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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Emtricitabine; Drug: Enfuvirtide; Drug: Ritonavir; Drug: Saquinavir; Drug: Tenofovir disoproxil fumarate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936-5067
    • Puerto Rico-AIDS CRS
• United States
  • Colorado
    • Aurora, Colorado, United States, 80262-3706
      • University of Colorado Hospital CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS
  • Missouri
    • Saint Louis, Missouri, United States, 63108-2138
      • Washington U CRS
  • New York
    • New York, New York, United States, 10016-6481
      • NY Univ. HIV/AIDS CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Unc Aids Crs
  • Ohio
    • Columbus, Ohio, United States
      • The Ohio State Univ. AIDS CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 1

Drug: Emtricitabine; Will be administered as one 200-mg capsule orally daily; Other Names: FTC; Emtriva; Drug: Enfuvirtide; Will be administered as a 90-mg (1.0 mL) subcutaneous injection twice daily; Other Names: T-20; Fuzeon; ENF; Drug: Ritonavir; Will be administered as one 100-mg capsule orally twice daily; Other Names: Norvir; RTV; Drug: Saquinavir; Will be administered as five hard gel capsules orally twice daily; Other Names: Invirase; Saquinavir mesylate; Drug: Tenofovir disoproxil fumarate; Will be administered as one 300-mg tablet orally daily; Other Names: TDF; Viread

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: AIDS Clinical Trials Group

Publications and helpful links

General Publications

• Blankson JN, Persaud D, Siliciano RF. The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med. 2002;53:557-93. doi: 10.1146/annurev.med.53.082901.104024.
• Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, Markowitz M, Ho DD. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997 May 8;387(6629):188-91. doi: 10.1038/387188a0.
• Pierson T, McArthur J, Siliciano RF. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol. 2000;18:665-708. doi: 10.1146/annurev.immunol.18.1.665.
• Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D, Matthews T, Johnson MR, Nowak MA, Shaw GM, Saag MS. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med. 1998 Nov;4(11):1302-7. doi: 10.1038/3293.
• Gandhi RT, Bosch RJ, Aga E, Albrecht M, Demeter LM, Dykes C, Bastow B, Para M, Lai J, Siliciano RF, Siliciano JD, Eron JJ; AIDS Clinical Trials Group A5173 Team. No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy. J Infect Dis. 2010 Jan 15;201(2):293-6. doi: 10.1086/649569.

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (ACTUAL): December 1, 2007
• Study Completion (ACTUAL): May 1, 2008

Study Registration Dates

• First Submitted: January 16, 2003
• First Submitted That Met QC Criteria: January 17, 2003
• First Posted (ESTIMATE): January 20, 2003

Study Record Updates

• Last Update Posted (ACTUAL): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Anti-HIV Agents; HIV-1; RNA, Viral; Viral Load; Treatment Naive; Ritonavir; Virus Replication; Immunologic Memory; Tenofovir Disoproxil Fumarate; CD4-Positive T-Lymphocytes; Saquinavir; Entry Inhibitors; Pentafuside; Fusion Inhibitors
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Tenofovir; Emtricitabine; Ritonavir; Enfuvirtide; Saquinavir
• Other Study ID Numbers: A5173; 10006 (REGISTRY: DAIDS ES); ACTG A5173