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Anti-HIV Treatment Interruptions in HIV Infected Adults in South Africa

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00100646
First Posted: January 5, 2005
Last Update Posted: August 27, 2014
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Luis Montaner, The Wistar Institute
  Purpose
HIV infected people often must take anti-HIV drugs for long periods, leading to long-term drug exposure and toxicity. Interruptions in anti-HIV therapy, also known as structured treatment interruptions (STIs), may have few negative health effects and may be helpful to the overall long-term health of HIV-infected people. The purpose of this study is to determine if sequential short-term STIs of antiretroviral therapy (ART) in HIV infected individuals in a resource-constrained environment can retain the immune reconstitution benefits of continuous treatment while potentially lessening rates of toxicity associated with continuous therapy strategies and at the same time, lessen costs associated with ART.

Condition Intervention
HIV Infections Behavioral: Structured treatment interruption Drug: Lamivudine Drug: Lopinavir/Ritonavir Drug: Stavudine Biological: Rabies de novo antigen

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Clinical Trial Assessing Continuous HAART Versus Interrupted HAART in a Resource Poor Clinic

Resource links provided by NLM:


Further study details as provided by Luis Montaner, The Wistar Institute:

Primary Outcome Measures:
  • To compare intermittent ART to continuous therapy by comparing endpoint CD4 counts between Groups 1 and 2 [ Time Frame: Throughout study ]
  • Response to rabies vaccination and booster [ Time Frame: Weeks 16, 22, and 92 ]

Secondary Outcome Measures:
  • Comparison of treatment-associated toxicity and safety of 2 to 8 weeks of antiretroviral therapy (ART) interruption versus continuous ART [ Time Frame: Throughout study ]
  • Determine the outcome of immune reconstitution by monitoring changes in T-cell subsets and the ability to maintain cell-mediated responses against various antigens [ Time Frame: Before and after intermittent strategy ]
  • Viral evolution and genotypic changes that confer drug resistance [ Time Frame: During intermittent and continuous treatment ]
  • Effect of treatment interruption on cardiovascular adverse experiences risk factors [ Time Frame: From Weeks 0 to 144 ]

Enrollment: 30
Study Start Date: March 2007
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Highly active antiretroviral therapy (HAART) consisting of lamivudine, lopinavir/ritonovir, and stavudine for 16 weeks with three structured treatment interruptions for 2, 4, and 8 weeks each; rabies vaccine at Weeks 16, 17, 22 and 92.
Behavioral: Structured treatment interruption
Interruptions in treatment will last 2, 4, and 8 weeks in between 16-week periods of ART
Other Name: STI
Drug: Lamivudine
300 mg tablet taken orally daily
Drug: Lopinavir/Ritonavir
400 mg lopinavir/100 mg ritonavir tablet taken orally twice daily
Drug: Stavudine
Dosage dependent on weight
Biological: Rabies de novo antigen
Vaccine injected intramuscularly
Active Comparator: 2
Continuous HAART consisting of lamivudine, lopinavir/ritonovir, and stavudine throughout the study; rabies vaccine at Weeks 16, 17, 22 and 92.
Drug: Lamivudine
300 mg tablet taken orally daily
Drug: Lopinavir/Ritonavir
400 mg lopinavir/100 mg ritonavir tablet taken orally twice daily
Drug: Stavudine
Dosage dependent on weight
Biological: Rabies de novo antigen
Vaccine injected intramuscularly

Detailed Description:

Long-term toxicity and the high cost of medications are two problems faced by HIV infected people taking ART. Previous studies in HIV-infected patients suggest that ART with STIs may decrease drug exposure and lessen long-term drug toxicity, while not sacrificing viral suppression and patient health. This study will determine if ART with STIs can maintain the same level of immune function in HIV-infected people as continuous ART. This study will recruit patients in South Africa.

This study will last 3.5 years. At study entry, all participants will begin daily ART consisting of lamivudine, lopinavir/ritonavir, and stavudine. At Month 6, only participants who have responded well to ART (CD4 count greater than 450 cells/uL and viral load less than 50 copies/ml at Month 6) will be randomly assigned to one of two groups. Group 1 participants will participate in STIs during therapy, and Group 2 participants will receive continuous therapy. People in Group 1 will have treatment interruptions of 2, 4, and 8 weeks of duration in between 16-week periods of ART. Group 1 participants will re-initiate therapy if their CD4 count drops below 350 cells or evidence of clinical disease progression is present. Group 2 participants will continue taking ART throughout the study.

At screening, participants will undergo medical history assessment, a physical exam, and magnetic resonance imaging (MRI) and dual energy x-ray absorptiometry (DEXA) scans. There will be at least 22 study visits occurring approximately every 8 weeks, each lasting 45 to 60 minutes. At each study visit, participants will be required to bring any remaining pills with them so adherence can be assessed and will undergo medical assessments. Blood collection will occur at nearly all visits. For female participants, urine collection will occur at all visits. Participants will receive rabies vaccinations at Weeks 16, 17, and 22. A visit at Week 92 will include an MRI and participants will receive a rabies vaccine booster.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV infected
  • CD4 count of 200 to 350 cells/mm3 within 60 days of starting study treatment
  • Antiretroviral naive. Participants who have received antiretrovirals through postexposure prophylaxis or short course therapy to prevent mother-to-child transmission are eligible for this study.
  • Willing to adhere to study treatment
  • Willing to be followed for the duration of this study

Exclusion Criteria:

  • History of AIDS-defining illness (CDC category C). Patients with a history of pulmonary tuberculosis are not excluded.
  • Newly diagnosed AIDS-defining opportunistic infection or other condition requiring acute therapy at study entry
  • Previous therapy with agents with significant myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic, or cytotoxic potential within 30 days prior to study entry
  • History of immunomodulatory therapy within 4 weeks prior to screening, or cannot abstain from immunomodulators during the study
  • Previously received rabies vaccine
  • Current alcohol or drug abuse that, in the opinion of the investigator, may interfere with the study
  • Diarrhea (more than 6 stools per day for 7 consecutive days) within 30 days prior to study entry
  • Active or suspected acute hepatitis within 30 days of study entry
  • Bilateral peripheral neuropathy of Grade 2 or higher at screening
  • Inability to tolerate oral medication
  • Any clinical condition that, in the opinion of the investigator, would interfere with the study
  • Pregnancy or breastfeeding
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00100646


Locations
South Africa
University of the Witwatersrand
Johannesburg, South Africa
Sponsors and Collaborators
The Wistar Institute
Investigators
Principal Investigator: Luis J. Montaner, DVM, MSc, DPhil The Wistar Institute
Principal Investigator: Ian M. Sanne, MBBCH, FCP(SA), DTM&H University of Witwatersrand, South Africa
  More Information

Publications:
Azzoni L, Foulkes AS, Firnhaber C, Yin X, Crowther NJ, Glencross D, Lawrie D, Stevens W, Papasavvas E, Sanne I, Montaner LJ. Metabolic and anthropometric parameters contribute to ART-mediated CD4+ T cell recovery in HIV-1-infected individuals: an observational study. J Int AIDS Soc. 2011 Jul 29;14:37. doi: 10.1186/1758-2652-14-37.
Firnhaber C, Azzoni L, Foulkes AS, Gross R, Yin X, Van Amsterdam D, Schulze D, Glencross DK, Stevens W, Hunt G, Morris L, Fox L, Sanne I, Montaner LJ. Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection. PLoS One. 2011;6(6):e21450. doi: 10.1371/journal.pone.0021450. Epub 2011 Jun 28.
Foulkes AS, Azzoni L, Li X, Johnson MA, Smith C, Mounzer K, Montaner LJ. Prediction based classification for longitudinal biomarkers. Ann Appl Stat. 2010 Sep;4(3):1476-1497.
Azzoni L, Crowther NJ, Firnhaber C, Foulkes AS, Yin X, Glencross D, Gross R, Kaplan MD, Papasavvas E, Schulze D, Stevens W, van der Merwe T, Waisberg R, Sanne I, Montaner LJ. Association between HIV replication and serum leptin levels: an observational study of a cohort of HIV-1-infected South African women. J Int AIDS Soc. 2010 Sep 7;13:33. doi: 10.1186/1758-2652-13-33.
Arnedo-Valero M, Garcia F, Gil C, Guila T, Fumero E, Castro P, Blanco JL, Miró JM, Pumarola T, Gatell JM. Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection. Clin Infect Dis. 2005 Sep 15;41(6):883-90. Epub 2005 Aug 4.
Azzoni L, Papasavvas E, Montaner LJ. Lessons learned from HIV treatment interruption: safety, correlates of immune control, and drug sparing. Curr HIV Res. 2003 Jul;1(3):329-42. Review.
Kumarasamy N, Flanigan TP, Vallabhaneni S, Cecelia AJ, Christybai P, Balakrishnan P, Yepthomi T, Solomon S, Carpenter CC, Mayer KH. A randomised control trial of structured interrupted generic antiretroviral therapy versus continuous therapy in HIV-infected individuals in Southern India. AIDS Care. 2007 Apr;19(4):507-13.
Papasavvas E, Grant RM, Sun J, Mackiewicz A, Pistilli M, Gallo C, Kostman JR, Mounzer K, Shull J, Montaner LJ. Lack of persistent drug-resistant mutations evaluated within and between treatment interruptions in chronically HIV-1-infected patients. AIDS. 2003 Nov 7;17(16):2337-43.
Papasavvas E, Kostman JR, Mounzer K, Grant RM, Gross R, Gallo C, Azzoni L, Foulkes A, Thiel B, Pistilli M, Mackiewicz A, Shull J, Montaner LJ. Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. PLoS Med. 2004 Dec;1(3):e64. Epub 2004 Dec 28.

Responsible Party: Luis Montaner, Professor and Director, HIV-1 Immunopathogenesis Laboratory, The Wistar Institute
ClinicalTrials.gov Identifier: NCT00100646     History of Changes
Other Study ID Numbers: 1R01AI051986-01A2 ( U.S. NIH Grant/Contract )
R01AI051986 ( U.S. NIH Grant/Contract )
Protocol 2411209
R01 A151986-01
First Submitted: January 4, 2005
First Posted: January 5, 2005
Last Update Posted: August 27, 2014
Last Verified: November 2013

Keywords provided by Luis Montaner, The Wistar Institute:
Treatment Interruption
Treatment Naive

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Lopinavir
Lamivudine
Stavudine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Antimetabolites


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