Akihiko Saitoh

An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children.

Objective:The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. Methods:Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. Results:The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C→T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. Conclusions:HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.

Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele.

We report the one case of sepsis caused by Bifidobacterium breve administered as probiotic therapy. Probiotics can be a potential cause of an invasive disease and should be used with care in vulnerable patients.

CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

Background:Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. Methods:In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. Results:NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). Conclusions:The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism

Background:The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. Methods:The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for ≥6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. Results:The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m2, n = 13) than in children with the G/T genotype (5.7 L/h/m2, n = 30; P = 0.02) or the G/G genotype (7.0 L/h/m2, n = 31; P = 0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (≥5 years of age) (9.7 L/h/m2 vs. 6.6 L/h/m2; P = 0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. Conclusions:CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.

Pneumonia in Hiv-infected patients: a case-control survey of factors involved in risk and prevention

OBJECTIVE To assess the factors that increase or decrease the risk of pneumonia with particular attention to immunization with pneumococcal and influenza vaccines in a group of HIV-infected persons. DESIGN A retrospective, case-control study based on information entered into a standard database and the medical record. SETTING Patients attending a referral clinic specializing in AIDS/HIV care at a public hospital. PATIENTS Among over 2000 subjects entered into a database in 8 years, 127 incidents of pneumonia were identified from the record. These cases were matched with 127 CD4 cell count matched, concurrent controls. INTERVENTIONS None. MAIN OUTCOME MEASURE The principal hypothesis was that chart review would find a decreased frequency of pneumococcal immunization in the pneumonia cases compared with matched controls. RESULTS Pneumococcal immunization was associated with a reduction of the risk of pneumonia by nearly 70%. The effect was seen even when immunization was given with a CD4 cell count of less than 100/mm3. Injection drug users and African-Americans had a twofold increased risk of pneumonia. CONCLUSION The study provides data to support the current recommendation for pneumococcal immunization of all HIV-infected persons. Although this conclusion could lead to renewed enthusiasm for increasing pneumococcal immunization rates in HIV-infected persons, it must be recognized that the study is observational and ascertainment bias cannot be excluded.

Persistence of Human Immunodeficiency Virus (HIV) Type 1 DNA in Peripheral Blood Despite Prolonged Suppression of Plasma HIV-1 RNA in Children

Human immunodeficiency virus (HIV) type 1 DNA in peripheral blood mononuclear cells (PBMC) was quantified in 31 children who received efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors for > or =2 years and in whom undetectable plasma HIV-1 RNA levels (< 50 copies/mL) were sustained, to determine the usefulness of HIV-1 DNA as a marker of virus suppression. The median baseline HIV-1 DNA level was 750 copies/10(6) PBMC. After initiation of highly active antiretroviral therapy (HAART), HIV-1 DNA levels decreased gradually, reaching a plateau from week 80 through week 104 (median HIV-1 DNA level, 263 copies/10(6) PBMC). Children who had plasma HIV-1 RNA levels < 50 copies/mL after receiving HAART for 8 weeks (n=16) had persistently lower quantities of intracellular HIV-1 DNA than children whose HIV-1 RNA levels reached < 50 copies/mL after 8 weeks of HAART (n=15). The median half-life for intracellular HIV-1 DNA was 60 weeks. Thus, despite prolonged maintenance of undetectable levels of plasma HIV-1 RNA, HIV-1 DNA remains detectable in PBMC of children and may be a useful marker of further virus suppression.

Dermatologic manifestations of human parechovirus type 3 infection in neonates and infants.

Background: Human parechovirus type 3 (HPeV3) infection can cause sepsis-like syndrome and meningoencephalitis in neonates and young infants. Although maculopapular rash is a reported clinical manifestation of HPeV3 infection, the frequency and detailed characteristics of rash in neonates and young infants with HPeV3 infection are unknown. Methods: We retrospectively reviewed the clinical characteristics of neonates and young infants who received a diagnosis of HPeV3 infection on the basis of real-time polymerase chain reaction analysis of serum and/or cerebrospinal fluid specimens at the National Center for Child Health and Development in Tokyo between November 2010 and September 2011. Results: Fifteen neonates and young infants were diagnosed as having HPeV3 infection; median age was 33 days (range: 10–81 days). The most common clinical presentation on admission was fever (80%), the median duration of which was 3 days (range: 1–4 days). Five (33%) children required admission to the intensive care unit for close observation, and 2 (13%) required mechanical ventilation for cardiovascular instability. After hospitalization, all children developed rash, mainly on the extremities, at a mean of 3 days (range: 1–5 days) after fever onset. The most striking finding was that 80% (12/15) of patients developed a distinctive palmar–plantar erythematous rash, which disappeared after a median of 3 days (range: 2–7 days). All patients were discharged from hospital without serious sequelae. Conclusions: Palmar–plantar erythema in febrile neonates and young infants may be a diagnostic clue of HPeV3 infection.

Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondria in Human Immunodeficiency Virus Type 1-Infected Children Receiving Highly Active Antiretroviral Therapy

ABSTRACT Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been reported to be responsible for various adverse effects. The relative impact of NRTIs on the mitochondria of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy (HAART) is unknown. Mitochondrial DNA (mtDNA) levels were quantified longitudinally from peripheral blood mononuclear cells (PBMCs) in 31 HIV-1-infected children from Pediatric AIDS Clinical Trial Group Study 382 who were receiving HAART, including nelfinavir, efavirenz, and different NRTIs, and who had had undetectable plasma HIV-1 RNA levels for >2 years. The median mtDNA levels in PBMCs increased from 137 copies/cell at the baseline to 179 copies/cell at week 48 (P = 0.01) and 198 copies/cell at week 104 (P < 0.001). Before the initiation of HAART, children who received regimens containing didanosine had mtDNA levels persistently lower than those in children not receiving didanosine (106 versus 140 copies/cell; P = 0.008). During HAART, the median increase in the mtDNA level from the baseline to week 104 was the lowest in children who received regimens containing didanosine (+26 copies/cell) compared to those in children who received other regimens (+79 copies/cell) (P = 0.02). A multivariate analysis also demonstrated that didanosine, as part of HAART, was the only NRTI associated with the change in mtDNA levels (P = 0.007). Children receiving didanosine-containing antiretroviral regimens have the lowest mtDNA levels in PBMCs and may be at greater risk for long-term adverse effects due to mitochondrial toxicity. This may be of particular importance in resource-limited countries where didanosine is widely used for the treatment of HIV-infected children.

Psychosis in a 12-Year-Old HIV-Positive Girl with an Increased Serum Concentration of Efavirenz

Clearance and adverse effects of efavirenz are associated with CYP2B6-G516T polymorphism. Little is known about the prevalence of genotypes and implications for screening in children. We report (to our knowledge, for the first time in a child) the emergence of psychosis in a 12-year old white girl with an increased efavirenz concentration and heterozygous gene polymorphism of the CYP2B6-G516T.

Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection.

OBJECTIVE. An unstructured treatment interruption in children with perinatally acquired HIV infection is an issue with unresolved significance. The objective of this study was to investigate the actual prevalence and clinical outcomes of a treatment interruption in children and adolescents with perinatally acquired HIV-1 infection. METHODS. Clinical data were analyzed for 72 children and adolescents who had HIV-1 infection and stopped their medications at 4 academic centers in the United States between January 2000 and September 2004. RESULTS. Among 405 patients with perinatal HIV-1 infection, 72 (17.8%) experienced a treatment interruption during the observation period. The mean age of patients at the time of the treatment interruption was 12.8 years, and the mean length of the treatment interruption was 14 months. Medication fatigue was the most common reason for a treatment interruption. The CD4+ T-cell percentage nadir before the treatment interruption did not predict CD4+ T-cell percentage declines during the treatment interruption; however, the CD4+ T-cell percentage gain from nadir to the time of the treatment interruption predicted CD4+ T-cell percentage declines during the treatment interruption. During the median follow-up of 19 months (range: 6–48 months), 48 (67%) patients resumed antiretroviral medications. As expected, there was a continuous CD4+ T-cell percentage decrease and plasma HIV-1 RNA increase during the observation period. Overall, 7 (10%) patients were admitted to the hospital; 2 (3%) patients experienced an AIDS-defining illness. CONCLUSIONS. An unstructured treatment interruption seems to be a major issue for youth with perinatally acquired HIV-1 infection. Patients who experienced the greatest rise in CD4+ T-cell percentage on treatment had the largest CD4+ T-cell percentage decline after the treatment interruption. Close monitoring is required when a treatment interruption occurs in children and adolescents with HIV infection.