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
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Darunavir/ritonavir; Lopinavir/ritonavir
Intervention type(s): Drug; Drug
Intervention description(s): Darunavir/ritonavir 800/100 mg once daily; Lopinavir/ritonavir 400/100 mg twice daily
Other intervention name(s): N/P; N/P
Intervention MeSH terms: Ritonavir; Lopinavir; Darunavir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Darunavir; Lopinavir; Monotherapy; Antiretroviral simplification strategy; HIV; Treatment experienced