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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.

Introduction: Long-term living with human immunodeficiency virus (HIV) and/or antiretroviral therapy (ART) is associated with various adverse effects, including neurocognitive impairment. Heterogeneous neurocognitive impairment remains an important issue, affecting between 15–65% of human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) patients and resulting in work performance, safety, and health-related outcomes that have a heavy economic burden.Methods: We identified 1,209 HIV/AIDS patients with neurological diseases during 2010–2017. The Kaplan–Meier method, log-rank test, and Cox proportional hazards model were used to analyze 308 CHM users and 901 non-CHM users within this population. Major CHM clusters were determined using association rule mining and network analysis.Results and Discussion: Results showed that CHM users had a 70% lower risk of all-cause mortality (adjusted hazard ratio (aHR) = 0.30, 95% confidence interval (CI):0.16–0.58, p < 0.001) (p = 0.0007, log-rank test). Furthermore, CHM users had an 86% lower risk of infections, parasites, and circulatory-related mortality (aHR = 0.14, 95% confidence interval (CI):0.04–0.46, p = 0.001) (p = 0.0010, log-rank test). Association rule mining and network analysis showed that two CHM clusters were important for patients with neurological diseases. In the first CHM cluster, Huang Qin (HQ; root of Scutellaria baicalensis Georgi), Gan Cao (GC; root of Glycyrrhiza uralensis Fisch.), Huang Lian (HL; root of Coptis chinensis Franch.), Jie Geng (JG; root of Platycodon grandiflorus (Jacq.) A.DC.), and Huang Bai (HB; bark of Phellodendron amurense Rupr.) were identified as important CHMs. Among them, the strongest connection strength was identified between the HL and HQ. In the second CHM cluster, Suan-Zao-Ren-Tang (SZRT) and Ye Jiao Teng (YJT; stem of Polygonum multiflorum Thunb.) were identified as important CHMs with the strongest connection strength. CHMs may thus be effective in treating HIV/AIDS patients with neurological diseases, and future clinical trials are essential for the prevention of neurological dysfunction in the population.

Hereditary Hemolytic Anemias (HHAs) are a rare but heterogeneous group of erythrocytic diseases, characterized by intrinsic cellular defects due to inherited genetic mutations. We investigated the efficacy of Chinese herbal medicine (CHM) in reducing the overall, diabetes-related, and cardiovascular diseases (CVDs)-related mortalities among patients with HHAs using a nationwide population database. In total, we identified 33,278 patients with HHAs and included 9,222 non-CHM and 9,222 CHM matched pairs after matching. The Cox proportional hazards model was used to compare the risk of mortality between non-CHM and CHM users. The Kaplan-Meier method and log-rank test were used to compare the cumulative incidence mortality between non-CHM and CHM users. The CHM prescription patterns were presented by the association rules and network analyses, respectively. The CHM prescription patterns were presented by the association rules and network analyses, respectively. CHM users showed significant reduced risks for of overall (adjusted hazard ratio [aHR]: 0.67, 95% confidence interval [CI]: 0.61–0.73, p < 0.001), diabetes-related (aHR: 0.57, 95% CI: 0.40–0.82, p < 0.001), and CVDs-related (aHR: 0.59, 95% CI: 0.49–0.72, p < 0.001) mortalities compared with non-CHM users. Two CHM clusters are frequently used to treat Taiwanese patients with HHAs. Cluster 1 is composed of six CHMs: Bei-Mu (BM; Fritillaria cirrhosa D.Don), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Hai-Piao-Xiao (HPX; Endoconcha Sepiae), Jie-Geng (JG; Platycodon grandiflorus (Jacq.) A.DC.), Yu-Xing-Cao (YXC; Houttuynia cordata Thunb.), and Xin-Yi-Qing-Fei-Tang (XYQFT). Cluster 2 is composed of two CHMs, Dang-Gui (DG; Angelica sinensis (Oliv.) Diels) and Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge). Further randomized clinical trials are essential to evaluate the safety and effectiveness of above CHM products and to eliminate potential biases in the current retrospective study.

Aplastic Anemia (AA) is a rare but fatal hematologic disease that may occur at any age and especially higher in Asia. We investigated whether Chinese herbal medicine (CHM) is beneficial to AA patients as a complementary therapy using a nationwide population-based database in Taiwan between 2000–2016. Patient survival was estimated by Kaplan‒Meier survival analyses and Cox proportional-hazard model. CHM-users presented lower risks of overall and anemia-related mortalities when compared to non-users. The risk of overall mortality for CHM-users in AA patients was 0.70-fold [adjusted hazard ratio (aHR): 0.70, 95% confidence interval (CI): 0.66-0.74, p < 0.001). The risk of anemia-related mortality was lower in CHM-users when compared to non-users (aHR: 0.46, 95% CI: 0.32-0.67, p < 0.001). The association rule analysis revealed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D. Don)→Bai-Hua-She-She-Cao (BHSSC; Oldenlandia diffusa (Willd.) Roxb.), followed by Dang-Gui (DG; Angelica sinensis (Oliv.) Diels)→Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge), and Xian-He-Cao (XHC; Agrimonia pilosa f. borealis (Kitag.) Chu)→Gui-Pi-Tang (GPT). Network analysis showed that BZL, BHSSC, DG, HQi, XHC, GPT, and Dan-Shen (DanS; Salvia miltiorrhiza var. charbonnelii (H.Lév.) C.Y.Wu) were commonly used CHMs for AA patients. Therefore, further studies for these commonly prescribed herbs are needed in functional investigations in hematopoiesis-stimulating effect and large-scale randomized controlled trials (RCT) in bone marrow failure related diseases.

Chinese herbal medicines (CHMs) are widely used in Asian countries. They show multiple pharmacological activities, including antiviral activities. The 5′-long terminal repeat (LTR) region of HIV-1, required for viral transcription, is a potential drug target for HIV-1 reactivation and intrinsic cell death induction of infected or latently infected cells. Modulation of HIV-1 reactivation requires interactions between host cell proteins and viral 5′-LTR elements. By evaluation of two CHMs- Xanthium strumarium and Pueraria montana, we found that 1) X. strumarium reactivated HIV-1 latently infected cells in J-Lat 8.4, J-Lat 9.2, U1, and ACH-2 cells in vitro; 2) 27 nuclear regulatory proteins were associated with HIV-1 5′-LTR using deoxyribonucleic acid affinity pull-down and LC-MS/MS analyses; and 3) among them, silencing of XRCC6 reactivated HIV-1 5′-LTR transcriptional activity. We found that X. strumarium inhibits the 5′-LTR associated XRCC6 nuclear regulatory proteins, increases its viral 5′-LTR promoter transcriptional activity, and reactivates HIV-1 latently infected cells in vitro. These findings may contribute to understanding the 5′-LTR activity and the host cell nuclear regulatory protein machinery for reactivating HIV-1 and for future investigations to eradicate and cure HIV-1 infection.

The survival of patients with HIV has greatly improved, due to Anti-Retroviral Therapy (ART). However, long-term HIV survivors often develop serious bone abnormalities, possibly due to the interplay of osteoblasts, osteoclasts, HIV ad ART. We evaluated in a nation-wide study in Taiwan the effect of Chinese herbal medicine (CHM) on overall mortality in HIV patients with osteoporosis or fractures. Enrollment period was between 1998 and 2011. Patients with osteoporosis or fractures before the HIV infection, and those with less than 14 days CHM use, were excluded. This left 498 patients, 160 CHM users, 338 without CHM. Univariate Kaplan-Meier and multivariate Cox regression analysis were used to compare the overall mortality in these 2 groups. Due to the nature of Chinese medicine, CHMs inevitably varied. We therefore also used rule mining and network analysis to determine which major CHM clusters were prescribed to the patients. CHM users had a much Lower mortality (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.24–0.77, p < 0.005) and higher survival (p = 0.004, log-rank test). Although the CHMs greatly varied, network analysis identified one main cluster of strongly related CHM combinations (Chuan-Xiong-Cha-Tiao-San (CXCTS), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Liu-He-Tang (LHT), Huang-Qin-Tang (HQT), Jia-Wei-Ping-Wei-San (JWPWS), and Dang-Gui-Long-Hui-Wan (DGLHuiW)). CHM as an additional treatment strongly improves overall survival in HIV-infected patients with osteoporosis and fractures.

The progression of acquired immunodeficiency syndrome is delayed in patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART). However, long-term ART is associated with adverse effects. Osteoporosis is one of the adverse effects and is a multifactorial systemic skeletal disease associated with bone fragility and an increased risk of fracture. We performed a longitudinal, comprehensive, nested case-control study to explore the effect of ART on the risk of osteoporosis in 104 osteoporotic and 416 non-osteoporotic patients with HIV infection at their average age about 29 years old in Taiwan. Patients with history of ART, current exposure to ART, higher cumulative defined daily doses (DDDs), or higher ART adherence were at a higher risk of osteoporosis (p < 0.05). Patients receiving nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine-lamivudine combination, lamivudine-abacavir combination, and abacavir alone) and protease inhibitor (PI)-containing regimen (lopinavir-ritonavir combination, ritonavir, and atazanavir) had a higher risk of osteoporosis (p < 0.05). Especially, patients receiving high doses of the PIs lopinavir-ritonavir combination had an increased risk of osteoporosis (p < 0.05). In conclusion, history of ART, current exposure to ART, higher cumulative DDDs, and higher ART adherence were associated with an increased risk of osteoporosis. Furthermore, NRTI- and PI-containing regimens and high doses of PIs lopinavir-ritonavir combination may be associated with an increased risk of osteoporosis in patients with HIV infection in Taiwan.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007–2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676–0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53–0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl.), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl.), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim.) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.

Pemphigus is a life-threatening and skin-specific inflammatory autoimmune disease, characterized by intraepidermal blistering between the mucous membranes and skin. Chinese herbal medicine (CHM) has been used as an adjunct therapy for treating many diseases, including pemphigus. However, there are still limited studies in effects of CHM treatment in pemphigus, especially in Taiwan. To more comprehensively explore the effect of long-term CHM treatment on the overall mortality of pemphigus patients, we performed a retrospective analysis of 1,037 pemphigus patients identified from the Registry for Catastrophic Illness Patients database in Taiwan. Among them, 229 and 177 patients were defined as CHM users and non-users, respectively. CHM users were young, predominantly female, and had a lesser Charlson comorbidity index (CCI) than non-CHM users. After adjusting for age, sex, prednisolone use, and CCI, CHM users had a lower overall mortality risk than non-CHM users (multivariate model: hazard ratio (HR): 0.422, 95% confidence interval (CI): 0.242–0.735, p = 0.0023). The cumulative incidence of overall survival was significantly higher in CHM users than in non-users (p = 0.0025, log rank test). Association rule mining and network analysis showed that there was one main CHM cluster with Qi–Ju–Di–Huang–Wan (QJDHW), Dan–Shen (DanS; Radix Salviae miltiorrhizae; Salvia miltiorrhiza Bunge), Jia–Wei–Xiao–Yao-–San (JWXYS), Huang–Lian (HL; Rhizoma coptidis; Coptis chinensis Franch.), and Di–Gu–Pi (DGP; Cortex lycii; Lycium barbarum L.), while the second CHM cluster included Jin–Yin–Hua (JYH; Flos lonicerae; Lonicera hypoglauca Miq.) and Lian–Qiao (LQ; Fructus forsythiae; Forsythia suspensa (Thunb.) Vahl). In Taiwan, CHMs used as an adjunctive therapy reduced the overall mortality to approximately 20% among pemphigus patients after a follow-up of more than 6 years. A comprehensive CHM list may be useful in future clinical trials and further scientific investigations to improve the overall survival in these patients.

Hip fracture is a major public health concern, with high incidence rates in the elderly worldwide. Hip fractures are associated with increased medical costs, patient dependency on families, and higher rates of morbidity and mortality. Chinese herbal medicine (CHM) is typically characterized as cost-effective and suitable for long-term use with few side effects. To better understand the effects of CHM on hip fracture patients, we utilized a population-based database to investigate the demographic characteristics, cumulative incidence of overall mortality, readmission, reoperation, and patterns of CHM prescription. We found that CHM usage was associated with a lower risk of overall mortality [P = 0.0009; adjusted hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.30–0.73], readmission (P = 0.0345; adjusted HR: 0.67, 95% CI: 0.46–0.97), and reoperation (P = 0.0009; adjusted HR: 0.57, 95% CI: 0.40–0.79) after adjustment for age, type of hip fracture, surgical treatment type, and comorbidities. We also identified the herbal formulas, single herbs, and prescription patterns for the treatment of hip fracture by using association rule mining and network analysis. For hip fracture patients, the most common CHM coprescription pattern was Du-Zhong (DZ) → Xu-Duan (XD), followed by Du-Huo-Ji-Sheng-Tang (DHJST) → Shu-Jing-Huo-Xue-Tang (SJHXT), and Gu-Sui-Bu (GSB) → Xu-Duan (XD). Furthermore, XD was the core prescription, and DZ, GSB, SJHXT, and DHJST were important prescriptions located in cluster 1 of the prescription patterns. This study provides evidence for clinical CHM use as an adjunctive therapy that offers benefits to hip fracture patients.

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.