Triple Therapy Arm Research Articles

Research Letter

Research Letter

P133 A Single Centre Retrospective Survival Analysis of Patients with Interstitial Lung Disease

IntroductionIdiopathic pulmonary fibrosis is a chronic, progressive condition. BTS guidelines indicate that the ‘triple therapy’ - Prednisolone, Azathioprine, N-acetylcysteine (NAC) – can be considered in the management of UIP (usual...

Effects of switching to PI monotherapy on measures of lipoatrophy: meta‐analysis of six randomized HIV clinical trials

BackgroundSwitching from triple combination treatment to protease inhibitor (PI) monotherapy may prevent or reverse adverse events related to long‐term nucleoside analogues. Lipoatrophy is associated with long‐term use of thymidine analogues (zidovudine and stavudine).MethodsA detailed MEDLINE search was conducted to identify randomised clinical trials of triple combination treatment versus PI monotherapy. Summary results from analysis of changes in body composition (DEXA analysis) were collected: the mean change in limb fat and trunk fat to Week 48 or 96, and the percentage of patients with lipoatrophy (20% reduction from baseline in limb fat) or lipohypertrophy (20% rise from baseline in trunk fat).ResultsSix randomised trials of PI monotherapy versus triple therapy with data on body composition changes, measured by DEXA scanning at baseline and Week 48 or 96, were identified: Abbott‐613 (LPV/r vs ZDV/3TC/EFV, induction‐maintenance trial, n=105), Monark (LPV/r vs ZDV/3TC/LPV/r, first‐line trial, n=63), Kalesolo (LPV/r vs LPV/r +2NRTIs, switch trial, n=42), MONOI (DRV/r vs DRV/r + 2NRTIs, switch trial, n=156), MONARCH (DRV/r vs DRV/r + 2NRTIs, switch trial, n=30) and KRETA (LPV/r vs LPV/r + ABC/3TC, switch trial, n=74). In the meta‐analysis, there were greater rises in limb fat in the PI monotherapy arms than the triple therapy arms (mean difference =277g, 95% CI=+36 to+517g, p=0.024). The percentage of patients with lipoatrophy was significantly lower in the PI monotherapy arms (4%) than the triple therapy arms (20%), (p=0.0005). There was no difference between PI monotherapy and triple therapy for mean change in trunk fat (mean difference=−73g, 95% CI = −621 to +475g, p=ns). There was also no significant difference in the risk of lipohypertrophy between the PI monotherapy arms (32%) and the triple therapy arms (27%) (p=ns). In each of the four analyses, there was no evidence for heterogeneity of treatment effects between the trials (Cochran's Q tests, p=ns for each comparison).ConclusionsIn this meta‐analysis, the risk of lipoatrophy was significantly lower for patients taking PI monotherapy, compared to triple therapy. There was no significant difference between the arms for lipohypertrophy. However, several of the trials included zidovudine in the control arm, which carries a higher risk of lipoatrophy than tenofovir and abacavir, which are now more widely used.

Predictors of long‐term HIV RNA suppression on darunavir/ritonavir monotherapy in the MONET trial

BackgroundIn previous studies of protease inhibitor (PI) monotherapy, patients with higher nadir CD4 counts, baseline HIV RNA<1 copy/mL and high adherence to treatment have been most likely to show sustained HIV RNA suppression<50 copies/mL.MethodsIn the MONET trial, 256 patients with HIV RNA <50 copies/mL at screening switched to DRV/r 800/100 mg once daily, either as monotherapy (n=127) or with 2 NRTIs (n=129). HIV RNA results were classified as either<5 (no detection), 5–49 (virus detected under quantification limit) or >50 copies/mL. Treatment failure was defined as two consecutive HIV RNA levels >50 copies/mL (TLOVR) by Week 144, or discontinuation of study drugs. Additional analyses were conducted (i) excluding discontinuations for adverse events or other reasons (ii) including patients who intensified with NRTIs. Multivariate logistic regression was used to identify factors predictive of treatment failure by Week 144.ResultsBy Week 144, the percentage of patients with HIV RNA <50 copies/mL (ITT, TLOVR, Switch=Failure) was 69% versus 75% in the DRV/r monotherapy and triple therapy arms respectively. In the Switch Included analysis, HIV RNA <50 copies/mL was 84.0% versus 83.5% in the DRV/r monotherapy and triple therapy arms respectively. In the multivariate analysis for the TLOVR endpoint, positive HCV serology correlated with treatment failure (odds ratio [OR]=2.44, 95% CI 1.20–5.00). In the analysis including only virological endpoints, both positive HCV serology (OR=2.77, 95% CI 1.18‐6.67) and baseline HIV RNA >5 copies/mL (OR=2.71, 95% CI 1.21‐6.08) predicted treatment failure. In the Switch Included analysis, only HIV RNA >5 copies/mL was predictive of treatment failure (OR=2.78, 95% CI 1.28–6.01). Nadir CD4 count and prior PI use were not predictive of treatment failure in any analysis. In the ITT TLOVR analysis, the response rates in the DRV/r monotherapy arm at Week 144 were 79% (66/84) for HCV‐ve patients with baseline HIV RNA <5 copies/mL, 63% (12/19) for HCV‐ve patients with baseline HIV RNA >5 copies/mL, 47% (9/19) for HCV+ve patients with baseline HIV RNA<5 copies/mL and 20% (1/5) for HCV+ve patients with baseline HIV RNA>5 copies/mL.ConclusionsIn the MONET trial, patients without HCV co‐infection (based on serology), and with baseline HIV RNA <5 copies/mL by the Roche Amplicor assay (i.e. no virus detected) were most likely to show sustained HIV RNA suppression<50 copies/mL on DRV/r monotherapy.

Triple therapy in idiopathic pulmonary fibrosis: an alarming press release

On October 21, 2011, the National Heart, Lung, and Blood Institute (NHLBI), announced by press release that the prednisolone/azathioprine/ N -acetylcysteine (triple therapy) arm of the PANTHER study (Prednisone, Azathioprine and N -acetylcysteine: a Study That Evaluates Response in IPF) had been discontinued [1]. Compared with patients receiving placebo, patients with idiopathic pulmonary fibrosis (IPF) treated with triple therapy had excess deaths (11% versus 1%), more hospitalisations (29% versus 8%) and a higher prevalence of serious adverse events (31% versus 9%). The study is continuing with the N -acetylcysteine and placebo arms only. No concerns have been raised as a result of preliminary analysis of the N -acetylcysteine monotherapy arm of the PANTHER study. The preliminary announcement by the NHLBI has no immediate implications with regard to the introduction or continuation of N -acetylcysteine in IPF. It is hardly surprising that this announcement has caused widespread alarm amongst medical practitioners and patients with IPF currently taking triple therapy, especially in Europe, where this therapy is largely used. In isolation, the small absolute number of excess deaths in the triple therapy arm, although statistically significant, could not be viewed as conclusive. In earlier IPF studies, the supposed efficacy of interferon-γ [2] and the protective effect of pirfenidone against acute exacerbations [3] were based on similarly low numbers of events and neither …

Body fat distribution in HIV‐infected patients treated for 96 weeks with darunavir/ritonavir monotherapy versus darunavir/ritonavir plus nucleoside reverse transcriptase inhibitors: the MONOI‐ANRS136 Substudy

The aim of the study was to evaluate fat tissue distribution in HIV-infected patients with suppressed viraemia treated with darunavir/ritonavir (darunavir/r) monotherapy versus darunavir/r triple therapy. This study was a substudy of the randomized, multicentre, open-label MONOI-ANRS 136 trial. Body fat distribution and metabolic parameters were measured at baseline, week 48 and week 96. In total, 156 patients of the 225 initially enrolled in the MONOI trial participated in this study, 75 in the darunavir/r monotherapy arm and 81 in the darunavir/r triple-therapy arm. The median limb fat increase from baseline was +0.34 kg [interquartile range (IQR) -0.040 to +1.140 kg; P < 0.001] at week 48 and +0.33 kg (IQR -0.14 to +1.26 kg; P = 0.001) at week 96 in the monotherapy arm, while there was no change (-0.02 kg; IQR -0.53 to +0.52 kg) at week 48 and then an increase of +0.23 kg (IQR -0.45 to +0.87 kg; P = 0.046) at week 96 in the triple-therapy arm. The two arms differed significantly at week 48 (P = 0.001) but not at week 96. The median increase in trunk fat was +0.73 kg (IQR -0.24 to +1.60 kg; P < 0.001) and 0.60 kg (IQR -0.41 to +1.49 kg; P = 0.03) at week 48 and +1.16 kg (IQR -0.17 to +2.75 kg; P < 0.001) and +0.90 kg (IQR -0.51 to +2.34 kg; P = 0.001) at week 96 in the monotherapy and triple-therapy arms, respectively, with no difference between arms. At week 96, the only biological change was a glucose level elevation in the monotherapy arm (median +4.0 mg/dL; IQR -4.0 to +7.0 mg/dL) compared with the triple-therapy arm (P = 0.012). Overall, body fat tissue increased in patients on darunavir/r monotherapy and triple therapy, with no difference between the arms over 96 weeks. The only difference found was a delayed increase in limb fat tissue in the triple-therapy arm compared with the monotherapy arm in the first year.

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 &lt; 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. 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. 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. 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.

Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy

To analyse the emergence of resistant viruses in patients failing darunavir monotherapy, including minority species, and to investigate the impact of baseline reverse transcriptase (RT), protease (PR) and gag resistance mutations on virological failure (VF) occurrence. Nine of the 225 HIV-1-infected patients enrolled in the MONOI trial (darunavir/ritonavir monotherapy or darunavir/ritonavir + two nucleoside reverse transcriptase inhibitors in a switch strategy) experienced VF, defined as two plasma HIV-1 viral loads >400 copies/mL at least 2 weeks apart. Among these nine patients with VF, five were in the darunavir/ritonavir monotherapy arm and four were in the darunavir/ritonavir triple therapy arm. Bulk sequences of the PR, RT and gag genes at baseline (on DNA) and at the time of VF (on RNA) were determined for all patients with two viral loads >50 copies/mL at least 2 weeks apart (n = 47). PR and gag gene clonal analysis was performed on plasma samples of the nine patients with VF. There was no association between mutations in RT, PR and gag genes in DNA and VF occurrence. None of the patients demonstrated selection of darunavir resistance mutations among the 47 patients with a viral load >50 copies/mL at least 2 weeks apart. The virus of one of the nine patients with VF presented minority variants with darunavir resistance mutations at positions 32, 47 and 50. Clonal analysis of the gag region for the nine patients with VF did not show any selection of minority variants. In patients with failure on darunavir/ritonavir monotherapy we did not find any selection of darunavir resistance mutations using standard genotype testing. However, the virus of one patient among nine failures presented minority variants plus darunavir resistance mutations.

Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study

Long-term results at week 96 are needed to evaluate the capacity of the darunavir/ritonavir monotherapy strategy to maintain a sustained control of the HIV-1 viral load. MONOI is a prospective, open-label, non-inferiority, randomized, 96 week trial comparing darunavir/ritonavir monotherapy versus a darunavir/ritonavir triple-therapy strategy to maintain HIV-1 viral load suppression in HIV-1-infected patients. NCT00412551. From 225 randomized patients, 219 patients reached the 48 week follow-up and 211 reached the 96 week follow-up (106 patients in the darunavir monotherapy arm and 105 in the darunavir triple-therapy arm). Baseline characteristics were well balanced between the two treatment groups. At week 96, in intent-to-treat analysis, 91/103 patients (88%, 95% CI 81-94) allocated to the darunavir/ritonavir monotherapy arm and 87/104 patients (84%, 95% CI 75-90) allocated to the darunavir triple-therapy arm achieved an HIV-1 viral load <50 copies/mL, with no statistical difference between the two groups. Throughout the 96 week follow-up, 66/112 patients (59%, 95% CI 49-68) and 79/113 patients (70%, 95% CI 61-78) consistently had HIV-1 RNA <50 copies/mL with darunavir/ritonavir monotherapy and darunavir/ritonavir triple therapy, respectively. The MONOI study establishes darunavir/ritonavir monotherapy as durable and efficacious for maintaining virological suppression in HIV-1 patients. Darunavir/ritonavir monotherapy should be considered as a (tailored) treatment option for standard triple-therapy patients who have had a substantial period of viral suppression.

Cost-Efficacy Analysis of the MONET Trial Using UK Antiretroviral Drug Prices

In virologically suppressed patients, switching to darunavir/ritonavir (DRV/r) monotherapy maintains HIV RNA suppression, and could also lower treatment costs. The purpose of this analysis was to calculate the potential cost savings from the use of DRV/r monotherapy in the UK. In the MONET trial, 256 patients with HIV RNA < 50 copies/mL on current highly active antiretroviral therapy (HAART) for over 24 weeks (non-nucleoside reverse-transcriptase inhibitor [NNRTI] based [43%] or protease inhibitor [PI] based [57%]), switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two NRTIs (n = 129). The UK costs per patient with HIV RNA < 50 copies/mL at week 48 (responders) were calculated using a 'switch included' analysis to account for additional antiretrovirals taken after initial treatment failure. By this analysis, efficacy was 93.5% versus 95.1% in the DRV/r monotherapy and triple therapy arms, respectively. British National Formulary 2009 values were used. Before the trial, the mean annual cost of antiretrovirals was £6906 for patients receiving NNRTI-based HAART, and £8348 for patients receiving PI-based HAART. During the MONET trial, the mean annual per-patient cost of antiretrovirals was £8642 in the triple therapy arm, of which 55% was from NRTIs and 45% from PIs. The mean per-patient cost in the monotherapy arm was £4126, a saving of 52% versus triple therapy. The mean cost per responder was £9085 in the triple therapy arm versus £4413 in the DRV/r monotherapy arm. Based on the MONET results, the lower cost of DRV/r monotherapy versus triple therapy in the UK would allow more patients to be treated for fixed budgets, while maintaining HIV RNA suppression at < 50 copies/mL. If all patients meeting the inclusion criteria of the MONET trial in the UK were switched to DRV/r monotherapy, there is the potential to save up to £60 million in antiretroviral drug costs from the UK NHS budget.

MGluR Control of Interneuron Output Regulates Feedforward Tonic GABAA Inhibition in the Visual Thalamus

Metabotropic glutamate receptors (mGluRs) play a crucial role in regulation of phasic inhibition within the visual thalamus. Here we demonstrate that mGluR-dependent modulation of interneuron GABA release results in dynamic changes in extrasynaptic GABA(A) receptor (eGABA(A)R)-dependent tonic inhibition in thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (dLGN). Application of the group I selective mGluR agonist dihydroxyphenylglycine produces a concentration-dependent enhancement of both IPSC frequency and tonic GABA(A) current (I(GABA)tonic) that is due to activation of both mGluR1a and mGluR5 subtypes. In contrast, group II/III mGluR activation decreases both IPSC frequency and I(GABA)tonic amplitude. Using knock-out mice, we show that the mGluR-dependent modulation of I(GABA)tonic is dependent upon expression of δ-subunit containing eGABA(A)Rs. Furthermore, unlike the dLGN, no mGluR-dependent modulation of I(GABA)tonic is present in TC neurons of the somatosensory ventrobasal thalamus, which lacks GABAergic interneurons. In the dLGN, enhancement of IPSC frequency and I(GABA)tonic by group I mGluRs is not action potential dependent, being insensitive to TTX, but is abolished by the L-type Ca(2+) channel blocker nimodipine. These results indicate selective mGluR-dependent modulation of dendrodendritic GABA release from F2-type terminals on interneuron dendrites and demonstrate for the first time the presence of eGABA(A)Rs on TC neuron dendritic elements that participate in "triadic" circuitry within the dLGN. These findings present a plausible novel mechanism for visual contrast gain at the thalamic level and shed new light upon the potential role of glial ensheathment of synaptic triads within the dLGN.

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

In virologically suppressed patients, switching to darunavir/ritonavir monotherapy could avoid resistance and adverse events from continuing nucleoside analogues. 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.

Analysis of Drug Resistance during HIV RNA Viraemia in the Monet Trial of Darunavir/Ritonavir Monotherapy

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. 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 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. Emergence of drug resistance after changing a suppressive triple antiretroviral therapy to DRV/r with or without nucleoside analogues is uncommon.

The MONET trial: correlation between Hepatitis C coinfection and HIV RNA responses during darunavir/ritonavir monotherapy, for patients with HIV RNA &lt;50 copies/mL at baseline

Results At baseline, more patients were HCV antibody positive by serology in the DRV/r arm (17%) than in the control arm (9%). In the primary efficacy analysis at Week 48, 86.2% of patients in the monotherapy arm and 87.8% in the triple therapy arm had HIV RNA <50 copies/mL. Only four of the confirmed elevations in HIV RNA were above 400 copies/mL (two in each arm). In multivariate analysis (Per Protocol), hepatitis C co-infection was a significant predictor of confirmed HIV RNA elevations (p < 0.01). For patients infected only with HIV (HCV antibody negative at baseline), the percent HIV RNA <50 was 88.1% in the monotherapy arm versus 87.3% in the triple therapy arm. For patients HCV antibody positive at baseline, the percent HIV RNA <50 was 61.9% for the monotherapy arm versus 58.3% for the triple therapy arm. Three patients had acute HCV infection during the trial (all in the DRV/r arm): all three had HIV RNA elevations at the time of acute HCV infection.

Lopinavir/ritonavir + tenofovir Dual Therapy versus Lopinavir/ritonavir-Based Triple Therapy in HIV-Infected Antiretroviral Naïve Subjects: The Kalead Study

Purpose: With reference to the clinical need for simple, potent and safe antiretroviral regimens, Lopinavir/ ritonavir + tenofovir (LPV/r+TDF) two-drug initial regimen was studied for efficacy and safety in HIV-infected patients. Methods: Kalead was a prospective, randomized, open-label, 72-week trial comparing LPV/r+TDF versus LPV/r+ two (non-TDF) NRTIs in HIV-infected adults with HIV-RNA >400 copies/mL and any CD4 count. Primary endpoint was the proportion of subjects with HIV-RNA <50 copies/mL at week 72. Results: 152 subjects were randomized. Eleven (15.3%) subjects in the dual therapy arm and seven (8.8%) in the triple therapy arm who did not achieve HIV-RNA <50 copies/mL at least twice prior to and including week 24 were discontinued per protocol (p=0.21). Overall discontinuations were 41.7% and 43.8% in the dual therapy and triple therapyarms. At week 72, 51.4% and 52.5% of subjects in the dual therapy and triple therapy arms had HIV-RNA <50 copies/mL (p=0.89, ITT, NC=F). In an on-treatment analysis, 87.2% and 93.0% of subjects in the dual therapy and triple therapy arms had a HIV-RNA <50 copies/mL (p=0.47). Over 72 weeks of therapy, mean CD4 count increases were greater in the dual therapy arm (+332 cells/mm3 vs +234 cells/mm3, p=0.01). Adherence, overall incidence of adverse events, drugrelated adverse events, and Grade I-IV laboratory abnormalities were comparable between the two arms. Conclusions: A two-drug regimen of LPV/r+TDF suggests sufficient safety and efficacy warranting further investigation. However, high discontinuation rate and study design limitations restrict overall interpretation.

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

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

Interferon-α (IFN), interleukin-2 (IL2) and 5-fluorouracil (5FU) vs IFN alone in patients with metastatic renal cell carcinoma (mRCC): Results of the randomised MRC/EORTC RE04 trial

5039 Background: Until the recent introduction of the targeted agents, standard of care for patients with mRCC in Europe has included therapy with single agent IFN. Several phase II studies of the triple regimen IFN+IL2+5FU have shown high response rates with a suggestion of a survival advantage over other therapies. The RE04 study was set up to investigate the efficacy of the triple regimen in the context of a large randomised phase III trial. Methods: Patients with mRCC were randomised 1:1 to receive single agent IFN 10 MU tiw until progression or toxicity (Arm A) or a combination of IFN+IL2+5FU for 2 cycles (Arm B). A total of 1,006 patients were randomised over 5 years. Overall survival (OS) was the primary outcome measure with 90% power to detect a 3 month improvement in OS. Results: Accrual into Arms A and B was 502 and 504 patients, respectively. Pretreatment characteristics were well balanced with a median age of 57 years, 57% were WHO performance status 0 and 90% were nephrectomised. Median follow up was 27.8 months. There was no evidence of differences in median OS (18.7 vs 18.5 months, HR=1.05, 95% CI 0.89–1.23, p=0.57) or progression-free survival (PFS, 5.5 vs 5.3 months, HR=1.04, 95% CI 0.91–1.19, p=0.56). Best overall response was significantly higher in the triple therapy arm (24 vs 16%, p=0.004). Incidence of grade 3/4 toxicity was significantly higher (p<0.01) for diarrhoea, fever, hypotension, neutropenia and cutaneous skin reaction in patients receiving triple therapy. Quality of life analyses showed no important differences between treatment arms. Conclusions: RE04 is the largest randomised controlled trial yet performed in patients with mRCC. We have shown an advantage to triple therapy over single agent IFN in terms of response but not PFS or OS. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche, Schering-Plough Chiron, Roche, Schering-Plough Roche, Schering-Plough

Therapy for Helicobacter pylori Infection Can be Improved

As with other bacterial infections, successful treatment of Helicobacter pylori infections depends on the use of antibacterial agents to which the organism is susceptible. In this article, we use the proposed report card grading scheme (i.e. grade A, B, C, D, F) for the outcome of clinical trials, where intention-to-treat cure rates >95% = A, 90-95% = B, 85-89% = C, 81-84% = D and <81% = F. The goal of therapy is to consistently cure >95% of patients (e.g. provide grade A results). Like tuberculosis, H. pylori infections are difficult to cure and successful treatment generally requires the administration of several antibacterial agents simultaneously. Duration of therapy is also important and depends upon whether resistance is present; 14 days is often best. With few exceptions, worldwide increasing macrolide resistance now undermines the effectiveness of the legacy triple therapy (e.g. a proton pump inhibitor [PPI], clarithromycin and amoxicillin) and, in most areas, cure rates have declined to unacceptable levels (e.g. grade F). The development of sequential therapy was one response to this problem. Sequential therapy has repeatedly been shown in head-to-head studies to be superior to legacy triple therapy. Sequential therapy, as originally described, is the sequential administration of a dual therapy (a PPI plus amoxicillin) followed by a Bazzoli-type triple therapy (a PPI plus clarithromycin and tinidazole) and has been shown to be especially useful where there is clarithromycin resistance. However, the cure rates of the original sequential treatment are grade B and can probably be further improved by changes in dose, duration or administration, such as by continuing the amoxicillin into the triple therapy arm. The sequential approach may also be more complicated than necessary, based on the fact that the same four drugs have also been given concomitantly (at least nine publications with >700 patients) as a quadruple therapy with excellent success. This article discusses the approach to therapy in the modern era where antimicrobial resistance is an increasing problem and legacy triple therapy is no longer an acceptable initial choice. Methods to achieve acceptable eradication rates (e.g. grade A or B results) are discussed and, specifically, sequential therapy is considered both conceptually and practically. Suggestions are provided regarding how sequential therapy might be improved to become a grade A therapy as well as how to identify situations where it can be expected to yield unacceptable results. New uses for current drugs are discussed and suggestions for subsequent randomized comparisons to overcome phenotypic and genotypic resistance are given. We propose a change in focus from comparative studies (designed to prove that a new therapy is superior to a known inferior therapy) to demanding that efficacious therapies meet or exceed a pre-specified level of success (i.e. grade A or B result). To do so, coupled with less concern about the effect of recommendations on the pharmaceutical industry, should provide clinicians with much higher quality information, and improve the quality of medical care and recommendations regarding treatment. Ultimately, there is little or no justification for comparative testing that includes an arm with known unacceptably low results. H. pylori gastritis is an infectious disease and should be approached and treated as such.

The MRC Randomised-controlled Trial of Interferon-α, Interleukin-2 and 5-Fluorouracil vs Interferon-α Alone in Patients with Advanced Renal cell Carcinoma (RE04): Rationale and Progress

Renal cell carcinoma is diagnosed in over 6000 people, and accounts for about 2% of malignant disease annually in the UK [1]. For early stage disease, surgery with curative intent is the treatment of choice, although 30–40% of patients diagnosed with disease, apparently limited to the kidney, subsequently will relapse systemically [2]. A further 25% of patients have metastatic disease at presentation. The prognosis for metastatic renal-cell carcinoma is poor, with a median survival of 6–8 months [3]. Response rates to combination chemotherapy [4] and hormonal agents [5] have been around 5–10%. It has been known for some time that the immune system has a role in the natural history of renal-cell carcinoma. For example, spontaneous regressions are rare but well documented [6,7]. Immunotherapy with interferon (IFN) in metastatic disease produces response rates of around 10–20%, with median response durations of 3–16 months [8]. Retrospective data have also shown that patients with a performance status of 0 or 1 are more likely to gain benefit (i.e. increase in median survival) from immunotherapy than are patients with a performance status of 2 or worse [9]. Randomisedcontrolled trials have shown a survival advantage to IFN compared with non-immunotherapy. A randomised trial comparing IFN-a plus vinblastine (VLB) with VLB alone reported a median survival of about 16 months for the 79 patients receiving IFN plus VLB, and 9 months for the 81 patients treated with VLB (PZ 0.0049). Overall response rates were 16.5% for patients treated with IFN plus VLB and 2.5% for patients treated with VLB alone (PZ 0.0025) [10]. The

A randomized study comparing a three- and four-drug HAART regimen in first-line therapy (QUAD study)

Evidence from randomized controlled trials supports the use of triple therapy. Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy (HAART) combinations. Antiretroviral-naive individuals (n = 53) with an HIV-1 viral load >100 000 copies/mL were randomized to receive three-drug HAART with zidovudine/lamivudine (Combivir) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir (Trizivir) and efavirenz (quad regimen). Patients continued on HAART for 48 weeks with regular clinical and immunological assessment. Standard and ultrasensitive (<5 copies/mL) viral load testing was carried out. A DAVG (difference in averages) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens. Triple therapy resulted in a -4.17 log change (95% CI, -4.48 to -3.85) and quadruple therapy in a -4.36 log change (95% CI, -4.68 to -4.03) in viral load. For CD4 counts, the triple therapy arm increased by 164 cells/mm(3) (95% CI 112-217) and the quadruple arm by 185 (95% CI, 133-237). In an intent-to-treat analysis, 77% of patients in the triple therapy group reached an undetectable viral load (<50 copies/mL) compared with 84.2% of the quadruple therapy group. For ultrasensitive viral load testing, 23% and 18% of each group, respectively, reached undetectable viral loads. The hazard ratio for attaining a viral load of <5 copies/mL was 0.59 (95% CI, 0.26-1.33) for quadruple versus triple therapy. Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment. No differences in any analyses were observed between a standard of care regimen (zidovudine/lamivudine and efavirenz) and the quad regimen (zidovudine/lamivudine/abacavir and efavirenz).