Anti-HIV Treatment Interruptions in HIV Infected Adults in South Africa - Full Text View

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 Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: 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:

MedlinePlus related topics: HIV/AIDS Rabies

Drug Information available for: Stavudine Lamivudine Ritonavir Lopinavir

U.S. FDA Resources

Further study details as provided by 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 ] [ Designated as safety issue: Yes ]
Response to rabies vaccination and booster [ Time Frame: Weeks 16, 22, and 92 ] [ Designated as safety issue: Yes ]

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 ] [ Designated as safety issue: Yes ]
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 ] [ Designated as safety issue: Yes ]
Viral evolution and genotypic changes that confer drug resistance [ Time Frame: During intermittent and continuous treatment ] [ Designated as safety issue: Yes ]
Effect of treatment interruption on cardiovascular adverse experiences risk factors [ Time Frame: From Weeks 0 to 144 ] [ Designated as safety issue: Yes ]


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

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


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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 R01AI051986 Protocol 2411209 R01 A151986-01
Study First Received:	January 4, 2005
Last Updated:	August 26, 2014
Health Authority:	United States: Federal Government

Keywords provided by 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 Lopinavir Ritonavir 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

ClinicalTrials.gov processed this record on September 26, 2016