摘要:

Anti-HIV-1 combination therapies, including protease and reverse transcriptase inhibitors, can reduce plasma viremia to undetectable levels within the first 2 weeks of treatment. This reduction is followed by a slower decline that primarily results from the presence of viral reservoirs such as CD4+memory cells, dendritic cells, and macrophages. For this reason, we evaluated a new drug combination therapy that includes a lympholytic drug: (2-fluoro-ara-AMP, fludarabine) to eliminate cells already infected and an antiviral drug (azidothymidine [AZT]) to protect cells not yet infected. We used C57BL/6 mice infected with the retroviral complex LP-BM5, which developed severe immunodeficiency (i.e., murine AIDS), to select the most effective fludarabine regimen to inhibit disease progression, and then to evaluate the efficacy and toxicity of the fludarabine and AZT combinations. The results obtained show that intraperitoneal administration of fludarabine at 3 mg/mouse twice a day for 4 weeks is the most effective regimen in reducing splenomegaly, lymphadenopathy, hypergammaglobulinemia, and proviral DNA content in spleen and lymph nodes and in restoring the architecture of lymph nodes. Subsequently, we evaluated the combined or sequential administration of fludarabine and AZT. The data reported in this paper show that the sequential administration of the two drugs provides additive antiviral effects that reduce spleen and lymph node weights to normal values and proviral DNA content by ≈ 95% in all infected organs; the phenotypes of blood T and B cells moved toward control values, although the number of B cells was significantly reduced by fludarabine treatment. Finally, we evaluated the outcome of the disease after suspension or continuation of different treatment regimens. In all treatment groups, the disease progressed and increased proviral DNA content was found in infected organs, but animals receiving the sequential administration of fludarabine and AZT were less affected than those receiving only fludarabine or the simultaneous administration of both. The results obtained suggest that fludarabine could be part of a new therapeutic approach aiming at eradicating HIV from those cells that have been already infected and that are not protected by highly active antiretroviral therapy (HAART).

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine the impact of prior nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy, genotypic resistance, and other variables on response to efavirenz (EFV)- and adefovir dipivoxil (ADV)-based salvage therapy.DesignRetrospective clinical cohort study.SettingOne university and one community-based HIV clinic.Study subjectsAll 33 patients who were coenrolled in both the EFV and ADV expanded access programs.InterventionsPatients received EFV 600 mg/day and ADV 120 mg/day in addition to other antiretroviral agents.Outcome measureHIV viral load (<500 copies/ml) at 12 and 24 weeks.Results10 of 33 (30%) patients at 12 weeks and 8 of 33 (24%) patients at 24 weeks had viral loads <500 copies/ml. Prior NNRTI use and a history of any NNRTI-associated mutations predicted failure. Patients with Y181C or G190A single mutations had an initial greater magnitude of viral load suppression than those with K103N, but this advantage was short lived. No one with any NNRTI mutations responded with a viral load <500 copies/ml at 12 or 24 weeks.ConclusionsEFV/ADV-based salvage yielded viral load suppression at 24 weeks in 42% (8 of 19) of patients who were highly NRTI and protease inhibitor experienced but NNRTI naive. NNRTI-experienced study subjects had a poor response regardless of the specific NNRTI resistance mutation they harbored.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and pharmacokinetics, we conducted a multicenter, randomized, double-blind, placebo-controlled trial of FZD monotherapy in 72 HIV-infected patients who had not previously received antiretroviral therapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice daily, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients were randomized to receive in a 10:2 ratio either FZD or a placebo for 4 weeks. Overall, FZD was well tolerated in all dosage groups; only 1 patient discontinued the drug, because of a moderate rise in aminotransaminase activity. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (−0.67 log10) was observed in the 600 mg twice daily group. The plasma half-life was significantly longer (∼3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as reflected by the area under the time-concentration curve, was much lower after FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo assess the probability that protease inhibitor (PI) therapy might be discontinued because of adverse events (AE) and to evaluate the incidence rate of adverse reactions during PI treatment.DesignA prospective cohort, multicenter study on HIV-positive patients starting treatment with at least one PI.SettingTen departments of infectious diseases in Northern Italy.PatientsA total of 1207 patients who started PI therapy in September 1997 and were consecutively observed up to April 1999.Main Outcome MeasuresAdverse reactions following initiation of PI therapy, and time to therapy discontinuation due to AE.ResultsDuring the study period, 35.9% patients presented adverse reactions of any grade, whereas 9.7% presented at least one serious AE. After 12 months of treatment, the percentage of patients who had interrupted treatment was 36% of ritonavir-treated patients, 14.2% of those treated with indinavir, 13.6% of ritonavir-saquinavir hard gel capsules (HGC)-treated patients, and 8.5% and 2.1%, respectively, for those treated with nelfinavir and saquinavir HGC. Women and patients with hepatitis experienced a significantly greater number of adverse events compared with other categories. Gastrointestinal events were more frequently observed in patients treated with either ritonavir alone or in combination with saquinavir HGC, as well as in patients receiving nelfinavir, although in this group serious events were rare. Here again, neurologic, metabolic, and hepatic toxicity occurred more frequently in ritonavir and ritonavir-saquinavir HGC treated patients. Allergic reactions were more often observed in patients receiving nelfinavir. Indinavir-treated patients presented the highest incidence of renal toxicity.ConclusionRitonavir is the drug associated with the largest number of reactions, which appear during the first few months of treatment. Saquinavir HGC and nelfinavir are the best tolerated drugs in a clinical setting.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundObservational studies suggest that poor nutritional status among HIV-infected pregnant women is associated with a higher risk of vertical transmission of HIV.MethodsWe randomized 1083 pregnant women infected with HIV-1 in a double-blind, placebo-controlled trial to examine the effects of supplements of vitamin A and/or multivitamins (excluding vitamin A) using a 2-×-2 factorial design. We report the effects of the supplements on HIV infection defined using polymerase chain reaction (PCR), or death up to 6 weeks postpartum.ResultsOf babies in the multivitamin arm 38, (10.1%) were HIV-positive at birth compared with 24 (6.6%) in the no-multivitamin arm (relative risk [RR] = 1.54; 95% CI, 0.94–2.51;p= .08). Of babies born to mothers in the vitamin A arm, 38 (10.0%) were HIV-positive at birth compared with 24 (6.7%) in the no–vitamin A arm (RR, 1.49; 95% CI, 0.91–2.43;p= 0.11). Neither multivitamins nor vitamin A had an effect on HIV status at 6 weeks among those who were HIV-negative at birth (RR = 1.04; 95% CI, 0.65–1.66;p= 0.88) and (RR = 1.30; 95% CI, 0.80–2.09;p= .29, respectively). Similarly, neither supplement was associated with being either HIV-infected or dead at birth (RR, 0.98; 95% CI, 0.76–1.27;p= .89 and RR, 1.01; 95% CI, 0.78–1.31;p= .95, respectively. A beneficial effect of multivitamins on birth weight was limited to babies who were HIV-negative at birth; babies in the multivitamin arm weighed +94 g more compared with those in the no-multivitamin arm (p= .02). Among babies who were HIV-positive at birth, the corresponding difference was −31 g (p= .82).ConclusionsVitamin A and multivitamins did not affect the risk of vertical transmission of HIV in utero nor during the intrapartum and early breastfeeding periods. Multivitamins resulted in a significant improvement in birth weight of babies who were HIV-negative at birth but had no effect among those who were HIV-positive. The effect of vitamin supplements on HIV transmission through breastfeeding and on clinical progression of HIV disease is yet to be ascertained.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo describe the response to combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) initiated early in the course of HIV infection under routine circumstances and to research prognostic factors indicating good virologic response.SettingPatients of the Aquitaine Cohort, a hospital-based open cohort that had been recruiting since 1987 in five public hospitals of the Aquitaine region in southwestern France.MethodsProspective cohort study of antiretroviral-naive patients with CD4+cell counts >0.350 × 109/L who started dual NRTI therapy between January 1996 and June 1997. Intent-to-treat analysis and multivariate logistic regression were used with data collected up to March 31, 1998.ResultsIn this study, 130 patients were enrolled with a median follow-up of 14 months. At the time of first prescription, 79% were in U. S. Centers for Disease Control and Prevention (CDC) group A, 16% in group B, and 5% in group C; median CD4+cell count was 0.466 × 109/L and median HIV RNA level was 4.52 log10copies/ml. The two main combinations used were zidovudine (AZT) plus zalcitabine (ddC; 38%) and AZT plus didanosine (ddI; 37%). At week 52, median CD4+and HIV RNA responses were, respectively, +80 cells and −1.6 log; the proportions of patients with HIV RNA level <5000 and <500 copies/ml were 70% and 45%, respectively, and 96% of the patients had a CD4+cell count >0.350 × 109/L at that time. At their last follow-up, 3 patients had reached been diagnosed with full-blown AIDS and the AIDS-free survival probability at 1 year was 98.2% (95% confidence interval [CI], 93.1–99.6); 1 death had occurred. The only significant variable associated with an undetectable HIV RNA level at 1 year was a lower HIV RNA level at the first prescription of dual therapy.ConclusionOur data indicate that dual nucleoside combinations could be a therapeutic option for patients diagnosed and observed during follow-up in the early course of HIV infection.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The aim of this study was to identify factors associated with serum triglyceride (TG) evolution in HIV-1–infected patients when highly active antiretroviral treatment (HAART) with or without protease inhibitors (PI) was introduced. Among 3191 patients of the Aquitaine Cohort (multirisk, both genders, multiple treatment patterns) observed during 1996 through 1998, 1429 had at least two measurements of TG, viral load, and CD4 cell count. Median follow-up was 21 months (interquartile range [IQR], 11–26) and median number of TG measures was 6 (IQR, 3–10). Median TG at baseline was 1.32 mmol/L (IQR, 0.91–2.05) and increased significantly over time (+2.5% for 100 days; 95% confidence interval [CI], 1.9–3.1). Longitudinal analysis of variations of TG was performed using mixed models. In crude analysis, baseline TG was higher in men, in those aged over 36 years, and in homosexuals. The following time-dependent variables were associated with an increase of TG: body weight increasing to >65 kg, diagnosis of AIDS, CD4 cell count falling to <50 cells/mm3, viral load falling to <500 cp/ml, and introduction of nucleoside analogues and PIs. In multivariate analysis, age >36 years (change of +17% of the TG level; 95% CI, 11–24), homosexuals (+13%; 95% CI, 4–23), AIDS stage (+12%; 95% CI, 5–19), weight >65 kg (+7%; 95% CI, 2–12) and PI (+21%; 95% CI, 17–27) remained significant. Factors identified before the availability of PI remain important but HAART with PI is a new major contributing factor to increased TG levels.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo examine optimism in the light of recent advances in HIV treatment among gay men and its association with sexual risk behavior.MethodsAn anonymous questionnaire was completed by gay men who visited gyms in central London in March and April 1998 regarding their HIV status, unprotected anal intercourse (UAI) in the previous 3 months, and their response on a five-point linear scale to two measures of optimism: “I am less worried about HIV now that treatments have improved,” and “I believe that new drug therapies make people with HIV less infectious.”ResultsTwo thirds of the men (67.5%, 522 of 773) did not agree with the statement, “I am less worried about HIV now that treatments have improved,” and only 42 (5.4%) said they agreed quite a lot or a lot. HIV-positive men were more likely to agree with this statement than HIV-negative men (p= .001) and men who had never been tested (p< .001). There was no association between agreement with this statement and frequency of UAI among HIV-positive or never-tested men (p> .3); there was, however, a positive association among HIV-negative men who reported UAI with a partner of unknown or discordant status (p= .003). The vast majority of men (81.4%; 634 of 779) did not agree with the statement, “I believe that new drug therapies make people with HIV less infectious.” Regardless of HIV status, no significant association was seen between agreement with this statement and frequency of UAI (p> .1 for all comparisons).ConclusionMost gay men surveyed in central London gyms did not endorse the optimism statements concerning improved treatments or reduced infectivity. Although HIV-positive gay men were more likely to be optimistic than other men, there was no association between their optimism and sexual risk behavior. Among HIV-negative men, optimism around improved treatments (but not around reduced infectivity) was associated with UAI with a partner of unknown or discordant HIV status. For some HIV-negative men in London, optimism in the light of recent advances in HIV treatment may have triggered, or have been used as a justification for, sexual risk-taking.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID