Leslie A. Kalish

The Women's Interagency HIV Study

The Womens Interagency HIV Study comprises the largest U.S. cohort to date of human immunodeficiency virus (HIV)-seropositive women (N = 2,058) with a comparison cohort of seronegative women (N = 568). The methodology, training, and quality assurance activities employed are described. The study population, enrolled between October 1994 and November 1995 through six clinical consortia throughout the United States (totaling 23 sites) represents a typically hard-to-reach study population. More than half of the women in each cohort were living below the federally defined levels of poverty. The women ranged in age from 16 to 73 years; approximately one-quarter self-identified as Latina or Hispanic, over one-half as African-American not of Hispanic origin, and less than 20% as white, non-Hispanic origin. Self-reporting of HIV exposure risk included injection drug use by 34% of the seropositive women and 28% of the seronegative women, heterosexual contact (42% vs 26%), transfusion risk (4% vs 3%) and no identified risk (20% vs 43%). Demographic and HIV exposure risk characteristics of the seropositive cohort were comparable with characteristics of nationally reported AIDS cases in U.S. women. This well characterized cohort of HIV-seropositive and high-risk seronegative women represents a rich opportunity for future studies of HIV disease progression and pathogenesis.

Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission

BACKGROUND The importance of plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA in pregnant women in relation to the other factors known to influence the risk of transmission of infection to their infants is incompletely defined. We studied the relation of maternal plasma HIV-1 RNA levels to the risk of perinatal transmission and the timing of transmission. METHODS We measured plasma HIV-1 RNA serially in 552 women with HIV-1 infection who had singleton pregnancies. The status of infection in their infants was assessed by culture of blood and further classified as early (if a culture of blood obtained within the first two days of life was positive) or late (if a culture of blood obtained in the first seven days of life was negative but subsequent cultures were positive). The rates of transmission at various levels of maternal plasma HIV-1 RNA were analyzed by tests for trend, with adjustment for covariates by stratification and logistic regression. RESULTS Increasing geometric mean levels of plasma HIV-1 RNA were associated with increasing rates of transmission: the rate was 0 percent among women with less than 1000 copies per milliliter (0 of 57), 16.6 percent among women with 1000 to 10,000 copies per milliliter (32 of 193), 21.3 percent among women with 10,001 to 50,000 copies per milliliter (39 of 183), 30.9 percent among women with 50,001 to 100,000 copies per milliliter (17 of 55), and 40.6 percent among women with more than 100,000 copies per milliliter (26 of 64) (P<0.001). The treatment status of one woman was unknown. The highest rate of transmission was among women whose plasma HIV-1 RNA levels exceeded 100,000 copies per milliliter and who had not received zidovudine (19 of 30 women, 63.3 percent). Neither higher HIV-1 RNA levels early in pregnancy nor higher levels late in pregnancy were associated with the timing of infection in the infants. CONCLUSIONS In pregnant women with HIV-1 infection the level of plasma HIV-1 RNA predicts the risk but not the timing of transmission of HIV-1 to their infants.

Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease

The introduction of combination antiretroviral therapy for HIV infection revolutionized treatment of AIDS and HIV disease. Such treatment, which usually includes two nucleoside analogue inhibitors of HIV reverse transcriptase and at least one HIV protease inhibitor or non-nucleoside inhibitor of HIV reverse transcriptase, is called highly active antiretroviral therapy (HAART). Early cohort and registry-based studies showed a lower incidence of AIDS and decreased rates of AIDS-related mortality after the introduction of HAART in late 1995 in the United States (1-3), France (4), Australia (5), Germany (6), and Switzerland (7). However, ecologic studiesthose that measured use of HAART and mortality in groups rather than in individual patientsmay be subject to confounding by calendar period changes in other unmeasured variables. In addition, many studies that directly measured the effects of HAART on survival of patients with AIDS did not provide specific evidence of such effects in the patients with the most advanced cases (8-10), with the exception of small cohorts of patients with cytomegalovirus (CMV) retinitis (11) and progressive multifocal leukoencephalopathy (12). We therefore studied the effect of HAART in a large multicenter trial of blood transfusion in patients with advanced HIV disease who were also anemic, an indicator of poor prognosis (13, 14). Because the study spanned the period before and after the introduction of HAART, we could directly assess the effect of HAART status on subsequent death or opportunistic events. In addition, because our person-year analysis was controlled for calendar time, our estimates of the magnitude of the effect of HAART on mortality and morbidity are less likely to be confounded by changes in patient mix or medical practice compared with previously published studies. Methods Patients and Study Design The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus nonleukoreduced red blood cell transfusion in HIV-infected patients who required a first transfusion for anemia. Details of the study design have been published elsewhere (15, 16). In brief, we enrolled patients who were HIV seropositive, were CMV seropositive or had a history of documented CMV disease, had an expected survival of at least 1 month, and required red blood cell transfusion for anemia. Data on clinical end points and prescribed medications were obtained by interview and medical record review at baseline and every 3 months thereafter. Ophthalmologic examinations to detect CMV retinitis were done at baseline and every 6 months thereafter. In patients who did not return for follow-up visits, vital status was ascertained by review of the medical record, a search for a death certificate, and tracing by using public databases. Of 528 patients, 58 were excluded before death or end of the study, including 29 for whom no follow-up information on opportunistic events was available and 3 for whom follow-up for death but not for opportunistic events was complete. The CD4+ lymphocyte count and plasma HIV RNA level were measured by using frozen blood specimens at the central study laboratory, as described elsewhere (15). The study protocol was approved by the institutional review boards of the 11 participating medical centers, and informed consent was obtained from all participants. Definitions of HAART and End Points The VATS did not dictate the choice of antiretroviral therapy for enrolled patients, except that prescription of new antiretroviral drugs was discouraged during the 2 weeks after the first two transfusion episodes. Highly active antiretroviral therapy was defined as prescription of at least three antiretroviral medications with activity against HIV, at least one of which was an HIV protease inhibitor or a non-nucleoside HIV reverse transcriptase inhibitor. Medication history collected at each quarterly visit included the names and start and stop dates of any HIV antiretroviral medications taken since the previous visit or in the 30 days before entry into the study. Patients taking no HIV antiretroviral medications and those taking HIV antiretroviral medications that did not fulfill our definition of HAART were classified as before HAART until the day that they began HAART. Once a patient initiated HAART, all of his or her subsequent follow-up time remained designated as after HAART even if they discontinued HAART, to approximate an intention-to-treat analysis. We made this conservative decision to avoid overestimating the effect of HAART, which would occur if patients who stopped HAART because of intolerance subsequently contributed outcomes to the before HAART person-years. Adherence to prescribed medications was not measured. End points of the current study were death, opportunistic events, and recurrent transfusions. Opportunistic events were defined a priori and confirmed by expert reviewers; they included clinical diagnoses corresponding to the Centers for Disease Control and Preventions AIDS-defining conditions (17), with some modifications. Presumptive diagnoses of central nervous system toxoplasmosis were allowed according to the Centers for Disease Control and Preventions definition. For CMV retinitis, progression of disease requiring initiation of or a change in anti-CMV medication counted as a clinical event. For analysis, end points were grouped as follows: CMV opportunistic events; non-CMV opportunistic events; all opportunistic events; death; and any end point, including death and all opportunistic events. We analyzed recurrent red blood cell transfusion (that is, occurring after the enrollment transfusion event) as a separate end point. Statistical Analysis We used a person-years approach to analyze event rates. The denominator for these rates was not the individual patient but was person-years of observation time, defined as study follow-up time for each patient classified as before or after initiation of HAART and summed over all patients. For example, patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively. Observation time for a patient extended from the date of study entry to death or the end of follow-up. Because some patients had no follow-up information for opportunistic events and a few had less follow-up for opportunistic events than for mortality, the total observation time for opportunistic events was shorter than that for overall survival. Events were assigned to the time period during which they occurred, and incidence was reported as the number of events per person-year of observation time. A single patient could contribute multiple events (except for the mortality analysis) to the same or to different time periods. The association between HAART use and incidence rates was expressed as a rate ratio. Confidence intervals and P values were calculated from a Poisson regression model using generalized estimating equations with exchangeable correlation structure to adjust for correlated observations across time within the same patient (18, 19). All P values are two sided. Because the use of HAART increased dramatically over the 4 years of the study, the comparison of post-HAART and pre-HAART data is confounded with calendar time. In addition, the mixture of HIV risk groups, prevalence of prophylaxis against opportunistic infections, diagnostic testing accuracy, and physician experience may have changed over time. To evaluate and control for these and other calendar time effects, each patients observation time was further categorized as four 1-year calendar time periods, starting in July 1995. Similarly, a patients time since entering the study was divided into five study time periods (0 to 6, 7 to 12, 13 to 18, 19 to 24, or >24 months from randomization). The Poisson regression generalized estimating equations method was then used to calculate the rate ratios associated with CD4 T-cell count, plasma HIV RNA level, calendar time, and time on study and to adjust the comparisons of post-HAART and pre-HAART data for these covariates, both in pairs and combined with patient characteristics. Results Participants The VATS enrolled patients with anemia and HIV infection who received a first red blood cell transfusion between August 1995 and July 1998. Patients were followed until death or their last scheduled quarterly visit before 30 June 1999. Of 531 patients enrolled in VATS, we excluded 3 patients for whom no data on medication were available; thus, the sample for analysis in this study was 528 patients. Table 1 shows the baseline characteristics of the study sample. Most patients were 30 to 49 years of age and male, and equal proportions of patients were of white and nonwhite ethnicity. Half of the patients were men who reported sex with other men as their only HIV risk factor; 19% each were injection drug users or sexually active heterosexuals without other risk factors for HIV; and 12% had multiple or other risk factors. At baseline, the median CD4+ lymphocyte count was 0.015 109 cells/L, and 69% of patients had a CD4+ lymphocyte count less than 0.050 109 cells/L. The median HIV RNA level was 4.8 log10 copies/mL, and only 8% of patients had plasma levels of HIV RNA levels less than 200 copies/mL. Table 1. Baseline Characteristics of 528 Patients in the Viral Activation Transfusion Study At baseline, most patients had previously taken antiretroviral medication; more than half had taken such medication for 12 months or longer. The proportion of patients taking prophylaxis or treatment of Pneumocystis carinii pneumonia and Mycobacterium avium complex infection decreased from 95% and 49%, respectively, in 19951996 to 82% and 44% in 19

Issues in the reporting of epidemiological studies: a survey of recent practice

Abstract Objectives To review current practice in the analysis and reporting of epidemiological research and to identify limitations. Design Examination of articles published in January 2001 that investigated associations between risk factors/exposure variables and disease events/measures in individuals. Setting Eligible English language journals including all major epidemiological journals, all major general medical journals, and the two leading journals in cardiovascular disease and cancer. Main outcome measure Each article was evaluated with a standard proforma. Results We found 73 articles in observational epidemiology; most were either cohort or case-control studies. Most studies looked at cancer and cardiovascular disease, even after we excluded specialty journals. Quantitative exposure variables predominated, which were mostly analysed as ordered categories but with little consistency or explanation regarding choice of categories. Sample selection, participant refusal, and data quality received insufficient attention in many articles. Statistical analyses commonly used odds ratios (38 articles) and hazard/rate ratios (23), with some inconsistent use of terminology. Confidence intervals were reported in most studies (68), though use of P values was less common (38). Few articles explained their choice of confounding variables; many performed subgroup analyses claiming an effect modifier, though interaction tests were rare. Several investigated multiple associations between exposure and outcome, increasing the likelihood of false positive claims. There was evidence of publication bias. Conclusions This survey raises concerns regarding inadequacies in the analysis and reporting of epidemiological publications in mainstream journals.

Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-α production in vitro and in vivo

Human newborns are susceptible to microbial infection related to incompletely defined aspects of the neonatal immune system. To characterize neonatal innate immunity, we studied production of two early response cytokines in response to Toll-like receptor (TLR)-activating microbial stimuli in vitro: the pro-inflammatory cytokine tumor necrosis factor (TNF)-α and IL-6, a multifunctional cytokine with antiinflammatory and Th2-polarizing properties. Neonatal cord blood responses to multiple TLR agonists, including poly dI:dC (TLR3), lipopolysaccharide (LPS) (TLR4), flagellin (TLR5), and CpG DNA (TLR9), are characterized by a higher IL-6/TNF-α ratio than in adult peripheral blood. Robust LPS-induced IL-6 production is due to both neonatal cellular (monocyte-) and humoral (serum-) factors. Remarkably, serum collected from newborns during the first week of life demonstrates higher IL-6/TNF-α ratios than does cord blood, associated with elevations of the IL-6-inducible acute phase reactants CRP and LPS-binding protein in the first days of life. A high ratio of stimulus-induced IL-6/TNF-α production is likely to profoundly modulate both innate and adaptive immune responses in the human newborn.

A prospective, randomized clinical trial of universal WBC reduction.

BACKGROUND : Recipient exposure to allogeneic donor WBCs results in transfusion complications for selected populations of recipients. Whether or not WBC reduction should be universally applied is highly controversial.

Stop Hypertension With the Acupuncture Research Program (SHARP) Results of a Randomized, Controlled Clinical Trial

Case studies and small trials suggest that acupuncture may effectively treat hypertension, but no large randomized trials have been reported. The Stop Hypertension with the Acupuncture Research Program pilot trial enrolled 192 participants with untreated blood pressure (BP) in the range of 140/90 to 179/109 mm Hg. The design of the trial combined rigorous methodology and adherence to principles of traditional Chinese medicine. Participants were weaned off antihypertensives before enrollment and were then randomly assigned to 3 treatments: individualized traditional Chinese acupuncture, standardized acupuncture at preselected points, or invasive sham acupuncture. Participants received ≤12 acupuncture treatments over 6 to 8 weeks. During the first 10 weeks after random assignment, BP was monitored every 14 days, and antihypertensives were prescribed if BP exceeded 180/110 mm Hg. The mean BP decrease from baseline to 10 weeks, the primary end point, did not differ significantly between participants randomly assigned to active (individualized and standardized) versus sham acupuncture (systolic BP: −3.56 versus −3.84 mm Hg, respectively; 95% CI for the difference: −4.0 to 4.6 mm Hg; P=0.90; diastolic BP: −4.32 versus −2.81 mm Hg, 95% CI for the difference: −3.6 to 0.6 mm Hg; P=0.16). Categorizing participants by age, race, gender, baseline BP, history of antihypertensive use, obesity, or primary traditional Chinese medicine diagnosis did not reveal any subgroups for which the benefits of active acupuncture differed significantly from sham acupuncture. Active acupuncture provided no greater benefit than invasive sham acupuncture in reducing systolic or diastolic BP.

Natural history of somatic growth in infants born to women infected by human immunodeficiency virus

OBJECTIVE To evaluate the nature and magnitude of the effect of congenitally or perinatally acquired human immunodeficiency virus (HIV) infection on somatic growth from birth through 18 months of age. STUDY DESIGN Anthropometry was performed serially in 282 term infants born to HIV-infected women in a multicenter prospective natural history cohort study. Repeated measures analysis was used to compare z-score anthropometric indexes of weight-for-age, length-for-age, weight-for-length, and head circumference-for-age between infected and uninfected infants, with adjustment for covariates including infant gender; maternal education; prenatal alcohol, tobacco, and/or illicit drug exposure; and mean prenatal CD4+ T-lymphocyte count. A separate repeated measures model was used to assess the effect of infant zidovudine treatment on growth. RESULTS Infants infected with HIV were an estimated average 0.28 kg lighter and 1.64 cm shorter than uninfected infants at birth, were 0.71 kg lighter and 2.25 cm shorter by 18 months of age, and had a sustained estimated average decrement of 0.70 to 0.75 cm in head circumference. Patterns of growth were similar in male and female infants. Infected infants had a progressive decrement in body mass index from birth through 6 months of age. Infection with HIV was associated with significant decrements across all standardized growth outcome measures after adjustment for covariates. Mean z scores were lower for weight by 0.612 (p < 0.001), for length by 0.735 (p < 0.001), for weight-for-length by 0.255 (p = 0.02), and for head circumference by 0.563 (p < 0.001) SD units compared with uninfected infants. Zidovudine treatment was not associated with improved growth. CONCLUSION The effect of congenitally or perinatally acquired HIV infection on infant growth is one of early and progressive decrements in attained linear growth and growth in mass, early and sustained decrements in head growth, and marked early decrements in body mass index.

Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine.

Zidovudine (ZDV) therapy during pregnancy and to the neonate reduced perinatal HIV transmission by nearly 70% in Pediatric AIDS Clinical Trials Group (PACTG) protocol 076. ZDV has been reported as positive in several in vitro carcinogenicity screening tests. We evaluated the short-term risk for tumors in 727 children with known ZDV exposure enrolled into the PACTG 076/219 and the Women and Infants Transmission Study (WITS). ZDV exposure in utero (antepartum) occurred in 97% and 99% of infants in PACTG 076/219 or WITS, respectively. Mean follow-up was 38.3 months with 366.9 person years follow-up for PACTG 076/219 and 14.5 months with 743.7 person years follow-up for WITS. No tumors of any nature were observed; relative risk was 0 (95% confidence interval [CI], 0-17.6). These data are reassuring regarding the short-term lack of tumors for ZDV-exposed infants observed to date. Longitudinal, standardized follow-up for infants with in utero antiretroviral exposure is necessary to assess long-term carcinogenicity.

Phase II study of topotecan in metastatic non-small-cell lung cancer.

PURPOSE Topotecan is an inhibitor of topoisomerase I that has shown preclinical activity against non-small-cell lung cancer (NSCLC). This phase II study was designed to determine the clinical activity and toxicity spectrum of topotecan in untreated patients with metastatic NSCLC. PATIENTS AND METHODS Twenty previously untreated patients received topotecan every 21 days at the dose of 2 mg/m2/d intravenously (IV) for 5 days for two cycles, at which point response was assessed. Patients with either clinical response or stable disease (SD) received additional cycles of the drug until toxicity developed or disease progression (PRG) occurred. RESULTS This study was designed to enter 30 patients. However, because no clinical responses were seen in the first 20 patients entered onto the study, the early-stopping rule was invoked and patient accrual was halted. Eleven patients (55%) had SD on topotecan, and nine (45%) had PRG. Toxicity included neutropenia and rash. The median survival duration for all patients was 7.6 months. CONCLUSION We observed no objective clinical responses despite producing high-grade neutropenia. Phase II trials of topotecan using different schedules or higher doses supported by growth factors may clarify the role of topotecan in the treatment of NSCLC. The combination of topotecan with cisplatin and topoisomerase II inhibitors such as etoposide should be explored. Finally, the median survival duration of 7.6 months for 20 patients treated with an agent that failed to produce any obvious clinical responses compares favorably to the survival obtained with combinations of existing agents. This supports the further study of novel compounds in this clinical setting.