Clinical trial NCT00100646: Anti-HIV Treatment Interruptions in HIV Infected Adults in South Africa
Official title: A Randomized Clinical Trial Assessing Continuous HAART Versus Interrupted HAART in a Resource Poor Clinic
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: Treatment Interruption
Treatment Naive
Lead sponsor: The Wistar Institute
Sponsor class: OTHER
First posted: 2005-01-05
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: To compare intermittent ART to continuous therapy by comparing endpoint CD4 counts between Groups 1 and 2
timeFrame: Throughout study
measure: Response to rabies vaccination and booster
timeFrame: Weeks 16, 22, and 92
Secondary outcomes:
measure: Comparison of treatment-associated toxicity and safety of 2 to 8 weeks of antiretroviral therapy (ART) interruption versus continuous ART
timeFrame: Throughout study
measure: Determine the outcome of immune reconstitution by monitoring changes in T-cell subsets and the ability to maintain cell-mediated responses against various antigens
timeFrame: Before and after intermittent strategy
measure: Viral evolution and genotypic changes that confer drug resistance
timeFrame: During intermittent and continuous treatment
measure: Effect of treatment interruption on cardiovascular adverse experiences risk factors
timeFrame: From Weeks 0 to 144
Other outcomes:
Locations:
city: Johannesburg
country: South Africa
facility: University of the Witwatersrand
Study officials:
affiliation: The Wistar Institute
name: Luis J. Montaner, DVM, MSc, DPhil
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Witwatersrand, South Africa
name: Ian M. Sanne, MBBCH, FCP(SA), DTM&H
role: PRINCIPAL_INVESTIGATOR
References:
citation: Arnedo-Valero M, Garcia F, Gil C, Guila T, Fumero E, Castro P, Blanco JL, Miro 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. doi: 10.1086/432881. Epub 2005 Aug 4.
citation: 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. doi: 10.2174/1570162033485212.
citation: 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. doi: 10.1080/09540120701213849.
citation: 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. doi: 10.1097/00002030-200311070-00008.
citation: 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. doi: 10.1371/journal.pmed.0010064. Epub 2004 Dec 28.
citation: 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.
citation: 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.
citation: 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. doi: 10.1214/10-AOAS326.
citation: 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.