum 25-hydroxyvitamin D area under the curve. After completing 12 months of study, 2 (6.7%) participants in the group that received vitamin D and calcium had a trough serum 25-hydroxyvitamin D concentration <20 ng/mL compared with 14 (50%) in the placebo group. Twelve (44.4%) in the group that received vitamin D and calcium had a trough serum 25-hydroxyvitamin D concentration of ≥30 ng/mL compared with 3 (11.1%) in the placebo group. CONCLUSIONS. Administration of oral cholecalciferol to HIV-infected children and adolescents at a dosage of 100000 IU every 2 months, together with 1 g/day calcium, is safe and results in significant increases in serum 25-hydroxyvitamin D concentrations.

Incident fractures in HIV-infected individuals: a systematic review and meta-analysis

Objective(s):Some but not all studies indicate that individuals with HIV infection are at an increased risk of fracture. We systematically reviewed the literature to investigate whether incidence of fracture (both overall and fragility) differs between individuals with and without HIV. Design:A systematic review and meta-analysis. Methods:Medline, Scopus and the Cochrane Library databases for all studies ever published up to 28 September 2012 and electronically available conference abstracts from CROI, ASBMR, IAS and AIDS were searched. All studies reporting incidence of all fracture and fragility fracture in HIV-infected adults were included. A random effects model was used to calculate pooled estimates of incidence rate ratios (IRRs) for studies that presented data for HIV-infected and controls. For all studies, incidence rates of fracture and predictors of fracture among HIV-infected individuals were summarized. Results:Thirteen eligible studies were analysed, of which seven included controls. Nine studies reported all incident fractures and 10 presented incident fragility fractures. The pooled IRR was 1.58 [95% confidence interval (CI) 1.25–2.00] for all fracture and 1.35 (95% CI 1.10–1.65) for fragility fracture. Smoking, white race and older age were consistent predictors for fragility fractures. Conclusion:Our results indicate that HIV infection is associated with a modest increase in incident fracture. Future research should focus on clarifying risk factors, designing appropriate interventions and the long-term implications of this increased risk for an ageing HIV-infected population.

Early Weaning Increases Diarrhea Morbidity and Mortality Among Uninfected Children Born to HIV-infected Mothers in Zambia

BACKGROUND Early weaning may reduce human immunodeficiency virus (HIV) transmission but may have deleterious consequences for uninfected children. Here we evaluate effects of early weaning on diarrhea morbidity and mortality of uninfected children born to HIV-infected mothers. METHODS HIV-infected women in Lusaka, Zambia, were randomly assigned to breastfeeding for 4 months only or to continue breastfeeding until the mother decided to stop. Replacement and complementary foods were provided and all women were counseled around feeding and hygiene. Diarrhea morbidity and mortality were assessed in 618 HIV-uninfected singletons alive and still breastfeeding at 4 months. Intent-to-treat analyses and comparisons based on actual feeding practices were conducted using regression methods. RESULTS Between 4 and 6 months, diarrheal episodes were 1.8-fold (95% confidence interval (CI), 1.3-2.4) higher in the short compared with long breastfeeding group. Associations were stronger based on actual feeding practices and persisted after adjustment for confounding. At older ages, only more severe outcomes, including diarrhea-related hospitalization or death (relative hazard [RH], 3.2, 95% CI, 2.1-5.1 increase 4-24 months), were increased among weaned children. CONCLUSIONS Continued breastfeeding is associated with reduced risk of diarrhea-related morbidity and mortality among uninfected children born to HIV-infected mothers in this low-resource setting despite provision of replacement and complementary food and counseling. CLINICAL TRIALS REGISTRATION NCT00310726.

Bone mineral content is lower in prepubertal HIV-infected children.

Summary: Total body bone mineral content (TBBMC) was measured by dual energy x‐ray absorptiometry in a cross‐sectional study of 51 prepubertal HIV‐infected children and 262 healthy prepubertal children aged 4.2 to 14.7 years. The mean TBBMC ± SD was lower in HIV‐positive children than in HIV‐negative controls (955 ± 325 vs. 1,106 ± 273 g, respectively; p = .0006). Reductions in TBBMC remained in the HIV‐positive group after adjusting for age, sex, and race by analysis of covariance (p < .001). Differences in TBBMC between HIV‐positive and HIV‐negative groups persisted when height and weight were also accounted for in the analysis (p = .027). The magnitude of the difference in TBBMC between the groups increased with age. In the HIV‐positive group, no associations were observed between TBBMC and use of a protease inhibitor, duration of treatment with antiretroviral medications, viral load, or CD4 cell count. TBBMC is decreased in HIV‐infected children. As a result of compromised bone mineral accrual, HIV‐infected children may be at increased risk for osteoporosis and related complications.

Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life.

Introduction:HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood. Methods:We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African–American or Hispanic Tanner stage 5 men aged 20–25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls. Results:HIV-infected men were similar in age and BMI, but were more likely to be African–American (P = 0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4–1.2 lower in HIV-infected men at the spine, hip, and radius (all P < 0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (P <0.05). HIV-infected men had dramatic deficiencies in plate-related parameters by individual trabeculae segmentation (ITS) analyses and 14–17% lower bone stiffness by finite element analysis. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR-pQCT parameters differed between men infected perinatally or during adolescence. Conclusion:At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age.

Effect of supplementation with cholecalciferol and calcium on 2-y bone mass accrual in HIV-infected children and adolescents: a randomized clinical trial

BACKGROUND Skeletal abnormalities have been reported in HIV-infected children and adolescents. Although the etiology is not well understood, vitamin D deficiency may be involved. OBJECTIVE The study objective was to evaluate the effect of vitamin D and calcium supplementation on bone mass accrual in HIV-infected youth. DESIGN Perinatally HIV-infected children were randomly assigned to receive vitamin D (100,000 IU cholecalciferol given every 2 mo) and calcium (1 g/d) (supplemented group) or double placebo (placebo group) for 2 y. The total-body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), spine bone mineral content (SBMC), and spine bone mineral density (SBMD) were assessed by using dual-energy X-ray absorptiometry at baseline and at 2 annual follow-up visits. RESULTS Fifty-nine participants, aged 6-16 y, were randomly assigned to either the supplemented (n = 30) or the placebo (n = 29) group. At enrollment, supplemented and placebo groups did not differ with respect to age, sex, dietary intakes of vitamin D and calcium, mean baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, TBBMC, TBBMD, SBMC, or SBMD. Significant increases in serum 25(OH)D were observed in the supplemented group but not in the placebo group. TBBMC, TBBMD, SBMC, and SBMD increased significantly at 1 and 2 y in both groups. No between-group differences were observed at any time before or after adjustment for stage of sexual maturation by mixed linear model analysis. CONCLUSION One gram of calcium per day and oral cholecalciferol at a dosage of 100,000 IU every 2 mo administered to HIV-infected children and adolescents did not affect bone mass accrual despite significant increases in serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00724178.

Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy

Background Few studies have assessed metabolic and body composition alterations in perinatally HIV-infected African children on antiretroviral therapy (ART). We compared metabolic profiles and regional fat of children on ritonavir-boosted lopinavir (lopinavir/ritonavir), lamivudine and stavudine to those switched to nevirapine, lamivudine and stavudine. Methods This study evaluated metabolic and body composition outcomes in 156 HIV-infected children completing a randomised trial that assessed the continued use of lopinavir/ritonavir-based ART or switch to nevirapine-based ART in Johannesburg, South Africa (2005–2010). Fasting total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides total and regional body fat (BF) were measured. A clinical assessment for lipodystrophy (LD) was conducted. Results 156 children (mean age 5.1±0.8 years, mean duration of treatment 4.2±0.7 years, mean time since randomisation 3.4±0.7 years) were enrolled. 85 were randomised to the lopinavir/ritonavir group and 71 to the nevirapine group. The lopinavir/ritonavir group had lower mean HDL (1.3±0.4 vs 1.5±0.4 mmol/l, p<0.001) and higher mean TC (4.4±1.0 vs 4.1±0.8 mmol/l, p=0.097), LDL (2.6±0.9 vs 2.3±0.7 mmol/l, p=0.018) and triglycerides (1.1±0.4 vs 0.8±0.3 mmol/l, p<0.001). The lopinavir/ritonavir group had more total BF by mean skinfold sum (43±11.1 vs 39±10.1 mm, p=0.031) and BF% by bioelectrical impedance analysis (17.0±7.0 vs 14.1±8.0%, p=0.022). Thirteen (8.4%) met criteria for LD. Conclusions Unfavourable alterations in lipid profile and triglycerides, and differences in fat are detectable in young HIV-infected South African children receiving lopinavir/ritonavir-based regimens versus those switched to nevirapine-based regimens. Interventions to mitigate these alterations are warranted to reduce long-term cardiovascular disease risk.

Antibodies to pneumococcal capsular polysaccharides in children with human immunodeficiency virus infection given polyvalent pneumococcal vaccine.

Antibody to 7 common pneumococcal capsular polysaccharides was measured in 11 children with human immunodeficiency virus (HIV) infection who had been previously vaccinated with 23-valent polysaccharide pneumococcal vaccine, 11 unvaccinated children with HIV infection, and 11 healthy subjects. No differences in capsule-specific IgG levels against serotypes 4, 6B, 8, 12F, 14, 19A, and 19F were observed among the vaccinees with HIV infection compared with unvaccinated children with HIV infection and age-matched control children.