The MONET Trial: DRV/r Monotherapy vs. DRV/r Plus Two NRTIs
Background 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.
Methods A total of 256 patients with viral load < 50 HIV-1 RNA copies/mL on current highly active antiretroviral therapy (HAART) for at least 6 months switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two NRTIs (n = 129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/mL [time to loss of virological response (TLOVR)] by week 144, or discontinuation of study drugs.
Results Eighty-one per cent of patients were male and 91% were Caucasian, and they had a median baseline CD4 count of 575 cells/uL. More patients in the DRV/r monotherapy arm had hepatitis C virus coinfection at baseline than in the control arm (18% vs. 12%, respectively). By week 144, the percentage of patients with HIV RNA < 50 copies/mL [intent to treat (ITT), TLOVR, switch = failure method] was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference = −5.9%; 95% confidence interval (CI) −16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), the percentage of patients with HIV RNA < 50 copies/mL was 84% vs. 83.5%, respectively (difference = +0.5%; 95% CI −8.7%, +9.7%). Twenty-one and 13 patients had two consecutive HIV RNA results above 50 copies/mL in the DRV/r monotherapy arm and triple therapy arm, respectively, of whom 18 of 21 (86%) and 10 of 13 (77%) had HIV RNA < 50 copies/mL at week 144.
Conclusions In this study, for patients with HIV RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed noninferior efficacy to DRV/r plus two NRTIs in a strict ITT (switches not considered failures) analysis, but not in a TLOVR switch equals failure analysis.
International HIV treatment guidelines recommend that patients should be treated with at least three antiretroviral drugs throughout the course of HIV infection, typically with two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI). However, recently published European treatment guidelines have included an option for patients to be switched to boosted PI monotherapy, if the patient has HIV RNA levels below 50 HIV-1 RNA copies/mL and no history of virological failure. The two PIs being considered for this switching option are darunavir/ritonavir (DRV/r) 800/100 mg once daily and lopinavir/ritonavir 400/100 mg twice daily.
Randomized trials have evaluated the efficacy of switching to DRV/r monotherapy vs. a standard treatment of DRV/r plus two NRTIs (DRV/r + 2NRTIs), for patients with HIV RNA < 50 copies/ml at baseline. The MONotherapy in Europe with Tmc114 (MONET) and MONOI trials showed noninferior efficacy for the monotherapy arms vs. the triple therapy arms in their primary efficacy analyses at week 48. However, longer term analyses showed a slightly higher risk of low-level viraemia for patients taking DRV/r monotherapy; so far, the patients with low-level viraemia have not developed phenotypic resistance to PIs. More detailed analyses of these trials may help to identify patients at the lowest risk of viraemia during monotherapy treatment, who could be most suitable for treatment with DRV/r monotherapy.
In the MONOI trial, patients with low-level viraemia at baseline, problems with adherence or higher HIV DNA levels at baseline were more likely to show elevations in HIV RNA up to week 96. In a similar analysis of the Only-Kaletra-04 (OK-04) trial of lopinavir/ritonavir monotherapy, patients with poor adherence, lower nadir CD4 cell counts and lower baseline haemoglobin levels were most likely to lose virological suppression over 96 weeks of randomized treatment. In other studies of standard triple combinations of antiretroviral treatment, coinfection with hepatitis C virus (HCV) has been a consistent predictor of lower HIV RNA suppression rates. This trend has been seen across trials of PIs and nonnucleoside reverse transcriptase inhibitors. Coinfection with HCV may be associated with prior or current injecting drug use, which could affect adherence to study medication.
In addition, the efficacy endpoint used in these HIV clinical trials – the time to loss of virological response (TLOVR) – can be difficult to interpret. This endpoint classifies virological failure as any confirmed elevation above 50 copies/mL, occurring at any time during the trial. However, these elevations in HIV RNA may be low level, may not be associated with drug resistance and may occur for short time periods, with subsequent resuppression of HIV RNA by the end of the trial.
The results of the MONET trial were analysed at the final week 144 time-point, to assess whether there were baseline factors affecting the efficacy in the two treatment arms. In addition, the efficacy data were analysed by a strict intent-to-treat (ITT) (switches not considered failures) endpoint, which classified patients as success or failure depending on their HIV RNA levels at the end of the trial, regardless of transient elevations in HIV RNA at earlier time-points.
Abstract and Introduction
Abstract
Background 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.
Methods A total of 256 patients with viral load < 50 HIV-1 RNA copies/mL on current highly active antiretroviral therapy (HAART) for at least 6 months switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two NRTIs (n = 129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/mL [time to loss of virological response (TLOVR)] by week 144, or discontinuation of study drugs.
Results Eighty-one per cent of patients were male and 91% were Caucasian, and they had a median baseline CD4 count of 575 cells/uL. More patients in the DRV/r monotherapy arm had hepatitis C virus coinfection at baseline than in the control arm (18% vs. 12%, respectively). By week 144, the percentage of patients with HIV RNA < 50 copies/mL [intent to treat (ITT), TLOVR, switch = failure method] was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference = −5.9%; 95% confidence interval (CI) −16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), the percentage of patients with HIV RNA < 50 copies/mL was 84% vs. 83.5%, respectively (difference = +0.5%; 95% CI −8.7%, +9.7%). Twenty-one and 13 patients had two consecutive HIV RNA results above 50 copies/mL in the DRV/r monotherapy arm and triple therapy arm, respectively, of whom 18 of 21 (86%) and 10 of 13 (77%) had HIV RNA < 50 copies/mL at week 144.
Conclusions In this study, for patients with HIV RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed noninferior efficacy to DRV/r plus two NRTIs in a strict ITT (switches not considered failures) analysis, but not in a TLOVR switch equals failure analysis.
Introduction
International HIV treatment guidelines recommend that patients should be treated with at least three antiretroviral drugs throughout the course of HIV infection, typically with two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI). However, recently published European treatment guidelines have included an option for patients to be switched to boosted PI monotherapy, if the patient has HIV RNA levels below 50 HIV-1 RNA copies/mL and no history of virological failure. The two PIs being considered for this switching option are darunavir/ritonavir (DRV/r) 800/100 mg once daily and lopinavir/ritonavir 400/100 mg twice daily.
Randomized trials have evaluated the efficacy of switching to DRV/r monotherapy vs. a standard treatment of DRV/r plus two NRTIs (DRV/r + 2NRTIs), for patients with HIV RNA < 50 copies/ml at baseline. The MONotherapy in Europe with Tmc114 (MONET) and MONOI trials showed noninferior efficacy for the monotherapy arms vs. the triple therapy arms in their primary efficacy analyses at week 48. However, longer term analyses showed a slightly higher risk of low-level viraemia for patients taking DRV/r monotherapy; so far, the patients with low-level viraemia have not developed phenotypic resistance to PIs. More detailed analyses of these trials may help to identify patients at the lowest risk of viraemia during monotherapy treatment, who could be most suitable for treatment with DRV/r monotherapy.
In the MONOI trial, patients with low-level viraemia at baseline, problems with adherence or higher HIV DNA levels at baseline were more likely to show elevations in HIV RNA up to week 96. In a similar analysis of the Only-Kaletra-04 (OK-04) trial of lopinavir/ritonavir monotherapy, patients with poor adherence, lower nadir CD4 cell counts and lower baseline haemoglobin levels were most likely to lose virological suppression over 96 weeks of randomized treatment. In other studies of standard triple combinations of antiretroviral treatment, coinfection with hepatitis C virus (HCV) has been a consistent predictor of lower HIV RNA suppression rates. This trend has been seen across trials of PIs and nonnucleoside reverse transcriptase inhibitors. Coinfection with HCV may be associated with prior or current injecting drug use, which could affect adherence to study medication.
In addition, the efficacy endpoint used in these HIV clinical trials – the time to loss of virological response (TLOVR) – can be difficult to interpret. This endpoint classifies virological failure as any confirmed elevation above 50 copies/mL, occurring at any time during the trial. However, these elevations in HIV RNA may be low level, may not be associated with drug resistance and may occur for short time periods, with subsequent resuppression of HIV RNA by the end of the trial.
The results of the MONET trial were analysed at the final week 144 time-point, to assess whether there were baseline factors affecting the efficacy in the two treatment arms. In addition, the efficacy data were analysed by a strict intent-to-treat (ITT) (switches not considered failures) endpoint, which classified patients as success or failure depending on their HIV RNA levels at the end of the trial, regardless of transient elevations in HIV RNA at earlier time-points.
Source...