A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus (CMV) in CMV-seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: In a phase 3 trial, letermovir reduced clinically significant cytomegalovirus infections (CS-CMVi) and all-cause mortality at week 24 versus placebo in CMV-seropositive allogeneic hematopoietic cell transplantation (HCT) recipients. This post hoc analysis of phase 3 data further investigated the effects of letermovir on all-cause mortality. METHODS: Kaplan-Meier survival curves were generated by treatment group for all-cause mortality. Observations were censored at trial discontinuation for reasons other than death or at trial completion. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox modeling, adjusting for risk factors associated with mortality. RESULTS: Of 495 patients with no detectable CMV DNA at randomization, 437 had vital-status data available through week 48 post-HCT at trial completion (101 deaths, 20.4%). Following letermovir prophylaxis, the HR for all-cause mortality was 0.58 (95% CI, 0.35-0.98; P = .04) at week 24 and 0.74 (95% CI, 0.49-1.11; P = .14) at week 48 post-HCT versus placebo. Incidence of all-cause mortality through week 48 post-HCT in the letermovir group was similar in patients with or without CS-CMVi (15.8 vs 19.4%; P = .71). However, in the placebo group, all-cause mortality at week 48 post-HCT was higher in patients with versus those without CS-CMVi (31.0% vs 18.2%; P = .02). The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21-1.00; P = .05) at week 48 for letermovir versus placebo. CONCLUSIONS: Letermovir may reduce mortality by preventing or delaying CS-CMVi in HCT recipients. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov, NCT02137772.

Outcomes of patients with detectable CMV DNA at randomization in the phase III trial of letermovir for the prevention of CMV infection in allogeneic hematopoietic cell transplantation.

Letermovir, a cytomegalovirus (CMV) terminase-complex inhibitor, is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). In a phase III, double-blind, randomized trial, letermovir significantly reduced the risk of clinically significant CMV infection (CS-CMVi) vs placebo through Week 24 post-HCT. This analysis investigated outcomes in participants with detectable CMV DNA at randomization, who were excluded from the primary efficacy analysis. In total, 70 of 565 randomized participants had detectable CMV DNA at randomization (letermovir 48; placebo 22). Study treatment completion rates were greater in letermovir-treated participants compared with placebo (52.1% vs 9.1%). The incidence of CS-CMVi or imputed primary endpoint events through Week 24 were 64.6% and 90.9% in the letermovir and placebo groups, respectively (treatment difference -26.1%; P = .010). Kaplan-Meier event rates for CS-CMVi onset through Week 14 (end-of-treatment period) were 33.1% for letermovir and 86.6% for placebo (P < .001). Median viral loads at the CS-CMVi events was similar in both treatment arms. All-cause mortality through Week 24 posttransplant was 15.0% for letermovir and 18.2% for placebo; through Week 48, mortality rates were 26.5% and 40.9%, respectively (P = .268). Overall, clinical outcomes were similar to those reported for participants with undetectable CMV DNA at randomization.

Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex. METHODS: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation. RESULTS: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients. CONCLUSIONS: Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).

Long-term safety from the raltegravir clinical development program.

BACKGROUND: Raltegravir has demonstrated potent and durable efficacy and a favorable safety profile in 3 phase III studies in treatment-naïve and treatment-experienced patients with HIV-1 infection. This manuscript provides a review of the raltegravir safety profile using data from these and other studies in the clinical development program. METHODS: Comprehensive 96-week safety data from STARTMRK (raltegravir versus efavirenz, each with tenofovir/emtricitabine) and BENCHMRK (raltegravir versus placebo, each with optimized background therapy) are summarized. A cumulative meta-analysis of raltegravir 400 mg bid was conducted across the entire development program. RESULTS: In STARTMRK, drug-related adverse events (AEs) occurred less frequently with raltegravir than efavirenz. In BENCHMRK, the most common drug-related AEs occurred at generally similar frequencies in both groups. Drug-related serious AEs were uncommon. Rash was observed in raltegravir-treated patients at a higher frequency than placebo but a lower frequency than efavirenz. Depression and immune reconstitution inflammatory syndrome occurred at similar rates for raltegravir and comparators. Isolated elevations of creatine kinase were more common with raltegravir than placebo but occurred without clinical manifestations. The frequency of aminotransferase elevations was greater in patients with viral hepatitis co-infection, but similar in the raltegravir and comparator groups. The relative risk (95% CI) of cancer was 0.75 (0.30, 1.91) indicating no difference between raltegravir and comparator. Overall trends in the cumulative meta-analysis were similar to those observed in the phase III studies. CONCLUSIONS: Long-term data from the phase III clinical trials demonstrate that raltegravir was generally well-tolerated in both treatment-naïve and treatment-experienced patients with HIV infection.

Safety and immunogenicity of the Merck adenovirus serotype 5 (MRKAd5) and MRKAd6 human immunodeficiency virus type 1 trigene vaccines alone and in combination in healthy adults.

Preexisting immunity to adenovirus serotype 5 (Ad5) diminishes immune responses to vaccines using Ad5 as a vector. Alternate Ad serotypes as vaccine vectors might overcome Ad5-specific neutralizing antibodies and enhance immune responses in populations with a high prevalence of Ad5 immunity. To test this hypothesis, healthy human immunodeficiency virus (HIV)-seronegative adults were enrolled in a blinded, randomized, dose-escalating, placebo-controlled study. In part A, subjects with baseline Ad6 titers of < or = 18 received the Merck Ad6 (MRKAd6) HIV type 1 (HIV-1) trigene vaccine at weeks 0, 4, and 26. In part B, subjects stratified by Ad5 titers (< or = 200 or >200) and Ad6 titers (< or = 18 or >18) received the MRKAd5-plus-MRKAd6 (MRKAd5+6) HIV-1 trigene vaccine at weeks 0, 4, and 26. Immunogenicity was assessed by an enzyme-linked immunospot (ELISPOT) assay at week 30. No serious adverse events occurred. MRKAd6 trigene vaccine recipients responded more often to Nef than to Gag or Pol. In part A, ELISPOT response rates to > or = 2 vaccine antigens were 14%, 63%, and 71% at 10(9), 10(10), and 10(11) viral genomes (vg)/dose, respectively. All responders had positive Nef-specific ELISPOT results. In part B, Nef-ELISPOT response rates at 10(10) vg/dose of the MRKAd5+6 trigene vaccine were 50% in the low-Ad5/low-Ad6 stratum (n = 8), 78% in the low-Ad5/high-Ad6 stratum (n = 9), 75% in the high-Ad5/low-Ad6 stratum (n = 8), and 44% in the high-Ad5/high-Ad6 stratum (n = 9). The MRKAd6 and MRKAd5+6 trigene vaccines elicited dose-dependent responses predominantly to Nef and were generally well tolerated, indicating that Ad6 should be considered a candidate vector for future vaccines. Although small sample sizes limit the conclusions that can be drawn from this exploratory study, combining two Ad vectors may be a useful vaccine strategy for circumventing isolated immunity to a single Ad serotype.

Safety and immunogenicity of adenovirus-vectored near-consensus HIV type 1 clade B gag vaccines in healthy adults.

Vaccines inducing pathogen-specific cell-mediated immunity are being developed using attenuated adenoviral (Ad) vectors. We report the results of two independent Phase I trials of similar replication-deficient Ad5 vaccines containing a near-consensus HIV-1 clade B gag transgene. Healthy HIV-uninfected adults were enrolled in two separate, multicenter, dose-escalating, blinded, placebo-controlled studies to assess the safety and immunogenicity of a three-dose homologous regimen of Ad5 and MRKAd5 HIV-1 gag vaccines given on day 1, week 4, and week 26. Adverse events were collected for 29 days following each intradeltoid injection. The primary immunogenicity endpoint was the proportion of subjects with a positive unfractionated Gag-specific IFN-gamma ELISPOT response measured 4 weeks after the last dose (week 30). Analyses were performed after combining data for each dose group from both protocols, stratifying by baseline Ad5 titers. Overall, 252 subjects were randomized to receive either vaccine or placebo, including 229 subjects (91%) who completed the study through week 30. Tolerability and immunogenicity did not appear to differ between the Ad5 and MRKAd5 vaccines. The frequency of injection-site reactions was dose dependent. Systemic adverse events were also dose dependent and more frequent in subjects with baseline Ad5 titers <200 versus > or =200, especially after the first dose. The percent of ELISPOT responders and the ELISPOT geometric means overall were significantly higher for all four vaccine doses studied compared to placebo, and were generally higher in vaccine recipients with baseline Ad5 titers <200 versus > or = 200. Ad5 titers increased after vaccination in a dose-dependent fashion. Both Ad5-vectored HIV-1 vaccines were generally well tolerated and induced cell-mediated immune responses against HIV Gag-peptides in the majority of healthy adults with baseline Ad5 titers <200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.

Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults.

BACKGROUND: The safety and immunogenicity of the MRK adenovirus type 5 human immunodeficiency virus type 1 clade B gag/pol/nef vaccine, a replication-incompetent adenovirus type 5-vectored vaccine designed to elicit cell-mediated immunity against conserved human immunodeficiency virus proteins, was assessed in a phase 1 trial. METHODS: Healthy adults not infected with human immunodeficiency virus were enrolled in a multicenter, dose-escalating, blind, placebo-controlled study to evaluate a 3-dose homologous prime-boost regimen of the trivalent MRK adenovirus type 5 human immunodeficiency virus type 1 vaccine containing from 3 x 10(6) to 1 x 10(11) viral particles per 1-mL dose administered on day 1, during week 4 and during week 26. Adverse events were recorded for 29 days after each intradeltoid injection. The primary immunogenicity end point was the proportion of study participants with a positive unfractionated Gag-, Pol-, or Nef-specific interferon-gamma enzyme-linked immunosorbent spot response measured 4 weeks after administration of the last dose. RESULTS: Of 259 randomized individuals, 257 (99%) received > or = 1 dose of vaccine or placebo and were included in the safety analyses. Enzyme-linked immunosorbent spot results were available for 217 study participants (84%) at week 30. No serious vaccine-related adverse events occurred. No study participant discontinued participation because of vaccine-related adverse events. The frequency of injection-site reactions was dose dependent. Vaccine doses of > or = 3 x 10(9) viral particles elicited positive enzyme-linked immunosorbent spot responses to > or = 1 vaccine component in > 60% of recipients. High baseline antibody titers against adenovirus type 5 diminished enzyme-linked immunosorbent spot responses at all doses except the 3 x 10(10) viral particle dose. CONCLUSIONS: The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive hiv-infected individuals with CD4 cell counts between 50 and 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (<0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70 percent and 61 percent, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated