Over a decade ago, doctors in Europe began reporting clusters of new hepatitis C infections among HIV-positive gay and bisexual men. Given their lack of other risk factors, the culprit appeared to be sexual transmission. This was greeted with surprise and skepticism, as it was assumed that sexual transmission of hepatitis C virus (HCV) was rare. But today there is a growing consensus that sex is a leading cause of new HCV infections among men who have sex with men (MSM), especially those who have HIV.
"Among gay men, I think the vast majority who acquired HCV in the past decade have gotten it from sex," says Daniel Fierer from Mount Sinai Medical Center in New York City.
HCV is a blood-borne virus that had been most often transmitted by sharing needles or by blood transfusions (before blood was tested for the virus). The CDC lists sex as an "inefficient means" of HCV transmission. Public health messages have said that the risk of sexual transmission is very low and that people with HCV do not need to change their sexual practices. This advice was based on studies showing that transmission is rare in monogamous heterosexual couples, ranging from 0% to about 3%.
But these findings don't hold for other groups. Other studies have shown that both heterosexual and gay people with multiple sex partners, HCV-positive partners, or partners who inject drugs have a higher chance of getting hepatitis C.
HCV and HIV
New HCV infections in gay men with HIV began to climb steeply around 2005. In Amsterdam, the proportion of MSM with HIV testing positive for HCV rose from 6% in 1995 to a peak of 21% in 2008, with nearly one-third having a new infection.
Because the transmission routes are similar, about a third of people with HIV also have HCV, and many people who got HIV through injection drug use also have HCV. But among gay and bisexual men with HIV, sex appears to be increasingly common as a means of HCV transmission.
"For gay men who don't inject drugs but have a lot of sex, if they get HCV, they're likely to have gotten it through sex," says Brad Hare, Director of HIV Care and Prevention at Kaiser Permanente in San Francisco.
In 2002 researchers reported several cases of new HCV infections among HIV-positive gay men at sexual health clinics in London. Within a year, the number of new cases approached 50. Before long, similar clusters were reported in France, Germany, the Netherlands, and Switzerland. These were followed a couple of years later by reports from Australia, the U.S., and Japan.
New HCV infections in gay men with HIV began to climb steeply around 2005. Investigators from Amsterdam's public health service have traced HCV prevalence, or total cases, among HIV-positive gay men over two decades. The proportion of these men testing positive for HCV antibodies rose from 6% in 1995 to a peak of 21% in 2008, with nearly one third having a new infection. The number then appeared to level off, which the researchers said could be due to greater awareness and prevention, or just that the pool of susceptible men was "saturated".
Similar reports emerged a bit later in the U.S. In 2006 Annie Luetkemeyer reported nine cases of new HCV among men with HIV seen at San Francisco General Hospital, with a majority reporting only sexual risk factors. The next year, Fierer first reported on a group of HIV-positive gay men in New York with new HCV infections despite no traditional, non-sexual, risk factors. Disturbingly, some of them had unusually rapid liver fibrosis. And in 2009, Lynn Taylor reported that 75% of new HCV infections among HIV-positive gay and bisexual men in several AIDS Clinical Trials Group studies were likely due to sexual transmission.
Genetic studies have shown that HCV strains from MSM closely follow sexual networks within and even across cities. Several HIV-positive gay men in European cities, for example, were infected with HCV genotype 4, a Middle Eastern strain that is otherwise uncommon in Europe. Notably, the HCV strains circulating among gay men are usually not closely related to the strains circulating among people who inject drugs in the same city.
By now the risk of HCV sexual transmission among HIV-positive gay and bisexual men is widely recognized. But what about their HIV-negative counterparts?
Since the topic first hit the radar a decade ago, researchers have seen few cases of apparently sexually transmitted HCV in HIV-negative men. But some experts have suggested that sexual transmission of HCV among HIV-negative men is found less often only because we don't look for it. HIV-negative people are seldom tested for HCV and don't usually have regular liver function tests. But the few studies that have specifically looked for HCV in HIV-negative gay men have found infection rates similar to those of the general population.
After clinicians in Brighton, England, observed a high rate of new HCV infections among men with HIV at their sexual health clinic, they decided to test all clients, regardless of HIV status, starting in 2000. While several cases of HCV were detected among HIV-negative men, they were 13 times less likely to get it than HIV-positive men.
In Amsterdam, while HCV prevalence among men with HIV rose from 6% to 21% between 1995 and 2008, cases in HIV-negative men stayed low and stable at around 0.5%. Other studies in Sweden, Switzerland, and the U.K. have seen HCV prevalence rates among HIV-negative gay men ranging from 0.2% to 0.7% -- similar to the general population of those countries.
At last year's ICAAC meeting, Katie McFaul from Chelsea and Westminster Hospital reported finding 44 HIV-negative gay men with new HCV at three sexual health clinics in London, out of about 34,000 clients tested for the virus (a rate of less than 1%). At the same conference, Swiss researchers reported that only one out of 654 mostly HIV-negative gay men tested at their clinic had HCV. His only risk was condomless anal sex.
What Are the Risk Factors?
A wide range of risk factors have been linked to HCV among MSM, including anal sex, fisting, rimming, multiple sex partners, group sex, sex at sex clubs or bathhouses, use of noninjected recreational drugs, sex while using drugs, and having other sexually transmitted diseases (STDs). Injection drug use does not appear to play much of a role.
The strongest predictor of HCV among gay men is anal sex, especially receptive sex without a condom. In some studies, every man with new HCV reported being an anal sex bottom.
This raises the question of whether HCV is sexually transmitted mainly through blood or through semen. HCV is known to spread most easily through direct contact with infected blood. Some experts, therefore, have concluded that HCV transmission is probably due to exposure to blood during sex.
Some sex activities like piercing and whipping can cause bleeding, and one recent study from Amsterdam found that gay men in the leather, rubber, or denim scenes have higher HCV rates. But sex doesn't have to be "rough" to be risky. Anal intercourse can cause small tears in the rectal lining that could increase the likelihood of infection.
"Researchers talk about traumatic sex, but that's an unfair thing to say about gay men," says Fierer. "Do they mean all anal intercourse is traumatic? People don't identify their anal sex as traumatic."
Even hangnails or minor cuts on the hands, genitals, or elsewhere could provide a portal for viral entry or exit. The amount of blood doesn't have to be large or even visible to allow for HCV transmission. "It doesn't have to be some blood-letting exercise," Fierer stresses. Being fisted, using sex toys, or bottoming with multiple partners can injure the rectal lining, providing easier access for the virus. During group sex, HCV in blood or semen may be transferred from one person to the next on penises, fists, or toys.
Non-injection drug use may play a role if people share straws or rolled bills for snorting drugs or pipes for smoking, since small amounts of blood may be left on the equipment. Some drugs enable prolonged sex, while others can dry out mucous membranes or cause numbness that allows more vigorous penetration.
Other STDs, including syphilis and genital herpes, cause sores or ulcers that make it easier for HCV to get in and out of the body. Anal warts caused by HPV may also add to the risk. Other infections like gonorrhea and chlamydia cause inflammation that may aid HCV transmission.
It's difficult to tease out the specific contributions of various risk factors because multiple activities often occur together and most gay men do not have only one kind of sex. If an HIV-positive man with undiagnosed chlamydia takes ecstasy and goes to a sex club where he fists one partner, is penetrated with a previously used sex toy, and then bottoms for anal sex, it's hard to tell which of these factors is to blame if he gets HCV.
But none of this explains why receptive anal sex is such a major risk factor. "Where is the HCV coming from?" Fierer asks. "I think it's coming from semen -- that's the simplest explanation, since penises don't bleed."
Several studies have detected HCV in semen, though usually at low levels and not all the time. One Australian study, for example, found that 44% of men with HCV had detectable virus in their semen at the start and 74% did at least once during follow-up. Other research has shown that men with HIV have higher HCV viral loads and are more likely to have HCV in their semen than HIV-negative men. Furthermore, men with new HCV infection have more HCV in their semen than those with chronic infection.
"Hepatitis C is more efficiently transmitted through blood and less through sex, so if a gay man has both types of exposure, it's probably blood that's causing it," Hare summarizes. "In the absence of blood, semen is a less efficient but possible route of HCV infection."
Why does sexually transmitted HCV mainly occur among men with HIV and why did it seem to crop up around the year 2000, even though gay men were having plenty of sex, doing drugs, and getting STDs long before that?
Overall immune deficiency may play a role in making HIVpositive men more susceptible to HCV, but many men with sexually transmitted HCV are on HIV treatment with undetectable HIV viral loads and high CD4 counts. Some started HIV treatment early and never experienced serious immune system damage. Current or lowest-ever CD4 cell count are not predictors of HCV infection. This suggests that the problem is not simply that a weakened immune system cannot fight HCV. Even well-controlled HIV leads to inflammation and subtle immune damage starting soon after infection, and that may facilitate HCV transmission.
"HIV significantly affects the immune system that lines the gut," Hare explains. "I think the best explanation is that once the immune system is damaged, it does not fully recover even if the blood CD4 count is normal, so [people with HIV] may be more vulnerable to HCV in the rectum."
In the '70s in the Castro or the West Village, HCV prevalence wasn't high, so men couldn't transmit it to each other. Over the years the seroprevalence rose until it reached the level of transmissibility, which happened remarkably around the same time in multiple cities around the world.
People with HIV are not only more at risk for getting HCV, but are also more likely to transmit it. Studies have found that men with HIV have higher HCV viral loads and more often have detectable HCV in their semen than HIV-negative men.
According to Lars van de Laar and colleagues studying the HCV outbreak in Amsterdam, viral evolution patterns imply that the virus was occasionally introduced into networks of gay men between 1975 and 1996, but that it didn't really take off until the late 1990s. Then, with the development of effective HIV treatment, men with HIV returned to active sex lives as their health improved. Serosorting (HIV-positive men having condomless sex with each other) led to more sexual transmission of HCV, along with other STDs.
Because sex is an inefficient way to transmit HCV, Fierer thinks it took a while for it to reach critical mass. Outbreaks were seen first in European countries because their centralized health systems collect data from a large number of people, allowing patterns to emerge sooner than in the U.S. HCV outbreaks occurred first among HIV-positive gay men, and serosorting tended to keep HCV within that population.
"In the '70s in the Castro or the West Village, HCV prevalence wasn't high, so men couldn't transmit it to each other," he suggests. "Over the years the seroprevalence rose until it reached the level of transmissibility, which happened remarkably around the same time in multiple cities around the world after decades of not seeing it."
The Role of PrEP
Just as condomless sex among serosorters may have triggered outbreaks of HCV among gay men with HIV, some fear PrEP could have a similar effect among HIV-negative men.
PrEP (pre-exposure prophylaxis) refers to HIV-negative men taking daily Truvada to prevent HIV infection. Although most studies have shown otherwise, it is widely assumed that many men taking PrEP either already do not use condoms regularly or would like to use them less, leaving them vulnerable to other STDs, including HCV.
At Kaiser Permanente in San Francisco -- the largest PrEP provider in the U.S. -- more than 500 people, mostly MSM, started PrEP from early 2012 through July 2014. While there have been no new HIV infections, other STDs have been common, including two cases of HCV -- an incidence rate of 0.7% per year. Both were gay men with multiple sex partners who had other STDs but reported no injection drug use or occupational exposure, leading Hare to conclude, "I'm comfortable saying both are sexual transmissions."
At this year's Conference on Retroviruses and Opportunistic Infections, Sheena McCormack reported four new HCV infections among 545 HIV-negative men in the U.K. PROUD study of Truvada PrEP. Jean-Michel Molina reported eight new HCV infections among 400 men in the French IPERGAY study, which tested on-demand PrEP. Both studies saw no new HIV infections, but other STDs were common
It's important for HIV-negative men thinking about PrEP to be counseled about HCV. If they're maybe going to decrease their condom use, they should know HCV is a risk. We talk about other STDs, but HCV is the big one to be concerned about.
In McFaul's study of 44 HIV-negative men with new HCV infections in London, two were participants in a PrEP trial and eight had received HIV post-exposure prophylaxis (PEP) within the previous six months.
"I worry Truvada could completely change the equilibrium," says Fierer. "Now men are not getting HIV, but they can still get HCV. As men become more confident about PrEP, unprotected sex becomes more and more common. It can have unintended consequences, like serosorting did. There's always something out there willing to take advantage."
CDC guidelines recommend that people should be tested for HIV and other STDs before starting PrEP and every few months while taking it. Kaiser's PrEP program includes annual HCV testing and liver function monitoring every three months. Both of the new HCV infections to date were detected because the men had high levels of ALT, an enzyme that rises during liver inflammation.
While PrEP could contribute to a rise in HCV by reducing condom use, it could also potentially have the opposite effect because it prevents HIV, which is the biggest risk factor for HCV among gay men. And the accompanying regular testing detects HCV early, which could interrupt transmission.
"It's important for HIV-negative men thinking about PrEP to be counseled about HCV," Hare stresses. "If they're maybe going to decrease their condom use, they should know HCV is a risk. We talk about other STDs, but HCV is the big one to be concerned about."
The uncertainty around sexual transmission of HCV makes it hard to offer definitive advice. We need to raise awareness about sexual transmission of HCV and to fight stigma so people can talk about it openly.
"There is so much uncertainty around the sexual transmission of HCV, especially when compared to other STDs like HIV or syphilis," says Andrew Reynolds, Project Inform's Hepatitis C Education Manager. "So we struggle with our educational messages or err on the side of caution. Nobody wants to tell a person they are not at risk, only to find out later that we were wrong."
Compared with HIV, HCV is a tougher virus and can live longer outside the body. Research shows that HCV can live in syringes for more than a month, in water (and maybe in lube) for a couple of weeks, and on surfaces for several days.
Most experts recommend using condoms for anal sex, which would offer good protection if HCV is spread by semen, and some protection if it is spread by blood. For men who have sex with women or transgender men, menstrual blood is a potential concern.
"The same sort of strategies that work for HIV could work for HCV," Hare says. "Condoms could be helpful, though we can't say for sure -- if transmission is through semen, it's helpful."
Gloves can potentially protect both tops and bottoms during fisting. Putting condoms on dildos or other sex toys helps keep things clean. During group sex, change condoms or gloves between partners, since HCV may be transferred from bottom to bottom on penises, fists, or toys. It makes sense to clean sex toys and surfaces after sex and between users.
Hare recommends using new condoms and clean gloves for each partner, and cleaning sex toys between uses. But, he acknowledges, "How best to clean is not clear -- even bleach may not be 100% effective [against HCV]. So I advise having multiple sets of toys that can be used for different partners -- lots of equipment is good!"
Unfortunately, there is no vaccine for HCV. And people who clear the virus either naturally or with treatment can get infected again. Some European studies have seen reinfection rates around 15%, with some men being reinfected two or even three times.
Guidelines recommend that all people should be tested for HCV at the time of HIV diagnosis, regardless of risk. In addition, the CDC recommends a one-time screening for all "baby boomers" (people born between 1945 and 1965). This age group accounts for about 80% of all HCV cases in the U.S. But a majority of men with sexually transmitted HCV are considerably younger, in their 30s and 40s. According to the CDC, "Testing for hepatitis C is not recommended for gay and bisexual men unless they were born from 1945 through 1965, have HIV, or are engaging in risky behaviors."
AASLD/IDSA guidelines released last year recommend annual HCV testing for people who inject drugs and for men with HIV who have unprotected sex with men, adding, "Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV." But those risk factors remain undefined.
Many providers do not recommend -- or may even discourage -- testing for men with only sexual risk factors. But this is starting to change, especially in cities with large gay communities. A growing number of experts think annual HCV testing is good practice for men with ongoing sexual risk, including HIV-negative men.
Regular liver function blood tests (ALT/AST) can also be useful for detecting a new HCV infection. ALT typically rises soon after HCV infection, before antibodies are produced (which can take up to six months).
"HIV-positive people should probably have their ALT checked every six months, maybe every three if they have a lot of risk," adds Hare. "If HIV-negative, they can have less frequent monitoring."
Treatment as Prevention
HCV treatment has changed dramatically over the past few years. Oral antivirals that target steps of the HCV lifecycle have replaced interferon and ribavirin, which had to be injected weekly for 6 to 18 months, caused difficult side effects, and cured only about half of people.
The FDA has now approved three oral HCV medications which can cure over 90% of people. Treatment lasts 12 weeks for most people and is very well tolerated. Many experts now think everyone with HCV should be eligible for prompt treatment, before developing advanced disease. This may be especially important for people with HIV, who can have rapid liver disease progression.
Today the main barriers to widespread treatment are people not knowing they have HCV and the high cost of the new drugs. With a list price of $80,000 to $95,000, many insurers are limiting access to the sickest patients, and government payers like Medicaid and prison health services do not have enough money to treat everyone.
So even though HCV is now easier to treat, it shouldn't be taken lightly. It isn't like syphilis, which can be quickly cured with a dose of penicillin, and it shouldn't be regarded as an expected part of an active sex life.
"Getting hepatitis C is certainly more serious than other STDs," says Hare. "Treatment is not a single shot -- it's more expensive and more intensive." While people who get HCV should receive prompt care, there's no demonstrated benefit to offering HCV drugs immediately after exposure, as is done for HIV. "There's no HCV PEP or PrEP," he adds.
It took ten years after the development of effective HIV treatment before we realized the benefits of HIV treatment as prevention, but this is already being discussed for HCV. With widespread treatment, some experts envision its elimination. Modeling studies by Gregory Dore at the University of New South Wales and his colleagues have shown that expanded treatment could dramatically reduce HCV transmission among people who inject drugs, and the same could be true for sexual transmission among MSM.
"To stop transmission, we need to treat the people who are actively transmitting," stresses Fierer. He estimates that while there are about three million people with HCV in the U.S., active transmitters are only in the thousands. "We need to get these guys treated as soon as we can. We should reconsider the idea of waiting for spontaneous clearance (see box on page 9). Instead of saving money, you may have caused extra infections. At this point, maybe we should just treat everyone as soon as we find them -- get them in and get rid of it."
Liz Highleyman is editor-in-chief of HIVandHepatitis.com and has written about HIV and hepatitis for various publications for 20 years.