Bach Yen Nguyen

A CONTROLLED TRIAL OF TWO NUCLEOSIDE ANALOGUES PLUS INDINAVIR IN PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND CD4 CELL COUNTS OF 200 PER CUBIC MILLIMETER OR LESS

BACKGROUND The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.

Raltegravir with optimized background therapy for resistant HIV-1 infection.

BACKGROUND Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

BACKGROUND We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial

BACKGROUND Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. METHODS Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941. FINDINGS 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. INTERPRETATION Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. FUNDING Merck.

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme Corp.

Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses

Background:We analyzed the 96-week results in the overall population and in prespecified subgroups from the ongoing STARTMRK study of treatment-naive HIV-infected patients. Methods:Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies per milliliter and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Results:At week 96 counting noncompleters as failures, 81% versus 79% achieved vRNA levels <50 copies per milliliter in the raltegravir and efavirenz groups, respectively [Δ (95% confidence interval) = 2% (−4 to 9), noninferiority P < 0.001]. Mean change in baseline CD4 count was 240 and 225 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Δ (95% confidence interval) = 15 (−13 to 42)]. Treatment effects were consistent across prespecified baseline demographic and prognostic subgroups. Fewer drug-related clinical adverse events (47% versus 78%; P < 0.001) occurred in raltegravir than efavirenz recipients. Both regimens had modest effects on serum lipids and glucose levels and on body fat composition. Conclusions:When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir exhibited durable antiretroviral activity that was noninferior to the efficacy of efavirenz through 96 weeks of therapy. Subgroup analyses were generally consistent with the overall findings. Both regimens were well tolerated.

Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial

BACKGROUND Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection. METHODS In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662. FINDINGS Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia. INTERPRETATION This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials. FUNDING Merck Sharp & Dohme Corp.

Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial

BACKGROUND Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. METHODS In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823. FINDINGS From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. INTERPRETATION Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. FUNDING Merck.

Long-term Treatment With Raltegravir or Efavirenz Combined With Tenofovir/Emtricitabine for Treatment-Naive Human Immunodeficiency Virus-1–Infected Patients: 156-Week Results From STARTMRK

BACKGROUND We compared 3 years of antiretroviral therapy with raltegravir or efavirenz as part of a combination regimen in the ongoing STARTMRK study of treatment-naive patients infected with human immunodeficiency virus (HIV). METHODS Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies/mL and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind, noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Outcomes included viral suppression, adverse events, and changes from baseline metabolic parameters. Dual energy X-ray absorptiometry scans were obtained on a convenience sample of patients at prespecified time points to assess changes in body fat composition. RESULTS At week 156 counting noncompleters as failures, 212 (75.4%) of 281 versus 192 (68.1%) of 282 had vRNA levels <50 copies/mL in the raltegravir and efavirenz groups, respectively [Δ (95% CI) = 7.3% (-0.2, 14.7), noninferiority P < .001]. Mean changes from baseline CD4 count were 332 and 295 cells/mm³ in the raltegravir and efavirenz arms, respectively [Δ (95% CI) = 37 (4, 69)]. Consistent virologic and immunologic efficacy was maintained across prespecified demographic and baseline prognostic subgroups for both treatment groups. Fewer drug-related clinical adverse events (49% vs 80%; P < .001) occurred in raltegravir than efavirenz recipients, with discontinuations due to adverse events in 5% and 7%, respectively. Elevations in fasting lipid levels (including LDL- and HDL-cholesterol) were consistently lower in the raltegravir than efavirenz group (P < .005). Fat gain was 19% in 25 raltegravir recipients and 31% in 32 efavirenz recipients at week 156. CONCLUSIONS When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir produced durable viral suppression and immune restoration that was at least equivalent to efavirenz through 156 weeks of therapy. Both regimens were well tolerated, but raltegravir was associated with fewer drug-related clinical adverse events and smaller elevations in lipid levels. Clinical Trials Registration. NCT00369941.

Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy a randomized trial

Background Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Design Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Setting Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). Intervention The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. Measurements The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary Funding Source Merck & Co.