2016 |
Young, James; Mucsi, Istvan; Rollet-Kurhajec, Kathleen C; Klein, Marina B Fibroblast growth factor 23: associations with antiretroviral therapy in patients co-infected with HIV and hepatitis C Journal Article HIV Med, 2016. Abstract | Links | BibTeX | Tags: Antiretroviral therapy, Fibroblast growth factor 23, HCV, HIV @article{Young2016, title = {Fibroblast growth factor 23: associations with antiretroviral therapy in patients co-infected with HIV and hepatitis C}, author = {James Young and Istvan Mucsi and Kathleen C. Rollet-Kurhajec and Marina B. Klein}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26307135}, doi = {10.1111/hiv.12305}, year = {2016}, date = {2016-05-15}, journal = {HIV Med}, abstract = {OBJECTIVES: Fibroblast growth factor 23 (FGF23) has been associated with cardiovascular mortality. We estimate associations between the level of plasma FGF23 and exposure to abacavir (ABC) and to other components of antiretroviral therapy in patients co-infected with HIV and hepatitis C. METHODS: Both intact and c-terminal FGF23 were measured in plasma using commercial assays for a sub-cohort of 295 patients selected at random from the 1150 patients enrolled in the Canadian Co-infection Cohort. The multiplicative effects of antiretroviral drug exposures and covariates on median FGF23 were then estimated using a hierarchical Bayesian model. RESULTS: The median level of intact FGF23 was independent of either past or recent exposure to abacavir, with multiplicative ratios of 1.00 and 1.07, 95% credible intervals 0.90-1.12 and 0.94-1.23, respectively. Median intact FGF23 tended to increase with past use of both nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, but tended to decrease with recent use of either tenofovir, efavirenz or lopinavir. There were no obvious associations between the median level of c-terminal FGF23 and individual drugs or drug classes. Age, female gender, smoking and the aspartate aminotransferase to platelet ratio index were all associated with a higher median c-terminal FGF23 but not with a higher median intact FGF23. CONCLUSIONS: The level of FGF23 in plasma was independent of exposure to ABC. Lower levels of intact FGF23 with recent use of tenofovir, efavirenz or lopinavir may reflect their adverse effects on bone and vitamin D metabolism relative to other drugs in their respective drug classes. © 2015 British HIV Association.}, keywords = {Antiretroviral therapy, Fibroblast growth factor 23, HCV, HIV}, pubstate = {published}, tppubtype = {article} } OBJECTIVES: Fibroblast growth factor 23 (FGF23) has been associated with cardiovascular mortality. We estimate associations between the level of plasma FGF23 and exposure to abacavir (ABC) and to other components of antiretroviral therapy in patients co-infected with HIV and hepatitis C. METHODS: Both intact and c-terminal FGF23 were measured in plasma using commercial assays for a sub-cohort of 295 patients selected at random from the 1150 patients enrolled in the Canadian Co-infection Cohort. The multiplicative effects of antiretroviral drug exposures and covariates on median FGF23 were then estimated using a hierarchical Bayesian model. RESULTS: The median level of intact FGF23 was independent of either past or recent exposure to abacavir, with multiplicative ratios of 1.00 and 1.07, 95% credible intervals 0.90-1.12 and 0.94-1.23, respectively. Median intact FGF23 tended to increase with past use of both nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, but tended to decrease with recent use of either tenofovir, efavirenz or lopinavir. There were no obvious associations between the median level of c-terminal FGF23 and individual drugs or drug classes. Age, female gender, smoking and the aspartate aminotransferase to platelet ratio index were all associated with a higher median c-terminal FGF23 but not with a higher median intact FGF23. CONCLUSIONS: The level of FGF23 in plasma was independent of exposure to ABC. Lower levels of intact FGF23 with recent use of tenofovir, efavirenz or lopinavir may reflect their adverse effects on bone and vitamin D metabolism relative to other drugs in their respective drug classes. © 2015 British HIV Association. |
2011 |
Thorpe, Julia; Saeed, Sahar; Moodie, Erica E M; Klein, Marina B Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-Hepatitis C virus Co-infection Journal Article AIDS, 25 (7), pp. 967-975, 2011. Abstract | Links | BibTeX | Tags: Antiretroviral therapy, HIV-HCV co-infection, Liver fibrosis @article{Thorpe2011, title = {Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-Hepatitis C virus Co-infection}, author = {Julia Thorpe and Sahar Saeed and Erica E. M. Moodie and Marina B. Klein}, url = {https://www.ncbi.nlm.nih.gov/pubmed/21330904}, doi = {10.1097/QAD.0b013e3283455e4b}, year = {2011}, date = {2011-04-24}, journal = {AIDS}, volume = {25}, number = {7}, pages = {967-975}, abstract = {OBJECTIVE: Despite potential negative consequences, HIV/hepatitis C virus (HCV) co-infected patients may discontinue antiretroviral treatment (ART) for several reasons. We examined the impact of ART interruption on liver fibrosis progression in co-infected adults, using the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate marker of liver fibrosis. METHOD: Data were analyzed from a multisite prospective cohort of 541 HIV-HCV co-infected adults. ART interruption was included as a time-updated variable and defined as the cessation of all antiretrovirals for at least 14 days. The primary endpoint was the development of an APRI score at least 1.5. Time-dependent Cox proportional hazards regression and inverse probability-of-treatment weighting (IPTW) in a marginal structural model were used to evaluate the association of baseline and time-varying covariates with developing significant fibrosis. RESULTS: Patients were followed for a median of 1.02 years; 10% (n = 53) interrupted ART and 10% (n = 53) developed significant fibrosis. After accounting for potential confounders, including CD4 T-cell count, HIV viral load, baseline APRI score, age and gender, the hazard ratio for ART interruption was 2.52 (95% confidence interval 1.20-5.28). Use of IPTW resulted in a similar effect estimate, suggesting that mediation by time-varying confounders was negligible. CONCLUSION: ART interruption was associated with an increased risk of fibrosis progression in HIV-HCV co-infection that was only partially accounted for by HIV viral load and CD4 T-cell counts. Our findings suggest that liver disease progression observed in ART-treated co-infected patients is partly due to the consequences of treatment interruptions.}, keywords = {Antiretroviral therapy, HIV-HCV co-infection, Liver fibrosis}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: Despite potential negative consequences, HIV/hepatitis C virus (HCV) co-infected patients may discontinue antiretroviral treatment (ART) for several reasons. We examined the impact of ART interruption on liver fibrosis progression in co-infected adults, using the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate marker of liver fibrosis. METHOD: Data were analyzed from a multisite prospective cohort of 541 HIV-HCV co-infected adults. ART interruption was included as a time-updated variable and defined as the cessation of all antiretrovirals for at least 14 days. The primary endpoint was the development of an APRI score at least 1.5. Time-dependent Cox proportional hazards regression and inverse probability-of-treatment weighting (IPTW) in a marginal structural model were used to evaluate the association of baseline and time-varying covariates with developing significant fibrosis. RESULTS: Patients were followed for a median of 1.02 years; 10% (n = 53) interrupted ART and 10% (n = 53) developed significant fibrosis. After accounting for potential confounders, including CD4 T-cell count, HIV viral load, baseline APRI score, age and gender, the hazard ratio for ART interruption was 2.52 (95% confidence interval 1.20-5.28). Use of IPTW resulted in a similar effect estimate, suggesting that mediation by time-varying confounders was negligible. CONCLUSION: ART interruption was associated with an increased risk of fibrosis progression in HIV-HCV co-infection that was only partially accounted for by HIV viral load and CD4 T-cell counts. Our findings suggest that liver disease progression observed in ART-treated co-infected patients is partly due to the consequences of treatment interruptions. |
2010 |
Potter, Martin; Odueyungbo, Adefowope; Yang, Hong; Saeed, Sahar; Klein, Marina B Impact of Hepatitis C viral replication on CD4+ T-lymphocyte progression in HIV-Co-infection before and after antiretroviral therapy Journal Article AIDS, 24 (12), pp. 1857-1865, 2010. Abstract | Links | BibTeX | Tags: Antiretroviral therapy, CD4, HIV-HCV co-infection, T-lymphocyte progression, Viral replication @article{Potter2010, title = {Impact of Hepatitis C viral replication on CD4+ T-lymphocyte progression in HIV-Co-infection before and after antiretroviral therapy}, author = {Martin Potter and Adefowope Odueyungbo and Hong Yang and Sahar Saeed and Marina B. Klein}, url = {https://www.ncbi.nlm.nih.gov/pubmed/20479633}, doi = {10.1097/QAD.0b013e32833adbb5}, year = {2010}, date = {2010-07-31}, journal = {AIDS}, volume = {24}, number = {12}, pages = {1857-1865}, abstract = {OBJECTIVE: HIV is known to have a negative impact on the progression of hepatitis C virus (HCV) infection, whereas the reverse remains unclear. We examined the impact of spontaneous clearance of HCV on CD4(+) T-lymphocyte count progression before and after initiation of antiretroviral therapy (ART) in HIV-HCV coinfected adults. METHODS: Data were analysed from participants in a Canadian, multisite prospective cohort of HIV-infected adults with serologic evidence of HCV infection. The rate of CD4(+) T-lymphocyte change was determined using multivariate mixed linear regression comparing chronically HCV RNA+ with spontaneous clearers (persistently HCV RNA- without HCV therapy). RESULTS: Baseline characteristics of the 271 participants analysed did not differ between individuals whose HCV RNA cleared (n = 35) and those whose HCV RNA persisted (n = 236) except with respect to markers of liver disease. HCV RNA+ individuals had on average seven-times slower recovery of CD4(+) T-cells on chronic ART compared with HCV RNA-: (adjusted change in absolute CD4 cell T-lymphocyte count per year: 4 (95% confidence interval, -0.6 to 8) cells/microl vs. 26 (95% confidence interval, 12 to 41) cells/microl; P < 0.001. Analyses restricted to individuals initiating ART showed similar results. There was also a trend to greater CD4 decline prior to ART initiation among those HCV RNA+, although this did not reach statistical significance. CONCLUSION: We found that CD4 cell progression is negatively affected by the presence of ongoing HCV replication in coinfected individuals initiating ART which persisted throughout stable ART suggesting active HCV infection affects immune restoration even after years of ART exposure.}, keywords = {Antiretroviral therapy, CD4, HIV-HCV co-infection, T-lymphocyte progression, Viral replication}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: HIV is known to have a negative impact on the progression of hepatitis C virus (HCV) infection, whereas the reverse remains unclear. We examined the impact of spontaneous clearance of HCV on CD4(+) T-lymphocyte count progression before and after initiation of antiretroviral therapy (ART) in HIV-HCV coinfected adults. METHODS: Data were analysed from participants in a Canadian, multisite prospective cohort of HIV-infected adults with serologic evidence of HCV infection. The rate of CD4(+) T-lymphocyte change was determined using multivariate mixed linear regression comparing chronically HCV RNA+ with spontaneous clearers (persistently HCV RNA- without HCV therapy). RESULTS: Baseline characteristics of the 271 participants analysed did not differ between individuals whose HCV RNA cleared (n = 35) and those whose HCV RNA persisted (n = 236) except with respect to markers of liver disease. HCV RNA+ individuals had on average seven-times slower recovery of CD4(+) T-cells on chronic ART compared with HCV RNA-: (adjusted change in absolute CD4 cell T-lymphocyte count per year: 4 (95% confidence interval, -0.6 to 8) cells/microl vs. 26 (95% confidence interval, 12 to 41) cells/microl; P < 0.001. Analyses restricted to individuals initiating ART showed similar results. There was also a trend to greater CD4 decline prior to ART initiation among those HCV RNA+, although this did not reach statistical significance. CONCLUSION: We found that CD4 cell progression is negatively affected by the presence of ongoing HCV replication in coinfected individuals initiating ART which persisted throughout stable ART suggesting active HCV infection affects immune restoration even after years of ART exposure. |
2009 |
Moodie, Erica E M; Pai, Nitika Pant; Klein, Marina B Is antiretroviral therapy causing long-term liver damage? A comparative analysis of HIV-mono-infected and HIV/Hepatitis C co-infected Cohorts Journal Article PLoS One, 4 (2), 2009. Abstract | Links | BibTeX | Tags: Antiretroviral therapy, HIV mono-infection, HIV-HCV co-infection, Liver damage @article{Moodie2009, title = {Is antiretroviral therapy causing long-term liver damage? A comparative analysis of HIV-mono-infected and HIV/Hepatitis C co-infected Cohorts}, author = {Erica E. M. Moodie and Nitika Pant Pai and Marina B. Klein}, url = {https://www.ncbi.nlm.nih.gov/pubmed/19223976}, doi = {10.1371/journal.pone.0004517}, year = {2009}, date = {2009-02-18}, journal = {PLoS One}, volume = {4}, number = {2}, abstract = {The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of -0.46% (-1.61% to 0.71%) in HIV mono-infected compared to 2.54% (-1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population.}, keywords = {Antiretroviral therapy, HIV mono-infection, HIV-HCV co-infection, Liver damage}, pubstate = {published}, tppubtype = {article} } The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of -0.46% (-1.61% to 0.71%) in HIV mono-infected compared to 2.54% (-1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population. |
2007 |
Al-Mohri, Huda; Murphy, Tanya; Lu, Ying; Lalonde, Richard G; Klein, Marina B Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and Hepatitis C coinfection using a noninvasive marker Journal Article JAIDS, 44 (4), pp. 463-469, 2007. Abstract | Links | BibTeX | Tags: Alanine aspartyl transferase-to-platelet ratio index, Antiretroviral therapy, HCV, Hepatic Fibrosis, HIV @article{Al-Mohri2007, title = {Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and Hepatitis C coinfection using a noninvasive marker}, author = {Huda Al-Mohri and Tanya Murphy and Ying Lu and Richard G. Lalonde and Marina B. Klein}, url = {https://www.ncbi.nlm.nih.gov/pubmed/17211282}, doi = {10.1097/QAI.0b013e318030ff8e}, year = {2007}, date = {2007-04-01}, journal = {JAIDS}, volume = {44}, number = {4}, pages = {463-469}, abstract = {The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in hepatitis C virus (HCV) coinfection with HIV are not well understood and are difficult to measure because of the need for repeated liver biopsy. We evaluated the evolution of a noninvasive measure of liver fibrosis, the alanine aspartyl transferase (AST)-to-platelet ratio index (APRI), longitudinally and determined its predictive value for hepatic outcomes in HIV-positive patients with and without HCV coinfection. A total of 673 HIV-positive patients without liver complications at baseline (540 with HIV only, 133 with HIV-HCV coinfection) were followed between 1991 and 2004 for a median of 4.6 years (3524 person-years). At baseline, HIV-HCV coinfection had a higher median APRI compared with HIV infection alone (0.59 vs. 0.33; P < 0.0001). The natural logarithm of the APRI [ln(APRI)] changed significantly over time, particularly among patients with HIV-HCV coinfection. The baseline ln(APRI) was predictive of liver complications (hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 2.5 to 6.4 per log), as was HCV (HR = 4.5, 95% CI: 1.5 to 14). Cumulative HAART did not protect against liver complications, although it was significantly associated with progression of APRI scores in HIV-HCV coinfection and in HIV alone. In conclusion, the APRI may be a useful marker for longitudinal evaluation of the progression of liver disease in HIV-HCV coinfection.}, keywords = {Alanine aspartyl transferase-to-platelet ratio index, Antiretroviral therapy, HCV, Hepatic Fibrosis, HIV}, pubstate = {published}, tppubtype = {article} } The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in hepatitis C virus (HCV) coinfection with HIV are not well understood and are difficult to measure because of the need for repeated liver biopsy. We evaluated the evolution of a noninvasive measure of liver fibrosis, the alanine aspartyl transferase (AST)-to-platelet ratio index (APRI), longitudinally and determined its predictive value for hepatic outcomes in HIV-positive patients with and without HCV coinfection. A total of 673 HIV-positive patients without liver complications at baseline (540 with HIV only, 133 with HIV-HCV coinfection) were followed between 1991 and 2004 for a median of 4.6 years (3524 person-years). At baseline, HIV-HCV coinfection had a higher median APRI compared with HIV infection alone (0.59 vs. 0.33; P < 0.0001). The natural logarithm of the APRI [ln(APRI)] changed significantly over time, particularly among patients with HIV-HCV coinfection. The baseline ln(APRI) was predictive of liver complications (hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 2.5 to 6.4 per log), as was HCV (HR = 4.5, 95% CI: 1.5 to 14). Cumulative HAART did not protect against liver complications, although it was significantly associated with progression of APRI scores in HIV-HCV coinfection and in HIV alone. In conclusion, the APRI may be a useful marker for longitudinal evaluation of the progression of liver disease in HIV-HCV coinfection. |
Research Papers
2016 |
Fibroblast growth factor 23: associations with antiretroviral therapy in patients co-infected with HIV and hepatitis C Journal Article HIV Med, 2016. |
2011 |
Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-Hepatitis C virus Co-infection Journal Article AIDS, 25 (7), pp. 967-975, 2011. |
2010 |
Impact of Hepatitis C viral replication on CD4+ T-lymphocyte progression in HIV-Co-infection before and after antiretroviral therapy Journal Article AIDS, 24 (12), pp. 1857-1865, 2010. |
2009 |
Is antiretroviral therapy causing long-term liver damage? A comparative analysis of HIV-mono-infected and HIV/Hepatitis C co-infected Cohorts Journal Article PLoS One, 4 (2), 2009. |
2007 |
Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and Hepatitis C coinfection using a noninvasive marker Journal Article JAIDS, 44 (4), pp. 463-469, 2007. |