AIDS Clinical Trials Group Study Research Articles

Pharmacokinetics and tolerance of zidovudine in preterm infants

Objective To determine zidovudine pharmacokinetics and tolerance in premature human human immunodeficiency virus-exposed infants. Study design Pediatric AIDS Clinical Trials Group Study 331 was a multicentered prospective, open-label study of the use of zidovudine in premature infants. Thirty-eight infants <35 weeks' gestational age (GA) were studied while receiving zidovudine 1.5 mg/kg every 12 hours until 2 weeks of age, then 2.0 mg/kg every 8 hours until 6 weeks of age. Population pharmacokinetics were evaluated at 1, 2, and 4 weeks' postnatal age; zidovudine doses were adjusted to maintain troughs <3 μM. Results Zidovudine clearance was lower than reported in term infants at similar postnatal ages. Nine premature infants required dose reduction because of high levels (7/19 <30 weeks' and 2/19 ≥30 weeks' GA). Postnatal age, GA, serum creatinine, and furosemide use independently predicted zidovudine clearance. Zidovudine was generally well tolerated in this high-risk population. Conclusions Zidovudine clearance is greatly reduced in premature infants. We recommend the following zidovudine dosing schedule in this population: 1.5 mg/kg (intravenous) or 2.0 mg/kg (oral) every 12 hours increased to every 8 hours at 2 weeks of age (≥30 weeks' GA) or at 4 weeks (<30 weeks' GA). (J Pediatr 2003;142:47-52)

Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies.

To obtain information on the prevalence of anovulation and early menopause and on pituitary-gonadal function among human immunodeficiency virus type 1-infected women, a study was undertaken that used stored serum samples from women aged 20-42 years who participated in selected Adult AIDS Clinical Trials Group protocols. Defined progesterone and follicle-stimulating hormone (FSH) levels were considered presumptive evidence of ovulation and of menopause, respectively. Anovulation occurred in 16 (48%) of 33 women for whom progesterone levels were tested; early menopause occurred in 2 (8%) of 24 women for whom FSH levels were tested. No statistically significant differences were seen in the demographic and clinical characteristics of anovulatory and ovulatory women, although women who ovulated had higher CD4 T cell counts and were less likely to have reported a recent change in menstrual periods. These data support the findings of prior studies of increased frequency of amenorrhea and/or irregular menstrual cycles, particularly among women with lower CD4 T cell counts.

Methods for conducting sensitivity analysis of trials with potentially nonignorable competing causes of censoring.

We consider inference for the treatment-arm mean difference of an outcome that would have been measured at the end of a randomized follow-up study if, during the course of the study, patients had not initiated a nonrandomized therapy or dropped out. We argue that the treatment-arm mean difference is not identified unless unverifiable assumptions are made. We describe identifying assumptions that are tantamount to postulating relationships between the components of a pattern-mixture model but that can also be interpreted as imposing restrictions on the cause-specific censoring probabilities of a selection model. We then argue that, although sufficient for identification, these assumptions are insufficient for inference due to the curse of dimensionality. We propose reducing dimensionality by specifying semiparametric cause-specific selection models. These models are useful for conducting a sensitivity analysis to examine how inference for the treatment-arm mean difference changes as one varies the magnitude of the cause-specific selection bias over a plausible range. We provide methodology for conducting such sensitivity analysis and illustrate our methods with an analysis of data from the AIDS Clinical Trial Group (ACTG) study 002.

Chemotherapy Consisting of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine With Granulocyte–Colony-Stimulating Factor in HIV-Infected Patients With Newly Diagnosed Hodgkin's Disease: A Prospective, Multi-institutional AIDS Clinical Trials Group Study (ACTG 149)

Chemotherapy Consisting of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine With Granulocyte–Colony-Stimulating Factor in HIV-Infected Patients With Newly Diagnosed Hodgkin's Disease: A Prospective, Multi-institutional AIDS Clinical Trials Group Study (ACTG 149)

HIV, pregnancy, and zidovudine: what do women know?

AIDS is a major cause of death among women and children, representing the fourth leading cause of death among women ages 25 to 44 and the seventh leading cause of death among children ages 1 to 4 in the United States. In 1994, National Institutes of Health announced the findings of the AIDS Clinical Trials Group study (076) that found that the use of the antiretroviral drug zidovudine (AZT) reduced perinatal transmission of HIV by two thirds. These findings have direct implications for the growing number of women with HIV disease, their children and families, and the multiple systems that deliver ongoing services and care. In response to these findings, complex clinical, legal, and ethical issues have emerged that must be addressed to decrease the incidence of perinatal HIV transmission and to provide quality health care services. The purpose of this research was to assess what HIV-infected women presently know regarding AZT use in pregnancy to reduce prenatal transmission and to identify their views of the impact of this information on reproductive decision making. A one-page survey developed for this study was used to address these questions. A convenience sample of 204 HIV-infected women completed the survey. Data from 192 were usable. Of the sample, 121 (63.7%) women reported knowledge regarding the use of AZT in pregnancy. Only 73.5% of those who reported knowledge regarding AZT prophylaxis demonstrated accurate knowledge about the effects of its use. A relationship was found between knowledge about AZT use during pregnancy and women's decision to consider pregnancy, chi 2(2, N = 146) = 32.7, p = .0001, with women who reported that they were knowledgeable about AZT prophylaxis as more likely to consider pregnancy than those who reported that they were not knowledgeable.

Clinical trials using HIV-1 RNA-based primary endpoints: statistical analysis and potential biases.

Clinical trial endpoints based on magnitude of reduction in HIV-1 RNA levels provide an important complement to endpoints based on percentage of patients achieving complete virologic suppression. However, interpretation of magnitude of reduction can be biased by measurement limitations of virologic assays, particularly lower and upper limits of quantification. Using data from two AIDS Clinical Trials Group (ACTG) studies, widely used crude methods of analyzing HIV-1 RNA reductions were compared with methods that take into account censoring of HIV-1 RNA measurements. Such methods include Kaplan-Meier and censored regression analyses. It was found that standard crude methods of analysis consistently underestimated treatment effects. In some cases, the bias induced by crude methods masked statistically significant differences between treatment arms. Although statistically significant, adjustment for baseline HIV-1 RNA levels had little effect on estimated treatment differences. Furthermore, convenient parametric analyses performed as well as more complex nonparametric analyses. It is concluded that conveniently implemented censored data analyses should be conducted in preference to widely used crude analyses of magnitude of HIV-1 RNA reduction. To obtain complete information about virologic response to antiretroviral therapy, such analyses of magnitude of virologic response should be used to complement analyses of the percentage of patients having complete virologic suppression.

Ethics of Placebo-Controlled Trials of Zidovudine to Prevent the Perinatal Transmission of HIV in the Third World

This letter responds to an article claiming that placebo-controlled trials of antiretroviral agents to reduce perinatal transmission of HIV in developing countries are unethical. In his capacity as executive director of the WHO Global Program on AIDS the author convened a 1994 meeting where 28 experts made decisions about application of the results of AIDS Clinical Trials Group (ACTG) Study 076 in developing countries. At that time data from the 12-week subgroup analysis of ACTG Study 076 and on the pharmacokinetics of zidovudine were not yet available. The meeting resulted in a unanimous recommendation that 2-to-3-week regimens be evaluated through a placebo-controlled design. This was decided because there was no information on the efficacy of zidovudine in a breast feeding population there was no information on drug tolerance among women suffering high rates of anemia accurate efficacy data were needed to justify expenditures on drugs and the placebo-controlled design required only a small sample size to provide information necessary to maximize the number of newborns saved. Cost and logistical constraints preclude adoption of the ACTG 076 regimen in developing countries.

Treatment of cytomegalovirus retinitis with the intraocular ganciclovir implant.

The treatment of cytomegalovirus retinitis (CMV-R) has improved considerably in the past two years. Local ocular therapy has proved to be effective and provides significant advantages over systemic therapy with regards to better control, preventing progression, avoiding bone marrow and renal toxicity. Direct intraocular injections of anti-CMV drugs and the sustained-release ganciclovir device are the mainstay of local therapy. The ganciclovir intraocular device has undergone rigorous testing and has recently been approved for clinical use. This review describes the surgical procedure, recommendations for use, and exchange and management of associated retinal detachment. In addition, the results of the initial studies and the multicenter, randomized clinical trial are discussed. Current data available from the Study for the Ocular Complications of AIDS (SOCA) and AIDS Clinical Trials Group (ACTG) studies are summarized in the context of CMV-R management.

Combination nucleoside therapy or ddI alone delayed the progression of HIV infection compared with zidovudine alone

Source Citation Hammer SM, Katzenstein DA, Hughes MD, et al., for the AIDS Clinical Trials Group Study 175 Study Team. A trial comparing nucleoside monotherapy with combination therapy in HIV-infec...

P47 Data management for a Phase III international collaborative study (AIDS clinical trial group study 204/Glaxo Wellcome protocol 123-014)

P47 Data management for a Phase III international collaborative study (AIDS clinical trial group study 204/Glaxo Wellcome protocol 123-014)

Women's Participation in AIDS Clinical Trials Group (ACTG) Trials in the USA: Enough or Still Too Few?

ABSTRACT This study evaluates women's enrollment in AIDS Clinical Trials Group (ACTG) protocols. Accrual trends of newly enrolled, adult females were summarized for ACTG studies using the Statistical and Data Analysis Center database. The yearly accrual rate of adult females in ACTG clinical trials has increased since its inception. Accrual rates of women in ACTG trials now compare favorably with the rate of female U.S. AIDS cases reported to the CDC: 14% vs 12% in 1991, 21% vs 13% in 1992, and 16% vs 16% in 1993. The percentage of white, African American, and Hispanic newly enrolled women has been fairly constant during 1991, 1992, and 1993, averaging 34%, 41%, and 24%, respectively. Conversely, the percentage of newly enrolled women with a history of injection drug use has diminished during this period: from 34% in 1991 to 26% 1992 and 20% in 1993. Two studies were responsible for 82% of the women enrolled in 1992. However, women identified through clinical trials and surveillance mechanisms differ in s...

AIDS Clinical Trials Group Study Numbers

Letters1 September 1995AIDS Clinical Trials Group Study NumbersMargaret A. Fischl, MD, Kenneth Stanley, PhD, and Ann C. Collier, MDMargaret A. Fischl, MDUniversity of Miami School of Medicine; Miami, FL 33101Harvard School of Public Health; Boston, MA 02115University of Washington; Seattle, WA 98104Search for more papers by this author, Kenneth Stanley, PhDUniversity of Miami School of Medicine; Miami, FL 33101Harvard School of Public Health; Boston, MA 02115University of Washington; Seattle, WA 98104Search for more papers by this author, and Ann C. Collier, MDUniversity of Miami School of Medicine; Miami, FL 33101Harvard School of Public Health; Boston, MA 02115University of Washington; Seattle, WA 98104Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-123-5-199509010-00029 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. von Reyn proposes an interesting precedent. We had not initially included the ACTG protocol number for this study to avoid ACTG jargon or vernacular. However, Dr. von Reyn is correct in that presentations and discussions of ACTG studies frequently refer to these studies by their ACTG protocol number. Dr. von Reyn has also correctly cited our study [1] as ACTG 155.

Zidovudine for the Prevention of Vertical HIV Transmission

The purpose of this study was to quantify the benefits of maternal-neonatal zidovudine (ZDV) administration for the prevention of vertical human immunodeficiency virus (HIV) transmission against the potential risks of drug-induced complications in uninfected children. A decision analysis model was created with use of a Markov cohort simulation, for evaluating both survival and quality of life for two hypothetical cohorts of HIV-exposed neonates: one with in utero and neonatal exposure to preventive ZDV therapy and the other not exposed. The model included the probability of congenital HIV infection with and without ZDV treatment (estimates derived from AIDS Clinical Trials Group study 076), the yearly probability of death with and without congenital HIV infection, a range of probabilities of adverse effects from ZDV use, and a range of ages in life when any adverse effect would manifest. In a series of scenarios, the impact of different estimates for the quality-of-life decrement from any adverse ZDV effect in HIV-uninfected children was assessed, and threshold values for this estimate were established, i.e., critical values below which withholding ZDV would be the preferred choice. Across a wide range of estimates for multiple contingencies, ZDV use was associated with a greater number of quality-adjusted life years than was non-use. Only in implausible, pessimistic scenarios (i.e., a high incidence of profound adverse effects beginning early in life) would withholding ZDV be the rational choice for an asymptomatic HIV-infected pregnant woman.(ABSTRACT TRUNCATED AT 250 WORDS)

High-Dose Pentoxifylline in Patients with AIDS: Inhibition of Tumor Necrosis Factor Production

Tumor necrosis factor-alpha (TNF) may activate human immunodeficiency virus (HIV), antagonize zidovudine activity, and contribute to AIDS wasting syndrome. Pentoxifylline decreases TNF production. In cell culture, pentoxifylline decreases HIV replication and gene expression. Since an AIDS Clinical Trial Group study suggested that pentoxifylline (400 mg thrice daily) is safe in AIDS patients and decreases TNF mRNA levels in peripheral blood mononuclear cells (PBMC), a second cohort received 800 mg thrice daily for 8 weeks. During treatment, the median decrease in TNF production by PBMC cultured with 0.1 microgram/mL lipopolysaccharide (LPS) was 40%. The median change in TNF mRNA was a 34% decrease. Pentoxifylline did not affect HIV levels as detected by quantitative microculture or serum p24 antigen measurements, nor did it alter zidovudine pharmacokinetics. The most common toxicity was gastrointestinal. Pentoxifylline at dosages of less than thrice-daily 800 mg is well tolerated and may decrease TNF mRNA levels and LPS-induced TNF production.

Phase I AIDS Clinical Trials Group (075) study of adriamycin, bleomycin and vincristine chemotherapy with zidovudine in the treatment of AIDS-related Kaposiʼs sarcoma

To determine the toxicity and maximum tolerated dose of doxorubicin (adriamycin) in combination with fixed doses of bleomycin, vincristine (ABV) and zidovudine in patients with advanced AIDS-related Kaposi's sarcoma. Twenty-six HIV-seropositive men with Kaposi's sarcoma were treated daily with 100 mg zidovudine orally every 4 h, along with combination chemotherapy using bleomycin 10 U/m2 and vincristine 1.4 mg/m2 (maximum, 2 mg) given intravenously in 2-week cycles. In addition, three successive cohorts of eight patients received escalating doses of doxorubicin each beginning with no doxorubicin (level I), doses of 10 mg/m2 (level II), and 15 mg/m2 (level III). The major dose-limiting toxicity experienced with the combination therapy was severe neutropenia in eight patients, four of whom received level III doxorubicin (15 mg/m2). Therefore, 10 mg/m2 of doxorubicin in combination with zidovudine and BV chemotherapy was defined as the maximum tolerated dose. Other dose-limiting toxicities included neuropathy (n = 2), cutaneous toxicity associated with bleomycin (n = 1), and diarrhea (n = 1). Seventeen patients (71%; 95% confidence interval, 46-85) experienced either partial (n = 13) or clinical complete remission (n = 4) to therapy after a median of five cycles (range, 2-9). The maximum tolerated dose of doxorubicin is 10 mg/m2 when given in combination with zidovudine and BV chemotherapy. Response rates observed with the combined antiretroviral and chemotherapy regimen are similar to those previously reported with ABV chemotherapy alone.

Future treatment strategies in HIV infection.

EFFECTIVENESS OF EARLY TREATMENT WITH ZIDOVUDINE: In terms of progression to AIDS-related complex, AIDS or death, clinical trials have not yet shown any long-term benefit for early compared with deferred treatment with zidovudine. The Concorde trial showed a short-term benefit, as did two of the AIDS Clinical Trials Group studies, but the number of deaths in these short-term trials was too small to draw definitive conclusions. USE OF CD4 CELL COUNTS AS A MARKER OF AIDS: Most trials of zidovudine treatment have shown a slower decline in CD4 cell counts. However, it is still not clear whether these markers can predict long-term survival although they appear to have some value in predicting short-term benefits. SECOND-LINE THERAPY: In patients who are intolerant of or have failed to respond adequately to zidovudine, treatment with didanosine or zalcitabine has shown some short-term benefit, mainly in asymptomatic patients or those with AIDs-related complex. No substantial long-term benefit was observed. Zalcitabine appeared to show a slight increase in survival compared with didanosine. Treatment strategies still being developed include multidrug combinations, the combination of a nucleoside with a non-nucleoside reverse transcriptase inhibitor, or the use of a combination of drugs that affect different stages of the HIV life cycle, such as proteinase inhibitors. More sensitive assays, such as RNA polymerase chain reaction, may allow treatment to be tailored more closely to the needs of the individual patient.

Performance evaluation in multicenter clinical trials: Development of a model by the AIDS Clinical Trials Group

The AIDS Clinical Trials Group (ACTG), supported by the National Institute of Allergy and Infectious Diseases (NIAID), is the largest federally funded program of AIDS clinical trials. It is a collaboration involving 59 institutions and affiliated clinical centers, known as AIDS Clinical Trials Units (ACTUs), NIAID staff, and a Statistical and Data Analysis Center (SDAC). An institutional evaluation tool was developed to evaluate ACTU performance, distinguish between clinical centers with superior performance and those not meeting standards, and assist NIAID in allocating funding based on performance. The evaluation tool was designed to reflect the many distinguishing features of ACTG study protocols and clinical trial centers in order to measure performance objectively. The evaluation focused on assessing the financial resources expended by the ACTU in recruiting, treating, and following study patients during the evaluation period; the number of women and minorities enrolled; and the ACTU's scientific contributions to the ACTG. To help quantify the ACTU's performance in enrolling study subjects, a formula was derived to assess the total effort required to screen, enroll, treat, and assess subjects participating in ACTG studies. A weighting system was developed for each study protocol to account for the variations in effort and resources required by the different protocols. Future directions in the ACTG evaluation process include strategies to evaluate performance in relation to quality of data and to determine ways in which the evaluation process can be used to enhance the achievement of programmatic goals.