BACKGROUND:MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration IC95 = 33 nM in 50% human serum) and good ...bioavailability in uninfected subjects. This study explored the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy in antiretroviral therapy-naive HIV-1-infected patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and CD4 T-cell counts of at least 100 cells/mm.
METHODS:This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect.
RESULTS:Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy; the mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On day 10, the mean decrease from baseline in the log10 HIV RNA level was −0.2 copies/mL for the placebo group and −1.9, −2.0, −1.7 and −2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively. All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo). At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10. Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated. The most common adverse experiences were headache and dizziness; these were similar between active and control groups. There were no discontinuations because of adverse experiences and no serious adverse experiences.
CONCLUSIONS:MK-0518 showed potent antiretroviral activity as short-term monotherapy and was generally well tolerated at all doses. Based on these results, part 2 of the study, a dose-ranging 48-week trial of MK-0518 versus efavirenz in a combination regimen, has been initiated.
For patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1), therapeutic options are limited. Raltegravir is a new molecule that inhibits HIV integrase. In two phase 3 ...studies, raltegravir was found to be superior to placebo, in the context of optimized background antiviral therapy, in suppressing HIV viral load at 48 weeks (62.1% vs. 32.9%).
In two phase 3 studies, raltegravir was found to be superior to placebo, in the context of optimized background antiviral therapy, in suppressing HIV viral load at 48 weeks (62.1% vs. 32.9%).
Highly active antiretroviral therapy is the standard of care for patients with advanced human immunodeficiency virus (HIV) infection.
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Combination regimens have resulted in improved survival, decreased morbidity, and cost-effective care for patients with a CD4 count of less than 350 per cubic millimeter.
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However, viral suppression cannot always be achieved or sustained with standard treatments because of the development of viral resistance, toxic effects of drugs, or lack of adherence.
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The majority of HIV-infected patients in whom highly active antiretroviral therapy fails have resistant viral quasispecies.
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Cross-resistance to agents within a drug class may exhaust . . .
In subgroups of two phase 3 studies, patients with high-risk features for failure of antiretroviral therapy, such as a low CD4 count, high base-line level of human immunodeficiency virus (HIV) type 1 ...RNA, or unfavorable genotypic or phenotypic sensitivity score, raltegravir was superior to placebo in terms of a virologic response at 48 weeks. However, among these patients, in whom antiretroviral therapy had been used previously, 23% of raltegravir recipients had virologic failure by 48 weeks.
In patients with high-risk features for failure of antiretroviral therapy, raltegravir was superior to placebo in terms of a virologic response at 48 weeks. However, among these patients, in whom antiretroviral therapy had been used previously, 23% of raltegravir recipients had virologic failure by 48 weeks.
Despite the substantial decrease in mortality and morbidity rates associated with highly active antiretroviral therapy over the past decade, there is still a substantial need for effective antiretroviral drugs for patients infected with resistant human immunodeficiency virus type 1 (HIV-1).
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The majority of licensed antiretroviral drugs belong to three classes targeting either the HIV-1 protease or reverse transcriptase, and considerable cross-resistance exists among drugs within each class.
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In patients with resistant virus, use of antiretroviral agents from new classes offers considerable potential benefit because of the absence of cross-resistance.
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HIV-1 integrase represents a new therapeutic target.
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The purpose of this multicenter, randomized, double-blind study, conducted in 520 patients, was to compare the efficacy and safety of omeprazole (40 and 20 mg once daily) with placebo in the ...treatment of benign gastric ulcer.
Treatment with omeprazole or placebo lasted 4 wk; those whose ulcers remained unhealed continued the same treatment regimen for an additional 4 wk. The effects of therapy were determined by endoscopy and assessment of GI symptoms. Safety and tolerability were evaluated through reported adverse events, physical examinations, and laboratory tests.
At weeks 4 and 8, the proportion of patients with healed ulcers was significantly greater in the omeprazole 40- and 20-mg groups than in the placebo group (p < 0.01). At week 8, the healing rate was significantly greater in the 40-mg group than in the 20-mg group (82.7 vs 74.8%, p < 0.05). In patients with large ulcers (>1 cm), the 40-mg regimen was associated with a significantly higher healing rate (78.9%) than both the 20-mg regimen (61.4%) and placebo (34.6%) at week 8 (p < 0.05 vs omeprazole 20 mg; p < 0.01 vs placebo). Healing rates in patients with small ulcers were similar for the 40- and 20-mg groups. Omeprazole was well tolerated, with no significant differences versus placebo in the overall incidence of clinical or laboratory adverse events.
Omeprazole 40 and 20 mg, administered once daily, healed a significantly greater proportion of patients than did placebo. The 40-mg regimen offered significant advantages over the 20-mg regimen in patients with large ulcers.
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