Hepatitis C drops among HIV-positive London gay men after direct-acting antiviral scale-up

New cases of hepatitis C virus (HCV) infection among HIV-positive gay and bisexual men seen at three clinics in London have declined by nearly 70% since 2015, according to a presentation yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI 2019) in Seattle.

The drop is largely attributable to regular HCV screening and a treatment-as-prevention effect resulting from wider use of direct-acting antiviral (DAA) therapy, said presenter Dr Lucy Garvey of Imperial College Healthcare NHS Trust.

"In order to eliminate hepatitis C as a major public health threat, we need to reduce the number of people who become newly infected or re-infected with the virus," Garvey said. "Our study has shown that greater access to new treatments, closer monitoring and screening can greatly reduce hepatitis C cases, which will lead to better outcomes for the most at-risk patients."

However, another study at the conference sheds doubt on whether it is possible to treat our way out of the HCV epidemic. Dr Daniel Fierer of the Icahn School of Medicine at Mt Sinai in New York City reported that gay and bisexual men who are cured of hepatitis C are becoming re-infected at a rate seven times higher than the primary or initial infection rate. He suggested that prevention is as important as treatment, but acknowledged that we don't really know how to prevent sexual transmission of HCV.

Now that DAAs can cure more than 95% of people with HCV in two or three months, the World Health Organization (WHO) has set a goal of eliminating hepatitis C as a public health threat by 2030; the British HIV Association aims to cure HCV in everyone with HIV and HCV co-infection by 2021. Elimination of 'microepidemics' in defined populations is a good way to start, Garvey said.

One such population is HIV-positive men who have sex with men (MSM), who appear to be mainly acquiring HCV via sexual transmission, as they mostly do not report injection drug use. Sexual transmission of HCV is quite uncommon overall, but it occurs more often among HIV-positive gay and bisexual men.

Falling HCV incidence in London

Garvey's team looked at trends in the incidence of acute HCV infection among HIV-positive MSM between July 2013 and June 2018, spanning the transition from the interferon era to the DAA era. Prior modelling studies have made projections about changes in the HCV epidemic; the present work analysed real-world experience.

This retrospective study included around 6000 HIV-positive men at risk for hepatitis C seen at three central London clinics: Royal Free NHS Trust, St Mary's Hospital of the Imperial College NHS Trust and Mortimer Market Centre, a sexually transmitted infection clinic.

As of 2016, the NHS offers access to HCV treatment at any stage of liver disease, but does not permit initiation of treatment for acute infection within the first six months (the window in which some people will clear the virus naturally) or a second course of DAAs for those who are re-infected. However, all three clinics were involved in clinical trials that provided treatment without these restrictions.

Every six months the researchers collected data on the number of first acute HCV diagnoses and subsequent diagnoses of acute HCV re-infection after treatment or spontaneous clearance, as well as the number of people treated and whether they received DAAs or interferon-based therapy.

The researchers identified 256 diagnoses of acute HCV infection during the study period; of these, 111 were first infections and 45 were re-infections. The median age at the time of diagnosis was 43 years. Three-quarters had HCV genotype 1a, followed by genotype 4 (11%), genotype 3 (7%) and genotype 1b (4%). An increasing proportion of men were on antiretroviral therapy (ART) with undetectable HIV viral load, reaching 100% on ART and 94% with viral suppression in 2018.

The rate of new HCV infections peaked in 2015, at 17 cases per 1000 person-years (PY). First acute infections – excluding re-infections – peaked the same year, at 15 per 1000 PY. After that, the rates declined steeply and steadily, falling to six total new infections and three first infections per 1000 PY in 2018. This represents a 68% reduction in new HCV infections overall and a 79% drop in first infections, according to Garvey.

The decline in London is similar to the drop in acute HCV infections in Amsterdam, which fell from 11 per 1000 PY in 2014 to 6 per 1000 PY in 2016, as reported at CROI 2017. However, this still does not meet the WHO goal of a 90% reduction, or 1.7 infections per 1000 PY.

The proportion of re-infections relative to all acute infections rose over time, from less than a tenth (9%) in 2013 to nearly half (47%) in 2018. The treatment pathway also shifted during the study period. From 2013 to 2016, a majority of patients received or were awaiting DAAs through the NHS programme, starting therapy an average of 23 months after diagnosis. From 2016 onward, a majority were treated in clinical trials, waiting an average of 10 months.

During the earliest years of the study, people delayed treatment by more than two years, likely reflecting "warehousing" as patients eschewed interferon-based therapy while waiting for DAAs to become available. This longer wait may have increased transmission due to longer duration of active infection, Garvey explained

"In this large London cohort of HIV-positive MSM, we have observed a sharp decline in new acute HCV diagnoses since peak in late 2015 with no change to screening practices," the researchers concluded.

However, Garvey cautioned that HCV re-infection remains high and may be increasing, highlighting the need for better risk reduction strategies and determination of appropriate screening policies for HIV-positive and HIV-negative gay and bisexual men. Further, she said, the opportunity for 'microelimination' may be lost without the ability to treat people in the first months after acute infection and to treat re-infections.

HCV re-infection in New York

Fierer's group analysed HIV-positive MSM in a New York City cohort followed since 2000. Around 50 centres that participate in the New York Acute Hepatitis C Surveillance Network refer HIV-positive gay and bisexual men diagnosed with HCV to Mt Sinai for further evaluation and treatment. Pooling these uncommon cases allows researchers to see larger patterns, Fierer said.

The researchers identified 305 men with cleared HCV infection: 33 with spontaneous HCV clearance, 106 who achieved sustained virological response to interferon-based therapy and 166 who were cured with DAAs. The median age was 45 years, about 80% were white, nearly 20% were black and 22% were Latino. Just over half were on public health coverage such as Medicaid while the rest had private insurance. Here too, most were on ART with suppressed HIV viral load. Again, most had HCV genotype 1a.

Within this group, 37 were re-infected, yielding an incidence rate of 4.4 per 100 PY, according to Fierer. Thirty-three men cleared their re-infection, and of these, six had a subsequent re-infection, for a rate of 8.6 per 100 PY. Importantly, Fierer reported rates per 100 person-years while Garvey reported rates per 1000 person-years, so they are not directly comparable.

The likelihood of re-infection did not differ according to whether clearance was spontaneous or the result of treatment with interferon or DAAs. Latinos were the only racial/ethnic group with a disproportionately high re-infection rate. Most re-infections occurred within the first two years after clearance, but were seen up to 12 years later, indicating that long-term surveillance is warranted for this population.

The HCV re-infection rate is more than seven times higher than the rate of initial infection in New York, and is in line with re-infection rates seen in Europe, Fierer said. The large difference between initial infection and re-infection rates suggests that the risk is not distributed evenly among HIV-positive gay and bisexual men, but rather is concentrated in small subgroups.

"Re-infections shouldn’t be stigmatized – they're a sign we're treating the people at risk," Fierer said, adding that if we don't treat this group, we won't be able to eliminate hepatitis C.

The high re-infection rate demonstrates an inadequate level of hepatitis C treatment, even though DAAs have ostensibly been available since late 2013, the researchers concluded. Fierer suggested that barriers to obtaining approval for DAAs have limited treatment uptake.

These findings, according to Fierer, show that "we cannot treat our way out of the epidemic" without also reducing new infections.

HCV prevention

It remains unclear how to prevent sexual transmission of HCV, Fierer said. It is uncertain whether HCV transmission during sex happens primarily through blood or via HCV in semen or rectal fluid. A prior study in London showed that condoms for anal sex may reduce the risk of HCV infection, and some experts have suggested that treating other sexually transmitted infections and changing behaviour around non-injection drug use may also play a role.

There is some indication that declines in condom use and more sex between HIV-positive and HIV-negative men in the era of pre-exposure prophylaxis (PrEP) may be contributing to higher rates of HCV sexual transmission. Sexually transmitted HCV among HIV-negative MSM has historically been rare but may be rising.

Commenting on Twitter, Dr Gregory Dore of the Kirby Institute at the University of New South Wales, a co-investigator with the Australian CEASE-D study aiming to eliminate HCV in people with HIV, concurred that a combination strategy will be needed to achieve this goal.

"Keys to effective HCV treatment as prevention [are] unrestricted DAA access, universal health care, engagement of marginalized populations, harm reduction access and rapid DAA scale-up," he wrote. "Only then can you 'treat your way out' of an epidemic."