Bret J. Rudy

Protease inhibitor therapy in children with perinatally acquired HIV infection.

Objective:To review the short-term response and safety of protease inhibitor therapy in HIV-infected children. Design:Retrospective chart review of open-label protease inhibitor-containing combination therapy. Setting:Two urban pediatric HIV centers. Patients:Twenty-eight HIV-infected children were prescribed 30 protease inhibitor-containing antiretroviral therapy combinations. The median age at initiation of protease inhibitor antiretroviral therapy was 79 months. Patients had been on previous antiretroviral therapy for a mean of 45.5 months. Results:Of the 28 children who completed at least 1 month of therapy, 26 experienced marked virologic and immunologic improvement (mean maximal decrease in viral load 1.90 log10 copies/ml; SD, 0.8; mean maximal rise in CD4+ lymphocytes of 279 × 106/l; SD, 300 × 106/l). Eleven patients achieved a viral nadir of < 400 copies/ml, and seven sustained this level of viral suppression for a mean of 6 months. Indinavir use was associated with a high incidence of renal side-effects, including two patients who developed interstitial nephritis. Two patients on ritonavir experienced a significant elevation of liver enzymes. Conclusions:Protease inhibitor therapy was associated with substantial short-term virologic and immunologic improvement in this primarily heavily pretreated cohort, with 25% maintaining a viral load of < 400 copies/ml after 6 months of therapy. There was a significant rate of adverse events. Pharmacokinetic and safety data are needed to guide aggressive antiretroviral therapy in HIV-infected children, and further treatment options are required for those failing or intolerant to the available protease inhibitors.

Responses to measles immunization in children infected with human immunodeficiency virus

The responses to measles immunization administered between 6 and 12 months and after 12 months were compared in children with and without human immunodeficiency virus infection. No difference in response was found when primary measles immunization was administered between 6 and 12 months; however, children with human immunodeficiency virus infection had a significantly poorer response when immunization was given after 12 months. Early measles immunization should be considered in children with human immunodeficiency virus infection.

The ACCESS (Adolescents Connected to Care, Evaluation, and Special Services) project: Social marketing to promote HIV testing to adolescents, methods and first year results from a six city campaign

The HIV. Live with it. Get Tested! campaign is an innovative approach of the Adolescents Connected to Care Evaluation and Special Services (ACCESS) project which aims to change youth attitudes about HIV testing and promote more routine testing practices among health providers. The campaign uses social marketing to promote HIV counseling testing and care among at-risk youth. This paper describes the methods of the campaign and the results of its implementation in 1999 and 2000. An independent evaluation team conducted both process and outcome evaluations of the campaign. Process measures demonstrated how the campaign was implemented nationally and in each city and the quantitative outcomes were based on phone calls HIV tests community surveys and press coverage. Overall results of the 1999 campaign have demonstrated its potential as an effective tool for reaching adolescents about HIV risk behaviors prevention and testing. The 2000 campaign on the other hand elicited more media coverage compared to the previous year.

Peripheral blood mononuclear cell markers in antiretroviral therapy-naive HIV-infected and high risk seronegative adolescents

The objective was to examine potential hematologic and immunologic markers for healthy adolescents and for adolescents infected with HIV. The REACH Project (Reaching for Excellence in Adolescent Care and Health) of the Adolescent Medicine HIV/AIDS Research Network (AMHARN) recruits HIV-infected and high-risk HIV-uninfected adolescents aged at least 13 but less than 19 years. The study evaluates biomedical and behavioral features of HIV infection as observed while under medical care for HIV infection and adolescent health. Blood samples were collected from HIV-infected and HIV-uninfected subjects at 16 clinical sites. Cell phenotypes were determined using standard single dual or three-color flow cytometry. This report includes data at enrollment for 94 HIV-positive adolescents who had never received antiretroviral therapy (ART) (mean age 17.4 ± 1.0 years for males and 16.5 ± 1.3 years for females) and 149 HIV-negative adolescents (mean age 16.7 ± 1.2 years for males and 16.6 ± 1.2 years for females); this is the antiretroviral therapy-naive subset drawn from 294 HIV-positive and 149 HIV-negative adolescents enrolled in the REACH Cohort. The total leukocyte count was significantly reduced in the HIV-positive females in comparison with the HIV-negative females (P < 0.001). There was a reduction in natural killer cells (P < 0.05) in HIV-positive females (mean 140.6 ± 104.2 x 10/6 cells/l) in comparison with HIV-negative females (184.3 ± 142.5 x 10/6 cells/l) whereas no differences were found between the two groups of males. The reduction in the total CD4 cell count in HIV-positive males and females in comparison with the HIV-negative subjects was the consequence of a decrease in both the naive CD4 and memory CD4 components. There was a striking increase in the mean number of CD8 memory cells in HIV-positive compared with HIV-negative adolescents and a corresponding increase in the percentage of these cells. In contrast naive CD8 cells were present in increased numbers but their percentage was decreased. These studies of adolescents provide normative data for high-risk healthy adolescents as well as baseline immunologic data for a cohort of ART-naive HIV-positive adolescents. This comparison suggests that this untreated recently infected group had relatively intact immunologic parameters. (authors)

Response to hepatitis B immunization by infants exposed to HIV.

Objective:To assess the antibody response to hepatitis B immunization in HIV-infected and uninfected infants. Design:Cohort, comparing hepatitis B surface-antibody responses of HIV-infected infants with HIV-exposed but uninfected infants. Setting:Urban childrens hospital outpatient clinic for families with HIV-infected members. Intervention:All infants received hepatitis B vaccine according to the American Academy of Pediatrics and Centers for Disease Control and Prevention recommended schedule. Results:Forty-one HIV-exposed or infected infants were immunized with hepatitis B vaccine in the first year of life. Twenty-two out of 24 (92%) HIV-exposed but uninfected infants demonstrated an antibody response to hepatitis B immunization, compared with six out of 17 (35%) HIV-infected infants (P<0.0005). CD4 percentage and CD4 counts were significantly lower in the HIV-infected infants than in the uninfected infants, but there was no significant difference in CD4 count or percentage between HIV- infected responders and nonresponders. Conclusion:The humoral immune response to hepatitis B immunization, administered before 12 months of age, is significantly reduced in HIV-infected children and is independent of CD4 count. Given the large number of infants born each year to pregnant women coinfected with HIV and hepatitis B, further studies to assess the efficacy of increased doses of antigen and variations in the dosage schedule are urgently needed.

Protease inhibitor therapy in HIV-infected children.

We reviewed the short-term response to and safety of protease inhibitor (PI) therapy in HIV-infected children by performing a retrospective chart review of open-label PI containing combination therapy at two urban pediatric HIV centers. Seventy HIV-infected children received 101 PI containing antiretroviral therapy (ART) combinations. Main outcome measures were follow-up CD4 counts, viral loads, and patient or caregiver reported compliance. During follow-up, treatment with PI ART was associated with a mean maximal increase in CD4+ lymphocyte count of 454 x 10(6)/L and a mean maximal decrease in viral load of 1.76 log units. Of the 32 patients who achieved undetectable viral loads, 28 (87.5%) remained undetectable through a mean follow-up of 8.9 months. Patients who reported good compliance achieved a higher rate of response (92.6%) than those who reported poor compliance (61.5%). Of 14 changes made to a second PI because of treatment failure, 11 (78.6%) resulted in a positive response to the second regimen. Nineteen of 101 courses of PI therapy resulted in significant side effects, including renal complications in 8 of 21 patients treated with indinavir. PI ART was associated with substantial short-term improvement in immunological and virological parameters in this heavily pretreated cohort, with 40% of patients maintaining an undetectable viral load after 9 months of therapy. Patients who failed one PI regimen usually responded to a second regimen. There was a significant rate of side effects from PI treatment.

Early Patterns of Adherence in Adolescents Initiating Highly Active Antiretrovial Therapy Predict Long-Term Adherence, Virologic, and Immunologic Control

Dear Editor: n nHighly active antiretroviral therapy (HAART) is effective in lowering viral load in adults and children when taken as prescribed. It is less clear how often or for how long patients can miss doses, or how patterns of inadequate adherence to different treatment regimens with different potency or dosing frequency influence virologic control and immune status.1,2 There is also lack of clarity in how best to measure patient adherence to treatment. Adolescents, who account for the majority of new HIV infections,3 often have difficulty adhering to new medication regimens.4,5 It has previously been demonstrated that adolescents starting HAART with “perfect” self-reported adherence at weeks 4–16 had better short (24 week) and long-term (144 week) virologic control.6 Perfect adherence was defined as the adolescent reporting no antiretroviral doses missed in the 3 days prior to each of four study visits. This measure was restrictive as it could not distinguish between adolescents who might only have missed one dose at one study visit, all doses at one visit, or all doses at all study visits. The goal in this report was to assess other measures of early self-reported adherence in their ability to predict long-term virologic, immunologic, and adherence outcomes. n nPediatric AIDS Clinical Trials Group (PACTG) Protocol 381 was an observational study of 120 adolescents 11–22 years of age infected with HIV through risk behaviors, initiating HAART and followed for up to 3 years.6 The study opened to enrollment in March 1999 and closed to follow-up in November 2004. The study was approved by the Institutional Review Board at each site and informed consent obtained from all participants. n n nAdherence to each study drug at all study visits was assessed by self-report using the PACTG standardized Adherence Questionnaire. Each participant was asked to identify which antiretrovirals they were taking and how often, and how many doses of each treatment they had missed on each of the 3 days prior to the study visit. The missed doses information was converted to percent doses taken of expected (pi) across the 3 days, calculated as: n n n n n(1) n n n nFive adherence summary measures were calculated for each participant using data from the first five study visits up to week 24: p4 to p24: (1) perfect (100% adherence at all time points versus <100%); (2) mean of all time points, reflecting average adherence levels; (3) standard deviation (SD) of all time points reflecting variability; (4) skewness of all time points, reflecting asymmetry (e.g., a few visits with low (or high) versus many with high (or low) adherence); and (5) area under the curve (AUC) created by plotting the adherence at each time point and calculating the area under this curve. n nThree outcomes at 48, 96, and 144 weeks of follow-up were defined: (1) controlled viral load: HIV-1 RNA ≤400 copies per milliliter by week 24 and sustained to each time point versus a confirmed HIV-1 RNA >400 copies per milliliter or off study, (2) immunologic reconstitution: CD4 cell count ≥100u2009cells/mm3 above CD4 count at entry versus CD4 95%). n nOf the 120 adolescents (49% male, 71% black non-Hispanic, 67% >18 years, 89% CDC Disease Category A) who started HAART (58% on efavirenz and 38% on unboosted nelfinavir-based regimens), only 41 (34%) completed 144 weeks of follow-up on HAART. Twenty-four remained on their initial regimen. Thirty-two (33%) of the 96 who switched from their initial regimen onto a different combination changed because of poor adherence. Fifty-seven of the 79 participants (72%) who came off HAART completely either had poor adherence or were lost-to-follow-up and none came off because of improved health status. Among participants on HAART who completed the self-report adherence form, the percent reporting no missed doses in the 3 days prior to a study visit ranged from 57% to 74% and remained relatively constant throughout follow-up (visits were every 12 weeks after week 24). n nOne hundred two adolescents stayed on HAART at least 24 weeks. Twenty were missing one of the five adherence assessments and an additional 8 were missing at least two. The adherence percentage was imputed from the previous visit (or the week 8 value if missing week 4) for these missing values. Shown in Table 1 are week 24 adherence measures by outcome. For all long-term outcomes at all time points, adolescents with improved outcomes were more likely to have perfect adherence (higher % in fourth column of Table 1), higher mean adherence (higher median week 4–24 adherence) and lower variability (lower median SD) over the first 24 weeks. AUC correlated strongly with mean adherence (ru2009=u20090.98) and gave similar results and skewness was not predictive of any outcomes (not shown). For controlled viral load, higher week 24 mean adherence predicted virologic control out to week 144 and lower SD to week 96. Higher week 24 mean adherence was marginally predictive of improved CD4 counts at week 96 and week 144. Higher week 24 mean adherence predicted good self-reported adherence at all subsequent weeks, while the perfect measure and lower SD were significant predictors at weeks 48 and 96. Modeling week 24 mean adherence using three levels ( 95%) gave results similar to those modeling it as a continuous measure. n n n nTable 1. n nRelationship of Week 24 Adherence Summary Measures and Long-Term Outcomes n n n nUsing the subset of participants staying on their initial efavirenz (nu2009=u200947) or unboosted nelfinavir (nu2009=u200934) regimen at least 24 weeks, the percent of participants with suppressed viral load was higher in the efavirenz arm within each adherence level ( 95%). At week 24 the percent with suppressed viral load in the efavirenz arm was 15% higher than the nelfinavir arm (86% versus 71%) among those with mean adherence greater than 95% and by 46% (63% versus 17%) among those with mean adherence less than 75% (pu2009=u20090.034). Similarly at week 48, the rate of viral suppression in the efavirenz arm was higher by 20% (82% versus 62%) in those with mean adherence greater than 95% and by 33% (50% versus 17%) in those with mean adherence less than 75% (pu2009=u20090.053). n nOutcomes were “intent-to-treat,” assuming participants who went off study were failures, but conclusions were similar (although less statistically significant) only analyzing participants remaining on study and with observed data. Among participants with perfect adherence during the first 24 weeks, 33% were lost to follow-up, compared to 46% of those without perfect early adherence. Results were also similar using only observed adherence measurements during the first 24 weeks, i.e., not based on imputation for missing adherence evaluations. n nAdherence to HAART and ability to stay on study in this cohort of adolescents initiating HAART was poor, resulting in disappointing rates of long-term virologic control. Self-reported mean adherence level (measured as a continuous outcome and also categorized into levels 95%) was more predictive of adherence and virologic control out to 144 weeks than the perfect measure (<100% versus 100%). Decreased variability (SD) in early adherence was predictive of viral control for up to 96 weeks, but asymmetry, represented by skewness (for example not taking medications on weekends) was not a useful predictor. Results also confirmed earlier reports that more potent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimens are more “forgiving” with respect to virologic suppression than non-boosted protease inhibitor (PI)-based regimens,2,7 most likely due to longer half-lives of these agents. At the time the study was conducted, boosted PIs were not standard of care. However, even now, while not recommended as an initial regimen, use of unboosted PIs may arise in particular circumstances,8 so these findings confirming less forgiveness for this regimen versus an efavirenz-based regimen remain relevant. n nThe adherence measures in this study were based on self-report that may not be an accurate measure of true adherence, and information was not collected on socioeconomic status, access to medical care, housing instability or other quality of life measures which have been related to adherence in other studies.4,5,9 Despite these limitations, self-reported adherence over the first 24 weeks on HAART was predictive of longer term adherence, virologic control, and improvements in CD4 counts in adolescents initiating HAART. Health care providers should monitor self-reported adherence by patients as they start new antiretroviral regimens and over the first few months. We recommend they ask about numbers of doses missed and over how many days, rather than just asking if subjects have missed any doses (yes/no). If providers identify problems, they can intervene early to establish better adherence patterns, which will result in better longer term outcomes.10

Aseptic meningitis from trimethoprim sulfamethoxazole in an Hiv-infected adolescent

Adolescents infected with the human immunodeficiency virus (HIV) often confront the clinician with difficult medical problems. Besides the host of opportunistic infections, which can affect these patients, side effects from medications can be frequent and, at times, life-threatening. We report a case of aseptic meningitis secondary to trimethoprim-sulfamethoxazole therapy for prophylaxis against Pneumocystis carinii in an HIV-infected adolescent.