title: Multicenter study of skin rashes and hepatotoxicity in antiretroviral-naïve HIV-positive patients receiving non-nucleoside reverse-transcriptase inhibitor plus nucleoside reverse-transcriptase inhibitors in Taiwan.
abstract: OBJECTIVE
  Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs.
  
  
  METHODS
  Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study. According to the national HIV treatment guidelines, patients were assessed at baseline, 2 and 4 weeks of cART initiation, and subsequently every 8 to 12 weeks. Plasma HIV RNA load, CD4 cell count and aminotransferases were determined. The toxicity grading scale of the Division of AIDS (DAIDS) 2014 was used for reporting clinical and laboratory adverse events.
  
  
  RESULTS
  During the 3.5-year study period, 2,341 patients initiated nNRTI-containing cART: NVP in 629 patients, EFV 1,363 patients, and RPV 349 patients. Rash of any grade occurred in 14.1% (n = 331) of the patients. In multiple logistic regression analysis, baseline CD4 cell counts (per 100-cell/μl increase, adjusted odds ratio [AOR], 1.125; 95% confidence interval [95% CI], 1.031-1.228) and use of NVP (AOR, 2.443; 95% CI, 1.816-3.286) (compared with efavirenz) were independently associated with the development of skin rashes. Among the 1,455 patients (62.2%) with aminotransferase data both at baseline and week 4, 72 (4.9%) developed grade 2 or greater hepatotoxicity. In multiple logistic regression analysis, presence of antibody for hepatitis C virus (HCV) (AOR, 2.865; 95% CI, 1.439-5.704) or hepatitis B surface antigen (AOR, 2.397; 95% CI, 1.150-4.997), and development of skin rashes (AOR, 2.811; 95% CI, 1.051-7.521) were independently associated with the development of hepatotoxicity.
  
  
  CONCLUSIONS
  The baseline CD4 cell counts and use of NVP were associated with increased risk of skin rashes, while hepatotoxicity was independently associated with HCV or hepatitis B virus coinfection, and development of skin rashes in antiretroviral-naïve HIV-positive Taiwanese patients within 4 weeks of initiation of nNRTI-containing regimens.
authors.affiliation: Center of Infection Control, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Tao-Yuan, Taiwan.|School of Public Health, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chun-Eng
authors.initials: CE
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lee
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Mao-Song
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Tao-Yuan, Taiwan.|School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shu-Hsing
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Tri-Service General Hospital and National Defense Medical College, Taipei, Taiwan.
authors.forename: De-Yu
authors.initials: DY
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Tri-Service General Hospital and National Defense Medical College, Taipei, Taiwan.
authors.forename: Ning-Chi
authors.initials: NC
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Lotung Poh-Ai Hospital, Medical Lo-Hsu Foundation, I-Lan, Taiwan.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsin-Yun
authors.initials: HY
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.|Department of Health and Nutrition, Chia Nan University of Pharmacy and Sciences, Tainan, Taiwan.
authors.forename: Hung-Jen
authors.initials: HJ
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chien-Ching
authors.initials: CC
authors.lastname: Hung
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D018791:CD4 Lymphocyte Count; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology*; D019468:Disease Management; D003875:Drug Eruptions / Q000453:epidemiology / Q000209:etiology*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000009:adverse effects* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D012720:Severity of Illness Index; D013624:Taiwan / Q000453:epidemiology; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase