The prevalence of AIDS-related neurological disorders ranges between 15.8% and 64.4%.1–4 According to pathological findings from autopsies of patients with AIDS, 80%–90% of patients exhibit signs of neurological disorders.5,6 Although the introduction of highly active antiretroviral therapy (HAART) has improved the survival of people living with HIV in Western countries, neurological disorders remain a significant burden for HIV-positive people.7,8
AIDS-related neurological disorders feature primary and secondary symptoms. Primary symptoms are caused by direct invasion of the central nervous system (CNS) by HIV or by damage to the immune system. Secondary symptoms are caused by opportunistic infections, tumors, or cerebrovascular diseases associated with HIV infection or side effects of HAART.9–12 The early-stage neurological disorders commonly observed are meningitis, encephalitis, spinal cord diseases, and peripheral neuropathies. End-stage symptoms include severe impairment of motor and cognitive functions [ie, HIV-associated neurocognitive disorders (HANDs), HIV-associated dementia], toxoplasma encephalitis, primary lymphoma, metabolic encephalopathy, and neurosyphilis.7,11 After the widespread use of HAART in the mid-1990s, there was a dramatic drop in the rates of AIDS-associated dementia.13 However, with the contributions of HAART, aging, immune reactivation, and chronic inflammation, the characteristics of HIV-related neurocognitive disorders have become much more heterogeneous. Unlike HIV-associated dementia, mild neurocognitive disorders and minor cognitive-motor disorders may present as the early stages of a spectrum of “dementia” syndromes seen at the beginning of HIV infection.14 These symptoms are typically observed in men (64.7%–89% of cases of neurological disorders) and middle-aged people (between 33.4 and 40.9 years).1,3,15–17 The risk factors are age, lower education level, antiretroviral therapy, and a decreased CD4 count.4,16,18,19 HAART reduces the risk of AIDS-related neurological disorders by 10%–30%.20–27 When a patient's CD4 count is below 200 cells/μL, the risk of developing neurological disorders increases by 15%,7 with a mortality rate ranging between 14.9% and 29.5%.15,28
More than 4.8 million HIV-positive persons now live in the Asia-Pacific region.29 However, the incidence and prevalence of neurological disorders among HIV-positive persons in the Asia-Pacific region have rarely been reported.30 Under the universal health care system of Taiwan, all HIV-infected patients have had free access to HAART since 1997, with free medical care and treatment for AIDS-related neurological disorders. According to the Taiwan Center for Disease Control guidelines for the diagnosis and treatment of HIV/AIDS issued in 2010, HAART is recommended for all HIV-infected persons with CD4 counts <350 cell/mm3 who present with AIDS-related opportunistic infections or tumors, exhibit severe clinical signs, or are pregnant.31 An estimated 70% of individuals living with HIV infection in Taiwan have sought HIV care, and 40% of individuals who have sought HIV care receive HAART if their CD4 cell counts are <350 cells/mm3.32 Therefore, we have the opportunity to study neurological disorders in a cohort of HIV-positive persons in the post-HAART era in Taiwan. In this study, we intend to determine the trends in the incidence of neurological disorders from 2000 to 2010 and their associated factors among a cohort of HIV-infected patients in Taiwan.
This was a retrospective population-based cohort study using outpatient clinic files retrieved from the Taiwan National Health Insurance Research Database (NHIRD) for the years 2000–2010.
The Bureau of National Health Insurance (BNHI) and the Department of Health of Taiwan, consolidated all health insurance claim records into an ongoing, prospective NHIRD beginning in 1995. The National Health Insurance (NHI) program was implemented on March 1, 1995, and has since provided compulsory universal health insurance for all citizens. As of 2007, the NHI program covered approximately 99% of the 23 million people living in Taiwan and contracted with 99% of the hospitals and clinics on the island. We used databases for admissions and outpatient visits, both of which included information on patient characteristics, including sex, date of birth, date of admission, date of discharge, dates of visits, and up to 5 discharge diagnoses or 3 outpatient visit diagnoses coded using the International Classification of Diseases, Ninth Revision (ICD-9) classification. The data files also contained information on patient prescriptions, including the names of prescribed drugs, the dosage, duration, and total expenditure.
Any identifying information for both patients and medical facilities was encrypted by the BNHI. This study adhered to strict confidentiality guidelines in accordance with regulations regarding personal electronic data protection and was approved by the ethics review board (NO. 101-5252B) of the Chang Gung Memorial Hospital, Chia-Yi Branch.
Patients With HIV
From the NHIRD, 15,228 HIV-infected people were identified by the ICD-9-CM codes (042, V08) on original claims and further confirmed using code 91, which refers to HIV cases reported for reimbursement by the Taiwan CDC. We defined the initial diagnosis of HIV during the study period as the index date. We excluded 171 individuals who lacked information on sex and 1452 individuals who had been diagnosed with neurological disorders before being diagnosed with HIV. To better understand the effect of HAART on neurological disorders, we excluded 289 patients who were diagnosed with neurological disorders before initiation of HAART. Ultimately, a total of 13,316 patients who were diagnosed with HIV between 2000 and 2010 were analyzed. Baseline demographic and clinical characteristics were compared between included patients and those who were excluded from the analysis. Patients excluded from the analysis were older at the time of diagnosis; were more likely to be diagnosed between 2007 and 2010; were more likely to be diagnosed with hypertension, substance abuse, and opportunistic infections; and had more emergency department (ED) visits and more regular visits, as shown in Supplemental Digital Content 1, http://links.lww.com/QAI/B30.
The primary outcome was the incidence of the first diagnosis of a neurological disorder after an HIV diagnosis. The selection of neurological disorders in this study was based on a previous study by Vivithanaporn et al (2010).7 HIV infection of the CNS is an important etiology in new-onset seizure disorder or epilepsy in young adults.33 HIV infection may also involve the basal ganglia and may be associated with Parkinson disease.34,35 Therefore, in this analysis, we included Parkinson disease (ICD-9-CM 332) and epilepsy (ICD-9-CM 345) as cognitive disorders. Neurological disorders were classified into 4 types: CNS infections (ICD-9-CM: 013, 047, 053, 094, 200, 320, 321, 322, 323, 0543, 054.4, 114.2, 130.0, 321.0, 003.21, 098.82, 112.83, and 115.91), cognitive disorders (ICD-9-CM: 290, 293, 294, 332, 345, 348.1, 348.3, and 780.3), vasculopathy (ICD-9-CM: 325, 430, 431, 432, 433, 434, 435, 436, and 437), and peripheral neuropathy (ICD-9-CM: 350, 351, 353, 354, 355, 356, 357, and 358).
Covariates included demographic data, comorbidities, frequency of ED visits, frequency of regular visits, and HAART use. Demographic data included sex, age, and index year. Comorbidity factors included hypertension (ICD-9-CM: 401, 402, 403, 404, and 405), hepatitis C (ICD-9-CM: 0704, 07041, 07044, 07051, 07054, and V0262), substance abuse (ICD-9-CM: 303, 304, and 305), opportunistic infections (ICD-9-CM: 0031, 0072, 0074, 0312, 0463, 0547, 0785, 112, 11284, 1141, 1143, 115, 1175, 118, 1300, 1363, 176, 180, 2001, 2002, and 7994), and syphilis infection (ICD-9-CM: 091, 092, 093, 095, 096, and 097) other than neurosyphilis (ICD-9-CM: 094). ED visits were defined according to the sequence of visiting divisions after diagnosis with HIV. The frequency of ED visits was classified into 4 groups as none, 1–3 times, 3–5 times, and more than 5 times. Regular physician visits were defined as having a record of physician visits at least twice per year with an interval of more than 180 days between the 2 clinical visits. Based on a participant's pharmacy refill record, antiretroviral drug code numbers and prescription dates were retrieved from outpatient and inpatient medical visit claim data. According to each individual's pharmacy refill records, the duration of HAART was classified into 3 groups: none, 0.5 years or less, and more than 0.5 years.36 Among patients taking HAART for more than 0.5 years, we distinguished between adherence (≥85%) and nonadherence. The cutoff for adherence, greater than 85% as a synonym for adherence, was determined using a sensitivity analysis. Adherence was measured using medication possessing ratio, which was calculated by the sum of the prescription fill date of each patient divided by the number of days between the first fill of the medication and the end of observation date. The end of observation date was defined by the occurrence of neurological disorders, withdrawal from the program, or the end of 2010.
Incidence rates were expressed per 1000 prospective person-years (PYs) of observation from 2000 through 2010. The termination date was the date of withdrawal from the NHIRD or the end of 2010. The incidence rates were further adjusted by age and sex using direct standardization based on the 2000 WHO world standard population. Cox proportional hazards models were used to compute the HRs and the corresponding 95% confidence intervals (CIs) after entering covariates. We additionally assessed the effect of HAART on the incidence of neurological disorders using Cox regression after controlling for demographic data, comorbidities, and the frequency of ED visits. Sensitivity analyses were performed to determine the cutoff parameters for adherence from 85% to the maximum efficacy of 95% to predict a reduced risk of neurological disorders,37,38 which were adjusted for demographic data, comorbidities, and the frequency of ED visits. Only selected frequencies of ED visits were used for the model analysis because of the collinearity between the frequency of ED visits and regular visits. All these analyses were conducted using SAS statistical software (version 9.3; SAS Institute, Cary, NC).
Demographic and Clinical Characteristics
The files of 13,316 HIV-infected persons had a median follow-up of 54.23 months (interquartile range, 37.27–71.93). A total of 1005 (7.55%) subjects were diagnosed with neurological disorders from 2000 through 2010. The mean time from the index date to diagnosis with a neurological disorder was 30.9 months (interquartile range, 10.0–45.4). Of the 13,316 HIV-infected people, 90.73% were men, and the mean age (±SD) at diagnosis was 33.31 ± 9.69 years. More than half (n = 7257, 54.50%) of the HIV-infected people received HAART therapy, and 5064 (38.03%) failed to maintain regular hospital visits (Table 1). Compared with HIV-infected people without neurological disorders, those with neurological disorders were older (35.78 ± 11.42 vs. 33.11 ± 9.51, P < 0.001) and more likely to be diagnosed with hypertension (9.85% vs. 4.66%, P < 0.001), substance abuse (12.14% vs. 8.33%, P < 0.001), opportunistic infections (14.83% vs. 7.62%, P < 0.001), and syphilis (30.25% vs. 24.35%, P < 0.001). They had more frequent visits to the ED (73.93% vs. 60.84%, P < 0.001) and were less likely to use HAART (62.89% vs. 53.81%, P < 0.001) (Table 1).
Trends in the Standardized Incidence of Neurological Diseases From 2000 Through 2010
The standardized incidence of neurological disorders in HIV-positive persons increased from 22.16 per 1000 PYs in 2000 to 25.23 per 1000 PYs in 2010, with a mean incidence of 21.67 per 1000 PYs (trend test P = 0.06). CNS infections were the most frequent disease, with a mean incidence of 10.85 per 1000 PYs, followed by peripheral neuropathy with a mean incidence of 4.26 per 1000 PYs, vasculopathy with a mean incidence of 3.34 per 1000 PYs, and cognitive disorders with a mean incidence of 3.04 per 1000 PYs. Among the 4 types of neurological disorders, cognitive disorders increased significantly from 0.36 per 1000 PYs in 2001 to 7.44 per 1000 PYs in 2010 (trend test P < 0.001) (Fig. 1). Figure 2 shows that the standardized incidence ratio of neurological disorders did not differ by sex but increased significantly with age (trend test P = 0.006).
Factors Associated With Neurological Disorders
The risk factors for neurological disorders based on the Cox proportional hazards models were higher age at HIV diagnosis (35–44 years: 1.33, 95% CI: 1.10 to 1.62; 45–54 years: 1.36, 95% CI: 1.05 to 1.76; for age ≥55 years: 2.54, 95% CI: 1.89 to 3.40, compared with age ≤24 years), hypertension [adjusted hazard ratio (AHR): 1.41, 95% CI: 1.12 to 1.76], substance abuse (AHR: 1.65, 95% CI: 1.36 to 2.02), opportunistic infections (AHR: 1.76, 95% CI: 1.47 to 2.11), syphilis infection (AHR: 1.27, 95% CI: 1.10 to 1.47), and frequent ED visits (<3 times: 1.49, 95% CI: 1.28 to 1.74; 3–5 times: 2.10, 95% CI: 1.70 to 2.59; >5 times: 2.41, 95% CI: 1.96 to 2.97, compared with no ED visits) (Table 2).
The Cox proportional hazards model was implemented to examine the effect of HAART on the incidence of neurological disorders (Table 3). Model 1 shows HAART use for ≥0.5 years (HAART ≥0.5 years AHR: 0.59, 95% CI: 0.50 to 0.69; HAART <0.5 years AHR: 2.78, 95% CI: 2.53 to 3.28) had a protective effect, with a reduced risk of neurological disorders among people who received HAART therapy at least once. The model 2 sensitivity analyses on different cutoff parameters after controlling for demographic data, comorbidities, and frequency of ED visits showed that an adherence rate of at least 85% is required as the minimum sufficient adherence for a reduced 21% risk of neurological disorders (adherence ≥85% AHR: 0.79, 95% CI: 0.64 to 0.97) compared with those with adherence <85%. Model 3 showed that patients with adherence between 85% and 95% had significantly lower risks of neurological disorders than those with adherence <85% (AHR: 0.53, 95% CI: 0.38 to 0.74).
This is the first study in Asia to use a population-based dataset to determine the incidence trend of neurological disorders among HIV-positive individuals over 11 years of observation. The study measured HIV-related neurological disorders among patients with free access to HAART and medical care in the post-HAART era. Our study indicated that the standardized incidence of neurological disorders in HIV-positive persons increased from 18.92 per 1000 PYs in 2000 to 23.24 per 1000 PYs in 2010, which is higher than the corresponding figures for various neurological disorders in the United States and the United Kingdom.39–41 Somewhat unexpectedly, the incidence trend of CNS infections in our study did not vary after HAART became available, even though the literature shows that after the introduction of HAART, the incidence of CNS diseases39,42 has decreased substantially. Consistent with other studies that reported that the prevalence of HANDs is high even in long-standing virally suppressed HIV-positive patients,22,43,44 our study found that the incidence of neurocognitive disorders in the post-HAART era exhibited a significant increase, and that the risk of neurological disorders among HIV-infected individuals aged >45 years was significantly higher than that among younger individuals.45,46 Considering the entire HIV spectrum and the long life expectancy of HIV-infected patients,47 it is difficult to detect affected patients early given the paucity or the absence of neurocognitive symptoms and patients' tendencies to not mention these symptoms to clinicians.42 It is urgent to understand the patient-specific factors associated with HIV-infected persons at the first HAND diagnosis. The application of a comprehensive neurological evaluation for patients with HIV infection at clinical visits is needed, particularly for the aging population.
HAART adherence rates of at least 85% among individuals receiving HAART for longer periods of time, especially when the duration exceeds a half year, significantly reduced the risk of neurological disorders and also represented the most important modifiable factor we found in this study. Our study contradicts the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials22 and the CNS HIV Antiretroviral Therapy Effects Research study43 in the United States and the EuroSIDA Study Cohort,39 which suggested that antiretroviral history was not significantly associated with the incidence of neurological disorders in the HAART era. The inconsistent findings between our longitudinal population-based study and the above findings generated by clinic-based, cross-sectional observational studies may be partially due to different outcome measures in some of these studies. The previous studies' endpoints were primarily neurocognitive disorders or central neurological disorders, but our study measured a broad spectrum of neurological disorders. Additional factors could include differences in the insurance coverage and the length of exposure to HAART in the study samples. In Taiwan, all HIV-infected patients with CD4 counts <350 cell/mm3 have been provided with free antiretroviral therapy and medical care at AIDS-designated hospitals since the early 1990s. The NHIRD used for analysis covers almost all HIV-infected patients and their claim records for medical services in Taiwan. HIV-related neurological disorders constitute a crucial problem in the history of HIV infection in the HAART era because of the increased life expectancy, the influence of aging, and the frequency of comorbidities that can hasten deterioration in patients with milder forms of neurological symptoms. Because most patients who developed neurological complications in the HAART period were diagnosed late or were unaware of their HIV infection, our data show the importance of early diagnosis and support the possibility that HAART has protective effects against neurological disorders in HIV-infected people.
Similar to previous studies, our study found that comorbid hypertension, substance abuse,48,49 and opportunistic infections2,3 increased the risk of developing a neurological disorder. In addition, our study identified syphilis as an independent risk factor for neurological disorders in HIV-infected individuals. The purpose of excluding patients with neurosyphilis in the study was to ascertain the potential impact of syphilis infection on neurological disorders among HIV-infected patients. Although patients previously diagnosed with neurosyphilis were excluded from the covariate analysis, 81.8% of HIV-infected patients with positive syphilis serology in this study did not undergo lumbar puncture or cerebrospinal fluid analysis, which might lead to a misdiagnosis of “probable” neurosyphilis. The accurate diagnosis of neurosyphilis in HIV-infected patients is a complex task because the clinical manifestations are polymorphic and include meningitis, ocular disturbances, and meningovascular manifestations.50 Patients with meningovascular neurosyphilis may present with symptoms of transient ischemic attack (TIA) or stroke, which are indistinguishable from atherothrombotic TIA and stroke.51 An Australian study reported a substantial prevalence of positive syphilis serology and meningovascular neurosyphilis in patients presenting with symptoms of TIA or stroke in a clinical setting.51 Our findings, consistent with previous case reports,50,52 suggest that syphilis plays a significant role in the pathogenesis of neurological disorders in HIV-infected persons, especially in young patients or HIV-infected people with stroke or stroke-like symptoms. This theory warrants further study on the effect of HIV and syphilis coinfection on the occurrence of neurological disorders in HIV-positive persons.
Our study has some limitations. First, we did not have CD4 cell counts and blood viral loads, which are both important predictors of outcomes in HIV-positive persons. However, we used opportunistic infection outside the CNS as a proxy for advanced HIV stage. Second, we did not have information on the HIV transmission route in the NHIRD. Although we used codes for substance abuse, hepatitis C, and syphilis coinfection as surrogates for transmission route in the model, our results may be subject to some confounding. Third, physicians who cared for these patients were nonneurologists with limited options in diagnostic coding or had high incidences of underdetection due to patients' irregular hospital visits, which could potentially generate underestimations of the proportion of neurological disorders. Finally, the study relied on existing data sources, and some patients may have poor adherence to HAART due to polyneuropathy side effects, which could not be identified in this study.
In conclusion, the rising incidence of neurological disorders among HIV-positive persons highlights the need to detect these disorders and intervene, even for patients with few or no neurocognitive symptoms. The elder people, a diagnosis of syphilis, hypertension, substance abuse, opportunistic infection, and a higher frequency of ED visits were risk factors that we identified for neurological disorders among HIV-positive persons. Furthermore, we found that adherence of at least 85% to HAART and treatment duration of more than a half year might reduce the risk of neurological disorders by 21% among HIV-positive patients. HIV-related neurological spectrum disorders constitute a principal problem in the natural history of HIV infection in the HAART era. Efforts to enhance adherence to HAART and to initiate treatment for comorbidities as early as possible will help health care providers to improve patients' outcomes. In addition, the integration of routine neurological screening programs into HIV care is also needed.
The authors thank all the authors who participated in the conception of the analysis.
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