Injection Drug Use and HCV and Risk for Mortality in HIV
Injection Drug Use and HCV and Risk for Mortality in HIV
Based on a large data set combined from 16 HIV cohort studies that recruited patients in Europe and North America, we examined the extent to which presumed HIV transmission through IDU and HCV infection independently predicted all-cause and cause-specific mortality. The association of transmission through IDU with all-cause mortality was attenuated after adjustment for HCV coinfection, but mortality remained more than 50% higher in IDU than in non-IDU. Effects of both IDU and HCV were greater in patients younger than 45 years (considered more likely to be active IDU) than in older individuals, but patterns of attenuation were similar. Sensitivity analyses confirmed that error in measuring both IDU and HCV status affects the extent of attenuation if there is greater measurement error in one than the other risk factor. Analyses of cause-specific mortality confirmed that HCV is a stronger predictor than IDU for liver-related mortality but identified particular causes of death for which associations with IDU are not explained by HCV.
We analyzed a large data set with more than 30,000 patients and more than 1000 deaths, of whom 85% had causes classified using standardized procedures. Our analysis may suffer from ascertainment bias as individuals with HCV serostatus available were more likely to have an injecting drug use history, which may have prompted testing for HCV compared with those excluded from the study. We did not know if IDU were chronic or past injection drug users as IDU status was based on self-reported likely transmission route of infection. It is likely that some patients reporting no history of IDU were either past or current IDU, and this possibility is consistent with our finding of a substantial prevalence of HCV among those recorded as non-IDU: this underscores the importance of testing and treating HCV among all individuals who are HIV-infected, particularly as incidence of HCV infection, has been reported to be increasing in MSM in some regions. Further work is needed to investigate modes of HCV acquisition among HIV-positive individuals to prevent reinfection after HCV treatment. We did not have information on HBV coinfection, which might differ between IDU and HCV+ and affect prognosis. Our information on HCV infection was limited as we did not have data on active Hepatitis C viremia. Previous research has shown that the presence of viremia increases mortality particularly that due to liver-related deaths. We did not have details of treatments for HCV infection. However, during the calendar period included in our analyses, HCV treatment rates among those with HIV infection were low. We did not analyze longitudinal HCV-RNA tests to see if patients had spontaneously cleared the virus or were successfully treated. However, the proportion that spontaneously clears HCV infection is substantially lower among HIV-infected than HIV-uninfected individuals. Furthermore, HIV-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of viremia. The results of the sensitivity analysis that attempted to quantify the possible effects of misclassification bias showed that our conclusions about the relative importance of HCV compared with IDU for predicting mortality were robust if both IDU and HCV were equally misclassified, although HR for both risk factors may have been underestimated. However, if only IDU were misclassified, then IDU and HCV might have similar mutually adjusted-mortality HR, which would imply that both factors are equally important predictors of mortality. Our results were also robust to the exclusion of the small proportion of patients with "other/unknown" transmission group, some of whom may have been IDU misclassified as non-IDU in the main analysis.
In our study, HIV-infected individuals with HCV coinfection experienced 2.5-fold greater mortality rates than those without HCV coinfection. Most of this excess mortality was not explained by other risks associated with IDU. Other studies have found that HCV causes substantial morbidity from liver and renal injury as well as increases the risk of coronary disease and diabetes. Our study confirmed higher rates of mortality in HCV+ for liver-related deaths and also for AIDS and non-AIDS, non–liver-related causes of deaths. Although HCV status is likely associated with lifestyle factors, such as tobacco use, which are associated with higher mortality rates, HCV infection may directly contribute to non–liver-related deaths by impaired immune responses to treatment for HIV infection. HRs for IDU were greater in younger patients suggesting that active IDU, which is more likely at younger ages, has additional harms compared with historic use. An alternative explanation is that differences in HR by age may be partly because of diversification of causes of death in IDU at older ages with increased risk of deaths due to cardiovascular disease and cancer. However, among older patients, for whom active IDU is less likely, HCV coinfection remained strongly associated with mortality. There may nonetheless be lifestyle factors that differ between those with and without HCV infection and are not captured by IDU status, for example, risky sexual behavior, commercial sex work, or intranasal drug use, which may contribute to the higher mortality in those with HCV infection.
Although there is a growing consensus on the importance of treating HCV coinfection among those living with HIV, many barriers remain. These include higher rates of contraindications and concerns regarding decreased antiretroviral adherence and drug–drug interactions from polypharmacy. Our analyses underscore the importance of overcoming these barriers if we are to achieve better survival among those aging with HIV, many of whom no longer use injection drugs but are continuing to suffer consequences of past use. New oral direct acting antiviral protease inhibitor–based therapies have been shown to result in cure rates exceeding 65% and have shortened the period during which the poorly tolerated drug interferon has to be used. Furthermore, interferon-free direct acting antiviral HCV treatment for HIV-infected individuals with markedly reduced toxicity, high efficacy (>90% cure), improved dosing schedules (once or twice-daily), and shortened treatment duration (6–24 weeks) are quickly becoming more widely available. This revolution in treatment of HCV could enable increased treatment uptake, not just among IDU, but also in the emerging MSM epidemic, which could have a major preventative impact. However, treatment costs may limit scale-up as new drugs are expensive.
Discussion
Main Results
Based on a large data set combined from 16 HIV cohort studies that recruited patients in Europe and North America, we examined the extent to which presumed HIV transmission through IDU and HCV infection independently predicted all-cause and cause-specific mortality. The association of transmission through IDU with all-cause mortality was attenuated after adjustment for HCV coinfection, but mortality remained more than 50% higher in IDU than in non-IDU. Effects of both IDU and HCV were greater in patients younger than 45 years (considered more likely to be active IDU) than in older individuals, but patterns of attenuation were similar. Sensitivity analyses confirmed that error in measuring both IDU and HCV status affects the extent of attenuation if there is greater measurement error in one than the other risk factor. Analyses of cause-specific mortality confirmed that HCV is a stronger predictor than IDU for liver-related mortality but identified particular causes of death for which associations with IDU are not explained by HCV.
Strengths and Limitations
We analyzed a large data set with more than 30,000 patients and more than 1000 deaths, of whom 85% had causes classified using standardized procedures. Our analysis may suffer from ascertainment bias as individuals with HCV serostatus available were more likely to have an injecting drug use history, which may have prompted testing for HCV compared with those excluded from the study. We did not know if IDU were chronic or past injection drug users as IDU status was based on self-reported likely transmission route of infection. It is likely that some patients reporting no history of IDU were either past or current IDU, and this possibility is consistent with our finding of a substantial prevalence of HCV among those recorded as non-IDU: this underscores the importance of testing and treating HCV among all individuals who are HIV-infected, particularly as incidence of HCV infection, has been reported to be increasing in MSM in some regions. Further work is needed to investigate modes of HCV acquisition among HIV-positive individuals to prevent reinfection after HCV treatment. We did not have information on HBV coinfection, which might differ between IDU and HCV+ and affect prognosis. Our information on HCV infection was limited as we did not have data on active Hepatitis C viremia. Previous research has shown that the presence of viremia increases mortality particularly that due to liver-related deaths. We did not have details of treatments for HCV infection. However, during the calendar period included in our analyses, HCV treatment rates among those with HIV infection were low. We did not analyze longitudinal HCV-RNA tests to see if patients had spontaneously cleared the virus or were successfully treated. However, the proportion that spontaneously clears HCV infection is substantially lower among HIV-infected than HIV-uninfected individuals. Furthermore, HIV-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of viremia. The results of the sensitivity analysis that attempted to quantify the possible effects of misclassification bias showed that our conclusions about the relative importance of HCV compared with IDU for predicting mortality were robust if both IDU and HCV were equally misclassified, although HR for both risk factors may have been underestimated. However, if only IDU were misclassified, then IDU and HCV might have similar mutually adjusted-mortality HR, which would imply that both factors are equally important predictors of mortality. Our results were also robust to the exclusion of the small proportion of patients with "other/unknown" transmission group, some of whom may have been IDU misclassified as non-IDU in the main analysis.
Results in Context With Other Studies
In our study, HIV-infected individuals with HCV coinfection experienced 2.5-fold greater mortality rates than those without HCV coinfection. Most of this excess mortality was not explained by other risks associated with IDU. Other studies have found that HCV causes substantial morbidity from liver and renal injury as well as increases the risk of coronary disease and diabetes. Our study confirmed higher rates of mortality in HCV+ for liver-related deaths and also for AIDS and non-AIDS, non–liver-related causes of deaths. Although HCV status is likely associated with lifestyle factors, such as tobacco use, which are associated with higher mortality rates, HCV infection may directly contribute to non–liver-related deaths by impaired immune responses to treatment for HIV infection. HRs for IDU were greater in younger patients suggesting that active IDU, which is more likely at younger ages, has additional harms compared with historic use. An alternative explanation is that differences in HR by age may be partly because of diversification of causes of death in IDU at older ages with increased risk of deaths due to cardiovascular disease and cancer. However, among older patients, for whom active IDU is less likely, HCV coinfection remained strongly associated with mortality. There may nonetheless be lifestyle factors that differ between those with and without HCV infection and are not captured by IDU status, for example, risky sexual behavior, commercial sex work, or intranasal drug use, which may contribute to the higher mortality in those with HCV infection.
Implications
Although there is a growing consensus on the importance of treating HCV coinfection among those living with HIV, many barriers remain. These include higher rates of contraindications and concerns regarding decreased antiretroviral adherence and drug–drug interactions from polypharmacy. Our analyses underscore the importance of overcoming these barriers if we are to achieve better survival among those aging with HIV, many of whom no longer use injection drugs but are continuing to suffer consequences of past use. New oral direct acting antiviral protease inhibitor–based therapies have been shown to result in cure rates exceeding 65% and have shortened the period during which the poorly tolerated drug interferon has to be used. Furthermore, interferon-free direct acting antiviral HCV treatment for HIV-infected individuals with markedly reduced toxicity, high efficacy (>90% cure), improved dosing schedules (once or twice-daily), and shortened treatment duration (6–24 weeks) are quickly becoming more widely available. This revolution in treatment of HCV could enable increased treatment uptake, not just among IDU, but also in the emerging MSM epidemic, which could have a major preventative impact. However, treatment costs may limit scale-up as new drugs are expensive.
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