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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00051831

Collaborator

AIDS Clinical Trials Group (Other)

Enrollment

Locations

Arm

Duration (Months)

2.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Emtricitabine Drug: Enfuvirtide Drug: Ritonavir Drug: Saquinavir Drug: Tenofovir disoproxil fumarate	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

19 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2003

Actual Primary Completion Date :

Dec 1, 2007

Actual Study Completion Date :

May 1, 2008

Arms and Interventions

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: ENF Fuzeon T-20 Drug: Ritonavir Will be administered as one 100-mg capsule orally twice daily Other Names: RTV Norvir 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

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:

ENF

Fuzeon

T-20

Drug: Ritonavir

Will be administered as one 100-mg capsule orally twice daily

Other Names:

RTV

Norvir

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

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Hospital CRS	Aurora	Colorado	United States	80262-3706
2	Massachusetts General Hospital ACTG CRS	Boston	Massachusetts	United States	02114
3	Washington U CRS	Saint Louis	Missouri	United States	63108-2138
4	NY Univ. HIV/AIDS CRS	New York	New York	United States	10016-6481
5	Unc Aids Crs	Chapel Hill	North Carolina	United States	27514
6	The Ohio State Univ. AIDS CRS	Columbus	Ohio	United States
7	Puerto Rico-AIDS CRS	San Juan		Puerto Rico	00936-5067