Accepted Manuscript Review Natural history and treatment of Hepatitis C/HIV coinfection: is it time to change paradigms? Joop E. Arends, Faydra Lieveld, Lauke L. Boeijen, Clara T.M.M. de Kanter, Karel J. van Erpecum, Dominique Salmon, Andy I.M. Hoepelman, Tarik Asselah, Andrew Ustianowski PII: DOI: Reference:

S0168-8278(15)00462-6 http://dx.doi.org/10.1016/j.jhep.2015.06.034 JHEPAT 5743

To appear in:

Journal of Hepatology

Received Date: Revised Date: Accepted Date:

8 June 2015 28 June 2015 30 June 2015

Please cite this article as: Arends, J.E., Lieveld, F., Boeijen, L.L., de Kanter, C.T.M., van Erpecum, K.J., Salmon, D., Hoepelman, A.I.M., Asselah, T., Ustianowski, A., Natural history and treatment of Hepatitis C/HIV coinfection: is it time to change paradigms?, Journal of Hepatology (2015), doi: http://dx.doi.org/10.1016/j.jhep.2015.06.034

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Joop E. Arends1,7, Faydra Lieveld1, Lauke L. Boeijen1, Clara T.M.M. de Kanter2, Karel

J.

van

Erpecum3,

Dominique

Salmon4,7,

Andy

I.M.

Hoepelman1,7,

Tarik Asselah5 and Andrew Ustianowski6

1

Department of Internal Medicine and Infectious Disease,

2

Department of Clinical Pharmacy2 and

3

Department of Gastroenterology and

Hepatology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands. 4

Department of Infectious Diseases, Hôpital Cochin, Paris, France.

5

Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, and INSERM, UMR1149,

Labex INFLAMEX, Université Denis Diderot Paris 7, France. France. 6

Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester,

United Kingdom. 7

Members of the European Study Group on Viral Hepatitis (ESGVH) of the European

Society of Clinical Microbiology and Infectious Diseases (ESCMID).

1

Natural history and treatment of Hepatitis C/HIV coinfection: is it time to change paradigms?

Joop E. Arends1,7, Faydra Lieveld1, Lauke L. Boeijen1, Clara T.M.M. de Kanter2, Karel J. van Erpecum3, Dominique Salmon4,7, Andy I.M. Hoepelman1,7, Tarik Asselah5 and Andrew Ustianowski5

Department of Internal Medicine and Infectious Diseases1, Department of Clinical Pharmacy2 and Department of Gastroenterology and Hepatology3, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands. Department of Infectious Diseases 4, Hôpital Cochin, Paris, France. Service d'Hépatologie5, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. Regional Infectious Diseases Unit6, Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, United Kingdom. Members of the European Study Group on Viral Hepatitis 7 (ESGVH) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).

Corresponding author Joop E. Arends, MD PhD, Department of Internal Medicine and Infectious Diseases University Medical Center Utrecht Huispostnummer F.02.126 P.O.box 85500 3508 GA Utrecht, the Netherlands T +31 88 7571180 and F +31 88 7555639

2

e-mail [email protected]

Word Count Abstract: 99 Text: 3450

Number of figures: 2 Number of tables: 1

List of abbreviations in the order of appearance HCV: hepatitis C virus; HIV: human immunodeficiency virus; MSM: men who have sex with men; iv: intravenous ; peg-IFN-alfa: pegylated interferon-alfa; RBV: ribavirin; SVR: sustained virological response; GT: genotype; DAA: direct-acting antiviral; NS3: nonstructural protein 3; SOF; sofosbuvir; LDV: ledipasvir; DAC: daclatasvir; CROI: Conference on Retroviruses and Opportunistic Infections; EASL ILC: European Association for the Study of the Liver Study International Liver Conference; cART: combination antiretroviral therapy; NNRTI: non-nucleoside reverse transcriptase inhibitor; PIs: protease inhibitors; P-gp: P-glycoprotein; BCRP: breast cancer resistance protein; HCC: hepatocellular carcinoma; ddI: didanosine; d4T: stavudine; HBV: hepatitis B virus.

Conflict of interest J.E. Arends: advisory board BMS, Janssen, MSD, Abbvie, ViiV, Gilead Speakers bureau; F.L.: none; L.L. Boeijen: none; C.T.M.M. de Kanter: none; K.J. van Erpecum: advisory boards Abbvie, Gilead and BMS; D. Salmon: advisory board for Gilead and

3

Janssen; A.I.M. Hoepelman: advisory board Janssen, Abbvie, MSD, Gilead; research grants from Gilead and ViiV; T. Asselah: a speaker and investigator for AbbVie, BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and Merck; A. Ustianowski: advisory board and speaker fees from Abbvie, Boehringer-Ingelheim, BMS, Gilead, Janssen, MSD, ViiV.

Contributions of authors J.E. Arends : literature search and writing manuscript; F. Lieveld.: writing manuscript; L.L. Boeijen: literature search and writing manuscript; C.T.M.M. de Kanter: writing manuscript; K.J. van Erpecum: writing manuscript; D. Salmon: writing manuscript; A.I.M.

Hoepelman: writing

manuscript; T. Asselah: writing manuscript; A.

Ustianowski: literature search and writing manuscript

Financial support: none

4

Abstract Over past decades evidence had demonstrated that HIV/HCV co-infected patients responded less well to HCV therapy than HCV mono-infected, and had more rapid progression of liver disease. Developments in both HIV and HCV care have caused us to reassess these paradigms. This article reviews the origins of these paradigms and the newer data that impacts upon them. Treatment efficacy now appears equivalent for HIV/HCV co-infected and HCV mono-infected patients while liver fibrosis progression is increasingly similar in optimally managed patients. Drug-drug interactions and the impact of HCV reinfection, with the possibility of transmitted drug resistance, have become increasingly important.

Key words: HIV; hepatitis C; liver fibrosis; pegylated interferon; direct-acting antiviral agents

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Introduction With an estimated 170 million patients infected with the hepatitis C virus (HCV) worldwide, the morbidity and mortality resulting from this infection are substantial (1, 2). Due to shared routes of viral transmission, coinfection with both HCV and the human immunodeficiency virus (HIV) range from around 10%-30% in men who have sex with men (MSM) up to 80%-90% in intravenous (iv) drug users (3, 4). Two types of HIV/HCV coinfected patients can be distinguished: those infected for decades who have often severe fibrosis and several comorbidities versus those recently infected with HCV. Over the years, several paradigms have been determined and accepted in those with HIV/HCV coinfection compared to the HCV mono-infected. In particular, the response to HCV therapy is significantly poorer in those co-infected, and liver fibrosis progression is worsened in the presence of HIV infection (5, 6). However, developments in both HIV and HCV care make that we should probably reassess these dogmas and determine if they still hold true. Especially for those HIVinfected patients who became recently HCV-infected, the natural history of the disease might resemble HCV mono-infected. This review will analyse these paradigms, and then focus on recent data on HCV treatment outcomes and determinations of liver fibrosis progression to see if they are still valid. We also present potential hypotheses for any differences or changes.

Differences in response to HCV therapy Following the presentation of the potential utility of interferon-alfa for treating chronic non-A non-B hepatitis in 1986 (7), this agent became the mainstay of therapy for HCV (8-11). Over time the modification of interferon-alfa to pegylated forms (pegIFN-alfa) and the addition of ribavirin (RBV) improved rates of viral clearance 24

6

weeks post-treatment (sustained virologic response 24 (SVR24)) from 17% overall to approximately 40-50% in genotype (GT) 1 and 70-90% in GT 2 and 3 mono-infected patients (12). When these agents were investigated in those also co-infected with HIV disappointing SVR24 rates of only 17-36% were seen in GT 1 and 4 patients. Thus, substantially lower than in HCV mono-infected patients (13-17). These differences resulted in HIV/HCV co-infected patients being classified as a 'hard to treat population' with consequent prolonged therapy regimens and decreased expectations of cure. With the availability of direct-acting antivirals (DAAs) in HCV a new era in anti-HCV therapy was introduced. SVR rates in naive GT 1 HCV mono-infected patients improved further to 63-74% with the addition of the first generation protease inhibitors, boceprevir or telaprevir to peg-IFN-alfa and RBV (18-21). It was assumed that HIV patients would remain poor responders and therefore they were excluded from the initial phase 2 and 3 studies of these newer therapies. They only entered into specific coinfection studies once data in the mono-infected became available (and usually only once initial drug-interaction studies with antiretrovirals had been completed). However, telaprevir and boceprevir – in combination with peg-IFN-alfa and RBV - demonstrated similar SVR rates in HIV/HCV coinfection compared to HCV mono-infected (22, 23). Equivalent efficacy in SVR rates between both patient groups was further demonstrated in real life cohort studies on telaprevir and boceprevirbased therapy (24-26). Moreover, side-effect profiles were consistent between the co-infected and mono-infected cohorts, with the exception of a potential decrease in the incidence of rash in co-infected patients exposed to telaprevir (27).

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Recently, several reviews have been published that discuss all previous studies in this area (28-30). Therefore, we focus on the most recent published studies in HIV/HCV coinfected patients and discuss potential explanations.

Newest DAAs in HIV/HCV coinfection The fixed-dose combination of sofosbuvir (SOF) with ledipasvir (LDV) has been investigated in 2 studies involving coinfected patients. First, Osinusi et al. recently reported an excellent SVR12 rate of 98% (49 of 50 patients) in HIV/HCV GT 1 infected non-cirrhotic patients after 12 weeks of therapy (31). Ion-4, a phase-3 study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2015), included 335 HIV/HCV GT 1 coinfected patients (both treatment naive and experienced) of which 20% had compensated cirrhosis (32). HIV treatment consisted of tenofovir and emtricitabine in combination with either efavirenz, rilpivirine or raltegravir. Again, a very high SVR12 rate of 96% was achieved, regardless of past treatment history, cirrhosis stage or antiretorviral regimen. The combination was well tolerated in most patients. The combination of paritaprevir/ritonavir/ombitasvir with dasabuvir was tested in HIV/HCV coinfected patients in the Turquoise program (33). The study included 63 HIV/HCV GT1 coinfected patients (treatment naive or prior peg-IFN/RBV failure) stable on an atazanavir- or raltegravir-containing HIV-regimen. Again SVR12 rates were high, 94% and 91% after either 12 or 24 weeks of treatment. Furthermore, adverse events were generally mild without serious complications leading to treatment discontinuation. The C-EDGE study investigated the use of a 12 week duration of grazoprevir/elbasvir in HIV/HCV mostly GT 1 infected population (34). The vast majority were on a tenofovir-based regimen in combination with an

8

integrase inhibitor. Again, excellent SVR rates of 95% were achieved with subgroup analysis not revealing any negative predictors to therapy. Finally, at the European Association for the Study of the Liver International Liver Conference (EASL ILC2015), the ALLY-2 study was presented demonstrating that a combination of SOF and daclatasvir (DAC) was efficacious with significantly higher SVR12 rates after 12 versus 8 weeks of treatment (96% versus 76%), irrespective of prior treatment experience (35). Next to registration trials, now real life data in HIV/HCV coinfected patients has recently become available with the new DAA regimens. First, the French HEPAVIH cohort analysed and reported on 142 HIV/HCV coinfected cirrhotic patients who were infected with GT 1a (37%), 1b (13%), 1 (8%), 2 (3%), 3 (20%) and 4 (19%) (36) respectively. Nearly 60% had previously failed peg-IFN/RBV therapy. The most frequently used DAA combinations were SOF+DAC±RBV (69%) and SOF+RBV (17%). Overall, an SVR12 of 95% was reported, which was generally irrespective of the given DAA regimen. The German cohort on SOF-based therapy for HIV/HCVand HCV-infection (GECOSO), included 393 HCV mono-infected and 125 HIV/HCV coinfected patients with GT 1 or 4. SVR12 rates of 84% and 85% independent of the used DAA (i.e. SOF/simeprevir or SOF/DAC) were found (37). The comparable efficacy of these agents in HIV/HCV coinfected (mostly GT 1 and 4) is graphically compared to the most closely matching studies in HCV mono-infected patients in Figure 1. 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 various anti-HCV therapies. With the introduction of DAAs, the pharmacological mechanism of action of HCV therapies has shifted from immune-regulation by peg-

9

IFN-alfa/RBV to direct viral inhibition (38). It is conceivable that with peg-IFNalfa/RBV therapy even minor defects in the host cellular responsiveness might impact on efficacy, whilst such minor deficits have little or negligible influence when the main activity is direct viral targeting. This view however may prove too simplistic. Extensive research over the past decade has shown a potential role for the cellular immune response in HCV drug-induced clearance. Exogenous interferon-alfa, has multiple effects upon the host immune system. However, to date very little is known about cellular immune responses during peg-IFN-free HCV therapies - although an interesting recent insight has been provided by Martin et al. (39). The authors treated 51 HCV treatment-naive HIV-negative patients with a combination of faldaprevir and deleobuvir and analysed T cell responses at baseline and during therapy. A rapid restoration of HCV-specific CD8+ T cells was apparent at week 4 of this IFN-free therapy in those patients who subsequently achieved an SVR. Another study in HCV mono-infected patients undergoing DAA therapy has shown a decrease in T cell exhaustion during a 24 week course of SOF/RBV (40). Furthermore, an increase in peripheral HCV-specific T cell IFN-gamma response was noted by the end of treatment. Contrary, impaired HCV-specific responses were more pronounced in HIV/HCV coinfected patients without subsequent restoration during peg-IFNalfa/RBV therapy (41-45). In addition, it was shown that intra-hepatic T cells were less capable of interferon-y production in an ELIspot assay (46). Whilst interferonbased therapies result in prolonged T cell unresponsiveness, it appears that the proliferative capacity and functioning of HCV-specific CD8+ T cells seems to return promptly after DAA-therapy induced viral clearance (i.e. antigen removal) (39). The observation that proliferative capacity of CMV- and EBV-specific CD8+ T cells (i.e. non-HCV-specific immunity) is also restored by HCV therapy (47), proves

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that the immunological response to anti-HCV therapy is probably not so straight forward and should be interpreted with caution. In addition, is it currently unclear whether such changes also occur in those with HIV coinfection. In all, it appears that co-infected patients enrolled in DAA studies to date have comparable, if not equivalent, SVR rates to mono-infected patients treated with the same regimen. Therefore, the HIV co-infected appear to be no longer a 'hard to treat population', and, as international organisations now suggest, should be treated in identical fashion to the mono-infected (48, 49).

Drug-drug interactions and reinfections Two further aspects need to be taken into account when treating HIV/HCV coinfected patients - drug-drug interactions and the possibility of HCV reinfection. There are significant possibilities of drug-drug interactions between antiretroviral medications and DAAs. Pharmacokinetic drug-drug interactions can result in higher or lower concentrations of the drugs involved. In turn, this may lead to toxicity or diminished efficacy and even to development of drug-resistance (50). Drug-drug interactions between antiretroviral medications and DAAs have been extensively reviewed elsewhere (51-53), and therefore we focus on interactions with the newer DAAs SOF/LDV and the ‘3D’ regimen of paritaprevir (with ritonavir), ombitasvir and dasabuvir. SOF or the combination of SOF/LDV, is the least involved in drug-drug interactions with combination antiretrovirals (cART). SOF and SOF/LDV can be used in combination with non-nucleoside reverse-transcriptase inhibitors (NNRTIs), integrase inhibitors or ritonavir-boosted HIV protease inhibitors (PIs) (excluding tipranavir).

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However, there are concerns regarding potential nephrotoxicity when combining sofosbuvir/ledipasvir with tenofovir, because of increased tenofovir concentrations in healthy volunteer studies. This finding has been attributed to the inhibition of the Pglycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters by ledipasvir (54). A number of enzymes and transporters, e.g. CYP3A4, CYP2C9, P-gp and BCRP, are involved in the metabolism of the 3D regimen consisting of paritaprevir/ritonavir, ombitasvir and dasabuvir. In addition, the 3D regimen inhibits various enzymes and transporters itself (55). As a result, these DAAs are frequently involved in drug-drug interactions with antiretroviral medications, especially with NNRTIs (56) and HIV PIs (57). These combinations are often not recommended for simultaneous use (58). The HIV PIs darunavir (only when once daily dosing is applicable and administered at the same time), and atazanavir can be given concomitantly with the 3D regimen, however, ritonavir used in the HIV regimen should be stopped during HCV treatment because sufficient ritonavir is already co-formulated with paritaprevir (33, 58). When treating an HIV/HCV co-infected patient, the intended HCV DAAs should be checked for possible drug-drug interactions with all the concomitantly used medications, not only the antiretroviral medication. Information on drug-drug interactions can be found at http://www.hep-druginteractions.org. Another important potential distinction between HCV mono-infected patients and HIV/HCV coinfected patients is the higher observed number of HCV reinfections in the latter group, either in iv drug users or MSM (59). Incidence of reinfections has been reported as high as 7.8 and 15.2 per 100 patient years of follow-up (60, 61). It is hypothesized that these reinfections occur because of unchanged sexual and other risk behaviors in combination with the emergence of national and international

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networks of HIV positive men preferentially having unprotected sex with HIV positive men (i.e. serosorting) (62). Therefore, in-depth quasispecies analysis should be performed to reliably distinguish between HCV relapse and re-infection in those patients who are diagnosed with a relapse in current clinical trials. This is important since treatment with DAAs may result in development of HCV resistance mutations in a small number of patients. Recently, the first case of transmission of a DAAresistant variant of HCV from a patient who was treated with telaprevir to his sexual partner was described (63). Increasing DAA use in combination with high rates of HCV reinfection has the potential to result in accumulation of HCV DAA-resistant variants which could ultimately impair future DAA treatment.

Differences in fibrosis progression In chronic HCV, the rate of progression of liver fibrosis to cirrhosis is known to be slow, usually taking decades to develop (64, 65). This varies according to individual factors such as duration of infection, age at time of infection, male sex, and amount of alcohol consumption (66-68). Contrary, reports have demonstrated a more accelerated liver fibrosis progression in the setting of HIV coinfection (69-72) and liver disease as a major cause of morbidity and mortality in the coinfected population (73, 74). The apparent increase in liver disease may have been partly due to the major decline in AIDS-related mortality and increase in life expectancy of HIV-infected individuals seen over the 1990’s and 2000’s, with consequent proportional rises in the incidences of viral hepatitis-induced liver complications such as cirrhosis, liver decompensation and hepatocellular carcinoma (HCC) (75, 76). However, studies specifically addressing fibrosis progression and the development of end-stage liver

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disease also demonstrated marked increases in the rates of such morbidities in HIV coinfection as compared to HCV mono-infection (77). Associations between faster fibrosis progression and low CD4 cell counts were reported (78, 79). Therefore, the paradigm that liver fibrosis progression was significantly worse in the setting of HIV infection was determined (5, 6). Since the widespread introduction of modern cART regimens, data on the effect of HIV coinfection on liver fibrosis progression and its complications have been conflicting. Some studies have continued to report higher progression rates in coinfected compared to mono-infected patients (73, 80-89) whilst others have shown similar rates (90-95) (Table 1).

Methodological issues How can these conflicting study outcomes be explained? First, there are methodological issues with most of these studies. For example, only the studies by Tovo et al. (94) and Sterling et al. (92) were longitudinal in nature while all others were cross-sectional. Unfortunately, in both former studies the interval between biopsies was shorter for the HIV/HCV coinfected compared to the HCV monoinfected patients. Another important variation among studies was the fibrosis assessment method utilised, predominately either transient elastography or liver biopsy. Moreover, the numbers of included patients were generally small in most studies hampering firm conclusions. Finally, it is well documented that baseline factors such as alcohol use, gender, the duration of HCV infection, and smoking status may influence liver fibrosis progression (96, 97), and these factors may be unequally distributed between the HIV/HCV co-infected and the HCV mono-infected cohorts. Some studies have attempted to correct for some of these confounding

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variables, as illustrated in a review by Thein et al. (77), but those that have, do not consistently corrected for the same factors. The roles of steatosis, insulin resistance and HBV coinfection in fibrosis progression are also vitally important in both HIV/HCV co-infected and HCV mono-infected patients.

HIV-related factors influencing liver fibrosis There are several potential factors that might influence liver fibrosis progression rate which are worth considering; 1) the ability of cART to control HIV viraemia; 2) changes in the degree of immune suppression (i.e. CD4 cell count); 3) the duration and extent of significant HIV-induced immune activation, in part maintained by microbial translocation from the gut (98); and 4) the hepatotoxic potential of antiretrovirals (93, 99-101). Over the past decade, all these factors have changed considerably (figure 2). cART has become increasingly successful in controlling HIV viraemia and is associated with a decrease in systemic inflammation (reviewed extensively elsewhere (102, 103)). Better control of viraemia results in lesser degrees of immune suppression, and therefore less patients with low CD4 counts. Low CD4 counts have previously been strongly correlated with liver fibrosis progression (78, 79). In addition, the threshold for commencing HIV treatment has been gradually adjusted. Whilst most guidelines originally advised treatment for patients with CD4 cell counts lower than 200/mm3, over decades there have been stepwise changes and many present guidelines advise to treat patients with CD4 cell counts lower than 500 cells/mm3 or to treat all HIV infected patients regardless of CD4 count (104-106). Therefore, the adjustment of the HIV treatment threshold and the increased antiviral efficacy of cART have led

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to shorter intervals between initial HIV-infection and treatment, with subsequently less patients in the lower CD4 count strata or with detectable HIV viraemia. This is illustrated for example when comparing the study by Castera et al. (81) with that of Suarez-Zarracina et al. (93) where the percentage of HIV/HCV coinfected patients on cART was 40% versus 100%. In addition, in a recent non-comparative study by Konerman et al. (107), liver biopsies were performed in a single cohort of longinfected HIV-patients (included from 1993 to 2008). 435 liver biopsy pairs were analysed from 282 patients without cirrhosis with a median interval between biopsies of 2.5 years. Fibrosis progression was observed in 34% of patients. However, only slightly more than half of the patients had HIV-RNA below 400 copies/ml and only 2/3 of patients were on cART. As previously mentioned, there may be other influences of HIV-RNA on the development of liver fibrosis that may be lessened or abrogated by modern cART (108). Particularly, the correlation between viral suppression (low HIV-RNA levels) and lower systemic immune activation although a direct causal relationship has not been conclusively established. Such systemic inflammation has also been associated with more rapid fibrosis progression (108). Over recent years the use of specific antiretroviral drugs has altered, partly due to new insights into their adverse, including hepatotoxic, effects. For example, the older nucleoside reverse transcriptase inhibitors (NRTI) didanosine (ddI) and stavudine (d4T), commonly prescribed in the nineties, have now been associated with the development of liver fibrosis and portal hypertension which has largely led to their abandonment (93, 99, 101). When assessing older studies that reported worsened fibrosis progression in HIV/HCV coinfection, it is interesting to note that up to 74% of patients received d4T/ddI compared to 19% in more recent studies (109-111). The

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present cART components are not free from hepatotoxicity. Contrary, NNRTIs are known for their potential to cause elevated liver enzymes, but have so far not been linked to fibrosis progression and remain commonly utilized (112). In addition, a recent study of liver biopsies in HIV-infected patients demonstrated drug induced liver injury due to antiretroviral therapy in a significant number of patients (113). Although some newer antiretroviral drugs have so far not been associated with liver fibrosis development (114), more prospective data are needed for the newer antiretrovirals before making more firm conclusions about their hepatic safety.

All these factors have over time led to the existence of roughly 2 types of HIV/ HCV coinfected patients. On the one hand those who, for decades, have been exposed to a long duration of unsuppressed HIV and to hepatotoxic drugs as opposed to HIV/HCV coinfected patients infected in more recent years who are put quickly on effective and safer cART. The latter group is distinctly different and the evidence suggests that they exhibit a much more similar liver fibrosis progression rate as HCV mono-infected. Of course, this is irrespective of the roles of steatosis, alcohol, insulin resistance and HBV coinfection in fibrosis progression, which are important in both HIV/HCV coinfected and HCV mono-infected patients. Furthermore, it remains to be established whether the incidence of HCC will also decrease the coming decade. A recent large cohort study in 189.332 HCV mono-infected (included between 1995–2010) and 8563 HIV/HCV coinfected (included between 1985– 2010) patients showed a higher incidence of HCC in latter group. However, HCC prevalence was significantly higher among coinfected patients diagnosed

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with HIV in the pre-cART compared to early cART and late cART eras (43.0% vs. 37.3% and 19.7%)(115). It is therefore still recommended by international guidelines to prioritize HIV/HCV coinfected patient either because of increased fibrosis progression or prevention of spread of HCV (public health aspect) (47,48).

Conclusions There have been many advances and changes in the management of both HIV and HCV over the past decade resulting in the need to review and reassess previous paradigms. Increased liver fibrosis progression (previously reported in the HIV/HCV co-infected) may be abrogated by improved control of HIV with safer, less hepatotoxic cART and with commencement of HIV therapy at an earlier stage and higher CD4 count. All these factors directly influence the degree of immune activation and dysregulation which impacts fibrosis progression. Furthermore, SVR rates in coinfected patients treated with DAAs are equivalent to those seen in the HCV monoinfected perhaps due to less reliance on direct immunological clearance with the newer DAAs. Clinicians however must remain observant for potential drug-drug interactions and also attempt to decrease an individual’s risk behaviour and the consequent potential for reinfections and the spread of DAA-resistant virus.

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Table 1: Summary of studies demonstrating equal fibrosis progression rates between HIV/HCV coinfected and HCV mono-infected patients Author

Sample size

Study design

Method of fibrosis evaluation

Follow-up time Result between HIV HCV measurements /HCV (median) Studies reporting similar fibrosis progression rates between HCV mono- and HIV/HCV co-infected patients Mazzocato, 2014 (95)

50

115

Longitudinal, retrospective

Transient elastography

Tovo, 2013 (94)

26

70

Longitudinal, retrospective

Serial biopsy

SuárezZarracina, 2012 (93) Sterling, 2010 (92)

111

68

Cross-sectional

Transient elastography

59

59

Longitudinal, prospective

Serial biopsy

Grünhage 2010 (90) Souza, 2008 (91)

57

84

Cross-sectional

53

65

Cross-sectional

Transient elastography Biopsy

Co: 3.1 y a (1.75 - 3.95) Mono: 1.9 y a (1.15 - 3.29) Co: b 50 m (12 - 99) Mono: b 65 m (21 - 159) na c

Co: 4.7 y (2.3) Mono: 5.8 y c (1.7) na na

Similar proportion of patients developed advanced fibrosis in both groups Similar fibrosis progression rate Liver fibrosis similar between groups Similar fibrosis progression rate Liver stiffness similar between groups Liver fibrosis similar between groups

Studies reporting increased fibrosis progression rates in co-infected patients Avihingsanon, 2014 (87)

130

331

Cross-sectional

Transient elastography

na

Prevalence of advanced fibrosis was higher in the co-infected group

Brescini, 2014 (88)

70

168

Cross-sectional

Transient elastography

na

Li Vecchi, 2013 (89)

68

69

Cross-sectional

Transient elastography

na

Sagnelli, 2013 (86)

440

374

Cross-sectional

Biopsy

na

Ragni, 2011 (85)

93

127

Cross-sectional

Biopsy

na

MartinCarbonero, 2009 (84)

133

448

Cross-sectional

Transient elastography

na

Castera, 2007 (81)

137

137

Cross-sectional

Biopsy

na

Gaslightwala, 2006 (82)

154

554

Cross-sectional

Biopsy

na

Gonzalez, 2006 (83)

89

117

Cross-sectional

Biopsy

na

Severe liver fibrosis was more frequent among coinfected patients Co-infected patients had higher liver stiffness values than the monoinfected patients Fibrosis was more advanced in co-infected group Fibrosis was more advanced in co-infected group Presence of significant liver fibrosis was found more often in co-infected patients Fibrosis was more advanced in co-infected group Severe fibrosis was more common in co-infected patients Fibrosis was more advanced in co-infected group

29

na = not applicable; y = years; m = months;

a

median and first to third quartiles;

b

median and

variation; c mean and standard deviation

30

Fig. 1: SVR12 rates in Interferon-free DAA studies in HIV/HCV co-infected patients with comparator data for HCV mono-infected patients.

Studies included solely or mostly HCV genotype 1 patients. HIV/HCV coinfected patients are depicted in black bars and the HCV mono-infected patients in white bars. Depicted studies are: SOF/LDV – ION-4 (31) and ION-1 (116); 3D+RBV – Turquoise1 (33) and PEARL-III and PEARL-IV (117); GZR/EBR – C-EDGE COINFECTION (34)

and

C-EDGE

(118).

3D=paritaprevir/ritonavir/ombitasvir/dasabuvir;

SOF=sofosbuvir;

LDV=ledipasvir;

RBV=ribavirin;

GZR=grazoprevir;

EBR=elbasvir; DAC=daclatasvir

Figure 2 : Factors influencing liver fibrosis progression

31

HIV coinfection: Is it time to change paradigms?

Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. Howev...
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