Treatment-experienced Adult Patients Research Articles

Setting Cost-Effective Price Thresholds before FDA Approval: Cost-Effectiveness of Iptacopan Monotherapy Versus Standard-of-Care Anti-C5 Therapy in Transfusion-Dependent, Treatment-Experienced Adult Patients with Paroxysmal Nocturnal Hemoglobinuria in the United States

Introduction: Oral complement inhibition therapy has the potential to transform the care of patients with paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening hematological disorder characterized by intravascular hemolysis, thrombosis, and bone marrow failure. Current standard-of-care (SOC) for PNH are monoclonal antibodies targeting the distal complement component 5 (C5) and include the intravenous agents eculizumab and ravulizumab. However, this distal mechanism of action allows extravascular hemolysis to persist. Intravenous therapy also requires patient and nursing time spent for infusion care. Iptacopan is one oral proximal complement pathway inhibitor that selectively inhibits complement factor B. Clinical trial data shows that iptacopan controls both intravascular and extravascular hemolysis, resulting in increased transfusion independence. Iptacopan was granted breakthrough therapy designation for expedited review by the FDA. The potential approval is anticipated by the end of 2023, after which point pricing will be set. A cost-effective price for iptacopan is currently not known. We sought to fill this gap by conducting the first cost-effectiveness analysis of oral versus intravenous complement inhibitor therapy in PNH to determine a cost-effective monthly price threshold for iptacopan monotherapy and to estimate patient and nursing time saved with transition to oral therapy. Methods: In this independent analysis free of industry influence, we built a Markov model to first determine the cost-effectiveness of iptacopan monotherapy at a monthly cost equivalent to SOC. Second, we solved for the cost-effective monthly maximum threshold cost of iptacopan across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). Transition probabilities for transfusion burden and breakthrough hemolysis were informed by the phase III study results (NCT 04558918). Probabilities of transfusion-associated adverse events were sourced from hemovigilance reporting in the 2015 National Blood Collection and Utilization Survey. Costs were assessed in 2023 US dollars and were informed from the Centers for Medicare & Medicaid Services and PNH-specific health resource utilization literature. The latter accounted for country- and PNH-specific direct and indirect medical costs, derived after adjustment for baseline characteristics, and isolated for transfusion-dependent treatment-experienced patients with PNH by comparison to transfusion-independent, treatment-experienced patients with PNH. Effectiveness was calculated in quality-adjusted life-years (QALY), and employed PNH-specific utilities. The two primary outcomes for iptacopan monotherapy were 1) the incremental cost-effectiveness ratio (ICER) or, the incremental net monetary benefit (iNMB) if the therapy was found to be cost saving, and 2) the cost-effective maximum monthly threshold price of iptacopan monotherapy, as compared to the SOC. The secondary outcome was the aggregated patient and nursing time saved with the use of oral versus intravenous treatment. We concluded with deterministic sensitivity analysis to isolate parameters that the model results are most sensitive to, and probabilistic sensitivity analysis to capture uncertainty in all parameters simultaneously over 10,000 Monte Carlo simulations. Results: In the base-case (i.e., where monthly price of iptacopan is equivalent to SOC), therapy with iptacopan versus C5 inhibition accrued 15.6 and 13.5 QALYs at costs of $9.7 million and $14.0 million, respectively. The iNMB with iptacopan was $4.4 million (95% credible interval $2.7-6.5 million) and threshold analysis for the maximum monthly price of iptacopan was $61,000. Iptacopan therapy projects to save patients and nurses approximately 730 and 2920 hours for ravulizumab and eculizumab, respectively, in PNH-specific care averted. Model results were most sensitive to iptacopan price. Conclusion: If the monthly price is no more than 149% of SOC, iptacopan monotherapy can be a cost-effective therapeutic option for transfusion-dependent, treatment-experienced patients with PNH. This is achieved by increasing the proportion of transfusion-independence in this patient population and, in turn, decreasing the burden of both the risks and costs associated with health resource utilization for patients with PNH.

Daclatasvir-Sofosbuvir Combination Therapy with or without Ribavirin for Hepatitis-C Virus Infection: An Experience from a Tertiary Care Hospital, Pakistan

Objective: To assess the impact and effectiveness of a pan-genotypic Directly Acting Antiviral (DAA) based regimen for patients with chronic Hepatitis-C (HCV) infection in our setup. Study Design: Cross-sectional study. Place and Duration of Study: Departments of Pathology and Medicine, Combined Military Hospital, Malir, Karachi, from Dec 2019 to Jan 2021. Methodology: Sofosbuvir and Daclatasvir were administered orally at 400mg and 60mg daily, respectively, with or without Ribavirin to treatment-naïve and treatment-experienced adult patients with chronic HCV infection. End-of-treatment response and Sustained virological response were determined among these patients by monitoring viral load using quantitative HCV RNA PCR and various genotypes. Results: Of the 59 patients, 39(66%) patients received sofosbuvir (SOF)+Daclatasvir (DCV), 12(20.3%) patients were placed on SOF+Ribavirin (Rib) and 8(13.5%) were given triple regime of SOF+DCV+Rib for 12 and 24 weeks respectively. Most of our patients were females, 32(54.23%), with a mean age of 31±17 years. Forty-eight patients (81.35%) were infected with genotype 3, followed by genotype 1 and 2, respectively. The rapid viral response was noted after four weeks of therapy among 27(45.76%) patients. The sustained viral response was noted in 38(64.40%) and 21(35.59%) patients after 12 and 24 weeks, respectively. The end-of-treatment response was observed in 40(67.8%) patients. Conclusion: Direct-acting antiviral-based regimens have shown favourable results with fewer adverse effects in our patients.

Real-World Data of Adherence and Drug Survival of Biologics in Treatment-Naïve and Treatment-experienced Adult Patients with Rheumatoid Arthritis.

Biologic disease-modifying anti-rheumatics drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) are important treatments for rheumatoid arthritis (RA). As more of these drugs become available, there is a greater need to assess their real-world adherence and drug survival. Treatment-naïve and treatment-experienced patients with RA who initiated treatment with bDMARDs and tofactinib during 2015-2018 in a large Israeli health maintenance organization were included. Adherence and time to treatment suspension were recorded. Odds for adherence were estimated using a multivariable logistic regression model. Risk for treatment suspension was estimated using a mixed-effect Cox proportional hazard model. The analysis included 753 eligible patients (61.8% treatment-naïve) treated with 1287 treatment episodes (tofacitinib 24.2%, tocilizumab 17.5%, etanercept 16.0%, adalimumab 10.4%, abatacept 9.9%, rituximab 9.0%, golimumab 6.9%, certolizumab pegol 3.6%, infliximab 1.9%, and sarilumab 0.5%). Good adherence was measured for almost all drugs, yet over 50% of all treatment episodes were suspended. Older age was associated with reduced risk for treatment suspension while higher number of primary care visits and higher Charlson's comorbidity score were associated with increased risk. Compared to etanercept, treatment with adalimumab, certolizumab, or rituximab was associated with increased risk for treatment suspension (HR 1.68 95% CI 1.27-2.22, HR 1.62 95% CI 1.00-2.60, and HR 2.72 95% CI 2.02-3.67, respectively). Treatment choice primarily depends on disease activity and prognosis. Real-world data, showing differences in drug survival of bDMARDs and tsDMARD, can also be used in the variety of considerations when choosing treatment. Future studies could separate patients with RA into subgroups, which would also account for potential drug survival differences and enable personalized therapy.

Evaluation of the effect of cellular SMS reminders on consistency of antiretroviral therapy pharmacy pickups in HIV-infected adults in Botswana: a randomized controlled trial

ABSTRACTObjective: Several studies have demonstrated that cellular phone short message service (SMS) improve antiretroviral adherence for people living with HIV in Africa, although less data are available to support using SMS reminders to improve timeliness of antiretroviral therapy (ART) pharmacy pick up. This study tested the efficacy of SMS reminders on timeliness of ART pharmacy pickups at an urban clinic in Gaborone, Botswana.Design: A randomized-controlled trial evaluating the effect of SMS reminders on ART collection for patients with HIV on treatment.Methods: One hundred and eight treatment-experienced adult patients were enrolled and randomly assigned to a control group or an intervention group. Participants in the intervention group received SMS reminders that were sent in advance of monthly ART refills that needed to be collected. The primary outcome was 100% timeliness of pharmacy ART pickups. Secondary outcomes included frequency of physician visits, CD4 cell counts and viral loads.Results: Baseline characteristics in the intervention (n = 54) and control arms (n = 54) were similar. After six months, 85% of those receiving SMS reminders were 100% on time picking up monthly ART refills compared to 70% in the control group (p = 0.064). In secondary analysis, there were no significant changes in the CD4 counts and viral loads over the course of the study.Conclusions: Timeliness of ART pickup was not significantly improved by SMS reminders. Additionally, the intervention had no impact on immunologic or virologic outcomes in treatment-experienced patients.

Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults.

IntroductionIn DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r.Materials and MethodsThis was a 48 week, Phase IV, open-label, single-arm, multicentre study. HIV-1-infected treatment-experienced adult patients on=8 weeks ARV therapy prior to screening, switching either for virologic failure (VF) (viral load [VL] =500 c/mL) or regimen simplification/AEs (RS/AE) (VL<50 c/mL), received active ETR 200 mg bid with an investigator-selected BR of =1 active ARVs, but excluding DRV/r or NRTIs only. The primary objective was to evaluate safety, tolerability and pharmacokinetics (PK).ResultsOf 211 treated patients, 55% were female, 61% black/African American. 155 patients (73%) had baseline (BL) VL=50 c/mL versus 56 (27%) with BL VL<50 c/mL. Between these two latter subgroups, median BL VL was 4.42 versus 1.28 log10 c/mL and CD4+ count 238 versus 410.5 cells/mm3. Overall, 96% previously used <2 NNRTIs and 99% used=5 PIs; median number of BL NNRTI RAMs was 2, PI RAMs 5 and NRTI RAMs 1. Overall, most common BR ARVs were PIs (83%), mostly lopinavir/r (62%) and mostly used alone (20%) or with 1 or 2 NRTIs (61%). Raltegravir was used in 9% of patients. Most frequent AEs (any cause/grade) were diarrhoea (17%) and URTI (8%). Incidence of grade 3–4 AEs was 13%, serious AEs 5% (no rashes; none ETR related), AEs leading to discontinuation 4%, AEs possibly related to ETR 23% and AEs of interest: rash (any type) 4%, hepatic 6% and neuropsychiatric 3%. At week 48, VF and RS/AE virologic responses (% patients with VL<50 c/mL; FDA Snapshot) were: 48% (74/155) and 75% (42/56), respectively. VF rates were 42% and 13%; 10% and 13% had no VL data in the week 48 window. The percentage of patients adherent to treatment (assessed based on PK sampling plus ETR pill count) was 47% (69/148) and 57% (30/53), in VF and RS/AE, respectively. Median CD4+ count (NC=F) increases were 0.0 and 24.0 cells/mm3. In 29/49 of VFs with genotypic data at failure, ETR RAMs emerging in =5 patients were Y181C, E138A and M230L. The geometric mean ETR AUC12h was 4877 ng.h/mL and C0h 293 ng/mL (N=199).ConclusionsResults of this study were consistent with those for ETR in other similar populations and support the use of ETR 200 mg bid with a non-DRV/r based BR.

Impact of etravirine use on hospitalization rates among highly pre-treated failing HIV-1 infected individuals between 2005 and 2011.

IntroductionEtravirine (ETR), a non-nucleoside reverse transcriptase inhibitor available in France since 2006, is indicated for the treatment of HIV-1 infection in combination with a ritonavir boosted protease inhibitor (PI) in antiretroviral treatment-experienced adult patients. To assess its impact in routine clinical care, our objective was to compare hospitalization rates in highly pre-treated failing HIV-1 infected individuals between 2005 and 2011 depending on whether or not they received ETR+PI.MethodsFrom the French Hospital Database on HIV (ANRS CO4), we selected highly pre-treated individuals (prior exposure to at least 2NRTI, 2PI and 1 NNRTI) with a viral load (VL)>50 copies/mL initiating a new regimen between 2005 and 2011. Hospitalization rates were calculated for each calendar month and depending on whether patients never received ETR+PI at any time or during months before initiating ETR+PI (no ETR+PI) or during months after initiating ETR+PI (ETR+PI), using an intention to continue treatment approach. Poisson regression models were used to compare incidence between the two groups, after adjustment for potential confounders (age, transmission group, origin, AIDS, PCP prophylaxis, viral load, CD4, nb of previous ARV).ResultsOverall 3884 patients fulfilled inclusion criteria. Among them 838 (21.6%) received ETR+PI at least once. Among all enrolled patients, 35.8% had CD4 <200/mm3, 17.5% had VL >100,000 copies/ml, 42.8% had had an AIDS event and 47.8% had received more than 10 different antiretroviral drugs. There were 2484 hospitalizations in 808 individuals over 13,986 patient-years. The hospitalization rates for 1000 P-Y were 169.0 for the ETR+PI group and 179.3 for the no ETR+PI group. After adjustment, the corresponding figures were 144.8 for 1000 P-Y and 192.7 for 1000 P-Y respectively, with a relative risk estimated as 0.75 (95% CI 0.67–0.84).ConclusionsAccess to ETR+PI between 2005 and 2011 was associated with a 25% reduction in the hospitalization rate among highly pre-treated failing HIV-1 infected individuals.

Eliglustat: First Global Approval

Eliglustat [Cerdelga™ (US, EU)], a small-molecule oral glucosylceramide analogue that inhibits the enzyme glucosylceramide synthase has been developed by Genzyme Corporation (a subsidiary of Sanofi) for the treatment of Gaucher disease type 1 in adults. Inhibition of this enzyme reduces the accumulation of the lipid glucosylceramide in the liver, spleen, bone marrow and other organs. Eliglustat received its first global approval in this indication in the US, for use in treatment-naïve and treatment-experienced adult patients. It is also under regulatory review in the EU and Japan. This article summarizes the milestones in the development of eliglustat leading to this first approval for Gaucher disease type 1.

Etravirine

Etravirine (Intelence®) is an orally administered next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). It is approved for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and are harbouring HIV-1 strains resistant to other antiretroviral (ARV) agents. In the US, etravirine must be used in combination with other ARV agents; in the EU, it must be used in combination with other ARV agents that include a boosted HIV-1 protease inhibitor. Etravirine shows good activity in vitro against most wild-type strains of HIV-1, as well as against several strains resistant to available NNRTIs. Furthermore, etravirine appears to present a higher barrier than first-generation NNRTIs against the development of drug resistance. Whereas the presence of a single mutation is sufficient to affect the virological response to efavirenz or nevirapine, the resistance profile of etravirine is more complex and a prediction of virological response may be calculated using a weighted genotypic score. Importantly, the most prevalent NNRTI-associated mutation, K103N, alone does not affect the etravirine response. In two identically designed randomized clinical trials, the addition of etravirine to an optimized background therapy (OBT) regimen improved virological responses to a greater extent than placebo plus OBT following 24 weeks' treatment in highly treatment-experienced adult patients with HIV-1 infection who had evidence of viral replication (HIV-1 RNA levels of >5000 copies/mL at baseline). Furthermore, pre-planned pooled analyses of the trials at 48 and 96 weeks showed that etravirine plus OBT provided durable virological suppression. Consistently higher virological response rates were observed for recipients of etravirine plus OBT than placebo plus OBT in a pre-specified subgroup analysis of baseline viral loads, CD4+ cell counts, HIV-1 subtype or the composition of background ARV therapy. Greater improvements from baseline in immunological outcomes were also observed for recipients of etravirine plus OBT compared with those receiving placebo plus OBT over the 96-week treatment period of the trials. When used as part of an OBT regimen in trials of up to 96 weeks duration, etravirine was well tolerated with an overall tolerabilty profile similar to that of placebo. The only treatment-emergent adverse event that occurred with a higher frequency for recipients of etravirine compared with placebo plus OBT was rash. In highly treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of etravirine to an OBT regimen provides an effective and well tolerated treatment that leads to improvements in both virological and immunological outcomes.

Etravirine: Clinical review of a treatment option for HIV type-1-infected patients with non-nucleoside reverse transcriptase inhibitor resistance

Despite our progressive understanding of HIV type-1 (HIV-1) infection and the development of a number of antiretroviral agents to delay the onset of AIDS, there remains a need for agents with improved efficacy and safety. In particular, therapy options for treatment-experienced adult patients have been limited by the presence of drug-resistant virus, which often leads to a reduced virological response in these patients. The recently approved non-nucleoside reverse transcriptase inhibitor etravirine has demonstrated durable and superior efficacy over placebo and a favourable tolerability profile in HIV-1-infected, treatment-experienced patients, offering a valuable new therapeutic option. This review examines the clinical development and drug profile of etravirine, placing it in the context of other antiretrovirals available for treatment-experienced patients.

Lack of specificity for the analysis of raltegravir using online sample clean-up liquid chromatography–electrospray tandem mass spectrometry

Background Raltegravir is the first antiretroviral agent to target the human immunodeficiency virus-1 (HIV-1) integrase. It is indicated, in association with other antiretrovirals, in the treatment of acquired immunodeficiency syndrome (AIDS) in antiretroviral treatment-experienced adult patients with viral resistance. To evaluate the feasibility of raltegravir therapeutic drug monitoring, we developed a rapid and specific analytical method for the quantification of raltegravir in human plasma by online sample clean-up liquid chromatography–tandem mass spectrometry (LC–MS/MS). Methods After protein precipitation (with 100 μL of acetonitrile/methanol (50/50)) of 25 μL of plasma, fast online matrix-clean-up was performed using a column switching program. The chromatographic step was optimized to separate raltegravir and its glucuronide metabolite (G-raltegravir). Multiple reaction monitoring (MRM) was used for detection of raltegravir and G-raltegravir. In the absence of G-raltegravir standard, G-raltegravir identification was confirmed by β-glucuronidase pre-treatment. Results A total analysis of 3.8 min was needed to separate raltegravir to G-raltegravir. The method was linear between 10 and 3000 ng/mL for raltegravir. Analytical recovery was 94 ± 1%. Variation coefficients ranged between 5% and 8.4%. Pre-treatment of plasma from a patient under raltegravir treatment with β-glucuronidase suppressed G-raltegravir peak. Conclusion We describe a fast online LC–MS/MS assay that is valid and reliable for the quantification of raltegravir, despite the lack of specificity that could occur in MRM scanning mode experiments.

Raltegravir

Raltegravir (Isentress), an integrase inhibitor, inhibits the insertion of HIV-1 complementary DNA into the host genome. It is indicated in combination with other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple ART agents. It is the first of a new class of ART agents to be approved that, as a result of a different mechanism of action to other ART agents, has good activity against multidrug-resistant HIV-1 strains. In clinical trials in treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of oral raltegravir to an optimized background therapy (OBT) regimen improved virological and immunological responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Raltegravir therapy was generally well tolerated, with a similar incidence of mild to moderate adverse events in the treatment and placebo arms. The introduction of integrase inhibitors extends the options available for managing treatment-experienced patients with multiple-drug-resistant HIV-1 infection. Results to date suggest that the combination of raltegravir and OBT will be a valuable treatment option for this difficult-to-treat patient group.

Effectiveness and cost of treatment with maraviroc in HIV infection

Since 1995, life expectancy and quality of life of HIV patients improved significantly due to the use of Highly Active Anti-Retroviral Therapy (HAART), consisting of different combinations of three classes of antiretroviral agents, nucleoside and non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Recently, new treatment options for individuals developing resistance to these drugs have become available, with the appearance of new drug classes like integrase inhibitors, fusion inhibitors and CCR5 antagonists. Maraviroc is the first antiretroviral agent belonging to the latter drug class approved for clinical use. CCR5 receptor antagonists act by blocking the interaction of the HIV virus with the CCR5 chemokine receptor, a co-receptor essential to the entry process of R5-tropic viruses. The drug is indicated, in combination with other antiretroviral products, for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable virus strains. Results of main phase III clinical trials indicate that maraviroc, in combination with optimized background therapy (OBT), causes significantly greater reductions in viral load and increases in CD4+ cell count, as compared to OBT alone in this kind of patients. In Italy, the monthly cost of maraviroc therapy is about € 780. A number of economic evaluations, performed for different settings, demonstrate that the therapy including maraviroc is cost-effective if compared to OBT alone, determining an ICER generally below the threshold of three times the GDP per capita. In the Italian context, the ICER determined by OBT + maraviroc vs OBT alone is approximately 45,000 €/LYG.

Raltegravir: the first in a new class of integrase inhibitors for the treatment of HIV

Raltegravir (formerly known as MK-0518; Isentress®) is the first in a new class of integrase inhibitors approved for the use in treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple antiretroviral agents. It is dosed twice daily with or without food. Raltegravir is a novel antiretroviral that has been shown to be well tolerated. It has demonstrated potent efficacy in the virologic suppression of HIV-1 RNA levels up to 48 weeks in two controlled studies that were conducted in clinically advanced, three-class antiretroviral, treatment-experienced adults.

The Power and Titan Trials: Darunavir/Ritonavir in the Management of HIV-Infected Patients

Darunavir is a new protease inhibitor (PI) active against wild-type and drug-resistant HIV-1 strains and has recently been approved for use in treatment-experienced adult patients. The main clinical trials, POWER and TITAN, have been conducted in treatment-experienced, HIV-1-infected patients. The Phase IIb POWER 1 and 2 trials compared the efficacy and safety of darunavir plus low-dose ritonavir (darunavir/ritonavir) with currently available PIs in highly treatment-experienced patients receiving an optimized background regimen. At 24 and 48 weeks in POWER 1 and 2, patients receiving darunavir/ritonavir had significantly higher efficacy responses than those receiving currently available PIs (45 vs 10% of patients reached a viral load &lt;50 copies/ml at week 48). The highest responses were observed with the darunavir/ritonavir 600/100 mg twice daily dose (also evaluated in the POWER 3 analysis), which was selected for the subsequent Phase III TITAN study. TITAN evaluated darunavir/ritonavir 600/100 mg twice daily in comparison with lopinavir/ritonavir in early treatment-experienced, lopinavir-naive patients. For the primary end point of a viral load of less than 400 copies/ml, darunavir/ritonavir was noninferior to lopinavir/ritonavir (77 vs 68%; 95% confidence interval [CI]: 2–16); for a viral load of less than 50 copies/ml, darunavir/ritonavir was again noninferior to the lopinavir/ritonavir group (71 vs 60%; 95% CI: 3–19). Both regimens were well tolerated, although discontinuations due to diarrhea and liver and lipid abnormalities were less frequent in the darunavir/ritonavir group. Darunavir/ritonavir has been shown to be effective in patients with a broad range of treatment experience and has the potential to become used across the HIV treatment spectrum, including in antiretroviral-naive patients.

Raltegravir: first in class HIV integrase inhibitor

On October 16, 2007, the US Food and Drug Administration (FDA) approved raltegravir for treatment of human immunodeficiency virus (HIV)-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.

Maraviroc : résultats des études cliniques

Just over a decade after identification of chemokine receptors CCR5 and CXCR4 as coreceptors for HIV, maraviroc (Celsentri ®), the first CCR5 antagonist, has recently obtained its Marketing Authorisation in the United States and Europe, for treatment of treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable. CCR5 antagonists, after fusion inhibitor enfuvirtide available since 2003, also belong to entry inhibitors. These molecules, unlike previous antiretrovirals, do not target the virus but its target cell by blocking viral penetration. Maraviroc has shown its clinical efficacy in patients failing other antiretroviral classes. Its safety profile was similar to placebo in two large phase III trials. However, careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed. Viral tropism testing has to be investigated before using maraviroc in the clinic, because CCR5 antagonists are not active against CXCR4 viruses. For the moment indicated for the treatment-experienced patient population, maraviroc could in the future benefit to other types of patients, depending on ongoing trials results.

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial

Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9-25; p=0.005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

O.161 High SVR rates with 24 weeks of peginterferon alpha-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in HCV genotype 1 or 4 patients with a week-4 virological response

Background: Since 1981, the AIDs epidemic has continued to expand and, at the end of 2007, there were ~33 million people worldwide living with HIV, including 1.2 million in North America.Objective: This article provides a comprehensive overview of the nonnucleoside reverse transcriptase inhibitor (NNRTI) etravirine when used in treatment-experienced adult patients with multidrug-resistant HIV infections.Methods: Relevant information was gathered through a search of MEDLINE ( 1966—December 2008) and International Pharmaceutical Abstracts (1970–December 2008) databases, as well as abstracts of the Conference on Retroviruses and Opportunistic Infections (2006–2008) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (2002–2008). Clinical trial data were limited to human studies that were Phase IIa or higher. The search terms used were etravirine and TMC125. References were also identified through screening of citations in the articles gathered.Results:Etravirine is an NNRTI that is able to adapt its binding orientation and overcome common NNRTI resistance associated mutations (RAMs) such as K103N. It was originally formulated in polyethylene glycol (PEG), but pharmacokinetic studies using an updated tablet formulation identified a more favorable absorption profile that has allowed the study of lower doses (200 mg instead of 900 mg BID). Phase IIa studies using the PEG formulation of etravirine found that viral loads were reduced in both treatment-naive and treatment-experienced patients with HIV (−1.99 vs −0.86 log10 copies/mL; P < 0.001). Phase IIb studies expanded on this finding by using various doses of the reformulated tablet to evaluate virologic efficacy in highly treatment-experienced patients with triple-class (protease inhibitor, nucleoside/nucleotide reverse tran-scriptase inhibitors [NRTI], and NNRTI) resistance. Patients in an open-label, partially blinded, Phase IIb study (N = 199) were randomized to receive an optimized background regimen alone or in combination with either 400 or 800 mg of etravirine BID. Regardless of the dose, patients in the etravirine arms had a greater decrease in viral load from baseline (−1.04 and −1.18 log10 copies/mL, respectively) compared with patients in the placebo arm (−0.19 log10 copies/mL; P = 0.005 and P < 0.001, respectively). The DUET studies (DUET-1, N = 612; DUET-2, N = 593) are 2 ongoing, international, randomized, double-blind, placebo-controlled, Phase III trials in which patients with preexisting RAMs are treated with darunavir/ ritonavir and an optimized NRTI background in combination with etravirine or placebo and the optional use of enfuvirtide. According to pooled, 48-week data from these studies, significantly more patients who received etravirine achieved an HIV RNA <50 copies/ mL (61% vs 40%; P < 0.001) and had greater viro-logic (−2.25 vs −1.49 log10 copies/mL reduction in HIV RNA from baseline; P < 0.001) and immuno-logic (98 vs 73 cells/mm3 CD4 cell count change from baseline; P < 0.001) responses compared with placebo. Additionally, the incidence of adverse events, including diarrhea, nausea, and headache, was similar between treatment groups in the DUET studies; rash, however, was significantly more common in the etra-virine group (17% vs 9%; P < 0.001).Conclusion: Etravirine is an NNRTI that was reported to be effective when used as part of an optimized, highly active antiretroviral therapy regimen in NNRTI treatment-experienced adult patients with HIV.