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Effect of HCV Infection on Cause-Specific Mortality After HIV Seroconversion, Before and After 1997- in CART Era HIV/AIDS mortality & hepatitis/Liver disease deaths higher among coinfected/routine screening & accelerated treatment needed
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"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......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 fibrosis"
Gastroenterology
Article in Press
CASCADE Collaboration in EuroCoord
Received 13 January 2012; accepted 18 December 2012. published online 26 December 2012.
Prevalent and Incident Hepatitis C Virus Infection among HIV-Infected Men Who Have Sex with Men Engaged in Primary Care in a Boston Community Health Center....'Worrisome Trend' - (02/07/13)....."HIV+ MSM should receive annual HCV screening to diagnose and treat infection at earlier stages; higher-risk patients should be screened more often".....from Jules: actually everyone with at risk behavior (which includes sex with anyone with a history of IDU) HIV should receive annual HCV screening
"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 with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease."
"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."
"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 fibrosis.28, 38 Direct-acting antivirals 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 patients.39 Although results with the HCV protease inhibitors telaprevir and boceprevir are highly encouraging, their effects in co-infected patients are still in the trial phase. This emphasizes the need for careful evaluation of uptake and effectiveness of the direct-acting antivirals in co-infected individuals. Extended follow-up in the cART era also will provide insight into the effect of current and future HCV therapy regimens on mortality."
"In the cART era this association was reversed, with co-infected individuals from all 4 risk groups having a higher risk of progression to HIV and/or AIDS-related death than monoinfected individuals: IDU (aHR, 2.43; 95% CI, 1.14-5.20), MSW or those with hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and MSM (aHR, 3.11; 95% CI, 1.49-6.48), compared with monoinfected individuals of the same risk group
"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 co-infected individuals from all risk groups were at increased risk of HIV- and/or AIDS-related mortality, compared with monoinfected individuals from the same risk group. This is in contrast to the meta-analysis whose investigators concluded that increased overall mortality was unrelated to HIV disease progression in the cART era because the risk of AIDS-defining events was not increased"
" in the cART era, co-infected individuals had significantly higher mortality than monoinfected individuals, 35% (95% CI, 31%-39%) vs 11% (95% CI, 9%-14%), respectively, by 15 years after HIV seroconversion. After adjustment for sex, risk group, and age, all-cause mortality did not significantly differ between co-infected and monoinfected individuals in the pre-cART era (aHR, 0.75; 95% CI, 0.41-1.37), but remained higher in co-infected individuals in the cART era (aHR, 1.84; 95% CI, 1.16-2.93)"
"the probability of dying of hepatitis or liver-related causes within 15 years from HIV seroconversion was 4.1% (95% CI, 1.7-6.6) in co-infected individuals but only 0.4% (95% CI, 0-1.2) in monoinfected individuals."
"In the pre-cART era, co-infected individuals had a much higher risk of hepatitis or liver-related mortality than monoinfected individuals (aHR, 21.8; 95% CI, 6.26-75.9 for IDU and aHR, 27.9; 95% CI, 8.39-92.6 for all other risk groups combined). The same association was seen in the cART era, although hazard ratios were slightly less increased (aHR, 7.86; 95% CI, 2.56-24.1 for IDU and aHR; 10.0; 95% CI, 95% CI, 3.14-32.2 for all other groups)."
Study Population
CASCADE is a collaboration within EuroCoord (www.EuroCoord.net), currently of 28 HIV seroconverter cohort studies in Europe, Australia, Canada, and sub-Saharan Africa. Details of CASCADE are described elsewhere.15 In brief, all cohorts included HIV-1-infected individuals for whom a date of HIV seroconversion could be estimated reliably. The end date used for this analysis was June 2007, when 21 seroconverter cohorts were included in the collaboration: 1 Canadian, 2 Australian, and 19 European cohorts.
Analyses were restricted to 16 cohorts from Europe and Canada for which the cause of death was available for at least 50% of reported deaths, and HCV status was known for at least 50% of study participants. Survival of individuals from the included and excluded cohorts was compared and did not differ significantly. Individuals younger than 15 years of age at HIV seroconversion and those with a time period of more than 3 years between the last HIV-seronegative and first HIV-seropositive test were excluded. For each cohort we collected information on the start date of routine HCV data collection/testing. HCV positivity was defined as any positive HCV test (anti-HCV antibody, HCV RNA, or test for HCV infection not recorded) during follow-up. HCV-positive individuals were assumed to be HCV positive from HIV seroconversion onward. Classification of cause of death (COD) was based on the 1993 clinical definition of AIDS from the Centers for Disease Control and the International Classification of Diseases 10th revision. Furthermore, the Coding of Death in HIV classification system was used to standardize causes of death reported by cohorts.16 COD were grouped into 4 categories: HIV and/or AIDS-related, hepatitis- or liver-related, other natural causes, and non-natural death. When more than one cause of death was given, the most likely underlying cause of death was scored independently by members of the CASCADE Clinical Advisory Board.
Abstract
Background & Aims
Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the 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, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution 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%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by 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 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 with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease.
Conclusions
Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy 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.
Introduction
Because of shared transmission routes, human immunodeficiency virus (HIV)-infected persons are at risk of other blood-borne and sexually transmitted infections. Hepatitis C virus (HCV) infection, which predominantly is transmitted parenterally, is common in this group. Because HIV-infected persons live longer in the era of combination antiretroviral therapy (cART), they are increasingly more likely to die from non-HIV-related causes,1 with the sequelae of hepatitis infections being a leading cause of non-HIV deaths.2 HIV infection adversely affects both the natural history and therapy outcome of HCV3 and even in the cART era HIV continues to accelerate HCV disease progression.4 However, there is conflicting evidence as to whether HCV co-infection accelerates HIV disease progression. A recent meta-analysis including 10 studies from the pre-cART era and 27 studies from the cART era5 reported that HIV-HCV co-infected individuals were not at higher risk of all-cause mortality compared with those with HIV monoinfection in the pre-cART era, but were at a higher risk of all-cause mortality in the cART-era. However, no effect of co-infection on the risk of acquired immune deficiency syndrome (AIDS)-defining events in the cART era was observed. Liver-related mortality was not studied in the meta-analysis but another study reported an increased risk of liver-related mortality in HIV-HCV co-infected individuals compared with HIV-monoinfected individuals in the cART era.6 The effect of HCV on specific causes of mortality, other than HIV and/or AIDS and liver-related causes, in HIV co-infected individuals is very limited.7
Only a few studies, all from individual countries, have explored changes in the impact of HCV co-infection on HIV disease progression in the cART era compared with the pre-cART era8, 9, 10, 11, 12, 13 and reported conflicting results. These studies, however, were limited by their design because they did not consider competing causes of death and accurate estimates of the duration of HCV and HIV infection were not available, except for one study that estimated HIV infection duration.8 Moreover, individuals with missing HCV status often were excluded from analysis, which can introduce serious bias.14 Better estimates of the effect of HCV co-infection on cause-specific mortality, including HIV and/or AIDS-related mortality, are needed to improve our understanding of prognosis and to guide the care of co-infected patients. The Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration, which includes a large group of HIV seroconverters, provides a unique opportunity to study the impact of HCV co-infection on both HIV and/or AIDS and hepatitis or liver-related mortality, adjusting for the duration of HIV infection. We studied the impact of HCV co-infection in HIV-infected persons on deaths from different causes and evaluated whether any effect changed after the introduction of cART.
Discussion
Our study had a number of clinically relevant findings. First, we found that although all-cause mortality did not differ significantly between co-infected and monoinfected individuals in the pre-cART era, it became significantly higher for co-infected individuals in the cART era. This is in concordance with a recent meta-analysis that reported an increased risk of all-cause mortality for co-infected compared with monoinfected individuals in the cART era.5 Second, among co-infected individuals, we found that their risk of hepatitis or liver-related mortality decreased in the cART era compared with 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 with monoinfected individuals. Third, 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 co-infected individuals from all risk groups were at increased risk of HIV- and/or AIDS-related mortality, compared with monoinfected individuals from the same risk group. This is in contrast to the meta-analysis whose investigators concluded that increased overall mortality was unrelated to HIV disease progression in the cART era because the risk of AIDS-defining events was not increased.5 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 owing to differences in follow-up duration, inability to correct for duration of HIV infection, different statistical methods, and differences in patient population (eg, 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 co-infected 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 dysfunction.28 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 outcome.29 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 individuals.26, 30 Moreover, virologic failure did not differ between co-infected and monoinfected individuals aged 25 years and older and differed only slightly among the youngest age group. We cannot unravel whether this is the result of toxicity or adherence. The difference in virologic failure is unlikely to be caused by progressive liver disease because in general the duration of HCV infection is longer in older individuals. More research on the effect of HCV co-infection on virologic failure is necessary.31
Co-infected individuals had a much higher risk of hepatitis or liver-related mortality compared with monoinfected individuals in the pre-cART as well as the cART eras. This has been reported previously,6 although a substantial proportion (>40%) of the study population in that seroprevalent cohort with a missing HCV status were excluded. Individuals with a missing HCV status often are excluded from studies6, 8, 11 and can bias the results.14 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 with 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 owing 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 individuals,32 especially in co-infected drug users who account for the majority of HCV infections in this population.33 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 caused by cART,36 but these studies are limited because 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 genotype.37 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 fibrosis.28, 38 Direct-acting antivirals 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 patients.39 Although results with the HCV protease inhibitors telaprevir and boceprevir are highly encouraging, their effects in co-infected patients are still in the trial phase. This emphasizes the need for careful evaluation of uptake and effectiveness of the direct-acting antivirals in co-infected individuals. Extended follow-up in the cART era also will 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 because 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 immunologic or virologic progression, would be reflected instead of the effect of HCV on mortality in the population. This would be of interest for future research. Because 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 because spontaneous clearance of HCV in HIV-infected individuals is rare.40
Although information on the duration of HIV infection is known for all patients, information on the duration of HCV infection for all is lacking. Thus, co-infected individuals were assumed to be HCV positive from the time of HIV seroconversion onward. 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 because HIV is spread more efficiently sexually than HCV. Because the main expansion of the HCV epidemic started after 2002,17 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 infection.4 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 after HIV seroconversion from hepatitis or liver-related causes among co-infected individuals in the cART era compared with the pre-cART era. We included an interaction between age at HIV seroconversion and co-infection status in the analysis as proxy for the duration of HCV infection. Although the lack of direct information on the 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 nonexistent.
Several potential limitations of our study should be mentioned. Because classification of COD might not have been uniform within cohorts, we cannot exclude the possibility of misclassification in COD. Furthermore, because 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 death.41
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 5 excluded cohorts (data not shown) and, given that our dataset was international, we believe that the results are generalizable to high-income countries.42
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 with 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.
Results
Description of the Study Population
Of the 9164 HIV seroconverters included in the analyses, 1279 contributed to both calendar periods. HCV status was available for 7892 (86.1%) and imputed for 1272 (13.9%). After imputation, 2015 (22%) were HCV co-infected. Total person-years of follow-up was 7158 in the pre-cART era and 22,230 in the cART era (Table 1). Men having sex with men (MSM) was the main risk for HIV transmission (57%), followed by sex between men and women (MSW) (25%), injection drug use (IDU) (16%), and hemophilia (2%). Compared with the pre-cART era, the proportion of IDU and hemophilic patients in follow-up was lower whereas that of MSW and MSM patients was higher in the cART era. HCV infection was much more frequent among those infected through IDU (90%) and hemophilia (99%) compared with MSM (7%) and MSW (9%). Consequently, 936 (53%) were HCV co-infected in the pre-cART era and 1767 (20%) were HCV co-infected in the cART era. In both periods, co-infected individuals were younger at HIV seroconversion than monoinfected individuals. In the cART era, co-infected individuals were infected with HIV in an earlier calendar year than monoinfected individuals. After adjustment for sex, risk group, age at HIV seroconversion, and the interaction between age at HIV seroconversion and HCV status, neither uptake of therapy (aHR, 1.10; 95% CI, 0.93-1.31 for those aged 25-29 years) nor achieving an HIV-RNA response of 500 copies/mL or less after therapy initiation differed significantly between monoinfected and co-infected individuals from all age groups in the cART era (aHR, 0.97; 95% CI, 0.82-1.15 for those <25 y; 0.92; 95% CI, 0.80-1.06 for those aged 25-29 y; 0.97; 95% CI, 0.80-1.17 for those aged 30-34 y; and 1.00; 95% CI, 0.82-1.21 for those aged ≥35 y). Virologic failure after initial suppression was comparable for monoinfected and co-infected individuals in all age groups of 25 years and older (aHR, 1.05; 95% CI, 0.85-1.30 for those aged 25-29 y; 1.02; 95% CI, 0.80-1.31 for those aged 30-34 y; and 0.98; 95% CI, 0.75-1.26 for those aged ≥35 y). However, co-infected individuals aged younger than 25 years had a slightly higher risk of virologic failure (aHR, 1.23; 95% CI, 1.02-1.48). In total, 718 individuals died. A specific cause of death was available for 576 (80%) individuals and 142 (20%) causes of death were imputed. After imputation, 395 deaths were caused by HIV and/or AIDS and 39 were caused by hepatitis or liver-related causes.
All-Cause Mortality
All-cause mortality unadjusted for possible confounders is shown in Figure 1. In the pre-cART era, all-cause mortality was higher, although not significantly, among monoinfected than co-infected individuals, with 78% (95% CI, 59%-88%) of the monoinfected group estimated to die within 15 years after HIV seroconversion compared with 58% (95% CI, 50%-64%) of the co-infected group. In contrast, in the cART era, co-infected individuals had significantly higher mortality than monoinfected individuals, 35% (95% CI, 31%-39%) vs 11% (95% CI, 9%-14%), respectively, by 15 years after HIV seroconversion. After adjustment for sex, risk group, and age, all-cause mortality did not significantly differ between co-infected and monoinfected individuals in the pre-cART era (aHR, 0.75; 95% CI, 0.41-1.37), but remained higher in co-infected individuals in the cART era (aHR, 1.84; 95% CI, 1.16-2.93). In each calendar period there was a significant difference in all-cause mortality by risk group (P < .001). Compared with MSM, all-cause mortality in the pre-cART era was 62% higher for IDU (aHR, 1.62; 95% CI, 0.97-2.71), almost equal in those with hemophilia (aHR, 0.98; 95% CI, 0.55-1.74) and 54% lower (aHR, 0.46; 95% CI, 0.24-1.88) for MSW. In the cART era, all-cause mortality was higher among all risk groups compared with MSM (aHR, 3.52; 95% CI, 2.35-5.26 for IDU; 4.77; 95% CI, 2.65-8.58 for those with hemophilia; and 1.51; 95% CI, 1.03-2.20 for MSW). Overall, there was a significant age effect, but the interaction between age and HCV status was not significant (P = .55).
Cause-Specific Cumulative Incidences
Cumulative incidences for each specific COD in the pre-cART era are shown in Figure 2 (upper panel). In this era, deaths from HIV and/or AIDS had the highest cumulative incidence in both co-infected and monoinfected individuals. The cumulative probability of dying from HIV and/or AIDS within 15 years from HIV seroconversion was lower in co-infected individuals than in monoinfected individuals. In contrast, the probability of dying of hepatitis or liver-related causes within 15 years from HIV seroconversion was 4.1% (95% CI, 1.7-6.6) in co-infected individuals but only 0.4% (95% CI, 0-1.2) in monoinfected individuals.
In the cART era (Figure 2, lower panel), HIV and/or AIDS-related mortality decreased drastically, compared with the pre-cART era for both monoinfected and co-infected individuals, although it was less pronounced for the latter with a cumulative incidence at 15 years of 3.7% (95% CI, 2.2-5.1) and 14.5% (95% CI, 11.1-17.7) for monoinfected and co-infected individuals, respectively. HIV and/or AIDS and non-natural causes were the most likely COD in co-infected individuals whereas HIV and/or AIDS and natural causes were the most likely COD in monoinfected individuals. The probability of dying from hepatitis or liver-related causes in monoinfected individuals in the cART era remained extremely low and was comparable with that in the pre-cART era (0.4% within 15 years; 95% CI, 0-0.9). Deaths from hepatitis or liver-related causes among co-infected individuals remained more frequent in the cART era (2.4% within 15 years; 95% CI, 0.8-4.0) but still decreased and had a somewhat later onset after HIV seroconversion.
Comparison of the Risk of Cause-Specific Mortality by HCV Status
Subdistribution hazards ratios for the relationship between death from each specific cause and HCV status are shown in Table 2. In the pre-cART era progression to HIV and/or AIDS-related death was comparable for co-infected and monoinfected individuals from the same risk group, except for IDU, whose risk was reduced if they were co-infected (aHR, 0.55; 95% CI, 0.33-0.90). In the cART era this association was reversed, with co-infected individuals from all 4 risk groups having a higher risk of progression to HIV and/or AIDS-related death than monoinfected individuals: IDU (aHR, 2.43; 95% CI, 1.14-5.20), MSW or those with hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and MSM (aHR, 3.11; 95% CI, 1.49-6.48), compared with monoinfected individuals of the same risk group. In the pre-cART era, co-infected individuals had a much higher risk of hepatitis or liver-related mortality than monoinfected individuals (aHR, 21.8; 95% CI, 6.26-75.9 for IDU and aHR, 27.9; 95% CI, 8.39-92.6 for all other risk groups combined). The same association was seen in the cART era, although hazard ratios were slightly less increased (aHR, 7.86; 95% CI, 2.56-24.1 for IDU and aHR; 10.0; 95% CI, 95% CI, 3.14-32.2 for all other groups). In the pre-cART era the risk of dying from natural causes was lower for co-infected individuals from all risk groups (aHR, 0.36; 95% CI, 0.16-0.82 for MSW or those with hemophilia; aHR, 0.33; 95% CI, 0.13-0.84 for MSM and aHR; 0.26; 95% CI, 0.10-0.63 for IDU), whereas in the cART era hazard rates for this COD were comparable for co-infected and monoinfected individuals from the same risk group. The risk of dying from non-natural causes did not differ significantly for co-infected and monoinfected individuals from all risk groups in both the pre-cART and post-cART eras, with the exception of a higher risk of mortality in the cART era among co-infected MSW individuals or those with hemophilia (aHR, 2.91; 95% CI, 1.02-8.29).
Changes in the Risk of Cause-Specific Death in the cART Era Within Groups With the Same HCV Status
Subdistribution hazards for the relationship between death from each specific cause and calendar period are shown in Table 3. Among co-infected MSM or MSW or men with hemophilia, the risk of death from both HIV and/or AIDS (aHR, 0.19; 95% CI, 0.10-0.35) and hepatitis or liver-related causes (aHR, 0.36; 95% CI, 0.16-0.81) was significantly lower in the cART compared with the pre-cART era within the same risk group. A similar pattern was seen for co-infected IDUs (aHR, 0.34; 95% CI, 0.22-0.52 and aHR; 0.36; 95% CI, 0.16-0.81, respectively). For the co-infected groups, the risk of natural and non-natural causes of death did not differ significantly between the pre-cART and cART eras. Among monoinfected MSM, MSW, or men with hemophilia the risk of death from both HIV and/or AIDS (aHR, 0.043; 95% CI, 0.03-0.07) and natural causes (aHR, 0.34; 95% CI, 0.20-0.58) was lower in the cART era compared with the pre-cART era, with similar patterns among the monoinfected IDUs (aHR, 0.077; 95% CI, 0.031-0.19; and aHR, 0.20; 95% CI, 0.07-0.57, respectively). Because of the small numbers of hepatitis or liver-related deaths among monoinfected individuals the effect of risk group could not be estimated.
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