Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ACTG 076 trial assessed the ability of zidovudine (AZT) to prevent the transmission of HIV from mother to child. In that trial, women received 100 mg of AZT 5 times daily beginning from 14-34 gestational weeks, then intravenous AZT during labor. This approach, followed by the administration of AZT to infants for 6 weeks, led to an 8% mother-to-child HIV transmission rate compared to 23% with placebo. Drug therapy proven in the ACTG 076 trial has now become the basis for current practice in developed countries. Placebo-controlled clinical trials were later launched in selected developing countries to assess the effect upon vertical transmission of providing only a short course of AZT therapy to HIV-infected mothers. In Thailand, 397 HIV-infected pregnant women were randomized to take orally either placebo or 300 mg of AZT twice daily from 36 weeks of gestation, then 300 mg every 3 hours during labor. Infants did not receive AZT and the women did not breast-feed. Kaplan-Meier analysis found a perinatal HIV-1 transmission rate of 18.6% in the placebo group and 9.2% in the treatment group. Based upon these preliminary data, the US Centers for Disease Control and Prevention (CDC), who collaborated with the Thai Ministry of Public Health in the study, announced on February 18 that all women in the CDC's Cote d'Ivoire collaboration will now receive active AZT treatment. Use of a placebo group in the Cote d'Ivoire study helped to identify the effect of the country's limited obstetric services upon neonatal mortality. UNAIDS is hosting an international meeting in March to find ways of rapidly and effectively implementing these and other data. In future perinatal trials, placebo arms should either be dropped or replaced with the CDC short-course regimen.
 ...
PMID:Short course of AZT halves HIV-1 perinatal transmission. 950 Mar 34

The promising findings of ACTG 076, which identified a hopeful strategy for substantially reducing HIV transmission from mother to fetus, has stimulated a debate on counseling and testing protocols for pregnant women. This article presents an analysis of five state policy alternatives that address HIV counseling and testing. The policy analysis utilizes vertical and horizontal equity, user preference including avoidance of stigma and the right to privacy, effectiveness, and feasibility as evaluative criteria for examination of the policies. Interviews with state health department personnel enhance the policy analysis. While universal HIV counseling and voluntary testing for pregnant women emerges as the most acceptable policy, public health professionals must assume a vital role in facilitating the adoption of ethical and just state policies in an atmosphere sometimes hostile to women at risk for HIV.
 ...
PMID:HIV testing of pregnant women: a policy analysis. 951 18

The aim of this study was to identify a safe and tolerable dose of recombinant interferon-beta (IFN-beta) used in conjunction with a fixed dose of zidovudine in patients with early-stage, good-prognosis AIDS-related Kaposi's sarcoma. We conducted a phase I, dose-escalation controlled trial of 22.5, 45 of 90 million units of IFN-beta given by daily subcutaneous injection with 500 mg per day of oral zidovudine. At the time of this study, this was standard of care for HIV infection. Patients were sequentially enrolled at three medical centers. Tumor response, drug tolerance, antiviral studies and CD4 changes were assessed. Four patients were enrolled at each dose level, and escalation proceeded when at least four patients had tolerated two weeks of therapy without dose-limiting toxicity. ACTG Kaposi's sarcoma tumor response criteria were used to assess response. Fifteen patients were enrolled. The combination of IFN-beta and zidovudine was well tolerated, and the dose-limiting toxicities were local skin necrosis and systemic symptoms. Despite generally good prognostic characteristics, only two patients achieved a clinical complete response and three addition patients had stable disease for a prolonged period of time (range 24-44 weeks). There was no correlation between baseline CD4 cell counts and tumor response, nor between the antiviral effect of IFN-beta as measured by decreases in immune-complex dissociated p24 antigen and tumor response. Higher doses of IFN-beta did not result in more tumor responses or in greater antiviral activity. The maximum tolerated dose of IFN-beta in combination with 500 mg per day of zidovudine was 45 million units by subcutaneous injection per day. IFN-beta is well tolerated in patients with AIDS-related Kaposi's sarcoma when used in conjunction with zidovudine. However, the antitumor response rate in good-prognosis patients is low. Further studies of this agent should be in the context of four-drug antiretroviral regimens where viral suppression is greatest and any antitumor activity of IFN-beta may be observed.
 ...
PMID:Open-label phase I study of combination therapy with zidovudine and interferon-beta in patients with AIDS-related Kaposi's sarcoma: AIDS Clinical Trials Group Protocol 057. 955 13

Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications in the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials.
 ...
PMID:Intention-to-treat vs. on-treatment analyses of clinical trial data: experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group. 962 Aug 7

The aim of this study was to determine the maternal and umbilical cord serum ZDV levels at delivery in HIV-1 infected parturients treated with a short-course ZDV regimens in late pregnancy and labour. Serum ZDV and its metabolite were measured by high-performance liquid chromatography. Concentrations of ZDV and its metabolite in umbilical cord blood appeared similar to maternal concentrations. There was a significant positive correlation between serum ZDV and its metabolite in maternal and umbilical cord concentrations. At delivery, maintenance of optimal virustatic ZDV concentration with oral antenatal and oral intermittent intrapartum ZDV dosage regimen can be achieved in only 53% of cases. The regimens used in this study were useful but not as effective as the ACTG 076 regimen with an intravenous dose intrapartum plus the oral administration to the infants for 6 weeks.
 ...
PMID:Maternal and umbilical cord serum zidovudine levels in human immunodeficiency virus infection. 976 Nov 55

Since the discover of AIDS in 1981 and the causal human immunodeficiency virus in 1983, therapeutic strategies have gone through many phases. When the ACTG 175 and Delta trials demonstrated the clinical improvement offered by regiments combining 2 nucleosides over monotherapy, combination therapy was being prescribed for less than 20% of all primary infections. Less than one year later, this rate suddenly rose to 90%. At the same time, the clinical benefit in terms of reduced morbidity and mortality was demonstrated for triple therapy and by the end of 1997, 65% of all treated HIV+ patients were taking the triple combination therapy, 34% were on bitherapy and only 1% on single drug regimens. This fantastically rapid evolution of management strategies appears even more exceptional when one realizes that these changes in prescription attitudes took place before expert groups were able to establish accepted guidelines. The number of patients under treatment also rose sharply from 57% in early 1994 to 87% in late 1997, while the number of active hospital files rose by 30%. These rapid changes in patient management schemes has had a major effect on HIV-related morbidity and mortality. In 1997, the number of deaths fell by 41% and the number of new AIDS cases by nearly 50%. The number of hospitalizations has also declined by 50% over the last 2 years. This is probably the first time in the history in medicine that preliminary clinical studies have led to direct patient benefit in so short a time. This achievement has been accomplished by the combined efforts of health care workers, patient associations, public authorities and the pharmaceutical industry. This global view must not however hide the fact that most all the prescriptions used today are based on the results of clinical trials in a small number of patients over short study periods. Long-term efficacy and tolerance remain unknown. One must also keep in mind one other figure which has not varied over this period. The percentage of new AIDS cases in patients no ith no prior treatment because they are unaware of the infection or because they do not want treatment remains unchanged at 40%.
 ...
PMID:[The concept of therapeutic management: exemplary implementation of antiretroviral treatments]. 976 61

The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a phase I/II clinical trial (ACTG 187) of patients with CD4 counts < or =500/mm3. In all, 34 HIV-1-infected patients were randomized to receive ATV for 12 weeks in doses chosen to achieve one of three serum trough levels: 5 to 13 microM, 14 to 22 microM, or 23 to 31 microM. Rash was the most common adverse event, with a grade 3 or 4 rash occurring in 4 patients. No significant change from baseline in HIV-1 plasma RNA mean copy number was detected at week 4 (+0.09 log10 copies/ml; p = .30). However, some evidence indicated moderate antiviral activity at week 4, based on median changes in CD4 count (+23/mm3; p = .05), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associated with RT mutations K103N and Y181C. In contrast, the Y181C mutation was not detected in ATV-resistant isolates obtained from patients enrolled in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate significant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with inadequate sampling at early time points following initiation of ATV therapy.
 ...
PMID:Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients. 976 22

Thirteen laboratories evaluated the reproducibility of sequencing methods to detect drug resistance mutations in HIV-1 reverse transcriptase (RT). Blinded, cultured peripheral blood mononuclear cell pellets were distributed to each laboratory. Each laboratory used its preferred method for sequencing proviral DNA. Differences in protocols included: DNA purification; number of PCR amplifications; PCR product purification; sequence/location of PCR/sequencing primers; sequencing template; sequencing reaction label; sequencing polymerase; and use of manual versus automated methods to resolve sequencing reaction products. Five unknowns were evaluated. Thirteen laboratories submitted 39043 nucleotide assignments spanning codons 10-256 of HIV-1 RT. A consensus nucleotide assignment (defined as agreement among > or = 75% of laboratories) could be made in over 99% of nucleotide positions, and was more frequent in the three laboratory isolates. The overall rate of discrepant nucleotide assignments was 0.29%. A consensus nucleotide assignment could not be made at RT codon 41 in the clinical isolate tested. Clonal analysis revealed that this was due to the presence of a mixture of wild-type and mutant genotypes. These observations suggest that sequencing methodologies currently in use in ACTG laboratories to sequence HIV-1 RT yield highly concordant results for laboratory strains; however, more discrepancies among laboratories may occur when clinical isolates are tested.
 ...
PMID:Interlaboratory concordance of DNA sequence analysis to detect reverse transcriptase mutations in HIV-1 proviral DNA. ACTG Sequencing Working Group. AIDS Clinical Trials Group. 982 May 78

Zidovudine was the first agent approved for treatment of HIV disease, and since its widespread availability in 1987, the pharmacokinetic disposition and clinical effects of ZDV have been extensively evaluated. In addition to its utility as a component of a multidrug combination regimen for the treatment of adult and pediatric HIV-1 infection, it is the only agent approved by the FDA for the prevention of mother-to-child HIV-1 transmission. The effectiveness of ZDV for the prevention of mother-to-child HIV-1 transmission has been demonstrated in several studies. The optimal time during gestation to initiate ZDV therapy and the relative importance of the intrapartum and newborn components is the focus of both current interventional and observational studies. Until more information is available from these trials, the combined maternal/newborn ZDV regimen studied in ACTG 076 remains the recommended treatment regimen of choice in the United States.
 ...
PMID:Zidovudine. 989 73

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 microM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.
 ...
PMID:ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team. 1034 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>