Easing the transition of HIV-infected adolescents to adult care.

The past two decades have witnessed dramatic reductions in HIV-related morbidity and mortality following the introduction of combination antiretroviral therapy (cART) for infants and children. Improved therapeutic outcomes have changed the face of the HIV epidemic and with it the needs of patients and families. Consequently, many perinatally- and behaviorally-infected adolescents are now transitioning to adult care. What follows is a brief review and commentary concerning original research, reviews, and clinical guidelines describing challenges and best practices in facilitating care transitions for HIV-infected youth to adult care. Over 25,000 HIV-infected US youth aged 13-24 years will require transition to adult care within the next decade. Transition planning must address issues of cognitive development and mental health, medication adherence, sexuality, reproductive, and gender identity, socioeconomic and health insurance status, stigma and disclosure, disrupted relationships with pediatric care providers, and communication. Clinical experience with HIV and other chronic illnesses supports a multidisciplinary, developmentally-sensitive approach to meeting the challenges inherent in care transition that begins early and is monitored with regular evaluation and revision. Specific clinical recommendations have been made by the U.S. Department of Health and Human Services and the New York State Department of Health AIDS Institute.

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.

Associations of proinflammatory cytokine levels with lipid profiles, growth, and body composition in HIV-infected children initiating or changing antiretroviral therapy.

OBJECTIVES: To measure proinflammatory cytokines (PIC) in HIV-infected children beginning or changing antiretroviral therapy (ART), evaluating associations with virologic, immunologic, serum lipid, growth, and body composition measures, markers of growth hormone action and glucose metabolism. METHODS: Forty-nine prepubertal HIV-infected children had measurements of viral load (VL), CD4 lymphocyte count and percentage, serum lipids, apolipoprotein AI/B, IGF-1, IGFBP-1, and IGFBP-3, anthropometry, bioelectrical impedance analysis, TNF-α, IL-1 ß, and IL-6 at baseline and 48 weeks of ART. RESULTS: Baseline levels were detectable (>0.1 pg/mL) for IL-1 ß in 28 of 48, and for TNF-α and Il-6 in all 49 children. TNF-α decreased with ART (P < 0.001) and IL-6 demonstrated a similar trend (P = 0.065). Children with 48-week VL <400 copies/mL had greater declines in TNF-α (mean 45%) than subjects with higher VL (5%; P = 0.009). Each 10% improvement in CD4% was associated with 26% lower TNF-α (P = 0.002) and 31% lower IL-6 (P = 0.016). Greater reductions in TNF-α were associated with lower total/HDL cholesterol ratio (P = 0.003) at week 48. CONCLUSIONS: In HIV-infected children initiating or changing ART, PIC were detectable at baseline and decreased over 48 weeks. Better immunologic responses were associated with greater reductions in TNF-α and IL-6. Reductions in TNF-α were associated with improved total/HDL cholesterol ratio.

Preventive efficacy and cost-effectiveness of point-of-use water filtration in a subacute care unit.

Infections with Pseudomonas aeruginosa and other waterborne pathogens (WBPs) are major contributors to serious morbidity and mortality in hospitals. We sought to determine whether point-of-use (POU) water filtration might result in decreased risk of infection in the subacute care unit (SACU) of a 208-bed medical center. Our findings indicate that POU water filtration can significantly and cost-effectively reduce colonization of and infection with WBPs, including ventilator-associated pneumonia, in an SACU.

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.

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 child's 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%, log(10) 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.

Leukocyte reduction's role in the attenuation of infection risks among transfusion recipients.

Despite advances in the screening of donated blood for infectious agents, the risk of transmitting viral, bacterial, and protozoal infections, as well as newly emerging diseases, via transfusion persists. A complementary approach is leukocyte reduction (LR), the removal of leukocytes from donated blood by filtration. Published evidence, establishing the benefit of LR in reducing the risk of febrile nonhemolytic reactions, cytomegalovirus transmission, and human leukocyte antigen alloimmunization has led to its use for some time for the care of immunosuppressed and other individuals considered to be at high risk for such complications. Recent literature suggests that LR may be effective in reducing the risk of transmission of a number of additional transfusion-transmitted infectious agents, including herpesviruses, retroviruses, bacteria, protozoa, and prions. There is also evidence that LR may reduce the risk of transfusion-related immunomodulation, further contributing to protection against infections that would complicate treatment. With the mounting evidence of potential benefit, a number of countries, as well as many hospitals and blood centers in the United States, have adopted a policy of performing LR for all donated blood. Physicians who care for immunosuppressed patients and those who are responsible for institutional infection-control practices should remain informed of the growing body of literature on LR.

Filters reduce the risk of bacterial transmission from contaminated heated humidifiers used with CPAP for obstructive sleep apnea.

RATIONALE: The treatment of choice for obstructive sleep apnea (OSA) is nasal continuous positive airway pressure (nCPAP) during sleep, but dryness of the upper airway compromises compliance. Heated humidifiers may mitigate such noncompliance; however, recent observations suggest that their use, particularly if not cleaned, increases the risk of respiratory infections. Humidifier water may be contaminated, but the long-held view that passive humidifiers cannot aerosolize water may obscure the perception of risk of infection. OBJECTIVES: This study challenges the long-held view that "passover" humidifiers do not aerosolize water. With such evidence, this study characterizes the performance of filters to reduce the potential risk of contamination. METHODS: Heated humidifier water contaminated with bacteria was studied under conditions simulating week-long use of nCPAP for OSA. RESULTS: Bacteria were recovered in 9 of 11 tests from the breathing tubes of CPAP devices fitted with heated humidifiers with water contaminated with Brevundimonas diminuta or Serratia marcescens. Recoverable bacteria ranged from tens to thousands of colony forming units when tested at air flow rates of 60 liters per minute for 90 minutes. Neither organism was recovered from the circuit tubing when a hydrophobic breathing-circuit filter was positioned between the humidifier and face-mask tubing with a commercially available nCPAP machine tested under simulated-use conditions. CONCLUSION: Data suggest that patients with OSA being treated with nCPAP fitted with humidifiers may be aerosolizing bacteria, putting them at risk for developing respiratory infections and that the use of a hydrophobic filter may attenuate the passage of microbes from contaminated humidifier water.

An overview of prion biology and the role of blood filtration in reducing the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease.

Prions are infectious proteins believed to be responsible for a variety of progressive and fatal neurodegenerative diseases, collectively referred to as transmissible spongiform encephalopathies (TSE). By 1996, it was recognized that ingestion of beef from cattle afflicted with a TSE known as bovine spongiform encephalopathy, could result in a devastating human TSE known as variant Creutzfeldt-Jakob disease (vCJD). Two recent reports of probable transfusion-transmitted vCJD have raised concerns about the safety of the blood supply. The relatively long asymptomatic latency of vCJD, as well as the lack of sensitive and specific antemortem tests, increase the risk that asymptomatic, infected individuals may become blood donors. To this point, donor deferral has been a strategy used to reduce this risk. Nevertheless, this strategy may be unreliable and, furthermore, may threaten blood availability. Leukoreduction has also been helpful in reducing cell-associated infectious prion, which has been reported to reduce up to 42% of the infectivity in blood. Proprietary prion affinity surface modifications have been developed and applied to filters, which exploit an understanding of the unique chemical characteristics of prion surfaces. These have been successfully adapted to existing high-efficiency blood filter matrices for the reduction of prions present in blood components for transfusion.

Prion biology in transfusion medicine: implications for lab testing.

Although eerily silent for many years after the recognition of scrapie in 1759, TSEs remained present within the genome of some mammals. Not since the mid-1950s when Dr. Carleton Gadjusek visited the Fore Indians of New Guinea to study kuru, however, has there been a more frenetic interest by governmental investigators. Certainly, the U.K. experience has heralded a renewed interest in TSEs due to the notoriety associated with younger subjects succumbing to a variant CJD traced to the ingestion of beef. Human TSEs and the potential for their transmission among and across species of mammals has also captured the attention of many. Yet, to date, there is no reliable antemortem test available to screen for infected animals or humans. Antibody-based assays are difficult to develop because most of them do not have specificity for the pathogenic form of prion protein. Whether or not prion testing efforts will change dramatically depends upon the incidence of disease. Some speculate a reduction in testing, because BSE incidence is waning since the adoption of remedial steps in the U.K. in 1989. Others remind us, however, of the long latency of prion diseases and of the recent observations of two patients who succumbed to vCJD after having received blood products from donors who subsequently died of vCJD. The growing incidence of CWD, combined with the emerging observation that as many as 26% of Alzheimer's patients may have been misdiagnosed--having died instead of prion disease--maintains pressure for legislators to adhere to the precautionary principle and support blood-donor exclusionary criteria, antemortem-test development, and pathogen removal from donated blood. The laboratorian can expect to see new tests for prion disease work their way into clinical-testing practice in the near future. In addition, the adoption of newer filtration technologies holds the promise of improved protection from transfusion-transmitted prion disease.

Enfuvirtide (T-20): a novel human immunodeficiency virus type 1 fusion inhibitor.

The development of highly active antiretroviral therapy has improved life expectancy and reduced progression to acquired immunodeficiency syndrome in human immunodeficiency virus (HIV)-infected patients. However, resistance to currently available classes of antiretroviral drugs has become a problem, limiting the options for patients with advanced disease who have been heavily treated. Enfuvirtide (T-20; ENF), a synthetic peptide, is the first of a new class of antiretrovirals that block entry of virus into host cells. ENF interferes with conformational changes required for membrane fusion and injection of virus into the host cell. Optimal treatment of HIV infection will likely require combinations of drugs that target novel stages of HIV type 1 entry and replication.

Diagnosis and management of infectious esophagitis associated with human immunodeficiency virus infection.

Esophageal disease is a common complication and cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Opportunistic infections are the leading cause of esophageal complaints and may be a predictor of poor long-term prognosis, presumably as a reflection of severe underlying HIV immunodeficiency. The esophagus may be the site of the first acquired immunodeficiency syndrome (AIDS)-defining opportunistic illness in a large number of patients. Barium esophagography and upper gastrointestinal endoscopy are diagnostic modalities, commonly used to evaluate esophageal complaints in patients with AIDS. Treatment for most etiologies of esophagitis generally has a high degree of success, with a resultant improvement in quality of life. In addition to optimizing antiretroviral therapy, a thorough diagnostic assessment of every HIV-infected patient with esophageal complaints is warranted, followed by timely and appropriate treatment.