Rofecoxib shows consistent efficacy in osteoarthritis clinical trials, regardless of specific patient demographic and disease factors.

OBJECTIVE: To evaluate the efficacy of rofecoxib (Vioxx) in subpopulations of patients with osteoarthritis (OA) identified by demographic or baseline disease characteristics, or varied OA involvement. METHODS: Data were combined from three 6-week double blind trials in patients with OA of the knee or hip. All trials contained placebo, 12.5 mg rofecoxib, and 25 mg rofecoxib arms (the only trials to date containing all 3 treatments). Analyses were performed on subgroups categorized according to the following baseline demographics and disease characteristics [age, sex, height, weight, body mass index, American Rheumatism Association (ARA) functional class, joint tenderness, joint stiffness, Western Ontario-McMaster University OA Index (WOMAC) functional subscale, unilateral/bilateral joint involvement, number of joint groups involved]. Three primary endpoints--Pain Walking on Flat Surface (WOMAC), Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status--were analyzed. The global assessments, which provided data on overall aspects of OA, regardless of affected joint, were used to assess effects among patients with one, 2, 3, or 4 joint groups affected (from among the following: interphalangeal/first carpal-metacarpal joint, spine, hip, or knee). RESULTS: Data from 1501 patients were included. No consistent treatment-by-subgroup interaction was observed with all 3 primary endpoints for patients taking placebo or 12.5 or 25 mg rofecoxib. Rofecoxib showed generally consistent efficacy across subgroups of patients identified by sex, race, age, OA location(s), prior OA therapy, baseline study joint tenderness or swelling (patients with knee OA only), and ARA functional class level. CONCLUSION: In this combined analysis, no specific factor predicted a differential treatment effect to rofecoxib.

Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.

BACKGROUND: In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs. METHODS AND RESULTS: CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen. CONCLUSIONS: This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.

A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis.

This 6-week study was conducted to test the efficacy, safety, and tolerability of rofecoxib (a selective COX-2 inhibitor) compared to nabumetone (a non-selective NSAID) and placebo in osteoarthritis (OA) patients aged 80 and older. Three hundred forty-one patients, mean age 83 years, were randomized. Allocations were made in an approximately 1:2:1:2 ratio (placebo: 12.5 mg rofecoxib: 25 mg rofecoxib: 1500 mg nabumetone). Least square mean changes from baseline in the primary efficacy endpoint, Patient Global Assessment of Disease Status, were as follows (with negative numbers indicating improvement): -14.85 mm for placebo; -25.34 mm for 12.5 mg rofecoxib; -25.40 mm for 25 mg of rofecoxib; and -25.95 mm for nabumetone (p<0.001 for all active treatments vs placebo.) Results from secondary endpoints, including the 3 WOMAC sub-scales (pain, stiffness, and disability) and the Investigator Global Assessment of Disease Status, were consistent with those for the primary endpoint. No significant between-group differences were observed in the proportions of patients who discontinued treatment due to either clinical or laboratory adverse experiences. Renal safety (edema and hypertension adverse experiences) was similar for rofecoxib and nabumetone. No gastroduodenal ulcers occurred; however, the demonstration of gastrointestinal risk with rofecoxib or nabumetone was beyond the scope of this trial. We conclude that in patients 80 years and older, rofecoxib, 12.5 mg and 25 mg once daily, demonstrated clinical efficacy for the treatment for OA as did 1500 mg of nabumetone. Rofecoxib and nabumetone were generally well tolerated in this elderly population.

The contribution of assay variation and biological variation to the total variability of plasma HIV-1 RNA measurements. The Women Infant Transmission Study Clinics. Virology Quality Assurance Program.

OBJECTIVES: To assess the specific contributions of assay variation and biological variation to the total variation of plasma HIV-1 RNA measured by the Roche Monitor assay and the extent to which batch assays reduced both assay variability and total variability compared with real-time determinations. DESIGN: A retrospective analysis of data obtained from three trials conducted by the Adult and Pediatric AIDS Clinical Trials Groups (ATCG), the Women and Infants Transmission Study (WITS) and the NIAID-sponsored Virology Quality Assurance Program. METHODS: Within-subject variation was assessed from stored, serially collected plasma samples from 663 subjects enrolled in the ACTG and WITS studies. Interassay and intra-assay variation were estimated from two of the clinical trials and 22 laboratories that participated in a quality assurance program and were used to estimate the effect of real-time testing on total variation. RESULTS: The total variation (standard deviation) from a random effects model was 0.26 log10 RNA copies/ml. The estimated interassay variation was 0.08 log10 and intra-assay variation was 0.12 log10 RNA copies/ml. Biological variation accounted for 56-80% of total variation. The effect of real-time testing compared with batch testing was minimal. CONCLUSION: Our estimates of total within-subject HIV-1 RNA variation support the current recommendation to obtain at least two specimens, preferably obtained less than 2 weeks apart, for viral RNA measurement before starting therapy. The major contribution of biological variation to the total variation supports the use of real-time HIV-1 RNA assays, provided that consistent specimen collection procedures are followed and acceptable assay proficiency is maintained.

Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076 Study Group.

OBJECTIVE: To identify modifiable obstetric factors associated with the failure of zidovudine chemoprophylaxis to prevent perinatal human immunodeficiency virus type 1 (HIV-1) transmission. METHODS: We analyzed data from Pediatric AIDS Clinical Trials Group protocol 076, a randomized, double-masked, placebo-controlled trial that demonstrated that a zidovudine regimen could prevent perinatal HIV-1 transmission. We estimated the zidovudine treatment effect using the relative reduction in transmission risk among women randomized to treatment with zidovudine compared with women randomized to receive placebo. Univariate and multivariate statistical analyses were used to assess whether the treatment effect differed in magnitude according to potential antepartum or intrapartum risk factors. RESULTS: In the univariate analysis, the zidovudine treatment effect was found to differ significantly in magnitude according to quartile of maternal weight at the time of study entry (interaction test, P = .03); among women in the heaviest-weight quartile (weight more than 82 kg), there was a 26% relative reduction in transmission risk, compared with a 79% relative reduction among the other three quartiles (interaction test, P = .05). In the zidovudine treatment group, women who transmitted HIV-1 were significantly more likely than nontransmitters to have had antepartum procedures or conditions associated with increased risk of fetal exposure to maternal blood or cervicovaginal secretions (43% compared with 19%, P = .04). In the multivariate analysis, adjustment for the plasma HIV-1 RNA level and CD4+ cell percentage did not eliminate the differential treatment effect according to these factors. CONCLUSION: High maternal weight and conditions associated with fetal exposure to maternal blood or cervicovaginal secretions may diminish the efficacy of zidovudine chemoprophylaxis.

The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol 076).

OBJECTIVE: To describe the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1) and on the course of disease in infants who became infected while they and their mothers received zidovudine preventive therapy or placebo in Pediatric AIDS Clinical Trials Group Protocol 076. STUDY DESIGN: Observational substudy of a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: We compared the progression of disease, timing of HIV-1 transmission, and the plasma HIV-1 RNA level in infected infants of mother-infant pairs who were randomly assigned to receive zidovudine (n = 14) or placebo (n = 43). The development of genotypic zidovudine resistance was assessed among infected infants in the zidovudine treatment group. RESULTS: In this limited study, zidovudine therapy during pregnancy and labor and in the neonatal period for 6 weeks failed to have a major effect on rapid progression of disease, timing of transmission, and viral replication in HIV-infected infants. When the zidovudine treatment regimen failed to prevent maternal-infant transmission of HIV-1, resistance to zidovudine did not develop during study treatment. CONCLUSIONS: Our study supports the safety of zidovudine use in pregnancy and in the newborn period but demonstrates the continued need for more potent antiretroviral treatment of the infected infant.

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.

Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study.

OBJECTIVE: To determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study. DESIGN: ACTG 076 was a randomized, double-blind, placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum. METHODS: Maternal complications, pregnancy outcomes, growth and development of the uninfected infants, and HIV-1 disease progression in the women were monitored prospectively. RESULTS: Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants, the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery, duration of maternal treatment, degree of maternal immunosuppression, or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age, uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women, at 6 months postpartum, there were no differences in clinical, immunologic, or virologic disease progression. CONCLUSION: There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother-child HIV-1 transmission.

Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team.

The safety, toxicity, and pharmacokinetics of intrapartum and early newborn nevirapine were evaluated in 17 human immunodeficiency virus type 1-infected women in labor and their newborns. No adverse effects of nevirapine were noted in any study mothers or infants. Following maternal dosing with 200 mg during labor, concentrations exceeding 100 ng/mL (10 times the in vitro IC50) were achieved in the newborns. Nevirapine elimination was prolonged in both mothers and infants, with median half-lives ranging from 36.8 to 65.7 h. Administration of 200 mg orally to the mothers in labor and of a single 2-mg/kg oral dose to the infants at 48-72 h after birth maintained serum concentrations in the infants > 100 ng/mL through 7 days of life.

Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus.

We used population analysis techniques to determine zidovudine (ZDV) pharmacokinetic parameters in 15 preterm neonates (mean gestational age, 29.4 weeks; mean birth weight, 1,230 g) at a mean age of 5.5 days. The values of the pharmacokinetic parameters were as follows: clearance, 2.53 +/- 0.44 ml/min/kg; volume of distribution, 1.59 +/- 0.51 liters/kg; and half-life, 7.2 +/- 1.5 h. For seven infants studied a second time, at a mean age of 17.7 days, an increase in the mean clearance (2.33 versus 4.35 ml/min/kg; P = 0.024) and a decrease in the half-life (7.3 versus 4.4 h; P = 0.003) were found. The ZDV clearance is low and the half-life is prolonged in premature neonates, but the clearance increases and the half-life decreases with postnatal age. Potentially toxic concentrations may accumulate in serum if the standard dosage for full-term infants is used. We suggest that initial ZDV dosing should be reduced to 1.5 mg every 12 h for preterm neonates.

Maternal viral genotypic zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in pediatric AIDS Clinical Trials Group Protocol 076.

Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, if zidovudine resistance developed on study, and the role of zidovudine resistance in vertical transmission of HIV-1 despite zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to zidovudine at study entry or delivery. For low-level zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).

Absolute copy number and relative change in determinations of human immunodeficiency virus type 1 RNA in plasma: effect of an external standard on kit comparisons.

Use of a common set of human immunodeficiency virus type 1 (HIV-1) RNA standards eliminated differences among absolute HIV-1 RNA copy number estimates made with three commercially available assays. The relative changes in the viral RNA levels determined by the commercial assays were similar and were unaffected by the use of a common set of standards.

Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.

BACKGROUND AND METHODS: A placebo-controlled trial has shown that treatment with zidovudine reduces the rate at which human immunodeficiency virus type 1 (HIV-1) is transmitted from mother to infant. We present data from that trial showing the number of infected infants at 18 months of age and the relation between the maternal viral load, the risk of HIV-1 transmission, and the efficacy of zidovudine treatment. Viral cultures were obtained, and HIV-1 RNA was measured by two assays in samples of maternal blood obtained at study entry and at delivery. RESULTS: In 402 mother-infant pairs, the rate of transmission of HIV-1 was 7.6 percent (95 percent confidence interval, 4.3 to 12.3 percent) with zidovudine treatment and 22.6 percent (95 percent confidence interval, 17.0 to 29.0 percent) with placebo (P<0.001). In the placebo group, a large viral burden at entry or delivery or a positive culture was associated with an increased risk of transmission (the transmission rate was greater than 40 percent in the highest quartile of the RNA level). In both groups, transmission occurred at a wide range of maternal plasma HIV-1 RNA levels. Zidovudine reduced plasma RNA levels somewhat (median reduction, 0.24 log). Zidovudine was effective regardless of the HIV-1 RNA level or the CD4+ count at entry. In the zidovudine group, however, after we adjusted for the base-line HIV-1 RNA level and CD4+ count, the reduction in viral RNA from base line to delivery was not significantly associated with the risk of transmission of HIV-1. CONCLUSIONS: A high maternal plasma concentration of virus is a risk factor for the transmission of HIV-1 from an untreated mother to her infant. The reduction in such transmission after zidovudine treatment is only partly explained by the reduction in plasma levels of viral RNA. To prevent HIV-1 transmission, initiating maternal treatment with zidovudine is recommended regardless of the plasma level of HIV-1 RNA or the CD4+ count.

Prevention of blood exposure. Body and facial protection.

Regardless of the specific clinical setting in the operating room, it is clear that better protection of all personnel is an appropriate objective in the current environment. Better protection through improved PPE and modification of operational practices is essential. A prompt response to blood contact when it does occur is likewise appropriate. With conscientious applications of methods to reduce blood exposure, it is hoped that the operating room can become a safer place with respect to occupational infections from bloodborne pathogens.

Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.

BACKGROUND AND METHODS: Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over one hour, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected. RESULTS: From April 1991 through December 20, 1993, the cutoff date for the first interim analysis of efficacy, 477 pregnant women were enrolled; during the study period, 409 gave birth to 415 live-born infants. HIV-infection status was known for 363 births (180 in the zidovudine group and 183 in the placebo group). Thirteen infants in the zidovudine group and 40 in the placebo group were HIV-infected. The proportions infected at 18 months, as estimated by the Kaplan-Meier method, were 8.3 percent (95 percent confidence interval, 3.9 to 12.8 percent) in the zidovudine group and 25.5 percent (95 percent confidence interval, 18.4 to 32.5 percent) in the placebo group. This corresponds to a 67.5 percent (95 percent confidence interval, 40.7 to 82.1 percent) relative reduction in the risk of HIV transmission (Z = 4.03, P = 0.00006). Minimal short-term toxic effects were observed. The level of hemoglobin at birth in the infants in the zidovudine group was significantly lower than that in the infants in the placebo group. By 12 weeks of age, hemoglobin values in the two groups were similar. CONCLUSIONS: In pregnant women with mildly symptomatic HIV disease and no prior treatment with antiretroviral drugs during the pregnancy, a regimen consisting of zidovudine given ante partum and intra partum to the mother and to the newborn for six weeks reduced the risk of maternal-infant HIV transmission by approximately two thirds.

Potential for bias in studies of the influence of human immunodeficiency virus infection on the recognition, incidence, clinical course, and microbiology of pelvic inflammatory disease.

As the human immunodeficiency virus (HIV) epidemic affects more women, clinicians are increasingly observing pelvic inflammatory disease (PID) in HIV-infected women. The extent to which PID is a factor in the recognition of HIV or HIV is a factor in the recognition of PID is unknown. Even less is known about how HIV infection influences the development, clinical course, and microbiology of PID. The paucity of existing data largely results from difficulties in designing studies that are free of bias. Several biases may distort studies of the effect of HIV on the recognition, incidence, clinical presentation and course, and microbiology of PID. Selection bias, diagnostic bias, and confounding bias are the most likely causes of invalid conclusions in studies of the influence of HIV infection on these aspects of PID, for three major reasons: Factors that determine patients' health care seeking behavior may be related to HIV status; the diagnosis of PID tends to be imprecise; and extraneous factors that cause or prevent PID may be distributed differently in HIV-infected and HIV-uninfected women. Appropriate study design and analytic techniques can eliminate, reduce, or estimate the magnitude and direction of these biases, thereby yielding more valid conclusions. To interpret properly existing and future studies of the influence of HIV infection on PID, clinicians must consider several biases that may distort results.

Zidovudine pharmacokinetics during pregnancy.

As the indications for zidovudine (ZDV) treatment in human immunodeficiency virus-infected individuals expand, we anticipate an increased use of this drug during pregnancy. We report pharmacokinetics data from a patient studied both in the third trimester and intrapartum. ZDV peak-plasma levels and serum half-lives were comparable to nonpregnant adults. High concentrations of ZDV and its glucuronide metabolite were found in umbilical cord blood and in amniotic fluid.

A survey of zidovudine use in pregnant women with human immunodeficiency virus infection.

BACKGROUND AND METHODS: The expanding indications for zidovudine treatment make it important to elucidate the safety and toxicity of this drug for pregnant women and their fetuses. We asked pediatricians and obstetricians at the AIDS (acquired immunodeficiency syndrome) Clinical Trials Units to report information about pregnant women infected with the human immunodeficiency virus (HIV) who were continuing their pregnancies and had received, or were receiving, zidovudine during gestation. RESULTS: Reports of 43 women were received from 17 institutions. Doses of zidovudine ranged from 300 to 1200 mg per day, and 24 women took the drug for at least two trimesters. There were two reported instances of maternal toxicity (one gastrointestinal and one hematologic). No teratogenic abnormalities occurred in the 12 infants with first-trimester exposure to zidovudine. All the infants, including two sets of twins, were born alive. The 38 singleton infants born at term for whom birth weights were reported had a mean birth weight of 3287 +/- 670 g; two cases of intrauterine growth retardation were reported among the infants delivered at term. Hemoglobin values, which were available for 31 newborns, ranged from 7.0 to 12.4 mmol per liter (11.2 to 20 g per deciliter); 3 of the 7 newborns with hemoglobin values of less than 8.4 mmol per liter (13.5 g per deciliter) were born prematurely. CONCLUSIONS: Zidovudine was well tolerated by the pregnant women and was apparently not associated with malformations in the newborns, premature birth, or fetal distress. No pattern of hematologic toxicity was observed in the newborns, but the anemia and growth retardation seen in a minority of the infants could, in part, have resulted from their mothers' treatment with zidovudine.

Treatment options for human immunodeficiency virus-infected pregnant women. Obstetric-Gynecologic Working Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

The increasing seroprevalence of human immunodeficiency virus (HIV) among women of reproductive age and the risks of vertical transmission of HIV have led to recommendations for routine prenatal HIV counseling and testing. The incentive to undergo such testing is related not only to fetal concerns, but also to the potential benefit of early and comprehensive therapy for women. Treatments that should be considered for use during pregnancy include the antiretroviral agent zidovudine and prophylactic agents to prevent Pneumocystis carinii pneumonia, the most common opportunistic infection seen in patients progressing to AIDS. Assessment of the risks and benefits of these treatments during pregnancy is complex and requires discussions between physician and patient. This paper reviews current information and provides recommendations for incorporating therapies into obstetric practice.