Effect of an Enfuvirtide-based Anti-HIV Drug Regimen on Latent HIV Reservoirs in Treatment Naive Adults

Study Overview
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Brief Summary
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HIV replication in resting CD4 cells is so minimal that anti-HIV drugs often fail to destroy the virus in these cells. Enfuvirtide, also known as T-20, is a type of anti-HIV drug called a fusion inhibitor. The purpose of this study is to test the ability of a T-20-enhanced treatment regimen to decrease the number of resting CD4 cells that become infected with HIV.

Detailed Description
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While current HIV treatment with combination antiretroviral therapy (ART) has reduced morbidity and mortality, it does not eradicate or cure HIV infection. A possible explanation for this failure is the persistence of virus in long-lived reservoirs. Resting memory CD4 cells have been proposed as providing a cellular reservoir. Most patients who initiate ART during chronic HIV-1 infection do not experience a detectable reduction in HIV in the latent reservoir; this may be due to low levels of ongoing viral replication that maintains the resting CD4 cell reservoir. Increasing the potency of therapy by inhibiting new viral targets may result in a decrease in the number of latently infected cells and clearance of the latent reservoir. Addition of the fusion inhibitor T-20 to ART including reverse transcriptase inhibitors and protease inhibitors (PIs) may help achieve this goal. This study will evaluate whether treatment naive, chronically infected HIV patients treated with T-20 plus emtricitabine (FTC), ritonavir (RTV), saquinavir (SQV), and tenofovir disoproxil fumarate (TDF) have a measurable decline in the latently infected CD4 cell reservoir. Patients and their physicians may choose different PIs than RTV and SQV, but they will not be provided by the study. Patients in this study will receive injections of T-20 twice daily in addition to oral FTC and TDF once daily and oral RTV and SQV twice daily. At Week 24, patients will have their latent cell reservoir sampled. Patients whose HIV viral loads are less than 50 copies/ml at or after Week 24 but prior to Week 48 will continue the treatment regimen through the end of the study; their latent cell reservoirs will be tested at Weeks 48, 72, and 96. Patients whose viral loads are between 50 copies/ml and 200 copies/ml will continue the treatment regimen and latent cell sampling, but their regimens may be intensified as determined by the study team. Patients whose viral loads are 200 copies/ml or greater after Week 24 may continue their study regimens, but will no longer contribute latent cell samples. This study will last 96 weeks. During the first 4 months of the study, patients will have 7 study visits; after that, study visits will be every 8 weeks until the end of the study. Medical history, clinical assessments, and blood collection will occur at every study visit. Pill and ENF vial counts will be assessed, and patients will be asked to complete a medication adherence questionnaire at selected study visits.

Official Title
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A Pilot Study to Measure the Clearance of Replication-Competent HIV-1 in Resting Memory CD4+ Cells in HIV-1-Infected Subjects Who Receive Enfuvirtide Plus Oral Combination Antiretroviral Therapy

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Emtricitabine
* Drug: Enfuvirtide
* Drug: Ritonavir
* Drug: Saquinavir
* Drug: Tenofovir disoproxil fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria HIV-1 infected Viral load of 1,000 copies/ml or greater within 60 days prior to study entry CD4 count of 100 cells/mm3 or greater within 60 days prior to study entry Willing to use acceptable methods of contraception Exclusion Criteria Previous treatment with any nucleoside analogue, nonnucleoside reverse transcriptase inhibitor, or fusion inhibitor for longer than 7 days Any previous treatment with T-20, lamivudine, or FTC HIV-related vaccine within 6 months prior to study entry Evidence of HIV seroconversion within 6 months prior to study entry Acute AIDS-defining opportunistic infection (OI). Patients who are not clinically stable or who have not been on therapy for the OI for at least 30 days prior to study entry are excluded. Patients who have no evidence of active disease and have been receiving maintenance therapy for AIDS-related OI for at least 30 days are not excluded. Systemic chemotherapy within 30 days of study entry or anticipated need for systemic chemotherapy before the end of the study Treatment with immune modulators such as systemic steroids, IL-2, alpha interferon, G-CSF, erythropoietin, or any investigational agent within 30 days of study entry Allergy to study drugs or their formulations Serious illness, substance abuse, or other medical condition that would compromise the patient's ability to participate in the study Certain primary resistance HIV mutations Pregnancy or breastfeeding

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Emtricitabine<br>* Will be administered as one 200-mg capsule orally daily<br>* Other names: Emtriva;Drug: Enfuvirtide<br>* Will be administered as a 90-mg (1.0 mL) subcutaneous injection twice daily<br>* Other names: T-20;Drug: Ritonavir<br>* Will be administered as one 100-mg capsule orally twice daily<br>* Other names: Norvir;Drug: Saquinavir<br>* Will be administered as five hard gel capsules orally twice daily<br>* Other names: Saquinavir mesylate;Drug: Tenofovir disoproxil fumarate<br>* Will be administered as one 300-mg tablet orally daily<br>* Other names: Viread;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of latently infected CD4+ T cells from peripheral blood with replication-competent HIV-1 (in infectious units per million cells) |  | Throughout study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any Grade 3 or 4 adverse experience, including Grade 3 or 4 laboratory value, sign or symptom, and all deaths. |  | Throughout study | 
| Targeted events and toxicities will also be considered and these include injection site reactions (any grade), bacterial pneumonia, cellulitis |  | Throughout study | 
| - Level of HIV-1 RNA in plasma as measured by the Roche Ultrasensitive assay |  | Throughout study | 
| - Level of HIV-1 DNA in PBMC |  | Throughout study | 
| - Frequency of 2-LTR in PBMC |  | Throughout study | 
| -Sequence of HIV env and HIV pol genes |  | Throughout study | 
| -CD8/CD38 antibody binding capacity (ABC) |  | Throughout study | 
| - Level of HIV-1 RNA in cerebrospinal fluid |  | Throughout study | 
| - Level of HIV-1 RNA in genital fluid |  | Throughout study | 
| - Level of HIV-1 RNA in plasma as measured by an ultra-ultrasensitive assay |  | Throughout study | 
| - Measures of cell surface density of chemokine (CCR5, CXCR5) receptors |  | Throughout study | 
| - Responses to subject preferences and injection administration concerns questionnaires |  | Throughout study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, Treatment Naive, Virus Replication, CD4-Positive T-Lymphocytes, Immunologic Memory, Pentafuside, Anti-HIV Agents, Drug Therapy, Combination, Saquinavir, Ritonavir, Tenofovir Disoproxil Fumarate, RNA, Viral, Viral Load, Fusion Inhibitors, Entry Inhibitors