Hepatitis B hasn’t gone away – and may come back

People with HIV who have been vaccinated for hepatitis B may still become infected, the fifth Annual Workshop on HIV and Hepatitis Co-infection in Lisbon heard this week. The conference also heard of a case where starting interferon-based hepatitis C therapy in a person with HIV apparently caused a reactivation of a dormant hepatitis B infection.

The conference also heard that HIV/hepatitis B co-infected people have considerably faster CD4 declines than people co-infected with HIV and hepatitis C or HIV alone, that rates of hepatitis B co-infection in HIV positive African immigrants are as high as they are in gay men and often go undetected, and that hepatitis B patients with high viral loads have a very high rate of liver cancer.

The good news is that at least two-thirds of patients treated with tenofovir and FTC or 3TC develop undetectable hepatitis B viral loads. However the 10-30% of patients who fail to respond are not always the same as those who fail HIV therapy, showing that transmitted drug resistance is becoming important in people with hepatitis B too.

One presentation from Toronto (Wong) discussed four cases of people with HIV who developed new hepatitis B infections despite previous hepatitis B vaccination. In two cases they developed chronic hepatitis B infection – an unusually high rate given that only about 10-15% of people with HIV who acquire hepatitis B normally go on to develop the chronic disease.

In one case the patient had had three full courses of hepatitis B vaccination, one before he acquired HIV, but had failed to develop immunity. Three years after being diagnosed with HIV he developed acute hepatitis with high liver enzymes, but was able to get rid of the infection. In the second case, the patient acquired hepatitis B in 2007 despite having been vaccinated and having immunity to hepatitis B in 2004 when he was diagnosed with HIV. He also resolved his infection.

In the other two cases, however, the patients developed chronic infections. In both cases the patients had had hepatitis B vaccination but their immunity status was unknown. The third case was vaccinated in 2004 at the time of his HIV diagnosis but presented with hepatitis symptoms a year later. He refused antiretroviral drugs and went on to develop chronic hepatitis B.

In the final case a long-term survivor of HIV (diagnosed in the 1980s) was vaccinated for hepatitis B in 2005 but presented with hepatitis symptoms in 2009. It was thought these were due to his HIV therapy (he was multi-drug-resistant and was on etravirine, darunavir and raltegravir, none of which work against hepatitis B), so this was stopped. However it later turned out he had had acute hepatitis B and went on to develop the chronic disease. He is now taking tenofovir/FTC (Truvada) for his hepatitis B but remains off HIV therapy.

Emma Page from London’s Chelsea and Westminster Hospital presented a case where hepatitis C therapy apparently caused a flare-up of hepatitis B infection in a patient, despite their having been vaccinated for hepatitis B (and hepatitis A) at the time of HIV diagnosis. It was known he had had hepatitis B infection many years previously but his immunity to it had waned, though there was no sign of chronic infection. He developed acute hepatitis C just a few months after his HIV diagnosis and was put on pegylated interferon and ribavirin for hepatitis C, but not on HIV therapy as he had a high CD4 count.

A couple of months into his treatment he developed hepatitis symptoms and very high liver enzyme levels (and also anaemia) and was found to have an acute hepatitis B infection. It was concluded that this was not a new infection but a resurgence of his original infection from years back. Dr Page hypothesised that the interferon therapy had caused a form of IRIS. In hepatitis C and A the liver damage is caused directly by the virus but in hepatitis B the damage is caused by the immune response to the virus, so what suppresses hepatitis C may, it appears, sometimes reactivate hepatitis B.

Dr Vincent Soriano of Carlos III Hospital in Madrid outlined some of the serious consequences of unchecked hepatitis B infection. In a cohort of 3500 HIV/hepatitis B co-infected patients, 10% developed cirrhosis in 11 years and 5% (184 patients) liver cancer.

In America, David Thomas of Johns Hopkins University told the conference that patients co-infected with HIV and hepatitis B had an annual mortality rate due to liver disease of 1.4%; in contrast in people with HIV alone annual liver-related mortality was 0.17% and in people with hepatitis B alone 0.08%.

Evidence has also been accumulating that hepatitis B infection exacerbates CD4 decline in patients with HIV. Sorriano said that in the SMART Trial, patients in the ‘Drug Conservation’ arm who stopped therapy at 350 CD4 cells/ml³ and resumed it at 250 were much more likely to resume therapy if they had hepatitis B: after 18 months, nearly 80% of HIV/hepatitis B co-infected patients had resumed therapy compared with 45% with HIV alone and 48% co-infected with hepatitis C.

However Thomas told the conference that patients with HIV and hepatitis B who started HIV therapy had exactly the same increases in CD4 count.

Worldwide, hepatitis B is most prevalent in sub-Saharan African and central and east Asia. A substantial proportion of Africans with HIV also have hepatitis B, though the majority of them get hepatitis B through mother-to-child transmission and then HIV through sex in adult life, whereas in the developed world both viruses are acquired most often sexually.

A team from London’s Royal Free Hospital surveyed its patients with chronic hepatitis B and found that 38% were African; a third were women compared with only 4% of the non-African group. African patients were three times less likely to have the hepatitis B e antigen, an indicator of current liver inflammation, than non-African patients but seven times more likely to have liver cirrhosis, an indicator of their long infection.

The authors commented that the high prevalence of chronic hepatitis B and the advanced nature of liver disease in African patients had implications for antiretroviral rollout in Africa, with the most commonly-available drugs either inactive against hepatitis B or, in the case of 3TC, causing resistance when given as monotherapy.

All patients in the Royal Free were on HIV regimens that contained drugs active against hepatitis B (tenofovir plus either FTC or 3TC) and seven out of every eight patients (87.5%) had an undetectable hepatitis B viral load (under 1000 copies/ml³).

There is however no standard definition of ‘undetectable’ and a study from the Chelsea and Westminster Hospital found that only 66% of patients were undetectable according to the stricter definition of below 34 copies/ml³, with another 23% partially suppressed (between 34 and 10,000 copies/ml³) and 11% over 10,000. However 74% of patients on tenofovir/FTC or tenofovir/3TC had fully suppressed viral loads; the lower average figure was due to less suppressive regimens.

While some hepatitis B treatment failures are due to poor adherence to what for most patients is essentially two-thirds of their HIV drug regimen, some is due to drug-resistant hepatitis B. A study of 119 HIV/hepatitis B co-infected patients in Portuguese clinics of whom 87% were on tenofovir/FTC, 9% on 3TC monotherapy and 4% on solo tenofovir found that 18% had detectable hepatitis B. Eight of these (38% of failures) had poor adherence. But two patients taking solo 3TC and 10 patients on tenofovir/FTC had one to three drug resistance mutations (57% of failures), mainly due to previous 3TC monotherapy.

Can chronic hepatitis B infection be cured? In the Portuguese cohort just three patients developed antibodies to the surface antigen of hepatitis B, which would indicate immunity if they were vaccinated. One Italian case achieved hepatitis B immunity and no sign of hepatitis B DNA sustained for over a year by adding a year’s course of interferon to antiviral drugs.