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Clinical Trial of Brain-Penetrating HIV Drugs to Prevent Cognitive Impairment in China

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ClinicalTrials.gov Identifier: NCT01340950
Recruitment Status : Completed
First Posted : April 25, 2011
Last Update Posted : April 4, 2016
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:
This primary aim of the project is to determine the association between antiretroviral therapy that better distributes into the central nervous system and prevention of HIV-associated neurocognitive impairment.

Condition or disease Intervention/treatment Phase
HIV Infections Central Nervous System Diseases Dementia Drug: zidovudine-lamivudine-nevirapine Drug: tenofovir-lamivudine-efavirenz Phase 4

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China
Study Start Date : July 2010
Primary Completion Date : July 2014
Study Completion Date : July 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
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


Outcome Measures

Primary Outcome Measures :
  1. Decline in neuropsychological performance at 96 weeks [ Time Frame: 96 weeks ]
    Comparison of decline in NP performance between treatment groups.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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): NCT01340950


Locations
China, Beijing
Beijing Ditan Hospital
Beijing, Beijing, China
Beijing YouAn Hospital
Beijing, Beijing, China
Sponsors and Collaborators
University of California, San Diego
National Institute of Mental Health (NIMH)
National Center for AIDS/STD Control and Prevention, China CDC
Beijing YouAn Hospital
Beijing Ditan Hospital
Peking University
Investigators
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 ( U.S. NIH Grant/Contract )
1R01MH092225-01 ( U.S. NIH Grant/Contract )
First Posted: April 25, 2011    Key Record Dates
Last Update Posted: April 4, 2016
Last Verified: March 2016
Individual Participant Data (IPD) Sharing Statement:
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 Scott Letendre, 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