This retrospective cohort study provides insight into the clinical impact of the clearance of HCV via DAA therapy in PLWH receiving ART. The main findings were as follows: 1) several differences between HIV monoinfected and HIV/HCV coinfected patients exist at baseline, which help to characterize and understand the population coinfected with HIV/HCV; 2) after hepatitis C treatment with DAAs achieving SVR12, although patients might recover from their liver disturbances and exhibit improved CD4 counts, inflammation, immune activation and some liver fibrosis persist in the short-medium term; and 3) clinical, biochemical and immunological differences at baseline and after SVR12 are associated with a greater risk of liver disease onset and death in HIV/HCV-coinfected patients, but previous exposure to HCV in PLWH is not associated with the development of any clinical event studied.
The present study aimed to analyze the influence of HCV on the natural history of HIV and the effect of HCV eradication. Thus, a cohort of PLWH suffering from hepatitis C who cleared HCV with DAAs achieving SVR12 was followed, and the development of non-AIDS events and mortality were monitored. These coinfected patients were compared to a cohort of HIV monoinfected patients, matched by age, gender and follow-up time.
According to the HIV baseline characteristics of the patients, the mean CD4 + T-cell count and CD4+/CD8 + ratio at ART initiation were less than 500 cells/µL and 0.4, respectively. Similar results were found in both groups, except for a significantly higher proportion of coinfected patients exhibiting CD4 + T-cell counts less than 200 cells/µL, which could explain the increase in AIDS-related events recorded in this group. After starting ART, both groups achieved successful immune recovery, as measured by CD4 + T-cell count greater than 500 cells/µL, highlighting the effectiveness of the treatment even when poorer adherence to ART is expected in coinfected patients.
Additionally, statistically and clinically significant differences at baseline were found in lifestyle habits, which are well-known risk factors for hepatitis C exposure and transmission. A higher proportion of smokers, and alcohol and parenteral drug users were observed in the HIV/HCV group, where there was also a higher proportion of heterosexual patients exposed to HIV via the parenteral route of transmission due to drug consumption. This cohort also exhibited a high rate of sexual transmission of hepatitis C, indicative of the epidemiological shift in the prevalence of HCV in industrialized countries13, suggesting that sexual transmission is currently one of the primary active sources of new hepatitis C infections currently14–18. In this HIV/HCV cohort, at least three-quarters of the individuals acquired HCV through sexual transmission, all of whom were MSM. Notably, there was a significantly greater consumption of psychoactive drugs for sexual purposes, with mephedrone being the most used substance. Approximately one-quarter of the patients were administered this drug parenterally (“SlamSex”). As might be expected, according to these data, more STIs were documented in coinfected patients than in monoinfected patients. Moreover, 13.1% of coinfected patients reported HCV reinfection after successful eradication of a primary infection with DAAs, a rate consistent with that of other published cohorts4.
To assess the effect of exposure to HCV on the development of non-AIDS-related events and HIV prognosis, risk factor information, such as baseline characteristics in those previously diagnosed with HCV infection, was collected, regardless of whether the diagnosis was made prior to or after HIV infection and before HIV diagnosis in the monoinfected group. Despite the low prevalence of comorbidities at baseline in both groups, disparities were found in favor of the coinfected group for hypertension, DM, renal disease, liver disease, and non-AIDS cancer. The lifestyle and/or chronic HIV infection of these individuals could explain why certain risk factors were more frequent in HIV/HCV patients.
These findings allowed the characterization of the study population (HIV/HCV coinfected) and the identification of groups at higher risk for HCV infection, which will facilitate early suspicion and diagnosis.
Before DAA therapy, higher levels of liver enzymes (AST, ALT and GGT), platelet count and increased levels of hepatic fibrosis markers (assessed by the APRI and FIB-4 scores) were found in HIV/HCV-coinfected patients compared with the PLWH cohort of patients who never had hepatitis C, which suggesting more severe liver damage in the HIV/HCV group. In the coinfected individuals, LS data measured with FibroScan and pre-DAA treatment were available. A third of these patients presented measurements greater than 7.1 Kpa, and the mean LS exceeded normal values. The increased stiffness data may reflect either fibrosis or necro-inflammatory activity in the liver, both of which are indicative of liver injury. However, according to clinical practice, LS data remeasured by transient elastography was not available after SVR12 with DAAs in most coinfected patients, nor is this a common practice for HIV monoinfected patients. Thus, other markers such as the APRI or FIB-4 scores were considered in this study to compare the two groups38.
After DAA therapy, the whole cohort of coinfected patients reached SVR12. Most of these patients normalized transaminase levels and reduced LS, as calculated by the APRI and FIB-4 indices. In line with previous research findings, these results suggest that DAA therapy may allow the recovery of liver injury following HCV clearance40. Nonetheless, despite most patients experiencing a reduction in LS within the normal range, the LS measurements remained significantly greater in the coinfected group (according to both the APRI and FIB-4), which is indicative of more severe hepatic involvement, at least at SVR12 post-DAA therapy. In previous research conducted by our group, systemic inflammation and endothelial activation were compared between subgroups of patients coinfected with HIV/HCV and those infected with HIV alone, which were all included in the cohort presented in this work. Independent associations between IP-10 (a systemic inflammation marker) and GGT levels, and between VCAM-1 (an endothelial activation biomarker) and AST levels were found, revealing the link between hepatic necro-inflammatory activity and endothelial activation in systemic inflammation during HIV/HCV coinfection41. In addition to its association with liver damage, the association of VCAM-1 with CVD in HIV infected populations is well established42. In this analysis, the levels of VCAM-1 and IP-10 remained elevated post-DAA treatment despite the clearance of HCV and normalization of transaminases, especially in patients with higher LS. This suggests the persistence of a proinflammatory and procoagulant state, at least in the short term, which could result in a potentially greater incidence of CVD and other comorbidities among HIV/HCV coinfected patients than among HIV monoinfected individuals41.
An interesting finding in the present study was the remarkable increase in CD4 + T-cell counts following HCV eradication to levels comparable to those in HIV monoinfected patients. This finding supports the negative impact of HCV on immune restoration in patients on ART43. However, after patients achieved SVR12, the CD8 + T-cell count remained significantly higher and the CD4+/CD8 + T-cell ratio was lower in coinfected patients. This persistent increase in CD8 + T-cell counts may not only indicate that immune activation is not influenced by IFN-based regimens, but also suggest that CD8 + T cells may become dysfunctional. Previous research has reported the significant negative impact of HCV infection on CD8 + T-cell exhaustion in coinfected PLWH44. Our group carried out another study comparing several immunological parameters of HIV among subgroups of HIV/HCV coinfected and HIV infected patients, all of which were included the cohort presented in this work. After HCV eradication, both the activation and exhaustion of CD8 + T cells remained significantly greater in coinfected patients. These results supported the fact that HCV clearance via treatment with DAAs does not fully reverse T-cell homeostasis alterations, at least in the short term30. In addition, T- lymphocyte exhaustion could influence viral escape from the immune response to both infections45. Therefore, both the activation and exhaustion of CD8 + T cells are significant factors in the pathogenesis of HIV, and contribute to the progression of this infection, which could have substantial clinical implications for coinfected patients44. Finally, it was reported that a persistent CD8 + T-cell count and, consequently, a low CD4+/CD8 + T-cell ratio in HIV-infected patients, even with CD4 + T-cell count greater than 500 cells/µL, are predictors of non-AIDS events and a greater risk of mortality46, which was also observed in this cohort.
The presence of more AIDS-related events at HIV diagnosis, additional risk factors, harmful lifestyle habits, a higher prevalence of coinfections such as STDs, and underlying signs of systemic inflammation, immune activation, and disruption of cellular homeostasis could predispose the coinfected group to exhibit a more advanced clinical presentation of HIV. This could be characterized by a more frequent or earlier onset of non-AIDS-related events or even increased mortality in this group compared to the HIV monoinfected group.
Univariate logistic regression revealed that the risk of hypertension, dyslipidemia and kidney disease onset during the follow-up period was greater in HIV monoinfected patients. The latter is a surprising association, as HCV infection can cause renal involvement. However, this study did not include the influence of several variables, such as historically used antiretroviral drugs or other chronic treatments, or the consumption of anabolic steroids or gym supplements with creatine, all of which are often observed in clinical practice, given the scope of the study. Therefore, these results should be interpreted with caution, as other factors might influence the results. Instead, in patients coinfected with HIV/HCV, a higher risk of liver disease was found, which could be explained by direct viral effects, and the abuse of alcohol and illegal substances47,48. The higher mortality risk in the HIV/HCV cohort might be explained by the slightly greater deterioration in health status at HIV diagnosis and the risk practices concerning lifestyle habits in these patients.
To determine whether the risk observed in the univariate analyses was due to HCV exposure, multivariate logistic regression models were used to adjust for the development of clinical events of interest according to the remaining significant variables for each group. There was no significant association between the group (HIV vs. HIV/HCV) and the development of any of the comorbidities. Moreover, no association between group and mortality was observed in multivariate models and Kaplan-Meier curves. The PS analysis confirmed the absence of relationship between HCV exposure and the development of comorbidities and/or mortality.
In contrast, the variables associated with the clinical events were the number of documented STIs, number of previous comorbidities, CD8 + T-cell count, drug consumption, time since HIV diagnosis to starting ART, FIB-4 fibrosis stage and time since HCV diagnosis to treatment with DAAs. It was particularly striking that the number of documented STIs was a protective factor in the models. It was hypothesized that patients with a greater health status could maintain a more active sex life, which could explain the results obtained. Nonetheless, further research should be conducted in this regard. In any case, the risk factors for each clinical event studied, identified in subgroup multivariate logistic regression, support the fact that the development of these events is not directly related to the HCV exposure.
Regarding the severity of fibrosis pre-DAA in coinfected patients, as measured by FibroScan, the APRI and FIB-4 scores, no associations were found between the liver fibrosis stage and the development of any event included in the study, except for hepatic disease It should be noted that the proportion of individuals exhibiting advanced fibrosis within the cohort was low. However, relationships were found with other aspects of HCV infection, for instance, associations between the number of hepatitis C episodes and an elevated risk of CVD, the diagnosis during the chronic HCV stage and an increased risk of non-AIDS cancers, and time from HCV diagnosis to DAA therapy and a greater risk of mortality. These findings underscore the clinical advantage of timely HCV diagnosis and prompt initiation of eradication therapy. Moreover, a higher viral load prior to DAA therapy initiation was linked to the onset of dyslipidemia.