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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. TL and telomerase activity was quantified on stored peripheral blood mononuclear cells (PBMC; n = 124) using quantitative real time PCR., Results: Patients in the sub-study had a mean age of 44 years and had received NRTI for a mean of 6.4 years (range 1-20 years). As expected, older patients have significantly shorter TL (p = 0.006), while women had significantly longer TL (p = 0.026). There was no significant association between TL and either the duration of prior NRTI treatment (p = 0.894) or the use of a PI versus NNRTI (p = 0.107). There was no significant difference between patients who continued or ceased NRTI in the mean change/year of TL or telomerase (p = 0.580 and 0.280 respectively)., Conclusion: Continuation versus cessation of NRTI treatment was not associated with an accelerated loss in TL or telomerase activity.

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. Retrospectively, Sanger sequencing was repeated with HIV-1 DNA from baseline peripheral blood mononuclear cells (PBMCSS); baseline plasma samples were retested by allele-specific PCR targeting seven RT RAMs (AS-PCR) and ultra-deep RT sequencing (UDS)., Results: By (plasma)SS, 16/193 (8.3%) patients showed ≥ 1 transmitted RAM affecting the NRTIs (10/193, 5.2%), non-nucleoside reverse transcriptase inhibitors (4/193, 2.1%) or protease inhibitors (2/193, 1.0%). No additional RAMs were detected by AS-PCR (n = 152) and UDS (n = 24); PBMCSS (n =  91) yielded two additional samples with one RAM each. Over 48 weeks, 4/79 (5.1%) patients on etravirine and 7/78 (9.0%) on efavirenz experienced virological failure; none had baseline RAMs. Conversely, 11/79 (13.9%) patients randomized to etravirine had one polymorphic RAM from the etravirine score in baseline plasma (V90I, V106I or E138A), without any impact on virological outcomes., Conclusions: The detection of resistance increased marginally with PBMC testing but did not increase with sensitive plasma testing. A careful consideration is required of the cost-effectiveness of different strategies for baseline HIV drug resistance testing.

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. For these patients, we assessed whether CD4 cell counts fell below 200 cells/μl from week 49 to week 192, while HIV-1 RNA suppression was maintained., Results: Of the 520 responders, five (1.0%) progressed to an AIDS-defining event during the first 48 weeks of the trial, whereas 19 of the 169 non-responders (11.2%) developed AIDS-defining events during this time (P = 0.001, Fisher's Exact test). Of the 449 patients with sustained HIV-1 RNA suppression below 400 copies/ml from week 49 to week 192, five patients (1.1%) had reductions in CD4 cell count below 200 cells/μl on two consecutive visits. These were all short-term reductions, with follow-up results equal or above 200 cells/μl., Conclusions: There was a benefit to testing for CD4 cell count in the first 48 weeks of treatment, to identify patients who have immuno-virological discordance and therefore a higher risk of progression to AIDS. However, after 48 weeks of antiretroviral treatment, for the 'responder' patients in the ARTEMIS trial who had both HIV-1 RNA below 50 copies/ml and rises in CD4 cell count equal or above 200 cells/μl, there appears to be little clinical benefit from continued testing for CD4 cell count.

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). The percentage of patients in each arm with HIV RNA < 5 copies/ml rose progressively from week 2 to week 192. For patients with baseline HIV RNA ≥ 100,000, the percentage with HIV RNA < 5 copies/ml at week 192 was 66% for darunavir/ritonavir and 63% for lopinavir/ritonavir. For patients with baseline HIV RNA < 100,000 copies/ml, the percentage with HIV RNA < 5 copies/ml at week 192 was 79% for darunavir/ritonavir versus 77% for lopinavir/ritonavir. Of the patients on darunavir/ritonavir with HIV RNA < 50 copies/ml, 63% had levels < 5 copies/ml at week 48, versus 80% at week 192. In summary, HIV-1 RNA suppression to < 5 copies/ml is dependent on baseline HIV RNA levels. The HIV RNA levels can remain under quantification limits but still detectable after 2-4 years of antiretroviral treatment.

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). Sparse sampling for etravirine plasma concentrations was conducted during the 48-week trial. Area under the curve over the dosing interval (AUC24h) and trough concentration (C0h) were estimated using a population pharmacokinetic model and compared with previous results using the 200-mg twice-daily dosage. The relationship between etravirine AUC24h and C0h with efficacy and safety was also assessed., Results: By week 48, the percentage of patients in the etravirine arm with HIV RNA <50 copies/ mL was 75.9% in the intent-to-treat switch equals failure analysis and 92.3% in the on-treatment analysis; no patient developed genotypic or phenotypic resistance to NRTIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) after virologic failure. Seventy-one subjects had evaluable etravirine pharmacokinetics. The median (interquartile range) of etravirine AUC24h and C0h were 12,447 (8,261-15,652) ng•h/mL and 330 (188-472) ng/mL, respectively. There was no correlation between etravirine exposure and virologic response or adverse events., Conclusions: In the SENSE trial, etravirine 400 mg once daily achieved similar exposures to historical reference data on etravirine when dosed at 200 mg twice daily. There was no apparent relationship between the pharmacokinetics of etravirine and virologic response or adverse events.

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., Results: Mean HIV-1 DNA levels at baseline vs week 144 were 2.50 vs 2.49 log10 copies/106 PBMC in the monotherapy arm and 2.59 vs 2.61 log10 copies/106 PBMC in the triple therapy arm, with mean (median) changes of -0.05 (-0.03) and +0.03 (+0.01) log10 copies/106 PBMC in the 2 arms, respectively. Overall baseline HIV-1 DNA levels were higher in patients with nadir CD4 counts <200 cell/µL (P<.05) and in patients who over 144 weeks experienced at least 1 HIV-1 RNA measurement >50 copies/mL (P < .05)., Conclusions: In this substudy of the MONET trial, HIV-1 DNA levels remained stable during 144 weeks of either DRV/r monotherapy or triple therapy with DRV/r + 2 NRTIs. In both treatment arms, baseline HIV-1 DNA levels were predicted by the nadir CD4 cell count and predictive of plasma HIV-1 RNA detection during follow-up.

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. Detection of treatment-emergent nucleoside/nonnucleoside reverse transcriptase inhibitor resistance differs significantly between clinical trials of the same first-line treatment (two nucleoside reverse transcriptase inhibitors/efavirenz), depending on the methods used for testing and analysis. Several clinical trials may have underestimated the prevalence of treatment-emergent drug resistance, by (i) not testing virologic failures with HIV RNA 50-400 copies/ml or (ii) not testing patients after discontinuation of treatment.

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., Results: The study population were 81% men and 85% whites, with a median age of 36 years, baseline CD4 cell counts of 302 cells/μl and HIV-RNA of 4.8 log10 copies/ml. In the intent-to-treat analysis, 13 of 79 individuals (16.5%) in the etravirine arm and 36 of 78 individuals (46.2%) in the efavirenz arm showed at least one grade 1-4 drug-related treatment-emergent neuropsychiatric adverse event (P < 0.001). The number with at least one grade 2-4 drug-related treatment-emergent neuropsychiatric adverse event was four of 79 individuals (5.1%) in the etravirine arm and 13 of 78 individuals (16.7%) in the efavirenz arm (P = 0.019). The change in HIV-RNA to week 12 was -2.9 log10 in both treatment arms. The median rise in CD4 cell counts was 146 cells/μl in the etravirine arm and 121 cells/μl in the efavirenz arm., Conclusions: After 12 weeks, first-line treatment with etravirine 400 mg once daily with two NRTIs was associated with significantly fewer neuropsychiatric adverse events when compared with efavirenz with two NRTIs. The virological and immunological efficacy profile was similar between the two arms.

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)., Results: A total of 63 patients had ≥ 1 HIV RNA result ≥ 50 copies/ml, of whom 38 were successfully genotyped. Most HIV RNA increases were transient and in the range of 50-200 copies/ml. Overall, 36 of the 38 (95%) successfully genotyped patients showed no International AIDS Society-USA major PI mutations, DRV mutations or NRTI mutations. Two patients showed some evidence of PI resistance during transient HIV RNA elevations: one patient in the monotherapy arm had a single DRV mutation (L33F) when HIV RNA was 63 copies/ml (the virus was phenotypically sensitive to DRV [fold change 0.8]) and one PI pretreated patient taking tenofovir disoproxil fumarate/emtricitabine/DRV/r had re-emergence of pre-existing NRTI (M184V) and PI (V82I and L90M) mutations after a short treatment interruption (this virus remained phenotypically sensitive to DRV/r). Both patients showed sustained HIV RNA suppression to week 48 remaining with the same treatment., Conclusions: Emergence of drug resistance after changing a suppressive triple antiretroviral therapy to DRV/r with or without nucleoside analogues is uncommon.

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). Patient-reported events were assessed by the Functional Assessment of HIV Infection (FAHI) questionnaire and included an assessment of cognitive function., Results: Of 256 subjects enrolled, clinician-reported grade 1-4 adverse events of the nervous system (all cause) were seen in 16% of patients in each treatment arm. FAHI questionnaires were completed by 206 subjects at 48 weeks. No differences in cognitive functioning or other FAHI scores were observed between study treatment groups: Cognitive Functioning score [mean (SD)] 8.9 (2.4) and 9.0 (2.6) in DRVrMono arm and 8.8 (2.6) and 8.9 (2.8) in DRVrNRTI arm at baseline and week 48, respectively (P value for difference = .76)., Conclusion: In this exploratory analysis, no differences in the evolution of neuropsychiatric adverse events over 48 weeks are observed in HIV-infected subjects randomised to switch antiretroviral therapy to darunavir/ritonavir with or without nucleoside reverse transcriptase inhibitors.

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. The trial had 80% power to show noninferiority for the monotherapy arm (delta = -12%)., Results: Patients were 81% male and 91% Caucasian, with mean age 44 years, and CD4 cell count of 574 cells/microl. In the primary efficacy analysis, HIV RNA less than 50 copies/ml by week 48 (per protocol) was 86.2 versus 87.8% in the monotherapy and triple therapy arms; by intent-to-treat switch equals failure, efficacy was 84.3 versus 85.3%; by a switch-included analysis, efficacy was 93.5 versus 95.1%: all three comparisons showed noninferior efficacy for DRV/r monotherapy. CD4 cell counts remained stable during the trial in both arms. One patient per arm showed at least one protease inhibitor mutation, and one patient in the triple therapy arm showed an NRTI mutation. Nine patients per arm discontinued randomized treatment for either adverse events or other reasons. No new or unexpected safety signals were detected., Conclusions: In this study for patients with HIV RNA less than 50 copies/ml on other antiretrovirals at baseline, switching to DRV/r monotherapy showed noninferior efficacy versus triple antiretroviral therapy.