Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial.

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received 50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.

Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease-inhibitor regimen: pharmacokinetic drug interactions and antiviral activity.

Patients with plasma viral RNA >50,000 copies/mL, despite a protease-inhibitor regimen, received abacavir, amprenavir, and efavirenz to assess efavirenz-amprenavir drug interactions and to evaluate safety and antiviral response. Patients first received amprenavir with abacavir and other nucleoside analogs. Amprenavir levels were measured before and after adding efavirenz. Patients then received a second protease inhibitor. There was evidence of genotypic and phenotypic resistance at study entry. No patient had study drugs discontinued because of toxicity. Efavirenz decreased the steady-state area under the curve, maximum plasma concentration, and minimum plasma concentration of amprenavir by 24%, 33%, and 43%, respectively. Three of 10 patients had >1.5 log10 viral response to abacavir and amprenavir. All 8 patients who added efavirenz had >0.5 log10 decline in viral load, and this response lasted >24 weeks for 3 of the patients. A combination regimen that included abacavir, amprenavir, and efavirenz was well tolerated and had sustained activity in some patients. Concomitant efavirenz therapy decreases amprenavir concentrations.

Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team.

BACKGROUND: Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen. METHODS: The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours). RESULTS: Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005). CONCLUSIONS: As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.

Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro.

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors are a promising class of antiretroviral agents that compromise enzymatic function through substrate mimicry. The in vitro susceptibility of a panel of HIV-1 clinical isolates demonstrating various drug resistance phenotypes to combinations of the HIV-1 protease inhibitors saquinavir and indinavir was determined. Antiviral effect was assessed by an HIV-1 p24 antigen reduction assay in phytohemagglutinin-stimulated peripheral blood mononuclear cells after harvesting of cell-free supernatant fluids at peak antigen production (days 4-7). Drug interactions were determined by median-dose-effect analysis, with the combination index (CI) calculated at several inhibitory concentrations (IC50, IC75, IC90, IC95, IC99). The interactive effects ranged from synergy at low efficacy doses to antagonism at higher doses against a pan-susceptible clinical isolate of HIV-1. Against a zidovudine-resistant isolate as well as a multidrug-resistant isolate, the combination of saquinavir and indinavir demonstrated antagonism at all doses.

Combination chemotherapy for human immunodeficiency virus-1.

Combination therapy approaches are becoming the mainstay of treatment for a variety of neoplastic and infectious diseases, including human immunodeficiency virus (HIV)-1 infections. The advantages of combination therapy include potentially additive-to-synergistic antiviral interactions, decreased emergence of or wider coverage against resistant viruses, and broadened effect both in terms of cell types and tissue reservoirs. However, combination drug interactions may range from synergy to antagonism. Both in vitro and in vivo studies have identified agents demonstrating additive-to-synergistic effects when used together and support the use of combination strategies in clinical practice. These will be reviewed in the context of their use in the setting of healthcare worker postexposure prophylaxis.

Susceptibility of human cytomegalovirus to two-drug combinations in vitro.

Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality for immunocompromised hosts. We sought to determine the in vitro susceptibility of HCMV reference laboratory strains, clinical isolates and strains with known resistance to currently available anticytomegaloviral drugs to two-drug combinations of the following compounds: ganciclovir, foscarnet, cidofovir and its cyclic congener, cyclic HPMPC (cHPMPC), and lobucavir. Cytotoxicity was determined by Trypan Blue exclusion of cells exposed both when proliferating (non-confluent) and once confluent. Antiviral effect was determined by a plaque-reduction assay in MRC-5 human embryonic lung cells. Drug interactions were determined by median-dose effect analysis with the combination index calculated at 50, 75, 90 and 95% inhibitory concentrations. No drug, either alone or in combination, reached a 50% cytotoxicity concentration in the dose ranges tested. Overall, 252/280 (90.0%) of the two-drug combinations demonstrated additive or synergistic interactive effects towards the panel of HCMV isolates tested. No combination demonstrated antagonism at all inhibitory concentrations to more than one isolate. Interestingly, the clinical isolate tested demonstrated the highest frequency of antagonistic combinations (3/10), as well as marked differences from pan-susceptible laboratory strains. The combinations of ganciclovir + foscarnet and cHPMPC + foscarnet demonstrated additive to synergistic effects against all isolates tested. In vitro combination drug studies could help in the rational choice of therapeutic regimens for use in clinical trials, potentially resulting in decreased toxicity, increased efficacy and delayed onset of drug resistance.

HIV-1 DNA in fibroblast cultures infected with urine from HIV-seropositive cytomegalovirus (CMV) excretors.

Interactions between HIV-1 and CMV may be important in the pathogenesis of AIDS. We have studied whether active CMV infection alters the cell tropism of HIV-1 in dually-infected individuals. Urines from HIV-seropositive individuals excreting CMV were compared to urines from CMV non-excretors. Sixty-six urines from HIV-seropositive individuals were tested. Infectious HIV-1 was not detected in any of the concentrated urines tested. The urines were filtered, concentrated, DNase-treated and cultured on HIV-1 non-permissive human forestin fibroblasts. HIV-1 DNA was detected by PCR with pol gene primers in 5 of 39 MRHF cell cultures inoculated with CMV culture positive urine (p = 0.037). HIV-1 DNA was not detected by PCR in uninfected fibroblasts, in fibroblasts inoculated with CMV uninfected urine from 27 HIV-seropositive patients or in fibroblasts cultured with 9 CMV culture positive urines from 16 HIV-seronegative renal transplant recipients. Supernatant fluid from an HIV-1 PCR-positive culture was passaged onto another fibroblast monolayer, and these cells were negative for HIV-1 DNA. Direct inoculation of fibroblasts with HIV-1 did not yield evidence of infection by PCR. CMV infection may facilitate HIV-1 DNA entry into ordinarily non-permissive cells.