Introduction
Nearly 2% of people in developed countries are infected with hepatitis C virus (HCV). It represents the most usual cause of chronic hepatitis and is also the main indication for liver transplantation [1]. Acute HCV infection has a characteristically high rate of evolution into chronic hepatitis, which occurs in more than 80% of cases, and is prone to lead to development of liver cirrhosis two to four decades later and eventually hepatocarcinoma [2].
The co-infection by HCV and HIV is quite common, mainly because both viruses share the same transmission routes [1,2]. The prevalence of HCV infection among injecting drug users (IDUs) varies from 75% to 90% [3], and rises to nearly 100% in some haemophiliac series. The main risk group for HIV infection comprises IDUs in some countries and, in those regions, the amount of HIV-infected patients co-infected with HCV is substantial. In the EuroSIDA cohort study [4], which includes data from 3,048 HIV-infected subjects, overall 33% of the population was anti-HCV positive; and amongst IDUs more than 75% were co-infected.
HCV and HIV interactions
As the prognosis for HIV infection has improved significantly, mainly due to the introduction of highly active antiretroviral therapies (HAART), chronic liver disease has become increasingly prevalent, and it seems destined to be a very important cause of morbidity and mortality in the HIV-HCV co-infected population [5,6]. In a retrospective analysis of the causes of hospital admission in a reference HIV/AIDS institution in Madrid: end-stage liver disease was diagnosed in 8.6% of 1,670 hospital admissions during the previous 5years; HCV, alone or in combination with other hepatotropic viruses, was involved in 88.6% of instances; and death directly related to liver complications occurred in 15 individuals, which represented 4.8% of the total causes of in-hospital mortality during the study period, and the fifth cause of death in- hospital for HIV-infected patients [5].
The immunodeficiency associated with HIV infection seems to accelerate the course of HCV infection [5,7-11]. In this way, up to 25% of HIV-infected IDUs had developed cirrhosis after 15years of carrying HCV in one Spanish series, whereas cirrhosis only occurred in 6.5% of those who were HIV-negative [10]. Furthermore, the simultaneous acquisition of HIV and HCV in a haemophiliac series was seen to increase by 21 times the risk of hepatic failure compared with patients infected only with HCV [6]. A recent report has suggested that the co-infection by HCV seems to be a detrimental prognosis cofactor for HIV disease, accelerating the drop of CD4 cells [12].
HCV infection is controlled by the cytotoxic lymphocytes (CTL), which eliminate the infected hepatocytes, and by cytokines produced by the T cells, which directly inhibit viral replication [13]. The immune response against viral infection appears in two ways: the CD4 Th1 cells produce cytokines which activate the CTL (CD8) response, whereas the CD4 Th2 cells induce the production of specific antibodies against HCV. It has been suggested that a poor response of the CD4 Th1 subset might be related to the chronicity of HCV infection. This defective response might induce a change in the CTL that makes it more difficult to eliminate HCV. This possibility could explain the higher activity (virulence) of HCV infection in HIV-infected patients, whose CD4 cells were defective in function and number.
The current availability of new antiretroviral drugs, and the recent change of the rationale in anti-HIV therapy, together with the use of HAART as the most common way to treat HIV infection, has improved the life expectancy of these patients [14,15]. This clinical benefit is the consequence of a maximal inhibition of virus replication [16]. The immunological restoration observed in patients under HAART occurs to defend against a wide range of pathogens, including HCV.
Similarities between HCV and HIV
HIV and HCV display some common biological features. Both are RNA viruses: HCV belongs to the Flaviviridae family, and HIV to the Retroviridae family. Flaviviruses have a single-RNA strand [17], whereas retroviruses have a double RNA strand [18]. The life cycle of both viruses also has some differences. The HIV-RNA, transcripted to DNA by the reverse transcriptase (RT), integrates in the infected cell‚s genome, constituting the integrated provirus; this integration is the cause of the irreversibility of HIV infection. In contrast, the HCV genome does not integrate into the cell‚s genome, and the replication of that virus takes place in the liver cell‚s cytoplasm. This non-integration makes it easier to eradicate HCV, and hence to cure the infection (Fig. 1).
Another characteristic of both viruses is the large heterogeneity of their respective viral genomes [19,20], producing a variety of genotypes and the so-called ‚quasispecies‚, genetic variants around a ‚master sequence‚ [21]. This genetic variability is the consequence of a high mutation rate in RNA viruses, derived from the high rate of replication errors, a direct result of the non proof-reading ability of their polymerases (RT for HIV and a RNA polymerase for HCV). This inability of these enzymes makes it, compared with DNA-dependent DNA polymerases, highly error prone. The mutation rate for RT is 1×104-105 nucleotides, which means a mutation at each completely transcripted HIV genome. Similar numbers have been described for HCV [21]. In this virus there is a variability among the nucleotide sequence of up to 34% among the most distant variants [20]. This genetic variability is higher for HIV, probably due to recombination among the two RNA chains of the virus, through a phenomenon known as ‚Strand choice‚ [18,21]. This variability allows both viruses to develop a better ‚fitness‚ in the presence of some environmental circumstances, and to avoid either the immune system or pharmacological pressure. The most heterogeneous region for both viruses is the envelope-codifying region, probably related to the pressure of the immune system exerted over the virus. The diversity of this region in HCV differentiates six genotypes (1 to 6), divided also into several subtypes [20]. In the same way, among the HIV-1, three main types are recognised: M (main) with ten subtypes inside, O (outlier) [22], and the recently described group N [23].
The interest in classifying the virus species is not exclusively academic or taxonomic, but also important for clinical practice. Some variants of the same virus might have either a particular target cell, or a different sensitivity to antiviral drugs, or are more often transmitted in a certain fashion. In this way, HCV subtype 1b has a worse response to interferon (IFN) therapy than all the other subtypes [24]. Also, it is known that some particular subtypes are predominant in a certain population, or in a geographic area, or even among patients belonging to a particular risk group (i.e., HCV subtype 3 in European IDUs) [25].
The availability of some amplification techniques that allow one to detect and quantify the number of viral particles circulating in the blood, has yielded some information about other similarities between HIV and HCV. Some recent reports have shown similar replication kinetic for both viruses, with an average life-span of a virion in the blood of less than 5h, and a surprisingly high rate of turnover in the viral population [26-28]. The total HCV production has been calculated as 1011 to 1012 virions per day. Furthermore, contrary to previous suggestions, the viral load in patients infected by HCV or HIV remains almost stable over time, with only small changes, usually not higher than 0.5log10 [29,30]. In spite of this, there are important variations among different patients. Some groups have reported a higher HCV viral load in patients co-infected with HIV, compared to those not co-infected [10,31-34]. Moreover, HCV viral load shows an inverse correlation with the level of immunodeficiency in HIV-infected patients, as reflected by the number of CD4 cells [31].
Why treat hepatitis C in HIV co-infected patients?
The interest in the management of chronic hepatitis C in HIV-infected patients has risen in recent years as awareness of the impact of liver disease on life expectancy of HIV-infected individuals has become more apparent. Table 1 summarises some of these evidences. At the last NIH Consensus Conference (September 1997), which focused on the management of HCV infection, it was specifically stated that ‚patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of disease. Therefore, those with stable HIV infection, and good clinical and functional status should be considered for treatment‚ [35]. According to the commonly used recommendations for HCV treatment, the eligible patients should have an age of less than 55years, persistently increased transaminases levels (more than 1.5-fold normal values), HCV viraemia detectable in serum, and signs of inflammatory activity in the liver biopsy.
The widespread use of HAART for the treatment of HIV infection in the last two years has been accompanied by an increasing number of reports of hepatotoxicity [36,37]. A recent study conducted at our institution showed hepatotoxic manifestations in nearly 14% of patients after starting HAART [38]. Hepatotoxicity was more frequent amongst IDUs than other risk groups, this being directly related to the higher prevalence of HCV infection in this risk population. So, chronic hepatitis C might constitute a predisposing factor for developing hepatotoxicity, and this observation confirms the importance of treating HCV infection in HIV-infected patients, with priority, before beginning HAART.
Treatment with alpha-interferon
Alpha-interferon (IFN) was until recently, the only approved treatment for chronic hepatitis C. The sustained response rate in patients not co-infected with HIV is around 21%, directly correlated with the total administered doses of IFN [39]. In patients co-infected with HIV, the response rate is similar (see Table 2), but it decreases in subjects with lower CD4 cell counts [40]. Moreover, HIV-infected patients who acquire a sustained response to IFN do not relapse more frequently than HIV-negatives, even after long-term follow-up, despite the worsening of their immunodeficiency, suggesting that these patients truly eradicated HCV infection [41].
The stage of liver fibrosis and the distortion of the hepatic architecture has been considered as a prognostic marker, and at baseline seems very closely related to the response to interferon therapy [42]. A recent study has reported that patients co-infected with HCV and HIV have a higher degree of fibrosis and histological distortion than HIV-negative subjects [43], which might contribute to limit their response to therapy.
The direct association between the rate of sustained response and the total dosage of IFN administered [44] has led to the conclusion that the commonly accepted dosage of that drug for hepatitis C treatment seems not to be the most appropriate one. In fact, the reduction of HCV viraemia is higher when a higher dose of IFN is recommended, and it persists for longer when shorter intervals between doses are used [26,28,45]. Some studies are currently under way, evaluating the use of ‚induction-maintenance‚ regimens, with initially higher and more frequent doses of IFN during the first few weeks of therapy [46].
The requirements for higher doses of IFN and at shorter intervals has led to the development, still under investigation, of new presentations of IFN, such as their PGEylated forms, with this drug covalently bound to polyethyleneglycol. This presentation allows a slower release of IFN, as the covalent bonds become degraded. It offers, in addition, the possibility of maintaining sustained levels of IFN, with a more effective viral suppression. Another important advantage of these forms of IFN is their ease of administration, which becomes an important factor when therapies need to be taken for long periods, and it is already proven that a longer duration IFN course is associated with a higher rate of sustained response [44].
New drugs and combination therapy for HCV infection
Since there are virological features in common between HCV and HIV, other approaches to therapy for HCV infection may be applied from those learnt in the HIV field. The substantial reduction of HCV viraemia within 24h after a single dose of alpha-interferon [26], significantly more quickly than HIV viraemia after beginning HAART, seems related to a much faster kinetic of infection with HCV [26-28]. This rapid kinetic, associated with the characteristically high mutation rate of RNA viruses, supports the use of combined therapy for HCV infection. A selective pressure over the virus with only one drug, e.g. interferon-alpha, together with the high mutation rate of the virus and its short life-span, might cause the rapid development of resistant strains, and subsequent virological failure. Although this circumstance is already proved for HIV infection, and is one of the main arguments for strong support of the use of combination therapy in the current guidelines for anti-retroviral therapy [47], up until now there is no evidence of emerging IFN-resistant HCV mutants in patients failing to benefit from the drug. However, the lower response to IFN in patients carrying HCV genotype 1b has been linked to the presence of a characteristic genetic sequence in the NS5A gene, where the interferon-sensitivity determining region (ISDR) is located [48,49]. This behaviour in HCV infection looks like that of HIV-2 or HIV-1 group O, which are intrinsically resistant to non-nucleoside RT inhibitors (e.g., nevirapine, efavirenz), since naturally occurring mutations conferring resistance to these drugs are predominant for these variants, but not for HIV-1 group M subtypes [22].
The armoury against HCV has increased significantly in the last year. Two antiviral drugs previously used for other diseases, ribavirin [50-52] and amantadine [53,54], combined with IFN for use in patients with chronic hepatitis C, leads to a significant improvement in the rate of sustained responses, up to nearly 50% for ribavirin. Currently, a few studies are examining the role of these combinations for the treatment of HCV infection in HIV-infected patients. Ribavirin is a synthetic nucleoside with activity against a broad spectrum of viruses. In the USA it was first approved for use in aerosol form for the treatment of respiratory syncytial virus infections in children. Several studies have shown a certain activity of this drug against HCV [55]. When this drug is used as a single agent for the treatment of chronic hepatitis C, it decreases ALT activity in serum, but a sustained response is rarely achieved. For this reason, ribavirin has not been approved as monotherapy for hepatitis C, and is almost always used in combination with alpha-interferon. Until recently, the treatment of chronic hepatitis C with IFN plus ribavirin was only allowed for ‚relapsers‚ and non-responders to IFN, as a second line option. However, recently their use in combination as a first line therapy has become the standard of care, providing a higher sustained response than with IFN alone. Most importantly, side effects occur with similar rates to those found with the use of IFN alone, except for the rare possibility of haemolytic anaemia caused by ribavirin.
Amantadine, another antiviral drug approved for the prevention and treatment of influenza infections, with an antiviral mechanism not yet well understood, has also been shown to be useful against HCV [53,54]. Some reports [54] have claimed a higher rate of response (HCV-RNA clearance at the third month) when amantadine is associated with alpha-interferon. Amantadine is inexpensive ($30 per month) compared to alpha-interferon ($500 monthly), and it is administered orally (100mg twice a day), and is very well tolerated. Currently, several studies are testing the efficacy and safety of double and triple therapies against HCV infection, using IFN with ribavirin and/or amantadine. Up until now amantadine has not been approved by the FDA for its use against HCV infections. Studies incorporating the early use of new anti-HCV drugs and their use in combination recall the steps already run by antiretroviral therapy a few years ago.
In spite of all the efforts to achieve HCV eradication, with the incorporation of new drugs and new therapeutic strategies, no more than half of patients with chronic HCV infection respond to standard treatment with IFN, or to combinations of IFN plus ribavirin. Therefore, new pharmacological options or novel therapeutic strategies are needed. Most likely, a more effective use of IFN, making it more convenient to block HCV viral kinetics (e.g., with PGEylated forms, or more frequent schedules at induction), might improve the sustained response rate. It seems to be necessary to take a ‚more virological‚ approach towards the treatment of HCV infection, following the steps already taken for treating HIV infection, with the design of specific antiviral agents based on thorough knowledge of the molecular structure of HCV proteins. Some of these new drugs currently under investigation are protease and helycase inhibitors, which have the potential advantages of blocking virus replication and also may be effective in preventing acute HCV infection. The structures of HCV protease [56] and helycase [57] have already been reported but the lack of a suitable cell culture or animal model to study the effect of their potential inhibitors represents a great obstacle for testing new compounds. Other molecular approaches for the treatment of HCV infection that are under study include the use of antisense oligonucleotides and ribozymes [58]. Antisense molecules would prevent the transcription of HCV proteins from the HCV genome, whereas ribozymes selectively degrade RNA, including viral RNA. There is no doubt that the recent approval by the FDA of the first antisense drug, formivirsen, for the treatment of cytomegalovirus retinitis, will accelerate the research and marketing of similar compounds against other viruses, including HCV.
In the HIV field, combination therapy is now standard practice; monotherapy or even double combinations are no longer recommended [47]. Moreover, whereas drug combinations were initially reserved for persons with severe immunodeficiency, currently there is no doubt about beginning these as soon as possible in most patients. With respect to HCV infection, treatment before end-stage liver disease (cirrhosis) has occurred is also strongly recommended. The role of viraemia is not so definitely established as in the case of HIV, but there is a direct association between the response rate to treatment and baseline HCV viraemia [59]. As confirmation, the sustained response to IFN alone is not higher than 7% in patients with high HCV viraemia. Although the combination regimens were restricted, until recently, to non-responder patients, or to those who had had a relapse after a previous course of IFN, it has been well acknowledged that they have become widely available as a first line option, particularly for patients with high HCV-RNA levels [50,51]. This trend towards the use of combinations will be accentuated when the first HCV protease and helycase inhibitors become available [56,57]. There are other reasons, including those of cost versus benefit [60], that also support for the use of combination regimens as the initial therapeutic option for HCV infection. Following in the footsteps of HIV therapy, it looks likely that anti-HCV therapy will soon follow the famous statement of treat ‚early and hard‚ [61].
Interactions and side effects of antiviral agents in HIV-HCV co-infected subjects
Alpha-interferon administered subcutaneously at doses of 3-5MUnits three times a week, as it is recommended for chronic hepatitis C, can induce a rapid decline in the CD4 lymphocyte count in 10-15% of subjects with HIV infection [62]. This decrease usually occurs between the sixth and fourteenth week of therapy and tends to be transient, even without stopping therapy. However, in a few subjects CD4 lymphocytopenia can be irreversible, even after withdrawing the medication. Some authors [63] have associated this unexpected side effect with the presence of specific HLA alleles, although this has not been found by others [62]. In most instances, peripheral CD4 lymphocytopenia induced after beginning IFN therapy most likely reflects a displacement of cells from the circulating compartment to the lymphoid organs rather than a real destruction of those cells. However, in subjects with low CD4 cell counts, in which the levels of endogenous alpha-IFN are elevated and contribute to the immunodeficiency [64], the administration of IFN may be found to be contraindicated.
The effect of HIV protease inhibitors on HCV infection has been explored in two ways. First, viral proteases are encoded by both HIV and HCV genomes, since they are essential for the maturation process of their respective virus particles; inhibitors against one of them could inhibit the other. However, the specificity of these drugs has been demonstrated in several studies [65,66] that failed to recognise any alteration in HCV viraemia in subjects who received HIV protease inhibitors for 2-3months, despite the fact that those patients experienced a dramatic drop in their HIV plasma viraemia. Thus, the design of specific compounds targeting the HCV NS3 serine protease seems to be required for effectively blocking HCV replication. Secondly, the immune recovery produced by HIV protease inhibitors hypothetically could have a protective effect on HCV replication [67], which typically is enhanced in HIV-infected patients. Unfortunately, there is no evidence for this occurring since HCV viraemia does not change significantly in patients having a dramatic recovery of their CD4 cell count after starting on HAART [68]. Moreover, in one study a transient increase in HCV viraemia and liver enzymes was found after beginning HAART, which was accounted for by an increased destruction of hepatocytes through cytotoxic T cells associated with the acute immune recovery [69].
Ribavirin is a nucleoside analogue that inhibits the replication of many different viruses. Its specific mechanism of antiviral activity against HCV is not well understood. Previous studies have shown that it shows no similar effect against HIV [70,71]. The literature on ribavirin‚s interactions with antiretroviral drugs is fairly sporadic. Clinically, no pharmacokinetic or pharmacodynamic interactions have been noted between ribavirin and anti-HIV compounds. Ribavirin is not a substrate for, nor does it inhibit or induce any cytochrome P450 enzymes, which could be potentially dangerous with the concomitant use of protease inhibitors. However, in vitro studies have shown that interactions might occur through three mechanisms: by effects on phosphorylation; alteration of enzyme activity; or effects on cellular nucleoside uptake mechanisms. Ribavirin inhibits in vitro the phosphorylation of some nucleoside analogues, such as zidovudine and stavudine, [72] and, conversely, increases the phosphorylation of didanosine [73]. On the other hand, haemolytic anaemia is the main side effect associated with the use of ribavirin, and caution should be used when other nucleoside analogues that cause bone marrow suppression (e.g., zidovudine) are co-administered with ribavirin. Two trials, one in the USA and another in Spain [74], are currently investigating the safety and efficacy of interferon plus ribavirin in treating HIV-infected individuals. Hopefully they will answer outstanding questions.
Conclusion
The life expectancy of HIV-infected persons has been prolonged substantially since the introduction of new highly potent drugs used in combination. Liver disease, mainly that secondary to chronic hepatitis C, is now a growing cause of hospital admission and mortality in HIV-positive persons, mainly those with a previous history of transfusion or of being IDUs. An accelerated course of HCV infection leading to cirrhosis more rapidly has been observed in subjects with HIV and HCV co-infection. On the other hand, patients with chronic hepatitis more often develop liver toxicity when they are exposed to antiretroviral drugs, and cannot take them, which really compromises their survival. Alpha-interferon provides a sustained response in 15-20% of patients with chronic hepatitis C, even in those co-infected with HIV. However, patients with lower CD4 cell counts and higher hepatitis C viraemia tend to have a poorer response to therapy. Biological similarities between HIV and HCV strongly support the use of combination therapy in hepatitis C infection. The availability of new drugs, such as ribavirin, has recently opened the opportunity for using this approach, although its efficacy and safety needs to be explored in patients co-infected with HIV.
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