Incidence of CXCR4 tropism and CCR5-tropic resistance in treatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1 and 2 trials.

Unlabelled: Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interaction between viral gp120 and cell-surface CCR5. Resistance to CCR5 antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-using virus or through selection of CCR5-tropic resistant virus, characterized by plateaus in maximum percent inhibition <95%. Here, we examine viral escape in maraviroc-treated participants during virologic failure through Week 48 in the MOTIVATE 1 and 2 trials.

First prospective comparison of genotypic versus phenotypic tropism assays in predicting virologic responses to maraviroc in a phase 3 study.

Maraviroc (MVC, a CCR5 antagonist) is only fully active against CCR5 tropic [R5] HIV-1, and tropism testing is required prior to initiating treatment. The MODERN study prospectively compared genotypic (GTT) and phenotypic (Trofile®) tropism testing with treatment-naive HIV-1-infected participants randomized 1:1 to either GTT or Trofile tropism assessments. Participants with R5 virus were randomized 1:1 to receive darunavir/ritonavir (DRV/r) with either MVC or tenofovir/emtricitabine.

Clonal analysis of HIV-1 genotype and function associated with virologic failure in treatment-experienced persons receiving maraviroc: Results from the MOTIVATE phase 3 randomized, placebo-controlled trials.

Detailed clonal phenotypic/genotypic analyses explored viral-escape mechanisms during maraviroc-based therapy in highly treatment-experienced participants from the MOTIVATE trials. To allow real-time assessment of samples while maintaining a blind trial, the first 267 enrolled participants were selected for evaluation. At failure, plasma samples from 20/50 participants (16/20 maraviroc-treated) with CXCR4-using virus and all 38 (13 maraviroc-treated) with CCR5-tropic virus were evaluated.

Analysis of Clinical HIV-1 Strains with Resistance to Maraviroc Reveals Strain-Specific Resistance Mutations, Variable Degrees of Resistance, and Minimal Cross-Resistance to Other CCR5 Antagonists.

Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients.

Social support and support groups among people with HIV/AIDS in Ghana.

HIV/AIDS, a chronic burden in Ghana, poses social and health outcome concerns to those infected. Examining the Medical Outcome Study Social Support Survey (MOS-SSS) instrument among 300 Ghanaians from a cross-sectional design, Principal Component Analysis yielded four factors (positive interaction, trust building, information giving, and essential support), which accounted for 85.73% of the total variance in the MOS-SSS.

Characterizing the Diverse Mutational Pathways Associated with R5-Tropic Maraviroc Resistance: HIV-1 That Uses the Drug-Bound CCR5 Coreceptor.

Unlabelled: Entry inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, CCR5, an HIV-1 entry coreceptor, and not viral protein. Lack of sensitivity can occur due to preexisting virus that uses the CXCR4 coreceptor, while true resistance occurs through viral adaptation to use a drug-bound CCR5 coreceptor. To understand this R5 resistance pathway, we analyzed >500 envelope protein sequences and phenotypes from viruses of 20 patients from the clinical trials MOTIVATE 1 and 2, in which treatment-experienced patients received maraviroc plus optimized background therapy.

Genotypic analysis of the V3 region of HIV from virologic nonresponders to maraviroc-containing regimens reveals distinct patterns of failure.

Changes in HIV tropism from R5 to non-R5 or development of drug resistance is often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials.

Correlation between genotypic (V3 population sequencing) and phenotypic (Trofile ES) methods of characterizing co-receptor usage of HIV-1 from 200 treatment-naïve HIV patients screened for Study A4001078.

Assessment of HIV-1 co-receptor usage is essential to identify patients who are likely to respond to maraviroc (MVC)-containing regimens. Co-receptor usage of plasma virus from all treatment-naïve patients screened for a MVC clinical trial was assessed using phenotypic and genotypic methodologies to evaluate concordance between testing methods and to assess the quantity of CXCR4-using (non-R5) virus in samples giving discordant results. Co-receptor usage was prospectively measured using the enhanced sensitivity Trofile assay (Trofile ES) to screen patients for enrollment in Study A4001078.

Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial.

Background: MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing.

Methods: HIV env V3-loop was amplified in triplicate using reverse transcriptase-polymerase chain reaction from stored screening plasma and sequenced.

Characterization of resistance to the nonnucleoside NS5B inhibitor filibuvir in hepatitis C virus-infected patients.

Filibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV-infected individuals receiving filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon filibuvir dosing.

An integrated transcriptomic and meta-analysis of hepatoma cells reveals factors that influence susceptibility to HCV infection.

Hepatitis C virus (HCV) is a global problem. To better understand HCV infection researchers employ in vitro HCV cell-culture (HCVcc) systems that use Huh-7 derived hepatoma cells that are particularly permissive to HCV infection. A variety of hyper-permissive cells have been subcloned for this purpose.

Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc.

Background: Deep sequencing is a highly sensitive technique that can detect and quantify the proportion of non-R5 human immunodeficiency virus (HIV) variants, including small minorities, that may emerge and cause virologic failure in patients who receive maraviroc-containing regimens. We retrospectively tested the ability of deep sequencing to predict response to a maraviroc-containing regimen in the Maraviroc versus Efavirenz in Treatment-Naive Patients (MERIT) trial. Results were compared with those obtained using the Enhanced Sensitivity Trofile Assay (ESTA), which is widely used in clinical practice.

Baseline CD4(+) T-cell counts and weighted background susceptibility scores strongly predict response to maraviroc regimens in treatment-experienced patients.

Background: Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies.

Methods: Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information.

Mutations in gp41 are correlated with coreceptor tropism but do not improve prediction methods substantially.

Background: The main determinants of HIV-1 coreceptor usage are located in the V3-loop of gp120, although mutations in V2 and gp41 are also known. Incorporation of V2 is known to improve prediction algorithms; however, this has not been confirmed for gp41 mutations.

Methods: Samples with V3 and gp41 genotypes and Trofile assay (Monogram Biosciences, South San Francisco, CA, USA) results were taken from the HOMER cohort (n=444) and from patients screened for the MOTIVATE studies (n=1,916; 859 with maraviroc outcome data).

Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients.

Background: The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies compared maraviroc versus placebo in treatment-experienced patients with CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1), screened using the original Trofile assay. A subset with non-R5 HIV infection entered the A4001029 trial. We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials.

The evolutionary analysis of emerging low frequency HIV-1 CXCR4 using variants through time--an ultra-deep approach.

Large-scale parallel pyrosequencing produces unprecedented quantities of sequence data. However, when generated from viral populations current mapping software is inadequate for dealing with the high levels of variation present, resulting in the potential for biased data loss. In order to apply the 454 Life Sciences' pyrosequencing system to the study of viral populations, we have developed software for the processing of highly variable sequence data.

Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies.

Background: The MOTIVATE-1 and 2 studies compared maraviroc (MVC) along with optimized background therapy (OBT) vs. placebo along with OBT in treatment-experienced patients screened as having R5-HIV (original Monogram Trofile). A subset screened with non-R5 HIV were treated with MVC or placebo along with OBT in a sister safety trial, A4001029.

Group-based randomized trial of contingencies for health and abstinence in HIV patients.

Objective: Contingency management (CM) treatments are usually applied individually for drug abstinence, but CM can also be targeted toward health behaviors and implemented in groups. This study evaluated effects of a group-based CM intervention that focused on reinforcing health behaviors.

Method: HIV-positive patients with cocaine or opioid use disorders (n = 170) were randomized to weekly CM or 12-step (TS) groups for 24 weeks (mean attendance was 10.

Detection of low-frequency pretherapy chemokine (CXC motif) receptor 4 (CXCR4)-using HIV-1 with ultra-deep pyrosequencing.

Objective: Identification of low-frequency variants is of clinical importance in the identification of preexisting drug resistance. Using 'ultra-deep' sequencing, we address the detection of potential resistance to the chemokine (C-C motif) receptor 5 (CCR5) antagonist, maraviroc, due to the pretreatment presence of low levels of chemokine (CXC motif) receptor 4 (CXCR4)-using virus.

Methods: We present a novel protocol for the phenotyping of HIV based on '454' pyrosequence data and apply this to two large data sets comprised of 104 628 (before treatment, day 1) and 191 637 (after treatment, day 11) reads from the envelope region.

Cocaine-exposed infant behavior during Still-Face: risk factor analyses.

Prenatal cocaine exposure and the role of gender were evaluated using risk factor analyses to determine whether 6-month-old cocaine-exposed male infants demonstrated greater disruptions in infant-caregiver socioemotional interactions during a Still-Face test. Overall, non-cocaine-exposed infants spent more time looking at toys, compared with cocaine-exposed infants; nonexposed female infants spent more time scanning the environment, compared with nonexposed male infants. When caregiver behavior during the Still-Face was evaluated, differences emerged in amount of time the caregiver spent vocalizing to the infant.

Participation in religious activities during contingency management interventions is associated with substance use treatment outcomes.

Many drug abuse treatment programs encourage participation in religious activities, yet there is scant research regarding their effectiveness. Contingency management (CM) interventions sometimes reinforce the completion of non-drug related activities, and church attendance is a popular activity. Cocaine abusers (n = 184) randomized to CM interventions were categorized based on whether or not they engaged in three or more religious activities.

Subjective effect of September 11, 2001 among pregnant women: is cumulative history of interpersonal violence important?

Prior history of trauma may sensitize individuals to subsequent trauma, including terrorist attacks. Using a convenience sample of secondary, cross-sectional data, pregnant women were grouped based on lifetime interpersonal violence history. Cumulative risk theory was used to evaluate the association of lifetime interpersonal violence history and subjective impact of the September 11, 2001 (9/11) terrorists attacks.

Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry.

Maraviroc is a CCR5 antagonist in clinical development as one of a new class of antiretrovirals targeting human immunodeficiency virus type 1 (HIV-1) coreceptor binding. We investigated the mechanism of HIV resistance to maraviroc by using in vitro sequential passage and site-directed mutagenesis. Serial passage through increasing maraviroc concentrations failed to select maraviroc-resistant variants from some laboratory-adapted and clinical isolates of HIV-1.

Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir.

Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result.

Relationship between custodial status and psychosocial problems among cocaine-abusing parents initiating substance abuse treatment.

Using the Addiction Severity Index and Brief Symptom Inventory, drug use and psychosocial problems are compared between 93 custodial and 125 non-custodial mothers and fathers initiating outpatient treatment for cocaine dependence. Compared to non-custodial parents, custodial parents experienced more severe current cocaine and alcohol problems, including spending more money on cocaine and alcohol, as well as using more cocaine and being intoxicated on more days. Non-custodial parents demonstrated more psychological distress, more prior history of alcohol problems, and greater current employment and legal problems than custodial parents.