Clinical trial NCT00855413: HIV Viremia and Persistence in Acutely HIV-Infected Patients Treated With Darunavir/Ritonavir and Etravirine
Official title: CID 0821 - Pilot Study to Evaluate HIV Viremia and Persistence in Acutely HIV-Infected Antiretroviral Naïve Patients Treated With Darunavir/Ritonavir and Etravirine
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Acute HIV Infection
HIV Infections
Keywords: Acute HIV
HIV
Treatment Naive
Acute Infections
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Janssen Pharmaceuticals
First posted: 2009-03-04
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Purpose: This is a pilot study to evaluate HIV viremia and persistence in acutely HIV infected antiretroviral naïve patients treated with Darunavir/ritonavir and Etravirine

Participants: 20 participants, age 18 and older, HIV infected, antiretroviral naïve patients

Procedures (methods): ARV treatment with Darunavir/ritonavir and Etravirine,

Optional studies:

Genital secretion samples, Cerebrospinal fluid samples, Leukapheresis, Endoscopy/colonoscopy

Detailed description: Study Design

This is a multicenter, single arm, 48-week open-label pilot study of DRV/R \& ETR in acute HIV infection. Study sites will be members of the Duke-UNC Acute HIV Infection Study Consortium. If baseline resistance is detected after treatment begins (e.g. evidence of pre-existing baseline resistance (genotypic or phenotypic) that may adversely affect the efficacy of the study regimen), the patient may elect to alter treatment as per best clinical practice. The new regimen will not be provided by the study, but will be obtained for the participant through available clinical resources.

After patients are identified with acute HIV infection, they will be offered the opportunity to participate in the study. Patients will also be offered the opportunity to co-enroll in CHAVI 001 and 012, studies that follow the virological and immunological response of patients with AHI, regardless of the initiation of ART. An overall consent form will be signed for study participation, and separate informed consents with signatures will be obtained for optional studies. Patients will be eligible for participation after signing the overall consent - agreeing to participate in studies of other compartment specimens is not required for enrollment. At the initial visit, patient eligibility will be confirmed with appropriate laboratory testing (see "STUDY POPULATION"). When eligibility is verified, entry laboratory studies will be obtained, and the participants will be started on DRV/r, and ETR. All participants will be followed at regular intervals thereafter as specified in the schedule of evaluations. Participants meeting criteria for virologic failure will be offered the opportunity to switch to the best available regimen as selected by their HIV provider.

Hypothesis

Combination therapy with DRV/R \& ETR will suppress plasma viremia and improve immunologic function in antiretroviral (ART)-naïve, acutely HIV-infected (AHI) patients, and will limit replication in HIV-1 cellular compartments.

Eligibility criteria: Inclusion Criteria:

1. Documentation of Acute HIV Infection as defined above.
2. Men and women age ≥18 years.
3. Participants will be ART naïve, defined as ≤14 days of antiretroviral treatment at any time prior to entry. The only exceptions are: Post-exposure prophylaxis (PEP) provided the patient was documented as HIV-1 negative at least 3-6 months after completion of the PEP treatment.
4. Screening HIV-1 RNA \>1,000 copies/mL obtained within 30 days at study entry.
5. Lab values obtained within 30 days prior to study entry:
6. Absolute neutrophil count \>500/mm3
7. Hemoglobin \> 8.5 g/dL for men and \> 8.0 g/dL for women
8. Platelet count \>50,000/mm3
9. AST (SGOT) ≤2.5 x ULN
10. ALT (SGPT) ≤2.5 x ULN
11. Total bilirubin \<2.5 x ULN
12. Calculated creatinine clearance (Cockcroft-Gault formula) \> 30mL/min:

    * CrCl = (140-age) x body weight (kg) (x 0.85 if female)
    * Serum creatinine \[mg/dL\] x (72)
13. For women of reproductive potential, a negative serum or urine pregnancy test within 7 days prior to initiating antiretroviral study medications. Reproductive potential is defined as females who have reached menarche and have not been post-menopausal for at least 24 consecutive months, or have not undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, or salpingotomy). Acceptable documentation of surgical sterilization includes patient-reported history.
14. If participating in sexual activity that could lead to pregnancy, female study patients must use at least one form of contraception, which could consist only of a barrier method. All patients must continue to use contraception for 6 weeks after stopping the study medications. Acceptable methods of contraception include: condoms (male or female) with or without spermicidal agent, diaphragm or cervical cap with spermicide, or IUD. Female volunteers not of reproductive potential are not required to use contraception.
15. Ability and willingness of patient to give written informed consent.

Exclusion Criteria:

1. Women who are pregnant or breast-feeding.
2. Women with a positive pregnancy test on enrollment or prior to study drug administration.
3. Women of reproductive potential who are unwilling or unable to use acceptable methods to avoid pregnancy for the entire study period
4. Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), 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.
5. Known allergy/sensitivity to study drugs or their formulations.
6. Difficulty swallowing capsules/tablets.
7. Inability to communicate effectively with study personnel.
8. Incarceration; prisoner recruitment and participation are not permitted.
9. 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.
10. Any active psychiatric illness including schizophrenia, severe depression, or severe bipolar affective disorder that, in the opinion of the investigator, could confound the analysis of the neurological examination or neuropsychological test results.
11. Active brain infection (except for HIV-1), brain neoplasm, space-occupying brain lesion requiring acute or chronic therapy. Participants with any fungal meningitis, parasitic infection, or CNS lymphoma are excluded from participation.
12. 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.
13. Known cardiac conduction disease.
14. Prior treatment with any other experimental drug for any indication (within 30 days of initiating study treatment).
15. Unable to discontinue any current medications that are excluded during study treatment.
16. A life expectancy less than twelve months.
17. Acute Viral Hepatitis, including, but not limited to, Hepatitis A, B, or C
18. Chronic Hepatitis B Infection documented by a detectable serum Hepatitis B surface antigen (HBsAg) or plasma HBV DNA

Primary outcomes:
measure: Number of Participants With Virologic Response
timeFrame: 24 weeks
Secondary outcomes:
measure: Number of Participants With Virologic Response
timeFrame: 48 weeks from enrollment
measure: Median Change in CD4 Cell Count From Week 0 to Week 24.
timeFrame: week 0, week 24
measure: Median Change in CD4 Cell Count From Week 0 to Week 48.
timeFrame: 48 weeks from enrollment
measure: HIV RNA Levels Immediately Prior to Initiating Study Treatment.
timeFrame: HIV RNA level at enrollment
measure: Median Time to HIV RNA Suppression to <200 Copies/mL
timeFrame: From enrollment to the date of HIV RNA suppression, assessed up to Week 48
measure: HIV RNA Detection in Semen
timeFrame: From enrollment through 48 weeks
measure: Number of Participants Who Stopped Study Treatment Due to Adverse Event or Intolerance
timeFrame: Enrollment to Week 48
measure: Adverse Events Possibly or Definitely Related to Study Treatment Through Week 48
timeFrame: Enrollment to week 48
measure: Maximum Etravirine Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture
timeFrame: Week 4 and week 48
measure: Minimum Etravirine Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture
timeFrame: Week 4 and week 48
measure: Maximum Darunavir Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture
timeFrame: Week 4 and week 48
measure: Minimum Darunavir Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture
timeFrame: Week 4 and week 48
measure: Maximum Ritonavir Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture
timeFrame: Week 4 and Week 48
measure: Minimum Ritonavir Exposure Range in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture
timeFrame: Week 4 and week 48
measure: Maximum Etravirine Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen
timeFrame: Weeks 0-4 and weeks 12, 48
measure: Minimum Etravirine Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen
timeFrame: Weeks 0-4 and weeks 12, 48
measure: Maximum Darunavir Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen
timeFrame: Weeks 0-4 and weeks 12, 48
measure: Minimum Darunavir Exposure Range in Semen Among Participants Who Consented to an Optional Collection of Semen
timeFrame: Weeks 0-4 and weeks 12, 48
measure: Maximum Ritonavir Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen
timeFrame: Weeks 0-4 and Weeks 12, 48
measure: Minimum Ritonavir Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen
timeFrame: Weeks 0-4 and Weeks 12, 48
measure: Maximum Etravirine Exposure in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure
timeFrame: between Week 4-12 and between Weeks 36-48
measure: Minimum Etravirine Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure
timeFrame: between Week 4-12 and between Weeks 36-48
measure: Maximum Darunavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure
timeFrame: between Week 4-12 and between Weeks 36-48
measure: Minimum Darunavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure
timeFrame: between week 4-12 and between weeks 36-48
measure: Maximum Ritonavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure
timeFrame: between week 4-12 and between Weeks 36-48
measure: Minimum Ritonavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure
timeFrame: between week 4-12 and between weeks 36-48
measure: Number of Participants With HIV RNA Measurement Above the Limits of Detection in Cerebrospinal Fluid
timeFrame: Week 4 and Week 48
measure: Number of Participants With Neurocognitive Impairment at Baseline
timeFrame: Week 2 or 4
measure: Number of Participants With Neurocognitive Impairment at Week 24
timeFrame: Week 24
measure: Number of Participants With Neurocognitive Impairment at Week 48
timeFrame: Week 48
measure: Overall Neurocognitive Impairment Score at Week 2 or 4
timeFrame: Week 2 or 4
measure: Overall Neurocognitive Impairment at Week 24
timeFrame: Week 24
measure: Overall Neurocognitive Impairment at Week 48
timeFrame: Week 48
measure: Change in Overall Neurocognitive Impairment From Baseline to Week 24 or 48
timeFrame: Baseline to Week 24 or 48
measure: Correlation of HIV RNA Levels in CSF and Drug Levels With Neurocognitive Functioning
timeFrame: From enrollment through Week 48
measure: Correlation of Time to HIV RNA Levels <200 Copies/mL With Improvement in Neurocognitive Functioning From Baseline to Week 24 and 48
timeFrame: Baseline to Week 24 and 48
measure: HIV RNA Detection in Ileal Biopsy Specimens
timeFrame: Weeks 4 and 48
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: The University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Cynthia Gay, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina, Chapel Hill
name: David M Margolis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gay CL, Mayo AJ, Mfalila CK, Chu H, Barry AC, Kuruc JD, McGee KS, Kerkau M, Sebastian J, Fiscus SA, Margolis DM, Hicks CB, Ferrari G, Eron JJ; Duke-UNC Acute HIV Infection Consortium. Efficacy of NNRTI-based antiretroviral therapy initiated during acute HIV infection. AIDS. 2011 Apr 24;25(7):941-9. doi: 10.1097/QAD.0b013e3283463c07.
citation: C Gay, O Dibben, A Stacey, N Gasper-Smith, M Liu, N Goonetilleke, G Ferrari, J Eron, C Hicks, A McMichael, B Haynes, P Borrow, M Cohen, the Duke-UNC CHAVI 001 Clinical Working Group. "Effect(s) of antiretroviral treatment on acute HIV infection." XVII International AIDS Conference, 2008 Abstract no. THPE0086.
citation: Gay CL, Neo DT, Devanathan AS, Kuruc JD, McGee KS, Schmitz JL, Sebastian J, Shaheen NJ, Ferrari G, McKellar M, Fiscus SA, Hicks CB, Robertson K, Kashuba ADM, Eron JJ, Margolis DM. Efficacy, pharmacokinetics and neurocognitive performance of dual, NRTI-sparing antiretroviral therapy in acute HIV-infection. AIDS. 2020 Nov 1;34(13):1923-1931. doi: 10.1097/QAD.0000000000002652.