A clinical textbook

Hepatology 2018

17. Management of HCV/HIV coinfection

Christoph Boesecke, Stefan Mauss, Jürgen Kurt Rockstroh

Epidemiology of HCV/HIV coinfection

HIV and HCV share transmission pathways which explain the high rate of coinfection with both viruses. In 2015, it was estimated that at least 6% of the 36.7 million people living with HIV globally had HCV coinfection (WHO 2016, Platt 2016). While both viruses are transmitted with high efficacy via blood-to-blood contact, HCV is less easily transmitted sexually. Thus, the prevalence of HCV coinfection within different countries, regions and populations is generally closely related to the prevalence of blood-borne HIV transmission – mainly among people who inject drugs (PWID).

However, this has changed for a subpopulation of HIV coinfected gay men, as there is an ongoing epidemic of sexually transmitted HCV that is closely related to the use of some recreational drugs. A high incidence of HCV among HIV positive men who have sex with men (MSM) is reported from several major European cities including London, Paris, Amsterdam and Berlin as well as from the US, Canada, Australia and Taiwan. This documents that HCV may well be sexually transmitted through traumatic sex practices or at least transmitted in the context of sexual intercourse (e.g., intravenous administration of recreational drugs called “chemsex”) and should therefore also be taken into account as a sexually transmitted disease in this context resulting in regular sexual health screenings including HCV (Gotz 2005, Danta 2007, Vogel 2009, Vogel 2010, Matthews 2011, Schmidt 2011, Boesecke 2015).

In the past before the wide spread use of interferon free HCV therapy in HIV cohorts in Europe, Australia and the US, in average one out of four patients was coinfected with HCV (Rockstroh 2004, Peters 2014). Higher prevalence rates of HCV/HIV coinfection, i.e. up to 70% have been reported for countries with the main transmission risk of intravenous drug use in Eastern European countries like Belarus and the Ukraine, and in Middle Eastern countries such as Iran (SeyedAlinaghi 2011). On the other hand, in Central European countries such as Belgium, Austria or Germany, where HIV is predominantly sexually transmitted, HCV coinfection rates were lower, i.e. between 10 and 15% (Rockstroh 2005, CDC 2011, Peters 2014). Similarly lower rates were reported for Australia (Jin 2009) and the UK (Turner 2009). Data from the US indicated that 25% to 35% of patients with HIV were coinfected with HCV (Singal 2009, CDC 2011), reflecting the contribution of at-risk populations such as prison inmates and a higher proportion of intravenous drug use to the overall numbers. 65-70% of HIV-infected prisoners in the US are coinfected with HCV, in contrast to 18 to 25% of the overall US HIV positive population (Weinbaum 2005, CDC 2014). In Asia, coinfection rates of up to 85% have been reported among Chinese plasma donors whereas in countries with predominantly heterosexual HIV transmission like Thailand, coinfection rates are around 10% (Qian 2006). In Sub-Saharan Africa, where the primary route of transmission of HIV is sexual, HCV coinfection rates have so far been reported to be low.

However, since 2015, the prevalence of HCV/HIV coinfection has substantially decreased in HIV patients in continuous care, due to the availability of highly effective direct acting antiviral (DAA) HCV treatment in most high-income countries (Berenguer 2018, Boerekamps 2018, Sacks-Davis 2018, Braun 2018).

Vertical transmission of HCV is a concern. HCV is detected after birth in 4 to 8% of infants born to HCV positive mothers (Bevilacqua 2009). HCV/HIV coinfection increases the risk for transmission of both viruses and high levels of HCV viraemia in the mother increases the risk of perinatal HCV transmission (Zanetti 1995). However, the risk of HCV transmission is reduced to less than 1% in mothers with HCV/HIV coinfection receiving antiretroviral therapy (ART) and undergoing caesarean section.

In summary, the prevalence of HCV within the HIV positive population is far higher than in the HIV negative population. This highlights the importance of preventing further spread of HCV as one of the major comorbidities in HIV positive people. The average estimated risks of transmission are included in Table 1. Although sharing common routes of infection, both viruses are transmitted with varying efficacy depending upon the mode of transmission.

Table 1. Average estimated risks of transmission for HIV, HCV and HCV/HIV simultaneously
Mode of transmission HIV HCV HCV / HIV coinfection
Perinatal 7–50% 1–7% 1–20%
Sexual contact* 1–3% <1% <4%
Needle stick injury 0.3% <1% Unknown
* For sexual contact the risk refers to cumulative exposure

Diagnosis of HCV in HIV coinfection

Detection of HCV antibodies via ELISA testing shows HCV exposure. However, the presence of HCV RNA is needed to prove active HCV infection. In acute hepatitis C, HCV RNA is detectable before the presence of HCV antibodies. In addition, in rare cases of HIC/HCV coinfection, the loss of HCV antibodies is observed in very advanced immune deficiency and does not necessarily indicate viral clearance (Cribier 1999). Therefore, a single negative HCV antibody ELISA does not necessarily exclude exposure to HCV in HIV positive patients, especially in severe immune deficiency. Additionally, a rise of liver transaminases (particularly ALT) may be more sensitive for detecting acute hepatitis C in HIV positive patients than repeated testing for the presence of HCV antibodies (Thomson 2009). In cases of suspected early acute hepatitis C testing for HCV RNA is therefore justified to establish the diagnosis.

Higher concentrations of HCV RNA are found in HIV positive individuals than in HIV negative patients with HCV monoinfection (Perez-Olmeda 2002). Interestingly, data from a cross-trial comparison showed that HIV positive patients were less likely to present with elevated serum ALT and clinical signs or symptoms of hepatitis than HIV negative patients (Vogel 2009). In observations patients with haemophilia, mean HCV RNA concentrations increased by 1 log10 over the first two years after HIV seroconversion (Eyster 1994). Levels of HCV viraemia increase eight times faster in HIV positive compared to HIV negative individuals. The highest concentrations for HCV viraemia have been reported in people who subsequently developed liver failure.

Spontaneous clearance of HCV RNA seems to be less frequent in the setting of HCV/HIV coinfection (Thomson 2011). However, interestingly spontaneous clearance of HCV RNA has been observed in some patients with chronic HCV/HIV coinfection that experience significant immune reconstitution following initiation of ART, particularly in patients with the favourable IL28B CC genotype (Fialaire 1999, Thomson 2009, Stenkyist 2014).

The distribution of HCV genotypes in HIV positive patients reflects the route of transmission. Genotype 1b accounts for two-thirds of post-transfusion HCV infections and is the predominant genotype in people with haemophilia. In contrast, genotypes 1a and 3a are more common in people who inject drugs (PWID) (Pol 1994, Soriano 2008) and specific clusters of viruses are traced in gay men engaged in chemsex with HCV genotype 1a and 4 being the most frequent (Caro.Perez 2017, Van de Laar 2009).

Natural course of HCV in HIV coinfection

Various studies have demonstrated that underlying HIV weakens the immune response to HCV, thereby reducing the chance of spontaneous HCV clearance. Data from the European cohorts of sexually transmitted acute HCV in HIV positive gay men suggest that with underlying HIV spontaneous resolution of HCV occurs in 10-20% of new HCV infections (Vogel 2010, Thomson 2010, Boesecke 2018). Genome-wide association studies identified single nucleotide polymorphisms (SNP) near the IL28B gene encoding for interferon lambda that comprise a crucial part of the innate immune defense against HCV in HCV monoinfection (Thomas 2009). Individuals with HCV monoinfection with the CC genotype were three times more likely to clear HCV RNA and to better respond to interferon-based HCV therapy compared with individuals with CT and TT genotypes (Rauch 2010, Grebely 2010, Nattermann 2011, Rallón 2011). Similar observations were made in individuals with HCV/HIV coinfection (Clausen 2010). Interestingly, these SNPs could explain differences in spontaneous clearance rates between different ethnicities as the frequency of the protective allele varies across ethnic groups. The prevalence of the CC genotype being lower in those of African origin compared to Asian patients, with Europeans being in-between (Thomas 2009).

Numerous large cohort studies have demonstrated that once chronic HCV is established, HIV leads to a faster progression of liver fibrosis due to the lack of critical CD4+ T cell responses against HCV (Danta 2008). In the American multicentre Haemophiliac Cohort Study liver failure occurred in 9% of multi-transfused HCV/HIV coinfected adult hemophiliacs without an AIDS-defining opportunistic infection or malignancy (Eyster 1993). In the same period, no cases of liver failure were observed in HCV positive haemophiliacs who were HIV negative. Subsequent studies confirmed the unfavourable course of HCV in haemophiliacs with HIV coinfection, particularly in the setting of progressive immunodeficiency and lower CD4 counts (Rockstroh 1996, Puoti 2000).

In addition, the time interval between HCV infection and development of cirrhosis is shorter in coinfection. Within the first 10 to 15 years of HCV infection, 15 to 25% of patients with HIV coinfection patients developed cirrhosis compared with only 2 to 6% of HIV negative patients (Soto 1997). Importantly, in men with haemophilia, mortality due to advanced liver disease occurs ten years earlier with HCV/HIV coinfection than with HCV monoinfection (Darby 1997). The incidence of hepatocellular carcinoma also seems to be higher in coinfected patients (Giordano 2004).

Effect of HCV on HIV

While the impact of HIV on accelerating HCV-associated liver disease is clear, the impact of HCV on the course of HIV disease seems less pronounced. The Swiss Cohort first revealed a blunted CD4+ T cell response associated with a faster progression to AIDS after initiation of ART in patients with HCV/HIV coinfection (Greub 2000). However, an updated analysis with additional four-years of follow-up from the same cohort study could not confirm this initial observation. There were no significant differences with regard to CD4+ T cell count recovery between HIV positive patients with and without HCV coinfection (Kaufmann 2003). Subsequent studies found that no difference in CD4+ T cell count recovery was observed after adjusting for use of ART (Sulkowski 2002). Updated information from an analysis of the EuroSIDA cohort, after taking into account ongoing chronic (persistent HCV replication) and resolved (positive HCV antibodies but negative HCV RNA) HCV infection, confirm that no difference in CD4+ T cell count recovery is observed in patients with chronic HCV and detectable HCV RNA in comparison to patients with HIV monoinfection (Rockstroh 2005). In addition, data from the same cohort revealed that CD4+ T cell recovery in HIV positive patients with maximal suppression of HIV replication is not influenced by HCV serostatus in general or HCV genotype or level of HCV RNA in particular (Peters 2009).

Effect of ART on HCV

In patients with HCV/HIV coinfection starting ART, a transient increase in HCV RNA levels may occur at week 4, but thereafter, no significant changes in concentrations of HCV RNA happen over the first six months of treatment (Rockstroh 1998). However, a 1 log10 decrease of HCV RNA has been reported in individuals with HCV/HIV coinfection individuals receiving more than 12 months of ART who have significant immune reconstitution (Rockstroh 2007). Moreover, case reports of HCV eradication has been reported in patients receiving ART following CD4 count recovery (Jones 2011). Other investigators, however, have not observed this decrease in HCV RNA (Grint 2013).

There is evidence that ART-induced immune reconstitution might reverse the unfavourable accelerated liver fibrosis progression in patients with severe HIV-associated immune deficiency (Verma 2006, Vogel 2009). Taking into account that liver disease progresses especially in those whose CD4+ T cell count drops below 200 cells/µL it is appealing to think that CD4 increases under ART may impact the further course of liver disease. In an early study of 162 individuals with HCV/HIV coinfection who underwent liver biopsy, the use of protease inhibitors as part of their ART was associated with significantly lower rates of progression of liver fibrosis that could not be explained by other cofactors (Benhamou 2000). These findings were then confirmed by several cohort analyses which showed that individuals with HCV/HIV coinfection on ART had significantly lower liver-related mortality than patients receiving either suboptimal ART (only one or two nucleoside reverse transcriptase inhibitors) or no ART (Qurishi 2003).

In line with these observations, the amount of immune reconstitution achieved on ART was reported to affect the subsequent risk for developing hepatic decompensation in individuals with HCV/HIV coinfection (Pineda 2007). Those patients who experienced the highest CD4+ T cell count gain on ART were the least likely to develop further complications of liver disease. Given that national and international HIV guidelines now recommend ART regardless of CD4 cell count the previous recommendations for earlier ART in HCV/HIV coinfection are obsolete in settings where universal ART is available (EACS 2016). Short-term and long-term virologic success rates of ART in HCV/HIV coinfection, however, may be limited by an increased risk of hepatotoxicity (Sulkowski 2000). Various studies have shown that the presence of HCV is independently associated with an increased risk of rises in serum aminotransferases, highlighting the need for close monitoring or better elimination of HCV (Vispo 2013).

Treatment of HCV in HIV coinfection

After the broad availability of interferon free DAA regimen with high efficacy, good tolerance and short treatment duration elimination of HCV in HIV coinfected individuals has become easy and the prevalence of HCV/HIV coinfected patients has declined substantially in countries with broad access to DAA regimen. From a medical point of view there are no reasons left not to treat HCV, however cost of therapy may be a challenge still to overcome.

Several studies have been able to demonstrate that successful treatment of coinfection dramatically reduces subsequent complications of preexisting liver disease in HIV positive patients (Erqou 2013, Mira 2013). This implies that once viral clearance is achieved the prognosis of liver disease dramatically improves (even in the presence of already developed liver cirrhosis) and once HCV is eradicated, further liver complications in patients with low-grade liver fibrosis are very unlikely. Therefore, regardless of stage of liver fibrosis, HCV treatment should be considered for all people living with HCV/HIV coinfection.

The degree of liver fibrosis is important for choosing the optimal therapy, as treatment duration may be prolonged or ribavirin (RBV) added in patients with liver cirrhosis. In patients with advanced liver cirrhosis (Child-Pugh B and C) the use of HCV protease inhibitors such as glecaprevir, voxilaprevir, simeprevir or paritaprevir is not advisable due to marked increases in drug levels (see also chapter 12).

In addition, patients with liver cirrhosis have to be regularly followed up after viral elimination as the risk of developing hepatocellular carcinoma or hepatic decompensation persists. Monitoring should include six monthly ultrasound examinations of the liver or alternative imaging procedures, when ultrasound is not available or the quality of the examination is low (EACS 2016).

Liver biopsy is not mandatory for assessing the degree of liver fibrosis when non-invasive methods such as serotests for fibrosis (e. g. Fibrotest) or transient elastography or acoustic radio force impulse (ARFI) are available (Rockstroh 2009, Resino 2011). When liver biopsy or non-invasive tests for assessing hepatic fibrosis demonstrate lower grades of liver fibrosis (F0-F1) regardless of HCV genotype, treatment can be deferred, if there are economic constraints. In this case, fibrosis progression should be frequently assessed (also see Chapter 19).

The goal of HCV treatment is to achieve persistently undetectable HCV RNA levels and to reverse liver fibrosis by terminating the necroinflammatory activity in the liver. Viral elimination is generally referred to as a sustained virologic response (SVR). It is defined as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after completion of HCV therapy.

Treatment in countries with access to interferon-free DAA combinations

For patients with HCV/HIV coinfection in countries with access to interferon-free DAAs, HCV treatment has changed dramatically. These simplified DAA-based and interferon-free HCV therapy regimens are characterised by high efficacy, good tolerance and short treatment durations. The use of ribavirin is reserved for specific situations, e.g. treating patients with liver cirrhosis or retherapy in the presence of resistance mutations. Treatment with DAA regimen has demonstrated comparable efficacy in HCV/HIV coinfection compared to HCV monoinfection. However some subpopulations, e.g. decompensated liver cirrhosis, were not extensively studied in patients with coinfection. Because of this, treatment recommendations are based on trial results from HCV monoinfection.

In clinical practice, the main remaining difference compared to HCV monoinfection is the higher number of possible drug-drug interactions which may lead to an adjustment of ART or other co-medications.

Generally HCV protease inhibitors such as glecaprevir, voxilaprevir, simeprevir or paritaprevir are not recommended in patients with decompensated liver cirrhosis due to marked increases in drug levels (summary of product characteristics EMEA).

As cost of non-generic DAA regimens are substantial and reimbursement differs on a local level the guidance below may be useful in a context of economic constraints and cost efficiency. Because of this approach, treatment is still structured by HCV genotype. In countries with broad access to pangenotypic regimen a much simpler decision tree exists.

For HCV genotype (GT) 1b sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, glecaprevir/pibrentasvir, sofosbuvir plus daclatasvir and sofosbuvir plus simeprevir have shown efficacy of close to 90% SVR or higher in clinical trials and large cohort studies (Hézode 2017 and chapter 12). Simeprevir plus sofosbuvir is the least effective DAA regimen and alternative regimen should be preferred when available (Höner zu Siederdissen 2018, Sulkowski 2016). For sofosbuvir/ledipasvir, data mainly from real world cohorts suggest that treatment duration can be shortened to 8 weeks in HIV coinfected treatment naïve patients without liver cirrhosis and HCV RNA <6 million IU/mL, as established for HCV monoinfection (Ingiliz 2016, Buggisch 2016). Data for glecaprevir/pibrentasvir show high efficacy in treatment naïve, non-cirrhotic, HIV coinfected patients treated for 8 weeks (Puoti 2018, Rockstroh 2018). For sofosbuvir/velpatasvir/voxilaprevir only data from HCV-monoinfection are available supporting 8 week therapy in treatment naïve, non-cirrhotic patients (Jacobson 2017). In contrast, a trial with sofosbuvir plus daclatasvir in HCV/HIV coinfection failed to establish 8 week treatment duration for this combination due to reduced efficacy (Wyles 2015). In patients with liver cirrhosis, adding RBV can be considered for sofosbuvir/ledipasvir and sofosbuvir/velpatasvir or alternatively, treatment duration can be extended to 24 weeks (Curry 2015, Reddy 2016).

For HCV GT1a, the main changes compared to GT1b are the addition of weight based RBV to ombitasvir/paritaprevir/ritonavir plus dasabuvir and elbasvir/grazoprevir and the extension of treatment duration to 16 weeks for elbasvir/grazoprevir, if HCV-RNA is >800.000 IU/mL (Hézode 2017).

For HCV GT2, sofosbuvir/velpatasvir for 12 weeks or glecaprevir/pibrentasvir 8-12 weeks have the best outcome overall (Puoti 2018, Rockstroh 2018, Wyles 2016). However, sofosbuvir plus weight based RBV for 12 weeks has also shown SVR rates close to 90% in patients without liver cirrhosis and may be an alternative option depending on the local situation (Molina 2015). In patients with advance fibrosis or a genotype 2k/1b chimeric virus, sofosbuvir plus RBV achieved substantially lower SVR rates and should be replaced by sofosbuvir/velpatavir, glecaprevir/pibrentasvir or sofosbuvir/daclatasvir. Some DAAs such as ledipasvir, dasabuvir, paritaprevir or simeprevir do not show substantial activity against HCV G2.

GT3 has emerged as a more difficult to treat genotype in the DAA era. From the earlier approved DAAs, only sofosbuvir and daclatasvir have substantial activity against GT3. Treatment with sofosbuvir plus RBV for 24 weeks achieved SVR rates up to 80% for easy to treat patients (Foster 2015). Lower SVR rates were observed in pretreated patients and in particular patients with liver cirrhosis. Daclatasvir was not conclusively studied in phase 3 studies for GT3, but study data with limited patient numbers in HCV monoinfection showed SVR around 90% for easy to treat patients with 12 weeks of therapy and improved results for patients with advanced fibrosis when weight based RBV was added (Nelson 2015). These findings were later confirmed by results reported from larger real life cohorts (Rockstroh 2016). Sofosbuvir/velpatasvir has demonstrated SVR rates of about 90% in a large phase 3 study with 12 weeks duration of therapy with the exception of slightly lower efficacy in pretreated patients and in patients with liver cirrhosis (Wyles 2016). Sofosbuvir/velpatasvir/voxilaprevir has shown high efficacy in treatment naïve and DAA pretreated GT3 patients with treatment duration of 8 or 12 weeks respectively (Jacobson 2017). For glecaprevir/pibrentasvir also SVR rates >90% were shown for treatment naïve patients with 8 weeks treatment duration and interferon or sofosbuvir pretreated patients with 16 weeks of therapy (Puoti 2018).

The treatment of HCV GT4 is generally similar to HCV GT1, with the exception that dasabuvir has no activity against GT4 and can be omitted, and the addition of RBV to ombitasvir/paritaprevir/ritonavir is recommended (Hézode 2017). For elbasvir/grazoprevir, addition of RBV and treatment extension to 16 weeks is recommended, if HCV RNA is >800,000 IU/mL, according to the European medical agency, but this is based on 5/5 patients responding to this regimen compared to 34/36 (94%) on elbasvir/grazoprevir without RBV for 12 weeks (Zeuzem 2015). Sofosbuvir/ledipasvir can be used for 8 weeks in GT4 according to an Egyptian trial (Shiha 2018). Sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir have shown robust activity against GT4 (Jacobson 2017, Puoti 2018). Sofosbuvir plus simeprevir or sofosbuvir plus daclatasvir have limited data indicating probably comparable efficacy in easy to treat patients (Hézode 2017). These combinations should be only used in the absence of better validated therapies as outlined above.

As a general guidance concerning drug-drug interactions any strong inducers of the cytochrome P 450 3A enzyme family or inducers of p-glycoprotein should be avoided. Antiretroviral drugs such as efavirenz, nevirapine, lopinavir/ritonavir and elvitegravir/cobicistat are generally not recommended with DAA regimens. Treatment with rifampicin, rifabutin, carbamazepine and phenytoin should also be avoided. Increases of tenofovir levels during treatment with sofosbuvir/ledipasvir are not considered clinically relevant (Kaur 2015). For specific information on drug-drug interactions consultation of the website http://www.hiv-druginteractions.org is recommended.

Table 2. HCV treatment options in people with HCV/HIV coinfection (adapted from EACS 2018)
IFN-free HCV treatment options (preferred regimen in bold)
HCV GT Treatment regimen Treatment duration & ribavirin usage
Non-cirrhotic Compensated cirrhosis Decompensated cirrhosis CTP
class B/C
1 & 4 SOF/LDV +/- RBV 8-12 weeks(i) 12 weeks + RBV(ii) 12 weeks + RBV(ii)
EBR/GZR 12 weeks(iii) 12 weeks(iii) Not recommended
GLE/PIB 8 weeks 12 weeks Not recommended
SOF/VEL 12 weeks 12 weeks 12 weeks + RBV
SOF/VEL/VOX 8 weeks(iv) 12 weeks Not recommended
SOF + SMP +/- RBV 12 weeks + RBV(ii) 12 weeks + RBV(ii) Not recommended
SOF + DCV +/- RBV 12 weeks 12 weeks + RBV 24 weeks +/– RBV
OBV/PTV/r + DSV 8–12 weeks in GT 1b(v) 12 weeks in GT 1b Not recommended
OBV/PTV/r + DSV + RBV 12 weeks in GT 1a 24 weeks in GT 1a Not recommended
OBV/PTV/r + RBV 12 weeks in GT 4 12 weeks in GT 4 Not recommended
2 SOF/VEL 12 weeks 12 weeks 12 weeks + RBV
GLE/PIB 8 weeks 12 weeks Not recommended
SOF/VEL/VOX 8 weeks 12 weeks Not recommended
SOF + DCV 12 weeks 12 weeks 12 weeks + RBV
3 SOF/VEL/VOX 8 weeks(iv) 12 weeks Not recommended
GLE/PIB 8 weeks/(16 weeks)(vi) 12 weeks/(16 weeks)(vi) Not recommended
SOF/VEL +/- RBV 12 weeks 24 weeks + RBV 12 weeks + RBV
SOF + DCV +/- RBV 12 weeks + RBV or 16 weeks no RBV 24 weeks + RBV 24 weeks + RBV
5 & 6 SOF/LDV +/– RBV 12 weeks 12 weeks + RBV or 24 weeks no RBV 12 weeks + RBV or 24 weeks no RBV
SOF/VEL 12 weeks 12 weeks 12 weeks + RBV
GLE/PIB 8 weeks 12 weeks Not recommended
SOF/VEL/VOX 8 weeks(iv) 12 weeks Not recommended
SOF + DCV +/- RBV 12 weeks 12 weeks + RBV 12 weeks + RBV
  • DCV = daclatasvir
  • DSV = dasabuvir
  • EBR = elbasvir
  • GLE = glecaprevir
  • GZR = grazoprevir
  • LDV = ledipasvir
  • OBV = ombitasvir
  • PIB = pibrentasvir
  • PTV/r = paritaprevir/ritonavir
  • RBV = ribavirin
  • SMP = simeprevir
  • SOF = sofosbuvir
  • VEL = velpatasvir
  • VOX = voxilaprevir
  • RAS = Resistance Associated Substitutions
  1. 8 weeks treatment without RBV only in treatment-naïve persons with F < 3 and baseline HCV-RNA < 6 million IU/mL.
  2. Treatment with RBV for 12 weeks in case of RBV intolerance treat 24 weeks.
  3. Extension of treatment to 16 weeks and addition of RBV in persons with GT1a with baseline HCV-RNA > 800.000 IU/mL and NS5A RASs and in HCV GT4 experienced persons with HCV-RNA > 800.000 IU/mL.
  4. Extension of treatment to 12 weeks in DAA treatment experienced persons.
  5. 8 weeks treatment without RBV only in persons with GT1b and without cirrhosis.
  6. Treatment duration in HCV GT3 who failed previous treatment with IFN and RBV +/- SOF or SOF and RBV should be 16 weeks.

Treatment in countries without access to interferon-free DAA combinations

Because treatment with the new DAAs, if patent protected, is very expensive, access to these drugs is not available in some healthcare systems. Access to generic drugs may be an alternative solution in these areas.

In case only interferon and ribavirin are available the standard dosage for PEG-IFN α-2a is 180 µg SC once weekly and for PEG-IFN α-2b 1.5 µg/kg body weight SC once weekly plus RBV 1000 mg (<75 kg body weight) and 1200 mg (≥75 kg body weight). Duration of therapy is individualised between 24 to 48 weeks taking into account factors for HCV treatment response such as genotype, baseline viral load and virologic response.

If an early virologic response (decline of at least 2 log10 reduction in HCV RNA at week 12 from baseline) is not achieved when treating HCV with PEG-IFN and RBV, treatment should be stopped.

During PEG-IFN+RBV therapy, didanosine (ddI) is contraindicated in persons with cirrhosis and should be avoided in persons with less severe liver disease. Stavudine (d4T) and zidovudine (ZDV) should also be avoided.

For details please consult previous recommendations (EACS 2015).

Treatment of HCV for relapse or non-response

For patients with coinfection in countries with access to DAAs, interferon-free DAA-based HCV treatment should be the first choice for retreating patients with chronic HCV. The rules are essentially the same as for HCV monoinfection (see Chapter 12). However, due to possible drug-drug interactions, the concomitant ART should be assessed before initiating HCV therapy (see EACS guidelines 2017 or visit www.hep-druginteractions.org). Before retreating patients with virologic failure, adherence should be assessed and reinfection excluded. In patients failing a first course with DAAs, current re-treatment strategies recommend resistance testing where available. The only approved DAA regimen for retreatment of DAA failures is sofosbuvir/velpatasvir/voxilaprevir (Bourlière 2017). In case this regimen is not available the choice of therapy can be guided by the resistance profile (Pfeiffer 2018). The next regimen should include at least two active drug classes according to resistance testing results with a preferential use of one drug with high genetic barrier to resistance. In some cases, extended treatment durations and addition of RBV may be warranted. In case no effective treatment options are available, new regimen should be awaited if deferred treatment can be justified. After waiting prolonged periods before retreating, another resistance test should be carried out, as some resistance associated mutations may disappear over time.

The main risk factor for virologic failure in adherent patients is liver cirrhosis. Because of this, these patients will accumulate in the group of patients requiring retreatment. In particular, patients with hepatic decompensation are challenging as treatment is associated with hepatic decompensation, infectious complications and has a mortality rate of up to 10% in clinical studies. In some patients, liver transplantation followed by DAA therapy may be an alternative strategy (see Chapter 22).

In countries with no access to interferon free DAA regimen, patients with a history of interferon based HCV therapy who were either non-responders or who relapsed while on previous HCV therapy need to be reassessed with regard to the next HVC treatment optimising the dose and duration of PEG-IFN and RBV as well as potentially adding simeprevir, daclatasvir or sofosbuvir as a third drug. Interferon-based therapy is contraindicated in patients with hepatic decompensation.

Treatment of acute HCV in HIV

In the past, interferon-based regimen were more efficacious, when used in the acute phase of HCV infection, but, given the SVR rate of >90% with most DAA regimen in chronic HCV, this advantage is no longer important.

Some DAA combinations have been investigated in the setting of acute HCV/HIV coinfection, generally with small pilot studies reporting a wide range of SVR rates between 21-100%. To date, SVR rates seem to be impaired by the choice of combinations with lower efficacy (e. g. sofosbuvir plus RBV), short treatment duration, high baseline HCV viral load, inclusion of early chronic HCV infection and emergence of resistance associated variants (RAVs) (Boesecke 2015). No specific DAA regimen is approved for treatment of acute HCV. In countries with access to DAAs and potentially individual cost reimbursement for DAAs in the setting of acute HCV, sofosbuvir/ledipasvir has currently the strongest data (Rockstroh 2016, Naggie 2017). Treatment duration of eight weeks seems feasible in most patients, when treated early.

After the diagnosis of acute HCV, HCV RNA should be measured at initial presentation and 4 weeks later. Treatment can be discussed with patients, who have experienced a decrease <2 log10 of HCV RNA at 4 weeks or later compared to baseline as the likelihood of spontaneous clearance of HCV is low (Boesecke 2018). Alternatively, due to the absence of approval of DAAs in the setting of acute hepatitis C the other option is to wait until hepatitis C becomes chronic and treatment is possible according to the label. However, early intervention may reduce infectivity reducing the further spread of HCV.

In case of interferon-based therapy as the only available option, duration of treatment should be based on rapid virologic response (RVR) regardless of genotype. Early discontinuation of interferon based therapy is justified in persons experiencing significant side effects of PEG-IFN and/or RBV. Also patients who do not achieve a ≥2 log10 decrease in HCV RNA level at week 12 should discontinue therapy (NEAT 2011).

Management of liver cirrhosis and liver transplantation in people with HCV/HIV coinfection

In general, compared to HCV monoinfection, individuals with HCV/HIV coinfection develop more rapid HCV-related hepatic injuries such as liver fibrosis and cirrhosis. Additionally, HCV/HIV coinfection is associated with an increased rate of hepatocellular carcinoma (HCC). Typically, HCC occurs in coinfection at an earlier age and the course is more aggressive, with a shorter survival compared to HCV monoinfection (Klein 2016). An ultrasound of the liver should be performed every six months for HCC surveillance in patients with F3/F4 fibrosis, according to the recommendations of the European Consensus Guidelines (Alberti 2005).

As upper gastrointestinal bleeding is another important complication the presence of oesophageal varices using upper-gastrointestinal endoscopy should be monitored in patients with liver cirrhosis every year.

Liver transplantation should be considered in patients with decompensated liver cirrhosis. To fulfil the selection criteria for a liver transplant in individuals with HCV/HIV coinfection, the CD4+ T cell count has to be at least 100 cells/µl. Additionally, the patient has to have either undetectable HIV viraemia (<50 copies/mL) or at least rational treatment options to control HIV infection successfully after liver transplantation. Further contraindications for transplantation are opportunistic diseases, ongoing alcohol or drug use, large multilocular HCC or HCC metastasis in other organs, a second malignant disease, advanced cardiopulmonary disease or older age with an elevated perioperative mortality risk.

The possibility to eradicate HCV in virtually all patients posttransplant due to the high efficacy of DAA regimen will positively affect transplant survival. On the other hand, the need for liver transplantation due to chronic HCV will be substantially reduced over the years to come in countries with large scale access to DAAs.

For more details, refer to chapter 22 on liver transplantation in HCV/HIV coinfection.

Conclusion

Uncontrolled HIV infection accelerates the progression of hepatitis C, resulting in higher liver disease-related mortality and morbidity in HCV/HIV coinfection compared to either HCV or HIV monoinfection. In countries with access to DAAs, interferon-free DAA-based treatment is strongly recommended in all patients. Treating with DAA based regimen has eliminated the lower efficacy of HCV therapy as known from interferon based therapies. Drug-drug interactions between ART and the DAAs inhibitors require careful selection of both HIV and HCV drugs before initiating therapy. After elimination of HCV monitoring for HCC and hepatic decompensation has to be implemented for patients with advanced liver fibrosis.

References

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