<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/NCT04453436</url>
  </required_header>
  <id_info>
    <org_study_id>SPARC-8</org_study_id>
    <nct_id>NCT04453436</nct_id>
  </id_info>
  <brief_title>HIV Drug Resistance Among Individuals Failing Tenofovir/Lamivudine and Dolutegravir First Line Regimen in Brazil</brief_title>
  <official_title>HIV Drug Resistance Profiles Among Individuals Failing Tenofovir/Lamivudine and Dolutegravir First Line Regimen in Brazil</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Federal University of São Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Gilead Sciences</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Federal University of São Paulo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Brazil was the first middle-income country to provide free and universal access to&#xD;
      antiretroviral drugs to HIV infected individuals. Since 2014 local guidelines recommend that&#xD;
      all HIV infected individuals be started on therapy regardless of CD4 count. Since January&#xD;
      2017, all patients are started on a DTG containing triple regimen. As of November 2018,&#xD;
      170,000 individuals were receiving DTG through the public health system. It is a public&#xD;
      health priority to evaluate the risk of virologic failure and the subsequent development of&#xD;
      INSTI resistance in these real-life settings. Our preliminary data from Brazil indicated a&#xD;
      high virologic failure rate of 8% after 18 months of treatment TL+D. Our central hypothesis&#xD;
      is that TDR may be associated and contribute to virologic failure with DTG in clinical&#xD;
      practice. To test this central hypothesis, we will identify PLWH failing DTG containing&#xD;
      regimens in Brazil. The insights generated with these studies will contribute to a more&#xD;
      effective use of second generation INSTI in the future.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      SPECIFIC AIMS We are on the verge of the global rollout of the second-generation integrase&#xD;
      strand-transfer inhibitor (INSTI) dolutegravir (DTG), as the World Health Organization (WHO)&#xD;
      now recommends the combination of DTG + 2 nucleoside reverse transcriptase inhibitors (NRTIs)&#xD;
      as first- and second-line therapy. As a result, millions of people living with HIV (PLWH)&#xD;
      will soon receive DTG. In clinical trials, which mainly included people infected with HIV-1&#xD;
      subtype B, the combination of DTG + 2 NRTIs demonstrated very high efficacy and acquired drug&#xD;
      resistance was absent (first-line treatment) or very rare (second-line treatment) in the&#xD;
      event of virologic failure. It is not clear if this high efficacy and lack of acquired drug&#xD;
      resistance can be extrapolated to clinical practice in low- and middle-income countries,&#xD;
      where the majority of PLWH live and where most infections are due to non-B subtypes.&#xD;
      Furthermore, in the pivotal studies for initial treatment with DTG, candidates harboring&#xD;
      virus resistant to NRTIs met the exclusion criteria of these studies. Although DTG failure in&#xD;
      first line regimens in clinical trials reveal the absence of integrase resistance, it is&#xD;
      conceivable that mutations at other HIV genomic regions such as 5´PPT (nef) could contribute&#xD;
      to DTG lack of efficacy.&#xD;
&#xD;
      Brazil was the first middle-income country to provide free and universal access to&#xD;
      antiretroviral drugs to HIV infected individuals. Since 2014 local guidelines recommend that&#xD;
      all HIV infected individuals be started on therapy regardless of CD4 count. Since January&#xD;
      2017, all patients are started on a DTG containing triple regimen. As of November 2018,&#xD;
      170,000 individuals were receiving DTG through the public health system. It is a public&#xD;
      health priority to evaluate the risk of virologic failure and the subsequent development of&#xD;
      INSTI resistance in these real-life settings. Our preliminary data from Brazil indicated a&#xD;
      high virologic failure rate of 8% after 18 months of treatment TL+D. Moreover, acquired drug&#xD;
      resistance was observed in first-line virologic failures (15 out of 84 investigated&#xD;
      individuals). A relatively high rate of transmitted drug resistance (TDR) was also observed&#xD;
      among those 84 individuals (15.6%) Our central hypothesis is that TDR may be associated and&#xD;
      contribute to virologic failure with DTG in clinical practice. To test this central&#xD;
      hypothesis, we will identify PLWH failing DTG containing regimens in Brazil, a model country&#xD;
      for large-scale DTG implementation where various HIV subtypes co-circulate. The insights&#xD;
      generated with these studies will contribute to a more effective use of second generation&#xD;
      INSTI in the future.&#xD;
&#xD;
      The specific aims of this proposal are as follows:&#xD;
&#xD;
        1. Investigate the influence of Transmitted Drug resistance, HIV clade profile and&#xD;
           immunological and virological features among individuals failing first line regimen with&#xD;
           Tenofovir/3TC + Dolutegravir after 24 weeks of treatment in Brazil.&#xD;
&#xD;
        2. Determine the genotypic resistance profile among individuals failing first line regimen&#xD;
           with Tenofovir/3TC + DTG after 24 weeks of treatment in Brazil.&#xD;
&#xD;
        3. Determine which changes in the 3'-PPT are observed in viruses from patients experiencing&#xD;
           TL+D failure and assess if this novel resistance pathway contributes to acquired drug&#xD;
           resistance in clinical practice.&#xD;
&#xD;
      The results from the proposed study can be used to optimize care of PLWH by improving&#xD;
      treatment guidelines and drug resistance interpretation algorithms.&#xD;
&#xD;
      RESEARCH PLAN SIGNIFICANCE The World Health Organization (WHO) recently changed the HIV&#xD;
      treatment guidelines and now recommends the second-generation integrase strand-transfer&#xD;
      inhibitor (INSTI) dolutegravir (DTG) + 2 nucleoside reverse transcriptase inhibitors (NRTIs)&#xD;
      as first- and second-line therapy for people living with HIV (PLWH). As a result, millions of&#xD;
      people living with HIV (PLWH) will soon receive DTG in low- and middle-income countries where&#xD;
      the majority of PLWH live. Considerations of the WHO for the transition from efavirenz-based&#xD;
      regimens to DTG-based regimens are the high efficacy of DTG-based regimens, the relatively&#xD;
      low costs of producing generic DTG formulations, and the low risk for baseline DTG resistance&#xD;
      and acquired DTG resistance. In clinical trials, DTG + 2 nucleoside reverse transcriptase&#xD;
      inhibitors (NRTIs) demonstrated high efficacy in treatment naïve patients with viral&#xD;
      suppression (&lt;50 c/mL) at week 48 in 90% (FLAMINGO), 88% (SPRING-2), 88% (SINGLE) and 82%&#xD;
      (ARIA) of the participants with only 1-2% of data not in the window of &lt;50 c/mL. Of major&#xD;
      importance, these trials showed that in the event of virologic failure no known resistance&#xD;
      associated mutations (RAMs) could be detected in the integrase and reverse transcriptase&#xD;
      gene. Similarly, DTG + 2 NRTIs showed high efficacy in treatment experienced INSTI naïve PLWH&#xD;
      and acquired drug resistance was rare5. However, clinical trial participants are selected and&#xD;
      closely monitored, including extra doctor's visits, more frequent viral load measurements and&#xD;
      genotypic resistance analyses, and are switched more rapidly to other combination&#xD;
      antiretroviral therapy (cART) in the event of virologic failure. It is not clear if this high&#xD;
      efficacy and lack of acquired drug resistance will carry on in clinical practice in low- and&#xD;
      middle-income countries. Therefore, it is now a public health priority to evaluate the risk&#xD;
      of virologic failure and subsequent development of INSTI resistance in real life settings in&#xD;
      these countries. We propose to perform such studies in Brazil, a country with 860,000 PLWH,&#xD;
      as this country already implemented DTG regimens and thus can serve as a model for other low-&#xD;
      and middle-income countries.&#xD;
&#xD;
      Preliminary data on efficacy and acquired drug resistance of DTG + 2 NRTIs in Brazil.&#xD;
&#xD;
      From January 2017, the recommended first-line regimen in Brazil is the fixed dose combination&#xD;
      of generic tenofovir 300 mg plus lamivudine 300 mg combined with DTG 50 mg (TL+D). In 2017,&#xD;
      54,175 PLWH started TL+D as first-line regimen in Brazil, and 26,417 PLWH were switched from&#xD;
      raltegravir-containing cART to TL+D, comprising 77% of individuals initiating cART in this&#xD;
      country. As shown in Figure 1, 8% of individuals receiving TL+D had a viral load &gt;50 c/mL&#xD;
      after 18 months of treatment which is higher than expected based on clinical trial results.&#xD;
      In general, from the 581,064 individuals on treatment in Brazil as of December 2017, 85%&#xD;
      presented with viral loads &lt; 50 c/mL (Source: MS/SVS/Departamento de IST, Aids e Hepatites&#xD;
      Virais, Brasil). As of November 2018, 170,000 PLWH receive DTG in Brazil.&#xD;
&#xD;
      Among 84 individuals who experienced virologic failure during first-line treatment with TL+D,&#xD;
      11 presented low level viremia (50-500 c/mL), In five patients (5.9%) major resistance&#xD;
      associated mutations were detected at IN: 2 patients with R263Q, one with G118R, one with&#xD;
      E138A, and one with R263R/K in IN plus K70E+M184V in RT. Six (7.1%) additional individuals&#xD;
      presented minor IN resistance mutations: L74I/M (2 cases); G140R+G163R; V151A; V151I; T97A;&#xD;
      E157Q; and M50I. The prevalence of the polymorphic IN mutations L101I and T124A, which are in&#xD;
      vitro pathway for resistance, were 53.5% and 46.4%, respectively, significantly higher than&#xD;
      in Brazilian INSTI naïve patients. Eight (9.5%) patients presented T+L RAM in the RT,&#xD;
      including 3 with K70E+M184V. Mutations not related to TL+D (e.g., TAMs, NNRTI and PI) were&#xD;
      present in 25.6% of the patients, significantly higher than in a representative national&#xD;
      sample of 1,568 antiretroviral naïve patients we have tested. All these results are depicted&#xD;
      in Table 1. Therefore, the detection of IN and RT RAMs upon virologic failure indicates that&#xD;
      selected resistance to first-line TL+D is more common than what has been reported in clinical&#xD;
      trials. The apparent association between TL+D failure in Brazil and TDR should be better&#xD;
      evaluated, as well as the role of IN polymorphic mutations that can emerge during DTG&#xD;
      failure. Together, these results warrant further investigations of virologic failure and&#xD;
      subsequent acquired INSTI resistance in this setting.&#xD;
&#xD;
      Among 84 individuals who experienced virologic failure during first-line treatment with TL+D,&#xD;
      11 presented low level viremia (50-500 c/mL), In five patients (5.9%) major resistance&#xD;
      associated mutations were detected at IN: 2 patients with R263Q, one with G118R, one with&#xD;
      E138A, and one with R263R/K in IN plus K70E+M184V in RT. Six (7.1%) additional individuals&#xD;
      presented minor IN resistance mutations: L74I/M (2 cases); G140R+G163R; V151A; V151I; T97A;&#xD;
      E157Q; and M50I. The prevalence of the polymorphic IN mutations L101I and T124A, which are in&#xD;
      vitro pathway for resistance, were 53.5% and 46.4%, respectively, significantly higher than&#xD;
      in Brazilian INSTI naïve patients. Eight (9.5%) patients presented T+L RAM in the RT,&#xD;
      including 3 with K70E+M184V. Mutations not related to TL+D (e.g., TAMs, NNRTI and PI) were&#xD;
      present in 25.6% of the patients, significantly higher than in a representative national&#xD;
      sample of 1,568 antiretroviral naïve patients we have tested. All these results are depicted&#xD;
      in Table 1. Therefore, the detection of IN and RT RAMs upon virologic failure indicates that&#xD;
      selected resistance to first-line TL+D is more common than what has been reported in clinical&#xD;
      trials. The apparent association between TL+D failure in Brazil and TDR should be better&#xD;
      evaluated, as well as the role of IN polymorphic mutations that can emerge during DTG&#xD;
      failure. Together, these results warrant further investigations of virologic failure and&#xD;
      subsequent acquired INSTI resistance in this setting.&#xD;
&#xD;
      APPROACH&#xD;
&#xD;
      Study design: This is a prospective nested case control study comparing the baseline HIV&#xD;
      profile of individuals experiencing virologic failure to TL+D regimen after 24 weeks of&#xD;
      treatment initiation (cases) to randomly selected 2:1 control individuals with viral load&#xD;
      bellow detection limits 24 weeks after treatment initiation.&#xD;
&#xD;
      Identification of PLWH who fail DTG in Brazil PLWH will be included at 5 large clinical sites&#xD;
      in Brazil: one collection site will be in the far South of Brazil where 85% of strains are&#xD;
      subtype C, the northeast of Brazil where 30% of samples are subtype F, the city of Santos,&#xD;
      South-east of Brazil where 50% of strains are BF recombinant forms (CRF_28, CRF_29, and&#xD;
      unique recombinant forms), Sao Paulo and Rio de Janeiro. At each site a research nurse will&#xD;
      identify PLWH that will initiate a TL + D regimen, and baseline samples will be collected and&#xD;
      send to the Central Laboratory (R Diaz, PI) after an informal consent. At this time,&#xD;
      epidemiological, virological and immunological data will be collected from each patient, and&#xD;
      stored in a Central database. We expect to recruit 2,500 patients initiating antiretroviral&#xD;
      therapy in a 24-week period. Those recruited patients will be oriented to perform a plasma&#xD;
      viral load after 12 and 24 weeks of recruitment. We expect that by week 24, 8% of recruited&#xD;
      individuals will reach the primary end point of the study which is the antiretroviral&#xD;
      virologic failure, and Blood samples from these individuals will be also sent to the Diaz&#xD;
      laboratory for genotypic resistance testing.&#xD;
&#xD;
      Cases and controls will be defined as:&#xD;
&#xD;
        -  Cases: HIV infected individuals with subtype C, subtype F, or BF recombinant forms who&#xD;
           use TL+D for at least 24 weeks and have a confirmed plasma viral load &gt; 200 copies/mL.&#xD;
           We expect to include samples from 200 individuals experiencing virologic failure as&#xD;
           defined above.&#xD;
&#xD;
        -  Controls: HIV infected individuals with subtype C, subtype F, or BF recombinant forms&#xD;
           who use TL+D for at least 24 weeks and have a confirmed plasma viral load &lt; 50&#xD;
           copies/mL. We will randomly select 400 samples from control individuals in order to&#xD;
           characterize by genomic sequencing the HIV strains present at baseline, before treatment&#xD;
           initiation.&#xD;
&#xD;
      Based on the total number of PLWH receiving DTG containing cART at these three sites, our&#xD;
      preliminary results showing a virologic failure rate of 8%, and assuming that 10% will be&#xD;
      lost to follow-up, we will recruit 2,500 PLWH in order to obtain 200 individuals experiencing&#xD;
      virologic failure. Based on our preliminary results, it is safe to conservatively assume that&#xD;
      10% of these patients will harbor TDR at baseline.&#xD;
&#xD;
      Coordination of inclusion of PLWH at the clinical sites:&#xD;
&#xD;
      In Brazil, all HIV infected individuals are entitled to free access to antiretroviral&#xD;
      therapy. As of November 2018, 170,000 individuals were receiving DTG through the public&#xD;
      health system. Participants for the present study will be recruited in 5 large clinical&#xD;
      units, all highly experienced in the conduct of multicenter studies. In each site a specially&#xD;
      dedicated research nurse will be hired. He/she will be responsible for identifying,&#xD;
      recruiting, consenting, and ensuring follow-up of study participants.&#xD;
&#xD;
      Database management:&#xD;
&#xD;
      A private repository will be set up on GitHub (https://github.com/) that will give access to&#xD;
      remote researchers (physicians and nurses) and to Central coordination for data management&#xD;
      and analysis at Diaz´s Retrovirology Laboratory. We will prepare a short form in Excel format&#xD;
      for the remote researchers to use to enter the data and serve as an electronic Case Report&#xD;
      Form. For every patient, remote researchers will enter the needed data, and all the entries&#xD;
      will be combined into a database and bring the individuals files down onto our computers at&#xD;
      the Retrovirology Lab to be stored offline. The analyses will be performed by Dr. James R&#xD;
      Hunter from the Retrovirology Lab.&#xD;
&#xD;
      Anticipated results and alternative approaches:&#xD;
&#xD;
      We do not anticipate difficulties in recruiting the expected number of cases and controls.&#xD;
      Nonetheless, expanding to other sites should not represent any major challenge. This is&#xD;
      because the laboratories in each of the five sites are responsible for performing viral loads&#xD;
      for several primary care facilities in their respective cities. Thus, the same procedures&#xD;
      could be expanded to recruit participants from primary care facilities located in the&#xD;
      proximity of the main hospitals.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 1, 2020</start_date>
  <completion_date type="Anticipated">January 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2021</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>24 Months</target_duration>
  <primary_outcome>
    <measure>HIV RNA Viral Load</measure>
    <time_frame>24 weeks</time_frame>
    <description>Viral load in patient trated with first line treatment withTenofovir/3TC + Dolutegravir</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>HIV transcriptase resitance mutations</measure>
    <time_frame>24 weeks</time_frame>
    <description>HIV reverse transcriptase resistance test in virologic failure patient</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIV integrase resitance mutations</measure>
    <time_frame>24 weeks</time_frame>
    <description>HIV transcriptase resistance test in virologic failure patient</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">2500</enrollment>
  <condition>HIV</condition>
  <condition>Drug</condition>
  <condition>Resistance</condition>
  <arm_group>
    <arm_group_label>Virologic failure</arm_group_label>
    <description>Viral load above detection limits at window period</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Virologic Success</arm_group_label>
    <description>Viral load bellow detection limits at window period</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tenofovir Disoproxil</intervention_name>
    <description>Genotipic resistance test</description>
    <arm_group_label>Virologic Success</arm_group_label>
    <arm_group_label>Virologic failure</arm_group_label>
    <other_name>Lamivudine</other_name>
    <other_name>Dolutegravir</other_name>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      plasma sample&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        2500 HIV positive brazilian&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patints starting first line anti HIV treatment with Tenofovir/laimudine + Dolutegravir No&#xD;
        previous antiretroviral treatment&#xD;
&#xD;
        ≥ 18 ≤ 65 y.o&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Not to be able to understand and sign the informed consent form&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Ricardo S Diaz, MD., PhD</last_name>
    <phone>+55 11 991090445</phone>
    <email>rsdiaz@catg.com.br</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tania R. C. Vergara, MD, PhD</last_name>
    <phone>+55 21 991621308</phone>
    <email>taniavergara@globo.com</email>
  </overall_contact_backup>
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    <citation>Phillips AN, Cambiano V, Nakagawa F, Revill P, Jordan MR, Hallett TB, Doherty M, De Luca A, Lundgren JD, Mhangara M, Apollo T, Mellors J, Nichols B, Parikh U, Pillay D, Rinke de Wit T, Sigaloff K, Havlir D, Kuritzkes DR, Pozniak A, van de Vijver D, Vitoria M, Wainberg MA, Raizes E, Bertagnolio S; Working Group on Modelling Potential Responses to High Levels of Pre-ART Drug Resistance in Sub-Saharan Africa. Cost-effectiveness of public-health policy options in the presence of pretreatment NNRTI drug resistance in sub-Saharan Africa: a modelling study. Lancet HIV. 2018 Mar;5(3):e146-e154. doi: 10.1016/S2352-3018(17)30190-X. Epub 2017 Nov 22.</citation>
    <PMID>29174084</PMID>
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    <citation>World Health Organization. Transition to new antiretrovirals in HIV programmes: Policy brief. WHO/HIV/2017.20. 2017.</citation>
  </reference>
  <reference>
    <citation>Mantovani NP, Azevedo RG, Rabelato JT, Sanabani S, Diaz RS, Komninakis SV. Analysis of transmitted resistance to raltegravir and selective pressure among HIV-1-infected patients on a failing HAART in Sao Paulo, Brazil. J Clin Microbiol. 2012 Jun;50(6):2122-5. doi: 10.1128/JCM.00539-12. Epub 2012 Mar 7.</citation>
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  </reference>
  <reference>
    <citation>Inocencio LA, Pereira AA, Sucupira MC, Fernandez JC, Jorge CP, Souza DF, Fink HT, Diaz RS, Becker IM, Suffert TA, Arruda MB, Macedo O, Simao MB, Tanuri A. Brazilian Network for HIV Drug Resistance Surveillance: a survey of individuals recently diagnosed with HIV. J Int AIDS Soc. 2009 Sep 18;12:20. doi: 10.1186/1758-2652-12-20.</citation>
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    <citation>Arruda MB, Boullosa LT, Cardoso CC, da Costa CM, Alves CR, de Lima ST, Kaminski HT, Aleixo AW, Esposito AO, Cavalcanti AM, Riedel M, Couto-Fernandez JC, Ferreira SB, de Oliveira IC, Portal LE, Wolf HH, Fernandes SB, de M C Pardini MI, Feiteiro MV, Tolentino FM, Diaz RS, Lopes GI, Francisco RB, Veras NM, Pires AF, Franchini M, Mesquita F, Tanuri A; HIV-BResNet. Brazilian network for HIV Drug Resistance Surveillance (HIV-BresNet): a survey of treatment-naive individuals. J Int AIDS Soc. 2018 Mar;21(3):e25032. doi: 10.1002/jia2.25032.</citation>
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  </reference>
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    <citation>Brindeiro RM, Diaz RS, Sabino EC, Morgado MG, Pires IL, Brigido L, Dantas MC, Barreira D, Teixeira PR, Tanuri A; Brazilian Network for Drug Resistance Surveillance. Brazilian Network for HIV Drug Resistance Surveillance (HIV-BResNet): a survey of chronically infected individuals. AIDS. 2003 May 2;17(7):1063-9. doi: 10.1097/00002030-200305020-00016.</citation>
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  </reference>
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    <citation>Sabino EC, Shpaer EG, Morgado MG, Korber BT, Diaz RS, Bongertz V, Cavalcante S, Galvao-Castro B, Mullins JI, Mayer A. Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil. J Virol. 1994 Oct;68(10):6340-6. doi: 10.1128/JVI.68.10.6340-6346.1994.</citation>
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  </reference>
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    <PMID>16438639</PMID>
  </reference>
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    <citation>Sucupira MC, Munerato P, Silveira J, Santos AF, Janini LM, Soares MA, Diaz RS. Phenotypic susceptibility to antiretrovirals among clades C, F, and B/F recombinant antiretroviral-naive HIV type 1 strains. AIDS Res Hum Retroviruses. 2013 Jun;29(6):880-6. doi: 10.1089/AID.2012.0259. Epub 2013 Mar 8.</citation>
    <PMID>23398474</PMID>
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    <citation>Quashie PK, Oliviera M, Veres T, Osman N, Han YS, Hassounah S, Lie Y, Huang W, Mesplede T, Wainberg MA. Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase. J Virol. 2015 Mar;89(6):3163-75. doi: 10.1128/JVI.03353-14. Epub 2014 Dec 31.</citation>
    <PMID>25552724</PMID>
  </reference>
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    <citation>Han YS, Mesplede T, Wainberg MA. Differences among HIV-1 subtypes in drug resistance against integrase inhibitors. Infect Genet Evol. 2016 Dec;46:286-291. doi: 10.1016/j.meegid.2016.06.047. Epub 2016 Jun 25.</citation>
    <PMID>27353185</PMID>
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    <citation>Cid-Silva P, Margusino-Framinan L, Balboa-Barreiro V, Martin-Herranz I, Castro-Iglesias A, Pernas-Souto B, Llibre JM, Poveda E. Initial treatment response among HIV subtype F infected patients who started antiretroviral therapy based on integrase inhibitors. AIDS. 2018 Jan 2;32(1):121-125. doi: 10.1097/QAD.0000000000001679.</citation>
    <PMID>29112068</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>June 27, 2020</study_first_submitted>
  <study_first_submitted_qc>June 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>July 22, 2020</last_update_submitted>
  <last_update_submitted_qc>July 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Federal University of São Paulo</investigator_affiliation>
    <investigator_full_name>Ricardo Sobhie Diaz, MD, PHD</investigator_full_name>
    <investigator_title>Associate Professor, Paulista School of Infectious Diseases, Federal University of Sao Paulo</investigator_title>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>treatment</keyword>
  <keyword>resistance</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Lamivudine</mesh_term>
    <mesh_term>Dolutegravir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04453436
org study id: SPARC-8
nct id: NCT04453436
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Brazil was the first middle-income country to provide free and universal access to
      antiretroviral drugs to HIV infected individuals. Since 2014 local guidelines recommend that
      all HIV infected individuals be started on therapy regardless of CD4 count. Since January
      2017, all patients are started on a DTG containing triple regimen. As of November 2018,
      170,000 individuals were receiving DTG through the public health system. It is a public
      health priority to evaluate the risk of virologic failure and the subsequent development of
      INSTI resistance in these real-life settings. Our preliminary data from Brazil indicated a
      high virologic failure rate of 8% after 18 months of treatment TL+D. Our central hypothesis
      is that TDR may be associated and contribute to virologic failure with DTG in clinical
      practice. To test this central hypothesis, we will identify PLWH failing DTG containing
      regimens in Brazil. The insights generated with these studies will contribute to a more
      effective use of second generation INSTI in the future.
SPECIFIC AIMS We are on the verge of the global rollout of the second-generation integrase
      strand-transfer inhibitor (INSTI) dolutegravir (DTG), as the World Health Organization (WHO)
      now recommends the combination of DTG + 2 nucleoside reverse transcriptase inhibitors (NRTIs)
      as first- and second-line therapy. As a result, millions of people living with HIV (PLWH)
      will soon receive DTG. In clinical trials, which mainly included people infected with HIV-1
      subtype B, the combination of DTG + 2 NRTIs demonstrated very high efficacy and acquired drug
      resistance was absent (first-line treatment) or very rare (second-line treatment) in the
      event of virologic failure. It is not clear if this high efficacy and lack of acquired drug
      resistance can be extrapolated to clinical practice in low- and middle-income countries,
      where the majority of PLWH live and where most infections are due to non-B subtypes.
      Furthermore, in the pivotal studies for initial treatment with DTG, candidates harboring
      virus resistant to NRTIs met the exclusion criteria of these studies. Although DTG failure in
      first line regimens in clinical trials reveal the absence of integrase resistance, it is
      conceivable that mutations at other HIV genomic regions such as 5´PPT (nef) could contribute
      to DTG lack of efficacy.

      Brazil was the first middle-income country to provide free and universal access to
      antiretroviral drugs to HIV infected individuals. Since 2014 local guidelines recommend that
      all HIV infected individuals be started on therapy regardless of CD4 count. Since January
      2017, all patients are started on a DTG containing triple regimen. As of November 2018,
      170,000 individuals were receiving DTG through the public health system. It is a public
      health priority to evaluate the risk of virologic failure and the subsequent development of
      INSTI resistance in these real-life settings. Our preliminary data from Brazil indicated a
      high virologic failure rate of 8% after 18 months of treatment TL+D. Moreover, acquired drug
      resistance was observed in first-line virologic failures (15 out of 84 investigated
      individuals). A relatively high rate of transmitted drug resistance (TDR) was also observed
      among those 84 individuals (15.6%) Our central hypothesis is that TDR may be associated and
      contribute to virologic failure with DTG in clinical practice. To test this central
      hypothesis, we will identify PLWH failing DTG containing regimens in Brazil, a model country
      for large-scale DTG implementation where various HIV subtypes co-circulate. The insights
      generated with these studies will contribute to a more effective use of second generation
      INSTI in the future.

      The specific aims of this proposal are as follows:

        1. Investigate the influence of Transmitted Drug resistance, HIV clade profile and
           immunological and virological features among individuals failing first line regimen with
           Tenofovir/3TC + Dolutegravir after 24 weeks of treatment in Brazil.

        2. Determine the genotypic resistance profile among individuals failing first line regimen
           with Tenofovir/3TC + DTG after 24 weeks of treatment in Brazil.

        3. Determine which changes in the 3'-PPT are observed in viruses from patients experiencing
           TL+D failure and assess if this novel resistance pathway contributes to acquired drug
           resistance in clinical practice.

      The results from the proposed study can be used to optimize care of PLWH by improving
      treatment guidelines and drug resistance interpretation algorithms.

      RESEARCH PLAN SIGNIFICANCE The World Health Organization (WHO) recently changed the HIV
      treatment guidelines and now recommends the second-generation integrase strand-transfer
      inhibitor (INSTI) dolutegravir (DTG) + 2 nucleoside reverse transcriptase inhibitors (NRTIs)
      as first- and second-line therapy for people living with HIV (PLWH). As a result, millions of
      people living with HIV (PLWH) will soon receive DTG in low- and middle-income countries where
      the majority of PLWH live. Considerations of the WHO for the transition from efavirenz-based
      regimens to DTG-based regimens are the high efficacy of DTG-based regimens, the relatively
      low costs of producing generic DTG formulations, and the low risk for baseline DTG resistance
      and acquired DTG resistance. In clinical trials, DTG + 2 nucleoside reverse transcriptase
      inhibitors (NRTIs) demonstrated high efficacy in treatment naïve patients with viral
      suppression (<50 c/mL) at week 48 in 90% (FLAMINGO), 88% (SPRING-2), 88% (SINGLE) and 82%
      (ARIA) of the participants with only 1-2% of data not in the window of <50 c/mL. Of major
      importance, these trials showed that in the event of virologic failure no known resistance
      associated mutations (RAMs) could be detected in the integrase and reverse transcriptase
      gene. Similarly, DTG + 2 NRTIs showed high efficacy in treatment experienced INSTI naïve PLWH
      and acquired drug resistance was rare5. However, clinical trial participants are selected and
      closely monitored, including extra doctor's visits, more frequent viral load measurements and
      genotypic resistance analyses, and are switched more rapidly to other combination
      antiretroviral therapy (cART) in the event of virologic failure. It is not clear if this high
      efficacy and lack of acquired drug resistance will carry on in clinical practice in low- and
      middle-income countries. Therefore, it is now a public health priority to evaluate the risk
      of virologic failure and subsequent development of INSTI resistance in real life settings in
      these countries. We propose to perform such studies in Brazil, a country with 860,000 PLWH,
      as this country already implemented DTG regimens and thus can serve as a model for other low-
      and middle-income countries.

      Preliminary data on efficacy and acquired drug resistance of DTG + 2 NRTIs in Brazil.

      From January 2017, the recommended first-line regimen in Brazil is the fixed dose combination
      of generic tenofovir 300 mg plus lamivudine 300 mg combined with DTG 50 mg (TL+D). In 2017,
      54,175 PLWH started TL+D as first-line regimen in Brazil, and 26,417 PLWH were switched from
      raltegravir-containing cART to TL+D, comprising 77% of individuals initiating cART in this
      country. As shown in Figure 1, 8% of individuals receiving TL+D had a viral load >50 c/mL
      after 18 months of treatment which is higher than expected based on clinical trial results.
      In general, from the 581,064 individuals on treatment in Brazil as of December 2017, 85%
      presented with viral loads < 50 c/mL (Source: MS/SVS/Departamento de IST, Aids e Hepatites
      Virais, Brasil). As of November 2018, 170,000 PLWH receive DTG in Brazil.

      Among 84 individuals who experienced virologic failure during first-line treatment with TL+D,
      11 presented low level viremia (50-500 c/mL), In five patients (5.9%) major resistance
      associated mutations were detected at IN: 2 patients with R263Q, one with G118R, one with
      E138A, and one with R263R/K in IN plus K70E+M184V in RT. Six (7.1%) additional individuals
      presented minor IN resistance mutations: L74I/M (2 cases); G140R+G163R; V151A; V151I; T97A;
      E157Q; and M50I. The prevalence of the polymorphic IN mutations L101I and T124A, which are in
      vitro pathway for resistance, were 53.5% and 46.4%, respectively, significantly higher than
      in Brazilian INSTI naïve patients. Eight (9.5%) patients presented T+L RAM in the RT,
      including 3 with K70E+M184V. Mutations not related to TL+D (e.g., TAMs, NNRTI and PI) were
      present in 25.6% of the patients, significantly higher than in a representative national
      sample of 1,568 antiretroviral naïve patients we have tested. All these results are depicted
      in Table 1. Therefore, the detection of IN and RT RAMs upon virologic failure indicates that
      selected resistance to first-line TL+D is more common than what has been reported in clinical
      trials. The apparent association between TL+D failure in Brazil and TDR should be better
      evaluated, as well as the role of IN polymorphic mutations that can emerge during DTG
      failure. Together, these results warrant further investigations of virologic failure and
      subsequent acquired INSTI resistance in this setting.

      Among 84 individuals who experienced virologic failure during first-line treatment with TL+D,
      11 presented low level viremia (50-500 c/mL), In five patients (5.9%) major resistance
      associated mutations were detected at IN: 2 patients with R263Q, one with G118R, one with
      E138A, and one with R263R/K in IN plus K70E+M184V in RT. Six (7.1%) additional individuals
      presented minor IN resistance mutations: L74I/M (2 cases); G140R+G163R; V151A; V151I; T97A;
      E157Q; and M50I. The prevalence of the polymorphic IN mutations L101I and T124A, which are in
      vitro pathway for resistance, were 53.5% and 46.4%, respectively, significantly higher than
      in Brazilian INSTI naïve patients. Eight (9.5%) patients presented T+L RAM in the RT,
      including 3 with K70E+M184V. Mutations not related to TL+D (e.g., TAMs, NNRTI and PI) were
      present in 25.6% of the patients, significantly higher than in a representative national
      sample of 1,568 antiretroviral naïve patients we have tested. All these results are depicted
      in Table 1. Therefore, the detection of IN and RT RAMs upon virologic failure indicates that
      selected resistance to first-line TL+D is more common than what has been reported in clinical
      trials. The apparent association between TL+D failure in Brazil and TDR should be better
      evaluated, as well as the role of IN polymorphic mutations that can emerge during DTG
      failure. Together, these results warrant further investigations of virologic failure and
      subsequent acquired INSTI resistance in this setting.

      APPROACH

      Study design: This is a prospective nested case control study comparing the baseline HIV
      profile of individuals experiencing virologic failure to TL+D regimen after 24 weeks of
      treatment initiation (cases) to randomly selected 2:1 control individuals with viral load
      bellow detection limits 24 weeks after treatment initiation.

      Identification of PLWH who fail DTG in Brazil PLWH will be included at 5 large clinical sites
      in Brazil: one collection site will be in the far South of Brazil where 85% of strains are
      subtype C, the northeast of Brazil where 30% of samples are subtype F, the city of Santos,
      South-east of Brazil where 50% of strains are BF recombinant forms (CRF_28, CRF_29, and
      unique recombinant forms), Sao Paulo and Rio de Janeiro. At each site a research nurse will
      identify PLWH that will initiate a TL + D regimen, and baseline samples will be collected and
      send to the Central Laboratory (R Diaz, PI) after an informal consent. At this time,
      epidemiological, virological and immunological data will be collected from each patient, and
      stored in a Central database. We expect to recruit 2,500 patients initiating antiretroviral
      therapy in a 24-week period. Those recruited patients will be oriented to perform a plasma
      viral load after 12 and 24 weeks of recruitment. We expect that by week 24, 8% of recruited
      individuals will reach the primary end point of the study which is the antiretroviral
      virologic failure, and Blood samples from these individuals will be also sent to the Diaz
      laboratory for genotypic resistance testing.

      Cases and controls will be defined as:

        -  Cases: HIV infected individuals with subtype C, subtype F, or BF recombinant forms who
           use TL+D for at least 24 weeks and have a confirmed plasma viral load > 200 copies/mL.
           We expect to include samples from 200 individuals experiencing virologic failure as
           defined above.

        -  Controls: HIV infected individuals with subtype C, subtype F, or BF recombinant forms
           who use TL+D for at least 24 weeks and have a confirmed plasma viral load < 50
           copies/mL. We will randomly select 400 samples from control individuals in order to
           characterize by genomic sequencing the HIV strains present at baseline, before treatment
           initiation.

      Based on the total number of PLWH receiving DTG containing cART at these three sites, our
      preliminary results showing a virologic failure rate of 8%, and assuming that 10% will be
      lost to follow-up, we will recruit 2,500 PLWH in order to obtain 200 individuals experiencing
      virologic failure. Based on our preliminary results, it is safe to conservatively assume that
      10% of these patients will harbor TDR at baseline.

      Coordination of inclusion of PLWH at the clinical sites:

      In Brazil, all HIV infected individuals are entitled to free access to antiretroviral
      therapy. As of November 2018, 170,000 individuals were receiving DTG through the public
      health system. Participants for the present study will be recruited in 5 large clinical
      units, all highly experienced in the conduct of multicenter studies. In each site a specially
      dedicated research nurse will be hired. He/she will be responsible for identifying,
      recruiting, consenting, and ensuring follow-up of study participants.

      Database management:

      A private repository will be set up on GitHub (https://github.com/) that will give access to
      remote researchers (physicians and nurses) and to Central coordination for data management
      and analysis at Diaz´s Retrovirology Laboratory. We will prepare a short form in Excel format
      for the remote researchers to use to enter the data and serve as an electronic Case Report
      Form. For every patient, remote researchers will enter the needed data, and all the entries
      will be combined into a database and bring the individuals files down onto our computers at
      the Retrovirology Lab to be stored offline. The analyses will be performed by Dr. James R
      Hunter from the Retrovirology Lab.

      Anticipated results and alternative approaches:

      We do not anticipate difficulties in recruiting the expected number of cases and controls.
      Nonetheless, expanding to other sites should not represent any major challenge. This is
      because the laboratories in each of the five sites are responsible for performing viral loads
      for several primary care facilities in their respective cities. Thus, the same procedures
      could be expanded to recruit participants from primary care facilities located in the
      proximity of the main hospitals.
observational model: Case-Control
time perspective: Prospective
measure: HIV RNA Viral Load
time frame: 24 weeks
description: Viral load in patient trated with first line treatment withTenofovir/3TC + Dolutegravir
measure: HIV transcriptase resitance mutations
time frame: 24 weeks
description: HIV reverse transcriptase resistance test in virologic failure patient
measure: HIV integrase resitance mutations
time frame: 24 weeks
description: HIV transcriptase resistance test in virologic failure patient
arm group label: Virologic failure
description: Viral load above detection limits at window period
arm group label: Virologic Success
description: Viral load bellow detection limits at window period
intervention type: Drug
intervention name: Tenofovir Disoproxil
description: Genotipic resistance test
arm group label: Virologic Success
arm group label: Virologic failure
other name: Lamivudine
other name: Dolutegravir
plasma sample
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ricardo S Diaz, MD., PhD
phone: +55 11 991090445
email: rsdiaz@catg.com.br
last name: Tania R. C. Vergara, MD, PhD
phone: +55 21 991621308
email: taniavergara@globo.com
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citation: Wijting IEA, Lungu C, Rijnders BJA, van der Ende ME, Pham HT, Mesplede T, Pas SD, Voermans JJC, Schuurman R, van de Vijver DAMC, Boers PHM, Gruters RA, Boucher CAB, van Kampen JJA. Reply to Darcis and Berkhout. J Infect Dis. 2018 Nov 5;218(12):2020-2021. doi: 10.1093/infdis/jiy475. No abstract available.
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citation: World Health Organization. Updated Recommendations on First-Line and Second-Line Antiretroviral Regimens and Post-Exposure Prophylaxis and Recommendations on Early Infant Diagnosis of HIV: Interim Guidance. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.18). Licence: CC BY.; 2018.
citation: Phillips AN, Cambiano V, Nakagawa F, Revill P, Jordan MR, Hallett TB, Doherty M, De Luca A, Lundgren JD, Mhangara M, Apollo T, Mellors J, Nichols B, Parikh U, Pillay D, Rinke de Wit T, Sigaloff K, Havlir D, Kuritzkes DR, Pozniak A, van de Vijver D, Vitoria M, Wainberg MA, Raizes E, Bertagnolio S; Working Group on Modelling Potential Responses to High Levels of Pre-ART Drug Resistance in Sub-Saharan Africa. Cost-effectiveness of public-health policy options in the presence of pretreatment NNRTI drug resistance in sub-Saharan Africa: a modelling study. Lancet HIV. 2018 Mar;5(3):e146-e154. doi: 10.1016/S2352-3018(17)30190-X. Epub 2017 Nov 22.
PMID: 29174084
citation: World Health Organization. Transition to new antiretrovirals in HIV programmes: Policy brief. WHO/HIV/2017.20. 2017.
citation: Mantovani NP, Azevedo RG, Rabelato JT, Sanabani S, Diaz RS, Komninakis SV. Analysis of transmitted resistance to raltegravir and selective pressure among HIV-1-infected patients on a failing HAART in Sao Paulo, Brazil. J Clin Microbiol. 2012 Jun;50(6):2122-5. doi: 10.1128/JCM.00539-12. Epub 2012 Mar 7.
PMID: 22403424
citation: Hemelaar J, Gouws E, Ghys PD, Osmanov S; WHO-UNAIDS Network for HIV Isolation and Characterisation. Global trends in molecular epidemiology of HIV-1 during 2000-2007. AIDS. 2011 Mar 13;25(5):679-89. doi: 10.1097/QAD.0b013e328342ff93.
PMID: 21297424
citation: Inocencio LA, Pereira AA, Sucupira MC, Fernandez JC, Jorge CP, Souza DF, Fink HT, Diaz RS, Becker IM, Suffert TA, Arruda MB, Macedo O, Simao MB, Tanuri A. Brazilian Network for HIV Drug Resistance Surveillance: a survey of individuals recently diagnosed with HIV. J Int AIDS Soc. 2009 Sep 18;12:20. doi: 10.1186/1758-2652-12-20.
PMID: 19765271
citation: Arruda MB, Boullosa LT, Cardoso CC, da Costa CM, Alves CR, de Lima ST, Kaminski HT, Aleixo AW, Esposito AO, Cavalcanti AM, Riedel M, Couto-Fernandez JC, Ferreira SB, de Oliveira IC, Portal LE, Wolf HH, Fernandes SB, de M C Pardini MI, Feiteiro MV, Tolentino FM, Diaz RS, Lopes GI, Francisco RB, Veras NM, Pires AF, Franchini M, Mesquita F, Tanuri A; HIV-BResNet. Brazilian network for HIV Drug Resistance Surveillance (HIV-BresNet): a survey of treatment-naive individuals. J Int AIDS Soc. 2018 Mar;21(3):e25032. doi: 10.1002/jia2.25032.
PMID: 29504269
citation: Brindeiro RM, Diaz RS, Sabino EC, Morgado MG, Pires IL, Brigido L, Dantas MC, Barreira D, Teixeira PR, Tanuri A; Brazilian Network for Drug Resistance Surveillance. Brazilian Network for HIV Drug Resistance Surveillance (HIV-BResNet): a survey of chronically infected individuals. AIDS. 2003 May 2;17(7):1063-9. doi: 10.1097/00002030-200305020-00016.
PMID: 12700457
citation: Sabino EC, Shpaer EG, Morgado MG, Korber BT, Diaz RS, Bongertz V, Cavalcante S, Galvao-Castro B, Mullins JI, Mayer A. Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil. J Virol. 1994 Oct;68(10):6340-6. doi: 10.1128/JVI.68.10.6340-6346.1994.
PMID: 8083973
citation: De Sa Filho DJ, Sucupira MC, Caseiro MM, Sabino EC, Diaz RS, Janini LM. Identification of two HIV type 1 circulating recombinant forms in Brazil. AIDS Res Hum Retroviruses. 2006 Jan;22(1):1-13. doi: 10.1089/aid.2006.22.1. Erratum In: AIDS Res Hum Retroviruses. 2006 Aug;22(8):824. Casiero, Marcos M [corrected to Caseiro, Marcos M].
PMID: 16438639
citation: Sucupira MC, Munerato P, Silveira J, Santos AF, Janini LM, Soares MA, Diaz RS. Phenotypic susceptibility to antiretrovirals among clades C, F, and B/F recombinant antiretroviral-naive HIV type 1 strains. AIDS Res Hum Retroviruses. 2013 Jun;29(6):880-6. doi: 10.1089/AID.2012.0259. Epub 2013 Mar 8.
PMID: 23398474
citation: Quashie PK, Oliviera M, Veres T, Osman N, Han YS, Hassounah S, Lie Y, Huang W, Mesplede T, Wainberg MA. Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase. J Virol. 2015 Mar;89(6):3163-75. doi: 10.1128/JVI.03353-14. Epub 2014 Dec 31.
PMID: 25552724
citation: Han YS, Mesplede T, Wainberg MA. Differences among HIV-1 subtypes in drug resistance against integrase inhibitors. Infect Genet Evol. 2016 Dec;46:286-291. doi: 10.1016/j.meegid.2016.06.047. Epub 2016 Jun 25.
PMID: 27353185
citation: Cid-Silva P, Margusino-Framinan L, Balboa-Barreiro V, Martin-Herranz I, Castro-Iglesias A, Pernas-Souto B, Llibre JM, Poveda E. Initial treatment response among HIV subtype F infected patients who started antiretroviral therapy based on integrase inhibitors. AIDS. 2018 Jan 2;32(1):121-125. doi: 10.1097/QAD.0000000000001679.
PMID: 29112068
responsible party type: Principal Investigator
investigator affiliation: Federal University of São Paulo
investigator full name: Ricardo Sobhie Diaz, MD, PHD
investigator title: Associate Professor, Paulista School of Infectious Diseases, Federal University of Sao Paulo
mesh term: Tenofovir
mesh term: Lamivudine
mesh term: Dolutegravir
sharing ipd: Undecided