Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART)

Abstract

Background and aimsHLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV-infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co-infection receiving HAART.MethodsIn 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis.ResultsAt recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV-infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV-co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma-glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients.ConclusionDifferences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances.

HLA-B*57 Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians

“…HLA-B * 57:01, B * 57:02 , and B * 57:03 share more than 90% sequence homology and as such have peptide-binding repertoires which substantially overlap (Illing et al, 2012 ; Ogese et al, 2017 ). Although in ART naïve patients HLA-B * 57 ( B * 57:01 in Europe and US, B * 57:03 in black Africans) confers protective effect against HIV-1 disease progression to AIDS (Costello et al, 1999 ; Migueles et al, 2000 ; López-Larrea et al, 2005 ; Frater et al, 2007 ), it may exert contradictory effect on treatment outcome when the disease course is altered by ARV therapy (Dold et al, 2015 ). Previous studies reported the association of HLA-B * 57 with increased all causes of mortality (Dold et al, 2015 ) and reduced virological responses during ARV therapy (Kuniholm et al, 2011 ).…”

The γ-glutamyl transpeptidase-to-platelet ratio as a predictor of liver fibrosis in patients co-infected with HBV and HIV

“…As GGT levels, and not platelet counts, were abnormally high overall, the need for modified thresholds would likely stem from elevated GGT. HIV-viral hepatitis co-infected patients tend to present with higher transaminase and GGT levels compared with either infection alone 5 6. The reasons for these increases are poorly understood for HIV-HBV co-infected patients in particular and worth further investigation.…”

TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients

“…On the other hand, high IL-6 serum levels are a hallmark of imminent death in bacterial infection and sepsis [16,17]. Thus, our in vitro findings seem to provide a hint why HLA-B*57 might be associated with an increased risk to die from bacterial infection in virally suppressed HIV patients [3].…”

“…Between June 2018 and November 2019, we recruited HLA-B*57 and HLA-B*44 HIV-mono-infected patients from the HLA-typed prospective Bonn cohort who had persistently suppressed HIV replication on antiretroviral therapy and consented to participate [3]. Control blood samples were obtained from HLA-matched healthy volunteers via the Cologne University blood banking service.…”

“…In particular, HLA-B*57 appears to be linked with low level viremia and delayed disease progression, which has been attributed to an exceptional efficacy of HLA-B*57-restricted T cells to control HIV infection [1]. While this protective effect was consistently observed in untreated HIV patients, even across different HLA-B*57 subtypes and diverse HIV strains [2], the risk to die from bacterial infection and sepsis was unexpectedly found to be substantially increased in HLA-B*57-positive patients, whose HIV replication was long-term suppressed by antiretroviral therapy [3]. This observation is not explained by the outstandingly efficient T cell responses associated with HLA-B*57 but may be a hint that the HLA system can also modify innate immune responses under certain conditions.…”