D. Robert Harris

RISK FACTORS FOR PERINATAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 IN WOMEN TREATED WITH ZIDOVUDINE

BACKGROUND Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

The Relationship of Acute Transfusion-Associated Hepatitis to the Development of Cirrhosis in the Presence of Alcohol Abuse

Seroprevalence data from the Third National Health and Nutrition Examination Survey (1984 to 1999) suggest that 3 million persons in the United States are infected with the hepatitis C virus (HCV) (1). Treatment fails to clear the virus in 80% to 85% of acutely infected persons. Not all persons who remain infected eventually develop progressive liver disease (2), but in those who do, clinical evidence of liver damage may not appear until decades later (3). It is widely believed that progression of liver disease in persons with chronic HCV infection is enhanced by concomitant heavy alcoholism (4-12). We sought to quantify the association of transfusion-associated HCV infection and history of alcohol abuse with development of cirrhosis among patients followed from the time of acute HCV infection. Methods The source of this investigation, described in detail elsewhere (13), is a long-term follow-up study of acute non-A, non-B hepatitis in patients included in earlier prospective studies of transfusion-related HCV infection. All patients provided informed consent, and the study was approved by the relevant institutional review boards. Briefly, non-A, non-B hepatitis was identified by otherwise unexplained elevations in serum alanine aminotransferase (ALT) levels developing 2 to 24 weeks after transfusion, in the absence of serologic evidence of hepatitis A or B (13). The ALT level had to be elevated on two consecutive measurements, and at least one of the values had to exceed twice the upper limit of normal. Stored sera from case-patients and controls from three of the prospective studiesthe second Veterans Administration Cooperative study (14), the Transfusion-Transmitted Viruses study (15), and the National Institutes of Health Blood Bank Study (16)were tested for anti-HCV by enzyme immunoassay (HCV EIA 2.0, Abbott Laboratories, North Chicago, Illinois). Transfusion-associated HCV infection was diagnosed if anti-HCV appeared and persisted, was temporally related to elevated ALT levels, and was confirmed by using the supplementary recombinant immunoblot assay (RIBA version 3.0, Ortho Diagnostics, Raritan, New Jersey). Because repository samples were not optimally stored for minimizing nucleic acid loss, HCV RNA testing was not performed. Controls consisted of transfused patients from the original three prospective studies who had not developed hepatitis (13). Controls were matched to case-patients by initial treatment center, sex, ethnicity, use of hepatitis immune globulin, presence or absence of a history of alcoholism, age, number of units of blood transfused, and date of transfusion. We excluded patients with anti-HCVpositive samples that predated the index transfusion and those with anti-HCV reactivity but no confirmatory test. Anti-HCVpositive/RIBA-negative and anti-HCVnegative patients were classified as having transfusion-associated non-A, non-B, non-C hepatitis. Controls with anti-HCV in repository samples were excluded. We used a multifaceted approach to gather information on each patients history of liver disease from participation in the prospective studies through initiation of the follow-up study (13). Vital status was ascertained through searches of death registries, and copies of death certificates were obtained. Patients or their designated proxies (if the patient was deceased or incompetent) were invited to participate in a personal interview that included questions about previous hospitalizations. Authorization for release of medical records was obtained, and information on all hospitalizations at each facility identified was requested. Medical records, death certificates, and biopsy and autopsy reports were reviewed by trained abstractors for the diagnosis of cirrhosis, which was based on the occurrence of features of portal hypertension and overt clinical manifestations of cirrhosis. Evaluation of a sample of records indicated a high level of agreement between abstractors and one of the investigators. Potential risk factors were derived primarily from personal interview. A composite variable aimed at identifying a history of heavy alcohol abuse was designed to minimize the possibility of misclassifying unexposed patients. The composite variable was based on one or more of the following criteria: loss of friends, family, or a job because of drinking; admitting to ever having a problem with alcoholism; evidence of heavy drinking abstracted from medical records; or quantification of usual intake of more than 80 g of alcohol per day during the years when the patient drank. Univariate methods (the Fisher exact, exact FisherFreemanHalton [17], and Wilcoxon rank-sum tests) were used to compare the distribution of characteristics between patients included in and those excluded from the analysis and to examine associations between potential risk factors and development of cirrhosis. The strength of the association between risk factors and cirrhosis was assessed by using the odds ratio obtained from multiple logistic regression. The likelihood of developing cirrhosis associated with a combination of risk factors was estimated from the logistic model (18). Results Of 1030 patients who were followed up from the original prospective studies that had collected repository samples, 836 (81.2%) were included in this analysis. We excluded 108 patients whose repository samples were exhausted, 79 with ALT levels or HCV assays that did not permit reliable classification of hepatitis status, 1 with cirrhosis that predated the index transfusion, and 6 with data inconsistencies that could not be resolved. As shown in Table 1, included and excluded patients differed only in median number of blood units originally transfused. The number of units received could affect the probability of developing acute transfusion-associated hepatitis or its severity but would probably not influence development of cirrhosis decades later. Table 1. Characteristics of Included and Excluded Patients Preliminary analyses indicated that development of cirrhosis was unrelated to tattooing, ear piercing, occupational exposures, extended travel to areas in which hepatitis is endemic, and use of injection or other illegal drugs. Information on prescription drug use was unavailable for analysis. Development of cirrhosis differed (P<0.05) according to transfusion-associated hepatitis status, study cohort, race/ethnicity, units of blood originally transfused, history of heavy alcohol abuse, and vital status at follow-up (Table 2). The absolute risk for developing cirrhosis was higher among patients with transfusion-associated HCV infection (17.0% [35 of 206 patients]) (P<0.001) than among those with transfusion-associated non-A, non-B, non-C hepatitis infection (3.2% [3 of 95 patients]) or controls (2.8% [15 of 535 patients]) but did not differ between the latter two groups (P>0.2). The median time from index transfusion to initiation of follow-up (15.6 years overall) did not differ by cirrhosis status, transfusion-associated hepatitis status, or race/ethnicity (P 0.10). Table 2. Association of Patient Characteristics with Development of Cirrhosis Logistic regression modeling indicated that patients with transfusion-associated HCV infection were 7.8 times (95% CI, 4.0 to 15.1 times) more likely to develop cirrhosis than controls, after adjustment for history of heavy alcohol abuse and study cohort. Patients with transfusion-associated non-A, non-B, non-C hepatitis were at increased risk for developing cirrhosis, but this finding was not significant (odds ratio, 1.4 [95% CI, 0.4 to 5.0]). Patients with transfusion-associated HCV were 5.6 times (CI, 1.6 to 19.3 times) more likely to develop cirrhosis than those with non-A, non-B, non-C hepatitis. A history of heavy alcohol abuse was associated with an increased risk for developing cirrhosis (odds ratio, 4.0 [CI, 2.1 to 7.7]). The HosmerLemeshow goodness-of-fit test indicated that the model fit the data well (P>0.2). From this model, it was estimated that patients with both transfusion-associated HCV infection and a history of heavy alcohol abuse were 31.1 times (CI, 11.4 to 84.5 times) more likely to develop cirrhosis than controls without a history of alcohol abuse. Patients with transfusion-associated non-A, non-B, non-C hepatitis and a history of heavy alcohol abuse were also more likely than controls without such a history to develop cirrhosis (odds ratio, 5.5 [CI, 1.3 to 24.3]). Although cirrhosis was less common among African-Americans (2.2%) than among persons of other ethnicities (7.2%), addition of race/ethnicity, follow-up duration, units of blood originally transfused, vital status, and receipt of additional transfusions to the model changed the risks associated with hepatitis status and history of heavy alcohol abuse only slightly. None of these factors made a significant independent contribution to the model (data not shown). Discussion Patients who contracted transfusion-associated HCV infection were at increased risk for developing cirrhosis (odds ratio, 7.8), and this risk increased substantially if the patient also had a history of heavy alcohol abuse (odds ratio, 31.1). Although numerous reports have identified a strong role of alcohol in promoting progression of liver disease among persons with chronic HCV infection (4-12), our findings provide a quantitative measure to assess the strength of this association. Some patients who were originally classified as having acute non-A, non-B hepatitis tested negative for HCV infection. These patients developed cirrhosis more frequently than controls, but not significantly so. This finding suggests that the elevated ALT levels observed during the original prospective studies were caused by intrinsic liver disease. It remains to be determined, however, whether these patients had been infected with a virus other than hepatitis A, B, or C virus or whether the elevated enzyme levels resulted from other causes (for example, nonviral infection

Performance characteristics of HIV-1 culture and HIV-1 DNA and RNA amplification assays for early diagnosis of perinatal HIV-1 infection.

A plasma HIV-1 RNA amplification assay (RNA assay), a quantitative peripheral blood mononuclear cell (PBMC) microculture (culture), and a PBMC HIV-1 DNA amplification assay (DNA assay) were compared for diagnosis of HIV-1 infection in infants receiving zidovudine in Pediatric AIDS Clinical Trials Group protocol 185; assays were performed for all 24 infected and 100 uninfected infants. HIV-1 infection was defined as ≥2 positive cultures or positive antibody to HIV-1 at ≥18 months. Cultures were performed at birth and 6 and 24 weeks of age; DNA and RNA assays were performed on cryopreserved specimens. The sensitivity of culture and DNA and RNA assays at birth was 20.8%, 10.5%, and 26.7%, respectively. At older ages, sensitivity typically exceeded 80%, remaining highest for the RNA assay (>85%). Assay specificity was >99%. Positive predictive values exceeded 93% for each assay at each age; negative predictive values were highest (>90%) for the RNA assay. At birth (P < 0.005) and age 6 weeks (P < 0.001), a significantly larger proportion of infected infants were identified by means of the RNA assay than by the other assays. The diagnostic performance of the RNA assay matched or exceeded that of culture and the DNA assay. Given that RNA assays require less blood volume and yield rapid results, our study adds to existing data suggesting that RNA assays may be used for early diagnosis of HIV-1 infection in infants.

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine

ObjectiveTo evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DesignRisk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. MethodsHIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. ResultsEighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34;P  < 0.001], multiple gestation (OR, 6.02;P  = 0.011), antenatal alcohol use (OR, 1.91;P  = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24;P  = 0.022) or pre-eclampsia (OR, 6.36;P  = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08;P  = 0.014) and pre-eclampsia (OR, 5.25;P  = 0.049), and baseline HIV culture titer (OR, 1.41;P  = 0.037). IUGR was associated with multiple gestation (OR, 8.20;P  = 0.010), antenatal cigarette use (OR, 3.60;P  = 0.008), and pre-eclampsia (OR, 12.90;P  = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. ConclusionsRisk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Prevalence and interactions of patient-related risks for nonadherence to antiretroviral therapy among perinatally infected youth in the United States.

Adherence to antiretroviral regimens continues to be a significant problem in HIV-infected individuals facing a lifetime of therapy. Youth who were infected through perinatal transmission enter into adolescence often with a history of multiple medication regimens. Thus, adherence can be a particularly important issue in these young people, as medication options can often be limited. This was a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations among the following barriers in subjects 12 to 24 years old: mental health barriers, self-efficacy and outcome expectancy, and structural barriers. Among the 368 study participants, 274 (74.5%) were adherent and 94 (25.5%) were nonadherent to highly active antiretroviral therapy (HAART). No significant differences were found between adherent and nonadherent subjects according to mental health disorders. Adherence was associated with some but not all structural barriers. Both self-efficacy and outcome expectancy were significantly higher in adherent versus nonadherent subjects (p < 0.0001). In subjects with low self-efficacy and outcome expectancy, adherence differed according to the presence or absence of either mental health or structural barriers, similar to findings in behaviorally- infected adolescents. Interventions that address the breadth and clustering of adherence barriers in adolescents are needed to have the maximum chance for positive effects.

Improving Health Outcomes for Youth Living With the Human Immunodeficiency Virus: A Multisite Randomized Trial of a Motivational Intervention Targeting Multiple Risk Behaviors

OBJECTIVE To determine if Healthy Choices, a motivational interviewing intervention targeting multiple risk behaviors, improved human immunodeficiency virus (HIV) viral load. DESIGN A randomized, 2-group repeated measures design with analysis of data from baseline and 6- and 9-month follow-up collected from 2005 to 2007. SETTING Five US adolescent medicine HIV clinics. PARTICIPANTS A convenience sample with at least 1 of 3 risk behaviors (nonadherence to HIV medications, substance abuse, and unprotected sex) was enrolled. The sample was aged 16 to 24 years and primarily African American. Of the 205 enrolled, 19 did not complete baseline data collections, for a final sample size of 186. Young people living with HIV were randomized to the intervention plus specialty care (n = 94) or specialty care alone (n = 92). The 3- and 6-month follow-up rates, respectively, were 86% and 82% for the intervention group and 81% and 73% for controls. Intervention Healthy Choices was a 4-session individual clinic-based motivational interviewing intervention delivered during a 10-week period. Motivational interviewing is a method of communication designed to elicit and reinforce intrinsic motivation for change. Outcome Measure Plasma viral load. RESULTS Youth randomized to Healthy Choices showed a significant decline in viral load at 6 months postintervention compared with youth in the control condition (beta = -0.36, t = -2.15, P = .03), with those prescribed antiretroviral medications showing the lowest viral loads. Differences were no longer significant at 9 months. CONCLUSION A motivational interviewing intervention targeting multiple risk behaviors resulted in short-term improvements in viral load for youth living with HIV. Trial Registration clinicaltrials.gov Identifier: NCT00103532.

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.

Quality Indicators Using Hospital Discharge Data: State and National Applications

BACKGROUND Demand for information about the quality of health care has escalated. Yet many organizations lack well-specified quality measures, statistical expertise, or the requisite data to produce such information. The Healthcare Cost and Utilization Project Quality Indicators (HCUP QIs) represent one approach to measuring health care quality using readily available data on hospital inpatients. METHODS The HCUP QIs, developed in 1994, address clinical performance rather than other dimensions of quality such as satisfaction or efficiency. The 33 indicators produce rates that represent measures of outcomes (mortality and complications), utilization, and access. In lieu of complex multivariate techniques, two methods were used: (1) restrictions in defining patient subgroups to isolate homogeneous at-risk populations and (2) standardization when populations are diverse. Stratified analyses are recommended when patient or hospital factors are believed to influence the outcome. A simple method for making statistical comparisons to national rates was developed. The HCUP QI software, available in both mainframe and microcomputer applications, have enabled organizations to use their own data to produce comparative statistics and examine trends over time. Results summarized at the individual hospital or aggregate level are being used to stimulate continuous quality improvement initiatives. CONCLUSIONS The HCUP QIs offer a low-cost alternative for organizations that have access to administrative data. Current users include hospital associations, state health departments, statewide data organizations, and individual hospitals. Although the HCUP QIs are intended to serve as indicators, not definitive measures, of quality, they were designed to highlight quality concerns and to target areas for more intensive study.

A multisite randomized trial of a motivational intervention targeting multiple risks in youth living with HIV: initial effects on motivation, self-efficacy, and depression.

PURPOSE Interventions targeting multiple risk behaviors are needed for youth living with HIV (YLH). A randomized clinical trial compared Healthy Choices, a four session motivational intervention targeting two of the three risk behaviors (HIV medication adherence, sexual risk behavior and substance use) to multidisciplinary specialty care alone. This article presents intermediary outcomes available at 3-month follow-up, variables proposed to be precursors to behavior change (motivation, self-efficacy, and depression). METHODS YLH (N=186) with at least one of the three problem behaviors were recruited from four sites in the Adolescent Trials Network and one non-Adolescent Trials Network site, and were assessed at baseline and 3 months. RESULTS Of the 94 youth randomly assigned to the treatment condition, 84% received at least one session, 67% received at least two sessions, 56% received at least three sessions, and 49% completed all four sessions. In intent-to-treat analysis, only depression was significantly improved in the treatment group as compared with controls. However, in per-protocol analysis, youth receiving at least two sessions of the intervention also showed significant improvements in motivational readiness to change as compared with youth in the control condition. CONCLUSION Results suggest the potential benefits of clinic-based motivational interventions for YLH who access these interventions. Delivering interventions in the community using an outreach model may improve access. Analysis of subsequent time points will determine effects on actual behavior change.

Sexual Risk Taking Among Transgender Male-to-Female Youths With Different Partner Types

OBJECTIVES We examined associations between partner types (categorized as main, casual, or commercial) and sexual risk behaviors of sexually active male-to-female (transgender female) youths. METHODS We interviewed 120 transgender female youths aged 15 to 24 years recruited from clinics, community-based agencies, club and bar venues, referrals, and the streets of Los Angeles, California, and Chicago, Illinois. RESULTS Sexual risk behaviors varied by partner type. Transgender female youths were less likely to use condoms during receptive anal intercourse with their main partner and were less likely to use condoms with a main partner while under the influence of substances. Youth participants were also more likely to talk to a main partner about their HIV status. Our data identified no demographic or social factors that predicted condom use during receptive anal intercourse by partner type. CONCLUSIONS Research and interventions that focus on understanding and mitigating risk behaviors by partner type, especially those that tackle the unique risks incurred with main partners, may make important contributions to risk reduction among transgender female youths.