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Looking for an End to the Waiting Game in Acute HCV

Somewhere between one-quarter and one-half of acute hepatitis C infections clear spontaneously, usually within 6 months, depending on the population or cohort. Accordingly, the authors of the joint American Association for the Study of Liver Diseases and Infectious Diseases Society of America HCV guidelines recommend a watching and waiting strategy for patients with recent or acute disease. The societies adopted this approach in the interferon era, when treatment was often more complicated and toxic than the disease itself, particularly for patients with no symptoms. But now that patients can be treated with direct-acting antivirals effectively and largely without incident, that approach may be outdated.

Katja Deterding, MD, of HepNet Study-House and the Hannover Medical School in Hannover, Germany, and colleagues presented a paper on acute HCV at the International Liver Congress in April that drew some attention. The study involved 20 patients with symptomatic acute HCV accrued during 2014 and 2015. There were 11 patients with genotype 1a disease and nine patients with genotype 1b. All patients completed 6 weeks of ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) treatment and 12 weeks of follow-up.

“After only 2 weeks of treatment, already nine patients had undetectable HCV RNA,” Deterding said in her presentation. She added that by week 4 of treatment, HCV RNA was below 15 IU/mL for all 20 patients. “After 6 weeks of treatment, all patients had undetectable HCV RNA.”

Although higher baseline viral load was associated with a slight delay in virological response, follow-up results indicated a 100% SVR12 rate, according to Deterding. “So 6 weeks of antiviral treatment was enough for all patients to clear the acute HCV infection,” she said. As with most DAA therapies, the regimen was well-tolerated.

These findings, then, provide a compelling jumpstart to the discussion of whether the clinical community should consider treating patients with acute infection.

Stacey A. Rizza, MD, associate professor of Medicine in the Department of Infectious Diseases at the Mayo Clinic in Rochester, Minn., discussed it with HCV Next. “If you leave HCV alone and follow the natural history of the disease, around 30% to 40% of people who become infected are likely to spontaneously clear the infection on their own,” she said. “We have seen evidence of this in longitudinal studies.”

Rizza acknowledged that in previous studies of acute HCV infection, 6 months of interferon actually was associated with good response rates. “But now that DAAs have revolutionized HCV therapy, we are going to see a lot more studies looking at DAAs in the setting of acute infection,” she said, referencing the encouraging data from Deterding’s group. “These results are very promising.”

Although there was no control group in the study, Rizza remains optimistic. “This is an incredibly exciting time,” she said. “Now price is our main obstacle. It will be interesting to see how more of these trials pan out.”

In truth, price is not the only issue at hand. HCV Next asked experts to dig deeper into the phenomenon of spontaneous clearance, the signs and symptoms of acute HCV, the ideal duration of therapy for DAAs and how to treat patients coinfected with HIV.

Guidelines Overview

The AASLD/IDSA HCV guidelines call for regular laboratory monitoring every 4 to 8 weeks for 6 to 12 months to determine whether spontaneous clearance will occur. Most patients who remain viremic at 6 months will likely develop chronic disease and should be considered candidates for therapy.

Jaundice, elevated ALT levels, hepatitis B virus surface antigen (HBsAg) positivity, female sex, younger age, HCV genotype 1 and host genetic polymorphisms, including those near the IL28B gene are all predictors of spontaneous clearance, according to the guidelines.

Although acute infections are often asymptomatic, clinicians should monitor signs and symptoms ranging from non-specific fatigue and nausea to jaundice and alanine aminotransferase, aspartate aminotransferase and bilirubin levels. The recommendations call for counseling of patients to avoid hepatotoxic insults such as use of alcohol and hepatotoxic medications while reducing habits that may lead to transmission of HCV, such as injection drug use and high-risk sexual habits. Referral to an addiction center should be used when appropriate.

Once treatment is initiated, clinicians should follow guidelines for the treatment of chronic disease. That said, the authors added, “If a decision has been made to initiate treatment during the acute infection period, monitoring HCV RNA for at least 12 weeks to 16 weeks before starting treatment is recommended to allow for spontaneous clearance.”

The same regimens that are used to treat chronic disease may be used to treat acute infections, due to their high efficacy and safety rates.

Andrew Lloyd, MD, professor of Infectious Diseases at the University of New South Wales in Australia, was quick to note that application of guidelines may vary depending on the country and region. “Guidelines in the U.S., Europe and Australia are broadly concordant,” he said. “And for the most part, clinical practice is mostly the same. However, in Australia and some countries in Europe, there is universal access to drugs and universal health care. The health infrastructure and organizational constraints on access to treatment are different than they are in the U.S.”

The way this manifests itself is that clinicians in other parts of the world — specifically, those with a robust form of national health service — can test and treat much more easily with ledipasvir/sofosbuvir and other therapies that have hit the market.

“We can treat injection drug users, prisoners, former prisoners, anybody,” Lloyd said. “In America, there are abstinence policies and insurance constraints that get in the way. No matter what the guidelines say, some of these jurisdictional bodies will have something to say.”

Spontaneous Clearance

Page and colleagues investigated associations between symptomatic acute HCV and interferon lambda 4 (IFNL4) genotypes and, like earlier reports, this IL28B-related genetic variant predicted spontaneous clearance. Findings from this multi-cohort database also indicated an independent association between host IFNL4 genotype and symptomatic disease. “This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease,” they wrote.

Lloyd suggested that there is evidence that a number of elements, including IFNL4, are part of spontaneous clearance. “The absolute details of how [IFNL4] modified the outcome of acute HCV are not fully understood,” he said. “We do know that it modifies production of type 1 interferons, which is the basis for the original interferon treatment paradigm.”

Another key immunological mechanism associated with spontaneous clearance is the adaptive immune response, according to Lloyd, which involves T-cells and neutralizing antibodies that specifically recognize the virus and mounts a robust and long-lasting immune response.

Bringing it back to clinic, Rockstroh spoke in favor of a certain period of waiting before treatment initiation. “As there is a chance of spontaneous clearance, it makes sense to wait 4 weeks and repeat the HCV-RNA test,” he said. “If there is a 2-log drop or more in HCV viremia, spontaneous clearance is quite likely. If there is no such drop, chronic disease is much more likely and treatment should be discussed. Obviously, early treatment offers the opportunity to prevent onward transmission of HCV.”

Lloyd focused further comments on the generally accepted spontaneous clearance rate of about 25% in most populations. “There are studies with higher rates, some of them I’ve been involved with,” he said. “But these patients tend to come from circumstances where populations being studied are special in one way or another. There are higher rates of clearance in some blood donor recipients, for example. It is possible that the virus that was transmitted via the blood product was less virulent than in other modes of transmission. So the clearance rates might be influenced by characteristics of the virus.”

Of particular interest to Lloyd are patients who clear the virus repeatedly. “We did a large cohort study in prisons,” he said. “We saw a large number of people who injected drugs who remained without HCV antibodies or virus, and so we followed them. About 200 of those individuals eventually become infected, but the clearance rate we observed was around 35%. When we continued to follow those who cleared the initial infection we found some of them did this repeatedly. Our leading case has done so five times”

They suspected that injection drug use may have played a part in their clearance, oddly enough, according to Lloyd. But this is only speculation. “We also found a small number of individuals who became viremic, were symptom-free, cleared the virus and never developed antibodies,” he said. “It seems there is a special subset of individuals who, physiologically, are more capable of clearing the virus than others. There may be a genetic factor. It’s a biological plausibility.”

The research community may benefit from investigating these so-called highly-exposed but uninfected cases, and also the ‘super-clearers,’ Lloyd suggested. “We can learn from these patients whose immune systems get it right repeatedly, where they get the virus, clear, get the virus, clear,” he said. “The underpinning of vaccine development is to understand how that natural process works in the special subset of individuals and then recapitulate it with a vaccine. But there is much we still don’t know.”

In terms of clinical approaches, Lloyd mentioned a final component. “In general, we have used a 6-month cutoff for initiating treatment,” he said. “But that is not necessarily a rigid boundary. There are some individuals who will clear the virus at 12 or 18 months. They are more rare, but it happens.”

Signs and Symptoms

Symptoms of acute disease may include jaundice, dark urine, white-colored stool, nausea or pain in the upper right quadrant of the abdomen. That said, a certain proportion of patients remain asymptomatic and even that may be up for debate. “Traditionally, we used to say that 50% of patients with recent or acute infection are symptomatic, while 50% are asymptomatic,” Lloyd said. “But this may be changing. In several cohort studies it is now apparent that ratio may be as high as 90% vs. 10%, with the great majority of them asymptomatic.”

If the ratio is indeed that unbalanced, this could present both research and clinical challenges, according to Lloyd. “You will really only be able to find these patients if you have large prospective cohorts of people who are at risk and follow them for long periods of time,” he said. “In clinical practice, depending on the setting in which the clinic is based, most of the referrals for acute HCV are biased toward that 10% of symptomatic patients. The only way to really catch the large proportion of asymptomatic patients, whatever it may be, is comprehensive and regular screening of those at risk.”

Duration of Therapy

Jürgen K. Rockstroh, MD, professor of medicine at the University of Bonn in Germany, and colleagues studied the fixed dosed combination of ledipasvir/sofosbuvir in a cohort of 26 patients with HIV who had acute HCV for less than 24 weeks. The aim was to determine whether a shorter treatment duration yielded SVR12 safely.

“We are all familiar with this fixed dosed combination for treatment of hepatitis C,” Rockstroh said during a presentation at the Conference on Retroviruses and Opportunistic Infections. “However, there is currently no approved DAA therapy for patients with acute hepatitis C virus infection, including those with HIV coinfection.”

Nineteen patients in the cohort (73%) had genotype 1a disease, whereas the remaining 27% had genotype 4. The median baseline HCV RNA level was 5.4 log10 IU/mL, according to Rockstroh.

All patients completed therapy. The 4-week SVR response rate was 85%. All patients who had HCV RNA less than 6.9 log10 IU/mL at baseline reached SVR4. Rockstroh reported that four treatment failures occurred. Three of those instances were relapses and one was a reinfection with a different strain of HCV. Apart from one serious adverse event that was unrelated to the study drug, 85% of events were mild or moderate. “Treatment with ledipasvir and sofosbuvir for 6 weeks resulted in 77% SVR12 rate in patients with HIV and acute HCV,” Rockstroh concluded. “Acutely HCV-infected patients with a higher viral load should be considered for longer duration of therapy.”

Rockstroh put the findings into context in an interview with HCV Next. “In HIV-negative patients with acute HCV, 6 weeks of ledipasvir/sofosbuvir led to a 100% SVR12 rate,” he said. “But the viremia was lower than in the HIV coinfected patients. For patients with acute HCV and a viral load below 6 mL, it appears that 6 weeks led to an SVR rate of 100%.”

Other results indicated that relapses were only observed in patients with a viral load above 7-log, according to Rockstroh. “In those highly viremic patients, longer treatment durations may be warranted,” he said. “In the absence of data, no one can say whether 8 weeks would be sufficient or if 12 weeks would be the safest approach.”

For Rizza, treatment duration is not separate from health care economics. “If cost were not an issue, DAAs are well enough tolerated that you would give them to anybody who comes in with acute HCV,” she said. “From other infections like HIV, we know that treating immediately is beneficial. With HCV, we should avoid the possibility that it would develop into chronic infection.”

Moreover, she added that acute disease is the highest level of viremia. “These patients are highly infectious,” she said. “Treating them could have a positive public health effect in terms of reducing transmission.

Rizza believes that the optimal duration is likely to be 6 weeks. “But how long that course will be remains to be seen,” she said.

For Lloyd, there are other more pressing concerns to deal with. “Acute infection may be a bit more amenable to a shorter duration than the 8 or 12 weeks we see for chronic infection, but the jury is out,” he said. “I feel a bit laid back about this at the moment. It is good in a health economic sense to cut drug costs by shortening from 12 to 8 or 6 weeks, but, on the other hand for the individual patient, I’m not convinced that adherence will differ greatly between 6 and 12 weeks.”

Patients with HIV

“In the context of treated HIV, where the patient has good biological control, spontaneous clearance rates for acute HCV are comparable to those we see in HCV monoinfected patients,” Lloyd said.

In another study involving patients with HIV, Vogel and Rockstroh wrote that in the U.S. and Australia, acute infections are on the rise among individuals with HIV, largely including men who have sex with men (MSM). The diagnosis of acute disease may be obscured by delayed anti-HCV antibody seroconversion in this population of individuals with HIV, according to the researchers. They estimated that as many as 85% of patients with HIV progress from acute to chronic HCV. Accordingly, treatment within 12 weeks of the presumed date of infection may be effective.

Although the study was conducted before the DAA era, the researchers concluded that early control of acute HCV is beneficial in preventing progression to chronic disease.

Lloyd suggested that the incidence of first infections are higher in patients with HIV, whereas reinfections are higher in MSM with HIV. “Susceptibility to reinfection is higher than in other populations such as injection drug users,” he said. “MSM with HIV are a special population that we should focus on in terms of public health strategies.”

This boils down to more frequent screening, according to Lloyd.

Ferns and colleagues also wrote that patients with HIV are more likely than those with acute HCV monoinfection to progress to chronic disease and liver infection. “Understanding early events in this pathogenic process is important,” they wrote.

They applied single genome sequencing of the E1 to NS3 regions and viral pseudotype neutralization assays in four patients, according to the results. The aim was to assess the consequences of viral quasispecies evolution from before seroconversion through to the beginning of chronic infection. The mean follow-up duration was 566 days. Results indicated that from one to three founder viruses were transmitted. There was a low rate of viral sequence diversity, the findings indicated. This outcome may have been associated with an impaired immune response, possibly due to HIV infection in three of the four patients. That said, the monoinfected patient displayed increasing E2 sequence evolution after an early purifying selection. This may have been the result of antiretroviral therapy.

“Viral pseudotypes generated from HCV variants showed relative resistance to neutralization by autologous plasma but not to plasma collected from later time points, confirming ongoing virus escape from antibody neutralization,” the researchers concluded.

“Transmission of acute HCV among MSM with HIV involves a different modality of transmission,” Lloyd said. “It is presumably permucosal transmission, effectively blood to blood as opposed to injection from a device into the bloodstream.”

Rockstroh stressed that in patient groups with known increased risk for HCV transmission, such as those with HIV and MSM without HIV but multiple sex partners, regular HCV screening should be established. “HCV antibody testing alone may not be sufficient because in HIV coinfection it can take prolonged times until these antibodies become detected,” he said. “So in the occurrence of newly elevated liver enzymes, HCV-RNA testing should also be considered.”

Moving Forward

Current screening practices of baby boomers and injection drug users are mostly identifying patients with chronic infection, according to Rizza. “If we want to pick up patients with acute disease, we have to do more frequent and regular screening,” she said.

What it comes down to for Rizza is awareness and education. “Acute HCV is the kind of thing that inner city hospitals find because it is on their radar,” she said. “We think of it in our HICV clinic, or if we see someone come in who recently had a tattoo who is not feeling well. But your average clinician and even the general population does not routinely think about acute HCV. It is important to educate health care providers in addition to people who are at risk.”

For Lloyd, it is a matter of reduced cost and increased availability of DAA therapies. “In more liberally minded social health systems like we have in Australia, where injection drug use is not a legislated constraint in treatment or even re-treatment, we have the opportunity to treat whenever and whomever we like,” he said. “I expect that as DAAs become more widely available, the watching and waiting period will be reduced, with the possible exception of injecting drug users with very chaotic lives who are unlikely to adhere to medication or follow-up.”

A shortened watching and waiting period will likely coincide with improved therapies, according to Rizza. “If we can identify patients with acute HCV, we should be able to treat them,” she said. “It’s good for the patients and good for society.”- by Rob Volansky

• References:
• Deterding K, et al. Abstract LB08. Presented at: International Liver Congress; April 13-17, 2016; Barcelona.
• Ferns RB, et al. Virology. 2016;doi:10.1016/j.virol.2016.02.003.
• Page K, et al. Open Forum Infect Dis. 2016;doi:10.1093/ofid/ofw024.
• Rockstroh JK, et al. Abstract #154LB. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 22-25, 2016; Boston.
• Vogel M and Rockstroh J. J Antimicrob Chemother. 2010;doi:10.1093/jac/dkp385

• For more information:
• Andrew Lloyd, MD, can be reached at UNSW Medicine, Room 414, Level 4, Wallace Wurth Building, UNSW AUSTRALIA NSW 2052; email: a.lloyd@unsw.edu.au.
• Stacey A. Rizza, MD, can be reached at 200 1st St SW, Rochester, MN 55905; email: Nellis.Robert@mayo.edu.
• Jürgen K. Rockstroh, MD, can be reached at Universitätsklinikum Bonn AöR Medizinische Klinik und Poliklinik I Immunologische Ambulanz – Tropenmedizinambulanz Sigmund-Freud-Str. 25 Gebäude 26 53127 Bonn; email: Juergen.Rockstroh@ukb.uni-bonn.de.

Disclosures: Lloyd has received investigator-initiated research support from Gilead Sciences and Merck. Rizza reports no relevant financial disclosures. Rockstroh reports consulting and speaking for Abbott, AbbVie, Bioner, Bristol-Myers Squibb, Cipla, Gilead Sciences, Janssen, Merck and ViiV.