<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02242799</url>
  </required_header>
  <id_info>
    <org_study_id>PK13</org_study_id>
    <nct_id>NCT02242799</nct_id>
  </id_info>
  <brief_title>Dolutegravir Interactions With Artemisinin-based Combination Therapies</brief_title>
  <acronym>DolACT</acronym>
  <official_title>Evaluation of Dolutegravir Interactions With Artemether-Lumefantrine and Amodiaquine-Artesunate</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Liverpool</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ViiV Healthcare</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Makerere University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Liverpool</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Malaria and HIV are found in the same regions of the world and developing countries are most&#xD;
      affected by both diseases. For malaria, new drugs have been introduced called ACTs. These&#xD;
      drugs are effective against malaria but little is known about how the levels of these drugs&#xD;
      in blood relate to how effective these drugs are. For HIV, a new drug has been developed&#xD;
      called dolutegravir which has potential to be widely used in developing countries. This&#xD;
      proposal will explore how dolutegravir affects the drug levels of these antimalarial drugs&#xD;
      and vice versa. In total, 46 healthy volunteers will participate in this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      More than 90% of the malaria occurs in sub-Saharan Africa (WHO 2008), the region bearing 67%&#xD;
      of the global HIV burden (WHO 2011). Given the extensive overlap in geographical distribution&#xD;
      of these diseases, interactions between them could have profound public health consequences.&#xD;
      Significant biological interactions exist between HIV and malaria. HIV is known to increase&#xD;
      susceptibility to malaria infection (Whitworth, Morgan et al. 2000), compromise the host's&#xD;
      ability to clear malaria parasites (characterised by higher parasite densities) (Francesconi,&#xD;
      Fabiani et al. 2001), increase the risk of symptomatic malaria and contribute to malaria&#xD;
      treatment failure (Hewitt, Steketee et al. 2006). In areas of unstable transmission, malaria&#xD;
      mortality is higher in HIV-positive individuals. Additionally, placental malaria infection in&#xD;
      HIV positive individuals is associated with higher perinatal mortality, low birth weight and&#xD;
      HIV transmission, and this effect is not attenuated in subsequent pregnancies, in contrast&#xD;
      with HIV-negative individuals. Conversely, malaria infection has been shown to increase HIV&#xD;
      viral load (Hoffman, Jere et al. 1999, Kublin, Patnaik et al. 2005), with the potential for&#xD;
      both accelerated HIV disease progression and increased HIV transmission (Abu-Raddad, Patnaik&#xD;
      et al. 2006).&#xD;
&#xD;
      As of September 2011, Uganda had 1.4 million people living with HIV/AIDS; of those with&#xD;
      clinically advanced disease, 54% (313 117) were receiving ART (WHO). As southern African&#xD;
      countries are scaling up coverage of ART, they have also stepped up the fight against Pf&#xD;
      malaria by increasing the coverage of Insecticide Treated Nets and by adopting the use of&#xD;
      artemisinin-based combination therapies (ACTs) as first line treatment of malaria (USAID&#xD;
      2011). AL and AS-AQ are the most commonly utilized regimens in sub-Saharan Africa for first&#xD;
      line treatment for malaria (WHO 2008).&#xD;
&#xD;
      As a consequence of high rates of HIV-malaria co-infection and increasing availability of&#xD;
      both ACTs and ART in southern Africa, progressively more co-infected people will receive both&#xD;
      classes of drugs. However, the pharmacokinetics, safety and/or efficacy of ACTs such as AL,&#xD;
      AS-AQ and DHA-piperaquine in HIV-infected individuals who are on ART are poorly understood.&#xD;
      Many efficacy studies conducted as part of the drug development process of ACTs have either&#xD;
      not assessed the HIV status of study participants or systematically excluded HIV-infected&#xD;
      individuals. Few studies have systematically evaluated for potential drug-drug interactions&#xD;
      in a healthy volunteer setting.&#xD;
&#xD;
      Study Design&#xD;
&#xD;
      Open label, fixed sequence healthy volunteer study to compare pharmacokinetic interactions&#xD;
      between DTG and AL (Study A; crossover design), or AS-AQ (Study B; parallel group design).&#xD;
      Whilst a cross-over study design would be theoretically ideal for investigating both ACTs in&#xD;
      combination with DTG, desethylamodiaquine, an active metabolite of AQ has an extensive&#xD;
      terminal t1/2 of approximately 10 days; therefore it is not considered feasible to undertake&#xD;
      a cross-over design for this arm of the study, since the washout period between the two&#xD;
      phases would exceed two months, risking subject attrition. Furthermore, during that time&#xD;
      period, intercurrent illnesses and other important changes may occur within a subject,&#xD;
      leading changes in eligibility for the study. Therefore, two study designs are planned as&#xD;
      detailed in the Study Design Section.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2015</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">September 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in area under time-concentration curve [AUC] of DTG and antimalarial drugs</measure>
    <time_frame>At steady state (after 3 days dosing for antimalarials and 7 days for DTG)</time_frame>
    <description>When subjects are at steady state (of single drug or combination, as detailed in the study design section) intensive PK sampling will be performed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in maximum concentration [Cmax] of DTG and antimalarials</measure>
    <time_frame>At steady state (3 days for antimalarials and 7 days for DTG)</time_frame>
    <description>PK sampling will be done when each drug is at presumed 'steady state'</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in time to maximum concentration [Tmax] for antimalarials and DTG</measure>
    <time_frame>At steady state (3 days for antimalarials and 7 days for DTG)</time_frame>
    <description>Medications will be dosed up to steady state before PK sampling is undertaken</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in clearance [Cl/F] for antimalarials and DTG</measure>
    <time_frame>Steady state - 3 days for antimalarials and 7 days for dolutegravir</time_frame>
    <description>Medications will be dosed up to steady state prior to PK sampling</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in trough concentration [Ctrough]) for antimalarial drugs and DTG</measure>
    <time_frame>Steady state - 3 days for antimalarials and 7 days for DTG</time_frame>
    <description>PK sampling will be performed at steady state</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of the drug combinations</measure>
    <time_frame>Until 2 weeks after all medication has been discontinued at the end of study</time_frame>
    <description>Patients will be assessed clinically to identify safety concerns, panels of 'safety bloods' will be performed at the time of rich PK sampling, and 12 lead ECGs will assess potential effects of the drugs/ combinations on the QT interval</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>Malaria</condition>
  <condition>HIV</condition>
  <arm_group>
    <arm_group_label>Study A Sequence 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Artemether-lumefantrine combination alone for 3 days with PK sampling at steady state, then 21 day washout period followed by Dolutegravir 50mg od dosing to steady state (7 days) with PK sampling then a further 3 days where Artemether-lumefantrine combination and Dolutegravir 50mg od are given together, with PK sampling at steady state.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Study A Sequence 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dolutegravir 50mg od given for 7 days with PK sampling at steady state, followed immediately by a further 3 days where Artemether-lumefantrine combination and Dolutegravir 50mg od are given together, again with PK sampling at steady state. Following a 21 day washout period, the subject will then receive Artemether-lumefantrine combination alone for 3 days, with PK sampling at steady state.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Study B Sequence 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Administration of artesunate-amodiaquine for 3 days with PK sampling at steady state</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Study B Sequence 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dolutegravir alone for 7 days with PK sampling at steady state, followed immediately by administration of both artesunate-amodiaquine and dolutegravir together for a further 3 days with PK sampling at steady state</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dolutegravir 50mg od</intervention_name>
    <description>Dolutegravir 50mg once daily will be given either alone or in combination, as specified</description>
    <arm_group_label>Study A Sequence 1</arm_group_label>
    <arm_group_label>Study A Sequence 2</arm_group_label>
    <arm_group_label>Study B Sequence 2</arm_group_label>
    <other_name>Tivicay, ViiV Healthcare</other_name>
    <other_name>GSK1349572</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artemether-lumefantrine combination</intervention_name>
    <description>Artemether-lumefantrine combination will be given both alone and in combination with Dolutegravir 50mg od in order to assess changes in PK</description>
    <arm_group_label>Study A Sequence 1</arm_group_label>
    <arm_group_label>Study A Sequence 2</arm_group_label>
    <other_name>Co-artem</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artesunate-amodiaquine</intervention_name>
    <description>Artesunate-amodiaquine will be given alone or in combination with Dolutegravir 50mg od (in a parallel study design) in order to assess the potential interaction causing changes in PK parameters</description>
    <arm_group_label>Study B Sequence 1</arm_group_label>
    <arm_group_label>Study B Sequence 2</arm_group_label>
    <other_name>Coarsucam</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Evidence of a personally signed and dated informed consent document indicating that&#xD;
             the participant has been informed of all pertinent aspects of the study.&#xD;
&#xD;
          2. Participants who are willing and able to comply with scheduled visits, treatment plan,&#xD;
             laboratory tests, and other study procedures.&#xD;
&#xD;
          3. Men and women aged 18 years and above&#xD;
&#xD;
          4. Weight ≥40 kg&#xD;
&#xD;
          5. HIV antibody negative at screening.&#xD;
&#xD;
          6. Malaria blood film negative at screening&#xD;
&#xD;
          7. Willing to use mosquito bednets routinely for the duration of the study&#xD;
&#xD;
          8. Women of childbearing potential must be willing to use an effective barrier&#xD;
             contraception method for the duration of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Significant disease affecting cardiac, respiratory, gastrointestinal or neurological&#xD;
             symptoms which in the clinician's medical judgment could be worsened by participating&#xD;
             in this study or the presence of medical or surgical conditions which could prevent&#xD;
             the subject from complying with study procedures.&#xD;
&#xD;
          2. Serum alanine transaminase (ALT) levels above 3x upper limit of normal&#xD;
&#xD;
          3. Serum creatinine levels above 2x upper limit of normal&#xD;
&#xD;
          4. Hepatitis B surface antigen positive&#xD;
&#xD;
          5. Use of medications which are known inducers/inhibitors of CYP or glucuronyl&#xD;
             transferase UGT1A1 within past 2 months (e.g. anticonvulsants, TB medications, HIV&#xD;
             agents for prophylaxis, azole antifungals)&#xD;
&#xD;
          6. Evidence of QT prolongation on electrocardiogram (ECG) QTc (Rate adjusted QT interval)&#xD;
             &gt;450ms (men) or &gt;470ms (women)&#xD;
&#xD;
          7. Pregnant women or female subjects who are unwilling to use a suitable contraceptive&#xD;
             method for the duration of the study (condom, diaphragm, IUD or contraceptive implant)&#xD;
&#xD;
          8. Likely to be poorly adherent based on clinician's medical judgement&#xD;
&#xD;
          9. Known to be current injection drug user&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mohammed Lamorde, PhD, MBChB</last_name>
    <role>Study Director</role>
    <affiliation>Infectious Diseases Institute</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Saye H Khoo, FRCP, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Liverpool</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Infectious Diseases Institute</name>
      <address>
        <city>Kampala</city>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Uganda</country>
  </location_countries>
  <link>
    <url>https://www.viivhealthcare.com/media/58599/us_tivicay.pdf</url>
    <description>Dolutegravir product information</description>
  </link>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>September 13, 2014</study_first_submitted>
  <study_first_submitted_qc>September 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 17, 2014</study_first_posted>
  <last_update_submitted>October 4, 2016</last_update_submitted>
  <last_update_submitted_qc>October 4, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 5, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Liverpool</investigator_affiliation>
    <investigator_full_name>Catriona Waitt</investigator_full_name>
    <investigator_title>Site sub-investigator</investigator_title>
  </responsible_party>
  <keyword>Malaria</keyword>
  <keyword>HIV</keyword>
  <keyword>Dolutegravir</keyword>
  <keyword>Artemisinin</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Interactions</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Artesunate</mesh_term>
    <mesh_term>Lumefantrine</mesh_term>
    <mesh_term>Artemether</mesh_term>
    <mesh_term>Artemether, Lumefantrine Drug Combination</mesh_term>
    <mesh_term>Amodiaquine</mesh_term>
    <mesh_term>Dolutegravir</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02242799
org study id: PK13
nct id: NCT02242799
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Malaria and HIV are found in the same regions of the world and developing countries are most
      affected by both diseases. For malaria, new drugs have been introduced called ACTs. These
      drugs are effective against malaria but little is known about how the levels of these drugs
      in blood relate to how effective these drugs are. For HIV, a new drug has been developed
      called dolutegravir which has potential to be widely used in developing countries. This
      proposal will explore how dolutegravir affects the drug levels of these antimalarial drugs
      and vice versa. In total, 46 healthy volunteers will participate in this study.
More than 90% of the malaria occurs in sub-Saharan Africa (WHO 2008), the region bearing 67%
      of the global HIV burden (WHO 2011). Given the extensive overlap in geographical distribution
      of these diseases, interactions between them could have profound public health consequences.
      Significant biological interactions exist between HIV and malaria. HIV is known to increase
      susceptibility to malaria infection (Whitworth, Morgan et al. 2000), compromise the host's
      ability to clear malaria parasites (characterised by higher parasite densities) (Francesconi,
      Fabiani et al. 2001), increase the risk of symptomatic malaria and contribute to malaria
      treatment failure (Hewitt, Steketee et al. 2006). In areas of unstable transmission, malaria
      mortality is higher in HIV-positive individuals. Additionally, placental malaria infection in
      HIV positive individuals is associated with higher perinatal mortality, low birth weight and
      HIV transmission, and this effect is not attenuated in subsequent pregnancies, in contrast
      with HIV-negative individuals. Conversely, malaria infection has been shown to increase HIV
      viral load (Hoffman, Jere et al. 1999, Kublin, Patnaik et al. 2005), with the potential for
      both accelerated HIV disease progression and increased HIV transmission (Abu-Raddad, Patnaik
      et al. 2006).

      As of September 2011, Uganda had 1.4 million people living with HIV/AIDS; of those with
      clinically advanced disease, 54% (313 117) were receiving ART (WHO). As southern African
      countries are scaling up coverage of ART, they have also stepped up the fight against Pf
      malaria by increasing the coverage of Insecticide Treated Nets and by adopting the use of
      artemisinin-based combination therapies (ACTs) as first line treatment of malaria (USAID
      2011). AL and AS-AQ are the most commonly utilized regimens in sub-Saharan Africa for first
      line treatment for malaria (WHO 2008).

      As a consequence of high rates of HIV-malaria co-infection and increasing availability of
      both ACTs and ART in southern Africa, progressively more co-infected people will receive both
      classes of drugs. However, the pharmacokinetics, safety and/or efficacy of ACTs such as AL,
      AS-AQ and DHA-piperaquine in HIV-infected individuals who are on ART are poorly understood.
      Many efficacy studies conducted as part of the drug development process of ACTs have either
      not assessed the HIV status of study participants or systematically excluded HIV-infected
      individuals. Few studies have systematically evaluated for potential drug-drug interactions
      in a healthy volunteer setting.

      Study Design

      Open label, fixed sequence healthy volunteer study to compare pharmacokinetic interactions
      between DTG and AL (Study A; crossover design), or AS-AQ (Study B; parallel group design).
      Whilst a cross-over study design would be theoretically ideal for investigating both ACTs in
      combination with DTG, desethylamodiaquine, an active metabolite of AQ has an extensive
      terminal t1/2 of approximately 10 days; therefore it is not considered feasible to undertake
      a cross-over design for this arm of the study, since the washout period between the two
      phases would exceed two months, risking subject attrition. Furthermore, during that time
      period, intercurrent illnesses and other important changes may occur within a subject,
      leading changes in eligibility for the study. Therefore, two study designs are planned as
      detailed in the Study Design Section.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in area under time-concentration curve [AUC] of DTG and antimalarial drugs
time frame: At steady state (after 3 days dosing for antimalarials and 7 days for DTG)
description: When subjects are at steady state (of single drug or combination, as detailed in the study design section) intensive PK sampling will be performed
measure: Change in maximum concentration [Cmax] of DTG and antimalarials
time frame: At steady state (3 days for antimalarials and 7 days for DTG)
description: PK sampling will be done when each drug is at presumed 'steady state'
measure: Change in time to maximum concentration [Tmax] for antimalarials and DTG
time frame: At steady state (3 days for antimalarials and 7 days for DTG)
description: Medications will be dosed up to steady state before PK sampling is undertaken
measure: Change in clearance [Cl/F] for antimalarials and DTG
time frame: Steady state - 3 days for antimalarials and 7 days for dolutegravir
description: Medications will be dosed up to steady state prior to PK sampling
measure: Change in trough concentration [Ctrough]) for antimalarial drugs and DTG
time frame: Steady state - 3 days for antimalarials and 7 days for DTG
description: PK sampling will be performed at steady state
measure: Safety and tolerability of the drug combinations
time frame: Until 2 weeks after all medication has been discontinued at the end of study
description: Patients will be assessed clinically to identify safety concerns, panels of 'safety bloods' will be performed at the time of rich PK sampling, and 12 lead ECGs will assess potential effects of the drugs/ combinations on the QT interval
arm group label: Study A Sequence 1
arm group type: Experimental
description: Artemether-lumefantrine combination alone for 3 days with PK sampling at steady state, then 21 day washout period followed by Dolutegravir 50mg od dosing to steady state (7 days) with PK sampling then a further 3 days where Artemether-lumefantrine combination and Dolutegravir 50mg od are given together, with PK sampling at steady state.
arm group label: Study A Sequence 2
arm group type: Experimental
description: Dolutegravir 50mg od given for 7 days with PK sampling at steady state, followed immediately by a further 3 days where Artemether-lumefantrine combination and Dolutegravir 50mg od are given together, again with PK sampling at steady state. Following a 21 day washout period, the subject will then receive Artemether-lumefantrine combination alone for 3 days, with PK sampling at steady state.
arm group label: Study B Sequence 1
arm group type: Experimental
description: Administration of artesunate-amodiaquine for 3 days with PK sampling at steady state
arm group label: Study B Sequence 2
arm group type: Experimental
description: Dolutegravir alone for 7 days with PK sampling at steady state, followed immediately by administration of both artesunate-amodiaquine and dolutegravir together for a further 3 days with PK sampling at steady state
intervention type: Drug
intervention name: Dolutegravir 50mg od
description: Dolutegravir 50mg once daily will be given either alone or in combination, as specified
arm group label: Study A Sequence 1
arm group label: Study A Sequence 2
arm group label: Study B Sequence 2
other name: Tivicay, ViiV Healthcare
other name: GSK1349572
intervention type: Drug
intervention name: Artemether-lumefantrine combination
description: Artemether-lumefantrine combination will be given both alone and in combination with Dolutegravir 50mg od in order to assess changes in PK
arm group label: Study A Sequence 1
arm group label: Study A Sequence 2
other name: Co-artem
intervention type: Drug
intervention name: Artesunate-amodiaquine
description: Artesunate-amodiaquine will be given alone or in combination with Dolutegravir 50mg od (in a parallel study design) in order to assess the potential interaction causing changes in PK parameters
arm group label: Study B Sequence 1
arm group label: Study B Sequence 2
other name: Coarsucam
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Mohammed Lamorde, PhD, MBChB
role: Study Director
affiliation: Infectious Diseases Institute
last name: Saye H Khoo, FRCP, PhD
role: Principal Investigator
affiliation: University of Liverpool
facility: 
country: Uganda
url: https://www.viivhealthcare.com/media/58599/us_tivicay.pdf
description: Dolutegravir product information
responsible party type: Principal Investigator
investigator affiliation: University of Liverpool
investigator full name: Catriona Waitt
investigator title: Site sub-investigator
mesh term: Malaria
mesh term: Artesunate
mesh term: Lumefantrine
mesh term: Artemether
mesh term: Artemether, Lumefantrine Drug Combination
mesh term: Amodiaquine
mesh term: Dolutegravir