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AIDS:
doi: 10.1097/QAD.0b013e3282f3f17f
Epidemiology and Social: Editorial Comments

The Monark trial: where now for boosted protease inhibitor monotherapy?

Hill, Andrewa; Hirschel, Bernardb; Katlama, Christinec

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From the aPharmacology Research Laboratories, University of Liverpool, Liverpool, UK

bDivision of infectious Diseases, Geneva University Hospital, Geneva, Switzerland

cHopital Pitie Salpetriere, Paris, France.

Received 30 October, 2007

Accepted 31 October, 2007

Correspondence to Andrew Hill, Pharmacology Research Laboratories, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK. E-mail: microhaart@aol.com

Minimizing the long-term toxicity profile of HAART is a high priority, as HIV-infected individuals will need to be treated with HAART for life, and the majority of discontinuations of HAART are for adverse events [1]. The strategy of ritonavir-boosted protease inhibitor (PI) monotherapy aims to use the high genetic barrier of this treatment class to suppress HIV RNA fully without the need for nucleoside analogue reverse transcriptase inhibitors (NRTI), which have been associated with a range of mitochondrial toxicities such as lipoatrophy, lactic acidosis, renal abnormalities and lipid elevations [2].

In this issue of AIDS, Delfraissy and colleagues [3] present the 48-week results from the Monark trial: 136 naive patients were randomly assigned to receive lopinavir/ritonavir (LPV/r) either as monotherapy or with the two NRTI zidovudine and lamivudine. At week 48, the rates of full HIV-RNA suppression less than 50 copies/ml were 67% for the LPV/r monotherapy arm and 75% for the LPV/r plus two NRTI arm in the intent to treat ‘switch equals failure’ analysis. The lower rate of full HIV-RNA suppression for LPV/r monotherapy was driven mainly by higher numbers of patients with 50–400 HIV-RNA copies/ml in the LPV/r monotherapy arm.

Interestingly, of the 21 patients genotyped for resistance at virological failure in the LPV/r monotherapy arm, only three showed evidence of PI resistance. Two of these patients already harboured PI mutations at baseline (K20I and M36I) known to lead to a loss of virological response to lopinavir in the most recent resistance algorithm [4], and the third patient had the L63P and V77I mutations at baseline, which are more weakly associated with lopinavir resistance [5]. One patient in the two NRTI plus LPV/r arm also failed virologically, with emergence of the M184V mutation, but showed the L63P and A71T mutations at baseline, also known to be associated with lopinavir resistance [5]. These findings suggest that more strict entry criteria in terms of baseline genotypic PI resistance might have lessened the difference in efficacy between the arms.

Another feature of the Monark trial is that three patients with incomplete suppression of HIV RNA on LPV/r monotherapy intensified their treatment by adding zidovudine and lamivudine. Patients intensifying with NRTI in the LPV/r arm can be analysed either as failures (‘switch equals failure’ analysis) or their HIV-RNA data can be included after intensification (‘switch included’ analysis). In the Monark trial, the three patients intensified with NRTI then showed full HIV-RNA suppression, but were classified as treatment failures in the ‘switch equals failure’ analysis. In a ‘switch included’ analysis, these patients would be classified as successes, raising the efficacy of the LPV/r arm from 67 to 71% (Table 1). Three other randomized trials have compared LPV/r monotherapy with standard HAART, and can be analysed with the two methods (shown in Table 1).

Table 1
Table 1
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In the Abbott M03-613 trial [6], 155 naive patients were randomly assigned to either LPV/r monotherapy or two NRTI plus efavirenz: 18 of 23 patients (78%) with viral breakthrough on LPV/r monotherapy showed re-suppression below 50 copies/ml after intensification with NRTI. At virological failure, there were three patients with PI resistance and two patients with M184V at failure in the LPV/r arm, versus one patient with NRTI resistance and one with non-nucleoside reverse transcriptase inhibitor resistance in the two NRTI plus efavirenz arm.

In the OK-04 trial [7], 200 patients with full HIV-RNA suppression at baseline were randomly assigned to either LPV/r monotherapy or two NRTI plus LPV/r: 5% of the LPV/r monotherapy group showed persistent, low-level HIV-RNA rebound without obvious non-adherence, and this group could be re-suppressed by intensifying with NRTI. At virological failure, two patients in each arm had evidence of PI resistance.

In the Kalmo trial, 60 patients with full HIV-RNA suppression were randomly assigned either to start LPV/r monotherapy or continue current HAART. The one patient with virological failure in the LPV/r monotherapy arm showed no PI or NRTI resistance at failure and was then re-suppressed after intensification with NRTI [8].

Across the four trials, LPV/r tended to show lower rates of efficacy than standard HAART in a standard ‘switch equals failure’ analysis. If re-intensification with NRTI was allowed in a ‘switch included’ analysis, however, longer-term HIV-RNA suppression rates were similar (Table 1), albeit with a slightly higher risk of accumulating drug resistance.

How do we interpret the results from the different analyses? The ‘switch equals failure’ approach examines the intrinsic efficacy and safety profile of a fixed treatment, allowing no modifications. The ‘switch included’ analysis allows the clinician to modify treatment according to ongoing laboratory monitoring, and assesses long-term outcomes [9].

In the Monark trial, those with HIV-RNA suppression below 400 copies after 4 weeks of treatment had a 90% chance of full HIV-RNA suppression by week 48. A strategy of using a short-term interval of boosted PI monotherapy, with a rule used to decide on intensification, could be used in future trials and might lower the risk of accumulating drug resistance.

There are several new trials evaluating the efficacy of PI monotherapy in patients with full HIV-RNA suppression at baseline: the MOST trial in Switzerland is re-evaluating LPV/r monotherapy, with a special focus on effects in the the central nervous system. The MONOI and MONET trials are evaluating ritonavir-boosted darunavir. These new trials might show improved efficacy and tolerability for boosted PI monotherapy, either by the use of the new formulation of LPV/r with its lower pill count [10] or the use of once-daily boosted darunavir, with its relatively long half life [11].

The potential advantages of boosted PI monotherapy include lower pill counts, lower costs of treatment, the prevention of long-term mitochondrial toxicities, and sparing other treatment classes for later use. The main disadvantage of boosted PI monotherapy is the potential for accumulating drug resistance from ongoing low-level virus replication. Only a low percentage of patients have, however, developed drug resistance on PI monotherapy to date, the correlation between HIV-RNA suppression between 50–400 copies/ml and the development of drug resistance is unclear, and there are increasing treatment options becoming available for those with virological failure.

A strategy of PI monotherapy for most patients, with intensification for the few who need it, may be attractive for many patients and clinicians. Current trials are concentrating on patients with full HIV-RNA suppression at baseline. To demonstrate that this treatment strategy provides the same efficacy as standard HAART, however, the use of a more pragmatic ‘switch included’ approach to the design and analysis of clinical trials will be needed.

Conflicts of interest: Andrew Hill has received consultancy payments from Tibotec. Bernard Hirschel has received travel grants and speakers honoraria from Abbott, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Merck and Roche and has participated in advisory boards for Merck, Tibotec and Pfizer. Christine Katlama has no declared conflicts of interest.

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References

1. Hill A, DeMasi R. Discordant conclusions from HIV efficacy trials – an evaluation of efficacy endpoints. Antivir Ther 2005; 10:367–374.

2. Miró O, López S, Cardellach F, Casademont J. Mitochondrial studies in HAART-related lipodystrophy: from experimental hypothesis to clinical findings. Antivir Ther 2005; 10(Suppl 2):M73–M81.

3. Delfraissy J, Flandre P, Delaugerre C, Ghosn J, Horban A, Girard P, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients: the Monark Trial. AIDS 2008; 22:385–393.

4. King M, Rode R, Cohen-Codar I, Calvez V, Marcelin A, Hanna G, Kempf D. Predictive genotypic algorithm for virologic response to lopinavi-ritonavir in protease inhibitor experienced patients. Antimicrob Agents Chemother 2007; 51:3067–3074.

5. Johnson V, Brun-Venizet F, Clotet B, Gunthard H, Kuritzkes D, Pillay D, et al. Update of the drug resistance mutations in HIV-1: 2007. Top HIV Med 2007; 15:119–125.

6. Cameron D, da Silva B, Arribas J, Myers R, Bellos N, Gilmore N, et al. A two-year randomised controlled clinical trial in antiretroviral-naive patients using lopinavir/ritonavir monotherapy after initial induction treatment compared to an efavirenz 3-drug regimen: 96 week results (Study M03-613). In: XVIth International AIDS Conference. Toronto, Canada; 13–18 August 2006. Abstract THLB0201.

7. Arribas J, Pulido F, Delgado R, Gonzalez-Garcia J, Perez-Elias M, Arranz A, et al. Lopinavir-ritonavir monotherapy vs lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. Ninety-six week results of a randomised controlled, open-lebel, clinical trial (OK-04 Study). In: 11th European AIDS Conference (EACS). Madrid, Spain; 24–27 October 2007. Abstract PS3.1.

8. Nunes E, Oliveira M, Almeida M, Pilotto J, Ribeiro J, Faulhaber J, et al. 96-Week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/ml on HAART – the KalMo Study. In: 11th European AIDS Conference (EACS). Madrid, Spain; 24–27 October 2007. Abstract P7.5/04.

9. Phillips AN, Walker S. Drug switching and virologic based endpoints in trials of antiretroviral drugs for HIV infection. AIDS 2004; 18:365–370.

10. Klein C, Chiu Y, Awni W, Zhu T, Heuser R, Doan TMD. The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. J Acquir Immune Defic Syndr 2007; 44:401–410.

11. Darunavir prescribing information 2006. Available at: www.aidsinfo.nih.gov/drugs. Accessed October 2007.

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Keywords:

Clinical trials; efficacy; hiv rna; monotherapy; nucleoside analogues; protease inhibitors

© 2008 Lippincott Williams & Wilkins, Inc.

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