Children and HIV

Pharmacokinetics of Enfuvirtide in Pediatric HIV-Infected Patients

Study Question(s): What are the pharmacokinetics (PK) of enfuvirtide in HIV-infected children and adolescents?

Study Participants: 25 HIV-infected pediatric patients (aged 5-16) were enrolled in this study. Participants were drawn from an ongoing study on the PK of enfuvirtide and were stratified by age and by sexual maturity.

Study Methods: Participants received enfuvirtide 2.0 mg/kg, administered subcutaneously, twice a day for 7 days. On day 7, blood samples were taken immediately before the morning dose of enfuvirtide and 2, 4, 8, and 12 hours after the morning dose. The 12-hour sample was taken immediately before the second daily dose. Plasma concentrations of enfuvirtide and its metabolite were measured.

Study Findings: Plasma concentration-time profile for enfuvirtide in the children was not significantly different from the profile for the adolescents. However, plasma concentrations of enfuvirtide did exhibit high interindividual variability. Similarly, there was no significant difference between children and adolescents in plasma concentrations of enfuvirtide metabolite, and plasma concentrations of enfuvirtide metabolite had high interindividual variability. Furthermore, no significant differences were found when PK measures were compared based on sexual maturity stages.

Limitations: The sample size was small.

Lessons Learned: The findings of the study indicate that body weight-adjusted dosing of enfuvirtide in a pediatric HIV population provides comparable drug exposure to that observed in HIV-infected adults. Furthermore, additional analysis shows that body weight-adjusted dosing shows consistent exposure through the age groups because the mean exposure measures showed no significant relationship with age, body weight, or body surface area. In sum, enfuvirtide dosed at 2.0 mg/kg sc bid provides consistent exposure in children and adolescents.

Source: Bellibas, S., Siddique, Z., Dorr, A., Bertasso, A., Sista, P., Kolis, S., Cotler, S., and Delora, P. Pharmacokinetics of Enfuvirtide in Pediatric Human Immunodeficiency Virus 1-Infected Patients Receiving Combination Therapy. Pediatric Infectious Disease Journal, 2004 December; 23(12):1137-41.

Clinical Outcomes for HIV-Infected Children Who Reconstitute CD4 T-Cells without Suppressing Viral Replication

Study Question(s): What are the long-term clinical outcomes among children who display discordant viral and immune responses to combination ARV therapy?

Study Participants: 40 HIV-infected children between the ages of 2 and 18. The median age was 7.1, the majority (85%) of the subjects were infected through maternal transmission, and 68% of the subjects were African-American. The study was limited to participants who had moderate or severe immune suppression by CDC immune categories and who were receiving a protease inhibitor for the first time.

Study Methods: Participants received antiretroviral therapy consisting of 2 nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor. Growth parameters, assessment of adherence, prevalence of HIV-associated illnesses, and measurements of viral load and T-cell subset analysis were assessed at regular 4-8 week intervals before and after beginning treatment. After 24 weeks of treatment, participants were classified into three groups based on viral and immune outcomes:

	viral suppression (VS) and successful immune reconstitution (IS)
	failure to suppress virus (VF) and failure at immune reconstitution (IF)
	discordant immune and viral responses (VF/IS)

Subjects who were either VS/IS or VF/IS continued with their medication for another 72 weeks while those who were classified as VF/IF received a new treatment regimen after 24 weeks, but remained in the study for follow up monitoring. All subjects who had not received a tetanus shot in the past 2 years received one 48 weeks into treatment. Age-matched, healthy subjects were given tetanus immunizations as control subjects.

Study Findings: The number of subjects in each category of this classification system was:

	18 (45%) VS/IS
	17 (42.5%) VF/IS
	5 (12.5%) VF/IF

VS/IS and VF/IS groups showed a similar increase in CD4% after 24 weeks, and in both groups this increase was sustained over the course of the 96 week study. Based on group criteria, CD4% did not increase in the VF/IF group. Additionally, antigen-specific responses after tetanus immunization were significantly increased as compared to before tetanus immunization for the healthy children, the VS/IS group and the VF/IS group, but not for the VF/IF group. Prevalence of HIV-related illnesses decreased in both the VF/IS and the VS/IS groups, but not in the VF/IF group. Lastly, the VF/IS group experienced significant increases in height and weight over the 96 week study.

Limitations: The specific protease inhibitor that each subject took was not randomized but was chosen by the child's primary care physician. This may have affected the results of the study, as those in the VS/IS group were more likely to have taken nelfinavir (NFV) as their protease inhibitor.

Lessons Learned: This study demonstrated that children who are treated with a protease inhibitor-containing ARV and reconstitute their CD4 T-cells have similar outcomes whether or not they suppress viral replication. CD4 T-cell counts may be a better predictor of disease progression, immune capabilities, and growth than viral load in HIV-infected children who receive a protease inhibitor as part of a HAART regimen. Therefore, continuing a therapy that fails to suppress viral load but leads to reconstitution of CD4 T-cells may be a worthwhile option for HIV-infected children with limited treatment options.

Source: Ghaffari, G., Passalacqua, DJ., Caicedo, JL., Goodenow, MM., Sleasman, JW. Two-year clinical and immune outcomes in human immunodeficiency virus-infected children who reconstitute CD4 T cells without control of viral replication after combination antiretroviral therapy. Pediatrics. 2004 November; 114(5). 604-11

Hepatitis C Prevalence in Children with Perinatal HIV Infection

Study Question: What is the prevalence of hepatitis C in children with perinatal HIV?

Study Participants: 525 children with perinatal HIV infection. 83% were of a minority race or ethnicity. Children were distributed evenly by sex. The children had a median age of 10.7 years and were relatively healthy. Participants were randomly selected from a group of 1841 eligible subjects participating in Pediatric Late Outcomes Protocol, a multicenter, prospective cohort study of HIV-infected and HIV-exposed but uninfected children.

Study Methods: Subjects had a single blood specimen obtained for Hepatitis C Virus (HCV) antibody and HCV RNA assays. If results were discordant, a second sample was taken.

Study Findings: Eight of the 525 children (1.5%) were infected with HCV. There were no demographic differences between the children infected with HCV and those not infected with HCV. In addition, there were no differences in birth events or liver disease between those infected with HCV and those not infected with HCV.

Limitations: This study was conducted as a substudy of a larger, nationwide observational study. Therefore, the sample may not have been representative of the general population. In addition, although the subjects were randomly selected from those participating in the larger study, those selected had a significantly higher CD4 cell count that those not selected. Lastly, because such a small number of children infected with HCV were identified, the power of statistical tests to detect anything other than very large differences was limited.

Lessons Learned: The findings of this study show that HIV-infected children are much less likely to be infected with HCV than HIV-infected adults. This difference most likely has to do with route of infection. However, this study also shows that HCV-infection rates are much higher among HIV-infected children than HIV-uninfected children. Indeed, the HCV infection rate for children with perinatal HIV infection was 8 to 10 times higher than for children of similar demographics in the United States. Because such a low percentage of HCV infection was found among the study participants, this study demonstrates that routine HCV testing of children perinatally infected with HIV is not warranted unless specific risk factors for HCV infection are known.

Source: Schuval, S., Van Dyke, RB, Lindsey, JC., Palumbo, P., Mofenson, LM., Oleske, JM., Cervia, J., Kovacs, A., Dankner, WN., Smith, E., Nowak, B., Ciupak, G., Webb, N., Eagle, M., Smith, D., Hennessey, R., Goodman-Kerkau, M., and Levin, MJ. Hepatitis C prevalence in children with perinatal human immunodeficiency virus infection enrolled in a long-term follow-up protocol. Archive of Pediatric Adolescent Medicine. 2004 October; 158(10).1007-13.

Duration of HIV Infection Associated With Increased Risk of Osteopenia and Osteoporosis in HIV-Infected Children

Note: Abstract of Conference Presentation: Clinical Care Options Capsule Summary - Coverage of the 44th ICAAC

Study Question: Is the duration of HIV infection associated with increased risk of osteopenia and osteoporosis in HIV-Infected Children?

Study Participants: 27 children (16 girls and 11 boys) participated in this study. They ranged in age from 2.5-15.9 years.

Study Methods: Bone mineral density (BMD) measurements were taken from the lumbar spine and entire skeleton by dual-energy x-ray absorptiometry (DEXA). An analysis of bone metabolism in serum and in urine was performed. PTH, bone specific alkaline phosphatase (BALP), total and ionized calcium, calcitonin, 1,25(OH)2 vitamin D, 25(OH) vitamin D, phosphorous, and creatinine were analyzed.

Study Findings: Osteopenia or osteoporosis was observed in 7 patients (26%). Furthermore, duration of HIV infection significantly related to both osteopenia and osteoporosis. No correlation between osteopenia or osteoporosis or PTH levels and duration of HAART were found. However, increased BALP levels significantly correlated with duration of HAART but not with osteopenia or osteoporosis.

Lessons Learned: HIV-infected children are at increased risk of developing osteopenia and osteoporosis. Metabolic changes associated with osteopenia and osteoporosis are seemingly related to prolonged duration of HIV but not to HAART exposure. Moderate, persistent increases in parathyroid hormone are (PTH) related to duration of HIV infection.

Source: Esposito S, Pinzani R, Plebani A, et al. Changes of bone mineral density (BMD) and metabolism in HIV-infected children. Program and abstracts of the 44th Annual ICAAC Meeting; October 30 - November 2, 2004; Washington, DC. Abstract H-858.

MMWR Treatment Guidelines for Treating Opportunistic Infections among HIV-Exposed and Infected Children

Study Question: How can health care professionals best treat opportunistic infections in HIV-exposed and infected children?

Background: The Center for Disease Control, the National Institutes of Health, and the Infectious Diseases Society of America together created a report providing evidence-based guidelines for healthcare providers on treatment and prophylaxis for opportunistic infections. The report focused on treatment of opportunistic infections that are particularly common in HIV-exposed and infected infants, children, and adolescents in the United States. HIV-exposed and infected children are at increased risk for opportunistic infections because women with HIV are more likely to vertically transmit opportunistic infections to their children than HIV-uninfected women. In addition, HIV-infected women or HIV-infected family members co-infected with certain opportunistic pathogens might be more likely to transmit these infections horizontally to their children as well. Furthermore, opportunistic infections in children with HIV are established when the child's immune system is both immature and already compromised. Additional precautions must be taken when treating these opportunistic infections that would not be necessary when treating HIV-infected adults.

Study Findings/Recommendations: This report includes evidence-based guidelines for the epidemiology, clinical manifestations, diagnosis, and treatment of the following opportunistic infections in HIV-exposed and infected children:

	Pneumocystis jiroveci (formerly carinii) Pneumonia
	Toxoplasmosis
	Cryptosporidiosis/Microsporidiosis
	Mycobacterium tuberculosis
	Mycobacterium avium Complex Disease
	Serious and Recurrent Bacterial Infections
	Syphilis
	Candida Infections
	Cryptococcosis
	Histoplasmosis
	Coccidioidomycosis
	Cytomegalovirus
	Herpes Simplex Virus
	Varicella-Zoster Virus
	Human Papillomavirus
	Hepatitis C
	Hepatitis B

Source: Mofenson, L., Oleske, J., Serchuck, L., Van Dyke, R., & Wilfert, C. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Morbidity and Mortality Weekly Report. 2004 December; 53(RR-14). 1-92.

Hyperlactatemia in HIV-Uninfected Infants

Study Question: What is the prevalence of hyperactatamia (HLA) in HIV-uninfected infants who were exposed to ARVS during gestation, labor and/or the neonatal period? What are the clinical consequences, evolution and risk factors for HLA in this population?

Study Participants: 127 HIV-uninfected infants who were born to HIV-infected mothers between January 2000 and December 2002 in Barcelona, Spain. Mothers of most infants received HAART during pregnancy (85%) and received IV zidovudine during labor (93%). HAART usually consisted of stavudine or zidovudine in combination with lamivudine plus either nevirapine or nelfinavir. Most infants received zidovudine for six weeks (96%), although a small number received zidovudine, lamivudine plus nevirapine.

Study Methods: Infants received physical examinations and blood biochemistry tests at birth, 15 days, 6 weeks, 3 months, 6 months and 12 months of life. The presence of HLA with hyperalanemia, which suggests mitochondrial injury, were evaluated at each visit.

Study Findings: Compared with anonymous blood samples from control subjects, LA levels were higher for ARV-exposed infants at all ages. LA values were above normal at least once for 63 of the 127 ARV-exposed infants (49.6%). By the time these infants reach 12 months of age, 44 of them had normal levels of LA while 19 of them still showed HLA. Three of these children still showed HLA at 2 years of age. In terms of specific ARVs, only gestational use of didanosine was associated with a higher risk of HLA. Three female infants demonstrated slight, self-limited delays in psychomotor development together with HLA. None of the children had symptoms of LA acidosis.

Limitations: LA levels, which were used as a marker for mitochondrial injury, are highly variable. In this study, samples that were not obtained under optimal conditions were excluded.

Lessons Learned: Study findings are consistent with the past studies documenting transient, asymptomatic elevated LA levels in HIV-uninfected infants exposed to ARVs. Although the benefits of using ARVs to prevent vertical HIV transmission far outweigh the potenital toxicity to infants, clinicians should be advised that certain NRTIs, such as didanosine, are more harmful to infants than others. An effort should be made to choose the least toxic ARV drugs for pregnant women and their infants.

Source: Noguera, A., Fortuny, C., Munoz-Almagro, C., Sanchez, E., Vilaseca, MA., Artuch, R., Pou, J., and Jimenez, R. Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals. Pediatrics. 2004 November; 114(5). 598-603.

Review - Oral Manifestations of HIV Infection in Infants

This article provides a review of recent literature and information about the oral manifestations of HIV in infants and children.

Study Findings: Oral manifestations are one of the first signs of HIV infection among children. These oral lesions are not the direct result of the HIV virus, but rather are manifestations associated with HIV. Furthermore, oral lesions often have prognostic value in the progression of the HIV. Risk factors associated with HIV that cause oral lesions include low numbers of CD4 lymphocytes, xerostomia, and the lack of antiretroviral therapy. One common oral manifestation of HIV is the opportunistic infection, oral candidiasis. Interestingly, oral lesions that appear in HIV-infected infants differ in type and prevalence from the types of lesions found in HIV-infected adults.

Lessons Learned: Because oral lesions are often markers of the progression of HIV, it is imperative that oral health care professionals understand the relationship between oral lesions and HIV progression. It is necessary to make oral health care an integral and important part of HIV treatment in HIV-infected children.

Source: Exposito-Delgado, AJ., Vallejo-Bolanos, E.,& Martos-Cobo, EG. Oral Manifestations of HIV Infection in Infants: A Review Article. Oral Medicine and Pathology. 2004 November-December; 9(5). 410-5.