EFFICACY AND SAFETY OF A SIMPLIFICATION STRATEGY BASED ON DOLUTEGRAVIR AND DARUNAVIR / COBICISTAT VS OPTIMIZED TREATMENT IN SUPPRESSED HIV-1-INFECTED PATIENTS CARRYING ARCHIVED MULTIDRUG RESISTANCE MUTATIONS
Condition: HIV-1 Infection
Study type: Interventional
Phase: Phase 4

Summary: 
      The availability of antiretroviral therapy has led to a reduction in morbidity and mortality
      in patients with chronic HIV infection. The treatment, however, is not free of side effects,
      has potential interactions with other medications, is expensive and can be complex,
      especially in those patients who are very experienced and with mutations that give them
      resistance to multiple drugs. For this reason, the development of simplification strategies
      that avoid unnecessary exposure to antiretroviral agents remains of great interest.

      This is a simplification study, in which the investigators try to evaluate that with less
      medication the investigator can maintain the same virological control of the disease. This
      would mean a lower burden of medication for patients, facilitating its administration and
      reducing the number of unwanted side effects.

      Specifically, the investigators intend to evaluate the treatment with Darunavir / cobicistat
      plus Dolutegravir as a simplification strategy, since both drugs are taken once a day, have a
      powerful antiviral activity, even against antiretroviral resistant viruses, and are among the
      best tolerated (with fewer side effects). The results reported in some observational studies
      suggest that two-drug therapy (bitherapy) as a simplification strategy could also be safe and
      effective, however, as far as the investigators know, there are no data and clinical trials
      that specifically evaluate darunavir / cobicistat plus dolutegravir as a strategy of
      simplification.
    

Detailed description: 
      The availability of antiretroviral therapy (ART) has led to a reduction in morbidity and
      mortality in patients with chronic HIV infection. ART, however, is not free of side effects,
      has potential pharmacological interactions with other drugs, is expensive and can be complex,
      especially in those patients with high therapeutic experience and archived antiretroviral
      drug resistance mutations (DRM). For this reason, the development of simplified and equally
      effective therapeutic strategies that save patients from exposure to antiretroviral agents
      remains of great interest, even in patients with DRM and limited therapeutic options.

      Currently, Darunavir (DRV) in combination with either ritonavir (RTV) or cobicistat (COBI) is
      the most widely recommended boosted protease inhibitor. It is used in most clinical settings,
      including those with limited therapeutic options and highly ART-experienced patients carrying
      multiple DRM. In addition, DRV has good tolerance and safety profiles, a high genetic barrier
      and can be administered once daily in patients harboring DRM in the viral protease with
      little or no impact on viral sensitivity (1). As a booster, RTV has an inducing effect on
      glucuronidation and a broad and potent inhibitory effect on cytochrome P-450 (CYP) isozymes
      and drug transporters, resulting in a significant number of drug interactions. A low dose of
      RTV does not appear to cause substantial antiviral activity, although its theoretical
      contribution to the emergence of drug resistance is still unclear. By contrast, the
      metabolism of COBI is predominantly via CYP3A4 oxidation and, to a lesser degree, CYP2D6.
      COBI does not undergo glucuronidation. In addition, 99% of COBI remains unchanged, and the
      resulting metabolites do not seem to show any clinically relevant inhibitory activity.

      Dolutegravir (DTG) is the latest available agent within the antiretroviral class of integrase
      strand-transfer inhibitors (INSTI). In this group, DTG is the drug with the greatest genetic
      barrier, derived from its greater affinity for integrase and its consequent longer
      dissociation time of the drug-integrase complex. The development of DTG resistance associated
      mutations reported in the clinical setting has been purely anecdotal, and it has not been
      observed in clinical trials in naïve patients. Moreover, DTG retains the ability to inhibit
      viral replication when integrase associated mutations have been selected by other INSTI-based
      treatments (i.e., raltegravir and elvitegravir/cobicistat). DTG may also favor therapeutic
      adherence due to its high tolerability and easy administration with once or twice daily
      dosages depending on the absence or presence of mutations in the integrase or prior failures
      with other INSTIs. Finally, DTG is eliminated mainly through metabolism by UGT1A1, and it is
      also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP. Therefore, all drugs that induce
      these enzymes may decrease DTG's plasma concentration and reduce its therapeutic effect. In
      one study, coadministration of DRV/rtv (600/100 mg twice daily) and DTG (30 mg once daily)
      decreased DTG Cmax, AUC and Ctrough by 11%, 22% and 38%, respectively (2). Despite these
      changes, it is assumed that DRV/rtv has no clinically significant effect on the
      pharmacokinetics of DTG and no dose adjustment is recommended.

      It has been established that it is necessary to have at least two active drugs within the
      optimized ART to achieve and maintain virological suppression in multi-treated patients with
      multiple DRM. In addition, some studies have shown that recycled NRTIs or NNRTIs with
      residual activity are not necessary and can be withdrawn from ART optimized regimens in
      extensively pretreated patients with sustained virological suppression (3). In fact, limited
      data from some observational and clinical studies further suggest that bitherapy as
      simplification strategy could be also safe and effective (4). Recently, an observational
      study performed on a limited and heterogeneous number of highly pretreated patients who were
      switched to DRV/rtv plus DTG reported efficacy rates of virological suppression of up to 98%
      at 48 weeks (5). In addition, there are two ongoing studies (NCT02491242 and NCT02486133)
      that are currently evaluating bitherapy consisting of DTG and DRV. The first of these studies
      is an observational study with no comparator arm which is evaluating the efficacy of
      DTG-based bitherapy, including RPV, 3TC, or boosted DRV (both with RTV and COBI) as the
      second agent. The second one is a clinical study comparing the switch to DTG plus DRV/rtv vs.
      triple ART based on DRV/rtv in patients with limited ART experience and virological
      suppression. Due to the greater specificity of COBI for CYP3A4 and its lack of effect on
      glucuronidation in comparison to RTV, DTG plus DRV/cobi bitherapy would constitute a
      simplification strategy for ART consisting of two drugs with well-known efficacy, safety,
      tolerability, high genetic barrier, once-daily administration, and relatively less potential
      for pharmacological interactions than traditional optimized based regimens. As far as the
      investigators know, however, there are no pharmacokinetic data and clinical trials
      specifically evaluating DRV/cobi plus DTG as a simplification strategy.
    

Intervention name(s): Dolutegravir (DTG) plus Darunavir/cobicistat (DRV/cobi).; Current ART
Intervention type(s): Drug; Drug
Intervention description(s): bitherapy based on DTG (50 mg QD) plus DRV/cobi (800/150 mg QD); To continue with their current ART
Intervention MeSH terms: Dolutegravir; Darunavir; Cobicistat; Cobicistat mixture with darunavir
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Experimental group: bitherapy based on DTG (50 mg QD) plus DRV/cobi (800/150 mg QD)
Control group: continuation of their current stable ART.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Simplification strategy; Multidrug resistant; Dolutegravir; Darunavir/cobicistat; Bitherapy