Clinical trial NCT00051831: Effect of an Enfuvirtide-based Anti-HIV Drug Regimen on Latent HIV Reservoirs in Treatment Naive Adults
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: Treatment Naive
HIV-1
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
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
First posted: 2003-01-20
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Frequency of latently infected CD4+ T cells from peripheral blood with replication-competent HIV-1 (in infectious units per million cells)
timeFrame: Throughout study
Secondary outcomes:
measure: Any Grade 3 or 4 adverse experience, including Grade 3 or 4 laboratory value, sign or symptom, and all deaths.
timeFrame: Throughout study
measure: Targeted events and toxicities will also be considered and these include injection site reactions (any grade), bacterial pneumonia, cellulitis
timeFrame: Throughout study
measure: - Level of HIV-1 RNA in plasma as measured by the Roche Ultrasensitive assay
timeFrame: Throughout study
measure: - Level of HIV-1 DNA in PBMC
timeFrame: Throughout study
measure: - Frequency of 2-LTR in PBMC
timeFrame: Throughout study
measure: -Sequence of HIV env and HIV pol genes
timeFrame: Throughout study
measure: -CD8/CD38 antibody binding capacity (ABC)
timeFrame: Throughout study
measure: - Level of HIV-1 RNA in cerebrospinal fluid
timeFrame: Throughout study
measure: - Level of HIV-1 RNA in genital fluid
timeFrame: Throughout study
measure: - Level of HIV-1 RNA in plasma as measured by an ultra-ultrasensitive assay
timeFrame: Throughout study
measure: - Measures of cell surface density of chemokine (CCR5, CXCR5) receptors
timeFrame: Throughout study
measure: - Responses to subject preferences and injection administration concerns questionnaires
timeFrame: Throughout study
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Joseph J. Eron, Jr., MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.