Switching at Low HIV-1 RNA into Fixed Dose Combinations: TDF/FTC/RPV is non-inferior to TDF/FTC/EFV in first-line suppressed patients living with HIV.

Background: In low- and middle-income countries (LMICs), a substantial unmet need for affordable single-tablet regimen (STR) options remains. Rilpivirine (RPV, TMC278) is formulated in a low-cost STR with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).

Objectives: Switching at Low HIV-1 RNA into Fixed Dose Combinations (SALIF) compared RPV with efavirenz (EFV), both as STRs with TDF and FTC, in maintaining virologic suppression.

Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial.

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve. Methods.

Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir in healthy volunteers: A randomized, two-way crossover trial.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, rilpivirine or etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals.

The PROTEA trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV-1 RNA below 50 copies/mL.

Introduction: In previous studies, protease inhibitor (PI) monotherapy has shown trends for higher low-level elevations in HIV-1 RNA compared to triple therapy, but no increase in the risk of drug resistance.

Methods: A total of 273 patients with HIV-1 RNA <50 copies/mL for over 24 weeks on current antiretrovirals switched to DRV/r (darunavir/ritonavir) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (nucleoside reverse-transcriptase inhibitors) (n=136), after a 4 week run-in phase with DRV/r + 2NRTI. Treatment failure was defined as HIV-1 RNA levels above 50 copies/mL (FDA Snapshot method) by Week 48, or switches off study treatment.

No difference in the rate of change in telomere length or telomerase activity in HIV-infected patients after three years of darunavir/ritonavir with and without nucleoside analogues in the MONET trial.

Objective: To determine whether nucleos(t)ide reverse transcriptase inhibitors (NRTI) contribute to an accelerated loss in telomere length (TL) in HIV-infected patients on antiretroviral therapy (ART).

Design: Substudy of randomised controlled trial.

Methods: Patients with HIV RNA <50 copies/mL on combination ART (n = 256) were randomised to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 127) or with 2 NRTIs (n = 129) for up to 144 weeks.

Etravirine as a Switching Option for Patients with HIV RNA Suppression: A Review of Recent Trials.

Unlike other nonnucleoside reverse transcriptase inhibitors, etravirine is only approved for use in treatment-experienced patients. In the DUET 1 and 2 trials, 1203 highly treatment-experienced patients were randomized to etravirine or placebo, in combination with darunavir/ritonavir and optimized background treatment. In these trials, etravirine showed significantly higher rates of HIV RNA suppression when compared with placebo (61% versus 40% at Week 48).

Time to HIV-1 RNA suppression below 5 copies/ml during first-line protease inhibitor-based antiretroviral treatment - any impact of residual viremia on treatment success?

When antiretroviral treatment suppresses HIV RNA levels to below 50 copies/ml, traces of viremia may still be detected with more sensitive assays. In the ARTEMIS trial, 689 antiretroviral treatment-naive patients were randomized to tenofovir/emtricitabine plus either darunavir/ritonavir (n = 343) or lopinavir/ritonavir (n = 346). HIV-1 RNA was evaluated using the Roche Amplicor® Ultrasensitive assay: plasma samples with HIV RNA < 50 copies/ml were classified as either "No HIV RNA detected" (< 5 HIV RNA copies/ml, optical density = background) or HIV RNA detected (5-50 copies/ml).

Sensitive testing of plasma HIV-1 RNA and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resistance prior to starting first-line antiretroviral therapy with etravirine or efavirenz.

Objectives: This study investigated strategies that may increase the yield of drug resistance testing prior to starting antiretroviral therapy (ART), and whether transmitted and polymorphic resistance-associated mutations (RAMs) correlated with virological outcomes.

Methods: We carried out retrospective testing of baseline samples from patients entering the SENSE trial of first-line ART in Europe, Russia and Israel. Prior to randomization to etravirine or efavirenz plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), plasma samples underwent routine Sanger sequencing of HIV-1 RT and protease ((plasma)SS) in order to exclude patients with transmitted RAMs.

Can we stop CD4+ testing in patients with HIV-1 RNA suppression on antiretroviral treatment?

Background: It is unclear whether regular CD4 testing is necessary for all patients during long-term antiretroviral treatment, after patients achieve full HIV-1 RNA suppression.

Methods: In the AntiRetroviral Therapy with TMC114 Examined in Naïve Subjects (ARTEMIS) trial, 689 treatment-naïve patients were randomized to tenofovir/emtricitabine and either darunavir/ritonavir or lopinavir/ritonavir. The number of patients with CD4 cell counts equal or above 200 copies/ml and HIV-1 RNA below 50 copies/ml at week 48 was assessed.

Pharmacokinetics and pharmacodynamics of etravirine 400 mg once daily in treatment-naïve patients.

Background: Etravirine is currently approved for HIV treatment-experienced patients at a dose of 200 mg twice daily. The long terminal elimination half-life of etravirine should support once-daily dosing.

Methods: In the double-blind 48-week SENSE trial, 157 antiretroviral treatment-naïve patients were randomly assigned to receive etravirine 400 mg once daily (n = 79) or efavirenz 600 mg once daily (n = 78), plus 2 nucleoside reverse transcriptase inhibitors (NRTIs).

Dynamics of cellular HIV-1 DNA levels over 144 weeks of darunavir/ritonavir monotherapy versus triple therapy in the MONET trial.

Background: In patients receiving combination antiretroviral therapy (ART), switching to monotherapy with ritonavir-boosted darunavir (DRV/r) can maintain plasma HIV-1 RNA suppression with no treatment-emergent drug resistance; effects on cellular HIV-1 DNA burden are less well characterized.

Methods: In MONET, patients on stable combination ART for at least 6 months with plasma HIV-1 RNA <50 copies/mL and no history of virologic failure switched to DRV/r 800/100 mg once daily, either alone (n = 127) or with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) (n = 129). In a representative subset of 146 patients, total HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) was tested retrospectively at baseline, week 48, week 96, and week 144.

Interpretation of resistance data from randomized trials of first-line antiretroviral treatment.

There are four key differences between HIV clinical trials in the analysis of HIV drug resistance: (i) baseline resistance testing used versus not used for patient inclusion; (ii) using HIV RNA cutoff levels of ≥ 50 versus ≥ 400 copies/ml to define virologic failure; (iii) testing versus not testing drug resistance in patients who discontinue treatment; (iv) analyzing drug resistance based on intent-to-treat analysis versus the subset of patients with samples genotyped. In this review we illustrate the importance of these issues, using data from 17 clinical trials of first-line nonnucleoside reverse transcriptase inhibitor-based treatment reported in the past 10 years. We also analyzed the data from the efavirenz arm of the SENSE trial, using all the different methods to show the range of results that can be obtained using different methods of analysis.

Impact of hepatitis C co-infection on response to antiretroviral treatment.

The MONET study, comparing darunavir/ritonavir-based triple therapy and monotherapy, has found higher risk of failure in patients with positive HCV serology, but the effects of HCV co-infection on the efficacy of antiretroviral treatment have not been clearly established. A detailed MEDLINE search was conducted to identify cohort studies and clinical trials with published analyses of the efficacy of antiretroviral treatment by HCV co-infection. A meta-analysis of the clinical trials was conducted, with the standardized endpoint of HIV RNA < 50 copies/ml at week 48 (intent to treat, time to loss of virologic response algorithm).

Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir monotherapy.

Background: When patients have HIV RNA suppressed to <50 copies/ml on current treatment, switching to darunavir (DRV)/ritonavir (DRV/r) monotherapy could prevent the development of resistance to other drug classes.

Methods: In the MONET trial, 256 patients with HIV RNA<50 copies/ml on current highly active antiretroviral therapy (57% with protease inhibitors [PIs] and 43% with non-nucleoside reverse transcriptase inhibitors) and no history of virological failure were randomized to DRV/r 800/100 mg once daily, either as monotherapy (monotherapy arm) or with two nucleoside reverse transcriptase inhibitors (NRTIs; triple therapy arm). All samples with HIV RNA ≥ 50 copies/ml were genotyped, and a virtual phenotype was calculated (VircoType HIV-1 assays; Virco BVBA, Mechelen, Belgium).

A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population.

Background: Although efavirenz is a universally recommended treatment for naive HIV-infected individuals, neuropsychiatric adverse events are common.

Methods: The Study of Efavirenz NeuropSychiatric Events versus Etravirine (SENSE) trial is a double-blind, placebo-controlled study in which 157 treatment-naive individuals with HIV-RNA higher than 5000 copies/ml were randomized to etravirine 400 mg once daily (n = 79) or to efavirenz 600 mg once daily (n = 78), with two investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs). The primary end point was the percentage of patients with grade 1-4 drug-related treatment-emergent neuropsychiatric adverse events up to week 12.

Neuropsychiatric adverse events with ritonavir-boosted darunavir monotherapy in HIV-infected individuals: a randomised prospective study.

Background: Protease inhibitor monotherapy is an attractive treatment option for HIV-infected subjects. Data assessing neuropsychiatric events with the use of protease inhibitor monotherapy are sparse.

Methods: Clinician- and patient-reported neuropsychiatric events were assessed over 48 weeks in HIV-infected subjects on stable antiretroviral therapy, with a plasma HIV RNA <50 copies/mL, randomised to commence on a one to one basis darunavir/ritonavir (800/100 mg once daily) alone (DRVrMono) or with nucleoside analogues (DRVrNRTI).

The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml.

Background: In virologically suppressed patients, darunavir-ritonavir (DRV/r) monotherapy could maintain virological suppression similarly to DRV/r and two nucleosides.

Methods: Two hundred and fifty-six patients with HIV RNA less than 50 copies/ml for over 24 weeks on current antiretrovirals [non-nucleoside reverse transcriptase inhibitor (NNRTI)-based (43%), or protease inhibitor-based (57%)], switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside reverse transcriptase inhibitors (NRTIs) (n = 129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/ml (TLOVR) by week 48, or switches off study treatment.