HIV Viremia and Persistence in Acutely HIV-Infected Patients Treated With Darunavir/Ritonavir and Etravirine

Study Overview
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Brief Summary
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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
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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.

Official Title
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CID 0821 - Pilot Study to Evaluate HIV Viremia and Persistence in Acutely HIV-Infected Antiretroviral Naïve Patients Treated With Darunavir/Ritonavir and Etravirine

Conditions
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Acute HIV Infection, HIV Infections

Intervention / Treatment
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* Drug: Darunavir
* Drug: Ritonavir
* Drug: Etravirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documentation of Acute HIV Infection as defined above. Men and women age ≥18 years. 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. Screening HIV-1 RNA >1,000 copies/mL obtained within 30 days at study entry. Lab values obtained within 30 days prior to study entry: Absolute neutrophil count >500/mm3 Hemoglobin > 8.5 g/dL for men and > 8.0 g/dL for women Platelet count >50,000/mm3 AST (SGOT) ≤2.5 x ULN ALT (SGPT) ≤2.5 x ULN Total bilirubin <2.5 x ULN 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) 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. 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. Ability and willingness of patient to give written informed consent. Exclusion Criteria: Women who are pregnant or breast-feeding. Women with a positive pregnancy test on enrollment or prior to study drug administration. Women of reproductive potential who are unwilling or unable to use acceptable methods to avoid pregnancy for the entire study period 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. Known allergy/sensitivity to study drugs or their formulations. Difficulty swallowing capsules/tablets. Inability to communicate effectively with study personnel. Incarceration; prisoner recruitment and participation are not permitted. 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. 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. 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. 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. Known cardiac conduction disease. Prior treatment with any other experimental drug for any indication (within 30 days of initiating study treatment). Unable to discontinue any current medications that are excluded during study treatment. A life expectancy less than twelve months. Acute Viral Hepatitis, including, but not limited to, Hepatitis A, B, or C Chronic Hepatitis B Infection documented by a detectable serum Hepatitis B surface antigen (HBsAg) or plasma HBV DNA

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Darunavir/Ritonavir and Etravirine<br>Darunavir/Ritonavir 800 mg/100 mg orally once daily. ETR will be given 200 mg orally twice daily, although patients may choose to take ETR 400 mg QD to have a simpler all QD regimen. | Drug: Darunavir<br>* 800 mg orally once daily<br>* Other names: Prezista;Drug: Ritonavir<br>* 100 mg orally once daily<br>* Other names: Norvir;Drug: Etravirine<br>* 200 mg orally twice daily, although patients may choose to take ETR 400 mg QD to have a simpler all QD regimen<br>* Other names: Intelence;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Virologic Response | Virologic response defined as plasma HIV RNA measurement <200 copies/mL at week 24 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Virologic Response | Virologic response to study treatment defined as plasma HIV RNA measurement <50 copies/mL at week 48 | 48 weeks from enrollment | 
| Median Change in CD4 Cell Count From Week 0 to Week 24. |  | week 0, week 24 | 
| Median Change in CD4 Cell Count From Week 0 to Week 48. |  | 48 weeks from enrollment | 
| HIV RNA Levels Immediately Prior to Initiating Study Treatment. |  | HIV RNA level at enrollment | 
| Median Time to HIV RNA Suppression to <200 Copies/mL |  | From enrollment to the date of HIV RNA suppression, assessed up to Week 48 | 
| HIV RNA Detection in Semen | Total cumulative levels of HIV RNA detected in the semen of participants from enrollment through week 48. | From enrollment through 48 weeks | 
| Number of Participants Who Stopped Study Treatment Due to Adverse Event or Intolerance |  | Enrollment to Week 48 | 
| Adverse Events Possibly or Definitely Related to Study Treatment Through Week 48 | Total number of adverse events observed that were possibly or definitely related to study treatment through week 48 | Enrollment to week 48 | 
| Maximum Etravirine Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture |  | Week 4 and week 48 | 
| Minimum Etravirine Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture |  | Week 4 and week 48 | 
| Maximum Darunavir Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture |  | Week 4 and week 48 | 
| Minimum Darunavir Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture |  | Week 4 and week 48 | 
| Maximum Ritonavir Exposure in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture |  | Week 4 and Week 48 | 
| Minimum Ritonavir Exposure Range in Cerebrospinal Fluid Among Participants Who Consented to an Optional Lumbar Puncture |  | Week 4 and week 48 | 
| Maximum Etravirine Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen |  | Weeks 0-4 and weeks 12, 48 | 
| Minimum Etravirine Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen |  | Weeks 0-4 and weeks 12, 48 | 
| Maximum Darunavir Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen |  | Weeks 0-4 and weeks 12, 48 | 
| Minimum Darunavir Exposure Range in Semen Among Participants Who Consented to an Optional Collection of Semen |  | Weeks 0-4 and weeks 12, 48 | 
| Maximum Ritonavir Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen |  | Weeks 0-4 and Weeks 12, 48 | 
| Minimum Ritonavir Exposure in Semen Among Participants Who Consented to an Optional Collection of Semen |  | Weeks 0-4 and Weeks 12, 48 | 
| Maximum Etravirine Exposure in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure |  | between Week 4-12 and between Weeks 36-48 | 
| Minimum Etravirine Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure |  | between Week 4-12 and between Weeks 36-48 | 
| Maximum Darunavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure |  | between Week 4-12 and between Weeks 36-48 | 
| Minimum Darunavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure |  | between week 4-12 and between weeks 36-48 | 
| Maximum Ritonavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure |  | between week 4-12 and between Weeks 36-48 | 
| Minimum Ritonavir Exposure Range in Ileal Tissue Among Participants Who Consented to an Optional Gut Biopsy Procedure |  | between week 4-12 and between weeks 36-48 | 
| Number of Participants With HIV RNA Measurement Above the Limits of Detection in Cerebrospinal Fluid |  | Week 4 and Week 48 | 
| Number of Participants With Neurocognitive Impairment at Baseline |  | Week 2 or 4 | 
| Number of Participants With Neurocognitive Impairment at Week 24 |  | Week 24 | 
| Number of Participants With Neurocognitive Impairment at Week 48 |  | Week 48 | 
| Overall Neurocognitive Impairment Score at Week 2 or 4 | Neuropsychological performance was assessed at Week 2 or 4, Week 24 and Week 48 in the following measures: Premorbid/language (Wide Range Achievement Test 4 -Reading Subtest), Learning (HVLT-R, Hopkins Verbal Learning Test-Revised), Memory (HVLT-R), Speed of Processing (Trailmaking A (Army Individual Test Battery, 1944), 1974, Stroop color, Attention (WAIS-III Symbol Search; Stroop word, Fine motor, Executive (Trailmaking B, Stroop interference, Letter, Category Fluency. An overall summary score was created by averaging all tests. Participants also completed the self-reported functional status Patient's Assessment of Own Functioning Inventory (PAOFI) and the Activities of Daily Living Scale (ADLS). Best available demographically corrected normative data were utilized to create z scores. A negative z score denotes below-average performance relative to a US normative comparison population. A higher z score is a better outcome. | Week 2 or 4 | 
| Overall Neurocognitive Impairment at Week 24 | Neuropsychological performance was assessed at week 2 or 4, week 24 and week 48 in the following measures: Premorbid/language (Wide Range Achievement Test 4 -Reading Subtest), Learning (Hopkins Verbal Learning Test - Revised), Memory (HVLT-R), Speed of Processing (Trailmaking A (Army Individual Test Battery, 1944), 1974, Stroop color, Attention (WAIS-III Symbol Search; Stroop word, Fine motor, Executive (Trailmaking B, Stroop interference, Letter, Category Fluency. An overall summary score of neurocognitive functioning was created by averaging all tests. Participants also completed Patient's Assessment of Own Functioning Inventory (PAOFI) and the Activities of Daily Living Scale (ADLS). Best available demographically corrected normative data were utilized to create z scores. A negative z score denotes below-average performance relative to a US normative comparison population. A higher z score is a better outcome. | Week 24 | 
| Overall Neurocognitive Impairment at Week 48 | Neuropsychological performance was assessed at baseline (week 2 or 4), week 24 and week 48 in the following domain (measures): Premorbid/language (Wide Range Achievement Test (WRAT) 4 - Reading Subtest), Learning (HVLT-R, Hopkins Verbal Learning Test - Revised), Memory (HVLT-R), Speed of Processing (Trailmaking A (Army Individual Test Battery, 1944), 1974, Stroop color, Attention (WAIS-III Symbol Search; Stroop word, Fine motor, Executive (Trailmaking B, Stroop interference, Letter, Category Fluency. An overall summary score of neurocognitive functioning was created by averaging all tests. Participants also completed the self-reported functional status Patient's Assessment of Own Functioning Inventory (PAOFI) and the Activities of Daily Living Scale (ADLS). Best available demographically corrected normative data were utilized to create z scores. A negative z score denotes below-average performance relative to a US normative comparison population. A higher z score is a better outcome. | Week 48 | 
| Change in Overall Neurocognitive Impairment From Baseline to Week 24 or 48 | Change in overall z score from baseline to week 24 or 48. A negative z score denotes below-average performance relative to a US normative comparison population. A higher z score is a better outcome. | Baseline to Week 24 or 48 | 
| Correlation of HIV RNA Levels in CSF and Drug Levels With Neurocognitive Functioning |  | From enrollment through Week 48 | 
| Correlation of Time to HIV RNA Levels <200 Copies/mL With Improvement in Neurocognitive Functioning From Baseline to Week 24 and 48 |  | Baseline to Week 24 and 48 | 
| HIV RNA Detection in Ileal Biopsy Specimens | Average HIV RNA detected in the ileal biopsy specimens per participant over weeks 4 and 48. | Weeks 4 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute HIV, HIV, Treatment Naive, Acute Infections