Atazanavir/r + Lamivudine Dual Therapy
Condition: Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to evaluate the virological efficacy of maintenance therapy with
      atazanavir with ritonavir combined with lamivudine in treatment experienced HIV positive
      patients with full and stable virological suppression.
    

Detailed description: 
      The introduction of combined antiretroviral therapy (cART) dramatically improved the
      prognosis of HIV infection [1]; nowadays, virological suppression (viral load < 50 copies/mL)
      can be obtained in the vast majority of patients receiving cART. Nevertheless, antiretroviral
      drugs have short- and long-term side effects mainly regarding mitochondrial toxicity,
      impaired lipid and glucose metabolism, impairment of renal function and bone density and may
      contribute to increase the patients' cardiovascular risk.

      Current treatment guidelines recommend three drug regimens with a "backbone" of 2
      nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs) and a "third drug" to be chosen
      among non-nucleoside reverse transcriptase inhibitors (NNRTIs) and ritonavir-boosted protease
      inhibitors (PIr). Regimens containing less than three antiretroviral drugs are currently not
      recommended based on the high risk of virological failure and selection of drug resistance
      mutations (DRM) with previous experience of NRTI-only based approaches with the exception of
      boosted PIs monotherapy which is optional in patients with intolerance to NRTIs or requiring
      treatment simplification provided that they never experienced virological failures or
      admitted in exceptional circumstances.

      Nevertheless, the investigation of possible new treatment paradigms remains attractive due to
      the high potency and low risk of selection of drug resistance mutations with PIr based
      therapies and the established long term toxicity of even newer and currently preferred
      N(t)RTIs, in particular the renal and bone toxicity of tenofovir and the debated potential
      association with increased cardiovascular risk of abacavir, which has been described in some
      cohort studies. Studies evaluating N(t)RTI-sparing treatment strategies are thus increasing
      in order to try to respond to the unmet medical needs of HIV-infected patients with metabolic
      complications and increasing risk of cardiovascular or renal diseases.

      These studies will need to investigate the safety and efficacy of these alternative
      strategies, also evaluating their possible effects on renal function, bone mass density and
      risk of premature osteoporosis.

      Atazanavir with ritonavir is a generally well tolerated lipid-friendly protease inhibitor
      with mild effects on lipid metabolism even when combined with low-dose ritonavir and is the
      only drug who achieved a non-significant difference in virological efficacy compared to
      efavirenz; like all other PIr-based regimens, failure of an atazanavir/ritonavir containing
      cART seems to protect against the development of drug resistance mutations to both the PI and
      the backbone. Lamivudine is a well tolerated NRTI which showed no significant toxicity in the
      short and long term and, together with its analog emtricitabine, is now a preferred option in
      most of the major international treatment guidelines; it has a good CNS penetration score and
      its only signature resistance mutation (M184V) deeply impairs the viral fitness and does not
      compromise the future treatment options.

      The combination of these two drugs could therefore be an appealing possibility for treatment
      switch in stably virologically suppressed treatment-experienced patients with
      toxicity-related issues. The results of a previously planned 24 weeks interim analysis of a
      monocentric 48 weeks Italian pilot study evaluating this strategy in 40 patients has recently
      been presented at IAS conference in Vienna and showed no virologic failures without any
      "blip" and good tolerability with a significant improvement of renal function as measured by
      MDRD. These data look very promising and allow us to be confident in designing a randomized
      study in order to confirm these findings.
    

Intervention name(s): Atazanavir, ritonavir, lamivudine
Intervention type(s): Drug
Intervention description(s): Lamivudine 300 mg 1 pill once-a-day, atazanavir 300 mg 1 pill with ritonavir 100 mg 1 pill once-a-day, taken together orally with a light meal
Other intervention name(s): Lamivudine (Epivir, GSK), Atazanavir (Reyataz, BMS), Ritonavir (Norvir, Abbott)
Intervention MeSH terms: Ritonavir; Atazanavir Sulfate; Lamivudine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV infection; Atazanavir; Lamivudine; Ritonavir; virological suppression; non-inferiority; Combined antiretroviral therapy