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HCV Sustained Viral Response in HIV Coinfected Reduces Non-Liver Related Mortality & Liver-Related Disease: cancers/CVD
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Juan Berenguer1, M.D., et al, and the GeSIDA HIV/HCV Cohort Study Group.
1Hospital, Spain
"HCV eradication (SVR) due to Peg/Rbv therapy is associated not only with a reduction in liver-related complications and mortality, but also with a reduction in HIV progression and mortality not related to liver disease. These findings support an increasingly strong rationale for earlier evaluation of new direct-acting antivirals against HCV in coinfected patients, a subgroup with a hugely unmet need for treatment.......We found that failure to achieve an SVR was associated with increased risk of liver decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death; findings consistent with our previous observations [11]. Interestingly, we also found that failure to achieve an SVR was associated with an increased risk of HIV progression and non-liver-related mortality. Most non-liver-related deaths were due to non-AIDS-defining cancers, cardiovascular events, and bacterial infections. Of note, both the risk of non-liver-related death, and non-liver-related non-AIDS-related death was significantly higher for nonresponders than for responders after adjustment......may be explained by several factors, including immune activation, defective immunity, systemic inflammation, and liver disease itself"
"In HIV/HCV-coinfected patients, SVR to IFN-RBV also improves fibrosis [10] and reduces liver-related complications and mortality, independently of the stage of fibrosis, as recently reported by our group. As HCV infection has been found to hasten HIV progression and mortality by some authors [12], we aimed to determine the effect of achieving an SVR after IFN-RBV on HIV progression and mortality not related to liver disease in HIV/HVC-coinfected.
the main observation that the risk of HIV progression, non-liver-related death, and non-liver-related non-AIDS-related death were
significantly higher for non-responders than for responders after adjustment for important baseline variables
Although the study design precluded determination of causality, our results suggest that eradication of HCV in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related complications and mortality, but also with a reduction in HIV progression and mortality not related to liver disease. These findings support an increasingly strong rationale for earlier evaluation of new direct-acting antivirals against HCV in coinfected patients, a subgroup with a hugely unmet need for treatment [33].
The percentage of patients with HIV viral load below the limit of detection was higher in responders than in non-responders at baseline and at the end of treatment with IFN-RBV (interferon has HIV antiviral activity, reduces HIV viral load by about 1 log or more)......a higher proportion of non-responders than responders had CD4+ cell counts < 200 cells/mL.
We evaluated the clinical course of 1599 HIV/HCV-coinfected patients who were followed up for a median perriod of approximately 5 years after therapy with IFN-RBV. We found that failure to achieve an SVR was associated with increased risk of liver decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death; findings consistent with our previous observations [11]. Interestingly, we also found that failure to achieve an SVR was associated with an increased risk of HIV progression and non-liver-related mortality. Most non-liver-related deaths were due to non-AIDS-defining cancers, cardiovascular events, and bacterial infections. Of note, both the risk of non-liver-related death, and non-liver-related non-AIDS-related death was significantly higher for nonresponders than for responders after adjustment for important baseline variables such as age, sex, HIV transmission category, nadir CD4+ cell count, cART, HIV-RNA level below the limit of detection, and liver fibrosis. The frequency of severe immunodeficiency-defined as a CD4+ T-lymphocyte count < 200 cells/mm3-after discontinuation of IFN-RBV was higher in non-responders than in responders; this finding could not be explained by differences in suppression of HIV replication between the groups.
The findings of reports on the effect of HCV on the progression of HIV infection are conflicting. One study found no evidence that HCV infection increases the risk of progression or death or affects the immune response to cART [17]; another reported that HCV serostatus did not affect the CD4 recovery in patients with fully suppressed HIV after cART [18]. Our findings, however, support the notion that HCV has a negative impact on HIV infection, an observation shared by other authors who found an association between HCV infection and increased risk of developing AIDS-defining conditions [12, 19]. Recent works have also shown that active HCV infection impairs CD4 recovery, even after years of exposure to cART [20].
The increased risk of non-liver-related death and non-liver-related non-AIDS-related death among non-responders than responders found in our study may be explained by several factors, including immune activation, defective immunity, systemic inflammation, and liver disease itself.
In HIV-infected patients, those who were coinfected with HCV had higher grades of immune activation than those not coinfected with HCV [21, 22], and this elevated immune activation may place these individuals at increased risk not only of HCV disease complications, but also of HIV progression [23]. In addition, in HIV/HCV-coinfected patients with liver cirrhosis, microbial translocation has been correlated with markers of systemic immune activation [24].
After adjustment for traditional risk factors, HCV infection was associated with increased carotid intima-media thickness [25], as well as with increased cardiovascular mortality among blood donors [26]. However, Weber et al found no association between HBV or HCV coinfection and development of myocardial infarction in a prospective cohort study of HIV-infected patients [27].
Interestingly, just as cART causes a decline in the high levels of inflammation and hypercoagulation that are characteristically associated with untreated HIV infection [28], eradication of HCV may have similar effects. In this regard, HIV/HCV coinfection has been found to increase serum levels of soluble adhesion molecules sICAM-1 and sVCAM-1, and SVR after therapy with IFN-RBV significantly reduces these cardiovascular markers [29]. This observation is of interest, because soluble adhesion molecules, especially sVCAM-1, are associated with cardiovascular death among patients with coronary artery disease [30].
Finally, liver disease could also have contributed to non-liver-related mortality among nonresponders in our study, particularly in the case of bacterial pneumonia. This is because progression of liver disease was more common in non-responders than in responders [31] and because mortality from infections such as pneumococcal pneumonia is high in patients with cirrhosis [32]. To address this issue, we carried out 2 sensitivity analyses, the results of which did not change the main observation that both the risk of HIV progression and non-liver-related death were significantly higher for non-responders than for responders."
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Sustained Virological Response to Interferon Plus Ribavirin Reduces Non-Liver-Related Mortality in Patients Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus
Clin Infect Dis. (2012) May 18, 2012
Abstract
Background Sustained virological response (SVR) after therapy with interferon plus ribavirin (IFN-RBV) reduces liver-related complications and mortality in patients coinfected with HIV and hepatitis C virus (HIV/HCV). We assessed the effect of SVR on HIV progression and mortality not related to liver disease.
Methods Observational cohort study including consecutive HIV/HCV-coinfected patients treated with IFN-RBV between 2000 and 2008 in 19 centers in Spain.
ResultsOf 1599 patients, 626 (39%) had an SVR. After a median follow-up of approximately 5 years, we confirmed that failure to achieve an SVR was associated with an increased risk of liver-related events and liver-related death. We also observed higher rates of the following events in non-responders than in responders: AIDS-defining conditions (ADC) (x 100 person-years) (0.84 [0.59 - 1.10] vs 0.29 [0.10 - 0.48], P=.003), non-liver-related deaths (0.65 [0.42 - 0.87] vs 0.16 [0.02 - 0.30], P=.002), and non-liver-related non-AIDS-related deaths (0.55 [0.34 - 0.75] vs 0.16 [0.02 - 0.30], P=.002). Cox regression analysis, showed that the adjusted hazard ratio of new ADC, non-liver-related deaths, and non-liver-related non-AIDS-related deaths for non-responders in comparison with responders was 1.90 (95% CI, 0.89 - 4.10; P=.095), 3.19 (95% CI, 1.21 - 8.40; P=.019), and 2.85 (95% CI, 1.07 - 7.60; P=.036), respectively.
Conclusions Our findings suggest that eradication of HCV after therapy with IFN-RBV in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related events, but also with a reduction in HIV progression and mortality not related to liver disease.
INTRODUCTION
Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, promoting more rapid progression to fibrosis and development of end-stage liver disease [1]. Following the decline in AIDS-related morbidity and mortality since the introduction of combination antiretroviral therapy (cART), end-stage liver disease emerged as a frequent cause of hospital admission and death in populations coinfected with HIV and hepatitis C virus (HCV) [2, 3]. For this reason, recommendations have considered HIV/HCV-coinfected patients as candidates for anti-HCV treatment [4].
Sustained virological response (SVR) to interferon plus ribavirin (IFN-RBV) enables a significant improvement in fibrosis in non-HIV-infected patients with chronic hepatitis C [5] and reduces liver-related complications and mortality in those with advanced fibrosis [6, 7]. One population-based cohort showed that alcohol consumption and an HCV diagnosis not made during systematic screening were significant determinants of poor outcome; interestingly, no deaths were observed among patients who achieved SVR [8]. A recent analysis found that SVR was associated with a reduction in all-cause mortality in US veterans monoinfected with HCV [9].
In HIV/HCV-coinfected patients, SVR to IFN-RBV also improves fibrosis [10] and reduces liver-related complications and mortality, independently of the stage of fibrosis, as recently reported by our group [11]. As HCV infection has been found to hasten HIV progression and mortality by some authors [12], we aimed to determine the effect of achieving an SVR after IFN-RBV on HIV progression and mortality not related to liver disease in HIV/HVC-coinfected.
DISCUSSION
We evaluated the clinical course of 1599 HIV/HCV-coinfected patients who were followed up for a median perriod of approximately 5 years after therapy with IFN-RBV. We found that failure to achieve an SVR was associated with increased risk of liver decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death; findings consistent with our previous observations [11]. Interestingly, we also found that failure to achieve an SVR was associated with an increased risk of HIV progression and non-liver-related mortality. Most non-liver-related deaths were due to non-AIDS-defining cancers, cardiovascular events, and bacterial infections. Of note, both the risk of non-liver-related death, and non-liver-related non-AIDS-related death was significantly higher for nonresponders than for responders after adjustment for important baseline variables such as age, sex, HIV transmission category, nadir CD4+ cell count, cART, HIV-RNA level below the limit of detection, and liver fibrosis. The frequency of severe immunodeficiency-defined as a CD4+ T-lymphocyte count < 200 cells/mm3-after discontinuation of IFN-RBV was higher in non-responders than in responders; this finding could not be explained by differences in suppression of HIV replication between the groups.
The findings of reports on the effect of HCV on the progression of HIV infection are conflicting. One study found no evidence that HCV infection increases the risk of progression or death or affects the immune response to cART [17]; another reported that HCV serostatus did not affect the CD4 recovery in patients with fully suppressed HIV after cART [18]. Our findings, however, support the notion that HCV has a negative impact on HIV infection, an observation shared by other authors who found an association between HCV infection and increased risk of developing AIDS-defining conditions [12, 19]. Recent works have also shown that active HCV infection impairs CD4 recovery, even after years of exposure to cART [20].
The increased risk of non-liver-related death and non-liver-related non-AIDS-related death among non-responders than responders found in our study may be explained by several factors, including immune activation, defective immunity, systemic inflammation, and liver disease itself.
In HIV-infected patients, those who were coinfected with HCV had higher grades of immune activation than those not coinfected with HCV [21, 22], and this elevated immune activation may place these individuals at increased risk not only of HCV disease complications, but also of HIV progression [23]. In addition, in HIV/HCV-coinfected patients with liver cirrhosis, microbial translocation has been correlated with markers of
systemic immune activation [24].
After adjustment for traditional risk factors, HCV infection was associated with increased carotid intima-media thickness [25], as well as with increased cardiovascular mortality among blood donors [26]. However, Weber et al found no association between HBV or HCV coinfection and development of myocardial infarction in a prospective cohort study of HIV-infected patients [27].
Interestingly, just as cART causes a decline in the high levels of inflammation and hypercoagulation that are characteristically associated with untreated HIV infection [28], eradication of HCV may have similar effects. In this regard, HIV/HCV coinfection has been found to increase serum levels of soluble adhesion molecules sICAM-1 and sVCAM-1, and SVR after therapy with IFN-RBV significantly reduces these cardiovascular markers [29]. This observation is of interest, because soluble adhesion molecules, especially sVCAM-1, are associated with cardiovascular death among patients with coronary artery disease [30].
Finally, liver disease could also have contributed to non-liver-related mortality among nonresponders in our study, particularly in the case of bacterial pneumonia. This is because progression of liver disease was more common in non-responders than in responders [31] and because mortality from infections such as pneumococcal pneumonia is high in patients with cirrhosis [32]. To address this issue, we carried out 2 sensitivity analyses, the results of which did not change the main observation that both the risk of HIV progression and non-liver-related death were significantly higher for non-responders than for responders.
Our study has several limitations, the most important being that it is not entirely prospective. We believe, however, that its characteristics make it unlikely that the results differ considerably from those that would have been obtained in an entirely prospective study. This is because follow-up was by the same physicians in the same reference hospitals throughout the course of their disease, with standard clinical and laboratory
parameters. Furthermore, all the information in the database was monitored to verify that it was consistent with the patient's medical history. Another limitation is the lack of information about adherence to cART during follow-up; however, the absence of differences in suppression of HIV replication between the groups during follow-up suggests that adherence to cART probably had little impact on the differences found in
outcomes. Our study is also limited by the lack of information about pneumococcal vaccination and other baseline comorbidities (smoking, diabetes, traditional cardiovascular risk factors); therefore, we cannot rule out the possibility that differences in these variables could have affected outcome.
Although the study design precluded determination of causality, our results suggest that eradication of HCV in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related complications and mortality, but also with a reduction in HIV progression and mortality not related to liver disease. These findings support an increasingly strong rationale for earlier evaluation of new direct-acting antivirals against HCV in coinfected patients, a subgroup with a hugely unmet need for treatment [33].
ReSULTS
Patient characteristics
Between January 2000 and January 2008, 1599 patients were included in the database. Their baseline characteristics are shown in Table 1. In brief, 75% were male, median age was 40 years, 23% had prior AIDS-defining conditions, median baseline CD4+ cell count was 527 cells/mm3, 70% had an undetectable HIV viral load, median time since HCV infection was 18 years, 61% were infected by genotypes 1 or 4, and 61% had an HCVRNA ≥ 500,000 IU/mL. Patients were asked about their alcohol intake at baseline, and 5% were considered to have a high intake, defined as the consumption of at least 50 g of alcohol per day for at least 12 months. Advanced fibrosis at baseline (F3-F4 in liver biopsy)
was present in 448/1153 (39%) patients before anti-HCV therapy was started.
A total of 790 (49%) patients were treated with pegylated interferon-α2a plus RBV, 602 (38%) were treated with pegylated interferon-α2b plus RBV, and 207 (13%) were treated with standard thrice-weekly interferon-α plus. The median duration of anti-HCV therapy was 11.07 months in responders and 6.97 months in non-responders; P < 0.001. Scheduled therapy was completed by 555 (89%) responders and 352 (36%) nonresponders; P < 0.001. Anti-HCV therapy was interrupted because of adverse events in 48 responders (8%) and 166 non-responders (17%); P < 0.001.
During treatment of hepatitis C, 1262 (79%) of the patients were on cART. The most common combinations were 2 nucleoside reverse transcriptase inhibitors (NRTI) plus 1 non-nucleoside reverse-transcriptase inhibitor (NNRTI) in 573 patients (45%), 2 NRTI plus 1 protease inhibitor (PI) in 176 (14%), 3 NRTI in 89 (7%), and other combinations in 424 (34%).
Sustained virological response
Overall, 626 (39%) of the patients achieved an SVR; this figure includes 42 of 174 retreated patients that achieved SVR after the second course of IFN-RBV. The response was 251/982 (26%) for genotypes 1 and 4 and 360/572 (63%) for genotypes 2 and 3. We used multiple logistic regression analysis to identify pre-treatment factors that were predictive of an SVR. The model included baseline factors that were associated with SVR by univariate regression analysis, for example, prior AIDS-defining conditions, nadir CD4+ cell count, HCV genotype, and HCV-RNA level. It also included the type of interferon used (pegylated vs. non-pegylated), the presence of advanced fibrosis, and alcohol intake higher than 50 g per day. The final model identified 3 variables that were independently associated with increased probability of an SVR: HCV genotype 2-3 (OR, 4.82; 95% CI, 3.53-6.58; P<.001), HCV-RNA level < 500,000 IU/mL (OR, 1.60; 95% CI, 1.17-2.19; P=.003), and absence of advanced fibrosis (OR, 1.91; 95% CI, 1.40-2.62; P<.001).
Outcomes
After a median follow-up of 62.0 (IQR, 41.9 - 80.7) months in non-responders and 56.9 (IQR, 41.6 - 79.9) months in responders (P=.204), we found a significantly higher frequency and rate (per 100 persons-years) of liver decompensation, hepatocellular carcinoma, and liver transplantation in non-responders than in responders (Table 2).
We also found a significantly higher frequency and rate of new AIDS-defining conditions in non-responders than in responders (Table 2). The different types of AIDS-defining conditions are listed in Table 3. There were 41 AIDS-defining conditions among nonresponders; the most frequent were recurrent pneumonia (n=11), tuberculosis (n=6), and esophageal candidiasis (n=5), progressive multifocal leukoencephalopathy (n=5), and invasive cervical cancer (n=5). There were only 9 AIDS-defining conditions among responders; the most frequent was recurrent pneumonia (n=4) (Table 3). At the time of the first new AIDS-defining condition, 34 non-responders (83%) and 9 responders (100%) were receiving cART. HIV viral load and CD4+ cell count were available for 40/41 nonresponders and 9/9 responders. HIV viral load was detected in 23 non-responders (57%) and in 5 responders (56%). The median (IQR) CD4+ cell count was 341 cells/mm3 (170 - 571) for non-responders and 400 cells/mm3 (159 - 466) for responders.
We also found a significantly higher frequency and rate of overall deaths, liver-related deaths, non-liver related deaths, and non-liver-related non-AIDS-related deaths in nonresponders than in responders (Table 2 and Figure 1). Non-liver-related deaths are summarized in Table 3. Five deaths in non-responders were caused by AIDS-defining conditions compared with none in responders. There were 27 non-liver-related non-AIDS-related deaths among non-responders; the most frequent causes were non-AIDS-defining cancers (n=7), cardiovascular events (n=6), and bacterial infections (n=6). There were 5 non-AIDS-related deaths among responders, including 2 due to non-AIDS-defining
cancers.
We applied Cox regression analysis to investigate the association between response to IFN-RBV and the development of new AIDS-defining conditions, non-liver-related death, and non-liver-related non-AIDS-related death. When we adjusted for age, sex, HIV transmission category, nadir CD4+ cell count, cART, HIV-RNA level below the limit of detection, and liver fibrosis, we found that the adjusted hazard ratio of each of these clinical endpoints was higher for non-responders than for responders, although it reached statistical significance only for non-liver-related death and non-liver-related non-AIDS-related death (Table 4). We carried out 2 sensitivity analyses. In the first, we excluded those patients with recurrent pneumonia as a new AIDS-defining condition and those who died of bacterial pneumonia. In the second, we did not exclude patients with recurrent pneumonia as a new AIDS-defining condition or those who died of bacterial pneumonia, although we did censor their follow-up until these events occurred. Interestingly, the results of these analyses did not change the main observation that the risk of HIV progression, non-liver-related death, and non-liver-related non-AIDS-related death were significantly higher for non-responders than for responders after adjustment for important baseline variables (data not shown).
The percentage of patients with HIV viral load below the limit of detection was higher in responders than in non-responders at baseline and at the end of treatment with IFN-RBV, although it did not differ among the groups during follow-up except at a single time-point in month 18 (Figure 2). Although the percentage of patients with CD4+ cell counts < 200 cells/mL was not significantly different between responders and non-responders at baseline and at the end of treatment, during the follow-up period we observed that a higher proportion of non-responders than responders had CD4+ cell counts < 200 cells/mL, reaching statistical significance at 3, 6, and 9 months after discontinuation of therapy (Figure 2)
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