Joseph Cervia

Probiotics and immune response

Current evidence supports the concept that oral administration of probiotic lactobacilli may be therapeutic in preventing antibiotic-associated diarrhea in children and in reestablishing normal flora in the gastrointestinal tract. Children with human immunodeficiency virus (HIV) infections may have episodes of diarrhea and frequently experience malabsorption associated with possible bacterial overgrowth; together these may interact to produce the growth abnormalities characteristic of this group. The overall objective of this investigation has been to determine whether oral administration of the probiotic Lactobacillus plantarum 299v could improve nutrient status and promote growth in children congenitally exposed to HIV. In addition, the possible beneficial effect of Lactobacillus plantarum 299v in modulating immune response was evaluated. In preliminary results described here, we report on the ability of Lactobacillus plantarum 299v to colonize children with HIV and to elicit specific systemic immune response after oral supplementation.

Effect of Probiotic Bacteria on Microbial Host Defense, Growth, and Immune Function in Human Immunodeficiency Virus Type-1 Infection

The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone. Pilot studies have shown that probiotic bacteria given as a supplement have improved growth and protected against loss of CD4+ T cells. The recognition that normal bacterial flora prime neonatal immune response and that abnormal flora have a profound impact on metabolism has generated insight into potential mechanisms of gut dysfunction in many settings including HIV-1 infection. As discussed here, current and emerging studies support the concept that probiotic bacteria can provide specific benefit in HIV-1 infection. Probiotic bacteria have proven active against bacterial vaginosis in HIV-1 positive women and have enhanced growth in infants with congenital HIV-1 infection. Probiotic bacteria may stabilize CD4+ T cell numbers in HIV-1 infected children and are likely to have protective effects against inflammation and chronic immune activation of the gastrointestinal immune system.

Prevalence of elevated cholesterol and associated risk factors among perinatally HIV-infected children (4-19 years old) in Pediatric AIDS Clinical Trials Group 219C.

Background:HIV protease inhibitors (PIs) are known to disturb lipid metabolism in adults, leading to hypercholesterolemia. A number of cross-sectional studies have also reported this phenomenon in perinatally HIV-infected children but differ greatly with respect to prevalence and/or methodology. Methods:The Pediatric AIDS Clinical Trials Group 219C (PACTG 219C) is a prospective cohort study designed to examine long-term outcomes in children born to HIV-infected women. The outcome of interest in this analysis was total cholesterol, and patients were classified as hypercholesterolemic if their total cholesterol was above the 95th percentile of US Third National Health and Nutrition Survey (NHANES III) standards for gender, race/ethnicity, and age. We hypothesized that hypercholesterolemia would be more common among older children receiving PI therapy who demonstrated excellent adherence and might be associated with hypertension and obesity. Information regarding treatment, adherence, and laboratory values was obtained using the date closest to the cholesterol measurement. Crude and adjusted effect measures were estimated using exposure odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) from univariate and multivariate logistic regression models. Results:Among 1812 HIV-infected participants between 4 and 19 years of age, 229 children had hypercholesterolemia (prevalence = 13.0%, 95% CI: 11.1-14.3) compared with 9 of 187 HIV-uninfected children (prevalence = 4.8%, 95% CI: 2.2-8.8). After adjusting for confounders, current PI use (OR = 5.3, 95% CI: 3.1-9.2), age from 4 to <6 years (OR = 2.9, 95% CI: 1.7-4.9), HIV-1 RNA <400 copies/mL (OR = 2.3, 95% CI: 1.7-3.2), self-report of no missed doses in the past 3 days (OR = 2.2, 95% CI: 1.3-3.8), white race (OR = 2.2, 95% CI: 1.4-3.3), age from 6 to <12 years (OR = 1.9, 95% CI: 1.3-2.9), Hispanic ethnicity (OR = 1.8, 95% CI: 1.2-2.5), and current nonnucleoside reverse transcriptase inhibitor use (OR = 1.7, 95% CI: 1.2-2.3) were independently associated with the presence of hypercholesterolemia among the HIV-infected children. There was a positive association with elevated systolic blood pressure in univariate but not multivariate analysis, and no association was present with body mass index. Conclusions:Among the HIV-infected children, the overall prevalence of hypercholesterolemia was 13.0% and the strongest associated risk factor for hypercholesterolemia was current use of a PI in the antiretroviral regimen. Continued follow-up is needed to assess the long-term effects of hypercholesterolemia in children.

Aging cohort of perinatally human immunodeficiency virus-infected children in New York City

BACKGROUND New York City (NYC) pediatricians are now caring for fewer HIV-infected infants and more school age children and adolescents than earlier in the epidemic. METHODS Clinical, laboratory and demographic data were abstracted from medical records at 10 NYC centers participating in the CDC Pediatric Spectrum of HIV Disease project. Pediatric AIDS cases and HIV-related deaths reported to the NYC Department of Health were examined. RESULTS Median age of HIV-infected children in care increased from 3 years in 1989 to 1991 to 6 years in 1995 to 1998. The number of HIV-infected women giving birth in NYC declined 50% from 1990 to 1997 (1630 to 831); increasing numbers were identified prenatally (14% in 1989; 78% after 1995); and most received prenatal zidovudine prophylaxis (73% in 1997). Estimated perinatal transmission decreased to 10% by 1997. Improved identification of seropositive status in infants was associated with an increased proportion of infected infants receiving Pneumocystis carinii pneumonia (PCP) prophylaxis, 84% in 1997. AIDS free survival was longer for children born 1995 to 1998 than for those born before 1995, P = 0.004. In 1998 among children with advanced immunosuppression (CDC category 3), 66% were prescribed 3 or more antiretroviral medicines and 88% received PCP prophylaxis. Citywide AIDS cases and HIV-related deaths fell precipitously beginning in 1996. CONCLUSIONS Based on the observations of this study, the cohort of NYC HIV-infected children in care is aging, associated with a decline in new HIV infections, high rates of PCP prophylaxis and increased time to AIDS. Falling HIV-related deaths citywide support these observations.

Energy balance, viral burden, insulin-like growth factor-1, interleukin-6 and growth impairment in children infected with human immunodeficiency virus.

ObjectiveTo determine the relationship between energy metabolism and growth abnormalities in HIV-infected children and to assess clinical or laboratory characteristics which may be contributing factors to their growth impairment. DesignA comparative study. MethodsWe measured energy intake by inpatient calorie count/outpatient 24 h food recalls, resting energy expenditure by indirect calorimetry, total energy expenditure by the doubly-labeled water technique, iron metabolism, protein metabolism, and lipid metabolism markers as well as CD4 count, viral load, insulin-like growth factor-1 (IGF-1), serum interleukin-6 (IL-6), and whole blood stimulated IL-6 levels in pre-pubertal congenitally HIV-infected children with normal and impaired growth patterns. Results and conclusionsDifferences in energy expenditures were not found between normal and growth-impaired HIV-infected children. Energy intake but not energy expenditure was significantly reduced when HIV-infected children were compared to expected normal values for age and gender. Advanced HIV clinical disease, severe immune suppression, increased viral burden, increased IL-6 activity, decreased total serum protein, and decreased IGF-1 levels were more likely to be found in HIV-infected children with growth impairment in comparison with HIV-infected children with normal growth.

Lipid and Glucose Alterations in HIV-Infected Children Beginning or Changing Antiretroviral Therapy

OBJECTIVE. The objective of this study was to describe lipid profiles and glucose homeostasis in HIV-positive children after initiating or changing antiretroviral therapy and their associations with viral, immune, antiretroviral therapy, and growth factor parameters. METHODS. Ninety-seven prepubertal HIV-positive children aged 1 month to <13 years were observed for 48 weeks after beginning or changing antiretroviral therapy. Fasting lipid panels, serum glucose, insulin, insulin-like growth factor-1 and binding proteins-1 and -3, plasma viral load, and CD4% were measured. Each child was matched on age, gender, and race/ethnicity to children from the National Health and Nutrition Examination Survey, used to give z scores for each childs lipid values. Multivariate regression was used to evaluate the association of changes in z scores over 48 weeks with suppression of HIV-1 RNA, change in CD4% and growth factors, and antiretroviral therapy, adjusted for entry z score, CD4%, log10 HIV-1 RNA, Centers for Disease Control and Prevention category, and total fat and cholesterol dietary intake. RESULTS. Lipid, apolipoprotein, and insulin levels all increased significantly by 48 weeks. Multivariate analysis of changes demonstrated that increased HDL and decreased total-HDL cholesterol ratio were associated with CD4% increase and with insulin-like growth factor-1, which increased to normal (versus remained stable or became low) over 48 weeks. Total cholesterol levels increased among children who achieved HIV-1 RNA of <400 copies per mL. Antiretroviral therapy regimens that included both a protease inhibitor and a non–nucleoside reverse transcriptase inhibitor were associated with greater increases in total-HDL cholesterol ratio than regimens that contained a protease inhibitor or a non–nucleoside reverse transcriptase inhibitor but not both. CONCLUSIONS. In these HIV-positive children with predominantly mild-to-moderate disease, initiation or change in antiretroviral therapy was associated with significant increases in multiple lipid measures and insulin resistance. Favorable lipid changes were associated with CD4% increases, suggesting a protective effect of immune reconstitution on atherosclerosis, and with increased insulin-like growth factor-1 levels, supporting the theory that reduced growth hormone resistance may be a mechanism by which lipid profiles are improved. Finally, antiretroviral therapy regimens that contain both a non–nucleoside reverse transcriptase inhibitor and a protease inhibitor are associated with worse lipid profiles than regimens that contain 1 but not both of these drug classes.

Characteristics of human immunodeficiency virus-infected children at the time of death: an experience in the 1990s.

OBJECTIVE To describe the changes in the characteristics of human immunodeficiency virus (HIV)-related deaths in children with perinatally acquired infection. METHODS A retrospective review of all deaths that occurred in HIV-infected children managed at The New York Hospital-Program for Children with AIDS during a 7-year period from January, 1990, to December, 1996. Differences in the characteristics at death between 15 children who died in 1990 and 10 children who died in 1996 were analyzed. RESULTS Fifty-eight deaths in our cohort of HIV-infected children were identified during the 7-year period. The mean age at death was 4.43 years. Sixty-nine percent of children were black, 55% were male and 94% were receiving Medicaid. The mean weight/age Z score was -3.9 and the mean CD4 index was 0.067 with 65% having <50 CD4 cells/microl at the time of death (TOD). The most common organ/organ systems to be involved at the TOD were lung (78%) and central nervous system (61%). Mycobacterium avium complex (MAC) was the most common isolate at the TOD (26%) followed by Pneumocystis carinii (20%) and Pseudomonas aeruginosa (17%). The leading non-infectious cause of death was cardiac failure (9%). Comparison of the characteristics at the TOD between 1990 and 1996 revealed significant differences in mean age (2.1 vs. 9.2 years, P < 0.0001), mean CD4 count index (0.18 vs. 0.02, P < 0.03), mean number of organ/organ system involvement (3.9 vs. 5.9, P < 0.05), percent receiving antiretroviral therapy (33% vs. 70%, P < 0.02), mean number of years receiving antiretroviral therapy (0.88 vs. 3.86 years, P < 0.01), percent receiving P. carinii pneumonia prophylaxis (27% vs. 100%, P < 0.001), percent receiving MAC prophylaxis/therapy (0% vs. 100%, P < 0.0001), and cause of death from P. carinii pneumonia (53% vs. 0%, P < 0.01). CONCLUSIONS Compared with children who died in 1990, HIV-infected children who died in 1996 were significantly older, more lymphopenic and more likely to have a greater number of organ system involvements and to have received antiviral therapy and antimicrobial prophylaxis. In 1996 no child died of P. carinii pneumonia. In 1996 MAC and P. aeruginosa were the two most important opportunistic infections causing death. These changes in the characteristics at death will warrant review of resources used in treating these children and may be critical in advising parents and care givers about the prognosis of this chronic infection.

Tuberculosis in human immunodeficiency virus-infected and human immunodeficiency virus-exposed children in New York City.

Background. Tuberculosis disease incidence increased sharply in New York City (NYC) in the late 1980s in children and adults. The relationship of tuberculosis disease in adults with the coincident epidemic of immunosuppression caused by HIV disease has been well-documented. This paper examines the relationship of tuberculosis and HIV in children in NYC. Methods. Information on tuberculosis was collected by retrospective chart abstraction in a cohort of HIV-exposed and infected children enrolled in a longitudinal study of HIV. Tuberculosis cases were ascertained by chart review or by matching HIV-infected and -exposed children to NYC Tuberculosis Registry cases. NYC Tuberculosis Registry data on children reported from 1989 to 1995, and not reported as HIV-infected, were used for comparison. Results. Tuberculosis disease was found in 45 (3%) of 1426 HIV-infected children (0.61 per 100 child years of observation) and in 5 (0.5%) of 1085 HIV-exposed uninfected children (0.2 per 100 child years). 30% of children were evaluated for HIV only after presenting with tuberculosis. Children with tuberculosis and HIV were more likely than other age-matched HIV-infected children to have decreased CD4+ T lymphocyte counts (66%vs. 37%, P = 0.02) and more likely than other NYC children with tuberculosis to have culture-confirmed and extrapulmonary tuberculosis. In this series 8 of 21 deaths in HIV-infected children with tuberculosis appeared to be related to tuberculosis. Conclusions. During a period of high tuberculosis incidence in NYC, 3% of HIV-infected children in our cohort had tuberculosis, higher than the rate in uninfected children born to HIV-positive mothers in the same cohort. Because of this association, HIV-infected children with pulmonary illness should be tested for tuberculosis; and all children with tuberculosis should be tested for HIV.

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

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Insulin-like growth factor-1 and lean body mass in HIV-infected children.

Objectives:To describe insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1-binding protein-1 (IGFBP-1) and IGFBP-3 in HIV+ children before and after initiating or changing antiretroviral therapy and to evaluate association of growth and body composition to growth factors at baseline and over time. Methods:Ninety-seven prepubertal HIV+ children aged 1 month to younger than 13 years were observed over 48 weeks after beginning or changing antiretroviral therapy. Serum IGF-1, IGFBP-1, and IGFBP-3 were measured and compared with age- and sex-specific norms. Anthropometric measures were compared as follows: subjects vs matched children from (a) the National Health and Nutrition Examination Survey to generate z scores and (b) HIV-exposed, uninfected children from Women and Infants Transmission Study; and subjects with normal vs abnormal IGF-1 and IGFBP concentrations at baseline. Anthropometric changes were compared for children whose IGF-1 level normalized vs remaining subjects. Multivariate analysis adjusting for sex, race, and baseline age evaluated associations between anthropometry and IGF-1 and IGFBP concentrations. Results:In multivariate analysis, lower baseline IGF-1 and IGFBP-3 were associated with lower mean weight, height, mid-arm muscle circumference, and mid-thigh circumference z scores. Twenty-four percent of children had a low IGF-1 level at baseline, 50% of whom normalized IGF-1 on study. Children whose IGF-1 normalized had greater increases in mean mid-arm muscle circumference z score (1.00 vs −0.03, P = 0.029), but a trend toward lesser mean height increase (P = 0.082) than remaining subjects. Likewise, in comparison to controls from Women and Infants Transmission Study, mean mid-arm muscle circumference also increased more in children whose IGF-1 normalized (P = 0.024) but mean height changed less (P = 0.003). Fifty-five percent of children had elevated IGFBP-1 at baseline, 69% of whom normalized. Conclusions:IGF-1 increases and IGFBP-1 decreases in HIV-infected children upon initiation or change in antiretroviral therapy. Improved muscle mass, but not linear growth, is associated with normalized IGF-1 concentration. These findings suggest that IGF-1 may merit evaluation as a potential therapeutic strategy to improve lean body mass in HIV-infected children.