Summary

Over the past few years it has become clear that large and previously hidden epidemics of hepatitis B and C infection have emerged among some groups of people already affected by HIV. People who share needles to inject drugs are most likely to be affected, although anyone with HIV can also be coinfected with hepatitis A, B or C.

Whilst vaccines exist to protect people from hepatitis A and B, there is no vaccine against one of the most serious of viral hepatitis infections, hepatitis C. In the UK there is currently an outbreak of recent (acute) hepatitis C infection, primarily affecting HIV-positive gay men in London and Brighton. But sexually transmitted HCV can also occur heterosexually: a recent French study^[1]

concluded that two HIV-positive women out of a group of 402 recently-infected people probably acquired HCV through vaginal sex. The risk, however, depends on how likely your partner is to have HCV: partners of injecting drug users would be at most risk.

Although hepatitis A is an unpleasant short-term illness, it is not associated with long-term harm to the liver. However, hepatitis B and C infections can lead to serious liver disease, and as people with HIV live longer due to the success of anti-HIV therapy, we are now seeing proportionally more liver disease due to hepatitis coinfections than ten years ago.

Complicating matters is the fact that, over time, many drugs used to treat HIV have the potential to harm the livers of people coinfected with chronic viral hepatitis. A recent study from the 11,000-strong EuroSIDA cohort^[2] which examined deaths from liver-related causes in people with HIV throughout Europe, found that although the overall death rate from liver-related disease fell after the introduction of potent anti-HIV treatment, coinfection with hepatitis B virus and/or hepatitis C virus and length of exposure to anti-HIV therapy were found to be significantly associated with an increased rate of liver-related death. "This may be due to longer survival in coinfected patients," suggested the EuroSIDA investigators, "or prolonged treatment with potentially hepato[liver]toxic drugs.”

That's the conundrum of hepatitis and HIV coinfection: the anti-HIV drugs keeping coinfected people alive longer may also be responsible for their ultimate demise. "Fortunately, we are finally taking hepatitis coinfection seriously," says Dr Mark Nelson, director of HIV services at London's Chelsea and Westminster Hospital, and one of the organisers of the Second International Workshop on HIV and Hepatitis Coinfection, held in Amsterdam in January. "Before highly active antiretroviral therapy (HAART) came along ten years ago, we used to tell coinfected patients, 'Don't worry, you're going to die from your HIV'. Then everyone got so excited about HAART they forgot about hepatitis, and that may have been the reason for the recent spate of studies that found coinfected people continued to die faster."

We already have better treatments for hepatitis B, and whilst hepatitis C treatments are becoming more effective, they still require coinfected individuals to put their lives on hold for a year or so. There is still much to learn about the ideal time to start and stop anti-hepatitis therapy. Dr Martin Fisher, HIV consultant at Brighton and Sussex University Hospitals, where around 8% of HIV patients are coinfected with hepatitis B and another 8% with hepatitis C, acknowledges that even the 'experts' don't know everything. "Finally, though, some good prospective studies are starting to address some of the key questions we have about treating hepatitis B and C in coinfected individuals," he says.

At long last, with the establishment of coinfection clinics at some HIV treatment centres, the development of the British HIV Association's (BHIVA's) coinfection guidelines, national and international coinfection meetings, and the recent establishment of the British Coinfection Association, HIV medicine is finally coming to terms with the seriousness of viral hepatitis in HIV-positive individuals. "But still it's a sleeping giant," warns Dr Nelson, who is diagnosing acute and chronic hepatitis B and C in his HIV patients every week. "As time goes on, unless we treat people with effective and tolerable drugs there is going to be a proportion of people who are going to get sick and die."

Question One

AIDS Treatment Update [ATU]: If there's a vaccine for hepatitis B, why are HIV-positive people still getting infected?

Martin Fisher [MF]: HIV care can be so centred around anti-HIV therapy that a lot of the very basic things can get missed, like screening for hepatitis A, B and C, and offering vaccination against both hepatitis A and B. Everybody with HIV should be tested and vaccinated against hepatitis B. If the first vaccination doesn't work, which can happen in people with HIV, it's worth having another go when CD4 cell counts are higher and viral load is undetectable.

Mark Nelson [MN]: There's no excuse for someone who is HIV-positive to get acute hepatitis B. It's usually the doctor's or nurse's fault, though, because everyone who is HIV-positive should be vaccinated. I think it's important that all doctors and nurses are aware of the importance of hepatitis B vaccination, and that patients are aware that once they start a course of hepatitis B vaccinations they should finish it.

Question Two

Who is at risk for hepatitis C, and what can you do to prevent infection?

MN: The major route of transmission is through either transfusion of blood products or sharing of needles associated with injecting drug use. But right now there is an outbreak of acute hepatitis C that is being spread sexually, mainly in gay men with HIV. We don't really know what's going on in the GU clinic or in the general heterosexual population, because you don't usually become sick from hepatitis C when you catch it, and we're diagnosing this as part of the standard of HIV care. When we do liver function tests, if they're abnormal, we then test for hepatitis C.

MF: Certainly, data coming from Brighton as well as London's Royal Free and Chelsea & Westminster Hospitals suggests that your chance of acquiring hepatitis C is related to both your number of sexual partners and also to the type of sex you have.

MN: We're finding that the gay HIV-positive men who are being diagnosed with hepatitis C are much more likely to have visited sex clubs, bathhouses, saunas; much more likely to have met their partners on sex internet sites; and have much higher rates of partners compared with gay HIV-positive men who don't have hepatitis C. They're also more likely to have insertive and receptive anal intercourse, and practice rimming and fisting - both receptive and insertive - and use sex toys.

MF: It's possibly related to recreational drug use, as well. So it may not just be the sex by itself but also the environment in which the sex is occurring. Clearly, some drugs may disinhibit sexual behaviour, whereas sharing 'straws' when snorting cocaine, for example, has the risk of contaminated blood spreading from one person to another.

Question Three

It seems we're much further along for treatments for hepatitis B compared with hepatitis C. What have we learned from the recent Amsterdam workshop?

MN:I think we're lucky in that we can treat HIV and hepatitis B with the same drugs: 3TC (lamivudine/Epivir/Zeffix) is already approved for both, and data on tenofovir (Viread) is looking great. The key messages from Amsterdam were: don't use 3TC against hepatitis B on it's own because of resistance; tenofovir - although not licensed for hepatitis B - is probably better than its brother drug adefovir (Hepsera); and you may as well give tenofovir and 3TC (or with FTC in the single pill, Truvada) together, since you're not going to lose anything because that's the 'gold standard' for HIV.

MF: And if you don't need to treat the HIV then you'd need to use agents that are only active against hepatitis B [like entecavir (Baraclude), adefovir or interferon] since just using one or two drugs that are also active against HIV, like 3TC or tenofovir, would potentially lead to HIV drug resistance.

Question Four

ATU: Are experts now agreed on when to treat acute hepatitis C?

MF: There wasn't any clear consensus from Amsterdam whether you should just get on and treat, or whether you should wait twelve weeks to see if you clear the virus spontaneously - which is what we've tended to do in the UK.

MN: There's never a consensus about anything! One-in-four people can clear this virus spontaneously, within about twelve weeks from infection. But while you're waiting you need to check hepatitis C viral load every four weeks. If it's going down, fine, I think you can wait twelve weeks. If not, then I think treatment makes sense. But there are some data in HIV-negative individuals that suggests treatment may not be as successful if you wait, so you have to balance the pros and cons. I leave it up to the patient. I think most would prefer to take the risk of the hepatitis C actually going away by itself rather than taking interferon straight away.

Question Five

Treating hepatitis C is much more challenging than HIV, particularly when it comes to side-effects like depression and fatigue. How do you support people?

MN: I think it's the idea of treatment that is actually more frightening than the reality. The treatment works - especially for acute hepatitis C - and it can be lifesaving for those people who are chronically infected. Yes, it's fairly toxic; yes, it can make you feel flu-like symptoms; yes, it can make you depressed; but I find that with the right support – including antidepressants and sleeping tablets  – most people can tolerate the treatment very well.

MF: Here in Brighton – and I think most coninfection clinincs in the UK are the same – we have clinical nurse specialists who support patients taking treatment on an ongoing basis. There's usually a lot of input with anti-HIV therapy at the beginning, and then things tend to sort themselves out and become easier, whereas with hepatitis C therapy the problems usually last throughout treatment, or may even get worse. So that input needs to be regular and ongoing. A lot of it is really acknowledging that people are having a really rough time, and then reassuring them that that's normal.

Question Six

Hepatitis C therapy does seem to be in the Dark Ages, especially compared with HIV therapy. When will the Age of Enlightenment arrive?

MN: HIV and hepatitis C were really discovered around the same time, so there does seem to be a huge contrast when you compare them: why are there no oral drugs for hepatitis C yet? There are some on the horizon [Schering-Plough's hepatitis C protease inhibitor SCH 503034 has just been fast-tracked by the United States' Food and Drug Administration (FDA), and Vertex Pharmaceuticals hepatitis C protease inhibitor, VX-950, is in Phase II studies] but the disappointing thing about them is that, in the studies so far, they're just an add-on to the interferon, not a replacement. In addition, something that came up repeatedly at the Amsterdam workshop is that people with HIV are excluded from the majority of these studies. So, even if they are approved, we'll have to wait while more studies are done in coinfected inviduals. I think it's really important that doctors, patients and advocates lobby the drug companies to get at least some data now in HIV-positive individuals, so that we can all benefit from the new drugs at the same time.

References

1. Ghosn J et al. Increase in HCV Incidence in HIV-1-infected Women and Men Followed in the French PRIMO Cohort. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 843, 2006.

2. Mocroft A et al. Is there evidence for an increase in the death rate from liver-related disease in patients with HIV? AIDS 19: 2117 - 2125, 2005.