Liver Enzymes Elevation and Immune Reconstitution Among Treatment-Naïve HIV-Infected Patients Instituting Antiretroviral Therapy

Abstract

Objectives-Because liver enzymes elevation (LEE) complicates antiretroviral (ARV) therapy, and because the strongest risk factor for ARV-related LEE is HBV/HCV coinfection, it is speculated that ARV-related LEE may be a form of immune reconstitution disease. This study summarizes the relation between immune reconstitution, ARV-induced LEE, and HBV/HCV coinfection.Methods-Medical records of ARV-naïve HIV-infected patients initiating ARV were reviewed for hepatitis coinfection, LEE (grade ≥2 AST/ALT) and changes in CD4 T-cell counts over time in an urban HIV clinic. Risk factors for LEE were statistically evaluated, and changes in CD4 Tcell counts were estimated by a mixed-effects linear model. (OR = 6.44) and stavudine use (OR = 2.33). Nelfinavir use was protective (OR = 0.45). The mean rate of change in CD4 T-cell counts was higher in HBV/HCV coinfected subjects who developed LEE (99 cells/μL per month) compared with non-coinfected subjects who did not develop LEE (59 cells/μL per month, P = 0.03), non-coinfected subjects who developed LEE (36 cells/μL per month, P = 0.01), and coinfected subjects who did not develop LEE, 38% higher (62 cells/μL per month; P = 0.11) Conclusions-A more robust immune restoration was observed among HBV/HCV coinfected subjects who developed liver enzyme elevation after antiretroviral initiation compared with other groups. This finding suggests that ARV-related liver enzyme elevation may be related in part to immune reconstitution, as measured by changes in CD4 T-cell counts. Liver enzymes elevations (LEE) of varying degree have been reported with all classes of antiretroviral (ARV) drugs approved by the Food and Drug Administration for the treatment of HIV infection. [1][2][3][4][5][6][7][8][9][10][11][12] Severe cases of hepatotoxicity with fatal outcomes have been reported with ARV therapy and LEE is a common reason for highly active antiretroviral therapy (HAART) discontinuation in clinical practice. Results-Predictors of LEE included HBV/HCV coinfection KEY INDEXING TERMS NIH Public AccessThe mechanisms of ARV induced hepatic injury are still poorly understood. Mitochondrial toxicity resulting from nucleoside reverse transcriptase inhibitors (NRTIs) use and hypersensitivity reactions to non nucleoside reverse transcriptase inhibitors (NNRTIs) are speculated to be partly responsible. It is however unclear whether the protease inhibitors (PIs) directly induce liver injury. Although higher plasma concentrations for PIs have been reported among HIV infected subjects with hepatic impairment (often due to HBV/HCV coinfection), [13][14][15] there are no published data linking elevated serum PI levels to the development of LEE.In studies addressing ARV-associated liver injury, 30-50% of subjects were coinfected with either HBV and/or HCV, and the strongest independent risk factor for ARV-associated hepatotoxicity was coinfection with HBV and/or HCV. [16][17][18][19] Given this association, it is speculated that hepatic injury after ARV therapy in the presence of chronic viral h...

HCV quasispecies evolution during treatment with interferon alfa-2b and ribavirin in two children coinfected with HCV and HIV-1

“…However, incompatible with IRIS were the facts that Patient C1 was not antiretroviral naïve and did not exhibit increased levels of CD4 + T cells when transaminases peaked. 22 In Patient C2, the variant profile was strikingly conserved. In fact, the dominant variant was identical to one of the variants initially identified in the same patient soon after birth, more than 16 years before.…”

Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

“…LEE in patients coinfected with HIV and HBV after commencement of ART may reflect worsening of underlying liver disease, antiretroviral hepatotoxicity, other medications, opportunistic infections, or an IRD (7). A recent retrospective cohort study associated LEE following ART in HBV-and HCV-coinfected patients with the overall increase in CD4 T cells (103), consistent with a role for immune reconstitution in pathogenesis.…”

Characteristics of Hepatitis B Co-infection and Disease Evolution in HIV-Positive Paediatric Patients in Romania

“…Increased ALAT can be correlated with HBsAg, HDV co-infection, virological HIV failure on ART and HIV-related mortality. However, high ALAT values are more commonly in patients with restored immunity of CD 4 -count over 500/mm 3 , which is probably explained by the pathology of immune reconstruction following ART (18). Increased serum ALAT levels are not statistically correlated with common risk factors such as alcohol, smoking, recreational drugs or concomitant anti-tuberculosis drugs for hepatotoxicity (Table 2).…”