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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Clinical Trial Assessing Continuous HAART Versus Interrupted HAART in a Resource Poor Clinic

Conditions
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HIV Infections

Intervention / Treatment
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* Behavioral: Structured treatment interruption
* Drug: Lamivudine
* Drug: Lopinavir/Ritonavir
* Drug: Stavudine
* Biological: Rabies de novo antigen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>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<br>* Interruptions in treatment will last 2, 4, and 8 weeks in between 16-week periods of ART<br>* Other names: STI;Drug: Lamivudine<br>* 300 mg tablet taken orally daily<br>Drug: Lopinavir/Ritonavir<br>* 400 mg lopinavir/100 mg ritonavir tablet taken orally twice daily<br>Drug: Stavudine<br>* Dosage dependent on weight<br>Biological: Rabies de novo antigen<br>* Vaccine injected intramuscularly<br>|
| Active Comparator: 2<br>Continuous HAART consisting of lamivudine, lopinavir/ritonovir, and stavudine throughout the study; rabies vaccine at Weeks 16, 17, 22 and 92. | Drug: Lamivudine<br>* 300 mg tablet taken orally daily<br>Drug: Lopinavir/Ritonavir<br>* 400 mg lopinavir/100 mg ritonavir tablet taken orally twice daily<br>Drug: Stavudine<br>* Dosage dependent on weight<br>Biological: Rabies de novo antigen<br>* Vaccine injected intramuscularly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare intermittent ART to continuous therapy by comparing endpoint CD4 counts between Groups 1 and 2 |  | Throughout study | 
| Response to rabies vaccination and booster |  | Weeks 16, 22, and 92 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of treatment-associated toxicity and safety of 2 to 8 weeks of antiretroviral therapy (ART) interruption versus continuous ART |  | 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 |  | Before and after intermittent strategy | 
| Viral evolution and genotypic changes that confer drug resistance |  | During intermittent and continuous treatment | 
| Effect of treatment interruption on cardiovascular adverse experiences risk factors |  | From Weeks 0 to 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Interruption, Treatment Naive