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Biomedical subjects

Ram Yogev

Publications and source records attributed to Ram Yogev.

At least 19 recordsLinked to original sources
PubMed2006

A behavioral and cognitive profile of clinically stable HIV-infected children.

OBJECTIVE: The purpose of this research was to characterize behavioral and cognitive profiles of clinically and immunologically stable antiretroviral-experienced HIV-infected children. METHODS: Two hundred seventy-four previously treated HIV-infected children aged 2 to 17 years were assessed for behavioral, developmental, and cognitive functioning. Correlations between neuropsychological measures, age, and CD4 lymphocyte count were investigated. RESULTS: The most common behavioral problems, as measured by the Conners' Parent Rating Scale, were psychosomatic (28%), learning (25%), hyperactivity (20%), impulsive-hyperactive (19%), conduct (16%), and anxiety (8%) problems. Mean Wechsler Intelligence Scale for Children-III scores were less than established population norms; the mean verbal IQ was 85, the mean performance IQ was 90, and the mean full-scale score was 86. Hyperactivity was more frequent in children with a Wechsler Intelligence Scale for Children-III performance IQ of <90. Anxiety problems were more likely in children > or =9 years of age. Children with CD4 counts of <660 cells per mm3 were more likely to be identified as having a conduct disorder. No association was noted between behavioral problems and neuroimaging. CONCLUSIONS: Clinically and immunologically stable HIV-infected children had more frequent behavioral problems and lower developmental and cognitive scores than established childhood norms.

Adolescent↗
PubMed2005

Antibody responses to hepatitis A virus vaccine in HIV-infected children with evidence of immunologic reconstitution while receiving highly active antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy. METHODS: A total of 235 children with CD4+ T cell percentages > or = 20% received 2 vaccine doses 24 weeks apart, and 117 received a third vaccine dose after 104 weeks. Anti-HAV antibody titers were measured at baseline and at 32, 104, and 112 weeks after the first vaccination. Subjects with antibody titers > or = 20 mIU/mL were defined as being seropositive. High and low antibody responses were defined as titers > or = 250 and <250 mIU/mL, respectively. RESULTS: Of 151 subjects who were HAV seronegative at baseline, 97% seroconverted after 2 vaccine doses, and 47% had low antibody responses. At 104 weeks, 90% of subjects had antibody titers > or = 20 mIU/mL, and those with low antibody responses were more likely to lose protective antibody titers. A third vaccine dose generated significantly higher antibody titers than those observed after the second vaccine dose. Undetectable HIV RNA at baseline was associated with higher anti-HAV antibody titers after the second vaccine dose. Antibody titers after the second and third vaccine doses were weakly correlated with CD4+ T cell percentages at the time when each vaccine dose was administered. In the 45 subjects who were HAV seropositive at baseline, responses to 2 and 3 vaccine doses were higher than those in subjects who were HAV seronegative at baseline, but the responses showed similar correlations. There were no serious adverse events associated with the vaccine. CONCLUSIONS: HIV-infected children with CD4+ T cell percentages > or = 20% responded better to the HAV vaccine if they had undetectable HIV RNA. The standard 2-dose immunization regimen generated low antibody titers with limited persistence. A third vaccine dose was safe and increased the antibody titers, suggesting that an increase in immunizations may be warranted in this population.

Adolescent↗
PubMed2005

The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis.

OBJECTIVE: Receipt of highly active antiretroviral therapy is associated with a decrease in the incidence of opportunistic infections (OIs) among HIV-infected adults. The goal of Pediatric AIDS Clinical Trials Group protocol 1008 was to evaluate prospectively the incidence of serious bacterial infections (SBIs) and other OIs after discontinuation of OI and/or Pneumocystis jiroveci pneumonia (PCP) prophylaxis among HIV-infected pediatric subjects who experienced immune reconstitution while receiving stable antiretroviral therapy. METHODS: HIV-infected children and adolescents, 2 to 21 years of age, who had received OI and/or PCP prophylaxis for > or =6 months were enrolled if they had sustained responses (>16 weeks before study entry) to antiretroviral therapy, with CD4+ cell percentages of > or =20% for patients >6 years of age or > or =25% for patients 2 to 6 years of age. Prophylaxis was discontinued at entry. To identify whether any correlation existed between functional immune reconstitution and protection from OIs, subjects were immunized with the hepatitis A virus vaccine. The association between the humoral immune response and the likelihood of developing an OI was evaluated. RESULTS: A total of 235 HIV-infected subjects from 43 participating sites had a median follow-up period of 132 weeks, yielding 547 person-years of observation. Twenty SBIs were observed among 19 subjects, resulting in an incidence rate of 3.66 SBIs per 100 person-years (95% confidence interval: 2.24-5.66 SBIs per 100 person-years). Sixteen of the events were presumed bacterial pneumonia, with 4 proven SBIs. One participant experienced 2 separate pneumonia episodes, of presumed bacterial cause. Ten subjects who developed SBIs had baseline CD4+ cell counts of > or =750 cells per mm3, and 15 had CD4+ cell percentages of > or =25% at the time of their SBIs. Two subjects died as a result of non-SBI-related causes. There were no statistically significant differences in changes over time in CD4+ cell counts or CD4+ cell percentages between subjects who experienced primary end points and those who did not. There was no evidence that baseline protease inhibitor use, gender, race/ethnicity, age, or CD4+ cell count or percentage affected the time to development of a SBI. CONCLUSIONS: OI or PCP prophylaxis can be withdrawn safely for HIV-infected pediatric patients who experience CD4+ cell recovery while receiving stable antiretroviral therapy. More studies are needed to assess the association between antibody responses to neoantigens and the development of SBIs.

AIDS-Related Opportunistic Infections↗
PubMed2005

Switch from ritonavir to indinavir in combination therapy for HIV-1-infected children.

BACKGROUND: Protease inhibitors are an effective component of combination antiretroviral treatment for children infected with human immunodeficiency virus 1 (HIV-1), but tolerance or toxicity issues sometimes require an alternative therapeutic strategy. METHODS: HIV-1-infected children aged 2-17 years received combination therapy with either stavudine plus ritonavir or with zidovudine, lamivudine, and ritonavir as part of a randomized clinical trial. Twenty-one months after the start of the trial, ritonavir in capsule formulation became unavailable. The treatment regimen for 25 children was switched from ritonavir capsules to indinavir capsules (500 mg/m(2) every 8 h). The other study drugs remained unchanged. A matched-pairs analysis was performed to compare the results for these 25 children with the results for 25 matched children whose treatment regimen continued to include ritonavir (in liquid formulation). RESULTS: There were no significant differences in the percentage of children with an HIV-1 RNA load of <or=200 copies/mL between the group receiving indinavir and the matched group receiving ritonavir (52% vs. 68%, at the start of indinavir treatment; 42% vs. 52%, at week 12; and 50% vs. 56%, at week 24). Similarly, there were no significant differences between the treatment groups with respect to median CD4 cell counts over time. Toxicities observed in the children treated with indinavir were most often flank pain or headache (16%), renal dysfunction (16%), hematuria (12%), and skin rash (12%) and were consistent with toxicities reported elsewhere. There was no evidence that the switch from ritonavir to indinavir therapy altered the pharmacokinetics of indinavir as a result of residual cytochrome P450 induction or inhibition caused by ritonavir. CONCLUSIONS: The switch from one protease inhibitor (ritonavir) to another (indinavir) as a component of combination antiretroviral treatment in this patient population was a practical therapeutic strategy.

Adolescent↗
PubMed2005

A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy.

BACKGROUND: A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). METHODS: One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. RESULTS: The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. CONCLUSIONS: Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.

Administration, Intranasal↗
PubMed2005

Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age.

BACKGROUND: Few data are available regarding clinical outcomes or dosing requirements for the protease inhibitor ritonavir in human immunodeficiency virus (HIV)-infected children younger than under 24 months of age. METHODS: This prospective, multicenter phase I/II open label treatment trial used ritonavir, zidovudine and lamivudine to treat protease inhibitor-naive, HIV-infected infants between the ages of 4 weeks and 24 months. Two sequential dosing cohorts were treated with 350 or 450 mg/m(2) ritonavir every 12 hours; this report includes results of pharmacokinetics, safety, tolerability and efficacy through 104 weeks of follow-up of all subjects. RESULTS: Fifty HIV-infected children were treated. By week 16, 36 had achieved HIV-1 RNA <400 copies/mL (72% intent-to-treat, 84% as-treated analysis); by week 104, 18 maintained durable viral suppression (36% intent-to-treat, 46% as-treated). Poor medication adherence by caregiver report contributed to virologic failure. Few subjects experienced treatment-limiting toxicity: emesis or ritonavir refusal in 6 (12%); and severe but reversible anemia or elevated serum hepatic transaminases in 1 (4%) each. Apparent oral clearance was higher and the median predose concentrations were substantially lower than those found in adults. Median z scores for weight and height for age/gender were below normal at baseline but improved by week 104. CONCLUSIONS: A combination regimen of ritonavir, zidovudine and lamivudine was generally safe and produced sustained viral suppression in more than one-third of infants who initiated therapy before 2 years of age. Improved palatability of liquid preparations of protease inhibitors, supporting infrastructure and behavioral approaches to improve medication adherence with antiretrovirals will likely be necessary to further improve efficacy.

Age Factors↗
PubMed2005

Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403.

INTRODUCTION: Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children. We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an NRTI, protease inhibitors +/- a nonnucleoside reverse transcription inhibitor (NNRTI). METHODS: This was a phase II, randomized, multicenter study. Forty-one children and youths between 5 months and 21 years with prior NRTI and no prior NNRTI or protease inhibitor experience received either nelfinavir (NFV) 30 mg/kg twice daily (bid), ritonavir (RTV) 400 mg/m bid and buffered didanosine (ddI) 240 mg/m daily (arm A) or NFV 50-55 mg/kg bid, nevirapine (NVP) 120 mg/m bid and stavudine (d4T) 1 mg/kg bid (arm B). Patients were evaluated clinically for 48 weeks after initiation of therapy. Intensive pharmacokinetic sampling occurred after 4 weeks of therapy. RESULTS: : The proportion of children with HIV-1 RNA < or =400 copies/mL and on randomized treatment at 48 weeks was 65% among children assigned NFV + RTV + ddI versus 28% among those assigned NFV + NVP + d4T (P = 0.039). No significant difference in median CD4% change from baseline to week 48 was found (3% versus 1%). No significant differences in safety or tolerability between children randomized to NFV + RTV + ddI versus NFV + NVP + d4T were identified. However, a trend toward a higher rate of permanent discontinuation of study treatment was noted among children assigned to NFV + NVP + d4T compared with NFV + RTV + ddI [7 of 20 (35%) versus 2 of 21 (10%); P = 0.12]. NFV pharmacokinetic measurements were not statistically different between the treatment groups, yet exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV. The pharmacokinetics for NVP, RTV and d4T were similar to those of previously reported data. CONCLUSION: : Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containing NFV + NVP + d4T. Differences in tolerability between the 2 treatment groups were not identified. Systemic exposure of these drugs was similar to that reported in other HIV-infected children and adults.

Adolescent↗
PubMed2005

Single-dose safety and pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, in HIV-infected children.

A phase I, open-label, dose-escalating trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of single, oral doses of amprenavir (141W94), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, in 20 HIV-infected children 4 to 12 years of age. The doses of amprenavir evaluated, 5, 10, 15, and 20 mg/kg of body weight, were comparable to those evaluated in adult phase I and II studies. The most common clinical adverse event associated with amprenavir, administered as soft gelatin capsules, was nausea. Amprenavir was rapidly absorbed, with a mean time to maximum concentration (T(max)) occurring 0.95 to 1.58 h after dosing. The area under the concentration-time curve (AUC(0)(-->)(infinity)) was dose proportional, and the mean maximum plasma concentration (C(max)) increased linearly in a less than dose-proportional manner. Amprenavir was eliminated relatively slowly, with a mean terminal-phase half-life (t(1/2)) of 6.17 to 8.28 h. The t(1/2), apparent total clearance, and apparent volume of distribution during the elimination phase were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters of amprenavir. The results of this study suggest that 20 mg of amprenavir/kg administered twice a day should be used in future pediatric studies.

Area Under Curve↗
PubMed2005

Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children.

OBJECTIVE: Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen. METHODS: Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load. RESULTS: Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA < or =400 copies/mL) still showed poorer neuropsychological functioning compared with established norms. CONCLUSION: Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

Adolescent↗
PubMed2005

Bacterial meningitis in children: critical review of current concepts.

Acute bacterial meningitis is still an important cause of morbidity and mortality in children worldwide. Recently, Haemophilus influenzae type b (Hib), once a common cause of meningitis, has virtually disappeared in developed nations, reflecting the overwhelming success of Hib vaccination. Unfortunately, Hib remains a significant pathogen in resource-poor countries. The introduction of the conjugated pneumococcal vaccine in 2000 may lead to similar future trends as witnessed with Hib. As the resistance of Streptococcus pneumoniae to penicillin and cephalosporins continues to evolve, vancomycin has become an important antibacterial in the treatment of bacterial meningitis. The unreliable penetration of this agent into cerebrospinal fluid is of concern, which is compounded by the controversial use of corticosteroids in paediatric meningitis. Some data suggest that in certain situations the addition of rifampicin (rifampin) to ceftriaxone may be a better choice. While dexamethasone is now considered the standard adjunctive therapy in the treatment of pneumococcal meningitis in adult patients, the benefit in children is not so clear and remains controversial; thus, there is no definitive paediatric recommendation. Several anti-inflammatory agents currently under investigation may be used in the future as adjunctive therapy for bacterial meningitis. It is clear that the current concepts in the treatment of childhood bacterial meningitis are evolving, and other antibacterial options and possible alternatives such as carbapenems and fluoroquinolones should be considered. Fluid restriction because of the Syndrome of Inappropriate Antidiuretic Hormone Secretion is widely advocated and used. Yet, this practice was recently challenged. It seems that most patients with meningitis do not need fluid restriction. The overwhelming success of the conjugated Hib vaccine and the encouraging results of the new conjugated pneumococcal and meningococcal vaccines suggest that the ideal management of bacterial meningitis is prevention and vaccines development against the most common bacterial agents are the best solution.

Child↗
PubMed2004

Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMZ) has been used extensively for the prevention of Pneumocystis carinii (also referred to as "Pneumocystis jiroveci") pneumonia (PCP) and other opportunistic infections in human immunodeficiency virus (HIV)-infected children. Because the efficacy of TMP-SMZ for treatment of bacterial infections is limited, it is sometimes poorly tolerated, and there is risk of emergence of drug-resistant strains associated with widespread use, we evaluated a regimen that included atovaquone and azithromycin. METHODS: A randomized, double-blind, placebo-controlled trial was designed to determine whether atovaquone-azithromycin had equivalent efficacy to TMP-SMZ for the prevention of serious bacterial infections and to compare the long-term tolerance, PCP breakthrough rates, and nonserious bacterial infection rates among HIV-infected children aged 3 months to 19 years. Children qualified for PCP prophylaxis (on the basis of Centers for Disease Control and Prevention recommendations) were randomized to receive atovaquone-azithromycin or TMP-SMZ daily for >or=2 years. RESULTS: Data from 366 of the 369 eligible patients (median duration of follow-up, 3 years) showed that the estimated rates of serious bacterial infection-related events were lower among atovaquone-azithromycin recipients than among TMP-SMZ recipients (17.3 vs. 24.2 events per 100 patient-years; difference, 6.9 events per 100 patient-years; 95% confidence interval [CI], -0.22 to 14.12). Rates for all end points (serious bacterial infection, PCP, Mycobacterium avium complex infection, and serious and nonserious bacterial infection-related deaths) were 19.7 and 27.7 events per 100 patient-years, respectively (difference, 7.9 events per 100 patient-years; 95% CI, -0.28 to 15.54 events per 100 patient-years). The results marginally favored atovaquone-azithromycin therapy statistically. Atovaquone-azithromycin and TMP-SMZ therapies had similar adverse event profiles. CONCLUSIONS: We conclude that, in HIV-infected children, atovaquone-azithromycin is as effective as TMP-SMZ for the prevention of serious bacterial infections and is similarly tolerated.

AIDS-Related Opportunistic Infections↗
PubMed2004

Pneumococcal endocarditis in children.

Endocarditis due to Streptococcus pneumoniae is unusual in children, accounting for 3%-7% of all cases of childhood endocarditis. The US Pediatric Multicenter Pneumococcal Surveillance Group has prospectively identified patients with invasive disease at 8 children's hospitals. During the period of 1 September 1993 through 28 February 2003, a total of 11 children with pneumococcal endocarditis were seen. Seven (64%) were 3-36 months old; 8 (73%) were boys. Ten (91%) had preexisting structural heart disease; 5 had undergone previous heart surgery. Concomitant sites of infection were noted in 6 patients (55%), including 3 patients with meningitis. One patient (9%) died during hospitalization, and 5 others (45%) experienced serious complications. Only 2 patients remained hospitalized for their entire course of parenteral antibiotic therapy. Eight of 10 pneumococcal isolates tested were vaccine or vaccine-related serotypes included in the currently licensed 7-valent conjugated pneumococcal vaccine. Pneumococcal endocarditis in children is unusual but often has serious complications.

Adolescent↗
PubMed2004

Rapid human immunodeficiency virus decay in highly active antiretroviral therapy (HAART)-experienced children after starting mega-HAART.

Increasing numbers of patients are treated with mega-highly active antiretroviral therapy (HAART), or multiple-combination antiretroviral therapy, in an attempt to overcome the viral resistance that has contributed to treatment failure. Studies of human immunodeficiency virus (HIV) viral dynamics are used to quantify the potency of a given regimen. While mega-HAART is expected to provide potent therapy, its potency among heavily experienced HIV-infected children who have failed previous treatment is untested. HIV dynamics studies performed in children have provided minimal information on viral dynamics during mega-HAART. The present study estimates first- and second-phase viral dynamics in six children on mega-HAART, following failure of combination therapy. The first phase of viral decay was rapid, relative to rates reported in previous pediatric studies (median delta = 0.778d(-1), range = 0.583 to 1.088, half-life 1 [t1(1/2)] = 0.894d), while the second phase revealed results similar to those of previous studies (median mu = 0.026d(-1), range = -0.005 to 0.206, t2(1/2) = 9.316d). This indicates that mega-HAART can provide potent therapy among heavily experienced pediatric patients.

Adolescent↗