Influence of Hepatitis C Virus Co-Infection and Hepatitis C Virus Treatment on Risk of Chronic Kidney Disease in HIV-Positive Persons

Amanda Mocroft; Lene Ryom; Cristiana Oprea; Qiuju Li; Andri Rauch; Christoph Boesecke; Vilma Uzdaviniene; Dalibor Sedlacek; Josep M. Llibre; Karine Lacombe; Lars N. Nielsen; Eric Florence; Inka Aho; Nikoloz Chkhartishvili; János Szlavik; Gordana Dragovic; Clifford Leen; Helen Sambatakou; Therese Staub; Montse Laguno; Hila Elinav; Janez Tomažič; Lars Peters

Disclosures

AIDS. 2020;34(10):1485-1495. 

In This Article

Discussion

This large study of almost 15 000 individuals with a median follow-up of approaching 7 years and with known anti-HCV and HCV-RNA status has found no reduction in CKD among those with cured HCV infection following treatment for HCV. To date, this is the largest study focused on CKD in HIV and HCV co-infected individuals comparing across HCV strata.

As previously reported by EuroSIDA and others,[1,3,23] we found the lowest rates of CKD in those who were anti-HCV-negative or those with spontaneous clearance of HCV -RNA, as well as traditional factors associated with CKD, including age, hypertension, diabetes, and the use of potentially nephrotoxic antiretrovirals, as reported by many previous studies.[24–26] Cure of HCV with treatment has a number of benefits, including a reduction on both all cause and liver-related mortality.[27] We were not able to demonstrate that HCV cure resulted in lower rates of CKD, consistent with previous studies,[12–14] which had smaller populations and less power, or which considered decline in eGFR rather than CKD. Our study defined CKD rigorously using a confirmed eGFR less than 60 ml/min per 1.73 m2 over a period of 3 months. Slopes or rate of change in eGFR is arguably less clinically relevant than the definition used here. Our study also adjusted for a number of important confounding variables. HIV-associated nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis are sometimes found at biopsy in HIV and HCV coinfected persons[28–30] and more studies on the role of HIV-infection, HCV coinfection, HCV-RNA, and cure of HCV-RNA on these diseases is warranted. The role of HCV in extrahepatic comorbidities is not fully understood but may be related to the direct effect of HCV, immune activation, or indirect effects, such as drug and alcohol use.[27]

In the pre-DAA era, there was some evidence in HCV monoinfected persons that interferon-based HCV treatment improved renal function and decreased the risk of CKD.[31–33] More recently, a study from Taiwan in monoinfected persons suggested a small decrease in renal function in persons treated with DAAs, although the changes were thought to be clinically insignificant.[34] The results from previous studies are difficult to compare to our findings. Although some were large studies, not all had information on HCV treatment outcomes, baseline eGFR, predated the introduction of DAAs or included specific subgroups, such as those with cirrhosis. In addition, the contribution of different factors in coinfected individuals, including lifestyle factors, socioeconomic status, and mechanisms other than HCV replication, may play a role in the development of CKD.[35–37]

We found the highest rates of CKD in those cured, although they were not significantly higher than those with chronic hepatitis C or those who were HCV-RNA-positive following HCV treatment. There are several possible reasons for our findings. Our study includes coinfected persons and follow-up to the middle of 2018. DAA treatment in EuroSIDA began to increase most notably around 2015;[22] prior to this, it is likely that the healthiest persons were selected for interferon treatment. Following 2015, those with F3/F4 liver fibrosis and more advanced liver disease were prioritized for DAA treatment. Those cured were also less likely to reverse their CKD and the proportion of follow-up with an eGFR greater than 90 ml/min per 1.73 m2 was lowest, possibly suggesting a higher risk for renal disease. More of those cured developing CKD had a prior diagnosis of ESLD and those developing CKD in both those treated and cured and HCV-RNA-positive following treatment were more likely to have been treated with interferon and ribavirin. Although we have adjusted for a wide range of confounders, it is possible that our findings reflect confounding by indication and further follow-up of persons treated with new generation DAAs is warranted.

Our study has a number of limitations. First and foremost, our data are from a cohort study and while we have defined five distinct HCV strata based on single values of anti-HCV tests and HCV-RNA, comparisons across these strata are limited by our ability to adjust for differences as well as the possibility of unknown or unmeasured confounding that we cannot adjust for. We were not able to adjust for duration of HCV infection, which may be an important confounder. As in a previous study,[38] we chose not to define SVR according to treatment guidelines[21] in part because of differences between the many centres in EuroSIDA in frequency of HCV-RNA monitoring following treatment. Persons HCV-RNA-positive after treatment may have only recently started treatment and with additional follow-up may be cured and move into this stratum. DAA regimens including sofosbuvir/ledipasvir and sofosbuvir/velpatasvir have been shown to increase the plasma concentration of tenofovir, especially when used with a boosted protease inhibitor,[39] but we were not able to investigate an interaction between DAAs and tenofovir because of limited power. The strength of our study is that it is one of the largest of coinfected persons reported to date, with an extensive quality assurance and data monitoring program.

Although HCV-RNA-positive persons have previously been shown to have higher rates of CKD, curing HCV with HCV treatment was not associated with a lower rate of CKD in this study. Further long-term follow-up is required to investigate the role of DAAs as their use becomes widespread to determine if the higher rates seen in this study were because of underlying high risk of CKD and new DAAs being targeted at the sickest individuals.

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