Association of combination antiretroviral therapy with risk of neurological diseases in patients with HIV/AIDS in Taiwan: a nested case-control study

Abstract

Heterogeneous neurocognitive impairment remains an important issue, even in the era of combination antiretroviral therapy (cART), with an incidence ranging from 15% to 65%. Although ART drugs with higher penetration scores to the central nervous system (CNS) show better HIV replication control in the CNS, the association between CNS penetration effectiveness (CPE) scores and neurocognitive impairment remains inconclusive. To explore whether ART exposure is associated with the risk of neurological diseases among patients with HIV/AIDS, this study in Taiwan involved 2,571 patients with neurological diseases and 10,284 matched, randomly selected patients without neurological diseases between 2010 and 2017. A conditional logistic regression model was used in this study. The parameters for ART exposure included ART usage, timing of exposure, cumulative defined daily dose (DDD), adherence, and cumulative CPE score. Incident cases of neurological diseases, including CNS infections, cognitive disorders, vasculopathy, and peripheral neuropathy, were obtained from the National Health Insurance Research Database in Taiwan. Odds ratios (ORs) for the risk of neurological diseases were conducted using a multivariate conditional logistic regression model. Patients with a history of past exposure (OR: 1.68, 95% confidence interval [CI]:1.22-2.32), low cumulative DDDs (< 2,500) (OR: 1.28, 95% CI: 1.15-1.42), low adherence (0 < adherence (ADH) ≤ 0.8) (OR: 1.46, 95% CI: 1.30-1.64), or high cumulative CPE scores (>14) (OR: 1.34, 95% CI: 1.14-1.57) had a high risk of neurological diseases. When stratified by classes of ART drugs, patients with low cumulative DDDs or low adherence had a high risk of neurological diseases, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets. Subgroup analyses also suggested that patients with low cumulative DDDs or low adherence had a high risk of neurological diseases when they had high cumulative CPE scores. Patients with high cumulative DDDs or medication adherence were protected against neurological diseases only when they had low cumulative CPE scores (≤ 14). Patients may be at risk for neurological diseases when they have low cumulative DDDs, low adherence, or usage with high cumulative CPE scores. Continuous usage and low cumulative CPE scores of ART drugs may benefit neurocognitive health in patients with HIV/AIDS.

Keywords: CNS penetration effectiveness score; antiretroviral therapy; cumulative defined daily dose; nested case-control study; neurocognitive impairment.

FIGURE 1

Flow chart for the recruitment of study subjects. Inclusion and exclusion criteria for neurological disease cases and non-neurological disease controls in patients with HIV/AIDS. HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome.

FIGURE 2

Follow-up time in patients with HIV/AIDS. (A) Patients with neurological diseases; (B) patients with non-neurological diseases. Past, recent, and current exposures to ART drugs were defined according to the latest ART prescription date before the index date. The date of the first neurological disease diagnosis was designated as the index date. Patients who received ART drugs during the time window of over 2 years before the index date but were currently non-users were defined as patients with past exposure to ART drugs. Patients who received ART drugs within the time window of 1–2 years before the index date were defined as patients with recent exposure to ART drugs. Patients who received ART drugs within the time window of 0–1 year before the index date were defined as patients with current exposure to ART drugs. Patients who continuously received ART since their first diagnosis of HIV/AIDS were also defined as those with current exposure to ART drugs.

FIGURE 3

Cumulative CPE score and risk of neurological diseases when stratified by cumulative DDD of ART. (A) Patients with cumulative DDDs < 2,500; (B) patients with cumulative DDDs ≥ 2,500.

FIGURE 4

Cumulative CPE score of ART drugs and risk of neurological diseases when stratified by adherence (ADH) to ART drugs. (A) Patients with low adherence (0 < ADH ≤ 0.8); (B) patients with high adherence (0.8 < ADH).