Efficacy and safety of long-term maraviroc use in a heterogeneous group of HIV-infected patients: A retrospective cohort study.

Since the registration of maraviroc (MVC) as an antiretroviral agent in 2008, only studies with a follow-up time of <5 years have been published. Therefore, little is known about its long-term safety and efficacy in clinical practice. In this cohort study, data on long-term follow-up of MVC treatment in routine practice were analysed. A retrospective cohort study was conducted at University Medical Centre Utrecht with a follow-up period up to almost 10 years. The efficacy and tolerability of MVC-containing antiretroviral therapy (ART) was analysed in human immunodeficiency virus type 1 (HIV-1)-infected patients. The cohort consisted of 111 HIV patients who were treated for a median of 11.0 years (IQR 4.0-15.0 years) and with a median of 4 (IQR 2-6) previous ART regimens. The median time of MVC use was 49 months (IQR 21-82 months). Mean CD4+ T-cell counts continued to increase up to 9 years following initiation of MVC. Patients with a detectable viral load (≥50 copies/mL HIV-RNA) at the start of MVC-containing ART reached high proportions of viral suppression. Only three patients (2.7%) experienced treatment failure despite optimal therapy. Nine patients (8.1%) discontinued MVC owing to intolerance of their ART regimen. Severe laboratory abnormalities were deemed to be unrelated to MVC use. During the 487 person-years of follow-up, 18 patients (16.2%) died. MVC use in this heavily pre-treated cohort was generally well tolerated during long-term follow-up. Furthermore, use of MVC resulted in a good immunological and virological response in clinical practice.

Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1.

BACKGROUND: Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4. METHODS: In this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (day 7) to day 14. RESULTS: A total of 31 patients completed the study. The mean baseline viral load was 4.5 log10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (P<0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy. CONCLUSIONS: In patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629 .).

Seguridad hepática de maraviroc en pacientes coinfectados con VIH y hepatitis C y/o B / Hepatic safety of maraviroc in HIV-1-infected patients with hepatitis C and/or B co-infection

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PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection.

Background PRO 140 is a humanized monoclonal antibody targeting CCR5 with potent antiviral activity in patients with CCR5-tropic HIV-1 infection. In phase 2b studies, we evaluated the long-term efficacy, safety, and tolerability of PRO 140 monotherapy in maintaining viral suppression for over 24 months in patients who were stable on combination antiretroviral therapy on entry into the trials. Methods and Results Forty-one adult patients, infected exclusively with CCR5-tropic HIV-1 with viral loads <50 copies/mL, were switched from daily oral combination ART regimens to weekly PRO 140 monotherapy for 12 weeks. Participants who completed 12 weeks of treatment without experiencing virologic rebound were allowed to self-administer PRO 140 as a 350 mg subcutaneous injection weekly, for up to an additional 160 weeks. Participants were monitored bi-weekly for one year, and every four weeks thereafter for virologic rebound. PRO 140 provided virologic suppression in 23/41 (56.1%) participants for 12 weeks and was well tolerated. Ten (10) participants are currently ongoing, of which nine participants have completed more than two years of monotherapy treatment (47-129 weeks). Participants experiencing virologic rebound achieved full viral suppression upon re-initiation of oral combination ART regimen. Anti-PRO 140 antibodies were not detected in any patient, and no drug-related major adverse events or treatment discontinuations were reported. Conclusions PRO 140 has a potential to address an unmet need for a long-acting, single-agent, maintenance regimen for HIV infection in selected patients. Studies are underway to determine host and/or virologic factors that may predict treatment success on PRO 140 monotherapy. Moreover, it has sufficient potency for a prolonged period of monotherapy that it would be an excellent component of a multi long-acting drug combination.

O-GalNAcylation of RANTES Improves Its Properties as a Human Immunodeficiency Virus Type 1 Entry Inhibitor.

Many human proteins have the potential to be developed as therapeutic agents. However, side effects caused by direct administration of natural proteins have significantly slowed expansion of protein therapeutics into the clinic. Post-translational modifications (PTMs) can improve protein properties, but because of significant knowledge gaps, we are considerably limited in our ability to apply PTMs to generate better protein therapeutics. Here, we seek to fill the gaps by studying the PTMs of a small representative chemotactic cytokine, RANTES. RANTES can inhibit HIV-1 infection by competing with it for binding to receptor CCR5 and stimulating CCR5 endocytosis. Unfortunately, RANTES can induce strong signaling, leading to severe inflammatory side effects. We apply a chemical biology approach to explore the potential of post-translationally modified RANTES as safe inhibitors of HIV-1 infection. We synthesized and systematically tested a library of RANTES isoforms for their ability to inhibit inflammatory signaling and prevent HIV-1 infection of primary human cells. Through this research, we revealed that most of the glycosylated variants have decreased inflammation-associated properties and identified one particular glyco variant, a truncated RANTES containing a Galß1-3GalNAc disaccharide α-linked to Ser4, which stands out as having the best overall properties: relatively high HIV-1 inhibition potency but also weak inflammatory properties. Moreover, our results provided a structural basis for the observed changes in the properties of RANTES. Taken together, this work highlights the potential importance of glycosylation as an alternative strategy for developing CCR5 inhibitors to treat HIV-1 infection and, more generally, for reducing or eliminating unwanted properties of therapeutic proteins.

Pharmacokinetics, Safety and Efficacy of Maraviroc in Treatment-experienced Pediatric Patients Infected With CCR5-Tropic HIV-1.

BACKGROUND: Maraviroc is a CC-chemokine receptor 5 antagonist approved to treat adults infected with CC-chemokine receptor 5-tropic (R5) HIV-1. Study A4001031 was conducted to evaluate the pharmacokinetics, safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced pediatric patients infected with R5 HIV-1 and support registration of maraviroc for pediatric use. METHODS: This is an open-label, 2-stage, age-stratified, noncomparative multicenter study. One-hundred and three participants were enrolled into 4 age/formulation cohorts and dosed twice daily. Initial doses were determined by body surface area and optimized background therapy, based on drug interactions with maraviroc in adults. Dose adjustment and pharmacokinetic reevaluation occurred if the average concentrations (Cavg) at Week 2 were <100 ng/mL (Stage 1-dose finding). RESULTS: Data from the Week 48 analysis demonstrated that 49/50 Stage 1 participants rolling over into Stage 2 (safety and efficacy) achieved Cavg ≥100 ng/mL. Doses were identified that achieved similar concentration ranges to those seen in adults. The majority (90/103) received optimized background therapy containing potent cytochrome P450 3A inhibitors. Maraviroc was well tolerated and the safety and efficacy were comparable to those of adults. All cohorts had a mean decrease from baseline in HIV-1 RNA of >1 log10. Increases from baseline in the median CD4+ cell count and percentage were seen for all age groups. CONCLUSIONS: The maraviroc dosing strategy resulted in participants achieving the target Cavg, with exposure ranges similar to those observed in adults on approved doses. The safety and efficacy of maraviroc in this pediatric population were comparable to those seen in adults.

Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial.

BACKGROUND: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP). OBJECTIVE: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection. DESIGN: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114). SETTING: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days. INTERVENTION: MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control). MEASUREMENTS: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment. RESULTS: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred. LIMITATIONS: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy. CONCLUSION: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Hepatic safety of maraviroc in patients with HIV-1 and hepatitis C and/or B virus: 144-week results from a randomized, placebo-controlled trial.

BACKGROUND: In the primary 48-week analysis of a hepatic safety trial in patients with HIV-1 coinfected with HBV and/or HCV, maraviroc-containing treatment regimens were not associated with increased hepatotoxicity. METHODS: In this randomized, double-blind, placebo-controlled, multicentre study, patients received maraviroc twice daily (n=70) or placebo (n=67) with concomitant antiretroviral therapy for 144 weeks (Clinicaltrials.gov identifier, NCT01327547). The primary end point was the proportion of patients with protocol-defined Grade 3/4 alanine aminotransferase (ALT) abnormalities through week 48. Key secondary end points included 144-week analysis of Grade 3/4 ALT abnormalities and liver fibrosis by enhanced liver fibrosis (ELF) testing, hepatic elastography and an optional biopsy substudy. RESULTS: Through 144 weeks of treatment, two (maraviroc) and three (placebo) patients met the protocol-defined Grade 3/4 ALT end point. Similar to the 48-week results, there were no statistically significant differences between groups in change from baseline in ELF or hepatic elastography. However, decreased elastography scores were noted in the maraviroc group. Blinded pathologist review suggested that 2 of 11 paired biopsies (both on maraviroc) showed signs of decreased fibrosis. One (maraviroc) and two (placebo) patients experienced treatment-related hepatobiliary adverse events (AEs). Five patients in the maraviroc group discontinued because of treatment-related AEs versus three in the placebo group. One death in the maraviroc group and two deaths in the placebo group were reported. CONCLUSIONS: Use of maraviroc did not increase hepatotoxicity in this population through 144 weeks. Further investigation regarding possible beneficial effects of maraviroc on liver fibrosis may be warranted.

Incidence and risk factors for liver enzymes elevations in highly treatment-experienced patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS-138 EASIER trial.

BACKGROUND: In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm. METHODS: We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses. RESULTS: During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up. CONCLUSION: The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00454337.

Combination of long-acting HIV fusion inhibitor albuvirtide and LPV/r showed potent efficacy in HIV-1 patients.

BACKGROUND: Long acting antiretroviral drugs represent a promising approach for chronic treatment of HIV infection. Here, we study the efficacy and safety of albuvirtide (ABT), an HIV-1 fusion inhibitor with a half life of 11-12 days in human. METHODS: ABT was evaluated in a 7-week, open-label and randomized trial, combining with LPV/r. Twenty HIV-1-infected adults were assigned to two dose groups, receiving ABT (160 or 320 mg) given weekly and LPV/r given twice daily. RESULTS: At week 7, the decline of HIV-1 RNA from baseline was 1.9 (1.3-2.3) log10 and 2.2 (1.6-2.7) log10 copies/ml, and suppression of HIV-1 RNA to below 50 copies/ml was achieved in 11.1 % (1/9) and 55.6 % (5/9) patients, for the 160 and 320 mg dose group respectively. CONCLUSION: A clear dose-efficacy correlation of ABT was demonstrated. ABT combining with LPV/r is a promising two-drug regimen to be tested in larger patient population.

Maraviroc: a review of its use in HIV infection and beyond.

The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug-drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.

Pharmacokinetic interactions between BMS-626529, the active moiety of the HIV-1 attachment inhibitor prodrug BMS-663068, and ritonavir or ritonavir-boosted atazanavir in healthy subjects.

BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4(+) T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (RTV-boosted ATV [ATV/r]), or BMS-663068 at 600 mg BID plus ATV at 300 mg QD plus RTV at 100 mg QD. Compared with the results obtained by administration of BMS-663068 alone, coadministration of BMS-663068 with ATV/r increased the BMS-626529 maximum concentration in plasma (Cmax) and the area under the concentration-time curve in one dosing interval (AUCtau) by 68% and 54%, respectively. Similarly, coadministration of BMS-663068 with RTV increased the BMS-626529 Cmax and AUCtau by 53% and 45%, respectively. Compared with the results obtained by administration of ATV/r alone, ATV and RTV systemic exposures remained similar following coadministration of BMS-663068 with ATV/r. BMS-663068 was generally well tolerated, and there were no adverse events (AEs) leading to discontinuation, serious AEs, or deaths. Moderate increases in BMS-626529 systemic exposure were observed following coadministration of BMS-663068 with ATV/r or RTV. However, the addition of ATV to BMS-663068 plus RTV did not further increase BMS-626529 systemic exposure. ATV and RTV exposures remained similar following coadministration of BMS-663068 with either ATV/r or RTV. BMS-663068 was generally well tolerated alone or in combination with either RTV or ATV/r.

Identification of potential clinically significant drug interactions in HIV-infected patients: a comprehensive therapeutic approach.

OBJECTIVES: The aim of the study was to determine the prevalence of potential clinically significant drug interactions (CSDIs) in HIV-positive individuals and to identify associated risk factors. METHODS: A cross-sectional study was conducted including all HIV-infected out-patients attending the Pharmacy Service of a regional reference hospital in Murcia, south-eastern Spain. The complete treatment was screened for possible CSDIs using the Spanish College of Pharmacists' online software resource, bot. Additionally, the severity level of the CSDIs involving antiretroviral (ARV) drugs was compared with that established in the specific antiretroviral database InteraccionesHIV.com. Multivariate logistic regression was used to identify associated risk factors. RESULTS: Two hundred and sixty-eight patients were included in the study. A total of 292 potential drug interactions were identified, of which 102 (34.9%) were CSDIs, of which 52.9% involved ARV drugs. Seven therapeutic drug classes were involved in 75% of CSDIs (protease inhibitors, benzodiazepines, nonsteroidal anti-inflammatory drugs, nonnucleoside reverse transcriptase inhibitors, corticosteroids, antithrombotics and proton pump inhibitors). Factors independently associated with CSDIs were treatment with more than five drugs [odds ratio (OR) 15.1; 95% confidence interval (CI) 6.3-36.2], and treatment with a protease inhibitor (OR 5.3; 95% CI 2.4-11.74). CONCLUSIONS: The findings of this study suggest that the prevalence of clinically relevant drug-drug interactions is high in HIV-infected patients, and could represent a major health problem. Awareness, recognition and management of drug interactions are important in optimizing the pharmaceutical care of HIV-infected patients and helping to prevent adverse events and/or loss of efficacy of the drugs administered.

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.

Safety and immunovirologic outcomes with maraviroc combination regimens in patients with a history of past treatment failures and virologic resistance in Brazil: an open-label, multicenter phase 3b study.

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

Pharmacokinetic profile and safety of 150 mg of maraviroc dosed with 800/100 mg of darunavir/ritonavir all once daily, with and without nucleoside analogues, in HIV-infected subjects.

BACKGROUND: Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not established. METHODS: HIV-infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/ritonavir once daily with plasma HIV RNA <50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10 and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with trough (C(trough)) and average (C(avg)) maraviroc concentrations <25 and <75 ng/mL, respectively; (ii) geometric mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated with total maraviroc exposure. RESULTS: Eleven subjects completed the study procedures (mean age 49 years; range 35-59 years). In three subjects, maraviroc C(trough) and C(avg) were <25 and <75 ng/mL, respectively (C(avg), 68 ng/mL and C(trough), 14 and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng·â€Šh/mL (95% CI: 2983-4294) and 2996 ng·â€Šh/mL (95% CI: 2374-3782) in periods 1 and 2, respectively, and the GM ratio was 0.84 (95% CI: 0.67-1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P=0.049; 95% CI: 0.01-0.91). No clinical safety concerns were observed. CONCLUSIONS: Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir exposure, which was slightly reduced in the absence of tenofovir/emtricitabine.

Maraviroc once-daily nucleoside analog-sparing regimen in treatment-naive patients: randomized, open-label pilot study.

OBJECTIVE: This study was performed to evaluate a once-daily dual-therapy regimen, maraviroc (MVC) + atazanavir/ritonavir (ATV/r), in treatment-naive patients. DESIGN: A phase 2b, randomized, open-label pilot study. METHODS: In Study A4001078 (NCT00827112), treatment-naive patients with CCR5-tropic HIV-1 (HIV-1 RNA ≥1000 copies/mL; CD4 cell count ≥100 cells/mm) were randomized to receive either MVC 150 mg once daily (n = 60) or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily (n = 61) + ATV/r 300/100 mg once daily. Primary endpoint was proportion of patients with HIV-1 RNA <50 copies per milliliter at week 48. RESULTS: At week 48, 44 (74.6%) and 51 (83.6%) patients in the MVC and TDF/FTC treatment groups, respectively, had plasma HIV-1 RNA <50 copies per milliliter. Median change from baseline in CD4 cell count at week 48 was +173 and +187 cells per cubic millimeter with MVC and TDF/FTC, respectively. Seven patients discontinued from each arm; there were no deaths. The incidence of serious adverse events (AEs) was similar in each group; however, there were more grade 3/4 AEs in the MVC group (18 vs 11), mostly due to hyperbilirubinemia. Three patients in each arm were evaluable for virological analysis at discontinuation or failure (HIV-1 RNA >500 copies/mL); no genotypic resistance, change in tropism, or loss of susceptibility relevant to treatment was observed. CONCLUSIONS: The virological activity and immunological benefit of once-daily MVC + ATV/r were confirmed. Indirect hyperbilirubinemia and associated signs were the most commonly reported AEs in both study treatment groups and were not associated with significant transaminase increases. No drug resistance occurred.

A reduced grade of liver fibros-steatosis after raltegravir, maraviroc and fosamprenavir in an HIV/HCV co-infected patient with chronic hepatitis, cardiomyopathy, intolerance to nelfinavir and a marked increase of serum creatine phosphokinase levels probably related to integrase inhibitor use / Grado reducido de fibroesteatosis tras la administración de raltegravir, maraviroc y fosamprenavir en un paciente co-infectado de VIH/VHC con hepatitis crónica, cardiomiopatía, intolerancia al nelfinavir y un aumento pronunciado de los niveles de creatina fosfoquinasa sérica probablemente debido al uso del inhibidor de la integrasa

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.