Soaring Sexually Transmitted HCV Rates in Gay/Bisexual Men

"Tentative" may be the kindest word to describe Centers for Disease Control and Prevention (CDC) online statements about sexual transmission of HCV. The CDC does recommend testing some gay and bisexual men for HCV infection, but in a statement that starts with a negative clause: "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."1

That fact sheet for gays, as well as CDC advice for professionals, make sexual transmission of HCV seem almost an anomaly: "While rare, spreading Hepatitis C through sex is possible."2

The CDC's longest fact sheet declaration on HCV transmission clearly states that "HCV is most efficiently transmitted through large or repeated percutaneous exposure to infected blood (e.g., through transfusion of blood from unscreened donors or through use of injecting drugs)."3 No one would argue with that. This transmission summary goes on to note that "although much less frequent, occupational, perinatal, and sexual exposures also can result in transmission of HCV." Sexual transmission takes third place in this list of "much less frequent" transmissions, though overwhelming evidence from the past decade documents an explosive HCV epidemic among men who have sex with men (MSM) throughout the United States, Europe, and Australia. No research suggests occupational or perinatal HCV transmission has grown at anywhere near the riptide pace seen in gay and bisexual men with and without HIV.

The most recent opportunistic infection guidelines from the CDC, National Institutes of Health, and HIV Medicine Association better reflect current research in MSM.4 "In HIV-infected MSM," this document notes, "multiple outbreaks of acute HCV infection demonstrate that sexual transmission is an important mode of acquisition in this population," adding that risk factors include condomless receptive anal intercourse, using sex toys or noninjection recreational drugs, and sexually transmitted infections (STIs).

In these guidelines the CDC recommends routine HCV testing for "all HIV-infected patients."4 For "at risk HCV-seronegative persons," the CDC advises HCV antibody testing "annually or as indicated by risk exposure." A positive antibody result calls for confirmatory HCV RNA testing to identify chronic -- versus cleared -- HCV infection.

But if a provider or layperson clicks their way to handy HCV summaries at the CDC website,1-3 they may easily come away with the impression that HCV jumps from one sex partner to the other too rarely to justify routine testing.

The perception that HCV seldom roves between sex partners reflects some U.S./Canadian research from the early 2000s in MSM and people with HIV.5-7 But other research from that era -- and volumes of more recent work -- amply demonstrate an epidemic of sexually transmitted HCV in MSM. Studies that identify transmission risk factors show why gay sex poses a much higher HCV transmission risk than heterosexual sex: it can be bloody. Rough anal sex, including sex toy use and fisting (inserting the fist into the rectum), and high rates of lesion-producing STIs offer HCV a direct route to the bloodstream and target cells throughout the body. Injection drug use and unscreened transfusions pose the highest risk of HCV transmission because big loads of blood carry more HCV than small loads. Less blood -- often no blood -- flows between partners during sex, but more blood typically gets mixed during gay sex than straight sex. Semen can also carry HCV RNA.

Doubled Chance of HCV With HIV/HCV-Positive Sex Partner

A clever analysis by Swiss HIV Cohort Study (SHCS) investigators offers strong evidence that, within HIV transmission pairs, having an HCV-positive sex partner doubles the risk of getting infected with HCV.8 The SHCS team turned to its antiretroviral resistance database and compared HIV genetic sequences to find 1555 HIV transmission pairs with known HCV status. Most pair members (78.5%) were men. Almost half (48.5%) picked up HIV during sex between men, while about one quarter became infected heterosexually and one quarter when injecting drugs.

Within likely HIV transmission pairs, having an HCV-positive partner boosted odds that the second partner would also have HCV more than 13 times (odds ratio [OR] 13.6, 95% confidence interval [CI] 10.5 to 17.6).

These higher odds held true when the researchers considered HIV transmission groups separately: 3.1 (95% CI 1.4 to 7.0) for MSM, 4.5 (95% CI 1.2 to 16.3) for MSM who injected drugs but attributed their HIV to sex, 5.4 (95% CI 2.9 to 10.3) for heterosexuals, 2.1 (95% CI 0.9 to 5.1) for heterosexuals who injected drugs but attributed their HIV to sex, and 2.7 (95% CI 1.3 to 5.5) for injection drug users (IDUs). Overall chances of having HCV if one's sex partner has HCV remained significant after statistical adjustment for HIV transmission group, calendar year, age, and sex (OR 3.2, 95% CI 2.2 to 4.7).

The SHCS team figured HCV incidence (the new-infection rate) by determining how many members of a likely HIV transmission pair tested negative for HCV then later tested positive. HCV-negative people who belonged to an HIV transmission pair in which the partner already had HCV proved twice as likely to acquire HCV infection as HCV-negative pair members whose partner did not already have HCV (hazard ratio [HR] 2.1, 95% confidence interval 1.1 to 3.8). This analysis adjusted for HIV transmission risk factor and calendar year.

The researchers stressed that their study does not involve confirmed sex partners: They relied on HIV phylogenetic analysis to infer partnerships (a well-accepted technique), and they did not phylogenetically analyze HCV in likely HIV pairs. The authors cautioned that the results may not apply to other HIV populations, but other Western HIV populations share more similarities than differences with the Swiss population. The twice higher risk of picking up HCV if a sex partner has HCV encouraged the SHCS team to underline "the importance of safe sex practices in HCV-discordant MSM couples and in sex with unknown partners even if HIV is suppressed by highly active antiretroviral therapy."8

The CDC's own research provides evidence strongly implicating sexual transmission of HCV in the United States. CDC analysis of 30,074 National Health and Nutrition Examination Survey (NHANES) participants from 2003 and 2010 identified illicit drug use (including injecting drugs) and getting a blood transfusion before 1992 as predictors of chronic HCV infection.9 Yet 49% of HCV-infected people in this analysis did not report either risk factor, a result leading the CDC team to propose that "risk-based screening alone is an incomplete approach to identifying chronically infected persons."

Epidemic Sexual Transmission of HCV in MSM

The impression that HCV rarely migrates between sex partners rests on research in monogamous heterosexual couples and in sexually active MSM, other men, and women tracked largely in the early 2000s. In Italy a study of 776 HCV-negative monogamous heterosexual partners of people with HCV found no HCV transmissions through 10 years of follow-up.10 No one in this study reported anal intercourse, sex during menstruation, or condom use. In a prospective study of 1085 Montreal MSM from January to September 2001, initial HCV prevalence stood at 2.9% and was attributed to injecting drugs much more often than to having sex (32.9% versus 0.3%, P < 0.0001).11 During 2653 person-years of followup, only 1 man picked up HCV, and he shared needles when injecting drugs.

A 1999-2003 study involved men and women offered HCV testing while attending STI clinics or seeking HIV testing in Seattle, San Diego, and New York City.12 Among 1699 MSM who did not inject drugs, only 26 (1.5%) tested positive for HCV. That rate proved almost 60% lower than the 3.6% prevalence among 3455 heterosexual men who did not inject drugs (prevalence ratio 0.42, 95% CI 0.28 to 0.64). Retrospective review of 5639 people attending a New York City hospital HIV clinic from January 1999 to May 2007 determined that MSM had lower odds of HCV coinfection than non-MSM (OR 0.565, P < 0.001).13 In contrast, coinfection odds were higher in heterosexual IDUs, MSM IDUs, and people who had transfusions.

Then clinicians started seeing something new. In mid-2004 three Paris hospitals told city public health officials they admitted several HIV-positive MSM with acute HCV infection who reported condom-free sex but denied injecting drugs.14 Checking records of those three hospitals from April 2001 to October 2004, authorities identified 29 cases of acute HCV in MSM with HIV. All these men had anal sex without condoms, and many reported "hard" sex, bleeding during sex, fisting, or STIs. No men injected drugs. The Paris team concluded that "HCV transmission probably occurred through bleeding during unprotected traumatic anal sex among HIV+ MSM and may be facilitated by STI mucosal lesions."14

Around the same time in Rotterdam, 275 miles north of Paris, clinicians reported a case of acute HCV in an HIV-positive man to the Municipal Health Service.15 The man had rectal lymphogranuloma venereum (LGV) at the time of acute HCV infection and belonged to a 2003 cluster of 15 LGV cases. A public health team studied this man, 2 recent sex partners, and 14 area men with LGV. Seven of these 17 (41%) recently became infected with HCV. Six of the 7 had HIV infection and 6 had LGV proctitis when they picked up HCV. None of these men injected drugs, but most used noninjection drugs. All 7 men with HCV practiced passive or active fisting. These men had many sex partners -- often anonymous partners -- throughout Europe.

As the millennium matured, reports of rocketing HCV incidence among MSM followed from Amsterdam,16 London and Brighton,17 Antwerp,18 Melbourne,19 Amsterdam again20 -- then from whole countries (France,21 Switzerland22 and the United States23) and international cohorts.24,25 Typically pussyfooted article headlines assumed a stampeding sense of urgency: "Is this an outbreak?"17 "An expanding epidemic."20 "A rapidly evolving epidemic."22 "A large international network."24 And consistent findings appeared from study to study: little or no injection drug use or other parenteral exposure to HCV, anal sex without condoms, rough anal sex without condoms, heavy recreational drug use, and lesion-leaving STIs.

In Amsterdam HCV incidence in HIV-positive MSM jumped 10-fold after 2000 to 0.87 per 100 person-years, meaning almost 1 in every 100 men with HIV picked up HCV every year.16 In a London/Brighton study of MSM with HIV, HCV incidence leapt 70% from 0.686 per 100 in 2002 to 1.158 per 100 during January-June 2006.17 An Antwerp study of HCV incidence in MSM with HIV traced an explosive surge from 0.2 per 100 in 2001, to 1.51 in 2008, all the way up to 2.9 in 2009.18

French researchers charted HCV incidence from 1996 through 2005 in the national PRIMO Cohort of people enrolled with primary HIV infection.21 Through a median follow-up of 36 months, the 402 cohort members had an HCV incidence of 0.43 per 100 person-years. Incidence measured 0.12 per 100 before January 2003 and 0.83 per 100 after that date -- almost a 7-fold spurt.

From 1998 through 2011, Swiss HIV Cohort Study investigators gauged HCV incidence in 3333 initially HCV-negative MSM, 123 IDUs, and 3078 heterosexuals.22 Everyone had HIV. Among MSM HCV incidence ballooned from 0.23 per 100 person-years in 1998 to 4.09 in 2011, almost an 18-fold leap. Overall HCV incidence was higher in IDUs than in MSM but fell during the study period among IDUs, while HCV incidence in heterosexuals remained below 1 per 100 person-years.

In the United States, Multicenter AIDS Cohort Study (MACS) investigators charted HCV incidence in 6417 MSM with and without HIV from the early days of the HIV epidemic (1984) until 2011.23 HCV incidence proved almost 4 times greater in a later MACS recruitment period, 2001-2003, than in the 1980s or 1990s (incidence rate ratio [IRR] 3.80, 95% CI 1.67 to 8.64, P = 0.001) (Figure 1). HIV-positive men had a 6 times higher HCV incidence than HIV-negative men (IRR 5.98, 95% CI 4.85 to 7.39, P < 0.001).

Figure 1. Rising HCV Incidence in HIV+ MSM in MACS
Figure 1. Rising HCV Incidence in HIV+ MSM in MACS Among HIV-positive MSM in the Multicenter AIDS Cohort Study (MACS), those recruited in 2000-2003 had higher HCV incidence than those recruited in 1984-1999.23 Higher incidence in later recruits held true for incidence in 2000-2004 and 2005-2011.

An international team compared HCV NS5B sequences from 200 HIV-positive MSM diagnosed with HCV from 2000 through 2006 in England, the Netherlands, France, Germany, and Australia.24 Sequence analysis determined that HCV from 156 men (78%) matched sequences from other men in the study. The investigators mapped 11 HCV transmission clusters, each involving between 4 and 37 men. Molecular clock analysis indicated that 15% of HCV transmissions happened before 1996, 22% from 1996 to 2000, and 63% after 2000. Among European men in the study, 74% carried an HCV strain circulating in several European countries.

A similar, smaller phylogenetic analysis involved 74 HIV-positive MSM with recent HCV infection seen from 2005 through 2010 at New York's Mount Sinai Medical Center.26 None of the men injected drugs. HCV sequencing disclosed five clusters of closely related HCV variants. A case-control comparison matching 22 HCV/HIV-infected men with 53 HIV-infected men without HCV found that receptive anal intercourse without a condom raised chances of HCV infection 23 times. Having sex while using methamphetamine boosted HCV risk 28 times.

Finally, an international CASCADE cohort analysis found evidence that HCV incidence has been climbing among HIV-positive MSM since the mid-1990s.25 But incidence steepened sharply starting in 2002, and even more so around 2005 (Figure 2). This analysis involved 3014 MSM with HIV, 43 from Canada and the rest from Western Europe.

Figure 2. Rising HCV Incidence in HIV+ MSM in Europe
Figure 2. Rising HCV Incidence in HIV+ MSM in Europe A CASCADE Cohort analysis of 3014 MSM with HIV determined that HCV incidence began to rise substantially in the mid-1990s.25 But incidence steepened even more sharply starting in the year 2000, then more steeply still after 2005.

The investigators used three methods to estimate HCV incidence from 1990 through 2007. In 1990 estimated HCV incidence ranged from 0.9 to 2.2 per 1000 person-years (Figure 2).25 By 1995 that range climbed to between 5.5 and 8.1 per 1000. In 2000 estimated HCV incidence stood between 8.0 and 13.7 per 1000. A big surge took HCV incidence up to 16.8 to 30.0 per 1000 in 2005. And by 2007 estimated HCV incidence ranged from 23.4 to 51.1 per 1000. Across these years the lowest and highest estimates mean that 1 per 1000 HIV-positive MSM picked up HCV in 1990, whereas 50 per 1000 got HCV infection in 2007.

Risk Factors for HCV Infection in MSM

Reasons gay and bisexual men have become so vulnerable to HCV infection parallel reasons for surging HIV incidence among MSM in many Western countries: They're having more sex with more partners while taking party drugs and bearing anogenital lesions that give viral intruders easy entry. And they don't wear condoms. To protect themselves from HIV, some MSM have adopted serosorting -- having condom-free anal sex with partners of the same HIV status. The value of serosorting in HIV prevention remains controversial, but HIV-serosorting clearly does nothing to protect an HCV-negative sex partner from hepatitis viruses. Rough anal sex including fisting has long been a feature of gay sex life, and studies dating to the early years of the HCV epidemic in gay men indicate that fisting plays a prominent role.14,15

HIV providers should be familiar with HCV risk factors in MSM, and they should make their HIV-positive and negative gay patients aware of these risks. (See Table 1 and the patient handout in this issue of RITA!) Ample research analyzed in the first article of this issue of RITA! indicates that HCV infection complicates the course of HIV. Direct-acting antivirals (DAAs) have transformed treatment of HCV infection, yielding high cure rates in 12 or fewer weeks. But these drugs are hugely expensive and may not be an option for people without excellent insurance. Avoiding HCV infection should be among the priorities of everyone with HIV.

Table 1 summarizes what's known about HCV risk factors in MSM based on research over the past decade.

Table 1. Risk Factors for HCV Infection in Gay or Bisexual Men*
SexDrugs
  • Having many sex partners27
  • Meeting sex partners online28
  • Group sex27
  • Fisting14,15,20,26,28
  • Rough sex14,16
  • Bleeding during sex14,28
  • Receptive anal sex without condom14,23,26,28
  • Inconsistent condom use22
  • Using sex toys26
  • Sex while high on drugs1,29
  • Sex while using methamphetamine26
  • Sex while using gamma hydroxybutyrate (GHB, cherry meth, liquid X)20,26
  • Shared intranasal drugs27
  • More than 13 alcoholic drinks weekly23
Sexually Transmitted Infections (STIs)HIV-Related Factors
  • Having an STI14,17
  • Syphilis20,22,23,26
  • Lymphogranuloma venereum (LGV)15,20
  • Gonorrhea26
  • Hepatitis B virus (HBV) infection23
  • Lower CD4 count23

* Risk factors identified by both univariate and multivariate analysis.

† hcvguidelines.org, from the American Association for the Study of Liver Disease and the Infectious Diseases Society of America, cites intranasal illicit drug use as an HCV risk factor that should prompt testing.

"Alarmingly High" HCV Reinfection Rate in MSM

Getting infected with HCV does not protect a person from reinfection, even after spontaneous clearance of the first infection or curative therapy. Researchers working with Amsterdam's MSM Observational Study of Acute Infection With Hepatitis C (MOSAIC) charted HCV reinfection in 51 HIV-positive MSM with sexually acquired HCV.29 All men got treated for HCV during acute primary infection and tested negative for HCV RNA after treatment, without relapse. The MOSAIC team defined HCV reinfection as detectable HCV RNA of a different HCV genotype or clade after undetectable HCV RNA at the end of treatment.

Eleven men (22% of 51) became reinfected for an incidence of 15.2 per 100 person-years (95% CI 8.0 to 26.5), meaning 15 of 100 men cured of HCV would become infected again in 1 year. Cumulative HCV reinfection incidence was 33% within 2 years. Calling the HCV reinfection rate "alarmingly high," the Amsterdam group offered three recommendations:29

  1. Discuss HCV prevention with people who test HCV RNA negative after being infected.
  2. Test for HCV RNA frequently after successful treatment.
  3. In cases of possible relapse after treatment, perform clade typing to rule out reinfection.

Researchers at London's Chelsea and Westminster Hospital tracked HCV reinfection in 191 sexually infected HIV-positive MSM who spontaneously cleared HCV or had successful treatment between January 2004 and April 2012.30 They defined reinfection as any newly detectable HCV RNA after (24-week) sustained virologic response in treated men or 24 weeks after spontaneous clearance. All reinfections involved virus with an HCV genotype different from that of the first infection.

Forty-four of these men (23%) became reinfected for an incidence of 7.8 per 100 person-years (95% CI 5.8 to 10.5). Eight men became reinfected a second time for an incidence of 15.5 per 100 person-years (95% CI 7.7 to 31.0). Among 145 men whose initial infection could be documented as their first-ever HCV infection, the overall reinfection rate was 8.0 per 100 person-years (95% CI 5.7 to 11.3). In this 145-man analysis, reinfection incidence was 9.6 per 100 person-years (95% CI 6.6 to 14.1) among men with successfully treated primary infection and 4.2 per 100 person-years (95% CI 1.7 to 10.0) among men who spontaneously cleared their primary infection.

UK hepatitis virus guidelines for people with HIV now recommend HCV RNA testing every 3 to 6 months after spontaneous clearance or successful therapy in people who remain at risk for HCV infection.31 The London team also recommends "directed education and prevention interventions" for HIV-positive MSM with HCV infection.30

What About HIV-Negative MSM?

Do sexually active HIV-negative MSM run a higher risk of sexually transmitted HCV infection than heterosexual men and women? Logic suggests that HIV-negative men may pick up HCV as often as HIV-positive men if they have condom-free sex, including fisting, while using party drugs. But studies in the U.S. MACS cohort,23 London,32 Sydney,33 and Zurich34 found much lower HCV prevalence or incidence in HIV-negative MSM than HIV-positive MSM. The reasons for this difference may not be abstruse. The same sex habits that put MSM at risk for HIV infection put them at risk for HCV. An MSM group without HIV probably has less membrane-rending, drug-propelled sex than men with HIV -- so they get HCV infection less often.

Systematic review of 21 published studies and four conference abstracts that appeared from January 2000 through May 2012 calculated a pooled HCV incidence of 1.48 per 1000 person-years (95% CI 0.75 to 2.21) in HIV-negative MSM and 6.08 per 1000 (95% CI 5.18 to 6.99) in HIV-positive MSM.35 (In contrast, estimated 2009 HCV incidence in the United States stood at 0.3 per 100,000.36) In studies that directly compared HIV-negative and HIV-positive men, HCV incidence was significantly higher in the HIV group (pooled risk difference 3.45 per 1000 person-years, 95% CI 1.63 to 5.27). Although these investigators concluded that evidence does not support routine HCV screening of HIV-negative MSM, they suggested that some HIV-negative MSM -- those who have high-risk sex -- should get tested for HCV.

HIV clinicians should bear in mind that HIV-negative MSM (and positive MSM) often have other recognized nonsexual risks for HCV infection, and providers should ask men about these risks. Most importantly, more than a few MSM inject drugs, and injection drug use easily accounts for most HCV infections in the United States. Other risk factors are (1) being born between 1945 and 1965 (regardless of other risk factors), (2) unexplained chronic liver disease or chronic hepatitis including elevated alanine aminotransferase, (3) incarceration, (4) intranasal illicit drug use, (5) getting tattooed, (6) long-term hemodialysis (ever), (7) organ transplantation before 1992, and (8) getting clotting factor before 1987.37

An HCV testing and treatment cascade framed by the CDC suggests that erring on the aggressive side in HCV screening makes sense.38 Crunching numbers from two large U.S. patient databases, CDC researchers figured that only half of an estimated 3.2 million people with HCV infection get diagnosed, about one third get referred to care, and about 10% get treated (Figure 3). There's no way to tell how many of the 1.6 million undiagnosed people are gay or bisexual men -- with or without HIV. But pushing for more HCV testing in MSM -- from the top (the U.S. government) and from the trenches (front-line clinicians) -- would probably make the CDC cascade less dreary. And with rapidly effective direct-acting antiviral regimens becoming available, aggressive HCV screening would get more people into care and cure them.

Figure 1. Risk of All-Cause Mortality With vs Without HCV
Figure 3. HCV Diagnosis and Treatment Cascade in United States Analyzing numbers from two large U.S. cohorts, the CDC figures that only half of HCV-infected people in the United States get diagnosed and only 7% to 11% get treated.38

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