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Protease Inhibitor Monotherapy: What Is Its Role?

  • Antiretroviral Therapies (A Pozniak, Section Editor)
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Abstract

Protease inhibitor monotherapy has been shown to be effective in maintaining long-term viral suppression in a majority of patients. Withdrawal of nucleoside analogues can prevent long-term toxicity related to these drugs. Clinical trials have recently reported preliminary data on the beneficial effect of protease inhibitor monotherapy on body fat distribution and bone metabolism. Some of the uncertainties possibly associated with protease inhibitor monotherapy such as the increased risk of neurological events and a higher level of subclinical inflammation will be discussed in this review.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Reiss P, Battegay M, Clumeck N, et al. European AIDS Clinical Society Guidelines. Version 6.0.Octuber 2011. http://www.europeanaidsclinicalsociety.org/index.php?option=com_content&view=article&id=59:eacs-guidelines&catid=37:guidelines&Itemid=41 (last accessed 10/January/2012).

  2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

  3. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral Treatment of Adult HIV Infection 2010 Recommendations of the International AIDS Society–USA Panel. JAMA. 2010;304:321–33.

    Article  PubMed  CAS  Google Scholar 

  4. Bierman WF, van Agtmael MA, Nijhuis M, et al. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. 2009;23:279–91.

    Article  PubMed  CAS  Google Scholar 

  5. Pérez-Valero I, Arribas JR. Protease inhibitor monotherapy. Curr Opin Infect Dis. 2011;24:7–11.

    Article  PubMed  Google Scholar 

  6. •• Mathis S, Khanlari B, Pulido F, et al. Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. PLoS One. 2011;6:e22003. This meta-analysis included 10 randomized clinical trials. Results at week 48 favor triple therapy, however reinduction with nucleoside analogues achieved viral suppression in the great majority of patients. Authors conclude that the indication of boosted PI monotherapy should be individualized and considered in patients with good adherence to antiretroviral treatment.

    Article  PubMed  CAS  Google Scholar 

  7. • Perez-Valero I, Bayon C, Cambron I, et al. Protease inhibitor monotherapy and the CNS: peace of mind? J Antimicrob Chemother. 2011;66:1954–62. This review discusses the evidence on the role of monotherapy and the risk of development of HAND. The authors conclude that the current evidence is insufficient to determine whether the monotherapy is a risk factor for discordant CSF HIV replication and neurocognitive impairment.

    Article  PubMed  CAS  Google Scholar 

  8. Arribas J, Clumeck N, Nelson M, et al. The MONET trial: week 144 analysis of efficacy of darunavir/ritonavir monotherapy versus DRV/r + 2NRTIs, for patients with HIV RNA <50 copies/mL at baseline. [Abstract MOPE216]. 6th IAS Conference on HIV pathogenesis, treatment and prevention 17–20 July 2011, Rome.

  9. • Lambert-Niclot S, Flandre P, Valantin MA, et al. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy. J Infect Dis. 2011;204:1211–6. This study evaluated factors associated with virologic rebound in patients receiving monotherapy arm at weeks 48 and 96 of the MONOI trial. It is very important to consider these risk factors in clinical practice for the selection of best candidates for switching to darunavir/ritonavir monotherapy. Optimal adherence and profound virological suppression before switching to monotherapy were associated with success.

    Article  PubMed  CAS  Google Scholar 

  10. •• Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24:223–30. This is the largest clinical trial evaluating the efficacy of darunavir/ritonavir monotherapy. This clinical trial demonstrates the non-inferiority of a boosted protease inhibitor (darunavir/ritonavir) used once daily as monotherapy versus darunavir/ritonavir and two nucleosides at week 48.

    Article  PubMed  CAS  Google Scholar 

  11. •• Clumeck N, Rieger A, Banhegyi D, et al. 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. J Antimicrob Chemother. 2011;66:1878–85. Two-year update of the MONET trial. Darunavir/ritonavir monotherapy did not demonstrate non-inferiority in the per protocol, switch equals failure. Reinduction with nucleoside analogues led to viral replication control in most of the patients.

    Article  PubMed  CAS  Google Scholar 

  12. •• Arribas J, Hill A, Van Delft Y, et al. Interleukin-6 and C-reactive protein levels after 144 weeks of DRV/r monotherapy versus DRV/r + 2NRTIs in the MONET trial, for patients with HIV RNA <50 copies/mL at baseline [abstract PS 10/2]. European AIDS Clinical Society Conference, Belgrade, Serbia, October 2011. Three-year update of the MONET trial. Il-6 and CRP levels were measured in a subgroup of patients at week 144. DRV/r monotherapy was not associated with higher level of the inflammation biomarkers in comparison with DRV/r triple therapy. Hepatitis C coinfection appears to be a risk factor for increased IL-6 level.

  13. • Pulido F, Arribas JR, Hill A, Van Delft Y, et al. Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir monotherapy. Antivir Ther. 2011;16:59–65. Authors genotyped all samples with HIV RNA ≥50 copies/mL during the MONET trial. One patient on DRV/r monotherapy had a single DRV mutation and one on DRV/r triple therapy had re-emergence of pre-existing NRTI (M184V) and PI (V82I and L90M) mutations after a short treatment interruption. In both cases, virus remained phenotypically sensitive to DRV/r.

    Article  PubMed  CAS  Google Scholar 

  14. Winston A, Fätkenheuer G, Arribas J, et al. Neuropsychiatric adverse events with ritonavir-boosted darunavir monotherapy in HIV-infected individuals: a randomised prospective study. HIV Clin Trials. 2010;11:163–9.

    Article  PubMed  CAS  Google Scholar 

  15. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65–70.

    Article  PubMed  Google Scholar 

  16. Winston A, Arribas J, Hill A, et al. Three-year evaluation of neuropsychiatric adverse events in the MONET trial of darunavir/ritonavir with or without nucleoside analogues [abstract P049]. Adverse Events/Lipodystrophy Workshop, Rome, Italy, June 2011.

  17. Rodger AJ, Fox Z, Lundgren JD, INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. 2009;200:973–83.

    Article  PubMed  CAS  Google Scholar 

  18. Kuller LH, Tracy R, Belloso W, INSIGHT SMART Study Group, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203.

    Article  PubMed  Google Scholar 

  19. Ueyama M, Nakagawa M, Sakamoto N, Ochanomizu-Liver Conference Study Group, et al. Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection with pegylated-interferon-α2b plus ribavirin. Antivir Ther. 2011;16:1081–91.

    Article  PubMed  CAS  Google Scholar 

  20. Oliveira CP, Kappel CR, Siqueira ER, et al. Effects of Hepatitis C virus on cardiovascular risk in infected patients: a comparative study. Int J Cardiol. 2011. [Epub ahead of print].

  21. •• Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. 2010;24:2365–74. An important clinical trial evaluating darunavir/ritonavir monotherapy. In this trial, darunavir/ritonavir was administered at doses higher (600/100 mg twice daily) than in the MONET study until week 48. Results concordant with MONET.

    PubMed  CAS  Google Scholar 

  22. •• Valantin MA, Lambert-Niclot S, Flandre P, et al.; on behalf of the MONOI ANRS 136 Study Group. Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study. J Antimicrob Chemother. 2011. Dec 7 [Epub ahead of print]. Two-year update of the MONOI trial. Switching to 800/100 mg once daily darunavir/ritonavir confirmed the MONET results. Virological failure was not associated with development of darunavir resistance mutation.

  23. •• Meynard JL, Bouteloup V, Landman R, KALESOLO Study Group, et al. Lopinavir/ritonavir monotherapy versus current treatment continuation for maintenance therapy of HIV-1 infection: the KALESOLO trial. J Antimicrob Chemother. 2010;65:2436–44. This trial compared switching to lopinavir/ritonavir monotherapy versus continuing with the triple therapy (containing or non-containing PI regimen). Non-inferiority was non-demonstrated, considering treatment intensification as failure. The DEXA substudy shows a significant recovery of fat mass in legs in monotherapy arm.

    Article  PubMed  CAS  Google Scholar 

  24. Duran S, Peytavin G, Carrieri P, Antiprotease Cohort (APROCO) study group, et al. The detection of non-adherence by self-administered questionnaires can be optimized by protease inhibitor plasma concentration determination. AIDS. 2003;17:1096–9.

    Article  PubMed  Google Scholar 

  25. • McKinnon JE, Delgado R, Pulido F, et al. Single genome sequencing of HIV-1 gag and protease resistance mutations at virologic failure during the OK04 trial of simplified versus standard maintenance therapy. Antivir Ther. 2011;16:725–32. This study assessed plasma samples from subjects in lopinavir/ritonavir monotherapy arm at virological rebound during the OK04 trial. The authors used single genome sequencing of HIV-1 gag and protease to identify low-frequency drug-resistant variants. Lopinavir/ritonavir monotherapy was not associated with higher risk of emergence of major PI resistance mutations by SGS in comparison with lopinavir/ritonavir triple therapy.

    Article  PubMed  CAS  Google Scholar 

  26. Pulido F, Arribas JR, Delgado R, OK04 StudyGroup, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. AIDS. 2008;22:F1–9.

    Article  PubMed  CAS  Google Scholar 

  27. Cahn P, Montaner J, Junod P, et al. Pilot, randomized study assessing safety, tolerability and efficacy of simplified LPV/r maintenance therapy in HIV patients on the 1 PI-based regimen. PLoS One. 2011;6:e23726.

    Article  PubMed  CAS  Google Scholar 

  28. Arribas JR, Delgado R, Arranz A, Muñoz R, OK04 Study Group, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr. 2009;51:147–52.

    Article  PubMed  CAS  Google Scholar 

  29. Nunes EP, Santini de Oliveira M, Merçon M, et al. Monotherapy with Lopinavir/Ritonavir as maintenance after HIV-1 viral suppression: results of a 96-week randomized, controlled, open-label, pilot trial (KalMostudy). HIV Clin Trials. 2009;10:368–74.

    Article  PubMed  Google Scholar 

  30. Delfraissy JF, Flandre P, Delaugerre C, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS. 2008;22:385–93.

    Article  PubMed  CAS  Google Scholar 

  31. Ghosn J, Flandre P, Cohen-Codar I, MONARK Study Group, et al. Long-term (96-week) follow-up of antiretroviral-naïve HIV-infected patients treated with first-line lopinavir/ritonavir monotherapy in the MONARK trial. HIV Med. 2010;11:137–42.

    Article  PubMed  CAS  Google Scholar 

  32. Delaugerre C, Flandre P, Chaix ML, MONARK Study Group, et al. Protease inhibitor resistance analysis in the MONARK trial comparing first-line lopinavir-ritonavir monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy. Antimicrob Agents Chemother. 2009;53:2934–9.

    Article  PubMed  CAS  Google Scholar 

  33. Ghosn J, Delaugerre C, Flandre P, et al. Polymorphism in Gag gene cleavage sites of HIV-1 non-B subtype and virological outcome of a first-line lopinavir/ritonavir single drug regimen. PLoS One. 2011;6:e24798.

    Article  PubMed  CAS  Google Scholar 

  34. Saumoy M, Tiraboschi J, Gutierrez M, et al. Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy (the FONT Study). HIV Med. 2011;12:438–41.

    Article  PubMed  CAS  Google Scholar 

  35. Cameron DW, da Silva BA, Arribas JR, et al. A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis. 2008;198:234–40.

    Article  PubMed  CAS  Google Scholar 

  36. Valantin MA, Flandre P, Kolta S, et al. Fat tissue distribution changes in HIV-infected patients with viral suppression treated with DRV/r monotherapy vs 2 NRTI + DRV/r in the MONOI–ANRS 136 randomized trial: results at 48 weeks [Abstract 721]. Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; San Francisco, California, 16–19 February 2010.

  37. • Guaraldi G, Zona S, Cossarizza A, et al. Impact of Switching to Darunavir/ritonavir monotherapy vs. triple-therapy on Body Fat Redistribution and Bone Mass in Virologically Suppressed HIV-Infected Adults [PE7.5/4.] The MONARCH randomized controlled trial. 13th European AIDS Conference EACS, Belgrade, Serbia, October 2011. This clinical trial evaluated the change in lipoatrophy and bone mineral density after switching to monotherapy in comparison with continuing triple therapy. The monotherapy group shows a stabilization of the body fat distribution and a mild improvement in bone metabolism. This study is limited by the small number of patients included, and the short-term follow-up of patients up to 48 weeks.

  38. Knysz B, Briot K, Roux C, Delfraissy JF, et al. Fat tissue distribution changes in HIV-infected patients treated with lopinavir/ritonavir. Results of the MONARK trial. Curr HIV Res. 2011;9:31–9.

    Article  PubMed  Google Scholar 

  39. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203:1791–801.

    Article  PubMed  CAS  Google Scholar 

  40. Gutiérrez F, Masiá M. The role of HIV and antiretroviral therapy in bone disease. The role of HIV and antiretroviral therapy in bone disease. AIDS Rev. 2011;13:109–18.

    PubMed  Google Scholar 

  41. Bonjoch A, Figueras M, Estany C, Osteoporosis Study Group, et al. High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study. AIDS. 2010;24(18):2827–33.

    Article  PubMed  Google Scholar 

  42. Briot K, Kolta S, Flandre P, et al. Prospective one-year bone loss in treatment-naïve HIV+ men and women on single or multiple drug HIV therapies. Bone. 2011;48:1133–9.

    Article  PubMed  CAS  Google Scholar 

  43. Brown TT, McComsey GA, King MS, et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune DeficSyndr. 2009;51(5):554–61.

    Article  CAS  Google Scholar 

  44. Mueller NJ, Fux CA, Ledergerber B, Swiss HIV Cohort Study, et al. High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS. 2010;24:1127–34.

    Article  PubMed  CAS  Google Scholar 

  45. Welz T, Childs K, Ibrahim F, et al. Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS. 2010;24:1923–8.

    Article  PubMed  CAS  Google Scholar 

  46. Fux CA, Baumann S, Furrer H, et al. Is lower serum 25-hydroxy vitamin D associated with efavirenz or the non-nucleoside reverse transcriptase inhibitor class? AIDS. 2011;25:876–8.

    Article  PubMed  Google Scholar 

  47. Fox J, Peters B, Prakash M, et al. Improvement in vitamin D deficiency following antiretroviral regime change: results from the MONET trial. AIDS Res Hum Retrovir. 2011;27:29–34.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a Fondo de Investigaciones Sanitarias (FIS) grant from the Spanish Ministry of Health PI10/00483.

Dr. Miriam Estebanez is supported by a grant from the FIS Rio Hortega program (CM10/00152). Dr. Jose R. Arribas is an investigator from the Programa de Intensificación de la Actividad Investigadora en el SNS (I3SNS).

IdiPAZ AIDS and infectious diseases investigator group is partially supported by “Red de Investigacion en SIDA” (AIDS Research Network) (RIS) RD07/0006/2007.

Disclosure

M. Estébanez: speakers’ bureaus for BMS and ViiV; J. R. Arribas: board membership, consultancy, speakers’ bureaus, and honoraria from Viiv, Tibotec, Janssen, Abbott, BMS, Gilead, and MSD.

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  1. Servicio de Medicina Interna, Unidad VIH Hospital La Paz, IdiPAZ, Madrid, Spain

    Miriam Estébanez & Jose R. Arribas

  2. Consulta Medicina Interna 2, Hospital La Paz, Paseo de la Castellana 261, 28046, Madrid, Spain

    Jose R. Arribas

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  1. Miriam Estébanez
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  2. Jose R. Arribas
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Correspondence to Jose R. Arribas.

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Estébanez, M., Arribas, J.R. Protease Inhibitor Monotherapy: What Is Its Role?. Curr HIV/AIDS Rep 9, 179–185 (2012). https://doi.org/10.1007/s11904-012-0112-1

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