Clinical Trial of Brain-Penetrating HIV Drugs to Prevent Cognitive Impairment in China
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Purpose
| Condition | Intervention | Phase |
|---|---|---|
|
HIV Infections Central Nervous System Diseases Dementia |
Drug: zidovudine-lamivudine-nevirapine Drug: tenofovir-lamivudine-efavirenz |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention |
| Official Title: | Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China |
- Decline in neuropsychological performance at 96 weeks [ Time Frame: 96 weeks ] [ Designated as safety issue: No ]Comparison of decline in NP performance between treatment groups.
| Enrollment: | 250 |
| Study Start Date: | July 2010 |
| Study Completion Date: | July 2015 |
| Primary Completion Date: | July 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Better-Penetrating ART
zidovudine 300 mg orally every 12 hours lamivudine 300 mg orally daily nevirapine 200 mg orally every 12 hours
|
Drug: zidovudine-lamivudine-nevirapine
96 weeks of zidovudine 300 mg orally twice daily, lamivudine 300 mg orally daily, nevirapine 200 mg orally daily for the first 14 days then 200 mg orally twice daily
Other Name: Retrovir, Epivir, Viramune
|
|
Active Comparator: Worse-Penetrating ART
tenofovir disoproxil fumarate 300 mg orally daily lamivudine 150 mg orally every 12 hours efavirenz 600 mg orally daily
|
Drug: tenofovir-lamivudine-efavirenz
96 weeks of tenofovir disoproxil fumarate 300 mg orally daily, lamivudine 300 mg orally daily, efavirenz 600 mg orally daily
Other Name: Viread, Epivir, Sustiva
|
Detailed Description:
Advances in treatment have transformed HIV disease to a chronic illness in most individuals in the U.S. The most common central nervous system (CNS) complication of chronic HIV disease is HIV-associated neurocognitive disorder (HAND). In the U.S., HAND prevalence estimates range up to 55% of treated individuals. HAND is also common outside the U.S. For example, our prior project in China identified that more than a third of nearly 150 treated HIV(+) individuals in Anhui and Yunnan provinces had HAND. Data such as these support that the benefits of antiretroviral therapy (ART) can be incomplete, with many patients not returning to normal neurocognitive performance or, worse, developing new neurocognitive impairment while taking ART.
One explanation for this is the limited penetration of some antiretrovirals into the nervous system. Recent reports have identified that worse antiretroviral penetration characteristics are associated with worse control of HIV replication and worse neurocognitive performance. Most reports, however, have focused on treatment - rather than prevention - of HAND. Like many other medical conditions, prevention of HAND may be a more cost-effective public health goal than treating disease that has already occurred.
We are building on our prior work in China by performing a phase 4, randomized, controlled clinical trial of the safety and effectiveness of ART that differs in its penetration characteristics in 250 ART-naive individuals who have normal neurocognitive performance. The primary objective will be to determine the effects of better penetrating (BP) ART (zidovudine-lamivudine-nevirapine) compared with worse penetrating (WP) ART (tenofovir-lamivudine-efavirenz) on the prevention of HAND. We hypothesize that volunteers who are randomized to BP-ART will be less likely to neurocognitively decline over 96 weeks of observation than those who are randomized to WP-ART. The secondary objective will be to assess the influence on study outcomes of two conditions: persistent immune activation and viral hepatitis. In an exploratory aim, the project will also assess the influence on study outcomes of a concise panel of drug disposition-associated genetic polymorphisms.
Demonstrating that HAND can be prevented by using BP-ART should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS.
Eligibility| Ages Eligible for Study: | 18 Years to 70 Years (Adult, Senior) |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Men and women of at least 18 years of age.
- Ability and willingness of subject to give written informed consent.
- HIV-1 infection, as documented by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot at any time prior to study entry. Plasma HIV-1 RNA is acceptable as an alternative confirmatory test.
- Antiretroviral drug-naïve, defined as ≤10 days of ART at any time prior to entry.
- Clinical HIV-1 RNA ≥1000 copies/mL obtained within 90 days of study screening.
- Clinical blood CD4+ cell count < 350/mm3 (for men) or <250/mm3 (for women) within 60 days of study screening.
- Performance within the expected normal range on the project's comprehensive, standardized battery of neuropsychological tests within 4 weeks.
- For women of child-bearing potential (WOCBP), negative serum or urine pregnancy test at screening and within 48 hours prior to initiating study medications.
Exclusion Criteria:
- Serious illness requiring systemic treatment or hospitalization within 4 weeks.
- Unacceptable laboratory values obtained within 4 weeks prior to study entry.
- Untreated syphilis.
- Child Pugh Class C hepatic impairment.
- Active Hepatitis B Virus infection.
- Known allergy/sensitivity to study drugs or their formulations.
- Severe or untreated conditions that could affect NP test performance.
- Such conditions include but are not limited to current substance use disorder, poorly controlled diabetes, uncontrolled seizure disorder, and any progressive CNS disorder (e.g., multiple sclerosis, CNS neoplasm) and evidence of acute intoxication or withdrawal, in the opinion of the study clinician.
- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
- Currently breast-feeding.
- Requirement for any medications that have an absolute contraindication with any study drugs. In addition, we will exclude people taking rifampin.
- Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness.
- Prior use of nucleoside analogues, such as tenofovir, adefovir, or lamivudine, for treatment of hepatitis B for greater than 8 weeks while the subject was known to be HIV-infected.
- Any condition that, in the opinion of the investigators, would compromise the subject's ability to participate in the study.
Contacts and LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT01340950
| China, Beijing | |
| Beijing Ditan Hospital | |
| Beijing, Beijing, China | |
| Beijing YouAn Hospital | |
| Beijing, Beijing, China | |
| Principal Investigator: | Scott L Letendre, M.D. | University of California, San Diego |
More Information
Additional Information:
Publications:
| Responsible Party: | Scott Letendre, Professor of Medicine, University of California, San Diego |
| ClinicalTrials.gov Identifier: | NCT01340950 History of Changes |
| Other Study ID Numbers: | R01MH092225 1R01MH092225-01 |
| Study First Received: | April 21, 2011 |
| Last Updated: | March 31, 2016 |
| Health Authority: | United States: Institutional Review Board China: Ethics Committee |
| Individual Participant Data | |
| Plan to Share IPD: | Yes |
| Plan Description: | Data will be shared in conference presentations and peer-reviewed publications. Data will also be made available on approval of requests for appropriate use. |
Keywords provided by University of California, San Diego:
|
Prevention Anti-Retroviral Agents Neuropsychological Tests |
Additional relevant MeSH terms:
|
HIV Infections Dementia Nervous System Diseases Central Nervous System Diseases Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Brain Diseases Neurocognitive Disorders Mental Disorders |
Tenofovir Lamivudine Zidovudine Efavirenz Nevirapine Lamivudine, zidovudine drug combination Antiviral Agents Anti-Infective Agents Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Retroviral Agents Anti-HIV Agents Antimetabolites |
ClinicalTrials.gov processed this record on September 26, 2016