UK-CAB 15 – Treatment access in eastern Europe – hepatitis C coinfection – Pfizer

25 November 2005

Draft programme for the meeting
Reading material
HIV Treatment – CCR5
Hepatitis C – overview
CCR5 antagonist
Meeting Report Word document [ 44 Kb]
CAB Steering Group Feedback – Mark McPherson PP Slides [ 164 Kb]
Drug Development in HIV CCR5 Michael Zaiac Pfizer [4.3 MB]
Feedback: 7th Lipodystrophy -Simon Collins Powerpoint slides [ 1.8 MB ]

Programme

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Reading material

HIV Treatment – CCR5

From www.AIDSMAP.com

1. Introduction – Ways of Attacking HIV

HIV contains nine genes which carry all the information needed to make new viruses.

Proteins on HIV’s outer envelope bind to CD4 receptors on the surface of its target cells. In addition to the CD4 receptors, it also binds to co-receptors called CCR5 or CXCR4.

After the virus has locked onto these receptors, its outer envelope fuses with the cell’s membrane and the virus’s genetic material is absorbed into the cell.

Drugs that stop HIV binding to CD4 T-cells are under development.

Other drugs, like T-20 (enfuvirtide, Fuzeon), can prevent the fusion process from occurring.

1.1 RTIs

HIV makes a copy of its genetic information when it is inside the cell. This copy is called a provirus. It uses an enzyme of its own called reverse transcriptase to do this.

Drugs called reverse transcriptase inhibitors can stop the virus from making these copies. 3TC (lamivudine, Epivir, abacavir (Ziagen), AZT (zidovudine, Retrovir), d4T (stavudine, Zerit), ddC (zalcitabine, Hivid), ddI (didanosine, Videx / VidexEC) and FTC (emtricitabine, Emtriva) are reverse transcriptase inhibitors. Efavirenz (Sustiva) and nevirapine (Viramune) are also reverse transcriptase inhibitors, but work in a different way.

1.2 PIs

The provirus is inserted into the genetic code of the cell. HIV uses another of its enzymes called integrase to do this. The provirus is put into the genetic code, or genome, by cutting the genome and slipping in the HIV provirus. Drugs are being developed to stop integrase from doing this.

Some of HIV ‘s genes can instruct the cell to use its own machinery to make new viruses. Drugs are being investigated that can stop these genes from sending their instructions.

When the cell receives these instructions, it makes another copy of the provirus that is bound up in its genetic material, and this copy is then used to generate the production of new viruses from materials supplied by the cell. So, in effect, the cell has been hijacked by HIV and turned into a virus factory. Each cell can produce dozens, if not hundreds, of virions.

The new viral building blocks need to be chopped up and assembled. An HIV enzyme called protease is produced to do this job. Drugs called protease inhibitors can stop this process. Amprenavir (Agenerase), atazanavir (Reyataz), fosamprenavir (Telzir), indinavir (Crixivan), lopinavir, nelfinavir (Viracept), ritonavir (Norvir) and saquinavir (Invirase / Fortovase) are protease inhibitors.

1.3 Other Approaches

If viruses can be assembled they are packaged in the wall of the cell and then push through the wall of the cell to float off into the bloodstream or to pass into other cells. Drugs called maturation inhibitors are being developed which might stop this packaging process.

Various other approaches are being tested that may prevent HIV from reproducing itself. These include drugs that target human cell factors that are necessary for HIV replication, blockers of other HIV proteins and gene therapy.

Strategies to kill or remove HIV-infected cells from the body have also been suggested by experts, in order to destroy the copies of HIV that are stored for long periods, hidden within the body’s cells. These are experimental approaches at present.

Treatment with anti-oxidant drugs, including vitamins and minerals, may have a role in reducing HIV viral loads and increasing CD4 cell counts, but the findings from clinical studies are mixed so far.

Other anti-HIV treatments aim to prevent HIV from gaining entry to its target cells. This is achieved by blocking the attachment of HIV to receptors on the cell surface, and by preventing the fusion of the cell membrane to HIV’s outer envelope. Blocking either of these processes stops HIV from gaining entry to human cells.

2. Fusion Inhibitors

Several HIV proteins and human cell receptors have been investigated as targets of attachment or fusion inhibitors. The gp120 and gp41 proteins on the outer surface of HIV, which HIV uses to attach to receptors on the outside of the human cell, are targets that have been exploited in the development of fusion inhibitors including the only licensed drug in this class, T-20 (enfuvirtide, Fuzeon).

To compare all antiretroviral drugs licensed in the European Union, see NAM’s drug chart. The chart contains illustrations of the drugs, as well as information on drug doses, formulations, pill burdens, main side-effects and food restrictions.

3. New Therapies

The CD4 receptor and other ‘co-receptors’ on the surface of the human cells are possible targets for new anti-HIV therapies. These include inhibitors of the two main co-receptors, CCR5 and CXCR4, as well as drugs to interfere with the CD4 receptor.

3.1 Blocking CD4 receptors

It may be possible to block the CD4 receptor on human cells, thus preventing viral attachment. Experimental CD4 inhibitors include sulphated polysaccharides such as dextran sulphate as well as peptide T. A test tube study has also found that a molecule similar to DNA called (s4dU)35 can inhibit HIV entry by binding to the CD4 receptor (Horváth 2005).

Another approach, abandoned some years ago but revived recently, is the targeting of specially designed monoclonal antibodies that target the CD4 receptor. TNX-355 targets domain 2 of the CD4 receptor, an area responsible for changes in the shape of the CD4 receptor that occur after binding to HIV’s gp120 protein. Studies have shown that the drug is effective at reducing HIV viral load. For more information, see TNX-355 in Drugs used by people with HIV: Entry and fusion inhibitors.

Blocking gp120

One approach is to change the structure of gp120 and thus prevent it from fitting CD4 any longer. Researchers are trying to develop treatments called glycosylation inhibitors that prevent the normal formation of the sugars that make up the gp120 glycoprotein. In laboratory tests experimental treatments such as butyl DNJ and castanospermine have shown some promise in disrupting the assembly of gp120, but have significant side-effects. Researchers are working on modified versions of both of these drugs.

An alternative approach is to block gp120 using experimental treatments such as artificial versions of CD4 produced through genetic engineering. Researchers tried using artificial CD4 molecules to target poisons to HIV-infected cells, although this approach has now been abandoned.

Bristol-Myers Squibb is pursuing the development of small molecules that will prevent attachment of HIV’s gp120 molecule to the CD4 receptor. The attachment inhibitors are designed to prevent viral infection of CD4 cells. The current drug under development is BMS-488043. A dosing study found viral load fell by over 1 log10 after just seven days of monotherapy (Hanna 2004). Other molecules under investigation that bind to gp120 include NBD-556 and NBD-557, although these have only been investigated in the test tube, as well as a protein called griffithsin that is derived from an alga (Mori 2005; Zhao 2005).

HIV-infected cells usually carry the gp120 protein on their cell membrane and this can also dock with receptors on uninfected cells, resulting in useless clumps of large numbers of CD4 cells called syncytia. Blocking gp120 may also help to minimise the formation of these syncytia.

Blocking gp41

HIV’s gp41 protein is exposed after gp120 has become attached to the CD4 receptor. When gp41 is exposed, it interacts with the cell surface to allow fusion to take place. Blocking the activity of crucial sites within gp41 limits the capacity for fusion to take place.

T-20 is the first fusion inhibitor to be approved for use as an anti-HIV drug. It acts by binding to the gp41 protein and preventing the fusion of HIV’s envelope to the cell membrane. Developed by Trimeris in collaboration with Roche, T-20 has strong antiviral effects and may be taken in combination with other classes of antiretroviral drugs by people with few treatment options. It is not currently approved as first-line therapy. T-20 is injected twice daily and injection site reaction is the most common side-effect. See T-20 – overview in Drugs used by people with HIV: Entry and fusion inhibitors for more information.

Another fusion inhibitor, T-1249, also showed promising suppression of HIV in animal and laboratory studies, although development was suspended due to formulation problems in 2004. For further information see T-1249 in Drugs used by people with HIV: Entry and fusion inhibitors.

Other experimental compounds that block gp41 include ADS-J1 and D-peptides. The D-peptides block a portion of the gp41 protein called the ‘pocket’. This creates the potential for a new class of drugs known as pocket inhibitors (Eckert 1999). Experiments have also suggested that it may be possible to make CD4 T-cells produce fusion inhibitors using gene therapy (Perez 2005).

3.2 The role of co-receptors

In addition to the CD4 receptor, HIV uses other ‘co-receptors’ to gain entry to its target cells. These co-receptors are present on immune cells as they detect the presence of immune system messenger chemicals called chemokines. By blocking these co-receptors, HIV is unable to gain entry to CD4 T-cells and macrophages.

Interest in co-receptors stemmed from studies showing that people with a naturally-occurring mutant form of the chemokine receptor CCR5, and to a lesser extent CCR2 and SDF-1, have a slower rate of HIV disease progression than those who do not. Approximately 35% of long-term non-progressors have at least one of these mutant chemokines.

Consequently, CCR5 has been identified by drug developers as the most promising drug target. In addition, it is the co-receptor that most strains of HIV use as their co-receptor. In contrast, HIV that uses the CXCR4 co-receptor is much less common until very advanced stages of disease.

For further information on co-receptors, see Receptors, co-receptors and immunity to HIV in The immune system and HIV: How HIV damages the immune system.

Co-receptor inhibitors in development

Several inhibitors of CCR5 and other co-receptors are currently being tested. The three compounds whose development is most advanced are CCR5 blockers: aplavriroc, maraviroc and vicriviroc.

• GlaxoSmithKline is developing a product discovered by the Japanese company Ono Pharmaceuticals known as aplaviroc, which partially blocks CCR5 co-receptors. Studies have already shown that this drug can reduce viral loads in HIV-positive patients, and is currently entering trials in combination with other anti-HIV drugs (Lalezari 2004). However, concerns have arisen over a link between the drug and liver toxicity. For further information, see Aplaviroc in Drugs used by people with HIV: Entry and fusion inhibitors.
• Under development by Pfizer, maraviroc has also shown promising potency and tolerability in phase I trials. Three further trials are underway, assessing the compound in combination with other anti-HIV drugs. See Maraviroc in Drugs used by people with HIV: Entry and fusion inhibitors for further details.
• Following the discontinuation of a related compound, Schering-Plough’s CCR5 blocker vicriviroc has produced significant falls in viral loads when given to HIV-positive patients. It is now being tested alongside other anti-HIV drugs in two trials. A preliminary dosing study found that viral load fell by between 1.0 and 1.5 log10 over ten days with the greatest reduction occurring among people who took the top dosage. However, a phase II trial of this drug in treatment-naive patients was halted due to early viral load rebound, casting doubt on the future of this drug. For further information, see Vicriviroc in Drugs used by people with HIV: Entry and fusion inhibitors.

The Aaron Diamond Centre and Progenics Pharmaceuticals are investigating the potential of a number of monoclonal antibodies to inhibit receptor and co-receptor binding and cell entry. Research to date shows that monoclonal antibodies called PRO 140 (also known as PA14) and 2D7 are the most promising inhibitors of cell fusion and entry but have not yet been tested in humans (Olson 2000a,b).

PRO 140 works by binding to a particular site on the CCR5 co-receptor which, in turn, inhibits HIV. Test-tube data indicated that resistance to this compound does not develop readily. However, following a single injection study in mice, it was found that HIV may escape inhibition by switching to CXCR4, suggesting that coreceptor usage should be closely monitored. PRO 140 is now entering phase I human studies (Cormier 2003; Franti 2004).

Other co-receptor blockers under development include Fuji ImmunoPharmaceutical’s FP-21399, which has had encouraging results in HIV-infected individuals. For further information see FP-21399 in Drugs used by people with HIV: Entry and fusion inhibitors. Another experimental CCR5 inhibitor is TAK-779. Test tube studies have found it is a highly potent inhibitor of CCR5 but that it does not affect other chemokine receptors including CXCR4.

A class of anti-HIV drugs called bicyclams have shown potent anti-HIV effects. The first of these to be investigated was AMD3100, but development of this compound has now been abandoned due to toxicities (Schols 2000). However, the Canadian biotech company AnorMED has reported in vitro anti-HIV activity of a CCR5 antagonist, AMD887, and a CXCR4 antagonist, AMD070, singly and together (Schols 2004). A related compound called AMD3451 has recently been shown to inhibit binding of HIV-1 and HIV-2 to both CCR5 and CXCR4 (Princen 2004).

Japanese researchers have reported that a peptide therapy called T22 inhibits replication of the T-tropic HIV by blocking the CXCR4 co-receptor (Murakami 1999). Similarly, Japan’s Kureha Chemical Industry Co. has reported that their CXCR4 inhibitor KRH-2731 has both potent and selective anti-X4 HIV-1 activity in vitro and in rats and dogs (Murakami 2004).

Problems with inhibiting co-receptors

Some researchers are concerned that, over time, use of agents which block the CCR5 co-receptor will favour the emergence of more lethal viruses that use the CXCR4 receptor. Viruses that favour the CXCR4 receptor are known to infect and kill CD4 T-cells much more rapidly than CCR5 viruses.

There is some evidence to support this theory. In the study of vicriviroc described above, one patient with a viral load reduction of greater than 1.5 log10 had evidence of a transient switch to CXCR4 virus after treatment. A phase I / II study of maraviroc showed that one patient with a mixed population of CCR5 and CXCR4-tropic viruses experienced no viral load reduction after 10 days of monotherapy. Instead, the population of X4-tropic viruses increased tenfold, suggesting that a CCR5 inhibitor will select for CXCR4 variants (Pozniak 2003). There is also some evidence from animal studies that blocking one receptor will select for virus which prefers other receptors (Mosier 1999; Zhang 2000), and that viral tropism may differ between the blood and the cerebrospinal fluid that surrounds the brain and spinal cord (Spudich 2005).

However, other researchers have not found a similar switch in virus isolates from humans. Virus with an R5 phenotype was exposed to a CCR5 antagonist in the test tube, but did not lose the ability to infect and replicate in CCR5 cell lines, and remained sensitive to some CCR5 inhibitors. The researchers concluded that the development of resistance to one CCR5 antagonist did not necessarily indicate a switch to a X4 phenotype (Moore 2001).

Although they are lagging behind CCR5 blockers in development, it is possible that the concomitant use of a CXCR4 blocker may be useful in preventing the switch from R5- to X4-using HIV. A phase I/II study of the CXCR4 antagonist AMD3100 found that three people treated with the drug switched from a mixed X4/R5 phenotype, suggesting that intermittent treatment with a CXCR4 antagonist might prevent the switch to an X4 phenotype (Fransen 2004). This study also found that the virus population in the three individuals had consisted of a mixture of R5, X4 and dual tropic virus at baseline. The use of compounds that block both co-receptors, such as AMD3451, may also prove to be a useful strategy to prevent the switch in co-receptor use, although further trials are required to examine whether this drug can be used in humans (Princen 2004).

CCR5 is often the co-receptor used by HIV during early infection, and some researchers have suggested that a CCR5 blocker may be most effective when someone has a relatively high CD4 count, because the virus will have less ability to exploit a wide range of chemokine receptors. Two cohort studies have investigated the distribution of R5 and X4 strains of HIV and found that X4 viruses became more common as CD4 cell counts decline.

In the British Columbia cohort individuals with CD4 cell counts below 200 cells/mm3 had a five to seven fold higher risk of carrying virus that used the X4 receptor when compared with people with CD4 cell counts above 500 cells/mm3 (Harrigan 2004). In the Chelsea and Westminster, London, cohort the prevalence of a mixed R5 / X4 population, or phenotype, ranged from 7% in those with CD4 cell counts above 300 to 46% in those with CD4 cell counts below 100 cells/mm3 (Moyle 2004). In both cohorts viral phenotype was predicted by CD4 cell count, not viral load. However, as even patients with low CD4 cell counts may still have R5-tropic HIV, baseline testing may be of use in determining whether a patient will benefit from a CCR5 blocker.

Another contention which supports the use of CCR5 inhibitors is that HIV’s ability to use other co-receptors may not be as significant as once thought. Researchers at the Aaron Diamond Centre have found that although HIV certainly can use other co-receptors to enter cells, the virus does not replicate in cells where the CCR5 co-receptor is missing or blocked. They argue that CCR5 and CXCR4 should remain the key target of co-receptor research (Zhang 1999).

Another potential question with this approach to treatment is whether all the cells which HIV infects can be protected by blocking the same chemokine receptors. Little is known about the distribution of different chemokine receptors amongst different types of immune cells, nor how important various receptors might be.

Furthermore, genetic variation affects the expression and activity of co-receptors. This means that there may be substantial variation in the effectiveness of chemokine antagonists due to these natural polymorphisms (Mosier 2000).

The pharmacokinetic aspects of chemokine inhibition are still poorly understood. In particular, it is unclear whether the peak or trough level will prove more important in determining efficacy. If the key requirement for efficacy is that all receptors are blocked, peak levels will be more important because saturation of the co-receptors will be key. On the other hand, some researchers think that trough levels may be more important, because HIV needs to engage with multiple CCR5 receptors to gain entry to a cell, and even if all receptors are not blocked, viral entry could be substantially limited.

Another pharmacokinetic problem already identified by Pfizer in the development of its CCR5 inhibitor is the difficulty of achieving adequate drug levels when the compound is taken with food.

Potential immunological side-effects are also uncertain. Could interference with particular chemokines induce other unwelcome immunological effects in the long-term? So far, studies of chemokine inhibitors have taken place only for short periods and there has been no evidence of immunological toxicity.

It is hoped that blocking certain chemokine receptors will not affect other immune functions because the chemokines in question can utilise several other receptors. However, chemokines are necessary for certain inflammatory reactions, and blocking particular receptors may lead to adverse consequences. A review of immune responses in mice genetically engineered to be CCR5 deficient by Schering-Plough found an impaired response to opportunistic infections such as leishmaniasis, cryptococcus and listeria (Huffnagle 1999; Zhou 2005). The potential for reduced immune responses will clearly require further research to prove that CCR5 antagonists are safe for use in HIV infection, especially in individuals with a prior history of opportunistic infections.

Blocking CCR5 co-receptors may produce a similar immunological profile to that seen in individuals with the CCR5 delta 32 deletion. Although this variety of the CCR5 co-receptor provides long-term protection against acquisition of HIV and most people with this polymorphism come to no long-term harm, there is evidence that it can impair immune function. For example, it has been linked to:

• Reduced incidence and severity of rheumatoid arthritis (Gomez-Reino 1999; Zapico 2000).
• Increased survival in transplant recipients (Fischereder 2001).
• Elevated aspartate aminotransferase (AST) levels, indicating liver toxicity (Laurence 2002).
• Inhibited antibody response to herpes-zoster (Wiencke 2001).

People with the CCR5 delta 32 deletion can also experience more severe cases of lupus, have poorer prognosis in certain types of breast cancer and may be less likely to clear hepatitis C virus (HCV) following infection (Aguilar 2003; Favorova 2002; Manes 2003; Woitas 2002). Conversely, the 32 deletion may be very protective against heart attacks (Gonzalez 2001). Nevertheless, researchers will need to consider the subtle and profound long-term effects of inhibiting CCR5 receptors, particularly in patients co-infected with HIV and HCV.

Modulation of CXCR4 expression may have wider consequences. CXCR4 abnormalities proved lethal in mice, and it may prove more important for humans than CCR5 due to its role in the maturation of white blood cells called B-cells and the production of blood cells. It may also be important for embryonic developmental processes such as the formation of organs and blood vessels (Murdoch 2000).

These subtle and serious effects may not be seen in the short-term, and might take over five or six years to develop. Furthermore, they are unlikely to be detected in short-term clinical trials.

Combining fusion inhibitors and co-receptor antagonists

Combining different types of fusion inhibitors and co-receptor antagonists is being investigated as a treatment strategy. Laboratory studies have provided some encouraging evidence that combinations of fusion inhibitors may significantly reduce HIV cell fusion and entry.

Researchers from Progenics have tested a combination of T-20, PRO 542 and PRO 140 individually and in combination against test tube samples of HIV to see whether the drugs could boost each other’s effects (synergy). T-20 and PRO 542 were found to be synergistic, to such an extent that when used together, concentrations of the drugs required to inhibit HIV replication could be reduced 30-fold in comparison with the concentrations required when used individually. PRO 140 was not synergistic, but in a separate test tube study, it was shown to be a potent inhibitor of HIV activity not only in lymphocytes, but also in macrophages, an important reservoir of HIV infection. PRO 542 is in advanced human studies, but PRO 140 has not yet been tested in humans.

Combining bicyclams (CXCR4 antagonists) with fusion blockers such as T-20 is also a developing area of research. Such a combination would target several sites of fusion, potentially creating a potent anti-HIV treatment. Strong synergy between AMD3100 and T-20 was observed in test-tube studies, but AMD3100 has now been discontinued due to cardiac toxicity.

The use of CCR5 antagonists in combination with drugs that block gp41 is particularly attractive because researchers have found that reducing the amount of CCR5 expression on a CD4 T-cell increases the amount of time that HIV’s gp41 region remains exposed. Multiple linkages between HIV and CCR5 are needed for swift fusion to occur, so blocking CCR5 may increase the time during which gp41 inhibitors like T-20 or T-1249 could act against the virus.

Potential for cross-resistance

Preliminary test-tube studies suggest that common mutations in the env gene of HIV may cause some level of cross-resistance amongst the fusion inhibitors. Furthermore, the bicyclam AMD3100 generates alterations in gp120 that seem to cause cross-resistance to drugs that target the co-receptors, suggesting there may be cross-class resistance (Este 1999)

4. European activists claim Pfizer’s CCR5 antagonist trial unnecessarily putting most vulnerable at risk; US activists disagree

Edwin J. Bernard & Gus Cairns, Tuesday, April 19, 2005

European HIV treatment activists, the European AIDS Treatment Group (EATG), are demanding that a worldwide trial of Pfizer’s investigational CCR5 antagonist, maraviroc (UK-427,857) in HIV-positive treatment-naïve individuals “be changed or stopped” since it is unnecessarily putting people with HIV who have severe immune suppression at risk. However, leading US activists are critical of the EATG’s position, claiming that it “fails to offer a balanced view,” and that it “is not an opinion shared by all HIV treatment activists.” Pfizer argues that the study “includes appropriate checks and balances to protect patient safety” and say that it and other stakeholders “believe our position is well considered.”

Pfizer’s A4001026 trial is a combined PhaseIIb/III study to define the dose, preliminary efficacy and safety of maraviroc in participants who have never taken treatment before, and whose HIV is thought to be susceptible to maraviroc via a test for R5-tropic virus (i.e. HIV that is attracted to a cell’s CCR5 receptor). It is one of three maraviroc studies currently enrolling worldwide. A4001028 will give the drug, plus the best available HAART regimen (often called an ‘optimised background regimen’), to people whose R5-tropic HIV has resistance to at least one drug in three of the four current anti-HIV drug classes. A third, smaller study, A4001029, will give maraviroc plus ‘optimised’ HAART to people who have both R5- and X4-tropic virus, to see what happens.

The EATG, which had been in discussions with Pfizer regarding its trial designs, has no problem with the other two studies, but it is greatly concerned that the 1026 trial’s inclusion criteria may be placing vulnerable people recently diagnosed with HIV at unnecessary risk.

The inclusion criteria allow individuals to enter the trial regardless of their CD4 count and viral load. This includes people with CD4 counts below 200 cells/mm³ and viral loads over 100,000 copies/ml who are at greater risk of disease progression, and who could benefit from currently available treatment options. It is often the case that individuals with advanced HIV disease who have never previously taken treatment have only recently been diagnosed with HIV and/or AIDS, and may not be in the best position to make informed treatment decisions.

“Pfizer has said it will informally recommend a limit of over 100 [CD4 cells],” Nikos Dedes, Chair of EATG’s European Community Advisory Board (ECAB) tells May’s issue of AIDS Treatment Update, “but we want it stated in the protocol so that less-informed physicians don’t enrol vulnerable patients…We don’t see that there’s any medical rationale to put people with 80 CD4 cells on these regimens. These days we have drugs that work for most people, so why be in such a hurry? Make it people who would not be endangered by one ineffective regimen, say with CD4 counts of 250-350.”

4.1 US activists disagree

However, Bob Huff, Editor of New York-based GMHC Treatment Issues, tells aidsmap that the “EATG fails to offer a balanced view of this controversial issue. This is not an opinion shared by all HIV treatment activists.

“The opinions about whether this trial is ethical are based on individual beliefs about ethics, not on a careful consideration of the specifics of the drug and the science,” he says. ”In fact, [most countries’] regulatory agencies have assumed their responsibility and decided to approve the current trial design. They did not do so in ignorance or without careful consideration of the EATG position.”

He points out that existing standard-of-care treatments are unacceptable to many people due to toxicity and do not assure sustained viral suppression. He also notes that it is important to acquire safety data in all populations that will ultimately be exposed to a new drug. “Due to close, expert monitoring and the attention of trial staff, patients in clinical trials often have better outcomes than patients treated [according to] guidelines”, he notes.

Jules Levin, founder of the New York-based National AIDS Treatment Advocacy Project (NATAP), has also criticized the EATG. “It’s unfortunate for patients, HIV research and for AIDS drug development that such an uninformed and harmful effect has occurred by a group of individuals, the European activists,” he wrote in a message on an HIV treatment discussion group board following the EATG’s announcement.

Maraviroc is an investigational compound that has so far only been tested in 63 HIV-positive people at eight different doses for 10 days. In that study, one person was inadvertently enrolled who had X4-tropic virus that should have been detected, and did not respond to the drug. X4-tropic virus emerged near the end of the dosing period in another two individuals. X4-tropic virus ‘went away’ in one of these two participants after the drug was stopped, but the other person still had a mixed R5- and X4-tropic virus population 40 days later.

David Haerry, ECAB Co-Chair, says that since there are so few clinical data on maraviroc, “it is totally unacceptable to treat naïve patients with severe immune suppression and high viral loads with a drug combination containing an investigational drug whose potency and ideal dose are still unknown”. Haerry adds that people who do not respond to the drug, either due to potency or adverse events, will have their physical and psychological wellbeing impacted and future treatment options may be reduced.

Pfizer says that “individual patient safety is paramount to Pfizer, and study 1026 has been designed to ensure patients receive excellent medical care…[The study design means that] future treatment options with the most potent of antiretrovirals – efavirenz (Sustiva), boosted protease inhibitors and tenofovir (Viread) – are preserved.

“Pfizer believes a thorough evaluation of maraviroc is required in a population representative of individuals initiating HIV therapy today. Such an evaluation in a well-controlled trial setting with clear individual patient stopping rules in the protocol, not only will yield valuable data to guide appropriate future use of this potential new medicine by clinicians, but also addresses individual patient safety within the trial.”

Pfizer is one of three pharmaceutical companies currently in a race to produce the first CCR5 antagonist, which would be the first oral anti-HIV drug to prevent HIV from entering cells. Schering-Plough and GlaxoSmithKline also currently have CCR5 antagonists in clinical trials, and activist and community consultations with these companies have gone much more smoothly.

When Pfizer was asked by aidsmap why it was necessary to include treatment-naïve patients in a study of a drug that has previously only been tested in 63 HIV-positive people, a spokesperson stressed the scientific and humanitarian issues involved.

“Typically, about 85% of treatment-naïve patients are R5-tropic [i.e. candidates for a CCR5 antagonist], compared to just 50% of heavily treatment experienced patients,” says Pfizer. “It is therefore possible that the response to an R5 antagonist may be different between these two populations, even when patients from both populations are confirmed to have R5-tropic virus before initiating treatment. As such, starting exclusively in treatment-experienced patients may not predict outcome in treatment-naïve patients.

“Secondly, transmission of resistance to at least one of the currently available drugs has been reported as being from 10% – 26% in treatment-naïve patients. Furthermore, existing drugs, although life-saving for HIV patients, are not ideal in their toleration profile….Therefore, new mechanisms without cross resistance and with different (better) toleration profiles are needed for treatment naive patients. The most appropriate place for CCR5 antagonists may well be in the treatment naive population.”

However, ECAB’s Nikos Dedes counters that “the development of new ARV drug classes is essential to treat experienced patients in need of effective salvage regimens. But in the case of naïve patients, new drug classes are less urgent given the number of effective treatment options available.” The EATG strongly feels that “pressure and requests for the fast development of investigational compounds in the name of patients with no options or other competitive considerations cannot justify putting naïve patients’ health at unnecessary risk.”

The maraviroc trial in treatment-naïve individuals is currently enrolling, or has approval to start, in Australia, Belgium, Canada, Italy, Mexico, Netherlands, Switzerland, the United Kingdom and the United States, but not currently in France, Germany or Spain, where state regulatory authorities have taken ECAB’s concerns seriously. Applications are pending in several other countries.

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Hepatitis C – overview

From www.AIDSMAP.com

• Transmission
• Disease progression
• Symptoms
• Fibrosis and cirrhosis
• Liver cancer / hepatocellular carcinoma
• Other conditions associated with hepatitis C virus
• Liver disease in the era of highly active antiretroviral therapy
• Does HIV affect hepatitis C?
• Does hepatitis C virus affect HIV disease?
• Diagnosis and monitoring
• Hepatitis C virus genotype
• Aims of hepatitis C virus treatment
• Who should receive treatment?
• Hepatitis C virus treatment
• Hepatitis C virus treatment in co-infected people
• Hepatitis C virus and HIV: which to treat first?
• Response rates in co-infected individuals
• Antiretroviral therapy in co-infected individuals
• Liver toxicity, liver disease and highly active antiretroviral therapy
• Side-effects of hepatitis C virus treatments
• Lifestyle changes and complementary approaches
• Experimental treatments for hepatitis C virus and hepatitis C virus / HIV co-infection
• Liver transplant

Hepatitis C is a form of hepatitis, or ‘inflammation of the liver,’ caused by a virus known as the hepatitis C virus, or HCV. HCV infection is more common in Europe and the United States than HIV infection. It is estimated that between a quarter and a half million people in the United Kingdom are infected with HCV. Co-infection with HCV and HIV is a growing concern. Experts believe that 15 to 30% of HIV-positive people are also infected with HCV, but among injecting drug users and haemophiliacs, the rate can be as high as 90%.

HCV was first identified in 1989 and is similar to the viruses that cause yellow fever and Dengue fever. It is not related to hepatitis B virus, although it causes similar symptoms. HCV inhabits both the liver and the lymphatic system, and over time it may infect other organs too.

Transmission

HCV is mainly transmitted by direct blood-to-blood contact. The sharing of needles and other drug injecting equipment, such as spoons and cotton, is the most common source of infection, and HCV prevalence is high among injecting drug users (IDUs; Hagan 2001; Rauch 2005; Sprinz 2003). Blood-to-blood HCV transmission has also occurred through transfusions of blood or blood products, such as the clotting factors required by people with haemophilia, prior to the introduction of screening and sterilisation procedures for donated blood in 1992.

Any objects that come into contact with blood can potentially spread HCV, a virus that is harder to kill than HIV. These include unsterilised tattooing, piercing, and acupuncture equipment and shared personal items such as razors and toothbrushes (Haley 2003). Health-care workers should employ universal precautions to prevent accidental exposure to HCV while at work. Sharing straws to snort drugs is another potential means of HCV transmission and should be avoided. HCV transmission also rarely occurs through household contact. For about 10% of people with HCV, the route of infection is unknown.

HCV is sometimes detectable in body fluids other than blood at very low concentrations. This raises the possibility that HCV may be transmitted without blood-to-blood contact. In most cases, levels of HCV in other body fluids are too low to lead to transmission.

HCV has been detected in menstrual blood, semen, vaginal and cervical secretions, and the genital tract. The evidence so far suggests that although HCV can be transmitted sexually, it is not passed on by this route very easily. Studies of long-term monogamous heterosexual partners of HCV-infected people demonstrate that sexual transmission rates are very low. A review of literature into sexual transmission of HCV found between 1 and 3% of heterosexual partners of HCV-infected people contract the virus (Rooney 1998).

The risk per sexual act also appears to be very low. A recent study that analysed more than 5800 acts of unprotected vaginal and anal intercourse between heterosexual couples in which one partner was HCV-positive and the other was HCV-negative detected no new HCV infections among the uninfected partners. The researchers concluded that that their results “are consistent with a low or null transmissibility of HCV in heterosexual relations” (Marincovich 2003). Another study that followed 895 monogamous heterosexual HCV-serodiscordant couples for up to 10 years found just three new HCV infections among the uninfected partners: an incidence rate of 0.37 per 1000 person-years. However, these individuals were infected with different strains of HCV than their partners, thus ruling out sexual transmission (Vandelli 2004). A more recent study found no new HCV infections among 216 HIV-negative heterosexual spouses of individuals with chronic hepatitis C during a 3 year period (Tahan 2005).

There is some evidence that people co-infected with both HIV and HCV are more likely to transmit HCV through sex, perhaps because they have higher levels of HCV in their genital fluids than HIV-negative people (d’Oliveira 2005; Pasquier 2003). However, several studies of women, including the large American Women’s Interagency HIV Study (WIHS) and two studies in Cameroon and the Ivory Coast, found low rates of HCV infection in both HIV-positive and HIV-negative women, suggesting that little or no sexual transmission of HCV occurred (Augenbraun 2003; Msellati 2003; Njouom 2003). In the Marincovich study cited above, no instances of sexual transmission of HCV were seen even among subjects co-infected with HIV.

Sexual practices that involve exposure to blood, such as fisting and unprotected anal intercourse, may increase the risk of HCV transmission, and there is evidence that people who have multiple sex partners and men who have sex with men are at higher risk for sexual transmission of HCV than monogamous heterosexual individuals (Rauch 2005). In 2003, British clinicians reported numerous new cases of hepatitis C among HIV-infected gay men in London. These new cases of HCV infection have been attributed to sexual transmission due to the lack of other risk factors. They were associated with the presence of other sexually transmitted infections (STIs) such as syphilis or gonorrhoea, anal sex and fisting, and sometimes recent snorting of drugs (Aizen 2003; Bhagani 2004; Browne 2003; Gilleece 2004; Lascar 2003; Nelson 2003).

A similar outbreak of apparently sexually transmitted HCV among gay men has also been reported in Paris (Chaix 2004, 2005; Ghosn 2004). At Paris’s Necker Hospital, ten of twelve HIV-positive men were newly infected with the relatively uncommon HCV genotype 4. Another cluster of apparently sexually transmitted HCV cases has been reported in the Netherlands (Götz 2005). These reports accord with other recent studies suggesting that sexual transmission of hepatitis C does occur, particularly in the presence of HIV or other STIs (Abrescia 2002; Craib 2001; Mendes-Correa 2002; Weisbord 2003; Williams 2003). However, some North American studies have not found an association between gay sex and increased risk of HCV co-infection among HIV-positive men (Alary 2005; Hammer 2003; Tedaldi 2003b).

Mother-to-baby transmission of HCV before or during birth is thought to be uncommon, although HIV co-infection may increase the risk of both HIV and HCV transmission (Catalano 1999; European Paediatric Hepatitis C Virus Network 2005; Hershow 1997). Rates of mother-to-baby transmission of HCV have ranged between 0 and 10% in published studies. The average incidence of mother-to-baby transmission is about 6%. A high level of HCV in the blood increases the likelihood that a woman will transmit HCV to her infant, as does co-infection with HIV. To date, no cases of vertical HCV transmission have been reported among children born to women with undetectable HCV viral load.

HCV transmission may be more likely to occur during birth, rather than in the womb, although one study has estimated that between a third and a half of transmissions occur late in pregnancy (Mok 2005). Evidence suggests that delivery by caesarean section reduces the likelihood of transmission, but the benefits of the procedure remain controversial (Gibb 2000; Schackman 2004; Semprini 2001).

A small amount of HCV may be present in breast milk, especially if the mother has a high HCV viral load. However, research into breast-feeding by HCV-infected women has produced inconclusive results. Some studies have found that breast-feeding increased the risk of HCV transmission to infants while others have found no association. Consequently, current United Kingdom and United States guidelines do not discourage breast-feeding by women with HCV, except when a woman has cracked nipples or HIV co-infection.

Research suggests that being infected with one strain of HCV does not prevent superinfection with other types. A study of young IDUs in San Francisco found that the incidence of HCV superinfection was almost as high as new first HCV infections. While superinfection did not lead to more aggressive disease, its presence suggests that cross-protective immunity against different HCV strains may not develop, which could hamper the development of an effective HCV vaccine (Herring 2004).

Disease progression

A minority of people infected with HCV manage to clear the infection without treatment. It has traditionally been assumed that approximately 80 to 90% of infected individuals go on to develop chronic or ongoing HCV infection (lasting more than six months), but recent studies have found higher rates of spontaneous HCV clearance (Bhagani 2004; Gilleece 2005; Nelson 2003). An Australian study found that as many as 42% of HIV-negative IDUs spontaneously cleared HCV within two years of becoming infected (Jauncey 2004). This study found that spontaneous clearance was not associated with specific demographic, behavioural, or clinical factors. However, in a recent study of United States veterans, heavy alcohol users and HIV / HCV co-infected people were less likely to clear HCV without treatment, while individuals co-infected with hepatitis B virus (HBV) were more likely to do so (Piasecki 2004). Previous studies have shown that women and whites are more likely to spontaneously clear HCV than men or people of African descent. People with acute HCV symptoms also seem more likely to clear the virus, perhaps because they produce a stronger immune response (Gerlach 2003; Nelson 2003).

A form of acute liver damage called fulminant hepatitis, characterized by massive necrosis (cell inflammation and death), can lead to rapid liver failure and death. This condition can occur in the acute phase of hepatitis A or B or, rarely, hepatitis C, or may be caused by drugs or other toxins. The only treatment for fulminant hepatitis is a liver transplant.

A minority of HCV-infected individuals develop liver disease progression, including severe fibrosis, cirrhosis, liver cancer, and end-stage liver disease (ESLD). This occurs in an estimated 10 to 25% of HIV-negative people, usually over the course of ten to 40 years (Thomas 2000). A large French study found that the average time from infection to cirrhosis was 30 years (Poynard 1997). The varying severity of hepatitis C may reflect differences between HCV strains or differing genetic, immunological, or behavioural characteristics of the infected individual. In the French study, progression was associated with age older than 40 years at the time of infection, daily alcohol consumption of 50g or more, and male gender. The average time to the development of fibrosis among men infected after the age of 40 was 13 years, while women who were infected before the age of 40 and did not drink alcohol took an average of 42 years to progress to fibrosis. Many studies have shown that heavy alcohol consumption is strongly associated with liver disease progression, but the impact of light consumption remains unclear (Córdoba 2004; Monto 2004). As discussed below, liver disease progression is more likely and occurs more rapidly in HIV / HCV-co-infected individuals.

Symptoms

Patterns of hepatitis C disease progression vary considerably from person to person. Some people never experience symptoms, some rapidly develop symptoms of acute hepatitis and others develop symptoms ten to 15 years after initial infection (Kenny-Walsh 1999).

Few people with HCV realise that there is anything wrong with them at or around the time they become infected. Less than 5% suffer acute hepatitis symptoms such as fatigue, nausea, loss of appetite, fever, abdominal tenderness, muscle and joint pains, elevated liver enzymes or jaundice (yellowing of the skin and eyes).

Over half of people who contract HCV will develop some symptoms over the long term. Most commonly, people with HCV present with chronic fatigue prior to any other evidence of liver disease. Other early symptoms may include a flu-like feeling, nausea, weight loss, loss of appetite and a swollen, painful liver or spleen. Hepatitis C patients also commonly report mental symptoms including depression and ‘brain fog’ (problems remembering or understanding information). The presence and severity of symptoms vary greatly among individuals, and do not necessarily give an accurate indication of the extent of liver damage.

Fibrosis and cirrhosis

Fibrosis refers to the development of hard, fibrous tissue in the liver. Fibrosis may progress to cirrhosis, in which normal liver tissue is replaced by non-functional scar tissue. Fibrosis may be reversible, but once cirrhosis has occurred it appears to be largely irreversible, even if HCV replication and liver inflammation are controlled.

Factors associated with a greater risk of HCV-related fibrosis and cirrhosis include age over 40, male gender, long-term HCV infection, and more than four standard alcoholic drinks per day. As discussed below, co-infection with HIV also can lead to more severe fibrosis. People who are obese or diabetic are also more prone to fibrosis and cirrhosis, as well as steatosis (‘fatty liver’).

People with cirrhotic livers may start to experience symptoms caused by the inability of blood to flow freely through the scarred organ. As a result, blood is diverted around the liver, which can cause a number of secondary symptoms.

Symptoms related to the deterioration in effective liver function may also occur. Since the liver performs many vital functions, such as metabolism of food, protein synthesis, energy production, vitamin storage and blood filtering, symptoms may be highly varied and may become quite severe. Compensated cirrhosis is when the liver is heavily damaged but is still able to function.

Decompensated cirrhosis is when the damaged organ can no longer perform its vital functions.

Symptoms of cirrhosis include:

• Muscle wasting.
• Swollen spleen.
• Ascites: swelling of the abdomen, caused by the accumulation of fluid. It is treated by reduced salt intake and diuretics (drugs which promote urination).
• Oedema: swelling, usually of the feet, ankles, and lower legs, due to the accumulation of fluid.
• Varices (abnormally distended blood vessels). Blood vessels around the gullet and stomach enlarge because the blood is trying to find a way around the scarred liver. These varices can bleed into the stomach causing vomiting of blood or passing black stools. Burst varices require immediate medical attention.
• Circulatory changes. The damaged liver may fail to produce blood-clotting proteins, leading to easy bruising and prolonged bleeding. Patients may also develop high blood pressure (portal hypertension) as blood backs up in the scarred liver. Drugs called beta-blockers may be used to relieve portal hypertension.
• Pruritis (itching). People with cirrhosis may experience an itching sensation of the skin or internal organs due to the build-up of bile and other toxic chemicals.
• Encephalopathy. Patients may experience impaired mental function and personality changes because the liver is not breaking down waste products such as ammonia in the blood as efficiently as it should or because blood is bypassing the liver. At its most severe, this can lead to coma or death. Laxatives are sometimes used to treat this.

These symptoms may indicate that cirrhosis is progressing to ESLD or liver failure.

Liver cancer / hepatocellular carcinoma

Both chronic HBV and HCV drastically increase the likelihood of a type of liver cancer called hepatocellular carcinoma (HCC). A person with HCV-related cirrhosis has an annual risk of 1 to 6% of developing liver cancer. Most cases occur after a person has been infected with HCV for 20 or more years, but HCC may develop sooner in people co-infected with HIV. Among people with HCV, HCC can occur in the absence of cirrhosis, but such cases are rare. The genetic predisposition of patients is thought to influence the likelihood of HCC, just as it is thought to influence the occurrence of other types of cancer. Although lifestyle factors are generally under-researched in HCV, alcohol intake is definitely a contributory factor in the development of HCC.

HCC is an aggressive cancer that is difficult to treat. It is hard to detect at early stages because it usually does not cause symptoms. Resection (cutting out a tumour) is the only option for some individuals. Some small tumours can be cut out, but the likelihood that a new tumour will develop is high. Tumours may also be destroyed by cryosurgery (freezing) or radiation. If tumours are large, the cancer has spread or there is a build-up of pressure (hypertension) in the portal vein in the liver, resection carries a high chance of liver failure. For patients for whom resection is not an option, injection of ethanol into the tumour is one treatment that may improve survival. Another method involves injecting chemotherapeutic drugs directly into the tumour’s blood supply.

Other conditions associated with hepatitis C virus

A small proportion of patients with HCV, particularly women, develop autoimmune disorders of varying severity. These include:

• Vasculitis: a painful blood circulation disorder.
• Autoimmune thyroid disease.
• Autoimmune hepatitis: this is a more serious form of liver disease than viral infection, but is less common in people with HCV than HBV.
• Glomerulonephritis: a serious form of kidney disease in which the blood filtering function becomes impaired.
• Polyarthritis: multiple joint pains and swelling.
• Cryoglobulinaemia: a condition in which abnormal proteins called cryoglobulins form in the blood.
• Porphyria cutanea tarda: a condition in which by-products of haemoglobin production build up in the body.
• Scleroderma: hardening of the skin.
• Sjøgren’s syndrome: a chronic condition characterized by dry eyes and dry mouth.

HCV infects the lymphatic system as well as the liver and the blood. Nearly all infected patients have HCV in their lymphatic vessels and organ. Hepatitis C has also been linked to low blood cell counts and to diabetes and other metabolic disorders.

Liver disease in the era of highly active antiretroviral therapy

Several studies done since the advent of protease inhibitors indicate that the prevalence of ESLD among HIV-positive individuals increased in the late 1990s. For example, a clinic in Boston reported that deaths among HIV-positive people due to liver disease rose from 12% in 1991 to 50% in 1998 and 1999 (Bica 2001). Fifty-five per cent of deaths in this cohort occurred among people with undetectable HIV viral load and CD4 cell counts above 200 cells/mm³.

In countries where combination antiretroviral therapy is widely available, liver disease has become more prevalent among HIV-positive people and is now a major cause of hospital admissions and death in this population, according to reports from the United States and Europe (Ahmad 2001; Bonnet 2001; Cacoub 2001; Martin-Carbonero 2001; Monga 2001; Puoti 2001a; Ragni 2001; Rancinan 2001; Rosenthal 2003; Salmon-Ceron 2005; Soriano 1999). A majority of these deaths are in people co-infected with hepatitis C. Individuals with both HCV and HBV in addition to HIV have a higher risk of death than HIV-positive people co-infected with only one hepatitis virus (Bonacini 2004; Salmon-Ceron 2005).

Prior to highly active antiretroviral therapy (HAART), people co-infected with HCV and HIV had a similar prognosis as those infected with HIV alone. After the introduction of HAART, however, HCV-positive people did not benefit to the same extent from the dramatic reduction in morbidity and mortality. One researcher found that in the HAART era, HIV / HCV co-infected individuals were approximately twice as likely to be hospitalised and three times more likely to die compared with HCV-negative individuals with HIV alone (Klein 2001, 2003). Another study found that HCV co-infection increased the risk of death amongst HIV-positive US veterans by between 30% and 80% (Backus 2005). It has been estimated that a 35-year-old HIV / HCV co-infected man with a CD4 cell count between 200 and 350 cells/mm3 and stage 2 liver fibrosis has a 21% chance of developing cirrhosis and a 16% chance of death due to liver disease over 20 years (Wong 2003). The increase in morbidity and mortality related to liver disease among HIV-positive people since the advent of HAART is due in part to the fact that individuals receiving effective anti-HIV treatment are much less likely to die from other causes such as opportunistic infections (OIs). In addition, as co-infected individuals live longer, there is more time for progressive liver damage due to chronic hepatitis B or C to develop. Finally, a small proportion of liver-related deaths in people with HIV may be due to hepatotoxicity associated with antiretroviral drugs.

Does HIV affect hepatitis C?

Research shows that HIV affects hepatitis C by hastening the process of liver damage. Consequently, co-infected people are more likely to develop severe liver disease, and to do so more rapidly, than people with HCV alone. A meta-analysis presented at a United States National Institutes of Health consensus conference on hepatitis C in June 2002 showed that HIV / HCV co-infected people had a two-fold greater risk of cirrhosis and a six-fold greater risk of ESLD than those with HCV alone (National Institutes of Health 2002). Although the likelihood of liver disease progression seems to be highest for co-infected people with advanced HIV disease and heavily compromised immune systems, even those with high CD4 cell counts may be at greater risk of liver damage due to HCV than HIV-negative people.

Early evidence that HIV increases the risk of HCV-related liver disease came from a study of haemophiliacs in the United Kingdom. Risk of liver disease, liver cancer or death over a 25-year period was 1% among men infected with HCV alone, and 7% among men with both HCV and HIV (Darby 1997). A study of haemophiliacs in Montreal found that co-infection with HIV increased the risk of progressive liver disease sevenfold (Lesens 1999). Spanish researchers also reported that HIV / HCV co-infection is associated with significantly faster progression to cirrhosis. Fifteen per cent of co-infected individuals developed cirrhosis within ten years, compared to less than 3% of people with HCV alone (Soto 1997). Another study found that co-infected patients experienced faster than expected fibrosis progression, even if they showed minimal scarring on initial biopsy (Sulkowski 2005a).

As stated above, the average time from HCV infection to the development of liver disease is about 30 years in people with HCV alone. Various studies have shown that in co-infected people, the average time to liver disease progression is 15 to 25 years. Looking at repeated biopsy samples, French researchers determined that HIV / HCV co-infected patients developed fibrosis in an average of 26 years, compared with 34 years in HIV-negative people with HCV (Benhamou 1999). In a London study, the corresponding averages were 23 and 32 years. That is, HIV co-infection accelerated fibrosis progression by 1.4-fold (Mohsen 2003). In another study, HIV co-infection significantly shortened the survival time of people with HCV-related ESLD (Pineda 2005).

Research has shown that HIV / HCV co-infection is associated with greater risk of developing steatosis, which can impair response to anti-HCV therapy (Sulkowski 2005b; Thomopoulos 2005).

There is also evidence that progression to HCC is faster in co-infected people (Bräu 2005; Garcia-Samaniego 2001) and that co-infected individuals have twice the risk of ESLD for each decade of HCV infection (Ragni 2001). HIV / HCV co-infection has been associated with higher levels of HCV RNA (genetic material) in the blood and reduced response to interferon-based HCV treatment (di Martino 2002).

Several studies showing that HIV infection accelerates HCV-related liver disease progression were conducted before the widespread adoption of HAART. Some later research suggests that patients who are receiving effective antiretroviral therapy and who have well-controlled HIV disease may fare about as well as people with HCV alone (Kramer 2005). Co-infected people with lower CD4 counts (below 50, 100, 200, or 500 cells/mm3 in different studies) are more likely to experience severe liver disease progression and death than those with less compromised immune systems (Benhamou 1999; Fultz 2004).

Although most evidence indicates that HIV accelerates hepatitis C progression, some studies suggest the contrary. For example, an Italian study found that HIV infection did not affect the speed at which liver fibrosis developed (Puoti 2001b). Tor (2001) found no difference in liver inflammation and fibrosis between co-infected patients and those with HCV alone. There is also some evidence that liver function markers and HCV viral load may not be higher in co-infected individuals (Sterling 2003). One study found that steatosis was lower in co-infected individuals than in patients with HCV alone (Monto 2005).

One caution when considering studies of co-infected individuals is the lack of attention to alcohol use when assessing the results. Studies that do not control for alcohol use should be treated with caution, since alcohol use is an independent risk factor for liver damage in co-infected individuals. Another problem is that it can be difficult to measure exactly how long people have been infected with HCV, which can lead to false estimates of the speed of HCV disease progression.

Does hepatitis C virus affect HIV disease?

Whether or not HCV infection leads to more rapid HIV disease progression has been a controversial issue. Until the late 1990s, most experts believed that HCV did not accelerate HIV disease. Although evidence has accumulated indicating that HCV may in fact lead to lower CD4 cell counts and an elevated risk of death, experts are still divided on the issue, and more research is needed to understand the relationship between the two viruses.

Several studies have shown that HCV does not affect HIV progression (Sulkowski 2002b). In the international CAESAR study, a retrospective analysis of data collected prior to the advent of HAART, median CD4 cell count changes and the rate of progression to new AIDS-defining illnesses were similar in co-infected patients and those with HIV alone, leading the researchers to conclude that HCV has no significant impact on HIV disease progression (Amin 2004). A recent study in Philadelphia found that HIV / HCV co-infected individuals did not have a greater rate of progression to AIDS than those with HIV alone (Tedaldi 2004). Similarly, a cohort study of haemophiliac men with known dates of HIV and HCV exposure conducted by the Royal Free Hospital in London did not find that HCV infection increased the risk of progression to AIDS over an average of 13.5 years of follow-up (Sabin 2002). More recently, an analysis of data from the US Women and Infants Transmission Study showed that HIV / HCV co-infected women did not progress to an AIDS-defining illness or death faster than those with HIV alone (Hershow 2005). In the large EuroSIDA study, again, HIV / HCV co-infected patients were not at increased risk for HIV disease progression (Rockstroh 2005).

However, other studies have found that co-infected individuals are at greater risk of HIV disease progression. In the Swiss HIV Cohort Study, co-infection was associated with greater HIV progression, a higher rate of OIs and higher mortality than seen amongst those with HIV alone (Greub 2000). Another study showed that co-infected individuals were two to three times more likely to develop OIs, enter a hospital or die than those with only HIV (Klein 2003). Other European and American data support the theory that HCV infection accelerates HIV disease progression, independent of antiretroviral therapy (Soriano 2001c). In a recent study of United States veterans, for example, HIV / HCV co-infected individuals had a shorter average survival period, although they did not progress more rapidly to AIDS, than those with HIV alone (Anderson 2004). An analysis of data from a cohort of recent seroconverters in Italy found that since the advent of HAART, co-infected individuals were significantly more likely to progress to AIDS, a difference that may be partly attributable to shorter use of combination antiretroviral therapy (Dorrucci 2004). A recent United Kingdom study, too, found that HIV / HCV co-infected patients were more likely to experience an AIDS-defining illness, although they found no effect of HCV on CD4 cell count declines (Stebbing 2005). Another analysis found that infection with multiple HCV genotypes was associated with more rapid HIV disease progression (van Asten 2004), while an analysis of HIV / HCV co-infected patients starting HAART in British Columbia showed that HCV co-infection doubled the risk of death (Braitstein 2005). Finally, Yoo (2005) found that haemophiliacs with HCV and HIV had lower CD4 cell counts than those monoinfected with HIV, particularly when co-infected with HCV genotype 1, while analysis of data from the Italian Cohort Naive for Antiretrovirals suggest that CD4 cell counts are lower in patients with HCV genotype 1 than those with genotypes 3 or 4 (Antonucci 2005a). As a result, experts in the field such as Dr Vincent Soriano now suggest that hepatitis C can be considered a co-factor in HIV progression (Soriano 2002).

Possible explanations for accelerated HIV disease progression in HCV-co-infected patients include failure to maintain effective anti-HIV CD8 T-cell responses (Harcourt 2005).

Several studies and a recent literature review and meta-analysis have shown that HIV / HCV co-infected individuals experience slower or blunted immune recovery after starting HAART (Braitstein 2004; Farmer Miller 2005). The reason for this is unknown, but experts have suggested that HCV may alter production or programmed cell death of T-cells (Graham 2002). Interferon-based therapy can lead to an overall decline in white blood cells. However, since this affects all types of white cells, the CD4 percentage may remain the same even as the absolute number of CD4 T-cells decreases.

In one Canadian study, co-infected individuals gained an average of 50 cells/mm3 after 18 months on HAART, compared with an average gain of 190 cells/mm3 in those with HIV alone (Braitstein 2003). Similarly, a study by Soriano’s group found that after two years on HAART, CD4 cell counts increased by 53 and 111 cells/mm³, respectively. In this study, co-infected subjects also had poorer virological response (Martin 2001).

In the Swiss cohort mentioned above, co-infected individuals were less likely to experience a CD4 cell count increase of at least 50 cells/mm3 after one year on HAART, but HIV-positive patients with and without HCV were equally likely to achieve undetectable HIV viral loads. An Australian study also found slightly lower CD4 cell count increases but similar virological responses in co-infected patients (Lincoln 2003). In Klein’s study (2003), co-infected individuals were less likely to achieve a CD4 cell increase than people with HIV alone. In the large international ATHENA cohort of more than 6400 participants, HIV / HCV co-infection did not appear to affect time to HIV viral suppression, but CD4 T-cell recovery was reduced (Cowling 2004). In a recent Italian study, HCV viraemia (detectable HCV RNA) was associated with poorer immune response to HAART, suggesting that successful anti-HCV therapy might facilitate anti-HIV treatment (Antonucci 2005b).

Other studies have not found a difference in immunological recovery, however, and a recent Thai study found that the early delay in CD4 T-cell recovery did not last, and was not associated with increased HIV disease progression (Anderson 2004; Duncombe 2004; Rockstroh 2005).

HIV / HCV co-infected people may be at higher risk for brain and psychological impairment than people with HIV alone (Cherner 2005; Yang 2004). However, co-infected people do not appear more likely to develop sensory neuropathy than HIV monoinfected people (McArthur 2004).

Diagnosis and monitoring

A blood test for the presence of antibodies to HCV will usually tell whether or not a person has been exposed to the virus. United Kingdom guidelines recommend that all HIV-positive patients be tested for HCV at least once, with subsequent tests for people at higher risk of HCV infection or with unexplained liver disease. Tests should also be performed to exclude co-infection with hepatitis B, and HIV-positive individuals should be vaccinated for both hepatitis A and B.

In some HIV-positive people, an antibody test may be negative even though they are infected with HCV, because their immune systems are too weak to produce enough antibodies (John 1998; Berggren 2001; George 2002). Thus, if hepatitis C is suspected in HIV-positive individuals, a negative HCV polymerase chain reaction (PCR) test may be necessary to confirm an antibody result.

The HCV PCR test, like the HIV PCR, is a test that measures the amount of viral genetic material (RNA) in the blood, i.e. the HCV viral load. An HCV viral load test can indicate whether someone is among the small percentage of people who clear HCV from the body naturally without treatment. Given that viral eradication is one of the goals of anti-HCV therapy, viral load testing is also used to monitor the effectiveness of treatment. Unlike HIV viral load, however, HCV viral load is not directly related to HCV disease progression. It also is not an indicator of when to commence treatment, but it does suggest how long treatment should last; people with high HCV viral loads (above 2 million copies/ml) may require a longer course of treatment.

Liver function tests include the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which often increase during liver inflammation. These tests may give an indication of whether HCV has caused liver damage, and can also help determine whether hepatitis C treatment is working or whether anti-HIV medications are harming the liver. But the tests are much less useful for HCV than for HBV, since some people have quite normal liver function tests even though they have sustained significant liver damage. In addition, liver enzyme levels may not reveal the full extent of liver disease in co-infected people, and test interpretation may be complicated in people taking antiretroviral drugs. For more on liver function tests, see Liver function in Viral load, CD4 cell counts and other tests: A to Z of medical tests.

In order to tell whether liver damage is present, it may be necessary to have a liver biopsy, in which a small sample of liver tissue is extracted via a needle and examined under a microscope, to look for signs of liver injury. Biopsy test results are often reported in terms of fibrosis stage (F0 to F4). Liver biopsies can help to determine what sort of treatment may be needed and how long it should last. Repeat biopsies may be performed to check if liver disease is progressing. Usually repeat biopsies are recommended every three to five years, but because liver damage can progress more quickly in co-infected people, some experts think such individuals should receive repeat biopsies more frequently.

Until recently, it was thought that liver biopsy was the only way to determine accurately whether a person with HCV has liver damage, but many researchers are working on non-invasive tests for liver damage that measure certain chemical markers in the blood and indices (e.g., APRI, SHASTA, FibroTest) of multiple factors that predict liver disease progression (Kelleher 2005; Lackner 2005; Quereda 2002, 2003). Another type of test, called elastography (e.g., FibroScan), measures liver stiffness, which is highly correlated with fibrosis stage (Ziol 2005).

Hepatitis C virus genotype

Tests may also be performed to determine HCV genotype. HCV has six major genotypes, which occur with different frequency in different parts of the world. Genotypes 1a and 1b are most common in Europe and the United States, and are the most difficult to treat. Genotype 3 is frequently seen in IDUs. Genotype tests can help guide hepatitis C treatment. People with genotype 1 typically require more aggressive treatment, usually lasting at least 48 weeks. People with genotypes 2 or 3 are typically treated for 24 weeks. Genotype 4, which accounts for a majority of cases in the Middle East and parts of Africa, has traditionally been considered difficult to treat, like genotype 1. However, some recent research suggests that it might respond to interferon therapy better than previously thought (Lyra 2004).

Some research suggests that different genotypes are associated with different degrees of liver disease severity and rate of progression. Genotype 3, for example, is linked to the development of steatosis. In a recent study of co-infected IDUs, genotype 1 was associated with faster HIV disease progression and immunological decline, while genotype 4 was linked to slower progression. Because HCV genotype is such a strong predictor of response to treatment, some experts recommend getting a genotype test before commencing treatment.

Aims of hepatitis C virus treatment

The main goals of hepatitis C treatment are:

• Sustained virological response (SVR), or undetectable HCV viral load (below 100 copies/ml) six months after completing a course of treatment.
• Undetectable, or significantly reduced, HCV viral load within three months of starting treatment. This is strongly predictive of achieving long-term virological response.
• Sustained normalisation of ALT levels.
• Improvement or disappearance of liver inflammation and associated symptoms.
• Prevention or reversal of progression to cirrhosis, liver cancer and liver failure.
• Reduction or delay of liver-related mortality.
• Improved quality of life.
• Among people with HIV / HCV co-infection, an additional aim is to improve tolerance of anti-HIV drugs.

Although it is often assumed that undetectable HCV viral load after a 24- or 48-week course of therapy signals the complete clearance of the virus, an editorial in the New England Journal of Medicine urged caution in describing undetectable HCV in the blood as a ‘cure’ for HCV (Schafer 2000). This caution is supported by the fact that HCV usually recurs after a liver transplant, even among people who previously achieved SVR, indicating that the virus was still present at low levels in the body.

Several recent studies indicate that even amongst people who are not long-term responders, interferon-based treatment still seems to reduce, and possibly even reverse, the level of liver damage (Abergel 2004). Several recent studies of peginterferon in HIV-negative individuals reported improvements in liver tissue health in some patients who still had detectable HCV viral load at week 72, suggesting that interferon may still benefit liver health even if it cannot completely control HCV viraemia. Clinical trials are underway to determine whether low-dose interferon maintenance therapy can help prevent progressive liver damage.

Who should receive treatment?

Not everyone with chronic HCV infection needs treatment. Therapy is indicated for people who are experiencing liver disease progression. Since HIV seems to accelerate HCV-related liver damage, some experts think co-infected people should be treated earlier in the course of the disease.

There is large variation in responses to anti-HCV treatments due to a variety of host and viral factors.

People less likely to respond well to treatment include:

• Symptomatic people with moderate or severe fibrosis or cirrhosis of the liver.
• People with HCV viral loads greater than 2,000,000 copies/ml.
• HIV / HCV co-infected people with CD4 cell counts below 500 cells/mm3.
• People with HCV genotype 1, especially subtype 1b.
• Men.
• Older individuals (above age 40).

People with fewer symptoms, lower HCV viral loads and genotypes other than 1 tend to respond better to treatment, but they also typically have a lower risk of liver disease progression in any case. A key paradox of hepatitis C treatments is that those who are most likely to benefit from treatment are those who need it least.

Current practice concerning HCV treatment is undergoing a shift. As anti-HCV therapies improve, the balance between benefits and risks of treatment are changing. Not all experts agree about who should receive treatment and when is the best time to start.

Traditionally, most doctors preferred to treat only individuals whose liver functions are consistently abnormal. However, recent research indicates that some people with persistently normal ALT levels may still experience liver disease progression and could benefit from therapy (Fonquernie 2004; Uberti-Foppa 2004). Because it is usually asymptomatic, HCV infection is rarely detected during the acute phase, in the first six months. However, among co-infected people on HAART who receive regular liver function tests, the detection rate is higher. HCV treatment during the acute phase of infection is highly effective, approaching 100% in some studies of HIV-negative people (Jaeckel 2001). Among HCV / HIV co-infected individuals, the response rate is lower but still good, around 60 to 75% in different studies (Bhagani 2004; Gilleece 2005; Nelson 2003). However, treating HCV at such an early stage means that many people who would have spontaneously cleared the virus or never developed liver fibrosis will receive unnecessary treatment. United Kingdom and United States guidelines recommend that early treatment should be considered, but that it is prudent to wait two or three months to see if spontaneous HCV clearance occurs (Santantonio 2005).

Interferon-based treatment does not work well and can be dangerous in people with decompensated cirrhosis. Clinical trials are underway to determine the best way to treat individuals with advanced liver disease.

Hepatitis C virus treatment

Treatment for hepatitis C has improved in recent years with the development of new therapies and the adoption of combination regimens. The current preferred regimen is a combination of peginterferon alfa plus ribavirin.

Interferons are human proteins that directly inhibit viral replication and stimulate the body’s immune response. Several different types of interferon have been studied to treat HCV. Conventional interferon alfa, the previous standard HCV therapy, was injected three times per week. Peginterferon alfa is removed more slowly from circulation due to pegylation, the attachment of polyethylene glycol, which allows for once-weekly dosing.

Two forms of peginterferon alfa have been licensed in Europe. Viraferon Peg or Peg-Intron is peginterferon alfa 2b, manufactured by Schering-Plough, licensed in 2001. Pegasys is peginterferon alfa 2a, made by Roche. Both forms of peginterferon are injected subcutaneously (under the skin) once weekly. It is not yet known whether the two types of pegylated interferon differ in efficacy or tolerability, although a head-to-head comparison trial is underway.

Ribavirin is not active against HCV when taken alone, but improves response rates and appears to help prevent relapse when used with interferon. European approval of ribavirin, in combination with interferon, was granted in May 1999. In Europe, ribavirin is marketed under the brand names Copegus, Rebetol and Virazole.

Not everyone responds to interferon-based therapy, but research has shown that peginterferon plus ribavirin works better than conventional interferon plus ribavirin (Fried 2002; Manns 2001), which in turn works better than concentional interferon monotherapy (McHutchison 1998; Poynard 1998; Reichard 1998).

In HIV-negative people, the SVR rate using peginterferon plus ribavirin is around 45% for people with genotype 1 and 80% for those with genotypes 2 or 3. A recent study found slightly higher SVR rates in children: 48% for genotype 1 and 100% for genotypes 2 and 3 (Wirth 2005). Factors that predict poorer response include male gender, older age, HCV genotype 1, higher HCV viral load, and advanced liver disease. In addition, studies show that people of African descent are less likely to respond to interferon-based therapy (Jeffers 2004; McHutchison 2000; Muir 2004).

Treatment for HCV is not life-long. The usual recommended length of treatment is 48 weeks for people with HCV genotype 1 and 24 weeks for people with genotypes 2 or 3. Some studies suggest that longer treatment duration may improve response rates, especially for HIV / HCV co-infected people.

Numerous studies have shown that response to therapy at twelve weeks predicts whether or not a person will achieve a sustained virological response six months after treatment is completed. If an individual has failed to achieve a reduction in their HCV viral load of at least 2 log10 by this time, many experts recommend discontinuing HCV therapy given the high incidence of side-effects and the low likelihood of achieving a sustained response. However, one randomised trial has shown that patients with genotypes 2 or 3 may be able to stop HCV therapy after twelve weeks if they have undetectable HCV viral loads at this point, or carry on for the full 24 weeks. The patients in the variable treatment duration group had similar SVR rates to the group randomised to receive treatment for 24 weeks (Mangia 2005).

Some doctors use peginterferon monotherapy as an initial treatment in people with less severe hepatitis C and those most likely to achieve a good response, and add ribavirin only if interferon alone has failed to produce undetectable HCV viral load after 12 weeks of treatment, or in case of subsequent relapse. In some individuals, peginterferon alone is an effective treatment, and this approach reduces the risk of a serious ribavirin side-effect called haemolytic anaemia (Heathcote 2000; Zeuzem 2000; Reddy 2001).

Despite the evidence that peginterferon is much more effective than conventional interferon, the combination of peginterferon and ribavirin has not received uniform funding throughout the United Kingdom.

See Interferon alfa in Drugs used by people with HIV: Immune-modulating drugs for further details.

Hepatitis C virus treatment in co-infected people

As is the case for people with hepatitis C alone, the standard anti-HCV regimen for HIV / HCV co-infected people is peginterferon plus ribavirin. In February 2005, the European Commission and the United States Food and Drug Administration (FDA) approved peginterferon alfa 2a (Pegasys) for use with or without ribavirin for co-infected patients with chronic hepatitis C.

Because co-infection with HIV accelerates HCV-related liver disease progression, some experts argue that all co-infected people should receive anti-HCV therapy (Soriano 2002). Researchers who found that HAART has no impact on the development of fibrosis in co-infected people have argued that treatment for hepatitis C should be started as soon as possible (Martin-Carbonero 2004).

United Kingdom guidelines recommend that HCV treatment should be considered for all HIV-positive individuals, particularly if they have developed moderate or worse liver disease. Treatment ideally should be initiated whilst a patient’s CD4 cell count is above 200 cells/mm3, as treatment at lower CD4 cell counts has been associated with a poorer response. Treatment should also be considered in the case of mild disease, particularly if the patient wishes to commence treatment and there are high hopes of success. In cases of advanced cirrhosis or liver cancer, co-infected patients can be good candidates for liver transplant if their HIV prognosis is good.

The usual recommendation is that co-infected individuals should continue HCV therapy for the same duration as people with HCV alone (48 weeks for genotype 1; 24 weeks for genotypes 2 or 3). However, some research suggests that co-infected people clear HCV more slowly after starting treatment, and some experts recommend lengthening treatment duration to 72 weeks for genotype 1 and 48 weeks for genotypes 2 or 3 (Soriano 2004a). The benefits of 48 weeks’ treatment for genotypes 2 or 3 have been confirmed in a small randomised controlled trial of HIV-co-infected patients. In this study, patients receiving peginterferon alfa and ribavirin for 48 weeks were over five times more likely to achieve an SVR than those who stopped therapy after 28 weeks (Zanini 2005).

As is the case for people with HCV alone, response to treatment at twelve weeks predicts whether or not co-infected individuals will ultimately achieve a sustained virological response (Camino 2004; Crespo 2004; Rodriguez-Torres 2004a; Soriano 2004a). One study suggested that early virological response at eight weeks might be adequately predictive of SVR (Cargnel 2005), but here too some experts think HCV treatment response is delayed in HIV-positive people and even twelve weeks is too early.

Although there is little evidence, treatment of early hepatitis C infection in HIV co-infected patients appears to be less successful than those without HIV (Chaix 2005).

Guidelines on the management of HIV / HCV co-infection published by the British HIV Association (BHIVA) in 2005 make the following recommendations (Nelson 2005):

• Screen all HIV-positive patients for HCV at HIV diagnosis and subsequently according to risk.
• Perform a PCR test in patients with unexplained liver disease.
• HIV / HCV co-infected individuals should be vaccinated against hepatitis A and B.
• Monitor patients thoroughly, including liver biopsy to assess disease severity.
• HIV / HCV co-infected patients should abstain from alcohol.
• Consider treatment with peginterferon plus ribavirin, or enter into a clinical trial. Treatment is most appropriate in patients with moderate disease.
• Treat patients who have a CD4 cell count above 200 cells/mm3 before commencing HAART, if possible, to reduce risk of liver toxicity.
• In patients who are already on HAART, delay HCV therapy until CD4 cell count is above 200 cells/mm³.
• AZT (zidovudine, Retrovir) and ddI (didanosine, Videx / VidexEC) ideally should be avoided in patients receiving ribavirin.
• Monitor liver function carefully if HAART is initiated and observe serum lactate for nucleoside analogue toxicity, especially in those on ribavirin.
• All HIV-positive patients with HCV who do not have evidence of liver damage should be screened annually.
• Patients who eradicate HCV should have PCR performed annually to detect relapse or re-infection.
• Patients diagnosed with acute hepatitis C may be treated with pegylated interferon plus ribavirin.

Ideally, assessment and treatment for HIV and HCV should be carried out in a specialised unit experienced in treatment of both conditions and there should be liaison with the local hepatology team.

Hepatitis C virus and HIV: which to treat first?

There remains some disagreement about whether HIV or HCV should be treated first in co-infected individuals. The best time to start treatment for HIV or hepatitis C depends on the stage of each infection. If tests show both diseases should be treated, doctors will usually start treating HIV first, as this is typically the more rapid and life-threatening of the two diseases. Secondly, once HIV is under control and CD4 cell counts rise above 200 cells/mm3, people respond better to interferon and are better able to tolerate the side-effects of HCV therapy (Uberti-Foppa 2003).

Conversely, hepatitis C may be treated first if, for example, a person has rapidly progressing or severe liver disease and a CD4 cell count above 350 cells/mm³.

An international consensus statement on the treatment of hepatitis C in co-infected people recommends anti-HCV treatment where the person has a fibrosis score between F1 and F4, because treatment is needed due to liver disease progression, or if the person is infected with anti-HCV genotype 2 or 3, because treatment is so likely to be successful. Given that people with higher CD4 cell counts have a better response to HCV treatment, the statement says that people with CD4 cell counts above 500 cells/mm3 are regarded as good candidates for treatment, as are people with CD4 cell counts between 200 and 500 cells/mm3 and HIV viral loads below 5000 copies/ml. As noted above, HCV therapy is not recommended for individuals with CD4 cell counts below 200 cells/mm3. The statement makes the case for early treatment of hepatitis C in co-infected people due to the role HIV plays in accelerated liver disease progression and the fact that hepatitis C is now a major cause of illness and death among people with HIV (Soriano 2004b). At the First European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients held in March 2005, a panel of specialists recommended that patients whose immune systems have been significantly depressed should receive antiretroviral treatment for HIV first to increase CD4 T-cell counts before beginning treatment for HCV (Alberti 2005).

United States experts have recommended that HCV treatment should be delayed in individuals with highly chaotic or stressful lifestyles, and in those suffering from depression, due to the potential psychiatric side effects of interferon. The 2002 United States National Institutes of Health hepatitis C guidelines recommend that active addictions should be treated prior to treatment for hepatitis C. However, they state that no group should be automatically excluded from treatment, and that each case should be considered on an individual basis.

Until more definitive data is available, concurrent treatment with HAART and interferon and ribavirin should be regarded as experimental, as possible drug interactions are unknown. Close monitoring of people taking both HAART and anti-HCV therapy is advised.

Response rates in co-infected individuals

Research shows that HIV / HCV co-infected people do not respond as well to hepatitis C treatment as those with HCV alone. However, a number of recent studies in Europe and the United States conducted in individuals with well-controlled HIV disease have produced promising results, including for people with hard-to-treat genotype 1.

In the largest co-infection study to date, known as APRICOT, which included 868 co-infected individuals, those treated with peginterferon alfa 2a plus ribavirin for 48 weeks had an SVR rate of 40% (29% for genotype 1; 62% for genotypes 2 or 3; Torriani 2004).

In the American ACTG 5071 study, which included 133 co-infected people, the SVR rate using the same regimen was 27% (14% for genotype 1; 73% for genotypes 2 or 3; Chung 2004). This study produced a good end-of-treatment response rate, but many individuals later relapsed.

The French RIBAVIC study, which included 412 co-infected participants, produced a less impressive SVR rate of 27% (15% for genotypes 1 or 4; 44% for genotypes 2 or 3) using peginterferon alfa 2b plus ribavirin (Carrat 2004).

A Spanish study of 95 co-infected individuals found an SVR rate of 44% for interferon alfa 2b plus ribavirin (38% for genotype 1; 53% for genotypes 2 or 3). This was the highest response rate yet seen in co-infected individuals with genotype 1 (Laguno 2004).

It is not yet clear why the SVR rates varied so much among these trials, but there were some important differences in study populations. For example, ACTG 5071 included more people of African descent (about one-third) than APRICOT (about one-tenth), a group that responds less well to treatment. RIBAVIC included patients with more advanced liver disease and more current and past IDUs. Also, the discontinuation rate in this study was high: more than 40%. Taken as a whole, these studies cannot show whether peginterferon alfa 2a (Pegasys) or peginterferon alfa 2b (Viraferon Peg / Peg-Intron) works better.

A major concern for HIV / HCV co-infected people has been the relatively high rate of relapse after clearing HCV (Hoffman-Terry 2002; Soriano 1997; Perez-Olemda 2003). In the APRICOT, ACTG A5071 and RIBAVIC studies, in which participants received 48 weeks of treatment, 10 to 15% of people with an end-of-treatment response relapsed during the subsequent six months and did not achieve SVR. The ACTG 5071 researchers suggested that their high relapse rate may have come about because the study started patients on lower initial doses of ribavirin in order to minimise toxicity. The ongoing Spanish PRESCO trial, which includes about 350 co-infected participants, is using relatively high weight-adjusted doses of ribavirin. Interim data show that after 24 weeks of treatment, 63% had undetectable HCV RNA (50% for genotype 1; 85% for genotypes 2 or 3; 44% for genotype 4; Nunez 2004).

Given their lower response rates, it is reassuring that hepatitis C treatment appears to slow liver disease progression in co-infected individuals, as it does in people with HCV alone (Lissen 2004; Rodriguez-Torres 2004b).

Antiretroviral therapy in co-infected individuals

On the whole, HAART is safe and effective in HIV / HCV co-infected people. However, several studies have shown that the risk of liver toxicity related to anti-HIV drugs is greater among people with viral hepatitis. In part, this increased toxicity is due to the reduced ability of a damaged liver to process antiretroviral drugs. Because their livers are already damaged, co-infected individuals are likely to be more vulnerable liver-related side-effects of anti-HIV drugs.

In addition, as HAART improves immune function, this can lead to a form of immune reconstitution syndrome characterized by transient ‘flares’ of liver inflammation and elevated liver enzymes as the immune system steps up its attack against HCV in liver cells (Flexman 1999). This condition is most likely to develop when people respond well to HAART, with a CD4 cell count increase of 50 cells/mm3 or more. If hepatitis flares up, HAART may need to be suspended temporarily to address the hepatitis.

In an Italian study, 26 cases of life-threatening liver disease (seven of them fatal) occurred among 755 people after they commenced HAART. Sixteen individuals received liver biopsies, which showed evidence of exacerbation of chronic active hepatitis, but no signs of drug-related hypersensitivity damage. Following a treatment interruption (which in some cases included a course of interferon), the 19 surviving individuals successfully recommenced HAART without recurrence of acute liver disease (Puoti 2003). Small studies have also suggested a link between use of fosamprenavir (Telzir) and liver toxicity in HCV-co-infected patients (DeJesus 2005), as well as reduced lopinavir and elevated efavirenz levels (Dominguez 2005).

Due to the increased risk of liver toxicity, co-infection may influence the choice of anti-HIV drugs. Ideally, care of co-infected individuals should be managed by clinicians who have experience with both diseases, and regular monitoring of liver function is recommended when co-infected people start HAART or change antiretroviral drugs.

People with hepatitis C who take HAART may be at greater risk of insulin resistance and diabetes than people with HIV alone, but some studies suggest that co-infected people may be at lower risk of elevated cholesterol (Duong 2001; Hoffman-Terry 2001; Mehta 2003; Patroni 2002; Polgreen 2004). See Body fat changes on antiretroviral therapy (lipodystrophy) – overview in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for more information about the metabolic side-effects of anti-HIV treatment.

While certain anti-HIV drugs are also active against HBV, they do not have a direct effect on HCV (Mendel 1998). HAART has been associated with a significant transient rise in HCV viral load (Chung 2002; Kottilil 2002; Perez-Cano 1998; Puoti 2000; Ragni 1999; Rutschmann 1998). This is particularly the case in people who had a baseline CD4 cell count below 350 cells/mm3 and greater HCV viral diversity. The clinical implications of this increase in HCV viral load are unknown, although it may play a part in liver damage in the short term. Most studies show that HAART is effective in people co-infected with HCV, although they appear to have a slower or blunted immunological or virological response to anti-HIV therapy.

In the long term, research clearly shows that the benefits of anti-HIV therapy outweigh the risks. Some studies have shown that HAART is associated with slower progression to fibrosis and cirrhosis, although a recent Spanish study found that antiretroviral therapy neither slowed nor accelerated the development of fibrosis (Benhamou 2001; Mariné-Barjoan 2004; Martin-Carbonero 2003, 2004; Ragni 2001). Anti-HIV therapy is also associated with a lower rate of mortality due to liver-related causes in co-infected individuals according to a German study published in The Lancet (Qurishi 2003). For HIV / HCV co-infected patients, stated an accompanying editorial, “the risks of hepatoxicity, although real, should not diminish the use of HAART, but should encourage more widespread use of pharmacokinetic testing and development of new agents against HIV-1 that have less effect on liver metabolism” (Alatrakchi 2003).

Liver toxicity, liver disease and highly active antiretroviral therapy

Among the total HIV-positive population, about 3 to 4% of individuals develop acute liver disease within two years of starting HAART (Monforte 2001). Hepatitis C co-infection has been shown to increase the risk of liver toxicity, characterised by an increase in liver enzyme levels after starting antiretroviral drugs (Monforte 2001; Aceti 2002; Nunez 2001; Sulkowski 2000).

In a cohort of nearly 2980 individuals, for example, having HCV significantly increased the risk of developing serious grade 4 liver side effects (Reisler 2003). Not surprisingly, the chances of drug-related liver toxicity are highest in individuals who already have advanced liver damage (Aranzabal 2005).

In a study of 394 patients who started a protease inhibitor-containing regimen between July 1996 and February 1998, 18% developed very high liver enzymes within 25 weeks, and co-infection with HCV or HBV was associated with a higher risk of liver toxicity (den Brinker 2000). In this study liver enzyme levels tended not to return to baseline in co-infected patients, regardless of whether they changed, stopped or continued their HAART regimen. In a Spanish cohort, 9% of all patients starting their first HAART regimen developed severe liver toxicity, but the incidence was 16% in those with HCV compared to 5% of those without HCV. This cohort largely comprised individuals also infected with HBV.

In addition to HCV co-infection, several other factors have been linked to liver toxicity among people starting HAART, including alcohol consumption, injection drug use, age over 35, hepatitis B or D co-infection, elevated liver enzymes at baseline, and good response to therapy (Flexman 1999; Monforte 2001; Nunez 2001).

Although many anti-HIV medications have occasionally been linked to liver problems, liver toxicity has most often been associated with protease inhibitors as a class (Dieterich 2003). This has particularly been seen with full-dose ritonavir (Norvir), although not all studies show this association. The lower ritonavir doses used to boost other protease inhibitors are less likely to cause liver problems. Ritonavir-boosted lopinavir (Kaletra) has also been linked to severe liver enzyme elevations, especially in individuals co-infected with HBV or HCV but other studies have yielded low liver toxicity rates (Bonfanti 2005; Chihrin 2004; Meraviglia 2004).

The non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune) can cause a hypersensitivity reaction characterized by liver damage and skin rash, and has also been associated with faster fibrosis progression (Macias 2004). In January 2005, the FDA issued a public health advisory confirming that nevirapine can cause potentially life-threatening liver toxicity, especially in women and in patients with higher pre-treatment CD4 cell counts (above 250 cells/mm³ for women and above 400 cells/mm3 for men). In contrast, another study found that people with HCV or HBV are not at increased risk of liver toxicity when taking nevirapine or efavirenz (Sustiva; Sulkowski 2002a).

Importantly, the absolute rate of serious side-effects associated with antiretroviral drugs remains quite low (Hoffman-Terry 2000; Dieterich 2002; Sulkowski 2002a). A Canadian study, for example, found that just 7% of co-infected patients developed an ALT level more than five times the upper limit of normal, and only 3% switched or discontinued anti-HIV medications due to liver problems, all of whom were taking full-dose protease inhibitors (Cooper 2004).

Side-effects of hepatitis C virus treatments

Side-effects of hepatitis C treatment are quite common, but can often be managed using adjunct medications and practical aids. Interferon side-effects may include a flu-like feeling with fevers and joint pain. These symptoms can range from mild to severe, but often lessen as treatment goes on. Conventional interferon and peginterferon produce similar side-effects.

The major side-effect of interferon is depression, and people who are prescribed this treatment should be made aware of the potential severity of the depressive symptoms that might occur. Necessary support and back-up anti-depressant medication should also be discussed before treatment. Some studies suggest taking prophylactic antidepressants before or at the same time as starting interferon is an effective strategy (Kraus 2005; Schaefer 2005).

A recent report has suggested that peginterferon plus ribavirin can cause eye lesions and affect colour vision in co-infected individuals (Farel 2004): nerve damage and other eye diseases have also been seen in people with HCV or HBV alone who are taking interferon.

In addition, interferon can cause neutropenia (low white blood cell counts, which may include a drop in CD4 T-cells) and thrombocytopenia (low platelet counts), while ribavirin can cause the blood disorder haemolytic anaemia (low red cell count). Colony stimulating factors can be used to treat neutropenia, and epoetin alfa (Eprex) can restore red blood cells (Sulkowski 2005c). Co-infected people taking anti-HIV drugs such as AZT (zidovudine, Retrovir), ddI and other nucleoside reverse transcriptase inhibitors (NRTIs) may be at increased risk of blood cell deficiencies.

Some studies have found that hepatitis C treatment side-effects are more common in co-infected individuals than in people with HCV alone, and coinfected people typically have higher trial drop-out rates and more often need to have their interferon or ribavirin doses reduced (Brau 2004). Further, people with advanced liver disease and those with more heavily compromised immune function appear more likely to develop severe side-effects from anti-HCV therapy (Moreno 2004). In the APRICOT study, co-infected people with advanced liver damage were at higher risk for decompensated cirrhosis and loss of liver function, which occurred in 10% of patients (Mauss 2004).

Concurrent treatment with ribavirin and NRTIs, in particular ddI or d4T (stavudine, Zerit), seems to increase the risk of mitochondrial toxicity, characterized by elevated lactate levels, and the rare but life-threatening conditions lactic acidosis and pancreatitis (Bani-Sadr 2005; Hor 2002; Lafeuillade 2001; Smith 2002). Symptoms may include abdominal pain, nausea, difficulty breathing and numbness. Use of ddI was also associated with decompensated cirrhosis in the APRICOT study.

Lifestyle changes and complementary approaches

Many people with HCV have chosen to use alternative and complementary therapies to reduce symptoms. Chinese herbal medicine in particular is used quite widely in the United Kingdom. Among the most common herbal remedies for hepatitis are milk thistle (silymarin) and licorice root (glycyrrhizin). Many herbs are potentially toxic to the liver, however, and cannabis (marijuana) – which many people use medicinally – was linked to aggressive fibrosis in one study (Hezode 2005).

Dietary adjustments and other changes in lifestyle are important. Reducing alcohol consumption or eliminating it entirely is among the most important lifestyle changes one can make as alcohol consumption increases the risk of liver damage in HCV infected people.

Sustained weight loss and exercise may improve liver functioning and quality of life in people with hepatitis C, according to a recent study of HIV-negative people (Hickman 2004). In particular, obesity can contribute to steatosis, which is linked to more severe fibrosis. Given the potentially detrimental effect of weight loss in people with HIV, and the complicating effect of HIV treatments, people with HIV and hepatitis C should consult a specialist dietitian before embarking on a weight loss strategy.

Experimental treatments for hepatitis C virus and hepatitis C virus / HIV co-infection

There is a range of drugs targeting HCV or HCV-related liver damage that are currently being tested in clinical studies.

The influenza drug amantadine (Lysovir / Symmetrel) in combination with interferon is being tested against HCV in treatment centres throughout the United Kingdom. In some past studies amantadine has led to lower ALT levels, but other trials found no benefit.

New types of interferons are under study for hepatitis C, including Albuferon (a long-acting form of interferon alfa bound to the blood protein albumin), interferon tau, and interferon lambda (Robek 2005).

Two other forms, consensus interferon alfa (Infergen) and interferon gamma 1b (Actimmune), both produced by InterMune, are being studied as potential treatments for people who do not respond or who relapse after initial treatment (Kaiser 2004; Leevy 2004; Soza 2005).

Several other immune-modulating therapies are under study including etanercept (Enbrel), an agent that blocks tumor necrosis factor (Zein 2005); Ceplene; thymosin (Zadaxin); and mycophenolate mofetil (CellCept).

HCV protease and integrase inhibitors are also currently being tested in trials. Boehringer Ingelheim has a serine-protease inhibitor called BILN-2061 in phase II trials (Hinrichsen 2004), while Vertex Pharmaceuticals recently presented the first clinical data on its HCV protease inhibitor, called VX-950 (Reesink 2005).

Another Vertex drug, merimepodib (VX-497), works similarly to ribavirin, inhibiting inosine monophosphate dehydrogenase (IMPDH). Other experimental IMPDH inhibitors in clinical trials include levovirin and viramidine, a prodrug of ribavirin. Experimental nucleoside analogues include valopicitabine (NM-283) and isatoribine (ANA245).

Other hepatitis C therapies in the pipeline include internal ribosome entry site (IRES) inhibitors (e.g., ISIS 14803); polymerase inhibitors (e.g., JTK-003); helicase inhibitors; budding inhibitors (e.g., UT-231B); caspase inhibitors (e.g., IDN-6556); monoclonal antibodies (e.g., HepeX-C, HuMax-HepC); ribozymes; antisense oligonucleotides; and small interfering RNA sequences (siRNAs).

Preventative and therapeutic vaccines for hepatitis C are also being developed, although these are in the early stages of development and are hampered by the difficulty of stimulating an immune response against all the many variant forms of HCV (Houghton 2003).

Liver transplant

In cases of severe cirrhosis or hepatocellular carcinoma, a liver transplant may be the only viable treatment option. There is currently a serious shortage of donated livers. Individuals who are psychologically unstable, who use illegal drugs or who consume large amounts of alcohol currently do not have access to transplants in the United Kingdom.

Recent studies have shown that transplant outcomes in selected HIV-positive people can be nearly as good as those seen in people without HIV (de Vera 2003; Neff 2002; Ragni 2003). A United States team studying both liver and kidney transplants in HIV-positive individuals has reported encouraging results (Roland 2005). Transplants in HIV-positive and co-infected people are also under study in the United Kingdom and elsewhere in Europe (Norris 2004; Rufi 2004; Vogel 2005).

Transplant outcomes are most successful in people with well-controlled HIV disease. Post-transplant survival is poorer among HIV-positive individuals with CD4 cell counts below 200 cells/mm3 and those who are unable to tolerate anti-HIV therapy (Ragni 2003). Some patients who formerly could not tolerate antiretroviral drugs can do so after they receive a new liver. Concerns that immunosuppressive drugs used to prevent organ rejection would worsen HIV disease progression have not been borne out, but such drugs must be used with caution due to interactions with antiretroviral medications (Teicher 2004). Survival rates will likely improve as doctors become more experienced in managing the complex immunological factors and drug interactions affecting HIV-positive transplant patients. However, HCV usually infects the new liver soon after a transplant (Neff 2002; Norris 2004).

Following the success of transplants in this patient group, some experts have advocated for a routine approach to liver transplants in HIV-infected patients. In 2005, BHIVA and the United Kingdom and Ireland Liver Transplantation Centres issued guidelines recommending that HIV-positive patients with hepatitis B or C should be considered for liver transplants if they have at least a 50% chance of surviving five years or more after receiving a new liver. They also recommend that patients have CD4 cell counts above 200 cells/mm3 (or 100 cells/mm3 with portal hypertension), undetectable HIV viral loads, no AIDS-defining illnesses and antiretroviral drug options available. Contraindications include alcohol-related liver disease, unless abstinent for over six months, intravenous drug use and other cancers or circulatory disorders (O’Grady 2005).

Efficancy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV – 1

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