Effect of Rifampin on the Single-Dose Pharmacokinetics of Oral Cabotegravir in Healthy Subjects.

Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection. This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir. Subjects received a single oral dose of cabotegravir (30 mg) on day 1 followed by plasma sampling on days 1 to 8. Treatment with once-daily oral rifampin (600 mg) occurred on days 8 to 28. Subjects received a second dose of 30 mg cabotegravir on day 21 followed by pharmacokinetic sampling on days 21 to 28. Fifteen subjects were enrolled and completed the study. Rifampin decreased the cabotegravir area under the concentration-time curve from 0 h to infinity and the half-life by 59% and 57%, respectively, whereas oral clearance was increased 2.4-fold. The maximum concentration of cabotegravir in plasma was unaffected by coadministration with rifampin. All adverse events were mild in severity, with chromaturia attributed to rifampin observed in all subjects. Rifampin induction of cabotegravir metabolism resulted in increased cabotegravir oral clearance and significantly decreased cabotegravir exposures. Rifampin is expected to increase cabotegravir clearance following long-acting injectable administration. Concomitant administration of rifampin with oral and long-acting formulations of cabotegravir is not recommended currently without further study. (This study has been registered at ClinicalTrials.gov under registration no. NCT02411435.).

Echocardiogram study to evaluate the effect of the novel hepatitis C virus NS5A inhibitor GSK2336805 on cardiac contractility in healthy subjects.

GSK2336805 is a hepatitis C virus NS5A inhibitor in clinical development for the treatment of chronic hepatitis C virus infection. This was a single-center, randomized, double-blind, placebo-controlled, two-period crossover study in healthy adults to evaluate the effects of a single 150-mg dose of GSK2336805 on echocardiographic measures of contractility. GSK2336805 had no effect on ejection fraction, and there was no significant correlation between GSK2336805 plasma concentration and ejection fraction. (This study has been registered at Clinicaltrials.gov under registration no. NCT01424540.).

Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1.

GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax (time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.).

Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor.

BACKGROUND: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. OBJECTIVE: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1-infected subjects. METHODS: This double-blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1-infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days. RESULTS: Dose-proportional increases in drug exposure were observed in healthy and HIV-1-infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half-life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1-infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms. CONCLUSIONS: GSK1265744 was well tolerated in healthy and HIV-1-infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load.

Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy.

We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.

Pharmacogenetics of hypersensitivity to abacavir: from PGx hypothesis to confirmation to clinical utility.

The hypersensitivity (HSR) to abacavir (ABC) pharmacogenetics (PGx) program represents the progression from an exploratory discovery to a validated biomarker. Within the program, two retrospective PGx studies were conducted to identify HIV-1 patients at increased risk for ABC HSR, a treatment-limiting and potentially life-threatening adverse event. A strong statistical association between the major histocompatibility complex allele, HLA-B*5701, and clinically diagnosed ABC HSR was identified but varied between racial populations. Subsequently, ABC skin patch testing was introduced as a research tool to supplement clinical case ascertainment. In a randomized, prospective study evaluating the clinical utility of HLA-B*5701 screening, avoidance of ABC in HLA-B*5701-positive patients significantly reduced clinically diagnosed ABC HSR and eliminated patch test-positive ABC HSR. Finally, a retrospective PGx study supports the generalizability of the association across races. Prospective HLA-B*5701 screening should greatly reduce the incidence of ABC HSR by identifying patients at high risk for ABC HSR before they are treated.

Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV-infected adults. Abacavir Phase 2 Clinical Team.

OBJECTIVES: To evaluate, over 12 weeks, the antiretroviral activity and safety of abacavir, used alone and in combination with zidovudine (ZDV), as treatment for HIV-1-infected subjects who had limited or no antiretroviral treatment. DESIGN: Seventy-nine HIV-1-infected subjects, with CD4 cell counts 200-500 x 10(6)/l and <12 weeks of previous treatment with ZDV were enrolled in a multicenter study. Subjects were randomly assigned to one of four cohorts receiving abacavir monotherapy for the first 4 weeks (200, 400, or 600 mg every 8 h daily, or 300 mg every 12 h daily) and, thereafter, combination therapy of abacavir with 600 mg ZDV or ZDV placebo, administered in a double-blind manner for an additional 8 weeks. METHODS: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4+ cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities during the 12-week period and for 4 weeks post-treatment. RESULTS: Treatment with abacavir, alone or in combination with ZDV, produced marked decreases in plasma HIV-1 RNA loads and increases in CD4+ cell counts in all groups. At week 4, median plasma HIV-1 RNA loads decreased by 1.11-1.77 log10 copies/ml and median CD4+ cell counts increased by 63-111 x 10(6)/l in all groups. At week 12, median HIV-1 RNA loads decreased by 1.02-2.24 log10 copies/ml (abacavir monotherapy) and by 1.81-2.01 log10 copies/ml (abacavir-ZDV); median CD4+ cell counts increased by 79-195 x 10(6)/l (abacavir monotherapy) and by 93-142 x 10(6)/l (abacavir-ZDV). At week 12, the percentage of subjects who had plasma HIV-1 RNA levels below 400 and 40 copies/ml were 28 and 11%, respectively (abacavir monotherapy) and 69 and 22%, respectively (abacavir-ZDV). Eight subjects (10%) discontinued the study prematurely because of adverse events; nausea (n = 4) and hypersensitivity (n = 3) were the most common reasons for withdrawal. There were no deaths among the study subjects. CONCLUSIONS: In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.

Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase.

OBJECTIVE: To characterize early and later indices of cellular restoration among HIV-1 infected persons treated with abacavir and one protease inhibitor and to identify predictors of CD4 cell increases. METHODS: Flow-cytometric analyses of lymphocyte phenotypes among 71 antiretroviral treatment naive adults in a 48 week treatment trial. RESULTS: During the first 4 weeks of therapy, increases in naive and memory CD4 cells and in B cells were seen; naive CD8 cells increased while CD8 cells remained stable as memory CD8 cells decreased. During the second phase total CD4 and naive CD4 and CD8 cells increased while total CD8 and memory CD8 cells decreased. The numbers of CD4 cells that expressed CD28 increased from a median of 308 x 10(6)/l at baseline to 477 x 10(6)/l at week 48. Higher baseline plasma HIV-1 RNA levels predicted the magnitude of early CD4 (r = 0.35; P = 0.01), memory CD4 (r = 0.38; P = 0.001) and CD28 CD4 cell (r = 0.29; P = 0.01) restoration but was not related to second phase changes. Younger age predicted a greater second phase (but not first phase) increase in naive CD4 cells (r = -0.31; P = 0.03). CONCLUSIONS: Higher baseline levels of HIV-1 replication determine the magnitude of first phase CD4 cell increases after suppression of HIV-1 replication. Second phase (primarily naive) CD4 cell increases are not related to HIV-1 replication but are inversely relate to age suggesting that thymic potential is a major determinant of long term cellular restoration in HIV-1 infected persons receiving antiretroviral therapy.

Immunological and virological responses in HIV-1-infected adults at early stage of established infection treated with highly active antiretroviral therapy.

OBJECTIVE: To evaluate the immunological and virological responses to highly active antiretroviral therapy (HAART) in blood and lymphoid compartments of HIV-1-infected patients at an early stage of infection. DESIGN: An open-label, observational, non-randomized, prospective trial of outpatients attending the Centre of Clinical Investigation in Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland. SUBJECTS: Forty-one antiretroviral-naive HIV-1-infected adults with 400 CD4 T cells/microl or greater and 5000 plasma HIV-1-RNA copies/ml or greater were enrolled, and 32 finished the study. Forty-nine HIV-negative individuals were included as controls. All subjects gave written informed consent. INTERVENTIONS: All patients received abacavir 300 mg by mouth every 12 h and amprenavir 1200 mg by mouth every 12 h for 72 weeks. MAIN OUTCOME MEASURES: The extent of immune reconstitution in blood and lymph nodes after 72 weeks of HAART was evaluated, and compared with immunological measures of 49 HIV-negative subjects. RESULTS: Virus replication was effectively suppressed (-3.5 log10 at week 72). Substantial increments of CD4 T cell count in blood and percentage in lymph nodes were observed over time, and these measures were comparable to HIV-negative subjects by week 24 in blood and by week 48 in lymph nodes. The increase was equally distributed between naive and memory CD4 T cells. Recovery of HIV-specific CD4 responses occurred in 40% of patients. CONCLUSION: The initiation of HAART at an early stage of established HIV infection induces systemic quantitative normalization of CD4 T cells, a partial recovery of HIV-specific CD4 cell responses, and effective and durable suppression of virus replication.

Antiretroviral activity and safety of abacavir in combination with selected HIV-1 protease inhibitors in therapy-naive HIV-1-infected adults.

OBJECTIVE: To assess antiretroviral efficacy and safety of abacavir in combination with selected HIV-1 protease inhibitors. DESIGN: A 48-week, open-label study. MATERIALS AND METHODS: Eighty-two antiretroviral naive HIV-1-infected adults (CD4 cell count > or = 100 cells/mm3, plasma HIV-1 RNA > or = 5,000 copies/ml) were randomly assigned to receive abacavir (300 mg twice daily) in combination with standard doses of one of five protease inhibitors: indinavir, saquinavir soft-gel, ritonavir, nelfinavir or amprenavir. Adults who met protocol-defined switch criteria at or after week 8 could modify their randomized therapy. Antiretroviral activity was assessed by the proportion of subjects with plasma HIV-1 RNA < or = 400 and < or = 50 copies/ml, and by changes in plasma HIV-1 RNA levels and CD4 cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities. RESULTS: At week 48, the proportion of subjects in the indinavir, saquinavir, ritonavir, nelfinavir and amprenavir groups with plasma HIV-1 RNA < or = 400 copies/ml was 53, 50, 50, 41 and 56%, respectively, and the proportion with HIV-1 RNA < or = 50 copies/ml was 47, 56, 50, 47, and 44%, respectively (by intent-to-treat analysis). Median reductions from baseline in plasma HIV-1 RNA for each group ranged from 1.7 to 2.4 log10 copies/ml. The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively. Overall, the most common adverse events attributed to study drugs were diarrhoea, nausea, malaise/fatigue, headache and perioral paresthesia. The frequency of treatment-limiting adverse events did not differ between groups. CONCLUSIONS: Abacavir is safe and effective when used in combination with a protease inhibitor.

Use of pairwise marker combination and recursive partitioning in a pharmacogenetic genome-wide scan.

The objective of pharmacogenetic research is to identify a genetic marker, or a set of genetic markers, that can predict how a given person will respond to a given medicine. To search for such marker combinations that are predictive of adverse drug events, we have developed and applied two complementary methods to a pharmacogenetic study of the hypersensitivity reaction (HSR) associated with treatment with abacavir, a medicine that is used to treat HIV-infected patients. Our results show that both of these methods can be used to uncover potentially useful predictive marker combinations. The pairwise marker combination method yielded a collection of marker pairs that featured a spectrum of sensitivities and specificities. Recursive partitioning results led to the genetic delineation of multiple risk categories, including those with extremely high and extremely low risk of HSR. These methods can be readily applied in pharmacogenetic candidate gene studies as well as in genome-wide scans.

CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis. An intravenous dose-escalation study.

OBJECTIVE: To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA). METHODS: Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H. RESULTS: There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks. CONCLUSION: CAMPATH-1H is a lymphocyte-depleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial.

CONTEXT: Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment. OBJECTIVE: To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen. DESIGN AND SETTING: A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe. PATIENTS: Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L. INTERVENTIONS: Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy. MAIN OUTCOME MEASURE: Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48. RESULTS: The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment. CONCLUSIONS: In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

A randomized, double-blind study of triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated human immunodeficiency virus type 1-infected children. The CNAA3006 Study Team.

OBJECTIVES: Abacavir (ABC) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We compared the efficacy, safety, and tolerability of combination therapy with ABC, lamivudine (3TC), and zidovudine (ZDV) versus 3TC and ZDV in antiretroviral experienced HIV-1-infected children over 48 weeks. METHODS: Two hundred five HIV-1-infected children who had received previous antiretroviral therapy and had CD4(+) cell counts >/=100 cells/mm(3) were stratified by age and by previous treatment. Participants were randomly assigned to receive ABC (8 mg/kg twice daily [BID]) plus 3TC (4 mg/kg BID) and ZDV (180 mg/m(2) BID; ABC/3TC/ZDV group) or ABC placebo plus 3TC (4 mg/kg BID) and ZDV (180 mg/m(2); 3TC/ZDV group). Participants who met a protocol-defined switch criteria (plasma HIV-1 RNA >0.5 log(10) copies/mL above baseline at week 8 or >10 000 copies/mL after week 16) had the option to switch to open-label ABC plus any antiretroviral combination or continue randomized therapy or withdraw from the study. RESULTS: The Kaplan-Meier estimates (95% confidence interval) of the proportion of participants who maintained HIV-1 RNA levels 10 000 copies/mL, a significantly higher proportion of participants in the ABC/3TC/ZDV group had HIV-1 RNA