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Effect Of HCV Infection On Cause-Specific Mortality Following HIV Seroconversion Before And After 1997
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Gastroenterology Dec 12 2012
Article in press
"Based on analysis of data from the CASCADE Collaboration, since 1997, when cART became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV....... with co-infected individuals from all four risk groups having a higher risk of progression to HIV and/or AIDS-related death than monoinfected individuals: IDU (aHR, 2.43; 1.14-5.20), MSW or those with hemophilia (aHR, 3.43; 1.70-6.93) and MSM (aHR, 3.11; 1.49-6.48), compared to monoinfected individuals of the same risk group."
"In conclusion, HCV co-infected individuals appear to be at increased risk of HIV- and/or AIDS-related mortality in the cART era. Although the risk of hepatitis or liver-related mortality has decreased since cART became available, it is higher among co-infected individuals compared to those with only HIV. This underscores the importance of early diagnosis of HCV infection in HIV-infected individuals and the need for routine screening of HCV among high risk groups, including those not (yet) infected with HIV. Our findings highlight the importance of interventions to increase the uptake of HCV treatment in co-infected individuals."
Abstract
Background and Aims
Individuals with HIV infection are frequently also infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or AIDS, and hepatitis or liver disease, adjusting for duration of HIV infection.
Methods
We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) Collaboration that included information on HCV infection and cause of death. A competing risks proportional sub-distribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural.
Results
Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) were also infected with HCV. Of 718 deaths, 395 (55.0%) were due to HIV infection and/or AIDS, and 39 (5.4%) to hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy (cART) became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection-drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93) and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared to individuals infected with only HIV, co-infected individuals had higher risk of death from hepatitis or liver disease.
Conclusions
Based on analysis of data from the CASCADE Collaboration, since 1997, when cART became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression.
Discussion
Our study has a number of clinically-relevant findings. Firstly we found that, although all-cause mortality did not differ significantly between co-infected and monoinfected individuals in the precART era, it became significantly higher for co-infected individuals in the cART era. This is in concordance with a recent meta-analysis which reported an increased risk of all-cause mortality for coinfected compared to monoinfected individuals in the cART era5. Secondly, among co-infected individuals, we found that their risk of hepatitis or liver-related mortality decreased in the cART era compared to the pre-cART era. In addition, despite the reduction in hepatitis or liver-related mortality in the cART era, co-infected individuals still experienced a higher rate of death from these causes compared to monoinfected individuals. Thirdly, and importantly, we found that, in the cART era, HCV co-infection increased the risk of HIV- and/or AIDS-related mortality. In fact, we found that coinfected individuals from all risk groups were at increased risk of HIV- and/or AIDS-related mortality, compared to monoinfected individuals from the same risk group. This is in contrast to the meta-analysis whose authors concluded that increased overall mortality was unrelated to HIV disease progression in the cART era because the risk of AIDS-defining events was not increased5. Interestingly, although HIV- and/or AIDS-related mortality was not assessed in that review, the pooled risk ratio of 1.49 reported for a combination of AIDS and death as outcome was statistically significant and in line with our finding. Conflicting results might be due to differences in follow-up duration, inability to correct for duration of HIV infection, different statistical methods and differences in patient population (e.g. ethnic background)26,27.
Thus, although the effect of HCV on HIV disease progression is still under debate, our large study provides strong evidence of an increased risk of HIV- and/or AIDS-related mortality among coinfected individuals in the cART era. The underlying mechanisms by which HCV affects HIV disease progression are not known, however, although, it has been suggested that high levels of T-cell activation in co-infected individuals may lead to immune dysfunction28. Cirrhosis and advanced liver disease might act as possible intermediate variables. These conditions affect immune function, thereby promoting AIDS-defining conditions, which might result in classification as an AIDS-related death. In addition, although therapy uptake in the cART era is similar for co-infected and monoinfected individuals, it might be that cART effectiveness was less in co-infected individuals by increasing the risk of drug-related hepatotoxicity which might explain the poorer outcome29. Another explanation might be lower adherence. In line with previous studies, we found no significant difference in the probability of experiencing an initial viral load response after starting therapy between co-infected and monoinfected individuals26,30. Moreover, virological failure did not differ between co-infected and monoinfected individuals aged ≥25 years and differed only slightly among the youngest age group. We cannot unravel whether this is due to toxicity or adherence. The difference in virological failure is unlikely to be due to progressive liver disease as in general duration of HCV infection is longer in older individuals. More research on the effect of HCV coinfection on virologic failure is necessary31.
Co-infected individuals had a much higher risk of hepatitis or liver-related mortality compared to monoinfected individuals in the pre-cART as well as the cART eras. This has previously been reported6, although a substantial proportion (>40%) of the study population in that seroprevalent cohort with missing HCV status were excluded. Individuals with missing HCV status are often excluded from studies6,8,11 and can bias the results14. To overcome this, we imputed missing HCV status and applied additional left truncation from the start of routine HCV data collection in each cohort.
Among co-infected individuals in our study, mortality from hepatitis or liver-related causes was lower in the cART era compared to the pre-cART era. This decrease might be explained by the use of cART, and by the wide availability of HCV therapy since 2001. We were not able to estimate at a population level the effect of cART before HCV therapy became available due to the small number of hepatitis or liver-related deaths observed between 1997 and 2000. Furthermore, no data on HCV treatment were available in the current CASCADE dataset. However, coverage and effectiveness of HCV treatment is low in co-infected individuals32 especially in co-infected drug users who account for the majority of HCV infections in this population33. Several studies have shown that use of cART is associated with a lower rate of liver fibrosis and cirrhosis34,35 and that these benefits outweigh the risks of hepatotoxicity due to cART36, but these studies are limited as they did not take time since HIV infection into account.
In monoinfected patients, guidelines recommend that the decision to start treatment for HCV infection is based on the degree of liver fibrosis and HCV genotype37. An increased risk of both HIV and/or AIDS and hepatitis or liver-related mortality among co-infected individuals in the cART era might suggest that co-infected patients should start HIV and HCV treatment sooner after diagnosis to reduce the likelihood of disease progression, even in the absence of liver fibrosis28,38. Direct acting antivirals (DAA) against HCV are likely to be available in the near future; these may provide a cure to a large number of HIV/HCV co-infected patients39. Although results with the HCV protease inhibitors telaprevir and boceprevir are highly encouraging, their effects in co-infected patients are still in trial phase. This emphasises the need for careful evaluation of uptake and effectiveness of the DAA in coinfected individuals. Extended follow-up in the cART era will also provide insight into the effect of current and future HCV therapy regimens on mortality.
CD4 cell count and HIV RNA were not taken into account in our analysis as they might be intermediate variables in the causal pathway of the effect of HCV on mortality. Then the residual effect of HCV on mortality, over-and-above that driven through immunological or virological progression, would be reflected instead of the effect of HCV on mortality in the population. This would be of interest for future research. Since HCV status is measured frequently in only a small group of individuals, HCV status could not be included as a time-dependent covariable in our analyses. In addition, a substantial proportion of individuals were not tested for HCV RNA, but it is most likely that they are chronically-infected as spontaneous clearance of HCV in HIV-infected individuals is rare40
Although information on duration of HIV infection is known for all patients, information on duration of HCV infection for all is lacking. Thus co-infected individuals were assumed to be HCV positive from the time of HIV seroconversion onwards. This is likely to be true for IDUs and those with hemophilia but MSM are more likely to be infected with HIV before HCV infection as HIV is spread more efficiently sexually than HCV. As the main expansion of the HCV epidemic started after 200217, most of the MSM in our study will have been infected with HCV for a relatively short time and this may be too short a time for us to witness the sequelae of HCV infection4. The increase in the proportion of recently HCV-infected MSM in the cART era might, in addition to cART use, explain a later onset of death following HIV seroconversion from hepatitis or liver-related causes among coinfected individuals in the cART, compared to pre-cART, era. We included an interaction between age at HIV seroconversion and co-infection status in the analysis as proxy for duration of HCV infection. Although the lack of direct information on duration of HCV infection is a potential limitation of our study, studies with information on the timing of both infections and sufficient follow-up to permit analyses of mortality are non-existent.
Several potential limitations of our study should be mentioned. As classification of COD might not have been uniform within cohorts, we cannot exclude the possibility of misclassification in COD. Furthermore, as all cohorts were initiated to evaluate the consequences of HIV infection, COD might have been more likely to be classified as HIV and/or AIDS when individuals had a low CD4 cell count. On the other hand, we did not have sufficient information on hepatitis B status and alcohol use, which might have resulted in hepatitis or liver-related death41.
In order to reliably impute missing HCV status and COD, the analyses were restricted to cohorts for whom information on COD was available for at least 50% of reported deaths and HCV status was known for at least 50% of individuals. There is no reason to expect the effect of HCV on HIV disease progression to differ between cohorts that collect data on COD and/or co-infection status, and those that do not. Furthermore, the relative hazard of dying did not differ significantly between the 16 included and the five excluded cohorts (data not shown) and, given that our dataset is international, we believe that results are generalizable to high-income countries42.
In conclusion, HCV co-infected individuals appear to be at increased risk of HIV- and/or AIDS-related mortality in the cART era. Although the risk of hepatitis or liver-related mortality has decreased since cART became available, it is higher among co-infected individuals compared to those with only HIV. This underscores the importance of early diagnosis of HCV infection in HIV-infected individuals and the need for routine screening of HCV among high risk groups, including those not (yet) infected with HIV. Our findings highlight the importance of interventions to increase the uptake of HCV treatment in co-infected individuals.
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