Clinical trial NCT00084019: Atazanavir/Ritonavir Maintenance Therapy
Official title: A Prospective, Open-Label, Pilot Trial of Regimen Simplification to Atazanavir/Ritonavir Alone as Maintenance Antiretroviral Therapy After Sustained Virologic Suppression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2004-06-07
Enrollment: 36
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: Long-term side effects, the expense of medications, and the difficulty of taking medications continuously for long periods of time are all problems with complicated anti-HIV drug regimens. The purpose of this study is to determine whether two drugs, atazanavir (ATV) and ritonavir (RTV), will control HIV infection when taken together without any other anti-HIV drugs after 48 weeks of viral suppression.

Hypothesis: Simplified maintenance therapy with ATV and RTV alone after virologic suppression does not markedly increase the risk of virologic failure.

Detailed description: The expense, difficulty, and long-term adverse events associated with sustained adherence to combination antiretroviral therapy emphasize the need for simpler, alternative treatment strategies for HIV infection. Studies have shown that single protease inhibitor (PI) maintenance therapy may provide sufficient virologic suppression while reducing the risk of nucleoside reverse transcriptase inhibitor (NRTI)-associated metabolic complications. However, it is not known whether ritonavir-boosted atazanavir (ATV/RTV) maintenance therapy would be effective in controlling HIV replication in the genital compartments and whether viral load testing by blood collection would be effective in detecting elevated levels of HIV in the genital compartments. This study will determine whether simplified maintenance therapy with ATV/RTV after 48-week virologic suppression will increase the likelihood of virologic failure.

This study will last 54 weeks. Participants will undergo an electrocardiogram (EKG) at screening. At study start, participants will switch from their current PIs to ATV/RTV and stay on their current NRTIs until Week 6, when they will discontinue their NRTIs and remain on a maintenance regimen of ATV/RTV alone for the duration of the study. Study visits will take place at Weeks 3 and 6, then every 4 weeks until Week 30, then every 8 weeks until the end of the study at Week 54. Medication assessment, physical exam, and blood work will occur at each study visit. At Week 30, viral load will be measured in the genital secretions of both male and female study participants.

Eligibility criteria: Inclusion Criteria:

* HIV infected
* On first antiretroviral regimen, including at least 2 NRTIs and 1 PI, for at least 48 weeks immediately prior to study entry
* CD4 count of 250 cells/mm3 or greater
* Viral load less than 50 copies/ml within 30 days prior to entry
* Willing to use acceptable methods of contraception

Exclusion Criteria:

* Current or prior use of an NNRTI
* Certain PI mutations
* Hepatitis B infection within 90 days prior to study entry
* Certain therapies or medications within 30 days prior to study entry
* Heartbeat abnormalities or symptoms potentially related to heart block, such as unexplained fainting, dizziness, or palpitations, occurring within 180 days prior to study entry
* Drug or alcohol use or dependence that would interfere with adherence to the study requirements
* Serious illness requiring systemic treatment or hospitalization until the participant either completes therapy or has been clinically stable on therapy for at least 14 days prior to study entry
* Allergy or sensitivity to study medications or their formulations
* Current involuntarily incarceration for treatment of either a mental or physical illness
* Treatment for an active AIDS-defining opportunistic infection within 30 days prior to screening
* Pregnant or breastfeeding

Primary outcomes:
measure: Virologic failure, defined as 2 consecutive viral load measurements of 200 copies/ml or greater, at or before Week 30 (24 weeks on ATV/RTV alone)
Secondary outcomes:
measure: Grade 3 and 4 laboratory abnormalities and signs and symptoms
measure: time to treatment discontinuation because of toxicity or intolerance
measure: virologic failure at or before Week 54
measure: viral load determined by modified ultrasensitive RT-PCR assay
measure: minor PI variants at virologic failure
measure: total cholesterol, high-density lipoprotein (HDL) cholesterol, calculated low-density lipoprotein (LDL) cholesterol, and triglycerides
measure: CD4 cell count and percentages at Weeks 30 and 54
measure: self-reported adherence scores
measure: plasma drug levels characterized by Cmin and AUC
measure: detectable viral load in the genital compartment at Week 30
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford AIDS Clinical Trials Unit CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Iowa City
country: United States
facility: Univ. of Iowa Healthcare, Div. of Infectious Diseases
state: Iowa
city: Omaha
country: United States
facility: Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
state: Nebraska
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati CRS
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Dallas
country: United States
facility: Dallas VAMC
state: Texas
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: University of Nebraska
name: Susan Swindells, MD
role: STUDY_CHAIR
References:
citation: Havlir DV, Marschner IC, Hirsch MS, Collier AC, Tebas P, Bassett RL, Ioannidis JP, Holohan MK, Leavitt R, Boone G, Richman DD. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med. 1998 Oct 29;339(18):1261-8. doi: 10.1056/NEJM199810293391801.
citation: Pialoux G, Raffi F, Brun-Vezinet F, Meiffredy V, Flandre P, Gastaut JA, Dellamonica P, Yeni P, Delfraissy JF, Aboulker JP. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team. N Engl J Med. 1998 Oct 29;339(18):1269-76. doi: 10.1056/NEJM199810293391802.
citation: Reijers MH, Weverling GJ, Jurriaans S, Wit FW, Weigel HM, Ten Kate RW, Mulder JW, Frissen PH, van Leeuwen R, Reiss P, Schuitemaker H, de Wolf F, Lange JM. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet. 1998 Jul 18;352(9123):185-90. doi: 10.1016/s0140-6736(98)06193-5.
citation: Kahlert C, Hupfer M, Wagels T, Bueche D, Fierz W, Walker UA, Vernazza PL. Ritonavir boosted indinavir treatment as a simplified maintenance "mono"-therapy for HIV infection. AIDS. 2004 Apr 9;18(6):955-7. doi: 10.1097/00002030-200404090-00017. No abstract available.
citation: Kelly M. Induction-maintenance antiretroviral strategies to reduce long-term toxicity. J HIV Ther. 2003 Feb;8(1):11-4.
citation: Swindells S, DiRienzo AG, Wilkin T, Fletcher CV, Margolis DM, Thal GD, Godfrey C, Bastow B, Ray MG, Wang H, Coombs RW, McKinnon J, Mellors JW; AIDS Clinical Trials Group 5201 Study Team. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA. 2006 Aug 16;296(7):806-14. doi: 10.1001/jama.296.7.806.
citation: McKinnon JE, Mailliard RB, Swindells S, Wilkin TJ, Borowski L, Roper JM, Bastow B, Kearney M, Wiegand A, Mellors JW, Rinaldo CR; A5201 study team. Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201). PLoS One. 2014 May 6;9(5):e95524. doi: 10.1371/journal.pone.0095524. eCollection 2014.
citation: Wilkin TJ, McKinnon JE, DiRienzo AG, Mollan K, Fletcher CV, Margolis DM, Bastow B, Thal G, Woodward W, Godfrey C, Wiegand A, Maldarelli F, Palmer S, Coffin JM, Mellors JW, Swindells S. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy: final 48-week clinical and virologic outcomes. J Infect Dis. 2009 Mar 15;199(6):866-71. doi: 10.1086/597119.