Christiane Moecklinghoff

The MONET trial: Week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load <50 HIV-1 RNA copies/mL at baseline

In the MONotherapy in Europe with Tmc114 (MONET) trial, darunavir/ritonavir (DRV/r) monotherapy showed noninferior efficacy vs. two nucleoside reverse transcriptase inhibitors (NRTIs) plus DRV/r at the primary 48‐week analysis. The trial was continued to week 144 to assess the durability of the results.

96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA <50 copies/mL at baseline

BACKGROUND In virologically suppressed patients, switching to darunavir/ritonavir monotherapy could avoid resistance and adverse events from continuing nucleoside analogues. METHODS Two hundred and fifty-six patients with HIV RNA <50 copies/mL on current antiretrovirals were switched to darunavir/ritonavir 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside analogues (n = 129). Treatment failure was defined as two consecutive HIV RNA levels at least 50 copies/mL by week 96, or discontinuation of study drugs. The trial had 80% power to show non-inferiority (δ = -12%) at week 48. Results Patients were 81% male, 91% Caucasian, and had a median baseline CD4 count of 575 cells/mm(3). There were more patients with hepatitis C co-infection at baseline in the monotherapy arm (18%) compared with the triple therapy arm (12%). In the efficacy analysis, HIV RNA <50 copies/mL by week 96 (per protocol, time to loss of virological response, switch equals failure) was 78% versus 82% in the monotherapy and triple therapy arms [difference -4.2%, 95% confidence interval (CI) -14.3% to +5.8%]; in a switch included analysis, HIV RNA <50 copies/mL was 93% versus 92% (difference +1.6%, 95% CI -5.0% to +8.1%). The percentage of patients with HIV RNA <5 copies/mL (optical density from the sample equal to the negative control) remained constant over time in both treatment arms. Conclusions In the week 96 analysis of the MONotherapy in Europe with TMC114 (MONET) trial, switching to darunavir/ritonavir monotherapy showed non-inferior efficacy to darunavir/ritonavir plus two nucleoside analogues in the switch included and observed failure analyses, but not in the main switch equals failure analysis.

Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial†

PROTEA is a randomized controlled trial to assess the efficacy and safety of darunavir/ritonavir (DRV/r) monotherapy as an alternative to triple therapy.

Neuropsychiatric Adverse Events With Ritonavir-Boosted Darunavir Monotherapy in HIV-Infected Individuals: A Randomised Prospective Study

Abstract 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.

Three-year evaluation of neuropsychiatric adverse events in the MONET trial of darunavir/ritonavir, with or without nucleoside analogues.

when there is the opportunity to discuss disclosure, confidentiality and practical issues with paediatric colleagues. If possible, siblings should be tested straight after maternal diagnosis, but several of our pregnant women preferred to wait until after the new baby was born and had negative results. We try to arrange for the siblings to attend for blood tests either with the baby’s third blood test or on the same day as the baby’s deferred BCG immunization. This methodology for HIV testing cannot be used in isolation, as it does not identify the children of women whom have not recently received care for HIV in pregnancy, nor does it address the children of male patients. However, we believe testing the siblings of the children born to HIV-positive women in the environment of a ‘family clinic’ offers a complementary approach to traditional HIV testing strategies.

When can HIV clinical trials detect treatment effects on drug resistance

Methods of sampling patients for resistance testing, and statistical analyses of HIV drug resistance, have not been standardised in HIV clinical trials. We analysed methods of genotyping and rates of treatment-emergent drug resistance from 27 clinical trials identified from a MEDLINE search. Sample size calculations were conducted using NQUERY software, assuming 5% significance level, 80% power and 1:1 randomisation. The percentage of patients with treatment-emergent IAS–USA mutations after 96 weeks ranged from 1.8% to 9.1% for first-line 2NRTI/NNRTI treatments, 0.6% to 6.3% for first-line 2NRTI/PI/r treatments and 0.0% to 2.0% in switch trials of boosted PIs. The prevalence of drug resistance was higher in trials with no screening for drug resistance at baseline, where the HIV RNA cut-off for genotyping was >50 copies/mL, where patients were tested for drug resistance after discontinuation of treatment, and where follow-up times were 96 weeks or longer. HIV clinical trials could be designed to detect differences in the risk of HIV drug resistance between treatments, as an analysis supporting HIV RNA suppression as the primary endpoint. However, this would require a standardised approach, with intent-to-treat analyses, testing of all samples with HIV RNA>50 copies/mL and genotyping after drug discontinuation.

Performance of the Abbott RealTime HIV-1 assay versus the Roche Amplicor HIV-1 MonitorTM Test, v1.5, UltraSensitive assay for samples with low plasma HIV-1 RNA copy numbers

Sir, The Roche Amplicor HIV-1 Monitor Test, v1.5, UltraSensitive assay has been used to measure HIV-1 RNA levels in HIV clinical trials, but this assay has recently been discontinued. The new replacement assay, Roche TaqMan HIV-1 Test, v2.0, tends to show low levels of quantifiable HIV-1 RNA in samples undetectable by the Roche Amplicor UltraSensitive assay. An alternative assay is the Abbott RealTime HIV-1 assay, which has a lower quantification limit of 40 copies/mL. Both the Roche Amplicor UltraSensitive assay and the Abbott RealTime assay can detect traces of HIV-1 RNA, below the standard quantification limits. Recent reports have suggested that low levels of detectable HIV-1 RNA may be a predictor of virological failure, particularly for patients receiving protease inhibitor monotherapy. The aim of this study was to compare the performance of the Roche Amplicor UltraSensitive assay (used in the MONET trial) and the Abbott RealTime assay (used in the PROTEA trial) in plasma samples with HIV-1 RNA ,200 copies/mL. The MONET and PROTEA trials recruited patients with screening plasma HIV-1 RNA ,50 copies/mL; patients were tested at screening then re-tested at the baseline visit, 4–6 weeks later. During both trials, patients remained on stable triple antiretroviral combination treatment between screening and baseline. The Roche Amplicor UltraSensitive assay was used for routine measurement of HIV-1 RNA in the MONET trial. Using this assay, HIV-1 RNA results were classified as: (i) no HIV-1 RNA detected; (ii) HIV-1 RNA ,50 copies/mL, but virus detected under the quantification limit; or (iii) HIV-1 RNA ≥50 copies/mL. The Abbott RealTime assay was used for routine measurement of HIV-1 RNA in the ongoing PROTEA trial. Using the Abbott assay, HIV-1 RNA results were classified as: (i) no HIV-1 RNA detected; (ii) HIV-1 RNA ,40 copies/mL, but virus detected under the quantification limit; or (iii) HIV-1 RNA ≥40 copies/mL. During the randomized phase of both trials, samples with lowlevel elevations in HIV-1 RNA (50–100 copies/mL in MONET and 40 –200 copies/mL in PROTEA) were re-tested using the same assay. In addition, 122 samples with HIV-1 RNA ,200 copies/ mL by the Roche Amplicor UltraSensitive assay were re-tested with the Abbott RealTime assay. In the MONET trial, there were 253 patients with both screening and baseline HIV-1 RNA data available using the Roche Amplicor UltraSensitive assay. Of the 247 patients who had HIV-1 RNA ,50 copies/mL at screening, 237 (96%) had HIV-1 RNA ,50 copies/mL at the baseline visit. There were six patients with HIV-1 RNA initially ≥50 copies/mL at screening (initially screening failures), of whom 3 (50%) had HIV-1 RNA ,50 copies/mL at baseline. Between the screening and baseline visits, there was substantial fluctuation between the categories of ‘HIV-1 RNA not detected’ and ‘HIV-1 RNA ,50 copies/mL, detected’ (Table 1). Of the 212 patients with HIV-1 RNA not detected at screening, 27 (13%) had HIV-1 RNA detected under the quantification limit at baseline, while 7 (3%) had HIV-1 RNA ≥50 copies/mL at baseline. Of the 253 patients tested overall, 188 (74%) had HIV-1 RNA in the same category at both screening and baseline. Given the fluctuations in HIV-1 RNA between the categories of ‘HIV-1 RNA not detected’ and ‘HIV-1 RNA , 50 copies/mL, detected’, individual patient results in these two categories need to be interpreted with caution. During the MONET trial, 36 samples with HIV-1 RNA initially between 50 and 100 copies/mL were re-tested with the same Amplicor UltraSensitive assay; the repeat sample showed HIV-1 RNA ,50 copies/mL in 25 patients (69%). Of the 11 quantifiable re-test results, all showed HIV-1 RNA levels ,200 copies/mL. In the PROTEA trial, there were 299 patients with consecutive HIV-1 RNA measurements taken at the screening and baseline visits. Of the 292 patients who had HIV-1 RNA ,40 copies/mL at screening using Abbott RealTime, 289 (99%) had HIV-1 RNA ,40 copies/mL at baseline. There were seven patients with HIV-1 RNA ≥40; all seven patients had HIV-1 RNA ,40 copies/mL at the baseline visit. Between the screening and baseline visits, there was also substantial fluctuation between the HIV-1 RNA categories (Table 2). Of the 246 patients who had HIV-1 RNA not detected at screening, there were 30 patients (12%) with HIV-1 RNA detected, but ,40 copies/mL, at baseline, and 1 patient (0.4%) with HIV-1 RNA ≥40 copies/mL at baseline. Of the 299 patients tested overall, 226 (76%) had HIV-1 RNA in the

Analysis of major and minor IAS-USA PI mutations in the MONET trial of darunavir/ritonavir monotherapy versus DRV/r + 2NRTIs

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Low-level viraemia during treatment with darunavir/r monotherapy versus DRV/r + 2NRTIs in the MONET trial

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK