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Extrahepatic Complications of Hepatitis C Virus Infection
in HIV and the Impact of Successful Antiviral Treatment
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from Jules: message - 'SVR Can Reduces or Prevent Comorbidities or Extra Hepatic Manifestations in HIV/HCV Coinfected & HCV Monoinfected'
"Extrahepatic mortality was high in HCV-coinfected persons, consistent with our previous observations.....Among HCV-seropositive individuals, treated participants without SVR vs those with SVR had a higher risk of liver events (IRR, 6.79 [95% CI, 2.33-19.81]), liver-related death (IRR, 3.29 [95% CI, 1.35-8.05]), and diabetes mellitus (IRR, 4.62 [95% CI, 1.53-13.96]). Similar but not statistically significant differences were found between untreated HCV RNA-positive patients and those with SVR"
"if successful treatment of chronic HCV with DAA regimens is shown to improve HCV-related extrahepatic diseases and can reduce nonhepatic morbidity and mortality, including among HIV/HCV-coinfected individuals, then extrahepatic manifestations of chronic HCV may become a major indication for antiviral treatment, even in the absence of advanced liver fibrosis"
from Jules: there is enough evidence that HCV cure improves extra hepatic HCV manifestations for this to be an indication as suggested above, if we wait for more studies on this it could take a long time, HERE is background study results supporting my statement. HIV+ with HCV usually have a history of IDU and perhaps alcohol & unhealthy lifestyle behaviors, so we know IDU increases inflammation & immune activation [http://www.natap.org/2016/CROI/croi_233.htm], kidney disease and CVD risks so its almost impossible to separate out this type of study - that is, whats causing these extra hepatic diseases: HCV or lifestyle - but there is plenty of data that HCV increases these extra hepatic risks & there is plenty of data that HIV increases risk for these comorbidities, likely by similar means - inflammation and then also likely additional separate mechanisms, but likely that too leads to greater inflammation. There are a bunch of studies showing SVR/cure can improve these comorbidities - particularly CVD, kidney & but bone I am not sure if it has been reporting that SVR improves bone & it may not, but cancer rates have been reported to have improved with SVR, and this ALL MAKES SENSE because you are impacting & reducing inflammation with SVR cure - read for yourself these reports links just below:......
This study at CROI 2016 by the same authors of the article in CID below so the publication is a followup of this CROI report found SVR reduced risk for liver, kidney & CVD risks but not for bone-
CROI/2016: Hepatitis C and the Risk of Non-Liver-Related Morbidity and Mortality in HIV+ Persons....kidney, bone, cardiovascular - (04/4/16)
Eradication of HCV and non-liver-related non-AIDS-related events (CVD/diabetes/kidney/cancers) in HIV/HCV coinfection - (02/01/17)
Reported at AASLD was this study showing improved renal function with SVR- AASLD: The Impact of Hepatitis C Viral Cure on Progression of Renal Disease - (11/14/16)
Extrahepatic Morbidity and Mortality of Chronic Hepatitis C Review - SVR Clears/Reduces Extrahepatic Manifestations.....
http://www.natap.org/2015/HCV/110515_04.htm HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality.....this review discusses the many extra hepatic manifestations of HCV including heart disease, NHL/cancer, neurologic & the brain, touches on kidney disease, mixed cryoglobulinemia (MC)....and describes how SVR reduces or clears these disease and improves overall survival....."In a long-term study of 530 patients with advanced fibrosis or cirrhosis, SVR was associated with significantly reduced all-cause mortality.9 Other studies have also shown the extrahepatic benefits of HCV eradication (Table 3); patients with SVR after peginterferon and ribavirin therapy have reduced steatosis, a lower incidence of malignant lymphoma,121 reduced risk of type 2 diabetes mellitus143 and insulin resistance,38, 39, 144, 145, 146 improved cognitive performance,105 reduction in fatigue,147, 148 improvement in myocardial perfusion defects,75 reduced incidence of stroke,76 reduced renal and cardiovascular outcomes in the presence of diabetes,51 complete resolution of MC-related complications,17, 117 and regression or complete remission of HCV-associated lymphoma.119 It is also clear that interferon and ribavirin-free treatment results in improved patient-reported outcomes in many patient groups after as early as 2 weeks of treatment. Clinically important gains in quality of life are associated with SVR.20, 21 Thus, multiple studies have shown that durable HCV eradication achieved with interferon-based therapies improves both liver-related and non-liver-related outcomes."
Figure 2. Incidence rate ratios and 95% confidence intervals for the development of clinical events and deaths in multivariable analysis according to hepatitis C virus (HCV) serostatus and HCV stage during a follow-up time period of 8.2 years (mean). Multivariable analysis adjusted for HIV acquisition category, age, HIV-1 RNA, smoking, alcohol use, active intravenous drug use, and duration of HIV and HCV infection. Abbreviations: CDC, Centers for Disease Control and Prevention; CI, confidence interval; HCV, hepatitis C virus; HIV, human immunodeficiency virus; SVR, sustained virologic response; Tx, treatment.
"The treated non-SVR participants had the highest risk of liver-related and also of non-liver-related events. The prevalence of advanced liver fibrosis was by far the highest in this group (Table 1). When we adjusted for advanced fibrosis, most IRRs decreased, indicating that liver fibrosis is an important contributor to non-liver-related morbidity and mortality.
after a mean follow-up of 8.2 years, we observed (HCV seropositive and HCV seronegative, respectively) 107 and 18 liver events, 41 and 14 kidney events, 230 and 121 osteoporosis/fractures, 82 and 94 diabetes mellitus, 114 and 129 cardiovascular events, 119 and 147 non-AIDS malignancies, 162 and 126 Centers for Disease Control and Prevention HIV category B/C events, 106 and 10 liver-related deaths, and 227 and 218 non-liver-related deaths. Compared with HCV-negative controls, HCV-seropositive participants had an increased risk of liver events (incidence rate ratio [IRR], 6.29 [95% confidence interval {CI}, 3.52-11.22]), liver-related death (IRR, 8.24 [95% CI, 3.61-18.83]), kidney events (IRR, 2.43 [95% CI, 1.11-5.33]), and osteoporosis/fracture (IRR, 1.43 [95% CI, 1.03-2.01]). Among HCV-seropositive individuals, treated participants without SVR vs those with SVR had a higher risk of liver events (IRR, 6.79 [95% CI, 2.33-19.81]), liver-related death (IRR, 3.29 [95% CI, 1.35-8.05]), and diabetes mellitus (IRR, 4.62 [95% CI, 1.53-13.96]). Similar but not statistically significant differences were found between untreated HCV RNA-positive patients and those with SVR."
"SVR caused a 7-fold reduction of liver-related events and a 3-fold reduction in liver-related deaths.....In this large nationwide community-based HIV cohort study, HCV exposure was associated with an increased risk of kidney disease and osteoporosis. This risk did not seem to be related to persistent HCV replication. Compared with those with SVR, non-SVR participants had an increased risk of diabetes mellitus.....We found that HCV seropositivity was associated with increased risk of chronic kidney disease in accordance with others [18]. HCV-treated non-SVR participants, but not those with SVR, had an increased risk of kidney events compared with HIV-monoinfected patients. .....When we compared non-SVR participants with those with SVR, the incidence in kidney disease was elevated but did not reach statistical significance.....Taken together, these results suggest that in HIV/HCV-coinfected persons, HCV exposure is associated with increased kidney disease risk, most probably due to a high prevalence of traditional renal risk factors in this patient group......HCV exposure was an independent risk factor for osteoporosis and fracture.... This suggests that osteoporosis and fracture risk in HIV/HCV-coinfected patients is multifactorial and mainly determined by lifestyle-related risk factors associated with HCV exposure, including illicit drug and alcohol abuse, poor nutrition, increased risk of trauma, and HIV and ART, rather than by HCV itself, and that achieving viral cure of chronic HCV infection will not significantly improve bone health."
"if successful treatment of chronic HCV with DAA regimens is shown to improve HCV-related extrahepatic diseases and can reduce nonhepatic morbidity and mortality, including among HIV/HCV-coinfected individuals, then extrahepatic manifestations of chronic HCV may become a major indication for antiviral treatment, even in the absence of advanced liver fibrosis"
from Jules: there is enough evidence that HCV cure improves extra hepatic HCV manifestations for this to be an indication as suggested above, if we wait for more studies on this it could take a long time, HERE is background study results supporting my statement. HIV+ with HCV usually have a history of IDU and perhaps alcohol & unhealthy lifestyle behaviors, so we know IDU increases inflammation & immune activation [http://www.natap.org/2016/CROI/croi_233.htm], kidney disease and CVD risks so its almost impossible to separate out this type of study - that is, whats causing these extra hepatic diseases: HCV or lifestyle - but there is plenty of data that HCV increases these extra hepatic risks & there is plenty of data that HIV increases risk for these comorbidities, likely by similar means - inflammation and then also likely additional separate mechanisms, but likely that too leads to greater inflammation. There are a bunch of studies showing SVR/cure can improve these comorbidities - particularly CVD, kidney & but bone I am not sure if it has been reporting that SVR improves bone & it may not, but cancer rates have been reported to have improved with SVR, and this ALL MAKES SENSE because you are impacting & reducing inflammation with SVR cure - read for yourself these reports links just below:......
This study at CROI 2016 by the same authors of the article in CID below so the publication is a followup of this CROI report found SVR reduced risk for liver, kidney & CVD risks but not for bone-
CROI/2016: Hepatitis C and the Risk of Non-Liver-Related Morbidity and Mortality in HIV+ Persons....kidney, bone, cardiovascular - (04/4/16)
Eradication of HCV and non-liver-related non-AIDS-related events (CVD/diabetes/kidney/cancers) in HIV/HCV coinfection - (02/01/17)
Reported at AASLD was this study showing improved renal function with SVR- AASLD: The Impact of Hepatitis C Viral Cure on Progression of Renal Disease - (11/14/16)
Extrahepatic Morbidity and Mortality of Chronic Hepatitis C Review - SVR Clears/Reduces Extrahepatic Manifestations.....http://www.natap.org/2015/HCV/110515_04.htm HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality.....this review discusses the many extra hepatic manifestations of HCV including heart disease, NHL/cancer, neurologic & the brain, touches on kidney disease, mixed cryoglobulinemia (MC)....and describes how SVR reduces or clears these disease and improves overall survival....."In a long-term study of 530 patients with advanced fibrosis or cirrhosis, SVR was associated with significantly reduced all-cause mortality.9 Other studies have also shown the extrahepatic benefits of HCV eradication (Table 3); patients with SVR after peginterferon and ribavirin therapy have reduced steatosis, a lower incidence of malignant lymphoma,121 reduced risk of type 2 diabetes mellitus143 and insulin resistance,38, 39, 144, 145, 146 improved cognitive performance,105 reduction in fatigue,147, 148 improvement in myocardial perfusion defects,75 reduced incidence of stroke,76 reduced renal and cardiovascular outcomes in the presence of diabetes,51 complete resolution of MC-related complications,17, 117 and regression or complete remission of HCV-associated lymphoma.119 It is also clear that interferon and ribavirin-free treatment results in improved patient-reported outcomes in many patient groups after as early as 2 weeks of treatment. Clinically important gains in quality of life are associated with SVR.20, 21 Thus, multiple studies have shown that durable HCV eradication achieved with interferon-based therapies improves both liver-related and non-liver-related outcomes."
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Editorial Commentary
Extrahepatic Complications of Hepatitis C Virus Infection in HIV and the Impact of Successful Antiviral Treatment
Clin Infect Dis (Feb 7 2017) Vincent Lo Re, III
Vincent Lo Re III1,2
1Division of Infectious Diseases, Department of Medicine, Penn Center for AIDS Research, Penn Center for Viral Hepatitis, and 2Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia
(See the Major Article by Kovari et al on pages 490-7.)
Chronic hepatitis C virus (HCV) infection exerts its main effects on the liver, promoting hepatic inflammation and fibrosis and increasing the risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma [1]. However, chronic HCV infection also affects organ systems outside of the liver and can contribute to the development of a variety of extrahepatic diseases, most notably atherosclerosis, metabolic alterations (eg, insulin resistance, diabetes mellitus, hepatic steatosis), renal disease (eg, proteinuria, membranoproliferative glomerulonephritis), bone disease (eg, arthralgias, osteoporosis, fractures), neuropsychiatric manifestations (eg, fatigue, cognitive impairment), B-cell non-Hodgkin's lymphoma, cutaneous disorders (eg, lichen planus, porphyria cutanea tarda), and autoimmune and immune-mediated conditions (eg, mixed cryoglobulinemia, thyroid disease, sicca syndrome) [2, 3]. Some studies have suggested that the incidence of these diseases might be higher for human immunodeficiency virus (HIV)/HCV-coinfected individuals than for those with HCV alone [4, 5]. Regardless of HIV status, HCV-related extrahepatic conditions contribute to morbidity and could increase the risk of nonliver-related mortality [6-9].
The mechanisms for the extrahepatic comorbidities associated with chronic HCV infection are incompletely understood but are likely multifactorial. HCV replication in extrahepatic cells, interactions between HCV proteins and intracellular signaling pathways, HCV-induced stimulation of B-lymphocytes, and immune activation leading to chronic inflammation have all been hypothesized to play a role in the development of these conditions [2, 3]. Lifestyle factors, such as drug and alcohol abuse, smoking, and poor nutrition, may also be important contributors to the development of HCV-related extrahepatic diseases.
There is evidence that successful eradication of chronic HCV infection with interferon-based therapy can ameliorate some extrahepatic complications. Achieving cure of chronic HCV has been associated with improvements in insulin resistance [10-12], reduced risk of diabetes [13], decreased incidence of stroke [14] and lymphoma [15], improvement in neurocognitive function [16], reduction in fatigue [17], and resolution of mixed cryoglobulinemia [18]. These studies were primarily conducted among HIV-uninfected patients, and it remains unclear if HIV differentially affects the impact of cured HCV on specific extrahepatic conditions. Successful treatment of chronic HCV also has been shown to reduce non-liver-related mortality. One cohort study of 530 chronic HCV-infected patients with advanced hepatic fibrosis or cirrhosis found that eradication of chronic HCV with interferon-based treatment significantly reduced rates of all-cause mortality [7], but this study excluded individuals with HIV coinfection. However, a separate cohort study of 1599 HIV/HCV-coinfected patients found that cure of chronic HCV with interferon plus ribavirin was associated with reductions in non-liver-related deaths as well as decreased HIV progression [8].
All-oral direct-acting antiviral (DAA) agents for the treatment of chronic HCV are now available and result in high (≥94%) rates of cure, regardless of HIV status, with minimal adverse effects [19-22]. Because of their high costs, access to these drugs has been limited in many settings, often only restricted to patients with advanced liver fibrosis or cirrhosis [23-26]. However, if successful treatment of chronic HCV with DAA regimens is shown to improve HCV-related extrahepatic diseases and can reduce nonhepatic morbidity and mortality, including among HIV/HCV-coinfected individuals, then extrahepatic manifestations of chronic HCV may become a major indication for antiviral treatment, even in the absence of advanced liver fibrosis.
There has been a paucity of data related to the risk of HCV-related extrahepatic diseases according to the presence of HCV viremia and successful antiviral treatment in the setting of HIV infection. In this issue of Clinical Infectious Diseases [27], investigators from the Swiss HIV Cohort Study, a nationwide community-based HIV cohort study, comprehensively examined the effects of HCV seropositivity, detectable HCV viremia, and successful HCV treatment with predominantly interferon-based therapy (10% were treated with DAAs) on a variety of important extrahepatic outcomes, including diabetes mellitus, chronic kidney disease, non-AIDS-defining malignancies, osteoporosis/fractures, and cardiovascular events. Data collection was prospective over a mean of 8.2 years, and stringent validation methods were used to minimize the likelihood of misclassification of extrahepatic events. The risk of each extrahepatic outcome was evaluated among 4 categories of HIV/HCV-coinfected patients-untreated HCV antibody-positive who spontaneously cleared their infection, untreated HCV antibody-positive with viremia, antiviral treated and cured, and antiviral treated but not cured-compared to HIV-monoinfected patients. These comparisons are valuable in helping to differentiate the potential contributions of HCV viremia-related mechanisms from lifestyle factors on the development of extrahepatic diseases and provide important insights on the effects of cured HCV on these conditions.
The study found that rates of chronic kidney disease and osteoporosis/fractures were significantly higher for HCV antibody-positive patients but not for those with HCV viremia compared to HIV-monoinfected individuals. Rates of diabetes, cardiovascular disease, and non-AIDS malignancies were not increased among either HCV-seropositive or HCV viremic persons compared to those with HIV alone. These findings suggest that behavioral factors associated with HCV infection might be more important contributors to the development of renal and bone disease among coinfected patients than HCV viremia-related mechanisms. This observation is consistent with that from a large Danish study that showed that HCV-exposed patients had a higher risk of all fracture types compared to uninfected persons and that fracture risk did not differ between patients with HCV viremia vs those who spontaneously cleared their HCV infection (ie, HCV antibody-positive but RNA-negative), though this study was largely comprised of HIV-uninfected individuals [28]. However, there are some data that suggest that HCV viremia and viremia-related inflammation might contribute, to some degree, to the development of chronic kidney and bone disease. A recent large cohort study from the North American AIDS Cohort Collaboration on Research and Design found that both HCV viremic and HCV antibody-positive but aviremic individuals were at increased risk for moderate and advanced chronic kidney disease compared to HIV-monoinfected persons [29]. Differences in the definitions of chronic kidney disease between the studies may account for the disparate results. Moreover, a recent cross-sectional study using tibia peripheral quantitative computed tomography found that HIV/HCV viremic women had decreased tibial trabecular volumetric bone mineral density, diminished cortical dimensions, and significant endocortical bone loss-a pattern observed in chronic inflammatory diseases (eg, rheumatoid arthritis, inflammatory bowel disease)-compared to uninfected persons [30]. Trabecular volumetric bone mineral density was lower and median tumor necrosis-α levels were higher in coinfected women compared to either HCV- or HIV-monoinfected women, suggesting that HIV- and HCV viremia-associated chronic inflammation might contribute to structural bone deficits among HIV/HCV patients. Additional studies are needed to understand the contributions of HCV viremia, lifestyle factors, and alternative mechanisms on the development of these and other extrahepatic diseases in the setting of HIV coinfection. Future analyses should also consider whether the stage of liver fibrosis or presence of hepatic decompensation modifies the risk of extrahepatic outcomes.
In analyses evaluating the effects of HCV eradication with interferon-based therapy on nonhepatic outcomes, patients who did not achieve cure of HCV had higher rates of diabetes, but not other extrahepatic events, compared to successfully cured persons. This finding persisted after adjustment for baseline stage of hepatic fibrosis. Of note, rates of liver complications and liver-related deaths remained higher for treated patients who did not achieve cure, which were valuable additional analyses that provide face validity to the findings. These results demonstrate the beneficial effect of antiviral therapy on at least 1 extrahepatic outcome but must be interpreted in the context of several limitations, particularly the small sample of antiviral-treated patients (626 patient overall; 345 with cured HCV), the limited number who received a DAA (10%), and the relatively few events for some of the extrahepatic outcomes.
The comprehensive approach taken by Kovari and colleagues [27] in evaluating a number of clinically important extrahepatic complications according to both HCV viremia and viral cure status provides a model for studies on this topic. However, more work in this area is needed. Specific cohorts, or preferably cohort collaborations, that include large samples of DAA-treated patients with long-term follow-up are needed to determine the impact of successful treatment with these new regimens on extrahepatic diseases among HIV/HCV patients. These data will help inform whether reductions in rates of extrahepatic outcomes can help to justify DAA-based HCV treatment and if extrahepatic diseases should be included as a major indication for DAA therapy, even in the absence of significant liver fibrosis.
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Editor's Choice
Hepatitis C Infection and the Risk of Non-Liver-Related Morbidity and Mortality in HIV-Infected Persons in the Swiss HIV Cohort Study
Abstract
Background.
Hepatitis C virus (HCV) infection has been associated with increased non-liver-related morbidity and mortality. However, studies have yielded inconsistent results.
Methods.
The incidence of clinical events in human immunodeficiency virus (HIV)-infected HCV-seropositive and incidence density-matched HCV-seronegative participants of the Swiss HIV Cohort Study from August 1994 to December 2014 was studied. We compared (1) HCV-seropositive with HCV-seronegative participants and (2) HCV-viremic with successfully treated nonviremic patients. Poisson regression was used to assess differences between these groups.
Results.
We included 2503 HCV-seropositive participants (540 with spontaneous HCV clearance, 1294 untreated HCV RNA positive, 345 treated with sustained virologic response [SVR], 43 during treatment, and 281 treated without SVR), and 2503 HCV-seronegative controls. After a mean follow-up of 8.2 years, we observed (HCV seropositive and HCV seronegative, respectively) 107 and 18 liver events, 41 and 14 kidney events, 230 and 121 osteoporosis/fractures, 82 and 94 diabetes mellitus, 114 and 129 cardiovascular events, 119 and 147 non-AIDS malignancies, 162 and 126 Centers for Disease Control and Prevention HIV category B/C events, 106 and 10 liver-related deaths, and 227 and 218 non-liver-related deaths. Compared with HCV-negative controls, HCV-seropositive participants had an increased risk of liver events (incidence rate ratio [IRR], 6.29 [95% confidence interval {CI}, 3.52-11.22]), liver-related death (IRR, 8.24 [95% CI, 3.61-18.83]), kidney events (IRR, 2.43 [95% CI, 1.11-5.33]), and osteoporosis/fracture (IRR, 1.43 [95% CI, 1.03-2.01]). Among HCV-seropositive individuals, treated participants without SVR vs those with SVR had a higher risk of liver events (IRR, 6.79 [95% CI, 2.33-19.81]), liver-related death (IRR, 3.29 [95% CI, 1.35-8.05]), and diabetes mellitus (IRR, 4.62 [95% CI, 1.53-13.96]). Similar but not statistically significant differences were found between untreated HCV RNA-positive patients and those with SVR.
Conclusions.
While HCV exposure was associated with an increased risk of kidney disease and osteoporosis/fracture, this risk did not seem to be dependent of persistent HCV RNA. Successful HCV treatment was associated with a lower incidence of liver disease, liver-related death, and diabetes mellitus, whereas the other conditions studied were less affected.
Figure 2. Incidence rate ratios and 95% confidence intervals for the development of clinical events and deaths in multivariable analysis according to hepatitis C virus (HCV) serostatus and HCV stage during a follow-up time period of 8.2 years (mean). Multivariable analysis adjusted for HIV acquisition category, age, HIV-1 RNA, smoking, alcohol use, active intravenous drug use, and duration of HIV and HCV infection. Abbreviations: CDC, Centers for Disease Control and Prevention; CI, confidence interval; HCV, hepatitis C virus; HIV, human immunodeficiency virus; SVR, sustained virologic response; Tx, treatment.
DISCUSSION
In this large nationwide community-based HIV cohort study, HCV exposure was associated with an increased risk of kidney disease and osteoporosis. This risk did not seem to be related to persistent HCV replication. Compared with those with SVR, non-SVR participants had an increased risk of diabetes mellitus. Replicating HCV infection was not associated with other non-liver-related diseases and death. As expected, the risk of liver disease and liver-related death was increased in both HCV-exposed and HCV-viremic patients. SVR caused a 7-fold reduction of liver-related events and a 3-fold reduction in liver-related deaths.
We noted that diabetes mellitus was the only non-liver-related disease associated with replicating HCV infection. In a recently published metaanalysis, diabetes mellitus was the most common extrahepatic manifestation of HCV infection, in addition to depression [14]. In line with our finding, in a Japanese study, achieving viral cure was associated with a significant reduction of developing diabetes [15]. Moreover, HCV eradication has been shown to ameliorate insulin resistance in hepatic tissues and whole body [16, 17]. HCV is considered to be a metabolic virus and is pathophysiologically linked to insulin resistance and type 2 diabetes [6]. Liver cirrhosis aggravates metabolic disorders [6]. Our results, however, indicate that the increased risk of diabetes in HCV-treated nonresponders cannot be solely explained by advanced liver fibrosis.
We found that HCV seropositivity was associated with increased risk of chronic kidney disease in accordance with others [18]. HCV-treated non-SVR participants, but not those with SVR, had an increased risk of kidney events compared with HIV-monoinfected patients. When we compared non-SVR participants with those with SVR, the incidence in kidney disease was elevated but did not reach statistical significance. In accordance with our findings, two large cohort collaboration groups [19, 20] found an increased risk in replicating but not cleared HCV infection compared with HIV-monoinfected participants. In a similar US and Canadian cohort study, results were contradictory, perhaps due to considerable differences between cohorts regarding patient characteristics [21]. Taken together, these results suggest that in HIV/HCV-coinfected persons, HCV exposure is associated with increased kidney disease risk, most probably due to a high prevalence of traditional renal risk factors in this patient group.
HCV exposure was an independent risk factor for osteoporosis and fracture. However, replicating compared with resolved HCV infection was not associated with bone-related events. Accordingly, several observational studies have shown that HIV/HCV-coinfected patients have an increased fracture incidence compared with HIV-monoinfected and HCV- and HIV-uninfected persons [22, 23]. Hansen et al demonstrated that fracture risk did not differ between viremic vs nonviremic HCV infection [24]. This suggests that osteoporosis and fracture risk in HIV/HCV-coinfected patients is multifactorial and mainly determined by lifestyle-related risk factors associated with HCV exposure, including illicit drug and alcohol abuse, poor nutrition, increased risk of trauma, and HIV and ART, rather than by HCV itself, and that achieving viral cure of chronic HCV infection will not significantly improve bone health.
We detected a trend of an increased risk of cardiovascular events in HCV nonresponders compared with successfully treated patients. In the current literature, reports regarding the association between chronic HCV infection and cardiovascular disease are conflicting. Although there is evidence that HCV should be considered a risk factor for carotid atherosclerosis, stroke, and heart failure (reviewed in [5, 25]), the association between HCV infection and coronary artery disease remains unclear (reviewed in [26]).
In line with a Spanish HIV/HCV cohort that found an increased frequency of new AIDS-defining events and deaths in HCV treatment nonresponders vs responders [7], we noted an increased risk of CDC HIV category B/C events in non-SVR compared with HIV-monoinfected patients. Non-SVR compared to those with SVR had a higher incidence of HIV/AIDS events, but without reaching statistical significance. As CD4 cell levels and suppression of HIV replication were similar between non-SVR and HIV-monoinfected participants at time of HIV/AIDS events, respectively, at last follow-up (Table 1), this finding cannot be explained by CD4 cell recovery, splenic sequestration in cirrhotic non-SVR patients [27], or control of HIV infection. One might speculate whether failure to achieve SVR might be due to an immunodeficiency predisposing also for HIV/AIDS-related opportunistic conditions.
Extrahepatic mortality was high in HCV-coinfected persons, consistent with our previous observations [2]. In HCV-seropositive participants, only one-third of deaths were liver related. Main causes of extrahepatic death were sepsis, substance abuse, and HIV/AIDS, indicating the important contribution of social and behavioral factors to mortality in this patient group. However, the risk of non-liver-related death in HCV-seropositive vs HCV-seronegative, and HCV-viremic vs nonviremic patients, was similar in adjusted analysis.
The treated non-SVR participants had the highest risk of liver-related and also of non-liver-related events. The prevalence of advanced liver fibrosis was by far the highest in this group (Table 1). When we adjusted for advanced fibrosis, most IRRs decreased, indicating that liver fibrosis is an important contributor to non-liver-related morbidity and mortality.
The strengths of our study include the use of a population-based, nationwide HIV/HCV cohort with a large number of patient-years with prospectively collected laboratory and clinical data, including regular HCV screening and coverage of incident events with use of structured event reporting forms. We were able to compare incidences of diseases and death between HCV-seropositive and demographically similar HCV-seronegative SHCS participants, and between HCV-viremic and nonviremic patients. Furthermore, to analyze viremia as a time-updated variable allowed us to assess longitudinal effects of spontaneous and treatment-related viral clearance.
Our study has some limitations. Although we adjusted for several potential confounders, we cannot exclude unmeasured confounding. Even with multiple adjustments, there may remain differences between the groups, including socioeconomic status and education. We did not adjust for multiple outcomes and therefore cannot rule out false-positive findings.
However, the observed patterns are consistent and pathophysiologically plausible throughout the various end points. The prevalence of less extensive renal disease is likely to be higher as kidney disease was defined by end-stage events, including dialysis and transplantation. As most SHCS participants were of normal weight, in cohorts with more overweight patients, the risk for diabetes and cardiovascular disease may be higher. Finally, in our study most of the HCV therapies consisted of pegylated interferon plus ribavirin. Future studies are expected to show whether the HCV clearance effect achieved by DAAs differs from that of the older regimen.
We conclude that HCV-exposed, HIV-infected individuals have an increased risk of kidney disease and bone-related events that does not seem to be related to persistent viral replication. In addition to a significant decrease of liver-related disease and death, therapeutic viral eradication leads to a reduction of diabetes mellitus. Prospective large-scale cohort collaborations are needed to further describe the impact of HCV eradication with DAAs on non-liver-related morbidity and mortality.
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