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Clinical Study to Evaluate the Efficacy and Safety of Lopinavir/Ritonavir Monotherapy Versus Darunavir/Ritonavir Monotherapies as Simplification Switching Strategies of PI/NNRTI-Triple Therapy Based-Regimens

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00994344
Recruitment Status : Completed
First Posted : October 14, 2009
Last Update Posted : February 13, 2014
Information provided by (Responsible Party):
Sílvia Gel, Germans Trias i Pujol Hospital

Brief Summary:
The purpose of this study is to determine the non-inferiority in the efficacy of DRV/r (900/100 mg) monotherapy at 48 weeks versus LPV/r (400/100 mg) as simplification strategy in subjects with sustained viral suppression on stable PI or NNRTI-antiretroviral regimens.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Darunavir/ritonavir Drug: Lopinavir/ritonavir Phase 4

Detailed Description:

The pillar of the current standard of care for highly active antiretroviral therapies (HAART) is the use of two nucleoside reverse transcriptase inhibitors (NRTIs).1 However, these agents can inhibit the mitochondrial DNA polymerase gamma, causing mitochondrial dysfunction, which, in turn, may cause NRTI-related adverse events such as peripheral neuropathy, pancreatitis, liver disturbances, lipid profile abnormalities or lipoatrophy.2 As a result, strategies aimed to avoid the long term exposure to NRTIs and their toxicities are desirable for the management of HIV-infected patients.

Monotherapy with protease inhibitors (PIs) as a simplification approach therapy after an induction period with conventional antiretroviral treatment, appears to be of great utility for minimizing mitochondrial toxicity because of NRTIs. This approach may also increase patient adherence, reduce costs and preserve future treatment options. However, concerns remain regarding compartmental HIV replication due to limited drug penetration into the central nervous system, risk factors associated with monotherapy failure as well as the extrapolation of results obtained in clinical trial settings to routine clinical practice, are still not well known.

In this regard, there are reports that have suggested that lopinavir/ritonavir (LPV/r) monotherapy may be an effective therapeutic option for treatment of HIV-1 infection in antiretroviral-naïve patients. 5,6 Moreover, some studies report that despite LPV/r allows CSF concentrations lower than plasma, its concentrations exceed levels that suppress wild-type HIV replication.7,8,9 However other authors have reported that LPV/r monotherapy results in suboptimal HIV suppression in the CSF compartment in approximately 10% of cases.10

Darunavir is the last PI with activity against wild-type and PI-resistant HIV. In ARTEMIS trial, DRV/r at doses of 800/100 mg once daily have demonstrated that it is non inferior and statistically superior than LPV/r and it is an effective treatment option for antiretroviral (ARV)-naïve patients. In this study, patients receiving once-daily DRV/r achieved high durable virologic response rates, which were comparable in patients with less favourable baseline characteristics or suboptimal adherence. In addition, they had a low discontinuation rate due to virologic failure or adverse events or both, did not develop protease inhibitor resistance upon failure, and had suitable drug exposure. 11,12

All these benefits, coupled with the higher genetic barrier, its favourable safety and plasmatic pharmacokinetic profile of DRV/r, suggest that DRV/r has the potential to be an excellent option for monotherapy simplification strategies.

The investigators propose a prospective and randomised clinical trial that compares the efficacy, safety and tolerability of DRV/r 900/100 mg monotherapy once daily versus LPV/r 400/100 monotherapy twice daily as simplification strategy in HIV-infected patients with stable NNRTI or PI-based antiretroviral regimen and sustained viral suppression.

Aside to the main goal of this project, the investigators are going to make use of the samples obtained from the CSF at 48 weeks of follow-up (as representative of the viruses replicating in the central nervous system) and genital tract and plasma at the different time points. The investigators will compare the sequence population of those organs from the different patients in order to state if viruses not found in plasma at one time point but found in reservoirs can be found in blood when the infection advance.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 73 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomised and Prospective Clinical Study to Evaluate the Efficacy and Safety of Lopinavir/Ritonavir Monotherapy Versus Darunavir/Ritonavir Monotherapies as Simplification Switching Strategies of PI/NNRTI-Triple Therapy Based-Regimens
Study Start Date : October 2009
Actual Primary Completion Date : October 2012
Actual Study Completion Date : October 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Darunavir/ritonavir
to switch from the triple therapy based regimens to Darunavir/ritonavir
Drug: Darunavir/ritonavir
Darunavir/ritonavir 800/100 mg once daily
Other Name: N/P

Active Comparator: Lopinavir/ritonavir
to switch from the triple therapy based regimens to Lopinavir/ritonavir
Drug: Lopinavir/ritonavir
Lopinavir/ritonavir 400/100 mg twice daily
Other Name: N/P

Primary Outcome Measures :
  1. Plasmatic HIV-1 Viral load [ Time Frame: week 48 ]

Secondary Outcome Measures :
  1. CD4 cell count [ Time Frame: baseline, weeks 12, 24, 36, 48 ]
  2. Changes in liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma GT, alkaline phosphatase) [ Time Frame: baseline, weeks 12, 24, 36, 48 ]
  3. Changes in total bilirubin [ Time Frame: baseline, weeks 12, 24, 36, 48 ]
  4. Changes in lipid parameters (total, HDL-, LDL-, cholesterol, triglycerides) [ Time Frame: baseline, weeks 12, 24, 36, 48 ]
  5. Administration of lipid-lowering drugs throughout the study (new administrations or the withdrawal of previous lipid-lowering drugs) [ Time Frame: baseline, weeks 4, 12, 24, 36, 48. ]
  6. Adverse events [ Time Frame: weeks 4, 12, 24, 36, 48. ]
  7. CSF and genital tract HIV-1 viral load [ Time Frame: baseline, weeks 24, 48 ]
  8. Plasmatic, CSF and genital tract trough-DRV and LPV concentration [ Time Frame: weeks 12, 24, 48 ]
  9. Resistance mutations in case of confirmed virological failure (plasmatic, CSF and genital tract) [ Time Frame: baseline, weeks 4, 12, 24, 36, 48. ]
  10. Neurocognitives changes [ Time Frame: baseline, week 48 ]
  11. Time to virological failure, defined as an increase in HIV RNA >50 copies in 2 determinations within 1 month. The first date with VL > 50 will be used to calculate time to virological failure. [ Time Frame: weeks 4, 12, 24, 36, 48. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • HIV-1 infected adults (=/+18 years old).
  • Patients having a diagnosis of HIV infection, on stable HAART including:

    2 NRTI/NtRTIs plus one of the following : 1 PI/ritonavir (lopinavir/ritonavir, atazanavir/ritonavir, fosamprenavir /ritonavir, tipranavir/ritonavir, darunavir/ritonavir) or ATV/unboosted (in a regimen without tenofovir) 1 NNRTI (nevirapine or efavirenz), raltegravir or maraviroc

  • Undetectable plasma HIV-1 RNA (VL < 50 copies/mL) while on HAART during at least 3 month prior to switching.
  • Nadir CD4 cell count > 100 cells/mm3.
  • Absence of major PI-resistance mutations in HIV-protease (IAS 2008).20 Good treatment adherence.
  • Voluntary written informed consent.
  • Patients and physician's preference to change the current HAART regimen for reasons of simplification and/or toxicity.

Exclusion Criteria:

  • History of virological failure to a previous antiretroviral protease-containing regimens.
  • History of virological failure defined as two consecutive plasma HIV-1 RNA > 50 copies/mL while on current antiretroviral therapy
  • Acute infections or uncontrolled chronic infection in the 2 months previous to the inclusion or physical examination that, in the investigator's opinion, would compromise the patient's safety or outcome of the study
  • Breastfeeding, pregnancy or fertile women willing to be pregnant.
  • Patients co-infected with hepatitis B.
  • Concomitant use of any drug with potential drug-drug interaction with DRV/r or LPV/r at study entry.
  • Therapies including interferon, interleukin-2, cytotoxic chemotherapy or immunosuppressors at study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00994344

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Germans Trias i Pujol Hospital
Badalona, Barcelona, Spain, 08916
Hospital Universitario de Canarias
Santa Cruz de Tenerife, Canarias, Spain, 38320
Sponsors and Collaborators
Germans Trias i Pujol Hospital
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Responsible Party: Sílvia Gel, Dr. Bonaventura Clotet, Germans Trias i Pujol Hospital Identifier: NCT00994344    
Other Study ID Numbers: LOPIDAR
First Posted: October 14, 2009    Key Record Dates
Last Update Posted: February 13, 2014
Last Verified: February 2014
Keywords provided by Sílvia Gel, Germans Trias i Pujol Hospital:
Antiretroviral simplification strategy
Treatment experienced
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors