T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment.

BACKGROUND: Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients. METHODS: Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses. RESULTS: Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration. LIMITATIONS: There was no placebo control. CONCLUSION: Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines.

The maraviroc expanded access program - safety and efficacy data from an open-label study.

PURPOSE: The maraviroc (MVC) expanded access program (EAP) was initiated to increase MVC availability to patients with limited treatment options. Darunavir (DRV), raltegravir (RAL), and etravirine (ETV) were either recently approved or under regulatory review at study initiation and available for coadministration with MVC. Thus, the safety of MVC in combination with new antiretroviral therapies (ARVs) could be assessed. This open-label safety study of MVC was conducted at 262 sites worldwide in 1032 R5 HIV-positive treatment-experienced patients with limited/no therapeutic options. METHODS: Study visits included screening, baseline, end of study or early discontinuation, and follow-up 30 days after last dose. Interim visits for HIV-1 RNA and CD4 cell counts occurred according to local HIV infection management guidelines. Safety data were analyzed overall and by subgroup based on ARV combination [MVC+optimized background therapy (OBT), MVC ± OBT+DRV/r, MVC ± OBT+RAL, MVC ± OBT+RAL+DRV/r, MVC ± OBT+RAL+ETV ± DRV/r]. RESULTS: Most (90.3%) adverse events (AEs) were of mild or moderate severity with few grade 3/4 events, discontinuations, or temporary discontinuations/dose reductions due to AEs or serious AEs. Similar results were observed across subgroups. Of treated patients, 79.9% and 50% had HIV-1 RNA < 400 copies/ml and < 50 copies/ml respectively, at the end of the study, early termination visits, or at last known status. Tropism changes and selection of MVC-resistant R5 virus, including high-level MVC dependence, were mechanisms of viral escape. CONCLUSION: MVC was well tolerated with virologic suppression observed in most patients.

Hepatic safety in subjects with HIV-1 and hepatitis C and/or B virus: a randomized, double-blind study of maraviroc versus placebo in combination with antiretroviral agents.

BACKGROUND: One of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents. OBJECTIVE: To evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1-infected subjects co-infected with HCV and/or HBV. METHODS: In this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (n = 70) or placebo (n = 67) in combination with other antiretroviral agents. PRIMARY ENDPOINT: the percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5 × upper limit of normal (ULN) if baseline ALT ≤ ULN or >3.5 × baseline if baseline ALT>ULN in the maraviroc versus the placebo arm. RESULTS: At week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hy's law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group. CONCLUSIONS: The use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48 weeks of treatment.

Safety profile of maraviroc in patients coinfected with HIV-1 and hepatitis B or C included in the maraviroc expanded access program.

OBJECTIVE: To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV-1 coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV). METHODS: This was a multicenter, noncomparative, open-label, expanded access program (EAP) initiated in February 2007. Patients with CCR5-tropic HIV-1 and HIV-1 RNA ≥ 1000 copies/mL on their current treatment received maraviroc 300 mg (150 mg with protease inhibitors) twice daily with optimized background therapy (OBT), which could include the newer agents raltegravir, etravirine, and darunavir. The adverse event (AE) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2, where the OBT did not include these agents. RESULTS: A total of 1,032 patients were enrolled: 51 HIV/HBV coinfected; 149 HIV/HCV coinfected, 9 HIV/HBV/HCV coinfected, and 823 HIV-1 monoinfected. Most (76%) received at least 1 newer agent. Overall AE frequency was comparable across coinfection groups (63%-72%). Hepatobiliary events were more common in HIV/HCV coinfection than in HIV monoinfection or HIV/HBV coinfection (10.0, 4.8, and 3.1 per 100 patient-years, respectively). Across all coinfection groups, there was a trend toward lower exposure-adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies. Grade 3/4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm. CONCLUSION: Maraviroc plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV-1-infected patients coinfected with HBV or HCV.

Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial.

BACKGROUND: Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. METHODS: Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of > or = 1 log10 less than the baseline level without treatment change at week 24. RESULTS: Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a > or = 1-log10 reduction in the HIV-1 load (intent-to-treat population; P<.0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. CONCLUSIONS: TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.

Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment.

OBJECTIVE: The aim of this study was to evaluate the efficacy of maraviroc along with darunavir/ritonavir, all once daily, for the treatment of antiretroviral-naive HIV-1 infected individuals. DESIGN: MODERN was a multicentre, double-blind, noninferiority, phase III study in HIV-1 infected, antiretroviral-naive adults with plasma HIV-1 RNA at least 1000 copies/ml and no evidence of reduced susceptibility to study drugs. METHODS: At screening, participants were randomized 1 : 1 to undergo either genotypic or phenotypic tropism testing. Participants with CCR5-tropic HIV-1 were randomized 1 : 1 to receive maraviroc 150 mg once daily or tenofovir/emtricitabine once daily each with darunavir/ritonavir once daily for 96 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml (Food and Drug Administration snapshot algorithm) at Week 48. A substudy evaluated bone mineral density, body fat distribution and serum bone turnover markers. RESULTS: Seven hundred and ninety-seven participants were dosed (maraviroc, n = 396; tenofovir/emtricitabine, n = 401). The Data Monitoring Committee recommended early study termination due to inferior efficacy in the maraviroc group. At Week 48, the proportion of participants with HIV-1 RNA less than 50 copies/ml was 77.3% for maraviroc and 86.8% for tenofovir/emtricitabine [difference of -9.54% (95% confidence interval: -14.83 to -4.24)]. More maraviroc participants discontinued for lack of efficacy, which was not associated with non-R5 tropism or resistance. Discontinuations for adverse events, Category C events, Grade 3/4 adverse events and laboratory abnormalities were similar between groups. CONCLUSION: A once-daily nucleos(t)ide-sparing two-drug regimen of maraviroc and darunavir/ritonavir was inferior to a three-drug regimen of tenofovir/emtricitabine and darunavir/ritonavir in antiretroviral-naive adults.

Treatment of Scedosporium apiospermum brain abscesses with posaconazole.

A 41-year-old man with acute lymphoblastic leukemia developed multiple Scedosporium apiospermum brain abscesses. The infection progressed despite neurosurgical drainage and treatment with itraconazole, amphotericin B, and ketoconazole, but the brain abscesses completely resolved after treatment with posaconazole alone.

Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients.

BACKGROUND: Maraviroc is unique among approved antiretroviral drugs in targeting the host-cell chemokine coreceptor type-5 receptor. With its novel mechanism of action, we sought to describe the 5-year safety profile of maraviroc. METHODS: Two large phase 3 studies of maraviroc enrolled HIV-infected treatment-experienced patients and followed them up for 5 or more years. Survival and selected clinical end points were identified and assessed. RESULTS: A total of 938 enrolled patients received maraviroc-containing regimens. Rates of death and selected clinical events (eg, hepatic failure, malignancy, and myocardial infarction) were low during follow-up. CONCLUSIONS: Maraviroc was generally safe in treatment-experienced participants for >5 years.

Efficacy and safety of maraviroc vs. efavirenz in treatment-naive patients with HIV-1: 5-year findings.

OBJECTIVE: Maraviroc, a chemokine co-receptor type 5 (CCR5) antagonist, has demonstrated comparable efficacy and safety to efavirenz, each in combination with zidovudine/lamivudine, over 96 weeks in the Maraviroc vs. Efavirenz Regimens as Initial Therapy (MERIT) study. Here we report 5-year findings. DESIGN: A randomized, double-blind, multicenter phase IIb/III study with an open-label extension phase. METHODS: Treatment-naive patients with CCR5-tropic HIV-1 infection (Trofile) received maraviroc 300 mg twice daily or efavirenz 600 mg once daily, and zidovudine/lamivudine 300 mg/150 mg twice daily. After the last patient's week 96 visit, the study was unblinded and patients could enter a nominal 3-year open-label phase. Endpoints at the 5-year nominal visit (week 240) included proportion of patients (CCR5 tropism re-confirmed by enhanced sensitivity Trofile) with viral load (plasma HIV-1 RNA) below 50 and 400 copies/ml, and change from baseline in CD4(+) cell count, as well as safety. RESULTS: The proportion of patients maintaining viral load below 50 copies/ml was similar between treatment arms throughout the study and at week 240 (maraviroc 50.8% vs. efavirenz 45.9%). Maraviroc-treated patients had a greater increase from baseline in mean CD4(+) cell count than efavirenz-treated patients at week 240 (293 vs. 271 cells/µl, respectively). Fewer patients on maraviroc vs. efavirenz experienced treatment-related adverse events (68.9 vs. 81.7%) and discontinued as a result of any adverse event (10.6 vs. 21.3%). CONCLUSION: Maraviroc maintained similar long-term antiviral efficacy to efavirenz over 5 years in treatment-naive patients with CCR5-tropic HIV-1. Maraviroc was generally well tolerated with no unexpected safety findings or evidence of long-term safety concerns.

Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers.

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.