Keywords

7.1 Introduction

Both human immunodeficiency virus (HIV) infections and hepatitis C virus (HCV) infections rank high among global causes of death [1]. Due to shared routes of transmission, prevalence of coinfection with both viruses is high and therefore an area of concern as progression of liver disease was known to be accelerated by HIV. However, due to a number of important changes in the management of HIV and HCV, our beliefs have radically changed. In this chapter the changing dynamics in the field of HIV/HCV coinfection is discussed.

7.2 Changes in Epidemiology of Hepatitis C in HIV Infection

At a global level, there are 37 million people infected with HIV and 115 million people with antibodies to hepatitis C virus (HCV) [2]. Worldwide, there are approximately 2,278,400 HIV/HCV coinfections (IQR 1,271,300–4,417,000), of which 1,362,700 (847,700–1,381,800) are in people who inject drugs (PWID), equaling an overall coinfection prevalence in HIV-infected individuals of 6.2% (3.4–11.9) [3]. This estimation comes from a recent systematic review and meta-analysis of 783 epidemiological studies published between January 1st 2002 and January 28th 2015 [2]. In this study, odds ratios of HCV infection were six times higher in people living with HIV (5.8, 95% CI: 4.5–7.4) than their HIV-negative counterparts. The study also showed a wide variation in the mode of transmission: from a low seroprevalence within pregnant or heterosexually exposed individual (4.0%, 95% CI: 1.2–8.4) to 6.4% (3.2–10.0) in men who have sex with men (MSM), up to even 82.4% (55.2–88.5) in people who inject drugs (PWID).

Since injecting drug use was popular in most European countries in the late twentieth century, the number of PWID that were coinfected with both HIV and HCV in Europe was relatively high between 15 and 30% [4]. In those countries that reacted upon this IV drug epidemic with adequate harm reduction strategies, prevalence rates remained low like in the Netherlands with about 10% coinfection rate. However, seroprevalence rates have also declined in countries that have introduced preventive strategies for PWID more recently, as was shown for Spain, where prevalence of HIV/HCV coinfection has decreased from 25.3% (95% CI: 23.1–27.5) in 2004–2005 to 8.2% (95% CI: 6.9–9.5) in 2010–2011 [5].

7.3 Pathophysiology of Liver Fibrosis Progression in Patients with HIV and Recent Changes in Natural History

7.3.1 The Pre-highly Active Antiretroviral Therapies (HAART) Era

It was widely observed that HIV/HCV-coinfected patients suffered from faster progression of liver fibrosis (LF) compared to HCV-mono-infected patients, resulting in increased rates of cirrhosis and decompensation of liver disease [6, 7]. This was well established from several large observational studies and further meta-analyses [8, 9]. In 2001, Graham et al. performed a meta-analysis of eight studies to assess the risk of cirrhosis and end-stage liver disease (ESLD) in HIV/HCV-coinfected patients compared to HCV-mono-infected patients, and found that the risk of progression to cirrhosis and ESLD was twofold and sixfold higher, respectively, in coinfected patients than those with HCV mono-infection [8]. This was confirmed in a meta-analysis by Deng et al. that involved 16,750 patients from 29 trials, to quantify the effect of HIV coinfection on progression in liver disease in patients with HCV infection [9]. In this study, the overall OR for histological cirrhosis or decompensated liver disease or liver cancer or death was 3.40 (95% CI: 2.45–4.73) for HIV/HCV-coinfected as compared to HCV-infected patients. In subgroup analysis, the authors found that there was a substantial increased risk for decompensated liver disease and death, 5.45 (95% CI: 2.54–11.71), and 3.60 (95% CI: 3.12–4.15), respectively, but smaller difference regarding the development of cirrhosis or liver cancer, 1.47 (95% CI: 1.27–1.70) and 0.76 (95% CI: 0.50–1.14), respectively [9].

The pathophysiology of liver fibrosis progression in patients with HIV results from a multifactorial process (Fig. 7.1). The viral replication of HCV is generally higher in HIV/HCV-coinfected than in mono-infected subjects [10]. Besides this high viral replication, chronic immune activation, and inflammation due both to HIV and bacterial translocation [11], mitochondrial toxicity and steatosis triggered by some older nucleos(t)ide reverse transcriptase inhibitors (NRTI) such as stavudine and didanosine [12, 13] have contributed in the past to more severe intrahepatic damage in HIV/HCV-coinfected compared to mono-infected subjects [13].

Fig. 7.1
figure 1

Pathophysiology of liver fibrosis progression in patients with HIV (from Arends et al. [17])

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7.3.2 Recent Changes in Natural History

The natural history of chronic HCV infection has dramatically changed over the past decade. Three steps have markedly changed the landscape:

First, from the early twenty-first century onwards, with the introduction of safe and effective antiretroviral drugs, the cutoff at which initiation of cART was recommended has increased gradually, from 200 to 350 cells/mm3 until since 2015 to systematic initiation of cART in all HIV-positive persons, irrespectively of their CD4 count [14]. This major shift in HIV treatment guidelines has resulted in a corrected immune deficit in most patients. It is well known that higher CD4+ T-cell recovery protects HIV-coinfected individuals from HCV-related clinical events, and that undetectable plasma HIV-RNA and high CD4+ T cell appeared to protect from progression of liver fibrosis as was shown by FIB-4 transitions to worse stage [15]. The second major change was withdrawal of NRTI with mitochondrial toxicity such as didanosine and stavudine from the cART armamentarium [16] and introduction of safer antiretroviral drugs without liver toxicity. The third and last important change was the development of all-oral direct-acting antiviral (DAA) regimens, leading to HCV cure in more than 95% of the patients.

With all these changes, it is generally accepted that HIV-infected patients, especially those who newly acquire HCV, have the same liver fibrosis progression rate as HCV-mono-infected individuals [17, 18]. A recent French study performed in cirrhotic patients confirmed this fact showing that HIV/HCV-coinfected patients have now a similar risk of liver decompensation and of hepatocellular carcinoma compared to HCV-mono-infected patients with cirrhosis [18]. HIV/HCV-coinfected patients however keep an increased risk of overall mortality than HCV-mono-infected patients, mainly due to death from extrahepatic causes such as infections, cancers, and cardiovascular events [18].

7.4 Specificities of HCV Treatments in HIV Infection and Drug–Drug Interactions (DDIs)

In the pre-HAART era, sustained virological response (SVR) rates to interferon-based therapy were lower in HIV/HCV-coinfected people than in those who were not and did not exceed 50% overall and 15% in patients with cirrhosis [19, 20]. This has been well described in the literature [21].

With the development of all-oral direct-acting antiviral (DAA) drug regimens, the treatment of chronic hepatitis C has dramatically improved [22]. Up to 93–98% of patients obtain an SVR at 12 weeks (SVR12) in clinical trials, whatever the combinations and the fibrosis stage [23,24,25,26,27,28]. And the response rate in HIV/HCV-coinfected individuals has become similar to that of HCV-mono-infected ones [29,30,31,32,33,34] (Fig. 7.2). Furthermore, in real-life settings, several cohorts in France, Italy, and Spain have shown that this high efficacy and safety of DAA were similar as in clinical trials [35,36,37]. It is now firmly established that coinfected patients treated with all oral DAAs have comparable, if not equivalent, SVR rates to mono-infected patients treated with the same regimen and thus appear to be no longer a “hard-to-treat population.”

Fig. 7.2
figure 2

Comparison of SVR rate after DAA treatment in clinical trials performed in HCV-mono-infected and HIV/HCV-coinfected populations

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Potential explanations for the improved, and now equivalent, SVR rates in coinfected and mono-infected patients are likely to rest with the differing mechanism of action of the different anti-HCV therapies. With the introduction of DAAs, the pharmacological mechanism of action of HCV therapies has shifted from immune regulation by peg-IFN-alfa/RBV to (predominately) direct viral inhibition. It is conceivable that with peg-IFN-alfa/RBV therapy even minor defects in the host cellular responsiveness might impact efficacy, while such minor deficits have little or negligible influence when the main activity is direct viral targeting. This view however may prove too simplistic [17].

The main particularity of the treatment of HCV in HIV infection remains in the fact that DAAs can cause drug–drug interactions (DDIs) with antiretrovirals and non-cART co-medication [38]. The ability of HCV protease inhibitors to inhibit cytochrome 450-3A4 (CYP3A4) and transporters (hepatic and/or intestinal and/or renal) can have significant clinical consequences [38].

Mainly throughout an induction or an inhibition of CYP3A4, most of the antiretroviral drugs can affect the metabolism of DAA and lead to abnormal drug exposures. But HCV DAA may also inhibit CYP3A4 and/or transporters leading to an increased exposure of several antiretrovirals (Table 7.1).

Table 7.1 Main interactions between antiretrovirals (ARV) and direct-acting antivirals (DAA)
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7.4.1 Effect of HIV Drugs on the Metabolism of HCV DAAs

HIV boosted protease inhibitors, and most HIV non-nucleoside reverse transcriptase inhibitors (NNRTI), interact via this mechanism of induction or inhibition of CYP3A4. In contrast, HIV integrase inhibitors (e.g., dolutegravir) do not or only marginally affect CYP3A4, and therefore are relatively free of DDI. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g., tenofovir and sofosbuvir, respectively) is subject to competition on drug transporters (e.g., P-glycoprotein) and requires special attention in patients with renal insufficiency.

7.4.2 Effect of HCV DAAs on the Metabolism of HIV Drugs

HCV protease inhibitors have the ability to inhibit cytochrome 450-3A4 (CYP3A4) and transporters (hepatic and/or intestinal and/or renal) and consequently can increase the drug concentrations of HIV proteases [38]. In contrast, HCV polymerase inhibitors, most HCV NS5A inhibitors, do not or only marginally affect CYP3A4, and therefore are relatively free of DDI.

7.4.3 Other Interactions Between DAA et Co-medications

Several other interactions are possible between DAA and co-medications often prescribed in HIV-infected patients such as statins or drug substrates of the CYP450 and/or transporters (e.g., P-glycoprotein, OATP1B1/1B3, BCRP) mainly with the HCV protease inhibitors and to a lesser extent with some HCV NS5A inhibitors.

These drug–drug interactions between DAA and cART should be known by physicians to prevent either toxicity due to drug overexposure or treatment failures due to suboptimal drug concentrations. These interactions can be easily found on the free-access checkers web site www.hcv-druginteractions.org or www.hiv-druginteractions.org. Interactions with cART are described in Table 7.1. Switching cART before DAA treatment can be an option and this was exemplified in a study from the Netherlands, in which category 2 and 3 DDIs were prevented by switching cART in 78 of 147 (53%) and 47 of 49 (98%) patients [39].

7.5 Beneficial Consequences of HCV Cure in HIV-Infected Patients

There have been many advances and changes in the management of both HIV and HCV over the past decade resulting in a decrease in liver fibrosis progression already demonstrated in the pre-DAA era. In addition to the increased SVR rates in coinfected patients treated with DAAs which are now similar to HCV-mono-infected patients, factors responsible for this favorable outcome are improved control of HIV with safer, less hepatotoxic cART and with commencement of HIV therapy at an earlier stage and higher CD4 count—all of which directly influence the degree of immune activation and dysregulation which impacts fibrosis (Fig. 7.3) [40]; the question is how this affects future development of liver-related complications.

Fig. 7.3
figure 3

Overview of benefits and challenges after HCV cure (Ref. [40])

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7.5.1 Liver Events

Although more evidence has surfaced in mono-infected patients treated with DAAs, already several studies have now evaluated liver-related complications in HIV/HCV-coinfected patients cured of HCV [41,42,43]. Indeed, a similar reduction in liver decompensation and increased survival were demonstrated [41].

It was also recently found that the incidence rates of diabetes mellitus, renal events, and non-AIDS-related infections were significantly lower in responders than in no responders to anti-HCV treatment [43].

7.5.2 Quality of Life

SVR is associated with improved long-term clinical outcomes, economic benefits, and improved health-related quality of life. DAA treatment has demonstrated to have less impairment on patient’s quality of life, in terms of physical and mental functioning and social activities. This was mostly observed in pegIFN/RBV-experienced patients who were retreated with a new DAA regimen [44]. A study conducted in Germany suggested that cure of HCV with direct-acting antivirals is associated with positive metabolic effects with weight gain during long-term follow-up of 1 year [45]. Similar conditions were observed in HIV-coinfected patient. During treatment with ledipasvir/sofosbuvir and sofosbuvir/velpatasvir, patients showed an improvement in patient-reported outcome measures (PROMs: activity/energy, physical component, and fatigue score) compared to those treated with sofosbuvir/ribavirin. Those improvements remained present also after treatment cessation [46].

7.6 Residual Risk After Cure?

Despite the numerous demonstrated clinical benefits of HCV cure, the risk of HCC is not abolished in patients with severe fibrosis or cirrhosis before HCV cure. Cirrhosis is the main factor influencing the propensity to develop HCC after SVR, with a risk ranging from 1.0 to 2.2% per year in cirrhotic patients, whereas the risk is very low in patients without cirrhosis [47].

In those patients with cirrhosis or severe fibrosis, specific added risk factors have been identified that increase the risk for HCC occurrence after cure:

  • Age is the most important risk factor, patients being older than 55, and especially 65+ being more likely than younger patients to develop HCC after SVR [47, 48]. This role of age among patients with cirrhosis was well demonstrated in a European study, in which the 8-year HCC incidence was 2.6% (95% CI: 0.0–5.5) among patients <45 years, 9.7% (95% CI: 5.8–13.6) among patients 45–60 years, and 12.2% (95% CI: 5.3–19.1) among patients >60 years at the start of therapy (aHR for those >60 years: 8.91; 95% CI: 1.12–70.79) [48].

  • Furthermore, the severity of cirrhosis, as assessed by a low albumin blood level and a low platelet count [48], or a high elastometry score (over 20 kPa) [49] increases the risk of events as compared with patients with less severe, compensated cirrhosis.

  • Finally, the metabolic syndrome and diabetes [defined by BMI ≥25 kg/m2 and/or diabetes and/or dyslipidemia] carry a much higher risk of HCC occurrence after cure [48, 50]. In one study from France, the HCC incidence among cirrhotic patients cured of HCV but with the metabolic syndrome was around 6% at 6 years, while it was nearly zero in those without the metabolic syndrome [50].

7.7 HCV Reinfections

Modelling studies predict that universal HCV treatment will lead to a decrease in the incidence of new infections [51]. However, HCV is not an infection that confers protective immunity after cure. Reinfection is defined as having detectable plasma HCV-RNA following an undetectable level more than 12 weeks after the end of the treatment (SVR12) with demonstration of different genotype or clade compared with the primary infection.

Risk of reinfection varies according to populations and risk factors. A recent meta-analysis suggested that the rate of HCV reinfection was higher among HIV-coinfected than mono-infected patients, even if there is a great variability among different groups, such as PWID, MSM, and prisoners [52, 53].

7.7.1 Risk of Hepatitis C Reinfection Among MSM

Epidemics of acute hepatitis C have been observed since more than a decade, mostly among MSM with previous HIV infection and with sexual high-risk behaviors in European countries, Australia, the USA, and Asia [53,54,55]. In the Swiss cohort, there was between 2014 and 2015 a 67.1% increase of the number of acute cases attributed to transmission among men who have sex with men, while it declined in PWID and remained stable <1 per 100 in heterosexuals [56]. In these populations, the transmission of HCV is linked to blood contacts via these extremely hard sexual behaviors. Several other factors have increased the incidence like increased cheap air travel, rising popularity of Internet, and use of drugs and stimulants for sexual pleasure (“chemsex”) (see Chap. 11).

In MSM, the risk of HCV reinfection after a first episode of hepatitis is also very high [57, 58]. Prevention strategies are needed for this high-risk group to reduce morbidity and accelerate diagnosis and treatment to avoid transmission. HIV-positive MSM with a prior HCV infection should then be tested frequently for reinfection (every 3–6 months).

7.7.2 Risk of Hepatitis C Reinfection Among PWID

There is uncertainty about reinfection rates among PWID due to lack of available data for good-quality studies (retrospective designs, exclusion of recent PWID from trials, inability to distinguish reinfection from relapse). A study conducted in Australia estimated an incidence of reinfection of 7.4 per 100 patient-years [59]. Among people who injected drugs, the risk of reinfection was found to be low after successful treatment. Risk of reinfection may vary depending on the local background epidemic among the PWID population of HCV. Therefore, in communities with a higher local background HCV epidemic, treated PWID are likely to have a higher risk of reinfection [60]. In addition, injecting behavior after treatment, as well as implementation of a needle exchange program, influences the risk of reinfection among PWID [61].

This ongoing risk underlines that regular monitoring for reinfection is important following SVR, particularly in persons who continue to engage in IDU and for high-risk MSM. In order to increase the success of HCV treatment, it will be essential to establish a posttreatment surveillance [62].