A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection.

ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were -2.72 to -2.78 log10  IU/ml with ATI-2173 and +0.17 log10  IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies.

Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens.

Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.

ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens.

ATI-2173 is a novel liver-targeted molecule designed to deliver the 5'-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5'-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5'-phosphoramidate to deliver the 5'-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5'-monophosphate is converted to the active 5'-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5'-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5'-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5'-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.

Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial.

BACKGROUND: Three perioperative factors impair host defence against recurrence during cancer surgery: the surgical stress response, use of volatile anaesthetic, and opioids for analgesia. All factors are ameliorated by regional anaesthesia-analgesia. We tested the primary hypothesis that breast cancer recurrence after potentially curative surgery is lower with regional anaesthesia-analgesia using paravertebral blocks and the anaesthetic propofol than with general anaesthesia with the volatile anaesthetic sevoflurane and opioid analgesia. A second hypothesis was that regional anaesthesia-analgesia reduces persistent incisional pain. METHODS: We did a randomised controlled trial at 13 hospitals in Argentina, Austria, China, Germany, Ireland, New Zealand, Singapore, and the USA. Women (age <85 years) having potentially curative primary breast cancer resections were randomised by computer to either regional anaesthesia-analgesia (paravertebral blocks and propofol) or general anaesthesia (sevoflurane) and opioid analgesia. The primary outcome was local or metastatic breast cancer recurrence. The secondary outcome was incisional pain at 6 months and 12 months. Primary analyses were done under intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT00418457. The study was stopped after a preplanned futility boundary was crossed. FINDINGS: Between Jan 30, 2007, and Jan 18, 2018, 2132 women were enrolled to the study, of whom 24 were excluded before surgery. 1043 were assigned to regional anaesthesia-analgesia and 1065 were allocated to general anaesthesia. Baseline characteristics were well balanced between study groups. Median follow-up was 36 (IQR 24-49) months. Among women assigned regional anaesthesia-analgesia, 102 (10%) recurrences were reported, compared with 111 (10%) recurrences among those allocated general anaesthesia (hazard ratio 0·97, 95% CI 0·74-1·28; p=0·84). Incisional pain was reported by 442 (52%) of 856 patients assigned to regional anaesthesia-analgesia and 456 (52%) of 872 patients allocated to general anaesthesia at 6 months, and by 239 (28%) of 854 patients and 232 (27%) of 852 patients, respectively, at 12 months (overall interim-adjusted odds ratio 1·00, 95% CI 0·85-1·17; p=0·99). Neuropathic breast pain did not differ by anaesthetic technique and was reported by 87 (10%) of 859 patients assigned to regional anaesthesia-analgesia and 89 (10%) of 870 patients allocated to general anaesthesia at 6 months, and by 57 (7%) of 857 patients and 57 (7%) of 854 patients, respectively, at 12 months. INTERPRETATION: In our study population, regional anaesthesia-analgesia (paravertebral block and propofol) did not reduce breast cancer recurrence after potentially curative surgery compared with volatile anaesthesia (sevoflurane) and opioids. The frequency and severity of persistent incisional breast pain was unaffected by anaesthetic technique. Clinicians can use regional or general anaesthesia with respect to breast cancer recurrence and persistent incisional pain. FUNDING: Sisk Healthcare Foundation (Ireland), Eccles Breast Cancer Research Fund, British Journal of Anaesthesia International, College of Anaesthetists of Ireland, Peking Union Medical College Hospital, Science Fund for Junior Faculty 2016, Central Bank of Austria, and National Healthcare Group.

Ebola virus disease: an update on post-exposure prophylaxis.

The massive outbreak of Ebola virus disease in west Africa between 2013 and 2016 resulted in intense efforts to evaluate the efficacy of several specific countermeasures developed through years of preclinical work, including the first clinical trials for therapeutics and vaccines. In this Review, we discuss how the experience and data generated from that outbreak have helped to advance the understanding of the use of these countermeasures for post-exposure prophylaxis against Ebola virus infection. In future outbreaks, post-exposure prophylaxis could play an important part in reducing community transmission of Ebola virus by providing more immediate protection than does immunisation as well as providing additional protection for health-care workers who are inadvertently exposed over the course of their work. We propose provisional guidance for use of post-exposure prophylaxis in Ebola virus disease and identify the priorities for future preparedness and further research.

A Randomized Trial of a Supplemental Alarm for Critically Low Systolic Blood Pressure.

BACKGROUND: Intraoperative hypotension is associated with complications that might be ameliorated by earlier intervention. We therefore tested the primary hypothesis that a supplemental decision support alert for critically low systolic blood pressure (SBP) decreases the duration of intraoperative hypotension. METHODS: We enrolled adults having surgery and anesthetized by attending anesthesiologists or nurse anesthetists under attending supervision. When invasive SBP <80 mmHg was detected for 3 consecutive minutes or any oscillometric SBP <80 mmHg, patients were randomly assigned to routine management or a visual alert and pager notification. Clinicians who received alerts were free to act on the alert or not. The primary outcome was time to return to SBP ≥ 80 mmHg. Secondary outcomes were time until SBP remained ≥ 80 mmHg for at least 10 minutes and the duration of hospitalization. RESULTS: One thousand five hundred ninety-eight patients were randomly assigned to the hypotension alerts and 1567 to no alerts. Randomized groups did not differ on time to return to SBP ≥ 80 mmHg after the first alert, with estimated adjusted hazard ratio of 0.99 (95% confidence interval, 0.92-1.06; P = 0.69). The median time [quartiles] to return to SBP ≥ 80 mmHg was 1 [0, 3] minutes in each group and 1 [0, 3] minutes in the nonalert group (P = 0.69). Hospital length of stay was also similar, with the median [quartiles] lengths of stay being 2 [1, 4] days in the alert group and 2 [1,5] in the nonalert group (P = 0.35). CONCLUSIONS: An additional warning for severe hypotension did not reduce the duration of hypotension or hospitalization. Decision support alerts may be more useful for more complicated situations.

A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4.

BACKGROUND & AIMS: Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4. METHODS: Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3days placebo or samatasvir 25-100mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10. RESULTS: Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3), and 3.6-3.9 (genotype 4) log10/ml respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/ml), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20h which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms. CONCLUSIONS: Samatasvir 25-100mg monotherapy for 3days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.

Current status of chemically synthesized inhibitors of Ebola virus.

The current Ebola virus outbreak is unprecedented in its scope and international impact. Given that there are currently no approved antivirals to treat Ebola virus, there is urgency to conduct more rapid development and evaluation of Ebola antivirals. Recently, the World Health Organization identified a number of antivirals as high priority to include AVI-6002 (AVI-7537 and AVI-7539), BCX4430, brincidofovir, favipiravir, and TKM-100802. This review describes these chemically synthesized inhibitors of Ebola virus, relevant patent development and gives an update on their current status.

IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C.

BACKGROUND: IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase. METHODS: This randomized, double-blind, placebo-controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-α2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA≥5 log10 IU/ml, alanine aminotransferase ≤3× upper limit of normal and compensated liver disease were dosed. Sequential cohorts of 20 patients, randomized 16:4 (active:placebo), received IDX184 for 14 days at rising daily doses of 50, 100, 150 or 200 mg in combination with P/R for 14 days. RESULTS: At the end of triple dosing, HCV RNA changes from baseline (mean ±sd log10) and proportion of patients achieving undetectable viral load (<15 IU/ml) based on the efficacy-evaluable population were -2.7 ±1.3 (13%), -4.0 ±1.7 (50%), -4.2 ±1.9 (50%), -4.1 ±1.2 (40%), -4.3 ±1.5 (29%) and -3.7 ±1.2 (25%) for the 50 mg once daily, 50 mg twice daily, 100 mg once daily, 150 mg once daily, 100 mg twice daily and 200 mg once daily IDX184 doses, respectively. P/R alone resulted in a reduction of -1.5 ±1.3 log10 with only 6% of patients with undetectable viral load. Patients with genotypes-1a or -1b responded similarly. No viral breakthrough or resistance associated with IDX184 was observed. Anti-HCV activity of IDX184 correlated with plasma exposure of its nucleoside metabolite 2'-methylguanosine. Most adverse events were mild or moderate in severity and were consistent with those associated with P/R. The most common adverse events were fatigue and headache. CONCLUSIONS: IDX184 in combination with P/R for 14 days was well tolerated and demonstrated greater antiviral activity with more patients achieving undetectable viral load than P/R.

Short-term monotherapy with IDX184, a liver-targeted nucleotide polymerase inhibitor, in patients with chronic hepatitis C virus infection.

IDX184 is a liver-targeted prodrug of 2'-methylguanosine (2'-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log(10) IU/ml, alanine aminotransferase (ALT) ≤ 2.5× the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184- and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ± standard deviations) were -0.5 ± 0.6, -0.7 ± 0.2, -0.6 ± 0.3, and -0.7 ± 0.5 log(10) for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (-0.05 ± 0.3 log(10)). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses ≥ 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2'-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2'-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate.

Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.

BACKGROUND: The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease. METHODS: This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8). RESULTS: In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group. CONCLUSIONS: Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor.

AIM: To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection. METHODS: A series of phase I drug interaction studies was conducted. RESULTS: GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings. CONCLUSIONS: These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.

Recombination between variants from genital tract and plasma: evolution of multidrug-resistant HIV type 1.

Multidrug-resistant (MDR) HIV-1 presents a challenge to the efficacy of antiretroviral therapy (ART). To examine mechanisms leading to MDR variants in infected individuals, we studied recombination between single viral genomes from the genital tract and plasma of a woman initiating ART. We determined HIV-1 RNA sequences and drug resistance profiles of 159 unique viral variants obtained before ART and semiannually for 4 years thereafter. Soon after initiating zidovudine, lamivudine, and nevirapine, resistant variants and intrapatient HIV-1 recombinants were detected in both compartments; the recombinants had inherited genetic material from both genital and plasma-derived viruses. Twenty-three unique recombinants were documented during 4 years of therapy, comprising ~22% of variants. Most recombinant genomes displayed similar breakpoints and clustered phylogenetically, suggesting evolution from common ancestors. Longitudinal analysis demonstrated that MDR recombinants were common and persistent, demonstrating that recombination, in addition to point mutation, can contribute to the evolution of MDR HIV-1 in viremic individuals.

Short-course Combivir after single-dose nevirapine reduces but does not eliminate the emergence of nevirapine resistance in women.

BACKGROUND: In the Treatment Options Preservation Study (TOPS) trial, 4 or 7 days of Combivir (CBV; zidovudine/lamivudine) with maternal single-dose nevirapine (sdNVP) significantly reduced the emergence of NVP resistance as determined by virus population genotyping. To detect NVP resistance with greater sensitivity, we analysed TOPS samples by allele-specific real-time PCR (ASP). METHODS: In a random subset of women from each arm of the trial, plasma samples from before and 6 weeks after sdNVP were analysed using ASP at codons 103, 181, 184 and 190. RESULTS: Samples were analysed from 27 women in the sdNVP arm and 24 each in the CBV 4-day (sdNVP/CBV4) and 7-day (sdNVP/CBV7) arms. ASP detected NVP-resistant variants in week 6 samples from 70% of women in the sdNVP arm, 29% in the sdNVP/CBV4 arm and 33% in sdNVP/CBV7 arm (P<0.01 for sdNVP/CBV4 or sdNVP/CBV7 versus sdNVP; P=1.0 for sdNVP/CBV4 versus sdNVP/CBV7). Lamivudine resistance was detected by ASP in only 1 of 51 women who received CBV. CONCLUSIONS: Short-course CBV significantly reduced but did not eliminate the emergence of NVP resistance after sdNVP. NVP-resistant variants were detected in about one-third of women despite CBV treatment, but the duration of persistence and clinical impact of these variants in response to antiretroviral therapy is uncertain.

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in healthy subjects.

IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2'-methylguanosine (2'-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t(1/2)) of approximately 1 h, while plasma concentrations of 2'-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2'-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2'-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng·h/ml. Mean 2'-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25- to 100-mg doses. Mean 2'-MeG t(1/2) values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2'-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.

Evolution and recombination of genes encoding HIV-1 drug resistance and tropism during antiretroviral therapy.

Characterization of residual plasma virus during antiretroviral therapy (ART) is a high priority to improve understanding of HIV-1 pathogenesis and therapy. To understand the evolution of HIV-1 pol and env genes in viremic patients under selective pressure of ART, we performed longitudinal analyses of plasma-derived pol and env sequences from single HIV-1 genomes. We tested the hypotheses that drug resistance in pol was unrelated to changes in coreceptor usage (tropism), and that recombination played a role in evolution of viral strains. Recombinants were identified by using Bayesian and other computational methods. High-level genotypic resistance was seen in approximately 70% of X4 and R5 strains during ART. There was no significant association between resistance and tropism. Each patient displayed at least one recombinant encompassing env and representing a change in predicted tropism. These data suggest that, in addition to mutation, recombination can play a significant role in shaping HIV-1 evolution.

Optimization of allele-specific PCR using patient-specific HIV consensus sequences for primer design.

Allele-specific PCR based on subtype consensus sequences is a powerful technique for detecting low frequency drug resistant mutants in HIV-1 infected patients. However, this approach can be limited by genetic variation in the region complementary to the primers, leading to variability in allele detection. The goals of this study were to quantify this effect and then to improve assay performance.

Absence of effect of telbivudine on cardiac repolarization: results of a thorough QT/QTc study in healthy participants.

The effect of telbivudine on cardiac repolarization was evaluated in healthy participants at clinical and supratherapeutic doses. Sixty-two participants were enrolled, stratified by sex, and randomized according to a crossover design among 4 treatment sequences: placebo, a single moxifloxacin 400-mg dose as positive calibrator, and telbivudine 600 and 1800 mg/d for 7 days. Intensive time-matched electrocardiogram measurements and pharmacokinetic sampling were performed at baseline and on day 7 over 24 hours. For telbivudine and moxifloxacin, time-matched, placebo-adjusted change from baseline in QT was calculated and corrected using Fridericia's formula (QTcF). While moxifloxacin produced the expected significant changes in QTcF, none of the changes in QTcF for either doses of telbivudine exceeded 5 ms, and none of the associated upper 1-sided 95% confidence intervals (CI) exceeded the limit of 10 ms. There was no increase in QTcF with increasing plasma telbivudine. The supratherapeutic dose of telbivudine was well tolerated with a safety profile similar to the clinical dose despite a 3-fold increase in plasma exposure. This study therefore met the criteria for a negative thorough QT study. Telbivudine had no adverse effect on cardiac repolarization in healthy participants, even at supratherapeutic exposure, suggesting a broad safety margin.

Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial.

BACKGROUND: Single-dose nevirapine (sdNVP)-which prevents mother-to-child transmission of HIV-selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care. METHODS AND FINDINGS: sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1ratio1ratio1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit. CONCLUSIONS: A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms. TRIAL REGISTRATION: www.ClinicalTrials.govNCT 00144183.