HCV In MSM: An Epidemic with a 'Shocking' Lack of Education

A rising tide of HCV infections in men who have sex with men began in the mid-2000s and continues to garner attention in certain sectors of the clinical community today. But for a number of reasons — uncertainty about the mechanics of transmission and more intense focus on advances in direct-acting antiviral therapies among these men — there has been unwillingness to recognize the increase as an epidemic at the national and international levels.

“We have seen increased HCV infection rates among HIV-infected MSM in the United States, Northern Europe and Australia,” Daniel S. Fierer, MD, associate professor of medicine and infectious diseases at the Icahn School of Medicine at Mount Sinai, told HCV Next in an interview. “The number of these infections in Tokyo and Taiwan are increasing, too. That’s both hemispheres and multiple continents. All of this is new and, frankly, surprising.”

Fierer noted that there has been reluctance to recognize HCV as a sexually transmitted infection in the U.S., which presents an obstacle to dealing with the infection in MSM. But there are other challenges, as well, many of which are linked to HIV, according to Lynn E. Taylor, MD, FACP, assistant professor of medicine in the Division of infectious diseases at The Warren Alpert Medical School of Brown University and The Miriam Hospital.

“Many MSM living with HIV are engaged in the health care system,” she said in an interview. “They are at risk for HCV but their HIV is generally under control.”

There is an opportunity, then, to capitalize on their engagement in the system to test for HCV and gain control of the disease if it is detected, she said. “Unfortunately, in the U.S., we are not seeing the kind of screening rates that are sufficient to improve HCV outcomes in MSM,” Taylor added.

Clinicians have had difficulty separating out the role of non-injection and injection drug use (IDU) among MSM with HCV. There have also been efforts to understand how serosorting and sexual practices likely to cause cuts and tears in fragile rectal tissue pose risk factors, with varying degrees of success.

Most experts believe that these problems will not be resolved until the clinical community, as a whole, recognizes that dealing with HCV in MSM is a critical component to attacking the disease overall.

Unrecognized Epidemic

Kristen Marks, MD, assistant professor of medicine in the division of infectious diseases at Weill Cornell Medical College, acknowledged that the CDC guidelines for sexually transmitted infections contain a component for HCV. “I wouldn’t necessarily say that HCV is not recognized as an STI, particularly for HIV-positive populations,” she said. “But it is certainly still under-recognized and underpublicized, especially among people not in the fields of HIV or HCV. Generally speaking, people in other fields do not know that MSM are at risk.”

Perhaps most importantly, Marks said that many patients or potential patients do not know they are at risk for HCV. “The risk is known among public health officials, but the knowledge of this risk has not reached the patient level,” she said.

Tracy Swan, hepatitis/HIV project director at Treatment Action Group, agreed. “When is the last time you saw any information about sexually transmitted HCV for HIV-positive men who have sex with men?” she said. “People cannot make informed decisions without information. This epidemic has been going on for 15 years and still there are no prevention messages. It’s shocking.”

The public health message for HCV has been honed over the years, according to Fierer. “Needle sharing causes HCV,” he said. “Most diseases do not have that simple of a message. But when you talk about anal sex for men with HIV and what proportion of women is having anal sex and with whom, the message gets muddy. It becomes harder to find that sound bite.”

David Wyles, MD, associate professor of Medicine in the Division of Infectious Diseases at the University of California, San Diego, suggested that the difficulty in diagnosing acute HCV infection may also play a role. “Unless patients are in care and getting routine follow-up, most will be missed,” he said. “This presents a problem for health officials as it is difficult to get good data on which to build a public health campaign or message.”

Fierer said that European countries generally accepted and reacted to HCV incidence among MSM more rapidly than the U.S. “Most HIV providers in big cities in the U.S. accept it now, but the traditional HCV community is having trouble accepting it,” he said. “Sometimes it is hard to think about a change in paradigm.”

Wyles believes that most HCV experts accept the sexually transmitted nature of the disease, but because transmission is mostly restricted to HIV positive men, it simply does not command as much attention. “The absolute small numbers compared to [injection drug use] transmission may have something to do with the perceived dragging of the feet by health officials,” he said.

Taylor and colleagues wrote about the evolving epidemiology and treatment paradigms in Clinical Infectious Diseases. They highlighted difficulties in HCV viral eradication among individuals coinfected with HIV and HCV, and that novel HCV therapies remain underused. “Increasingly, incident HCV among HIV-infected men who have sex with men is associated with sexual risk behavior,” they wrote. “The observed phenomenon of aggressive hepatic fibrogenesis when HIV infection precedes HCV acquisition requires longer-term observation to ensure optimal timing of HCV therapy.”

Conflicting Views on Screening

An often simple solution to unrecognized infections is a change in screening practices. “New HCV infections are mostly silent,” Taylor said. “The fact that we don’t know they are there does not mean they are not occurring.”

She suggested that HIV guidelines should call for annual HCV antibody screening not just when risk factors are present, possibly as part of Ryan White HIV/AIDS programs, which aim to subsidize care for people who cannot afford HIV-related services.

“Some critics might say that we don’t have evidence to screen HIV-infected MSM every year, that we should screen every few years, but the precedent has been set by testing for syphilis and tuberculosis every year,” she said. “We should be doing the same for HCV. In 2 years, we would have a national map of seroconversion. With these data, we could be enhancing care more systematically.”

Wyles put a different spin on the issue. “We may be seeing more HCV in MSM because of better awareness on the part of clinicians and more vigilant screening,” he said. “Data suggest that HIV practitioners do a good job initially screening for HCV with antibody testing on entry to care. The numbers fall off quite a bit on repeated testing in those who remain at risk, despite recommendations for yearly antibody testing with other methods such as liver function testing every 6 months to better capture incident infection. Still, despite the possibility of improved case finding, this certainly does not account for all (or even much) of the recent increases in incidence.”

In MSM With HIV

The data for HCV in HIV-infected cohorts have long been available. Findings from van de Laar and colleagues indicated an increase in sexually transmitted HCV among HIV-positive MSM in Amsterdam in 2007. They gathered data from 1984 to 2003 and reported a 10-fold increase in HCV among men with HIV after 2000.

Also after 2000, 59% of patients reported ulcerative sexually transmitted infections and 55% of the cohort reported engaging in rough sex. “The emergence of an MSM-specific transmission network suggests that HIV-positive MSM with high-risk sexual behaviors are at risk for sexually acquired HCV,” they wrote. “Targeted prevention and routine HCV screening among HIV-positive MSM is needed to deter the spread of HCV.”

Marks targeted serosorting as a possible reason for increased HCV risk among MSM with HIV. “Serosorting based on HIV-infected status also increases the odds of having sex with someone with HCV,” she said. “HCV prevalence in HIV-positive populations is higher than in HIV-negative populations.”

Another factor may be an increase in susceptibility due to the effects of HIV on the immune system, according to Marks. “This may be associated with factors in the rectal mucosa, but this has not been proven,” she said.

Fierer and colleagues followed a cohort of HIV-infected men with primary HCV infection in New York City. Decompensated cirrhosis developed within 17 months to 6 years in four men who did not achieve SVR after their primary HCV infection developed. Within 8 years, three of these patients died. “The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign,” they wrote. “The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.”

In another study, Taylor and colleagues studied 1,830 men who had a negative HCV antibody test result at an initial visit and then at least one subsequent HCV antibody test result. This accounted for more than 7,000 person-years, according to the data. There were 36 seroconversions with overall incidence rate of 0.51 cases per 100 person-years (95% CI, 0.36-0.7). The researchers observed an association between seroconversion and HIV RNA level > 400 copies/mL.

“Incident HCV infection occurs in HIV-infected men involved in U.S. HIV therapeutic trials, primarily through nonparenteral means, despite engagement in care and [highly active antiretroviral therapy],” the researchers wrote. “HCV antibody development was not related to immune status but was associated with inadequate HIV suppression. At-risk HIV-infected persons should have access to HCV surveillance.”

Vigorous Sexual Practices

The rectal mucosa is a central focus for some experts who attribute HCV infections in MSM to vigorous sexual practices. These data, too, are emerging.

McFaul and colleagues investigated a population of 44 HIV-negative MSM with HCV during January 2010 to May 2014. Unprotected anal sex was reported by 93.2% of the individuals, while 87.8% practiced both insertive and receptive intercourse, 27.3% engaged in group sex, 25% practiced fisting and 25% also reported using drugs during sexual activity. Twenty-nine of the 44 patients were aware of their partner’s HCV status, while 13.6% engaged in sexual activity with an HIV/HCV coinfected partner.

“Similar to the ongoing epidemic of acute HCV infection in HIV-positive MSM, HIV-negative MSM remain at risk,” they concluded.

“We have seen increased risk in MSM who engage in practices where bleeding occurs,” Taylor said. “When there is blood-blood or blood-semen contact during unprotected anal intercourse, there is going to be HCV transmission. If you factor in genital ulcerative disease, that adds to it.”

Complicating the picture is the fact that different sexual practices exist in various cities and countries where studies have been conducted. “Simply put, a bottom with no condom is most likely to be infected,” Fierer said. “But we have seen varying activities in Berlin, London and New York, and that bleeding may not even be necessary. This makes it harder to figure out exactly how the infection is being transmitted.”

While practices like those described above are linked to increased risk, even anal sex, which results in semen in the rectum, has been associated with increased infection rates. “This is a new understanding in the way we think about things,” Fierer said. “Unfortunately, the men at risk do not seem to know all of this, and they end up shocked that they acquired HCV.”

Swan built on this point. “Since we don’t know which behaviors transmit HCV, it is difficult to determine exactly what is unsafe,” Swan said. “Researchers have identified a cluster of risk factors that are biological, social and cultural —including non-injection drug use, group sex, rougher sex, fisting and sharing sex toys — but some people who have not done any of these have acquired HCV from sex.”

Due to the nature of these sexual acts causing potential blood exchange, some experts have referred to them as traumatic acts, but there is a semantic issue at hand that should not be ignored, according to Swan. “‘Traumatic’ is a stigmatizing term,” she said. “Most of us use ‘rough’ or ‘vigorous’ instead because these don’t imply rape or abuse.”

Another important factor pertains to alanine aminotransferase elevation, Fierer added. “If there is any ALT elevation, HCV needs to be considered,” he said. “ALT of 300 is HCV until proven otherwise.”

Substance Abuse

Substance abuse often goes hand-in-hand with high-risk sexual practices, according to most experts. But what seems particularly troubling is that associations are emerging for non-injection drug use and HCV.

Other findings from the 2011 study by Taylor and colleagues indicated that 75% of seroconverters did not report injection drug use (IDU). In this group, HCV incidence rate was 2.67 cases per 100 person-years among IDUs vs. 0.4 cases per 100 person-years among non-IDUs.

The most frequent culprits are stimulants, including methamphetamines and cocaine. “For the most part, these are party drug people,” Marks said. “But we see people whose use of crystal meth escalates to IV drug use.”

Taylor hypothesized further: “Crystal meth use may raise pain thresholds, which could lead to more aggressive sexual practices. ... This, in turn, can lead to prolonged blood exposure.”

The self-reported nature of drug use also plays a role, according to Marks. “Some of the people we see use IV drugs once or twice but do not disclose it,” she said. “They don’t consider themselves in the category of ‘injection drug user.’”

Another paper by Taylor and colleagues looked at interactions between various drug types. “Drug-drug interaction studies between [antiretroviral therapy], DAAs, and opiate substitution therapy must be expedited,” they wrote. “Coinfected [people who inject drugs] should have equitable and universal access to HIV/AIDS, HCV and addiction prevention, care, and treatment.”

In MSM Without HIV

Richardson and colleagues published a paper in the Journal of Infectious Diseases in 2008 in which they argued that HCV in MSM may not be restricted to HIV-positive individuals. They assessed 6,124 MSM at a single clinic between 2000 and 2006. There were 1.5 cases of incident HCV per 1,000 person-years among MSM without HIV and 2 cases per 1,000 person-years among men with unknown HIV status. There were 11.8 cases per 1,000 person-years among those with known HIV infection. Moreover, rates of HCV increased from 0 to 5.8 cases per 1,000 person-years among individuals with unknown or negative HIV statuses between 2000 and 2003 as well as between 2005 and 2006.

“To our knowledge, this is the first report of significant sexual transmission of HCV to MSM whose HIV status was either negative or unknown at the time of their first HCV test,” they wrote.

They added that all MSM in settings where HCV is present should be screened for HCV, regardless of HIV status. “It is also clear that incident HCV infection reflects ongoing HIV risk and that all individuals, particularly those with incident HCV infection, should be targeted by behavioral interventions to reduce ongoing transmission,” the researchers wrote.

For Marks, the main concern with HIV-negative populations is that they are not being tested for HCV. “People with HIV who are engaged in the health care system are getting liver enzymes tested every 3 months,” she said. “This makes it easy to find infections when their enzymes are sky high. HIV-negative populations are not getting this kind of attention.”

That said, Marks described HCV in MSM without HIV or IDU as still a “relatively rare occurrence.”

Fierer agreed, saying that the simplest explanation is that HIV is significantly more infectious through sex than HCV.

“If HIV-negative MSM are having sex with HIV-positive MSM who have HCV, almost everyone will get HIV before they get HCV, and getting HCV while still being HIV-negative would be rare (which it has been),” he said. “But with the increasing use of HIV pre-exposure prophylaxis [PrEP; Truvada, Gilead], HIV infection is effectively prevented, so HIV-negative men will then be getting HCV and staying HIV-negative.”

Just such an occurrence has recently been published from San Francisco, and Fierer notes he has seen two cases himself in New York, so this issue is worthy of a more systematic investigation.

“The point, therefore, is that the sex itself doesn’t need to be ‘riskier’ — many men who are choosing to take PrEP are already having risky enough sex to get HCV. This last year, with expansion of Truvada, there is a rise in sex without condoms among men with HIV, some of who turn out to also have HCV,” Fierer said. “Many are no longer serosorting. Unfortunately, Truvada does not protect against HCV.”

The data, though, are preliminary about whether individuals taking PrEP actually engage in riskier sexual practices, according to Wyles. “Increased risk behaviors in young HIV-positive MSM has been suggested,” he said. “This may be due, in some part, to arrival of well tolerated, widely available HAART. HIV is no longer seen as a death sentence. Also, with widespread use of the internet and serosorting, many individuals may be engaging in increased high-risk sexual behaviors.”

Marks, though, remains unconvinced. “The data are not showing riskier behavior in those on PrEP in clinical trials,” she said. “At least not much riskier sex than they were already having. But that is a concern that requires further study in the real world.”

“It actually doesn’t matter if your sex becomes ‘riskier,’” Fierer explained.

Moving Forward

Despite a wave of hope that DAA therapy will be a cure-all for everything related to HCV, Fierer is adamant that the incidence rates in MSM are real and that transmission in this community needs to be stopped. His research has yielded evidence of real consequences for failing to recognize the epidemic.

“In the health care field, very few things that start happening just disappear and stop, especially when human sexual interaction is involved,” Fierer said. “When was the last time a disease like this just went away?”

It is for this reason that Fierer stressed screening. “The sooner we find people, the sooner we can stop it,” he said. “The messages about transmission and screening still haven’t reached everybody. The messages need to get out.”

“Guidelines recommend annual screening, but for people who are sexually active and/or using party or injection drugs, risk-based screening may be the best strategy,” Swan said. “Also, if people have been infected with hepatitis C in the past and been cured by treatment or spontaneously cleared it, they will remain antibody-positive. They should be screened using viral load testing instead of antibody testing.”

Taylor put this in practical terms. “Our goals as clinician researchers are to collect and report on the data that will change the standard of care so that HIV-infected patients are routinely and repeatedly screened for HCV,” she said. “We need to fully define the scope of this problem and intervene.”

She said that simple studies can be effective. “We are asking a straightforward question: what is the rate of new infections?” she said. “We also ask ourselves whether there are increasing incidence rates or whether we are detecting infections more. It seems to be the case that transmissions are on the rise.”

Clinicians and patients alike are still surprised when sexual transmission occurs. This, in some ways, is due to the effectiveness of the simple message about injection drug use Fierer discussed earlier. “People continue to be surprised that HCV is being transmitted by people who don’t or didn’t inject heroin,” Taylor said.

Then there is the ever-present issue of the cost of DAA therapies. “Most payers are restricting payment for HCV infections to persons with advanced liver disease,” Taylor said. “Therefore, not everybody is going to have access to these drugs for new HCV infections. It will be challenging to use DAAs in early HCV to stem forward transmission (for prevention and for the public health benefit as well as treatment of the individual) if we cannot access DAAs for persons without advanced fibrosis.”

Wyles stressed that many aspects of HCV in HIV-positive MSM remain unanswered. “We still do not know how HIV infection modulates the risk of sexually acquiring HCV and the exact mode of transmission,” he said.

For Fierer, it comes back to the message. “We are often flooding our patients with information, which can lead to prevention fatigue,” he said. “But the fact remains that people are not using condoms because HIV is a treatable or even a preventable disease. If this trend continues, we are going to be seeing more HCV in MSM.” – by Rob Volansky

• References:
• Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines. Available at: http://www.cdc.gov/std/treatment/2010/hepc.htm. Accessed June 1, 2015.
• Fierer DS, et al. Clin Infect Dis. 2013;doi: 10.1093/cid/cis1206.
• McFaul K, et al. J Viral Hepat. 2014;doi: 10.1111/jvh.12366.
• Richardson D, et al. J Infect Dis. 2008; doi:10.1086/533454.
• Taylor LE, et al. Clin Infect Dis. 2011;doi:10.1093/cid/ciq201.
• Taylor LE, et al. Clin Infect Dis. 2012;doi:10.1093/cid/cis367.
• Taylor LE, et al. Clin Infect Dis. 2013;doi:10.1093/cid/cit326.
• van de Laar TJ, et al. J Infect Dis. 2007;196:230-2388.
• Volk J, et al. Clin Infect Dis. 2015;doi: 10.1093/cid/civ129.

• For more information:
• Daniel S. Fierer, MD, can be reached at the Division of Infectious Diseases, Box 1009, 1 Gustave L. Levy Place, New York, NY 10029; email: daniel.fierer@mssm.edu.
• Kristen Marks, MD, can be reached at 525 East 68th St, F2437, New York, NY 10065; email: markskr@med.cornell.edu.
• Tracy Swan can be reached at 261 Fifth Avenue, Suite 2110, New York, NY 10016; email: tracy.swan@treatmentactiongroup.org.
• Lynn Taylor, MD, can be reached at 164 Summit Avenue, Center for AIDS Research (CFAR), Building Room 156, Providence, RI 02906; email: LTaylor@Lifespan.org.
• David Wyles, MD, can be reached at University of California, San Diego, 9500 Gilman Drive, SCRB #404, La Jolla, CA 92093-0711; email: dwyles@ucsd.edu.

Disclosures: Fierer reports associations with Gilead. Marks reports associations with Gilead, Janssen and Merck. Taylor reports associations with Gilead. Swan reports no relevant financial disclosures. Wyles reports associations with AbbVie, Bristol-Myers Squibb, Gilead, Merck and Tacere.