Leslie Serchuck

Treating Opportunistic Infections among HIV-Exposed and Infected Children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America

In 2001, CDC, the National Institutes of Health, and the Infectious Diseases Society of America convened a working group to develop guidelines for therapy of human immunodeficiency virus (HIV)-associated opportunistic infections to serve as a companion to the Guidelines for Prevention of Opportunistic Infections Among HIV-Infected Persons. In recognition of unique considerations related to HIV infection among infants, children, and adolescents, a separate pediatric working group was established. Because HIV-infected women coinfected with opportunistic pathogens might be more likely to transmit these infections to their infants than women without HIV infection, guidelines for treating opportunistic pathogens among children should consider treatment of congentially acquired infections among both HIV-exposed but uninfected children and those with HIV infection. In addition, the natural history of opportunistic infections among HIV-infected children might differ from that among adults. Compared with opportunistic infections among HIV-infected adults, which are often caused by reactivation of pathogens acquired before HIV infection when host immunity was intact, opportunistic infections among children often reflect primary acquisition of the pathogen and, among children with perinatal HIV infection, infection acquired after HIV infection has been established and begun to compromise an already immature immune system. Laboratory diagnosis of opportunistic infections can be more difficult with children. Finally, treatment recommendations should consider differences between adults and children in terms of drug pharmacokinetics, dosing, formulations, administration, and toxicities. This report focuses on treatment of opportunistic infections that are common in HIV-exposed and infected infants, children, and adolescents in the United States.

A Phase I/II Study of the Protease Inhibitor Ritonavir in Children With Human Immunodeficiency Virus Infection

Background. Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. Methods. HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m2 given every 12 hours) were evaluated in two age groups (≤2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. Results. A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m2 for the 24-week period. Conclusions. The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

Adherence to antiretroviral treatment among pregnant and postpartum HIV-infected women

Abstract Among women with HIV infection, pregnancy is a time when maintenance of maternal health and reduction of vertical HIV transmission are primary concerns. Few studies have examined adherence to Antiretroviral Treatment (ART) during pregnancy and in the postpartum period when the demands of childcare may significantly interfere with womens self-care behaviors. This study examined ART use and adherence in HIV-infected pregnant and postpartum women participating in the Women and Infants Transmission Study (WITS-IV) in the US. Adherence was assessed through a self-report interview during the third trimester of pregnancy and six-month postpartum. Data were also collected on demographics, biomedical markers and health related symptoms. During the third trimester visit, 77% (309/399) of women completed the self-report adherence measure; 61% (188/309) reported complete adherence. Factors associated with non-adherence included advanced HIV disease status, higher HIV-RNA viral load, more health-related symptoms and alcohol and tobacco use. At six-month postpartum, 55% (220/399) completed the measure; 44% (97/220) of these women reported complete adherence. Factors associated with non-adherence during the postpartum period were ethnicity, more health-related symptoms and WITS clinical site. Results of multivariate analyses using Generalized Estimated Equation analyses across the two visits revealed that more health-related symptoms, higher HIV-RNA viral load, increased alcohol use and clinical site were independently associated with ART non-adherence. These analyses indicate that medication adherence is more likely during pregnancy than postpartum in HIV-infected women, perhaps provoked by motivation to reduce vertical transmission and/or intensive antepartum surveillance. Further investigation is warranted to clarify factors implicated in womens decision-making process regarding ART medication adherence.

Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results.

Objective:To investigate pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r)-based therapy in HIV-1-infected infants 6 weeks to 6 months of age. Methods:A prospective, multicenter, open-label trial of 21 infants with HIV-1 RNA > 10 000 copies/ml and treated with LPV/r 300/75 mg/m2 twice daily plus two nucleoside reverse transcriptase inhibitors. Intensive pharmacokinetic sampling was performed at 2 weeks and predose concentrations were collected every 8 weeks; safety and plasma HIV-1 RNA were monitored every 4–12 weeks for 24 weeks. Results:Median age at enrollment was 14.7 weeks (range, 6.9–25.7) and 19/21 completed ≥ 24 weeks of study. Although LPV/r apparent clearance was slightly higher than in older children, the median area under the concentration–time curve 0–12 h (67.5 μg.h/ml) was in the range reported from older children taking the recommended dose of 230/57.5 mg/m2. Predose concentrations stabilized at a higher level after the first 2 weeks of study. In as-treated analysis at week 24, 10/19 (53%) had plasma HIV-1 RNA < 400 copies/ml (median change, −3.33 log10 copies/ml); poor adherence contributed to delayed viral suppression, which improved with longer follow-up. Three infants (14%) had transient adverse events of grade 3 or more that were possibly related to study treatment but did not require permanent treatment discontinuation. Conclusion:Despite higher clearance in infants 6 weeks to 6 months of age, a twice daily dose of 300/75 mg/m2 LPV/r provided similar exposure to that in older children, was well tolerated and provided favorable virological and clinical efficacy.

Early Initiation of Lopinavir/Ritonavir in Infants Less Than 6 Weeks of Age: Pharmacokinetics and 24 Week Safety and Efficacy

Background: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). Methods: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m2 twice daily plus 2 nucleoside analogs in HIV-1-infected infants ≥14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 μg/mL and area under the curve (AUC) <170 μg hr/mL. Results: Ten infants enrolled [median age 5.7 (range, 3.6–5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7–7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246–305) mg/m2 q12 hours; median measures were AUC = 36.6 (range, 27.9–62.6) μg hr/mL; predose concentration = 2.2 (range, 0.99–4.9) μg/mL; maximum concentration = 4.76 (range, 2.84–7.28) μg/mL and apparent clearance (L/h/m2) = 6.75 (range, 2.79–12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. Conclusions: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m2 BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

Increased incidence of asthma in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes of Health Women and Infants Transmission Study

BACKGROUND Immunoreconstitution of HIV(+) patients after treatment with highly active antiretroviral therapy (HAART) appears to provoke inflammatory diseases. OBJECTIVE We sought to determine whether HIV(+) children receiving HAART (HIV(+) HAART(+)) have a higher incidence of asthma than HIV(+) children not receiving HAART (HIV(+) HAART(-)). METHODS Two thousand six hundred sixty-four children (193 HIV(+) and 2471 HIV(-) children) born to HIV(+) women were evaluated for the incidence and prevalence of asthma (ie, asthma medication use) and change of CD4(+) T-cell percentage with time. RESULTS The HIV(+) HAART(+) children had higher CD4(+) T-cell percentages, lower CD8(+) T-cell percentages, and lower viral burdens than the HIV(+) HAART(-) children (P < or = .05 to P < or = .01). The cumulative incidence of asthma medication use in HIV(+) HAART(+) children at 13.5 years increased to 33.5% versus 11.5% in HIV(+) HAART(-) children (hazard ratio, 3.34; P = .01) and was equal to that in the HIV(-) children. In children born before the HAART era, the prevalence of asthma medication use for HIV(+) HAART(+) children at 11 years of age was 10.4% versus 3.8% for HIV(+) HAART(-) children (odds ratio, 3.38; P = .02) and was equal to that of the HIV(-) children. The rate of change of CD4(+) T cells around the time of first asthma medication for HIV(+) HAART(+) versus HIV(+) HAART(-) children was 0.81%/y versus -1.43%/y (P = .01). CONCLUSION The increased incidence of asthma in HIV(+) HAART(+) children might be driven by immunoreconstitution of CD4(+) T cells.

Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS clinical trials group protocol P1021

BACKGROUND. Compliance with complex antiretroviral therapy regimens is a problem for HIV-1–infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success. METHODS. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for ≥96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV <400 or 50 HIV copies per mL and safety and tolerability of the regimen. RESULTS. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to <400 RNA copies per mL, and 26 (72%) of 37 subjects maintained sustained suppression at <50 copies per mL through week 96. The median baseline CD4 count was 310 per μL (17%), which increased at week 96 by a median of +329 cells per μL (by +18% CD4). Pharmacokinetic results were as predicted for emtricitabine, didanosine, and efavirenz capsules, whereas efavirenz concentrations in children receiving efavirenz oral solution were lower than anticipated, requiring a dose escalation after the planned assessment point. CONCLUSIONS. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study.

Hepatitis C Virus Coinfection and HIV Load, CD4+ Cell Percentage, and Clinical Progression to AIDS or Death among HIV-Infected Women: Women and Infants Transmission Study

BACKGROUND Despite previous study, it remains unclear whether hepatitis C virus (HCV) coinfection affects the progression of human immunodeficiency virus (HIV) type 1 infection. The Women and Infants Transmission Study provided an opportunity to assess this issue. METHODS Longitudinal data on 652 HIV-1-infected women enrolled in the study before the availability of highly active antiretroviral therapy (HAART; 1989-1995) were analyzed. Random effects models were used to determine whether HCV coinfection was associated with different CD4+ cell percentages and HIV-1 RNA levels over time, and Cox proportional hazards models were used to compare the rates of clinical progression to acquired immunodeficiency syndrome (AIDS) or death. RESULTS Of 652 women, 190 (29%) were HCV infected. During follow-up, 19% of women were exposed to HAART. After controlling for indicators of disease progression (CD4+ cell percentages and HIV-1 RNA levels determined closest to the time of delivery in pregnant women), ongoing drug use, receipt of antiretroviral therapy, and other important covariates, no differences were detected in the HIV-1 RNA levels, but the CD4+ cell percentages were slightly higher in HCV-infected women than in HCV-uninfected women. During follow-up, 48 women had progression to a first clinical AIDS-defining illness (ADI), and 26 died with no documented antecedent ADI. In multivariable analyses, HCV-infected participants did not have faster progression to a first class C AIDS-defining event or death (relative hazard, 0.75; 95% confidence interval, 0.37-1.53). CONCLUSIONS In this cohort, the rate of clinical progression of HIV-1 infection was not greater for HCV-infected women.

Long-term Virologic and Immunologic Responses in Human Immunodeficiency Virus Type 1-Infected Children Treated with Indinavir, Zidovudine, and Lamivudine

Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for > or = 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4+ T cells/microL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of > or = 0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4+, CD4+ CD45RA+, and CD4+ CD45RO+ T cell counts. CD4+ CD45RA+ (naive) T cells were the major contributor to CD4+ T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression.

Cohort Profile: NICHD International Site Development Initiative (NISDI): a prospective, observational study of HIV-exposed and HIV-infected children at clinical sites in Latin American and Caribbean countries

This pediatric protocol has the following scientific goals: to describe the characteristics of HIV-exposed infants and HIV-infected infants children and adolescents cared for at clinical sites in Latin America and the Caribbean to describe early and late outcomes related to HIV disease and ARV therapy and to describe early and late outcomes related to in utero exposure to ARVs and HIV and to neonatal exposure to ARVs.