Drug Exposure Registry for GSK2248761, an Investigational NNRTI
Status:
Unknown status
Trial end date:
0000-00-00
Target enrollment:
Participant gender:
Summary
The World Health Organization has estimated that as many as 10% of the population worldwide
may at some point experience at least one seizure. The percentage with active epilepsy is
from 0.4% to 1%. From 40% to 65% of patients with HIV infection have been estimated to have
some neurological involvement; the percentage reaches as high as 70% to 80% when post-mortem
assessments are included. Estimates of the percentage of HIV-infected patients with seizure
occurrence have varied widely, with one review finding a range from 2% to 20%. The highest
percentage in this range was reported at a center that exclusively treated patients with
neurological involvement, in India where HIV clade C subtype is predominant. Query of
another neurology department's database determined that of the HIV-infected patients treated
at the center, all of whom were referred for neurological symptoms, 6.1% experienced
seizures. Underlying neurologic diseases in these patients included HIV-associated
encephalopathy, progressive multifocal leukoencephalopathy, and toxoplasmosis. In a Spanish
population, 3% of HIV-infected patients over a one-year study period were found to have
new-onset seizures, which were attributed to drug toxicity in 47%, intracranial lesions in
35%, and metabolic derangements in 12%.
Drug-discontinuation studies, magnetic resonance imaging studies, and animal studies have
produced recent evidence that some antiretroviral therapies may have neurotoxic effects,
warranting further research. Individuals who are treated with highly active antiretroviral
therapy are at risk for immune reconstitution inflammatory syndrome (IRIS), in which immune
recovery triggers clinical deterioration as the newly invigorated immune system reacts to
pathogens that either represent ongoing opportunistic infection or were previously
successfully controlled. In a population initiating combination antiretroviral therapy
between 1999 and 2007, 0.9% developed neurological manifestations of IRIS. Seizures may
occur as part of a neurological IRIS syndrome, such as encephalitis and toxoplasmosis.
Two randomized, Phase 2b dose-finding studies were conducted in HIV-1 infected adults to
compare GSK2248761 100 mg and 200 mg given once daily as part of an antiretroviral treatment
regimen. One of the studies (SGN113399) was in subjects with prior exposure to
antiretroviral therapy where GSK2248761 100 mg and 200 mg once daily were compared to
determine the best dose in this population. A contemporary control arm receiving etravirine
200 mg twice daily was also included, and all arms included a twice-daily background therapy
consisting of darunavir/ritonavir 600 mg/100 mg plus raltegravir 400 mg. The other study
(SGN113404) was in treatment-naïve subjects, comparing GSK2248761 100 mg and 200 mg once
daily to determine the best dose in this population. A contemporary control arm receiving
efavirenz 600 mg once daily was also included, and all arms were given background therapy
selected by investigators from either once-daily abacavir/lamivudine 600 mg/300 mg or
tenofovir/emtricitabine 300 mg/200 mg. Of a planned total population in both studies of 300
subjects, 35 were enrolled before the studies were terminated because of the occurrence of
seizures in five subjects. All of the subjects who experienced seizures were enrolled into
SGN113399, four randomized to receive 200 mg GSK2248761 and one randomized to receive 100 mg
GSK2248761. There were no seizures in the subjects receiving GSK2248761 in study SGN113404.
At the time of study termination, subjects had been enrolled and received GSK2248761 at 19
sites in four countries: France, Romania, United States, and Germany. Although potential
contributory conditions have been identified in some cases, definitive causative factors for
the seizure occurrence have not been established.
The purpose of this study is to follow subjects who previously received GSK2248761 while
enrolled in the Phase 2b studies, which were halted due to unexpected seizures. The study
will collect data on all subjects and will be used to monitor for additional seizures as
well as collect additional clinical data on all subjects.