Clinical trial NCT01340950: Clinical Trial of Brain-Penetrating HIV Drugs to Prevent Cognitive Impairment in China
Official title: Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Central Nervous System Diseases
Dementia
Keywords: Prevention
Anti-Retroviral Agents
Neuropsychological Tests
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
name: National Center for AIDS/STD Control and Prevention, China CDC
name: Beijing YouAn Hospital
name: Beijing Ditan Hospital
name: Peking University
First posted: 2011-04-25
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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 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.

Primary outcomes:
measure: Decline in neuropsychological performance at 96 weeks
timeFrame: 96 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Ditan Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing YouAn Hospital
state: Beijing
Study officials:
affiliation: University of California, San Diego
name: Scott L Letendre, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heaton RK, Cysique LA, Jin H, Shi C, Yu X, Letendre S, Franklin DR, Ake C, Vigil O, Atkinson JH, Marcotte TD, Grant I, Wu Z; San Diego HIV Neurobehavioral Research Center Group. Neurobehavioral effects of human immunodeficiency virus infection among former plasma donors in rural China. J Neurovirol. 2008 Nov;14(6):536-49. doi: 10.1080/13550280802378880.
citation: Cysique LA, Letendre SL, Ake C, Jin H, Franklin DR, Gupta S, Shi C, Yu X, Wu Z, Abramson IS, Grant I, Heaton RK; HIV Neurobehavioral Research Center group. Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China. AIDS. 2010 Apr 24;24(7):983-90. doi: 10.1097/QAD.0b013e32833336c8.
citation: Spector SA, Singh KK, Gupta S, Cystique LA, Jin H, Letendre S, Schrier R, Wu Z, Hong KX, Yu X, Shi C, Heaton RK; HNRC Group. APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors. AIDS. 2010 Jun 19;24(10):1471-9. doi: 10.1097/QAD.0b013e328339e25c.
citation: Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ; CHARTER Group. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008 Jan;65(1):65-70. doi: 10.1001/archneurol.2007.31.
citation: Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, Grant I, Ellis RJ; HNRC Group. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol. 2004 Sep;56(3):416-23. doi: 10.1002/ana.20198.