HIV/HCV coinfection – part 1

Leighton Davies MD, MSc for HIV i-Base

This is the first of a two-part article. Part two will be included in a future issue of HTB and will focus on clinical management including treatment and controversies in HIV/HCV co-infected patients.


Co-infection with HIV and HCV is common in Europe and the USA affecting approximately 30% of HIV-infected individuals and 10% of HCV-infected patients, respectively. [1] Approximately 170 million people worldwide have chronic HCV infection, including 17 million people with HIV/HCV coinfection. In Europe the incidence of co-infection in HIV-positive patients varies by countries from less than 5% (Netherlands) to around 50% (Spain, Italy). Because HCV is a blood borne virus, incidence is highest where HIV has primarily been driven as an IVDU epidemic. This figure is likely to be higher still in some Eastern European countries.

The high prevalence of co-infection is attributed to common risk factors for transmission – blood and blood products. HCV is much more infectious than HIV by percutaneous blood exposure, being transmitted by 15 to 30 of every 1000 needlestick injuries, compared with 3 per 1000 for HIV. [2] HCV can remain infectious in dried blood for several hours and replication competent virus was reported in dried blood after several weeks in one study (although those conditions were unusual). HIV becomes uninfectious in less than a minute outside the body. Replication rates of HCV are much higher than for HIV, resulting in higher viraemia, which itself is a factor for transmission.

In the UK, the prevalence of HCV co-infection is high amongst intravenous drug users (IVDUs) (91%), or people who used transfusion of blood or blood products (71%) prior to 1985, when heat treatment of blood products was introduced. Even though HCV was not discovered until 1988, and a test for HCV was not marketed until 1991, heat treatment was effective at preventing infection with HCV.

Several large studies have shown that the prevalence of sexual transmission is negligible between monogamous heterosexual partners. [3] Sexual transmission is higher (estimates 4-8%) among HIV-positive gay men and men who have sex with men (MSM), who do not otherwise have traditional risk factors for acquiring HCV. London HIV clinics have collectively reported data on several hundred HIV-positive MSM who have become infected with HCV in the past 2-3 years and this is now regarded as an epidemic of HCV in HIV positive men in South-East England. [4, 5]

Risk factors for sexually acquired HCV, in addition to HIV, include sexual practices that have higher risk of trauma, including brachio-proctal stimulation (fisting), receptive and insertive anal intercourse without condoms, group sex and recreational (non-IV) drug use including cocaine and ketamine. It is speculated that these drugs when administered intranasally may facilitate the transmission of HCV through traumatic nasal mucosal damage and traces of blood on shared drug paraphernalia. Given the infectiousness of HCV, this is plausible, but verified cases of transmission have not been documented through this route. High HCV acquisition rates in HIV positive MSM have been linked to reports of lymphogranuloma venereum (LGV) infection, for example in the recent cluster reported in Rotterdam. [6] There is therefore accumulating evidence that HCV is a sexually transmitted infection amongst HIV-positive MSM. The presence of other sexually transmitted infections seems to enhance the infectivity of HCV. [7, 8] HCV viraemia is higher in co-infected patients, and correlates with that in semen, which may also facilitate sexual transmission. [9]

Vertical transmission accounts for 2-5% of infants born to HCV-infected mothers becoming infected with HCV [10], which increases to 17-20% if the mother is co-infected with HIV. Unlike HIV, however, there is no association between breast-feeding and acquisition of HCV, unless the mother’s nipples are cracked or bleeding. [11]

Natural history and diagnosis

Around 15-40% of people monoinfected with HCV spontaneously clear the virus, although this occurs less frequently in people who are coinfected with HIV, and this may be related to CD4 count at infection. If it is not spontaneously cleared, HCV infection enters a long chronic phase during which 20-30% of immunocompetent patients will progress to cirrhosis after 15-30 years. HIV coinfection increases both the incidence and rate of HCV disease progression.

HCV infection can be diagnosed with a second or third generation screening enzyme immunoassay (EIA) in HIV-co-infected individuals, however this assay frequently produces negative results with low CD4 counts or after spontaneous clearance. The gold standard, in terms of sensitivity and specificity, in diagnosing HCV infection – particularly in immunosuppressed populations – is HCV RNA PCR. It is also necessary to use PCR distinguish a prior resolved infection from chronic infection. Because HCV RNA can occasionally be detected intermittently, diagnosis and treatment decisions should not be based on the result of a single PCR result. Quantitive PCR are generally more sensitive than quantitive PCR, and currently have a lower level of detection of 200 copies/mL.

Quantitative RNA testing, unlike HIV-1 RNA testing, does not offer prognostic information on HCV disease. Its use lies in stratifying the response to anti-HCV therapy, with lower viral loads (<800,000 MIU) generally being associated with higher response rates. Normal range for HCV vireamia is several logs higher than for HIV disease.

Current recommendations call for testing of all HIV positive individuals at time of diagnosis and periodically (~ 6 monthly) for those considered to be at higher risk (high risk sexual practices, intravenous drug use) by HCV antibody, with subsequent confirmation of viraemia by HCV RNA PCR. In patients with unexplained liver disease with a negative HCV antibody test, PCR should be performed. [12] However as the HCV antibody EIA often generates false negative results, community organisations have called for RNA PCR testing to be the standard of care and is increasingly being adopted as such in most UK centres.

There are 6 main genotypes of HCV, with over 100 subtypes. Type 1 is the commonest in the USA, accounting for over two thirds of infections. Types 2 & 3 are more common in Europe. Type 4 has a predilection for infections in Egypt.

HCV genotype is the most significant determinant in response to achieving sustained viralogical response (SVR) after treatment regardless of HIV status, with genotypes 2 and 3 being more sensitive than 1 and 4.

Genotyping of all individuals should be performed at the time of first diagnosis, and in cases where exposure to HCV is suspected, the genotype may change over time through reinfection, and should be retested periodically. [12]

Clinical course

Acute HCV infection is usually asymptomatic, although a typical presentation of hepatitis with jaundice (in about 20% patients), anorexia, malaise and elevation of hepatic transaminase enzymes may be seen. High levels of on-going viraemia are commonly observed, with more than 10 trillion viral particles per day being produced (compared with 10 billion per day with HIV). [13]

If HCV is spontaneously cleared, and HCV viral load becomes undetectable, ALT/AST levels normalise and anti-HCV antibodies may persist for many years. It seems that adaptive immune responses are delayed, raising the hypothesis that the virus ‘outpaces’ the immune system. Accordingly, clinical symptoms such as jaundice, attributable to T-cell mediated liver injury are rarely observed in acute HCV infection.

Chronic HCV infection is often asymptomatic, with normal transaminases despite persistent viraemia. Alanine aminotransferase (ALT) has been considered the most sensitive liver enzyme for HCV infection, although the severity of infection does not correlate well with ALT elevation, which may vary considerably from month to month.

Additionally, people with normal ALT can have serious liver damage, and ARV drugs can elevate ALT. Neither ALT or HCV RNA indicate or predict severity of liver disease very clearly and this is both counter-intuitive and confusing given the reliance on surrogate markers in the management of HIV. Elevated serum bilirubin levels and prothrombin times, with depressed albumin and platelet levels, signify more advanced hepatic disease.

Although recent research into using non-invasive ultrasound, serum biomarker panels and fibroscan are looking to reduce reliance on invasive procedures, these have not been validated in coinfected patients. Liver biopsy remains the gold standard for assessing the grade and stage of liver disease.

UK guidelines recommend that use of biopsy should balance the risks and benefit for each individual. Many centres feel that the risk of a liver biopsy outweighs the benefit in people with bleeding disorder, although this also depends on the experience of the doctor performing the biopsy. There remains debate on the value of biopsies in HIV infection, even in those without haemophilia or similar disorders.

Mild liver damage is classified as a modified Ishak score of 3 or less and a fibrosis score of 2 or less. Moderate liver damage has an inflammatory score of 4 or more and/or a fibrosis score of 3 to 5. The clinical severity of advanced liver disease can also be graded by scores such as the Child-Pugh system. With the improved results of treatment with pegylated interferon for genotypes 2 and 3 many physicians may consider treatment without liver biopsy for those infected with these genotypes. [12]

Of the 85% developing chronic infection approximately 70% will have an indolent course, with low ALT elevation and progression to cirrhosis over several decades, if ever. Fatigue and depression are the two most common symptoms of chronic HCV.

Approximately 20% of people with chronic HCV will develop cirrhosis over an interval of 15 to 20 years, some may develop cirrhosis much later and others will not develop any significant liver damage. [14] HIV also accelerates HCV progression.

A UK study also reported that 15% HIV-positive MSM who are sexually infected with HCV may have a more severe course with rapid disease progression, often as early as 6 years post-infection. [15] Of those developing cirrhosis about 1-4% each year will go on to develop hepatocellular carcinoma (HCC).[16] HCV accounts for approximately 40-50% of liver related deaths in the USA and Europe and is the leading cause of liver transplants in these countries. Factors associated with fibrosis progression are duration of infection, male gender, age >40 years, older age at infection, alcohol consumption >50 grams/day and HIV co-infection, especially among persons with <200 CD4 cells/mm3– this population is at greatest risk for serious liver damage.

Hepatocyte damage is not thought to be mediated by direct viral cytopathic effects but through induction of apoptosis in HCV infected cells. However, the molecular mechanisms that cause liver cell damage during HCV infection have not yet been fully and clearly defined.

Early studies in the pre-HAART era failed to show that HCV accelerates HIV progression as assessed by immunological [17] or clinical parameters [18], although HCV may act as a co-factor for HIV disease progression in several ways: non-specific immune stimulation driven by chronic HCV infection may enhance HIV replication; the infection of immune cells by HCV could favour the depletion of the CD4 cell pool and partly blunt the immune recovery that follows successful anti-retroviral therapy; and finally, HCV could compromise the benefit of HAART as a result of a higher incidence of hepatic toxicity and therapy discontinuation. Indeed the Swiss HIV Cohort study demonstrated that HCV infection was independently associated with an increased risk of progression to AIDS or death, despite a similar use of HAART as those mono-infected HIV positive individuals. It also suggested that co-infected patients were less likely to achieve a CD4 count rise of at least 50 cells mm 3 within 1 year than their mono-infected counterparts. The virological response to HAART was, however, not deemed to be affected by HCV co-infection. [19] There is compelling evidence that HIV, however, accelerates the course of HCV infection and this will be discussed subsequently.


Research into HCV pathogenesis has been hampered by the lack of small animal models of infection – the nearest animal model being the chimpanzee, which is an endangered species and therefore expensive. Some success has been obtained by producing HCV replicons in hepatoma cell lines [20], allowing for the expression of the complete HCV open reading frame, encoding for both structural and non-structural proteins. Another approach has been to transfect SCID mice with human hepatocytes [21], which supports productive HCV infection.

Finally, a different approach has been recently developed: laser capture microdissection (LCM) technique allows the isolation and analysis of single infected cells chosen by histological and immunohistochemical criteria from liver sections. [22]

The mechanisms responsible for tissue injury in acute and chronic infection are not well understood. HCV is generally not considered to be a cytopathic virus because of the absence of classic cytopathic features in liver biopsy samples, although HCV appears to have important interactions with host cell proteins that might adversely affect hepatocyte survival or regeneration. The classic understanding of the pathogenesis of liver disease is that it is due to the cellular immune response against the virus, including that of CD8+ cytotoxic lymphocytes (CTLs), which activates hepatic stellate cells, leading to inflammation and fibrosis.

There is little evidence to suggest a direct virological interaction between HIV and HCV in the liver. HIV is lymphotropic, but does not infect hepatocytes directly. HCV, on the other hand appears to be lymphotropic as well as hepatotropic as viral sequences have been amplified from peripheral blood mononuclear cells (PBMCs) of infected individuals. [23] Overall, infection of non-hepatocytic cells may constitute a ‘reservoir’ that would favour selection of HCV variants and viral persistence. In fact the almost universal recurrence of HCV infection after orthotopic liver transplantation corroborates the existence of extra-hepatic sites where HCV can persist and replicate.

HCV is a small RNA virus of the genus Hepacivirus and is a member of the Flaviviridae family, previously termed “non A-non B hepatitis virus” before it was first identified in 1989. Very little is known about the mechanism of entry of the HCV into its target cell – the hepatocyte. Some limited evidence suggests that this may be partially mediated by binding to a receptor complex that probably includes the ubiquitous tetraspanin CD81 and as-yet-unknown hepatocyte-specific factors. Further research into identifying the precise mechanism of cellular entry is warranted as potential therapeutic agents akin to the fusion inhibitors and CCR5/CXCR4 antagonists of HIV could be developed.

Following infection of a hepatocyte and internalisation, the 9.6-kb positive single-stranded RNA genome comprising the coding sequences of the structural proteins (C, E1, E2, and p7) and the non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B), is uncoated and undergoes two fates:

  1. It is translated by host cellular ribosomes into a long polyprotein, which is subsequently cleaved by both host (signal peptidase) and virus derived (NS2/NS3 metalloproteinase, NS3/NS4A serine) proteases to form mature viral proteins. These proteins comprise the structural components, which constitute the viral particle, and the non-structural proteins that are generally involved in protein processing and genome replication.
  2. The virus-encoded RNA-dependent RNA polymerase (NS5B) replicates the HCV RNA genome is replicated by into new genomic strands, packaged with structural proteins into mature viral particles. These particles are then released by cell lysis or exocytosis.

It is becoming apparent that HCV may circumvent the host’s innate anti-viral response at several levels:

  • Inhibiting genes that stimulate interferon production;
  • Inhibiting interferon signalling; and
  • Blocking interferon-inducible protein kinases.

Three possible mechanisms have been proposed to account for this resistance to IFN-alpha and IFN-beta (the so-called Type 1 interferons):

First, the HCV serine protease NS3-NS4A blocks interferon regulatory factor-3 (IRF3)-mediated induction of type 1 IFN. [24]

Second, specific sequences within E2 and the NS5A proteins seem to inhibit the activity of RNA-stimulated protein kinase R (PKR), which is responsible ultimately for inhibiting viral RNA and protein synthesis. [25] Intriguingly E2 sequences of HCV genotype 1 appear to inhibit PKR more efficiently than E2 sequences of HCV genotypes 2 and 3.

Finally, specific HCV proteins might interfere with the function of innate effector cells, such as natural killer (NK) cells. Recent in vitro studies have shown that high concentrations of recombinant E2 crosslink the tetraspanin CD81 at the surface of NK cells, inhibiting their cytotoxicity and cytokine production. [26]

Patients who spontaneously recover from HCV typically mount vigorous multi-epitope-specific CD4+ and CD8+ T-cell responses that are readily detectable in blood samples. By contrast, patients with chronic HCV tend to have late, transient or narrowly focused T-cell responses. [27]

Individuals who have a polyclonal HCV-specific CD4+ cell response are more likely to clear HCV, as opposed to individuals who do not (e.g. HIV infected persons); and are more likely to become persistently infected. As with the CD4+ cell response, polyclonal and multi-specific CD8+ CTLs are also associated with spontaneous clearance – whereas a more narrowly focused response during acute infection tends to lead to chronic infection.

Recent studies have suggested that there is functional “stunning” of the immune response in acute HCV infection, with impaired production of IFN-gamma by virus-specific CD8+ cells, and that this persists in patients with chronic HCV infection.

The normal, uninfected liver maintains a largely tolerogenic environment and contains a large number of intrahepatic T-cells. Why this normally tolerogenic environment should change to an inflammatory one is currently unclear. [28]

It is clearly established, however, that HCV mainly produces persistent infection accompanied by a viral escape mechanism through viral sequence mutations. HCV RNA exhibits significant genetic variability, with a mutation rate of 1 in 1000 bases per year, in all its domains producing populations of ‘quasi-species’. These quasi-species may favour the selection of RNA molecules that are ‘resistant’ to anti-viral factors. Its quasi-species nature, comparatively high replication rate and lack of proofreading capacity of its RNA polymerase all contribute to a rapid diversification of the viral population.

At the T-cell cell level, such viral escape seems to affect eiptope processing, MHC binding, and T-cell receptor (TCR) stimulation. Very recent findings have challenged conventional thinking that the large numbers of sequence mutations were simply random in the virus’s ever-changing genome.

This new research suggests that Darwinian genetic selection is at play – the virus’s genome changes in ways that render it reproductively more fit in the face of each immune system it encounters. Stuart Ray and colleagues from the Johns Hopkins University, found that when the immune response weakens, the virus naturally mutates towards a set of 3,000 common amino acids – the virus’s “preferred” state. During the acute phase, under intense immune pressure, the virus is forced to drift away from an ancestral set of sequences (the consensus sequence), using mutations to evade the immune system. Once the virus successfully evaded a particular immune cell, its amino acids reverted back to the consensus set. Thus it is proposed that this genetic drift is the mechanism for how the virus escapes the acute immune response and establishes a chronic state of infection. [29]

The effect of HIV on HCV cellular immune responses

Numerous studies have demonstrated that patients with HIV have a higher rate of progression of fibrosis, especially those with CD4 cell counts less than 200 cells/mm 3. Before the advent of HAART, patients co-infected with HIV and HCV had an approximate 3.6 fold increase in risk of developing cirrhosis. In the HAART era, End Stage Liver Disease (ESLD) resulting from HCV coinfection has emerged as a leading cause of death among HIV-positive people. Reconstitution of immunity may lead to a decrease in the rate of progression to fibrosis and risk of clinical events due to liver disease. However, this is still controversial as some people die from HCV complications at high CD4 cell counts on HAART.

Apoptosis in HCV infection

Both with liver damage and oncogenesis, a disturbance of apoptosis has been implicated. HCV-triggered liver injury is mediated mainly by host immune mechanisms. Caspases are enzymes that are involved in the final steps of apoptotic signalling pathways, and their activation is postulated to be triggered by death ligands. Other cytokines, granzyme B or HCV proteins, appear to be closely correlated with the immune response. There is growing evidence that death receptor mediated apoptosis plays a critical role in HCV-associated liver injury. The Fas/Fas ligand (or CD95/CD95L) death receptors probably have the most pathogenic role. Similarly Tumour Necrosis Factor (TNF) has been shown to activate effector caspases efficiently in HCV infection. Besides death receptors, the granzyme B/perforin pathway almost certainly plays a role in HCV-mediated apoptosis.

Thus activated CTLs recognise viral antigens by the TCR in the context of MHC antigens. TCR activation induces the expression of death ligands, such as CD95L or TNF-related apoptosis-inducing ligand (TRAIL), which bind to their cognate receptors on hepatocytes and trigger caspase-8 activation. Simultaneously CTLs release cytotoxic granules containing granzymes and perforins. Internalised granzyme B can directly activate caspase-8 and other caspases. Both mechanisms converge in a mitochondria-dependant pathway at the level of executioner caspases, which cleave various proteins and lead to cell death.

Interferons produced upon viral infection may modulate apoptosis by a number of mechanisms, such as activation of the JAK-STAT pathway, PKR, the 2’, 5’ oligoadenylate system (in particular RNase L); or upregulation of TRAIL and its receptors. Moreover, HCV proteins, in particular the core protein, may either positively or negatively regulate cell death. The HCV core protein has been reported to sensitise cells to death-receptor-mediated apoptosis, whereas it may exert inhibitory effects through the activation of NF-kappa-B and subsequent induction of anti-apoptotic gene products including Bcl-XL, Bcl-2 and inhibitor of apoptosis proteins (IAPs). The pro-apoptotic pathway may be involved in liver damage, whereas inhibition of apoptosis may contribute to viral persistence and development of hepatocellular carcinoma. Recently it has been demonstrated that the E2 protein, in conjunction with HIV gp120, induces apoptosis in hepatocytes via a Fas-FasL-dependant pathway, which ultimately leads to the release of cytochrome c from mitochondria, as well as activation of downstream apoptotic signalling cascades. [30]

Hepatic fibrogenesis

The alterations in cytokine production that accompany HIV infection may aggravate the already blunted endogenous interferon response seen in chronic HCV infection. Liver fibrosis (termed cirrhosis when it affects the entire liver parenchyma) is a dynamic process involving complex cellular and molecular mechanisms initiated by chronic inflammation due to liver-tissue damage, led by the activation of quiescent hepatic stellate cells (HSCs), and resulting in the re-modelling and deposition of the extra-cellular matrix (ECM).

Fibrosis results from excessive accumulation of ECM. The collagens are the most important molecular targets: since they represent the major matrix proteins; they form important mechanical cytoskeletal scaffolds; and their proteolysis by specific proteases appears to be rate limiting for ECM removal. The fibril forming interstitial collagens type I and III, and the sheet-forming basement membrane collagen type IV are the most abundant ECM components in the liver. In cirrhosis their content increases up to 10-fold. Adverse stimuli, including viruses, toxins, hypoxia, and bile stasis can trigger fibrogenesis either by cytokine release or simply by mechanical stress.

In the acute phase of liver disease, fibrogenesis is balanced by fibrolysis – the removal of excess ECM by proteolytic enzymes, the most important of which are the matrix metalloproteinases (MMPs). MMP-1, -2, -3, -8, -9, -12, -13 and -14 are expressed in human liver cells. With repeated injury of sufficient severity, fibrogenesis prevails over fibrolysis, resulting in excess ECM deposition, i.e. fibrosis. Fibrogenesis is characterised by an upregulation of ECM synthesis, a downregulation of MMP secretion and activity and by an increase of the physiological inhibitors of the MMPs, the tissue inhibitors of MMPs (TIMPs). Collagens, MMPs and TIMPs are mainly produced by myofibroblastic cells, which are derived from HSCs or from activated (portal and perivascular) fibroblasts. Activated liver macrophages (Kuppfer cells) or proliferating bile ductular epithelia or endothelia, other mononuclear cells and myofibroblasts themselves are sources of fibrogenic cytokines and growth factors that can stimulate HSC and perivascular fibroblasts to become MFs. [31]

The severity and progression of fibrosis in chronic liver disease is exacerbated by additional factors that include alcohol use, and, of particular relevance to HCV/HIV co-infection, Non-Alcoholic Steato-Hepatitis (NASH). This is a disorder related to the metabolic syndrome (hypertriglyceridaemia, insulin resistance, obesity) which has recently been closely associated with exposure to NRTI therapy and with stavudine use in particular. [32]

There is an increased risk of diabetes among people with HCV, and this has also been reported with use of use of protease inhibitors among coinfected people.

Hepatocellular carcinoma

The precise mechanism by which HCV causes HCC is not known. Unlike the hepatitis B virus (HBV), HCV is not a DNA virus and does not become incorporated within the nucleus of hepatocytes. It is more likely that HCC occurs against a background of inflammation and regeneration, associated with liver injury due to chronic hepatitis. Virtually all cases of HCV-related HCC occur in the presence of cirrhosis, suggesting that it is the underlying liver disease per se that is the risk factor for HCC rather than HCV infection [33] – although cirrhosis would not have occurred without the initial HCV infection. The prevailing hypothesis has been that some cirrhotic nodules that grow larger than others (referred to as adenomatous hyperplasia) were the precursor for HCC. Recently, however, it has been suggested that foci of transformed hepatocytes may arise in between cirrhotic nodules and grow to become adenomatous hyperplasia and, eventually, HCC. [34]

Host factors, which have been implicated in increasing the risk for development of HCC, are the same as for HCV progression: age, male gender, and severity of underlying liver disease. Viral genotype may be important, although early suggestions that infection with genotype 1b is more likely to result in the development of HCC have not been confirmed in larger studies. No clear link has been established between serum levels of HCV RNA and progression to HCC.

Some external factors that might add to the risk for HCC in patients with HCV infection include alcohol consumption, coexistent HBV infection, and porphyria cutanea tarda (PCT, an aquired or inherited photosensitivity with increased skin porphyrins, associated with iron loading and often with HCV) although this latter condition is found only in some geographic areas. [35] Other extrahepatic manifestations of HCV include non-Hodgkin’s lymphoma, membranoproliferative glomerulonephritis, lichen planus, autoimmune thyroiditis, diabetes mellitus and Sjogren’s Syndrome.

The risk for a patient with HCV infection developing HCC cannot be calculated with any precision. It is known that up to 20% of patients with chronic HCV infection develop histological evidence of cirrhosis over a 20-year period. Furthermore, among patients with established cirrhosis due to HCV infection in screening programs, it has been found that 3-4% per year develop HCC, at least for the first 4-5 years of screening. By extrapolation, after 20 years of infection, 6-8% of patients with chronic hepatitis C can be expected to have developed HCC, although these calculations need to be validated by more prospective studies. Studies from Japan have found that the mean interval from HCV monoinfection to the development of HCC is approximately 25 years, but these periods have a very wide range of variation. For reasons that are unclear, HCV outcomes seem to be worse in Japan than the US. In the United States, HCC has been described as soon as 5 years from the onset of HCV infection, although this is rare.

UK guidelines recommend that patients who are known to have cirrhosis or transition to cirrhosis should be considered for regular screening with biannual or more frequent ultrasound and alpha-fetoprotein (AFP) measurements to enable the early detection of hepatocellular carcinoma (HCC). It should be recognised that even with frequent screening a treatable HCC may not be detected. [12]

Typically, HCC carries a poor prognosis, with survival times from diagnosis measured in months. Screening studies have shown that small amounts of HCC can be detected at an early stage when it may be more amenable to curative therapy. At present surgical resection offers the best hope for prolonged disease-free survival. This may take the form of partial or total hepatectomy. Unfortunately, partial hepatectomy for HCC is associated with a very high recurrence rate (approximating 25% per year) while total hepatectomy implies liver transplantation. [36]


The above account of the postulated mechanisms by which HCV and HIV cause severe liver damage highlight targets for therapeutic intervention. These include direct inhibition of viral replication, immuno-modulation and anti-fibrotic measures, which will be discussed in the second part of this review article, together with clinical management of HIV/HCV coinfection.

Further reading: British HIV Association (BHIVA) guidelines for treatment and management of HIV and Hepatitis C co-infection. October 2004.Online at:

The British HIV Association

Thanks to Tracy Swan and Daniel Raymond for editorial comments on this article.


  1. Sherman KE et al. Hepatitis C prevalence among patients co-infected with HIV: a cross-sectional analysis of the US Adult AIDS Clinical Trials Group. Clin. Infect. Dis. 2002; 34: 831-837.
  2. Centres for Disease Control and Prevention. Updated U.S. Public Health Service guidelines on the management of occupational exposures to HBV, HCV and HIV and recommendations for post-exposure prophylaxis. MMWR 2001; 50: 1-67.
  3. Halfon P et al. Molecular evidence of male-to-female sexual transmission of hepatitis C virus after vaginal and anal intercourse. J Clin Microbiol 2001; 39: 1204-1206.
  4. Danta M et al. Evidence for sexual transmission of HCV in a recent epidemic in HIV-infected men in Southeast England. 11th BHIVA Conference, 20-23 April, Dublin, Oral Abstract 25.
  5. Fletcher S et al. Sexual transmission of hepatitis C and early intervention. J. Assoc. Nurses AIDS Care. 2003; Sep-Oct, 14 (Suppl. 5) 87S-94S.
  6. Gantz HM et al. A cluster of Acute Hepatitis C virus Infection among men who have sex with men – results from contact tracing and Public Health Implications. AIDS 2005; 19.
  7. Nelson M et al. Increasing incidence of acute hepatitis C in HIV positive men secondary to sexual transmission, epidemiology and treatment. 9th EACS, 25-29 October, Warsaw. Abstract F12/3.
  8. Browne R et al. Increased numbers of acute HCV in HIV positive homosexual men; is sexual transmission feeding the increase? Sex. Transm. Infect. 2004; 80: 326-327.
  9. Matthews-Greer J et al. Comparison of HCV viral loads in patients with or without HIV. Clin. Diagn. Immunol. 2001; 8(4): 690-694.
  10. Zanetti AR et al. Mother-to-infant transmission of hepatitis C virus. Lancet. 1995; 345: 289-291.
  11. Roberts EA, Yeung L. Maternal-infant transmission of hepatitis C virus infection. Hepatology. 2002 Nov;36(5 Suppl 1):S106-13.
  12. British HIV Association (BHIVA) guidelines for treatment and management of HIV and Hepatitis C co-infection. October 2004.
  13. Pawlotsky JM. Symposium: Rational Use of Diagnostic Tests for HCV. S112; IDSA, Philadelphia PA, November 1999.
  14. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001 Aug 15;33(4):562-9.
  15. Alter H. Symposium: Natural History of HCV S111; IDSA, Philadelphia, PA, Nov. 1999.
  16. Di Bisceglie AM. Hepatitis C. Lancet. 1998 Jan 31;351(9099):351-5.
  17. Llibre JM et al. Hepatitis C virus infection and progression of infection due to human immunodeficiency virus [letter; comment]. Clin. Infect. Dis.1993; 16 (1): 182,
  18. Dorrucci M Co-infection of hepatitis C virus with human immunodeficiency virus and progression to AIDS. Italian Sero-conversion Study. J. Infect. Dis.1995; 172 (6): 1503-1508.
  19. Greub G et al. Clinical progression, survival and immune recovery during anti-retroviral therapy in patients with HIV-1 and HCV: the Swiss HIV Cohort Study. Lancet. 2000; 356: 1800-1805.
  20. Lohmann V et al. Replication of subgenomic HCV RNAs in a hepatoma cell line. Science. 1999; 285: 110-113.
  21. Mercer DF et al. HCV replication in mice with chimeric human livers. Nat. Med. 2001; 7: 927-933
  22. Fend F et al. Laser capture microdissection: methodical aspects and applications with emphasis on immuno-laser capture microdissection. Pathobiology. 2000; 68: 209-214.
  23. Zignego AL et al. HCV as a lymphotropic agent: evidence and pathogenetic implications. Clin Exp Rheumatol. 1995; 13 (Suppl 13): S33 –S37.
  24. Foy E et al. Regulation of interferon regulatory factor-3 by the HCV serine protease. Science 2003; 300: 1145 – 1148.
  25. Taylor DR et al. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999; 285: 107-110.
  26. Tseng CT et al. Binding of the HCV envelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med. 2002; 195: 43-49.
  27. Weidermeyer H et al Impaired effector function of HCV-specific CD8+ T-cells in chronic HCV. J. Immunol. 2002; 169: 3447-3458.
  28. Crispe I N. Hepatic T-cells and liver tolerance. Nature Rev. Immunol. 2003; 3: 51-62.
  29. Bowen DG et al. Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. J Exp. Med. June 6 2005.
  30. Bantel H et al. Apoptosis in hepatitis C virus infection. Cell Death and Differentiation. 2003; 10: S48-S58.
  31. Schuppan D et al Hepatitis C and liver fibrosis. Cell death and Differentiation. 2003; 10: S59-S67.
  32. Pessayre D et al NASH: a mitochondrial disease, J. Hepatology. June 2005.
  33. Di Bisceglie AM et al. Development of hepatocellular carcinoma among patients with chronic liver disease due to HCV infection. J. Clin. Gastroenterol. 1994; 19: 222-226.
  34. Tong MJ et al. Clinical outcomes after transfusion-associated hepatitis C. NEJM. 1995; 332: 1463-1466.
  35. Silini E et al. HCV genotypes and risk of hepatocellular carcinoma in cirrhosis: A case-control study. Gastroenetrology 1996; 111: 199-205.
  36. Zoli M et al. Efficacy of a surveillance program for early detection of HCC. Cancer. 1996; 78: 977-985.

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