Pharmacokinetics of Tacrolimus and Cyclosporine in Liver Transplant Recipients Receiving 3 Direct-Acting Antivirals as Treatment for Hepatitis C Infection.

Background: Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.

Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir.

Background & Aims: Paritaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.

Methods: Mechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin.

An interferon-free antiviral regimen for HCV after liver transplantation.

Background: Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection.

Methods: We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks.

Determination of viral tropism by genotyping and phenotyping assays in Brazilian HIV-1-infected patients.

The clinical application of CCR5 antagonists involves first determining the coreceptor usage by the infecting viral strain. Bioinformatics programs that predict coreceptor usage could provide an alternative method to screen candidates for treatment with CCR5 antagonists, particularly in countries with limited financial resources. Thus, the present study aims to identify the best approach using bioinformatics tools for determining HIV-1 coreceptor usage in clinical practice.

Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.

Background: The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis.

Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B).

CCR5 expression is reduced in lymph nodes of HIV type 1-infected women, compared with men, but does not mediate sex-based differences in viral loads.

Background: Human immunodeficiency virus type 1 (HIV-1)-infected women have lower viral loads than men but similar rates of disease progression. We hypothesized that sex-based differences in CCR5 expression mediate viral load differences.

Methods: CCR5 was analyzed by flow cytometry in disaggregated lymph node cells from untreated HIV-1-infected women (n = 28) and men (n = 27).

HIV-1 tropism testing in subjects achieving undetectable HIV-1 RNA: diagnostic accuracy, viral evolution and compartmentalization.

Background: Technically, HIV-1 tropism can be evaluated in plasma or peripheral blood mononuclear cells (PBMCs). However, only tropism testing of plasma HIV-1 has been validated as a tool to predict virological response to CCR5 antagonists in clinical trials. The preferable tropism testing strategy in subjects with undetectable HIV-1 viremia, in whom plasma tropism testing is not feasible, remains uncertain.

A case-based reasoning system for genotypic prediction of HIV-1 co-receptor tropism.

Accurate co-receptor tropism (CRT) determination is critical for making treatment decisions in HIV management. We created a genotypic tropism prediction tool by utilizing the case-based reasoning (CBR) technique that attempts to solve new problems through applying the solution from similar past problems. V3 loop sequences from 732 clinical samples with diverse characteristics were used to build a case library.

HIV Drug Resistance Profiles and Clinical Outcomes in Patients with Viremia Maintained at Very Low Levels.

We describe an observational study of clinical, virologic and drug resistance profiles in HIV-positive antiretroviral adherent subjects with stable low level viremia (LLV) 50-1,000 copies/mL for more than 12 months. Subjects were followed from time of first detectable viral load (VL). In total, 102 episodes of LLV were detected among 80 individuals.

Vicriviroc resistance decay and relative replicative fitness in HIV-1 clinical isolates under sequential drug selection pressures.

We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol.

Short communication: Phenotypic protease inhibitor resistance and cross-resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes.

To test tipranavir (TPV) or darunavir (DRV) as treatment options for patients with phenotypic resistance to protease inhibitors (PIs), including lopinavir, saquinavir, atazanavir, and fosamprenavir, the PhenoSense GT database was analyzed for susceptibility to DRV or TPV among PI-resistant isolates. The Monogram Biosciences HIV database (South San Francisco, CA) containing 7775 clinical isolates (2006-2008) not susceptible to at least one first-generation PI was analyzed. Phenotypic responses [resistant (R), partially susceptible (PS), or susceptible (S)] were defined by upper and lower clinical cut-offs to each PI.

HIV-1 clinical isolates resistant to CCR5 antagonists exhibit delayed entry kinetics that are corrected in the presence of drug.

HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C- and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC).

Transmitted drug resistance among antiretroviral-naive patients with established HIV type 1 infection in Santo Domingo, Dominican Republic and review of the Latin American and Caribbean literature.

Emergence of HIV resistance is a concerning consequence of global scale-up of antiretroviral therapy (ART). To date, there is no published information about HIV resistance from the Dominican Republic. The study's aim was to determine the prevalence of transmitted drug resistance (TDR) to reverse transcriptase and protease inhibitors in a sample of chronically HIV-1-infected patients in one clinic in Santo Domingo.

HLA-DR+ CD38+ CD4+ T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo.

Percentages of activated T cells correlate with HIV-1 disease progression, but the underlying mechanisms are not fully understood. We hypothesized that HLA-DR(+) CD38(+) (DR(+) 38(+)) CD4(+) T cells produce the majority of HIV-1 due to elevated expression of CCR5 and CXCR4. In phytohemagglutinin (PHA)-stimulated CD8-depleted peripheral blood mononuclear cells (PBMC) infected with HIV-1 green fluorescent protein (GFP) reporter viruses, DR(-) 38(+) T cells constituted the majority of CCR5 (R5)-tropic (median, 62%) and CXCR4 (X4)-tropic HIV-1-producing cells (median, 61%), although cell surface CCR5 and CXCR4 were not elevated in this subset of cells.

Detection of inferred CCR5- and CXCR4-using HIV-1 variants and evolutionary intermediates using ultra-deep pyrosequencing.

The emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants is associated with accelerated disease progression. CXCR4-using variants are believed to evolve from CCR5-using variants, but due to the extremely low frequency at which transitional intermediate variants are often present, the kinetics and mutational pathways involved in this process have been difficult to study and are therefore poorly understood. Here, we used ultra-deep sequencing of the V3 loop of the viral envelope in combination with the V3-based coreceptor prediction tools PSSM(NSI/SI) and geno2pheno([coreceptor]) to detect HIV-1 variants during the transition from CCR5- to CXCR4-usage.

Short communication prevalence of susceptibility to etravirine by genotype and phenotype in samples received for routine HIV type 1 resistance testing in the United States.

Abstract The prevalence of susceptibility to etravirine was investigated among clinical samples submitted for routine clinical testing in the United States using two separate weighted genotypic scoring systems. The presence of etravirine mutations and susceptibility to etravirine by phenotype of clinical samples from HIV-1-infected patients, submitted to Monogram Biosciences for routine resistance testing between June 2008 and June 2009, were analyzed. Susceptibility by genotype was determined using the Monogram and Tibotec etravirine-weighted genotypic scoring systems, with scores of ≤3 and ≤2, respectively, indicating full susceptibility.

Connection domain mutations in HIV-1 reverse transcriptase do not impact etravirine susceptibility and virologic responses to etravirine-containing regimens.

Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on susceptibility and virologic responses to etravirine were analyzed. Seventeen CDMs were evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, and E399G.

Reanalysis of coreceptor tropism in HIV-1-infected adults using a phenotypic assay with enhanced sensitivity.

The enhanced-sensitivity Trofile assay (TF-ES; Monogram Biosciences) was used to retest coreceptor tropism samples from 4 different cohorts of HIV-1-infected patients. Nine percent to 26% of patients with CCR5-tropic virus by the original Trofile assay had CXCR4-using virus by TF-ES. Lower CD4 cell counts were associated with CXCR4-using virus in all cohorts.

Combined antiretroviral therapy and immune pressure lead to in vivo HIV-1 recombination with ancestral viral genomes.

Background: Studies on drug interruption have provided new insights on the adaptive evolution of rebounding HIV-1 during antiretroviral pressure. We investigated the origin of new viral variants after discontinuation of protease (PR) inhibitors as a treatment remained exclusively based on reverse transcriptase inhibitors, and whether drug susceptibility, viral fitness, and neutralizing antibodies could be major driving forces for the evolution of virus populations.

Methods: The study comprised 3 treatment-experienced subjects.

Differences in reversion of resistance mutations to wild-type under structured treatment interruption and related increase in replication capacity.

Background: The CPCRA 064 study examined the effect of structured treatment interruption (STI) of up to 4 months followed by salvage treatment in patients failing therapy with multi-drug resistant HIV. We examined the relationship between the reversion rate of major reverse transcriptase (RT) resistance-associated mutations and change in viral replication capacity (RC). The dataset included 90 patients with RC and genotypic data from virus samples collected at 0 (baseline), 2 and 4 months of STI.

Three-year safety and efficacy of vicriviroc, a CCR5 antagonist, in HIV-1-infected treatment-experienced patients.

Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity.

Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14.

Comparison of standard PCR/cloning to single genome sequencing for analysis of HIV-1 populations.

To compare standard PCR/cloning and single genome sequencing (SGS) in their ability to reflect actual intra-patient polymorphism of HIV-1 populations, a total of 530 HIV-1 pro-pol sequences obtained by both sequencing techniques from a set of 17 ART naïve patient specimens was analyzed. For each specimen, 12 and 15 sequences, on average, were characterized by the two techniques. Using phylogenetic analysis, tests for panmixia and entropy, and Bland-Altman plots, no difference in population structure or genetic diversity was shown in 14 of the 17 subjects.

Susceptibility of HIV-1 to tipranavir and other antiretroviral agents in treatment-experienced patients: The UTILIZE Study.

Objectives: The primary objective was to assess HIV-1 susceptibility to the protease inhibitor (PI) tipranavir and other antiretroviral (ARV) agents among treatment-experienced patients (TEP). Secondarily, clinicians' use of resistance testing was examined.

Methods: UTILIZE was an observational study conducted at 40 sites in the United States.

Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection.

Background: The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection.

Methods: Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed.