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

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.

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.