Short Course Antiretroviral Therapy for Early HIV-1 Infection

Official Title: “An Open-Label Randomized Clinical Trial to Evaluate the Efficacy and Safety of Short Course Antiretroviral Therapy for Acute or Recent HIV-1 Infection in Zimbabwe and the United States (Version 1.0.1)”

DESIGN

This study is a randomized clinical trial designed to evaluate the efficacy and safety of a three drug antiretroviral regimen administered to persons with acute or recent HIV-1 infection in Denver, CO and Harare, Zimbabwe. Participants will be randomized to either antiretroviral treatment for 12 weeks followed by treatment interruption or to CD4+ T cell-guided antiretroviral therapy. The primary endpoints for the study are:

1. the plasma virus load 24 weeks after antiretroviral therapy (ART) interruption in subjects randomized to early treatment (i.e., week 36 of the study) compared to the plasma virus load 24 weeks after study entry in subjects randomized to CD4+ T cell count-guided treatment;

2. The safety of short course antiretroviral therapy compared to CD4+ T cell count-guided treatment over 24 weeks.

HYPOTHESIS

Persons with early HIV-1 infection in Zimbabwe and the US who receive 12 weeks of potent ART followed by treatment interruption will have significantly lower plasma HIV-1 RNA concentrations 24 weeks after treatment interruption compared to persons with early HIV-1 infection who do not receive early ART.

Intervention(s) in this Clinical Trial

• Drug: tenofovir/emtricitabine, lopinavir/ritonavir
• Drug: antiretroviral treatment

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: A
  • Participants will receive co-formulated tenofovir/emtricitabine 1 tablet ONCE DAILY + co-formulated lopinavir/ritonavir 2 tablets BID for 12 weeks. Those subjects in arm A which meet criteria for treatment interruption (CD4+ T cells >450) will be registered to step 2. During treatment interruption participants will continue to receive clinical and laboratory monitoring. If the subject does not meet criteria for treatment interruption (confirmed CD4+ T cells <450, or an AIDS defining event), registration into step 3 will occur and treatment will be continued. Truvada (Tenofovir DF 300/Emtricitabine 200 mg) orally once daily plus Lopinavir/ritonavir 2 tablets (400 mg/100mg) orally twice daily.
• Active Comparator: B
  • Participants will receive clinical and laboratory monitoring. If an AIDS-defining event occurs, or if CD4+ T lymphocytes are confirmed to decrease to < 350 mm3 on two consecutive measurements at least 4 weeks apart, antiretroviral therapy will be initiated. Treatment will be introduced based on occurrence of an AIDS-related illness or confirmed CD4+ T cell count < 350 on two consecutive measurements at least 4 weeks apart. Subjects who meet criteria to re-initiate treatment in arm A (CD4+ T lymphocytes are confirmed decrease to < 350 mm3 on two consecutive measurements at least 4 weeks apart during the period of treatment interruption) or initiate treatment in arm B, will register to step 3.

Inclusion Criteria:

• 1. Early HIV-1 infection, defined as meeting the following criteria for either acute or recent HIV-1 infection:
• Acute HIV-1 infection is defined as: detectable plasma HIV-1 RNA > 2,000 copies/ml copies/mL by RT-PCR within 14 days prior to study entry and one of the following:
• a negative ELISA within 14 days of study entry; OR
• positive ELISA but negative or indeterminate Western blot (< 2 bands within 14 days of study entry; OR
• a positive ELISA and Western blot within 14 days of study entry but with documented negative ELISA or plasma HIV-1 RT-PCR (< 2,000 copies/ml copies/mL) within 30 days prior to study entry.
• Recent HIV-1 infection is defined as:
• a positive ELISA and Western blot (>2 bands) within 14 days of study entry but with documented negative ELISA or plasma HIV-1 RT-PCR (<2,000 copies/ml) within 6 months prior to study entry; OR
• a positive ELISA and Western Blot within 14 days of study entry but with a non-reactive 3A11-LS ("detuned") ELISA documented within 14 days of study entry (as performed at the CDC or by a CDC-certified laboratory). The detuned assay has been reported by the CDC to be able to identify subjects who have recently seroconverted as having been infected with HIV-1 within 140-150 days of their seroconversion.
• 2. CD4+ cells > 500 mm3 obtained within 21 days prior to study entry at any laboratory that has a CLIA certification or its equivalent.
• 3. No evidence of a current or prior AIDS-defining illness (any illness in the ACTG list of AIDS Defining Events, Appendix I.)
• 4. No signs or symptoms of HIV infection that, in the opinion of the site investigator, require antiretroviral therapy.
• 5. Laboratory values obtained within 21 days prior to study entry:
• Absolute neutrophil count (ANC) > 750 cells/mm3
• Hemoglobin > 7.0 g/dL
• Platelet count > 50,000 cells/mm3
• Serum phosphorus > 2.0mg/dl
• AST (SGOT), ALT (SGPT), and alkaline phosphatase < 5 x ULN
• Total bilirubin < 2.5 x ULN
• Serum creatinine < 1.5 x ULN,
• calculated creatinine clearance (CrCl) > 50mL/min according to the

Cockcroft-Gault formula:

• Male: (140 - age in years) x (wt in kg) = CrCl (mL/min); 72 x (serum creatinine in mg/dL)
• Female: (140 - age in years) x (wt in kg) x 0.85 = CrCl (mL/min); 72 x (serum creatinine in mg/dL)
• 6. Men and women > 18 years of age.
• 7. Ability and willingness to provide written informed consent:
• Candidates must express understanding of the importance of adhering to protocol requirements, particularly in regards to not crossing over from non-treatment to treatment or treatment to non-treatment unless study criteria are met. Study subjects must be willing to be randomized to treatment vs. observation with CD4+ T cell guided therapy and to remain in their assigned arm. In addition, subjects must be willing to go off treatment after 12 weeks if randomized to the treatment arm.
• 8. Female study volunteers of reproductive potential (defined as girls who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e. who have had menses within the preceding 24 months, or have not undergone surgical sterilization (e.g. hysterectomy, bilateral oophorectomy, or salpingotomy) must have a negative serum or urine pregnancy test performed within 48 hours prior to study entry.
• 9. Contraception Requirement:
• • Female Candidates With Reproductive Potential: Female candidates of reproductive potential, who are participating in sexual activity that could lead to pregnancy must agree to use at least one reliable method of contraception (male or female condoms, diaphragm or cervical cap with or without spermicide, an IUD; or a hormone-based contraceptive) while receiving the protocol-specified drugs and for 6 weeks after stopping the medications.
• Interactions of study drugs with oral contraceptives: the effectiveness of estrogen-based contraceptives when co-administered with LPV/RTV is unknown; LPV/RTV decreases plasma levels of ethinyl estradiol; therefore, estrogen-based oral contraceptives are not reliable for women receiving LPV/RTV, and an alternative contraception method must be used.
• • Female Candidates Without Reproductive Potential: Acceptable documentation for lack of reproductive potential is 1) written documentation or oral communication of lack of reproductive potential from a clinician or clinician's staff documented in source documents of one of the following: physician report/letter, discharge summary, or FSH measurement elevated into the menopausal range, as established by the reporting laboratory or 2) the woman's self-reported history of surgical sterilization, menopause, or male partner's azoospermia. Any statement of self-reported sterility or that of her partner's must be entered in the medical record.
• Women without reproductive potential or whose male partner(s) have azoospermia are eligible to start study drugs without requiring the use of contraceptives.
• 10. Subjects must be antiretroviral naïve (< 7 days of ART).

Exclusion Criteria:

• 1. Pregnancy or breast-feeding.
• 2. Use within 21 days prior to study entry of drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with life-threatening adverse events: astemizole, cisapride, ergot alkaloids and derivatives, flecainide, St. John's wort, lovastatin, midazolam, pimozide, propafenone, rifampin, simvastatin, terfenadine, triazolam.
• 3. Prior receipt of investigational anti-HIV-1 vaccine.
• 4. Ongoing therapy with any of the following:
• Systemic corticosteroids. Short course less than 21 days of corticosteroids is allowed.
• Systemic chemotherapeutic agents
• Nephrotoxic systemic agents, including aminoglycosides, amphotericin B, cidofovir, cisplatin, foscarnet, pentamidine
• Immunomodulatory treatments including Interleukin-2
• Investigational agents
• 5. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations.
• 6. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• 7. Serious medical or psychiatric illness that, in the opinion of the site investigator, would interfere with the ability to adhere to study requirements.
• 8. Hepatitis B surface antigen positive prior to study entry.
• 9. Prior treatment with any antiretroviral agent for > 7 days.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 95 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of Colorado, Denver Other

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01030172

Study ID Number: UCD-01-COZI

ClinicalTrials.gov Identifier: NCT01030172

Health Authority: United States: Institutional Review Board