Elvucitabine/Efavirenz/Tenofovir Versus Lamivudine/Efavirenz/Tenofovir in Human Immunodeficiency Virus (HIV)-1 Infected, Treatment-naive Participants

A Randomized, Blinded, 12-week Comparison of Elvucitabine/Efavirenz/Tenofovir Versus Lamivudine/Efavirenz/Tenofovir in HIV-1 Infected Treatment-naive Participants. There is a 36 Week, Open-label, Extension Phase for Eligible Participants.

Elvucitabine, a novel nucleoside analog, is being studied as a treatment for participants with human immunodeficiency virus (HIV)-1. This Phase 2 study will enroll 60 HIV-1-naive participants to assess the efficacy and safety of elvucitabine compared to lamivudine in combination with tenofovir and efavirenz as measured by changes in the participant's HIV-ribonucleic acid (RNA) level and CD4 cell count. The study treatment will be 12 weeks of blinded study medication followed by an additional 84 weeks of open-label treatment if the participant's response to treatment meets certain endpoints. The pharmacokinetics of elvucitabine will also be assessed during the study.

Sixty HIV-1-infected, clinically stable, treatment-naïve adults with no acquired immunodeficiency syndrome (AIDS)-defining events during the 3 months prior to screening will be randomly assigned to 1 of 2 treatment groups. Participant plasma HIV-1 RNA levels must be greater than or equal to 5000 copies/millimeter (mL), and CD4 cell counts must be greater than 200 cells/mL and less than 500 cells/mL at Screening. Participants must be sensitive to elvucitabine, lamivudine, and emtricitabine as demonstrated by the absence of the M184V, M184I, and D237E mutations by TRUGENE HIV-1 Genotyping Kit. Participants must be genotypically sensitive to efavirenz (negative for K103 or Y188L mutations) and tenofovir (negative for K65R mutation) as demonstrated by TRUGENE HIV-1 Genotyping Kit. They must have acceptable hematologic and chemistry parameters.

Participants whose HIV-1 RNA levels have decreased at least 2 logs or to below 400 copies/mL by Week 10 may be considered eligible to enter the extension phase of up to 36 weeks of additional treatment. Participants in the extension phase will be evaluated at Weeks 14 and 16 and every 4 Weeks until Week 96.

Once all participants have completed 12 weeks of treatment, and the data are available for all visits through Week 12, the database will be locked and the treatment assignments will be unblinded. Any participant who has had less than 48 weeks of treatment will be allowed to continue on the same treatment as initially assigned on an open-label basis through 48 weeks. All participants will have 2 post-treatment follow-up visits, at 1 and 4 weeks after the end of treatment. Concentrations of elvucitabine in the plasma will be measured on Day 1, at Weeks 4, 6, 8, 12, 16, 24, 48, 72, 96, and at Follow-up

Efficacy will be assessed by measuring plasma HIV-1 RNA levels and CD4 counts at each study visit.

Safety evaluation will include vital signs, physical examinations, electrocardiograms, assessments of adverse events (AEs), measurement of plasma HIV-1 RNA levels and CD4 counts, determination of HIV-1 genotype at Screening and at Weeks 12, 24, 48, and 96, determination of HIV-1 phenotype at Visit 1 and at Weeks 12, 24, 48, and 96 urine and serum pregnancy tests, as well as laboratory analyses that include hematology, chemistry, and urinalysis.

Inclusion Criteria:

A participant must meet the following criteria at Screening to be enrolled in this study:

1. Are male or female. Sexually active men with partners of childbearing potential must agree to use an acceptable form of contraception as determined by the investigator (for example, oral contraceptives, double-barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or vasectomy) during participation in the study. Female participants cannot be pregnant or lactating/breast-feeding and must be surgically sterile, postmenopausal as defined later, or practicing an effective method of birth control as determined by the investigator (for example oral contraceptives, double-barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner with vasectomy). A woman may be considered postmenopausal if she is at least 50 years or older, has a history of no menses for at least 12 months, and has a follicle-stimulating hormone (FSH) level over the upper limit of normal for reproductive aged women.

2. Are 18 through 65 years old

3. Have documented HIV-1 infection by written prior history and clinically stable with no AIDS-defining events in the 3 months prior to Screening

4. Have plasma HIV-1 RNA levels greater than or equal to 5000 copies/mL at Screening

5. Are HIV-1 strain sensitive to elvucitabine, lamivudine, or emtricitabine as demonstrated by the absence of the M184V, M184I, and D237E mutations by TRUGENE HIV-1 Genotyping Kit

6. Are HIV-1 strain genotypically sensitive to efavirenz (negative for K103 and Y188L mutations) and tenofovir (negative for K65R mutation) by TRUGENE HIV-1 Genotyping Kit

7. Have a CD4 count greater than or equal to 200 cells/mL and less than 500 cells/mL

8. Have acceptable hematologic and chemistry parameters, including the following:

   • Hemoglobin (Hgb) greater than or equal to 11 grams (g)/deciliter (dL)
   • Absolute neutrophil count greater than or equal to 2000 cells/mm^3
   • Platelets greater than or equal to 125 000/mm^3
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 1.5 times the upper limit of normal
   • Total bilirubin less than or equal to 1.5 times the upper limit of normal
   • Creatinine within normal range

9. Are capable of understanding and has signed the informed consent document

10. Are able and willing to comply with protocol requirements

Exclusion Criteria:

Participants meeting any of the following criteria at Screening will be excluded from the study:

1. Are hepatitis B surface antigen positive, and/or hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive
2. Have previous therapy with agents with significant systemic myelosuppressive or cytotoxic potential within the 3 months prior to Screening or the expected need for such therapy during the study
3. Have previous use or need for bone marrow colony-stimulating factors such as Epogen, Procrit, or Neupogen
4. Have had previous antiretroviral therapy
5. Have evidence or history of cirrhosis
6. Have recent (within 3 months of Screening) history of alcohol abuse, physical dependence to any opioid, cocaine, lysergic acid diethylamide (LSD) or amphetamines, or history of drug addiction within the last 12 months
7. Have inability to tolerate oral medication
8. Are pregnant or breast-feeding if female
9. Have any clinical condition or prior therapy that, in the investigator's opinion, would make the participant unsuitable for the study or unable to comply with the dosing requirements
10. Have received treatment with any other investigational drug within 30 days prior to Screening
11. Have current active mental illness or a history of significant mental illness (for example, severe depression, schizophrenia, history of suicidal ideations, or suicide attempts)