Safety and Efficacy of Fixed Dose Combination Dolutegravir/Abacavir/Lamivudine FDC Initiated During Acute HIV Infection
NCT ID: NCT02384395
Last Updated: 2021-11-22
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
NA
Total Enrollment
40 participants
Study Classification
INTERVENTIONAL
Study Start Date
2015-09-30
Study Completion Date
2021-09-17
Brief Summary
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This is a multicenter, single arm, 96-week open-label study of the safety and virologic efficacy of fixed dose combination Dolutegravir/Lamivudine/Abacavir (DTG/3TC/ABC FDC) initiated during acute HIV infection (AHI).
Detailed Description
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The study will be conducted at the University of North Carolina in Chapel Hill, NC and Duke University in Durham, NC. The investigators plan to enroll up to 44 participants who will be enrolled for 96 weeks and will receive DTG/3TC/ABC FDC.
The investigators propose to evaluate the efficacy and time to viral suppression with DTG/3TC/ABC FDC as initial therapy for acute HIV infection (AHI), as well as the feasibility of prompt administration using a rapid human leukocyte antigen-B57 (HLA-B57) screening antibody assay. In addition to validating the restriction of resting cell infection (RCI) by antiretroviral therapy (ART) including a DTG-based regimen initiated during AHI, the investigators will seek correlations between low RCI, residual gastrointestinal associated lymphoid tissue (GALT) HIV expression, and measures of immune activation. The investigators hypothesize that rapid reduction in plasma viremia with this regimen will limit the area under the pre-ART viral load curve, and thus reduce the latent reservoir size as measured by a viral outgrowth assay one to two years following ART start, and as compared with the latent reservoir size in acutely infected individuals started on regimens without an integrase inhibitor based regimen. In addition, the investigators will examine the longitudinal impact of the proposed integrase-based regimen initiated during the acute period on immune activation through week 96. If residual viral expression and persistent immune dysfunction is related to the burden of the latent viral reservoir (and presumably its periodic activation) these abnormalities should be ameliorated by early ART with rapid viral suppression. The investigators hypothesize that earlier treatment coupled with more rapid ART-mediated virus suppression will be associated with better long-term T cell function, specifically better T cell function after 2 years of durable HIV suppression.
The investigators propose to evaluate the efficacy and time to viral suppression with DTG/3TC/ABC FDC as initial therapy for acute HIV infection (AHI), as well as the feasibility of prompt administration using a rapid human leukocyte antigen-B57 (HLA-B57) screening antibody assay. In addition to validating the restriction of resting cell infection (RCI) by antiretroviral therapy (ART) including a DTG-based regimen initiated during AHI, the investigators will seek correlations between low RCI, residual gastrointestinal associated lymphoid tissue (GALT) HIV expression, and measures of immune activation. The investigators hypothesize that rapid reduction in plasma viremia with this regimen will limit the area under the pre-ART viral load curve, and thus reduce the latent reservoir size as measured by a viral outgrowth assay one to two years following ART start, and as compared with the latent reservoir size in acutely infected individuals started on regimens without an integrase inhibitor based regimen. In addition, the investigators will examine the longitudinal impact of the proposed integrase-based regimen initiated during the acute period on immune activation through week 96. If residual viral expression and persistent immune dysfunction is related to the burden of the latent viral reservoir (and presumably its periodic activation) these abnormalities should be ameliorated by early ART with rapid viral suppression. The investigators hypothesize that earlier treatment coupled with more rapid ART-mediated virus suppression will be associated with better long-term T cell function, specifically better T cell function after 2 years of durable HIV suppression.
Conditions
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HIV
Acute HIV Infection
Keywords
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Dolutegravir
Abacavir
Lamivudine
acute HIV infection
human leukocyte antigen
latent HIV reservoir
integrase-based regimen
viremia
antiretroviral therapy
fixed dose combination
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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DTG/3TC/ABC FDC
Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily
Group Type
EXPERIMENTAL
Dolutegravir 50 mg
Intervention Type
DRUG
Initial therapy for AHI
Lamivudine 300 mg
Intervention Type
DRUG
Initial therapy for AHI
Abacavir 600 mg
Intervention Type
DRUG
Initial therapy for AHI
Interventions
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Dolutegravir 50 mg
Initial therapy for AHI
Intervention Type
DRUG
Lamivudine 300 mg
Initial therapy for AHI
Intervention Type
DRUG
Abacavir 600 mg
Initial therapy for AHI
Intervention Type
DRUG
Other Intervention Names
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DTG
Tivicay
3TC
Epivir
ABC
Ziagen
Eligibility Criteria
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Inclusion Criteria
1. Documentation of Acute HIV infection at or within 30 days of study entry.
2. Men and women age ≥18 years.
3. ART naive, defined as ≤14 days of antiretroviral treatment at any time prior to entry. The only exceptions are:
* Pre-exposure prophylaxis (PrEP) and documented as HIV-1 negative at least 1 month prior to AHI diagnosis during PrEP, and
* Post-exposure prophylaxis (PEP) provided the participant was documented as HIV-1 negative at least 3-6 months following completion of PEP treatment.
4. Lab values obtained within 30 days prior to study entry:
* Absolute neutrophil count \>500/mm\^3
* Hemoglobin \> 8.5 g/dL for men and \> 8.0 g/dL for women
* Platelet count \>50,000/mm\^3
* Lipase ≤ 3 X upper limit of normal (ULN), single repeat test is allowed to determine eligibility
* Calculated creatinine clearance (CrCl, Cockcroft-Gault formula) ≥ 50 mL/min:
CrCl = (140-age) x body weight (kg) (x 0.85 if female) Serum creatinine \[mg/dL\] x (72)
5. Testing for HBsAg is pending. Note: Participants who test positive for HBsAg will be terminated from the study prior to starting study treatment.
6. Testing for HLA-B57 and/or HLA-B\*5701 is pending. Note: Participants who test positive for HLA-B\*5701 will be terminated from the study prior to starting study treatment.
7. A female is eligible to enter and participate in the study if she:
* Is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy; or,
* Is of child-bearing potential, with a negative pregnancy test at screening and at enrollment, who agrees to use one of the methods of contraception listed below.
* Complete abstinence from intercourse from 2 weeks prior to administration of study medication, throughout the study, and for at least 2 weeks after discontinuation of all study medication;
* Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);
* Approved hormonal contraception - used alone is not considered a sufficient form of contraception for the study see Protocol Appendix 1 for a listing of examples of approved hormonal contraception;
* Any intrauterine device (IUD) with published data showing that the expected failure rate is \<1% per year; see Protocol Appendix 2 for a listing of IUDs meeting this criterion;
* Male partner sterilization confirmed prior to the female participant's entry into the study, and this male is the sole partner for that patient;
* Any other method with published data showing that the expected failure rate is \<1% per year.
* Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of the study medication.
8. Females who meet the post-menopausal definition, noted in inclusion criterion 7, will have a follicle stimulation hormone (FSH) test to verify menopause,
9. Ability and willingness of participant to give written informed consent.
2. Men and women age ≥18 years.
3. ART naive, defined as ≤14 days of antiretroviral treatment at any time prior to entry. The only exceptions are:
* Pre-exposure prophylaxis (PrEP) and documented as HIV-1 negative at least 1 month prior to AHI diagnosis during PrEP, and
* Post-exposure prophylaxis (PEP) provided the participant was documented as HIV-1 negative at least 3-6 months following completion of PEP treatment.
4. Lab values obtained within 30 days prior to study entry:
* Absolute neutrophil count \>500/mm\^3
* Hemoglobin \> 8.5 g/dL for men and \> 8.0 g/dL for women
* Platelet count \>50,000/mm\^3
* Lipase ≤ 3 X upper limit of normal (ULN), single repeat test is allowed to determine eligibility
* Calculated creatinine clearance (CrCl, Cockcroft-Gault formula) ≥ 50 mL/min:
CrCl = (140-age) x body weight (kg) (x 0.85 if female) Serum creatinine \[mg/dL\] x (72)
5. Testing for HBsAg is pending. Note: Participants who test positive for HBsAg will be terminated from the study prior to starting study treatment.
6. Testing for HLA-B57 and/or HLA-B\*5701 is pending. Note: Participants who test positive for HLA-B\*5701 will be terminated from the study prior to starting study treatment.
7. A female is eligible to enter and participate in the study if she:
* Is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy; or,
* Is of child-bearing potential, with a negative pregnancy test at screening and at enrollment, who agrees to use one of the methods of contraception listed below.
* Complete abstinence from intercourse from 2 weeks prior to administration of study medication, throughout the study, and for at least 2 weeks after discontinuation of all study medication;
* Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);
* Approved hormonal contraception - used alone is not considered a sufficient form of contraception for the study see Protocol Appendix 1 for a listing of examples of approved hormonal contraception;
* Any intrauterine device (IUD) with published data showing that the expected failure rate is \<1% per year; see Protocol Appendix 2 for a listing of IUDs meeting this criterion;
* Male partner sterilization confirmed prior to the female participant's entry into the study, and this male is the sole partner for that patient;
* Any other method with published data showing that the expected failure rate is \<1% per year.
* Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of the study medication.
8. Females who meet the post-menopausal definition, noted in inclusion criterion 7, will have a follicle stimulation hormone (FSH) test to verify menopause,
9. Ability and willingness of participant to give written informed consent.
Exclusion Criteria
1. Alanine Transaminase (ALT) ≥ 5 times Upper Limit of Normal (≥5xULN)
2. Aspartate Aminotransferase (AST) ≥ 3x ULN
3. Bilirubin ≥1.5x ULN (with \>35% direct bilirubin)
4. Weight \<40 kg
5. Women who are breast-feeding.
6. Women with a positive pregnancy test on enrollment or prior to study drug administration.
7. Women and men of child bearing potential unwilling to agree to use an effective methods of contraception required by the study.
8. History or presence of allergy to the study drugs or their components.
9. Requires or is anticipated to require any of the prohibited concomitant therapy: barbiturates, dofetilide, fampridine (dalfampridine), modafinil, oxcarbazepine, pioglitazone, pilsicainide, pimozide, rifampin, rifapentine, phenytoin, phenobarbital, carbamazepine, and St. John's wort.
* Dofetilide, fampridine, and pilsicainide are prohibited, as DTG may inhibit its renal tubular secretion resulting in increased dofetilide concentrations and potential for toxicity.
10. Unable to discontinue any current medications that are excluded during study treatment.
11. Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), radiation therapy, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
* Prednisone at a daily dose of 10 mg or less (physiologic replacement dose) is permitted.
12. Treatment with radiation therapy or cytotoxic chemotherapeutics agents within 28 days prior to screening or has an anticipated need for these agents during the study.
13. Administration of an HIV-1 immunotherapeutic vaccine within 90 days prior to screening.
14. Prior treatment with any other experimental drug for any indication (within 30 days of initiating study treatment).
15. Difficulty swallowing capsules/tablets.
16. Inability to communicate effectively with study personnel.
17. Incarceration; prisoner recruitment and participation are not permitted.
18. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements or confound the analysis of study endpoints.
19. Any condition (including but not limited to alcohol and drug use) or any active clinically significant disease or findings during screening of medical history or physical examination, which, in the opinion of the Investigator would interfere with patient safety or compliance.
20. Serious illness requiring systemic treatment and/or hospitalization until patient either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.
Note: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) have no restriction.
21. A life expectancy less than twelve months.
22. Acute viral hepatitis, including, but not limited to, hepatitis A, B, or C.
23. History of myocardial infarction or diagnosis of coronary artery disease.
24. History of ongoing or clinically relevant pancreatitis within the previous 6 months.
25. Chronic hepatitis C infection with an anticipated need for treatment during the study period (through week 96).
26. Chronic hepatitis B infection (see inclusion criterion 5).
27. Evidence for moderate to severe hepatic impairment (as defined by the presence of cirrhosis, ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice or Child-Pugh class B or greater hepatic impairment).
28. Evidence of biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
29. Any verified grade 4 laboratory abnormality with exception of ALT as defined in exclusion criterion 1
2. Aspartate Aminotransferase (AST) ≥ 3x ULN
3. Bilirubin ≥1.5x ULN (with \>35% direct bilirubin)
4. Weight \<40 kg
5. Women who are breast-feeding.
6. Women with a positive pregnancy test on enrollment or prior to study drug administration.
7. Women and men of child bearing potential unwilling to agree to use an effective methods of contraception required by the study.
8. History or presence of allergy to the study drugs or their components.
9. Requires or is anticipated to require any of the prohibited concomitant therapy: barbiturates, dofetilide, fampridine (dalfampridine), modafinil, oxcarbazepine, pioglitazone, pilsicainide, pimozide, rifampin, rifapentine, phenytoin, phenobarbital, carbamazepine, and St. John's wort.
* Dofetilide, fampridine, and pilsicainide are prohibited, as DTG may inhibit its renal tubular secretion resulting in increased dofetilide concentrations and potential for toxicity.
10. Unable to discontinue any current medications that are excluded during study treatment.
11. Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), radiation therapy, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
* Prednisone at a daily dose of 10 mg or less (physiologic replacement dose) is permitted.
12. Treatment with radiation therapy or cytotoxic chemotherapeutics agents within 28 days prior to screening or has an anticipated need for these agents during the study.
13. Administration of an HIV-1 immunotherapeutic vaccine within 90 days prior to screening.
14. Prior treatment with any other experimental drug for any indication (within 30 days of initiating study treatment).
15. Difficulty swallowing capsules/tablets.
16. Inability to communicate effectively with study personnel.
17. Incarceration; prisoner recruitment and participation are not permitted.
18. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements or confound the analysis of study endpoints.
19. Any condition (including but not limited to alcohol and drug use) or any active clinically significant disease or findings during screening of medical history or physical examination, which, in the opinion of the Investigator would interfere with patient safety or compliance.
20. Serious illness requiring systemic treatment and/or hospitalization until patient either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.
Note: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) have no restriction.
21. A life expectancy less than twelve months.
22. Acute viral hepatitis, including, but not limited to, hepatitis A, B, or C.
23. History of myocardial infarction or diagnosis of coronary artery disease.
24. History of ongoing or clinically relevant pancreatitis within the previous 6 months.
25. Chronic hepatitis C infection with an anticipated need for treatment during the study period (through week 96).
26. Chronic hepatitis B infection (see inclusion criterion 5).
27. Evidence for moderate to severe hepatic impairment (as defined by the presence of cirrhosis, ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice or Child-Pugh class B or greater hepatic impairment).
28. Evidence of biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
29. Any verified grade 4 laboratory abnormality with exception of ALT as defined in exclusion criterion 1
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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ViiV Healthcare
INDUSTRY
Sponsor Role
collaborator
University of North Carolina, Chapel Hill
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Cindy Gay, MD, MPH
Role: PRINCIPAL_INVESTIGATOR
University of North Carolina
Locations
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University of North Carolina
Chapel Hill, North Carolina, United States
Site Status
Duke University Health System
Durham, North Carolina, United States
Site Status
Countries
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United States
References
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Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Teppler H, Nguyen BY; BENCHMRK Study Teams. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008 Jul 24;359(4):355-65. doi: 10.1056/NEJMoa0708978.
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DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, Yale K, Szwarcberg J, White K, Cheng AK, Kearney BP; GS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012 Jun 30;379(9835):2429-2438. doi: 10.1016/S0140-6736(12)60918-0.
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Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010 Jan;54(1):254-8. doi: 10.1128/AAC.00842-09. Epub 2009 Nov 2.
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Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection. J Antimicrob Chemother. 2010 Dec;65(12):2485-8. doi: 10.1093/jac/dkq350. Epub 2010 Sep 18.
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Song I, Borland J, Chen S, Patel P, Wajima T, Peppercorn A, Piscitelli SC. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012 Mar;56(3):1627-9. doi: 10.1128/AAC.05739-11. Epub 2011 Dec 19.
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Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, Baril JG, Domingo P, Brennan C, Almond S, Min S; extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927-35. doi: 10.1016/S1473-3099(13)70257-3. Epub 2013 Sep 25.
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Walmsley SL, Berenguer J, Kuong-Josses M-A, Kilby JM, Lutz T, Podzamczer D, et al. Dolutegravir Regimen Statistically Superior to Efavirenz/Tenofovir/Emtricitabine: 96-Week Results From the SINGLE Study (ING114467) In: 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA; 2014.
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Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S; extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013 Aug 24;382(9893):700-8. doi: 10.1016/S0140-6736(13)61221-0. Epub 2013 Jul 3.
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Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G; SINGLE Investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013 Nov 7;369(19):1807-18. doi: 10.1056/NEJMoa1215541.
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D:A:D Study Group; Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, D'Arminio Monforte A, Friis-Moller N, Kirk O, Pradier C, Weller I, Phillips AN, Lundgren JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371(9622):1417-26. doi: 10.1016/S0140-6736(08)60423-7. Epub 2008 Apr 2.
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Costagliola D, Lang S, Mary-Krause M, Boccara F. Abacavir and cardiovascular risk: reviewing the evidence. Curr HIV/AIDS Rep. 2010 Aug;7(3):127-33. doi: 10.1007/s11904-010-0047-3.
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Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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http://www.unc.edu
University of North Carolina website
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
14-0549
Identifier Type: -
Identifier Source: org_study_id