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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Center for AIDS/STD Control and Prevention, China CDC
Beijing YouAn Hospital
Beijing Ditan Hospital
Information provided by (Responsible Party):
Scott Letendre, University of California, San Diego
ClinicalTrials.gov Identifier:
NCT01340950
First received: April 21, 2011
Last updated: April 17, 2013
Last verified: January 2012
  Purpose

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 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

Resource links provided by NLM:


Further study details as provided by University of California, San Diego:

Primary Outcome Measures:
  • Decline in neuropsychological performance at 48 weeks [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Comparison of decline in NP performance between treatment groups.


Estimated Enrollment: 250
Study Start Date: July 2010
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Better-Penetrating Antiretroviral Therapy
BP-ART: zidovudine, lamivudine, nevirapine
Drug: zidovudine-lamivudine-nevirapine
48 weeks of zidovudine 300 mg orally twice daily, lamivudine 300 mg orally daily, nevirapine 200 mg orally daily for the first 14 days then 400 mg orally twice daily
Other Name: Retrovir, Epivir, Viramune
Active Comparator: Worse-Penetrating Antiretroviral Therapy
WP-ART: tenofovir, lamivudine, efavirenz
Drug: tenofovir-lamivudine-efavirenz
48 weeks of tenofovir disoproxil fumarate 300 mg orally daily, 3TC 300 mg orally daily, EFV 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
Genders Eligible for Study:   Both
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
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: 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 Center for AIDS/STD Control and Prevention, China CDC
Beijing YouAn Hospital
Beijing Ditan Hospital
Investigators
Principal Investigator: Scott L Letendre, M.D. University of California, San Diego
  More Information

Additional Information:
Publications:

Responsible Party: Scott Letendre, Associate Professor, 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: April 17, 2013
Health Authority: United States: Institutional Review Board
China: Ethics Committee

Keywords provided by University of California, San Diego:
Prevention
Anti-Retroviral Agents
Neuropsychological Tests

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Central Nervous System Diseases
Dementia
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
Slow Virus Diseases
Brain Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Zidovudine
Nevirapine
Lamivudine
Tenofovir
Tenofovir disoproxil
Efavirenz
Lamivudine, zidovudine drug combination
Anti-Retroviral Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 31, 2014