Rolando M. Viani

Decrease in Hospitalization and Mortality Rates among Children with Perinatally Acquired HIV Type 1 Infection Receiving Highly Active Antiretroviral Therapy

BACKGROUND The impact of highly active antiretroviral therapy (HAART) on human immunodeficiency virus type 1 (HIV-1) disease progression in perinatally infected children is not well documented. This study aims to identify the effect of evolving antiretroviral therapy on the immunologic and virologic status of and hospitalization and mortality rates among perinatally infected children. METHODS Children receiving outpatient care during 1994-2001 at 3 HIV clinics in southern California were observed longitudinally for CD4+ cell percentage, plasma HIV-1 RNA load, antiretroviral treatment, Pneumocystis jiroveci pneumonia (PCP) prophylaxis, and rate of hospital admissions. RESULTS A total of 129 children were observed during the study period; 51% were girls, and 40.3% were Hispanic, 29.5% were African American, and 27.1% were white. The mean CD4+ cell percentage increased from 22.5% in 1994 to 31.2% in 2001 (P<.01), and the mean plasma HIV-1 RNA load decreased from 4.53 log10 copies/mL in 1996 to 3.27 log10 copies/mL in 2001 (P<.001). The use of HAART increased from 0% in 1994 to 93% in 2001 (P<.01), whereas the use of PCP prophylaxis decreased from 55% to 16% during this time (P<.001). The hospitalization rate decreased from 6.49 to 0.60 admissions per 100 person-years during 1994-2001 (P<.001). Acquired immunodeficiency syndrome-associated hospital admission rates decreased from 15.6% in 1994 to 0% in 2001 (P<.0001). Similarly, the admission rate for patients with Centers for Disease Control and Prevention category B decreased from 29.7% in 1994 to 5.9% in 2001 (P<.0001). Logistic regression analysis showed that CD4+ cell percentage and viral load were independently associated with risk of hospitalization. Survival was significantly longer for those who received HAART. CONCLUSIONS HIV-1-associated mortality and hospitalization rates decreased significantly between 1994 and 2001 in perinatally infected children. This correlated with an increase in CD4+ cell percentage and a decrease in HIV-1 RNA load concurrently with the expanded use of HAART.

Virologic and Immunologic Outcomes after 24 Weeks in HIV Type 1-Infected Adolescents Receiving Highly Active Antiretroviral Therapy

BACKGROUND Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. METHODS We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. RESULTS Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. CONCLUSIONS Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.

Obturator Internus Muscle Abscess in Children: Report of Seven Cases and Review

Obturator internus muscle (OIM) abscess is an uncommon entity often mistaken for septic arthritis of the hip. We describe seven children with OIM abscess and review seven previously reported cases. The most common presenting symptoms were hip or thigh pain (14 patients), fever (13), and limp (13). The hip was flexed, abducted, and externally rotated in 11 patients. Magnetic resonance imaging and computed tomography (CT) were diagnostic for OIM abscess in the 14 patients. Associated abscesses were located in the obturator externus muscle (5 patients), psoas muscle (2), and iliac muscle (1). The etiologic agents were Staphylococcus aureus (8 patients), Streptococcus pyogenes (2), Neisseria gonorrhoeae (2), and Enterococcus faecalis (1). Three patients underwent CT-guided percutaneous drainage, and three had surgical drainage. Three patients had ischial osteomyelitis in addition to OIM abscess. The 11 children with uncomplicated OIM abscess were treated for a median of 28 days. All patients had an uneventful recovery.

Prevalence of Primary HIV-1 Drug Resistance among Recently Infected Adolescents: A Multicenter Adolescent Medicine Trials Network for HIV/AIDS Interventions Study

This study examined the prevalence of primary human immunodeficiency type 1 (HIV-1) drug resistance among recently infected youth in the United States. Of the 55 subjects studied, major mutations conferring HIV drug resistance were present in 10 (18%). Eight (15%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations, with the majority (6) having the K103N mutation; 2 (4%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; and 2 (4%) had protease inhibitor (PI) mutations. Phenotypic drug resistance was present in 12 (22%) subjects: 10 (18%) for NNRTIs, 2 (4%) for NRTIs, and 3 (5.5%) for PIs. The prevalence of primary HIV-1 drug resistance, particularly to NNRTIs, in this group of recently infected youth was high.

Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection

ABSTRACT The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects ≥18 to <25 years old receiving (≥28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC0-24), maximum concentration of drug in serum (Cmax), concentration at 24 h postdose (C24), and total apparent oral clearance (CL/F) values were 35,971 ng·hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC0-24, Cmax, C24, and CL/F values were 2,762 ng·hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P ≤ 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir Cmax and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.

Pediatric Imported Malaria in New York: Delayed Diagnosis

The records of 20 children with imported malaria admitted to Kings County Hospital between October 1987 and May 1995 were reviewed. All had a history of recent travel or immigration from a malaria endemic area (West-Africa [16], Central-America [three], and the Caribbean [one]). None of the 10 children with a travel history received appropriate malaria chemoprophylaxis. The most common symptoms and signs were daily fever, chills, and hepatomegaly. Diagnosis was delayed in seven children who were initially felt to have pharyngitis or viral syndrome. Common laboratory findings were anemia and thrombocytopenia. P falciparum was identified in 70% of the patients. Other species were P malariae and P vivax. Complications occurred in six children, hyponatremia in five, seizures in three, and cerebral malaria in one patient. The high incidence of chloroquine-resistant malaria makes chemoprophylaxis difficult in children. The clinical presentation of malaria is nonspecific, and diagnostic delays occur, so a high index of suspicion is needed in children with a travel history.

Perinatal HIV counseling and rapid testing in Tijuana, Baja California, Mexico: seroprevalence and correlates of HIV infection.

Objective:To evaluate the acceptance of counseling and rapid HIV testing and to determine the associated risk factors for HIV infection in pregnant women in Baja California, Mexico. Methods:Pregnant women attending Tijuana General Hospital who consented to participate in the study had blood drawn for a rapid HIV test (Determine HIV-1/2; Abbott Diagnostics, North Chicago, IL). A confirmatory enzyme immunoassay and Western blot were performed and demographic and risk factor data were obtained. Results:From March to November 2003, 1529 (92.5%) of 1653 women who sought prenatal care and 1068 (95.2%) of 1122 women in labor consented to participate. HIV seroprevalence was significantly higher among women screened during labor (12/1068, 1.12%) compared with those seeking prenatal care (5/1529, 0.33%). HIV-infected women were significantly more likely to use injection drugs (12% vs. 1%, P = 0.02), “other” drugs, including methamphetamine, marijuana, and cocaine (65% vs. 6%, P < 0.001), to have more sex partners (3.6 vs. 2.6, P = 0.0002), to not have received prenatal care (41% vs. 13%, P = 0.03), and to have a spouse/partner who used injection drugs (36% vs. 4%, P < 0.001) or “other” drugs (73% vs. 23%, P < 0.001). In multivariate regression analysis, use of methamphetamine (adjusted odds ratio, 17.8, 95% CI, 5.6-56) was independently associated with the risk of HIV infection. Conclusions:These findings indicate a wide acceptance of HIV counseling and testing and document a higher HIV seroprevalence among pregnant women delivering at Tijuana General Hospital than current established estimates in Mexico.

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.

Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy

Background: The goal of HAART is to promote reconstitution of CD4+ T cells and other immune responses. We evaluated the extent and the kinetics of immune reconstitution in HIV-infected children over 144 weeks of successful HAART. Methods: Thirty-seven children receiving their first HAART regimen had plasma HIV RNA; T cells and subpopulations; T-cell rearrangement excision circles (TREC) DNA; candida, HIVCD4 and HIVCD8 enzyme-linked immunospot measured at regular intervals. Results: Plasma HIV RNA became undetectable in 81% of patients at 24 weeks and remained undetectable in 77% at 144 weeks. In contrast, CD4+% continuously increased. Distribution of T-cell subpopulations changed rapidly during the first 48 weeks of HAART and more slowly thereafter. At 144 weeks, total, naive and activated CD4+% and naive CD8+% of HIV-infected children were not significantly different from those of healthy age-matched controls, whereas total and activated CD8+% remained elevated. CD4+ and CD8+ TREC content increased only during the first 48 weeks of HAART. They positively correlated with each other and with total CD4+%, naive CD4+% and naive CD8+%. Candida and HIVCD4 enzyme-linked immunospot increased over time reaching peak values at 48 weeks and 144 weeks, respectively. HIVCD8 enzyme-linked immunospot decreased in magnitude over 144 weeks of HAART but retained its breadth. Baseline CD4+% positively correlated with CD4+% and with functional immune reconstitution at week 144, whereas baseline TREC correlated with TREC at week 144. Conclusion: HIV-infected children acquired normal distribution of CD4+ T cells and other subpopulations and recovered CD4-mediated HIV immunity after 144 weeks of HAART.

Sarcoidosis and interstitial nephritis in a child with acquired immunodeficiency syndrome: implications of immune reconstitution syndrome with an indinavir-based regimen

A child with perinatally acquired AIDS and profound immunodeficiency was treated with zidovudine, lamivudine and indinavir and had excellent immunologic and virologic response. His subsequent clinical course was complicated by multisystem sarcoidosis characterized by granulomatous hepatitis, nephritis, duodenitis and a CD4+ lymphocytic alveolitis as part of the immune reconstitution syndrome.