Antiretroviral therapy in HIV-infected adolescents: clinical and pharmacologic challenges.

INTRODUCTION: With the currently available combined antiretroviral therapy regimens, durable suppression of viral replication, preservation of immune function and normalizing life expectancy, are all becoming achievable goals. Teenagers and young adults living with HIV present unique clinical and pharmacologic challenges to optimizing antiretroviral treatment outcomes. Areas covered: In this expert review of the topic, we examine recent clinical trial data and draw on our program's 25 year experience working with both perinatally and behaviorally HIV infected adolescents. Expert commentary: In order to be effective, the antiretrovirals we provide must be combined with multidisciplinary interventions and ongoing socio-behavioral support to ensure treatment adherence and prevent the emergence of viral resistance.

Use of Integrase Inhibitors in HIV-Infected Children and Adolescents.

Resistance to antiretroviral drugs is an increasingly prevalent challenge affecting both the adult and pediatric HIV-infected populations. Though data on the safety, pharmacokinetics, and efficacy of newer antiretroviral agents in children typically lags behind adult data, newer agents are becoming available for use in HIV-infected children who are failing to respond to or are experiencing toxicities with traditional antiretroviral regimens. Integrase strand transfer inhibitors are one such new class of antiretrovirals. Raltegravir has been US Food and Drug Administration (FDA) approved for use in patients over the age of 4 weeks. Elvitegravir is a second member of this class, and has the potential for use in children but does not yet have a Pediatric FDA indication. Dolutegravir, a second-generation integrase inhibitor, is approved for those older than 12 years. This review summarizes the use of integrase inhibitors in children and adolescents, and highlights the results of recent clinical trials.

Impact of HIV-1 infection and pregnancy on maternal health: comparison between perinatally and behaviorally infected young women.

BACKGROUND: The introduction of combination antiretroviral therapy has resulted in improved survival and quality of life for individuals infected with the human immunodeficiency virus (HIV). There is, as expected, a growing population of perinatally HIV-infected women who are, have been, or will become pregnant. We describe a large cohort of perinatally infected women, compare it with a similar age-matched behaviorally HIV-infected group, and examine factors affecting maternal and infant health. METHODS: We reviewed the records of 30 perinatally infected women who gave birth at two hospitals between January 2000 and December 2011. The comparison group comprised behaviorally infected women who delivered at these hospitals during the same period. The outcome measures were differences in CD4 counts and viral load between the cohorts, and comparisons of maternal morbidity, mortality, and mother-to-child HIV transmission. RESULTS: Median CD4 counts were significantly lower in the perinatal group before, during, and after pregnancy. The median viral load was significantly higher in the perinatal group. Interval prepregnancy to post partum viral load decline was also greater in the behavioral group. Viral load decreases in the perinatal population were not sustained in the post partum period, at which time viral load trended back to prepregnancy levels. There was one mother-to-child HIV transmission in a perinatally infected woman. Over an extended 4 years of follow-up, there were four deaths in the perinatal group and none in the behavioral group. CONCLUSION: After delivery, the differences between perinatally and behaviorally infected mothers accentuate, with immunologic deterioration in the former group. The perinatal population may require novel management strategies to ensure outcomes comparable with those observed in the behavioral group.

Pregnancy in women with perinatally acquired HIV-infection: outcomes and challenges.

This is a retrospective comparison of pregnant women with perinatally acquired HIV-infection (PAH) with a cohort of pregnant women with behaviorally acquired HIV-infection (BAH). PAH cases (11 women) included all pregnant adolescents followed at our HIV clinic from January 2000 to January 2009. BAH cases (27 women) were randomly selected from all deliveries within the study period at the same institution. Demographics, mode of delivery, CD4+ counts, and viral loads (VLs) before, during, and six months postpartum, as well as neonatal outcomes, were reviewed. CD4 counts were significantly lower in the PAH group. VLs were statistically higher in the PAH group. VLs were undetectable at delivery in 60% of the PAH group compared with 88% of the BAH group. No cases of vertical transmission occurred. PAH women may be at a higher risk for HIV-related disease progression. This may increase vertical transmission risks. Further studies and interventions with this growing population are warranted.

Profile of darunavir in the treatment of HIV-infected pediatric and adolescent patients.

The introduction of protease inhibitors (PI) containing antiretroviral regimens in the treatment of HIV infection in infants, children, and adolescents has dramatically decreased morbidity and mortality. Darunavir, the latest PI to be FDA approved for pediatric patients older than 6 years and currently the preferred PI for use in adult patients, was added as an alternative PI for use in children based on a combination of data from both adult and pediatric trials. This review of darunavir in the treatment of HIV-infected children and adolescents looks at the major published clinical trials findings, pharmacokinetic and resistance studies, and preliminary data on use in younger children.

Proliferative glomerulonephritis in lupus patients with human immunodeficiency virus infection: a difficult clinical challenge.

OBJECTIVES: To describe the unusual occurrence of systemic lupus erythematosus (SLE) with nephritis in human immunodeficiency virus (HIV)-infected individuals. METHODS: Chart review-based report of a case of SLE with diffuse proliferative glomerulonephritis (DPGN) in an HIV-infected man, together with a literature review of previously published cases. We searched the English language medical literature from 1987 to 2009 using the following PubMed and Medline terms: "SLE," "HIV," "DPGN." In addition, we researched the role of mycophenolate mofetil (MMF) in the treatment of patients with HIV by using the keywords "MMF" and "HIV". RESULTS: An 18-year-old male patient with vertically transmitted HIV-1 infection presented with malaise, weight loss, malar rash, arthritis, proteinuria, and hematuria. Kidney biopsy confirmed the diagnosis of lupus nephritis (Class IV). He was treated successfully with high-dose corticosteroids and MMF, which were added to his baseline treatment of highly active antiretroviral therapy. The review of the literature identified a total of 18 cases of SLE appearing in HIV+ individuals, of which 11 patients had lupus nephritis. Among the latter, there were only 5 cases of proliferative (focal or diffuse) glomerulonephritis, and their treatment consisted mainly of high-dose corticosteroids. The short-term outcome was favorable in 4 cases and 1 patient died. CONCLUSIONS: Proliferative lupus nephritis is rare in HIV-infected patients. A detailed analysis of the cases may lead to important insights into the pathogenic mechanisms of both diseases. Considering its complex interaction with antiviral medications, MMF may be considered for the treatment of lupus with severe proliferative glomerulonephritis in HIV-infected individuals.

Elevated levels of vitamin B12 and folate in vertically infected children with HIV-1.

OBJECTIVE: Neurologic and hematologic abnormalities are common in HIV-infected children and may be related to concomitant deficiencies in serum B12 and folate, which are highly prevalent in HIV-infected adults. We sought to determine the prevalence of B12 and folate deficiencies in HIV-infected children in the United States. METHODS: Cross-sectional information on demographics, folate and B12 levels, hematological parameters, concurrent CD4%, HIV-viral load and antiretroviral regimens were abstracted from the medical records of 103 vertically infected children followed in an outpatient pediatric HIV clinic in the Bronx, during 2001-2002. RESULTS: Mean age was 10 years (+/-4.4 years), 46% were male, 53% African-American and 46% Hispanic. Nineteen percent had significant immunologic suppression and 18 children had AIDS. All were receiving combination antiretroviral therapy and 66% were on a protease inhibitor-based regimen. Sixteen were taking cotrimoxazole prophylaxis. None were taking multivitamins or manifested clinical evidence of gastrointestinal malabsorption. All patients had serum folate or B12 levels within or above the normal range. Children with elevated B12 were significantly more likely to be younger (P = 0.0002) and have higher mean folate levels (P = 0.0004) compared with children with normal serum B12. In a multivariate logistic regression analysis, factors independently associated with elevated levels of vitamin B12 included: elevated serum folate [odds ratio (OR): 3.2; P = 0.01], nonnucleoside reverse transcriptase inhibitor use (OR: 0.38; P = 0.05) and female sex (OR: 0.67; P = 0.42) CONCLUSION: Folate and B12 deficiencies are uncommon in HIV-infected children in the United States, suggesting that routine supplementation with B12 and folate is not indicated without confirmation of micronutrient deficiency.

Prevalence of hepatitis B and C virus infections in children infected with HIV.

We evaluated the prevalence and transmission mode of hepatitis B and C in an inner-city, pediatric cohort of human immunodeficiency virus (HIV)-infected persons, as well as the demographic characteristics of the cohort. Hepatitis B or C was found in 13 (5.8%) of 228 children. This analysis suggests that chronic hepatitis is prevalent and should be routinely screened for in the pediatric HIV-infected population.

Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity.

NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children.

Partial treatment interruption of protease inhibitor-based highly active antiretroviral therapy regimens in HIV-infected children.

Treatment guidelines for HIV-infected children recommend using combinations of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). Successful suppression of HIV replication and adherence to these regimens are often suboptimal because of multiple factors. For patients with detectable viremia and limited treatment options, therapy simplification consisting of RTIs, referred to as partial treatment interruption (PTI), may represent a temporizing option. We describe a cohort of 26 HIV-infected children who underwent treatment simplification by discontinuing the PI and continuing therapy with 2 or more RTIs. The subjects, who were identified retrospectively, were followed for a period of 24 to 96 weeks. Data collected included clinical information, viral load, and CD4T lymphocyte percentage (CD4%) at baseline and 24, 48, and 96 weeks after PTI. Twenty-six, 21, and 11 patients were evaluated at 24, 48, and 96 weeks, respectively. No child had Centers for Disease Control and Prevention-defined disease progression, and there were no significant changes in viral loads (P > 0.5) across all study intervals after interruption of the PIs. Although most children maintained a CD4% > 15%, comparisons of CD4% at 24 and 48 weeks demonstrated a statistically significant decrease compared with baseline. Therapy simplification by PTI may provide a practical option in patients intolerant of or failing PI-based highly active antiretroviral therapy.

VH3 gene expression in children with HIV infection.

OBJECTIVE: To study immunoglobulin heavy chain variable region (V(H)) gene expression in HIV-uninfected (HIV-) and HIV-infected (HIV+) children. METHODS: A retrospective, observational study was performed by PCR-ELISA to examine IgM and IgG V(H) gene family expression among peripheral CD19-positive B cells. The subjects were 10 HIV+ children with, and 11 HIV+ children without a history of invasive pneumococcal disease (IPD) and 12 HIV- children. The ages of the HIV+ and HIV- children, and the CD4 lymphocyte counts and viral loads (VL) of the HIV+ /IPD- and HIV+ /IPD- children were statistically similar. Rearranged V(H)3 gene libraries were constructed from 3 HIV+ /IPD- children to examine individual gene expression. RESULTS: The proportion of IgG V(H)3 expression among HIV+ /IPD- was lower than that of HIV- children, but the proportion of IgG V(H)3 expression among HIV+ /IPD+ children was not significantly different from that of HIV- children. IgG V(H)3 expression was positively, whereas IgM V(H)3 expression was inversely correlated with the VL among HIV+ /IPD+, but not HIV+ /IPD- children. IgM V(H) gene family expression did not differ between HIV+ and HIV- children. CONCLUSION: HIV+ children manifest qualitative and quantitative differences in V(H)3 expression, which may be influenced by IPD.