Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children. Pediatric AIDS Clinical Trials Group

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.     

Simultaneous Pneumocystis carinii and pneumococcal pneumonia in human immunodeficiency virus-infected children

Three children with acquired immunodeficiency syndrome who had pneumonia develop were infected simultaneously with Pneumocystis carin?i and Streptococcus pneumoniae. Such coexistence has not been previously reported in children. One patient received prophylactic treatment against Pneumocystis carin?i before his illness.     

Routine vaccination and vaccine-preventable infections in children born to human immunodeficiency virus-infected mothers. European Collaborative Study

Information on vaccinations and vaccine-preventable infections collected in a prospective study of children born to human immunodeficiency virus (HIV)-infected mothers was analysed for reports of adverse reactions and to estimate the clinical efficacy of vaccines. No vaccinated, HIV-infected child developed measles (56 child-years' follow-up), mumps (33), rubella (33) or pertussis (239), and only one adverse reaction - to Bacillus Calmette-Guerin (BCG) - was reported. These findings provide limited evidence of the safety and efficacy of routine vaccination of HIV-infected children.     

Serum and plasma markers of nutritional status in children infected with the human immunodeficiency virus

OBJECTIVE: To determine whether reduced serum or plasma protein and micronutrient levels are common in children infected with the human immunodeficiency virus (HIV) and whether these levels are different in children with growth retardation compared to those with normal growth. SUBJECTS: Children were separated into three groups: (a) HIV-infected with growth retardation (HIV + Gr); (b) HIV-infected with normal growth (HIV+); (c) HIV-uninfected with normal growth (HIV-). All children were afebrile and free of acute infection at the time of study. During a 24-hour stay in the Pediatric Clinical Research Unit, blood was drawn for analysis of total protein, albumin, zinc, selenium, and vitamin A levels; growth measurements were obtained; and dietary intake was assessed by 24-hour weighed food intake and 24-hour dietary recall. STATISTICAL ANALYSIS: Mean differences between groups were assessed by analysis of variance, and differences in the frequency of nutrient deficiency were determined by chi 2 analysis. RESULTS: Thirty-eight children between 2 and 11 years of age were studied: 10 HIV + Gr, 18 HIV+, and 10 HIV-. No statistically significantly differences were noted in mean levels of albumin, prealbumin, zinc, and selenium. Mean serum level of vitamin A was significantly higher in the HIV + Gr group than in the other two groups. There were no significant differences between groups in the frequency of deficiency for any nutrient studied. Mean energy and nutrient intake was similar among groups. APPLICATIONS/CONCLUSIONS: Abnormal serum or plasma protein or micronutrient levels were uncommon in this cohort of HIV-infected children, even in children with growth retardation. Routine monitoring of the level of proteins and micronutrients studied is unnecessary in the absence of specific clinical indicators of deficiency.     

Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients

The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h] alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (Cmax) of ZDV plasma decreased from 748 +/- 375 (mean +/- standard deviation) to 546 +/- 296, and area under the concentration-time curve from 0 to 24 h (AUC0-24) decreased from 3,052 +/- 1,007 to 2,261 +/- 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide Cmax and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3'-amino-3'-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.     

Cancer in human immunodeficiency virus-infected children: a case series from the Children's Cancer Group and the National Cancer Institute

PURPOSE: To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. METHODS: We retrospectively surveyed the Children's Cancer Group (CCG) and the National Cancer Institute (NCI) for cases of cancer that occurred between July 1982 and February 1997 in children who were HIV seropositive before or at the time of cancer diagnosis. We used Kaplan-Meier survivorship curves, hazard function estimates, and Cox proportional hazards models to evaluate survival. RESULTS: Sixty-four children (39 boys, 25 girls) with 65 tumors were reported. Thirty-seven children (58%) acquired HIV infection vertically (median age at cancer diagnosis, 4.3 years); 22 children (34%) acquired HIV through transfusion of blood or blood products (median age at cancer diagnosis, 13.4 years). Forty-two children (65%) had non-Hodgkin's lymphoma (NHL). Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. Other malignancies included acute leukemia (five children), Kaposi's sarcoma (KS; three children), Hodgkin's disease (two children), vaginal carcinoma in situ (one child), and tracheal neuroendocrine carcinoma (one child). Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The average monthly death rate after NHL diagnosis was 12% in the first 6 months, which decreased to about 2% thereafter. In contrast, the monthly death rate after leiomyosarcoma diagnosis increased from 5% in the first 6 months to about 20% thereafter. CONCLUSION: After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates; improved outcome for NHL, in particular, may depend on earlier diagnosis and therapy.     

Immune compromise and prevalence of Candida vulvovaginitis in human immunodeficiency virus-infected women

The San Lazaro Hospital of Seville that was established in the middle of the 13th century was one of the most important in Spain and Europe throughout nearly eight centuries in terms of caring for leprosy patients. In the 1930s the exclusive treatment of leprosy patients ceased and San Lazaro became a general hospital. The Spanish Crown (Alfonso X) accorded certain privileges and rules to the hospital which also were conferred by subsequent monarchs. These rules and ordinances contributed to the establishment and functioning of many lazarettos throughout the Americas of which we have documentation, notably those of Santo Domingo, Tlaxplana (Mexico City), Lima, Cartagena de Incias, La Habana, and Yucatan.     

Immunophenotypic analysis of peripheral blood mononuclear cells undergoing in vitro apoptosis after isolation from human immunodeficiency virus-infected children

Lymphocytes of human immunodeficiency virus (HIV)-infected individuals undergo accelerated apoptosis in vitro, but the subsets of cells affected have not been clearly defined. This study examined the relationship between lymphocyte phenotype and apoptotic cell death in HIV-infected children by flow cytometry. Direct examination of the phenotype of apoptotic lymphocytes was accomplished using a combination of surface antigen labeling performed simultaneously with the Tdt mediated Utp nick end-labeling (TUNEL) assay. In comparison to live cells, apoptotic lymphocytes displayed an overrepresentation of CD45RO and HLA-DR expressing cells, while CD28 and CD95 expressing cells were underrepresented. Lymphocytes expressing CD4, CD8, and CD38 were equally represented in apoptotic and live populations. When percent lymphocyte apoptosis follow- ing culture was examined independently with lymphocyte subsets in fresh blood, apoptosis was negatively correlated with the percentage of CD4 cells, but not with specific CD4 T-cell subsets. Although not correlated with the percentage of total CD8 cells, apoptosis was positively correlated with specific CD8 T-cell subsets expressing CD45RO and CD95 and negatively correlated for CD8 T cells expressing CD45RA. These results provide direct evidence that a population of activated lymphocytes with the memory phenotype lacking the costimulatory molecule CD28 are especially prone to undergo apoptosis. The findings related to CD95 expression in fresh and apoptotic cells implicate Fas-dependent and Fas-independent pathways of apoptosis in HIV disease in children.     

Isoniazid preventive therapy in human immunodeficiency virus-infected persons. Long-term effect on development of tuberculosis and survival

BACKGROUND: Although the short-term benefit of isoniazid prophylaxis in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis has been shown, long-term benefits are unknown. METHODS: Historical cohort study in an acquired immunodeficiency syndrome unit at a tertiary referral hospital. A sample of 121 HIV-infected patients with positive results on a purified protein derivative test were followed up for development of active tuberculosis and survival. Patients who received isoniazid prophylaxis were compared with patients who did not receive prophylaxis. RESULTS: Of the 121 patients examined, 29 (24%) completed a 9- to 12-month course of isoniazid prophylaxis (median follow-up, 89 months), and 92 (76%) did not receive the drug (median follow-up, 60 months). Active tuberculosis developed in 46 patients (38%). The incidence of tuberculosis was higher among patients with no prophylaxis (9.4 per 100 patient-years) than among patients with isoniazid prophylaxis (1.6 per 100 patient-years) (P = .006). Risk for development of tuberculosis was associated with the absence of isoniazid prophylaxis (relative risk [RR], 6.55; 95% confidence interval [CI], 2.02-21.19). Death during the period of study was more frequent in patients who did not receive isoniazid (50/92 or 54%) than in patients who received isoniazid (7/29 or 24%) (P = .008). Median survival was more than 111 months in patients who received isoniazid compared with 75 months in patients who did not receive isoniazid (P < .001). In a proportional hazards analysis, the development of tuberculosis (RR, 1.88; 95% CI, 1.09-3.27), the absence of isoniazid prophylaxis (RR, 2.68; 95% CI, 1.16-6.17), and a CD4+ cell count lower than 0.20 x 10(9)/L (RR, 3.03; 95% CI, 1.39-6.61) were independently associated with death. Patients who received isoniazid had a longer survival after stratifying for the CD4+ cell count. CONCLUSIONS: Preventive therapy with isoniazid confers long-term protection against tuberculosis and significantly increases survival in patients dually infected with HIV and Mycobacterium tuberculosis.     

Cross-reactions between the cytotoxic T-lymphocyte responses of human immunodeficiency virus-infected African and European patients

The great variability of protein sequences from human immunodeficiency virus (HIV) type 1 (HIV-1) isolates represents a major obstacle to the development of an effective vaccine against this virus. The surface protein (Env), which is the predominant target of neutralizing antibodies, is particularly variable. Here we examine the impact of variability among different HIV-1 subtypes (clades) on cytotoxic T-lymphocyte (CTL) activities, the other major component of the antiviral immune response. CTLs are produced not only against Env but also against other structural proteins, as well as some regulatory proteins. The genetic subtypes of HIV-1 were determined for Env and Gag from several patients infected either in France or in Africa. The cross-reactivities of the CTLs were tested with target cells expressing selected proteins from HIV-1 isolates of clade A or B or from HIV type 2 isolates. All African patients were infected with viruses belonging to clade A for Env and for Gag, except for one patient who was infected with a clade A Env-clade G Gag recombinant virus. All patients infected in France were infected with clade B viruses. The CTL responses obtained from all the African and all the French individuals tested showed frequent cross-reactions with proteins of the heterologous clade. Epitopes conserved between the viruses of clades A and B appeared especially frequent in Gag p24, Gag p18, integrase, and the central region of Nef. Cross-reactivity also existed among Gag epitopes of clades A, B, and G, as shown by the results for the patient infected with the clade A Env-clade G Gag recombinant virus. These results show that CTLs raised against viral antigens from different clades are able to cross-react, emphasizing the possibility of obtaining cross-immunizations for this part of the immune response in vaccinated individuals.     

Highly active antiretroviral therapy decreases the incidence of bacteremia in human immunodeficiency virus-infected individuals

Dandruff is a clinical alteration of the skin that consists histologically of orthokeratotic clumps with minute parakeratotic foci found in inflammatory pathologies such as seborrheic dermatitis and psoriasis. Therefore, some nucleated cells should be found in dandruff and hence there is a possibility that forensically typeable DNA could be extracted from dandruff. Because of a particular case in which we were involved, a study was carried out to determine whether or not DNA could be extracted from dandruff, and if the two most widely used extraction techniques (Chelex and organic) would be applicable. Results show that sufficient quantities of DNA (more than 30 to 40 ng) can be obtained from as little as 1.0 to 1.5 mg of dandruff. Both methods yield DNA, although the organic procedure seems to yield more (72.5 ng Chelex vs. 183.3 ng organic). All the DNA samples extracted were typed correctly for the loci HUMTH01 and HUMvWA. Therefore, dandruff can be considered a potential source of DNA for forensic identification.     

Serum lactate-dehydrogenase isoenzymes in HIV positive children. A longitudinal study

The impairment of humoral immunity with rapid turn-over of cellular B clones in children with HIV infection is known as well as the conduct of LDH isoenzymes in B cell lymphoproliferative diseases like Burkitt's lymphoma. Therefore, serum lactate-dehydrogenase activity (LD, EC 1.1.1.27) and its isoenzymes have been evaluated twice (within 12 months) in 11 children with HIV infection with respect to a control group (30 subjects). Furthermore, the relationship between those and other clinical and immunologic parameters (total lymphocytes, CD4/CD8, immunoglobulins, classification according to the Atlanta CDC 1987) has been studied. HIV infected children have shown a significant decrease in LD1 rates, which was directly correlated to CD4/CD8 values. After the follow-up, this correlation became even more significant. Thus, these findings may suggest the usefulness of LDH isoenzymes evaluation as a marker of disease activity in children with HIV infection.     

Absence of detectable human herpesvirus 8 in the semen of human immunodeficiency virus-infected men without Kaposi's sarcoma

The prevalence of human herpesvirus 8 (HHV-8)/Kaposi's sarcoma (KS)-associated herpesvirus was investigated in the semen of 99 human immunodeficiency virus (HIV)-infected men (median CD4 cell count, 357/mm3) by use of a polymerase chain reaction (PCR) assay capable of detecting <10 copies of HHV-8 DNA. Of the subjects, 95 (96%) self-identified as men who have sex with men (MSM), and 3 had a history of clinical KS. Seminal cell specimens were negative for HHV-8 in 98 subjects. None of the 26 without KS (27.1% of 96 tested) who were seropositive for HHV-8 by IFA for latency-associated nuclear antigens had HHV-8 detected in their semen. The only subject with any evidence for seminal HHV-8 DNA was seropositive for HHV-8 and had active KS. HHV-8 was detected in 10 (10.4%) of 96 peripheral blood mononuclear cell specimens. The prevalence of HHV-8 DNA by PCR in semen of HIV-infected MSM without KS is low.     

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.     

Gastrointestinal leishmaniasis in human immunodeficiency virus-infected patients: report of five cases and review

We describe five cases of gastrointestinal leishmaniasis in patients with human immunodeficiency virus infection and review 10 additional cases reported in the literature. All of the patients had CD4+ cell counts of < 200/mm3, and AIDS had been previously diagnosed for 12 patients. Fever and splenomegaly were present in 46% of cases. Thirteen patients had digestive symptoms; these symptoms included diarrhea (6), dysphagia and/or odynophagia (6), abdominal pain (2), epigastric pain (2), gastrointestinal hemorrhage (1), and rectal discomfort (1). The regions of the digestive tract most frequently affected by Leishmania organisms were the duodenal mucosa (90%) and the gastric mucosa (75%). Endoscopy showed normal-appearing mucosa in 45% of cases. In 10 cases the diagnosis of visceral leishmaniasis was first made by biopsy of the gastrointestinal mucosa. In most cases treatment with antimonial agents was not effective.     

Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients

To determine whether matrix metalloproteinase (MMP)-9 is a potential mediator involved in the frequently detected blood-brain barrier leakage in human immunodeficiency virus (HIV)-infected patients, zymography was used to detect MMP-9 activity in cerebrospinal fluid (CSF) samples of 80 HIV-infected patients and of 10 control patients. CSF MMP-9 activity was detected in 40% of HIV-infected patients (but not in controls) and was significantly more frequent in HIV-infected patients than in those without neurologic deficits (50% vs. 13.6%). The frequency of CSF MMP-9 activity did not significantly differ between neurologically symptomatic HIV-infected patients with or without opportunistic central nervous system disease (51.6% vs. 48.1%). Additionally, the presence of CSF MMP-9 activity in HIV-infected patients was associated with an increased CSF white blood cell count and an elevated CSF-to-serum albumin ratio, suggesting that it may play a role in blood-brain/CSF barrier leakage in HIV-infected patients.     

Pyogenic bacterial pneumonia in human immunodeficiency virus-infected inpatients: a clinical, radiological, microbiological, and epidemiological study

We prospectively studied features of pyogenic bacterial pneumonia in 263 consecutive human immunodeficiency virus-infected inpatients over a 6-month study period. Risk factors for bacterial pneumonia were examined by a case-control study that included 33 cases who presented with at least one episode of bacterial pneumonia and 80 controls without bacterial pneumonia. The estimated cumulative incidence of bacterial pneumonia per year was 12.5 cases per 100 inpatients (95% confidence interval [CI], 8.8-17.2). The 38 episodes of bacterial pneumonia that occurred in the 33 inpatients were mainly unilateral, but 32 episodes were patchy lobar or diffuse infiltrates. Microbiological etiologies were obtained in 33 of the 38 episodes of bacterial pneumonia. Thirty-seven pathogens were identified, including Streptococcus pneumoniae (16, of which 12 had a decreased susceptibility to penicillin), Haemophilus influenzae (6), and Pseudomonas aeruginosa (6). The risk factors for bacterial pneumonia that were identified after logistic regression included prior sinusitis within 1 month before admission (odds ratio [OR], 3.2; 95% CI, 1.1-9.1) and prior bacterial infection of the lower respiratory tract within 6 months before admission (OR, 3.1; 95% CI, 1.1-8.3).