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A Case For Sexual Transmission of HCV: is there a higher risk among men who have sex with men?
Introduction by Jules Levin
  Whether or not HCV is transmitted sexually and what the risk is for sexual transmission has been controversial. This is because the studies that have so far been conducted have had differing results. Studies have not conclusively characterized how much risk there is of sexual transmission and whether or not the risk is significant. One reason it is hard to characterize the risk for sexual transmission in these studies is because the researchers are not certain if study participants may have had an exposure, even if only once, to a needle or syringe infected with HCV. Oftentimes, individuals do not want to reveal this prior behavior due to stigma or perhaps they don't realize that only one exposure is enough to contract HCV, or maybe they forgot a one-time experience that may have occurred 20 years ago. Using an infected needle in IV drug use just once is enough to transmit HCV. In my opinion, sexual transmission is possible, and the risk for an individual is based on a number of related factors. Studies do show that individuals with multiple sex partners and active sexually are at a risk for contracting HCV. Study results suggest that the presence of open sores, herpes, and STDs may increase the risk of sexual transmission. It's suggested that anal sex and sex during a woman's menstruation period may increase risk for sexual transmission. The English authors of the paper below make a case that HCV is transmissible sexually, and that gay men may be at a further increased risk for HCV transmission due to high numbers of multiple partners, the potential presence of STDs, and risky sexual behavior such as rimming, fisting, and anal sex. A high viral load present in the infected person may increase the risk for transmission. In HIV-infected individuals, HCV viral load can be higher and therefore sex with an HIV-infected person can increase the risk for sexual transmission of HCV.
I've been closely following HCV in coinfection for 4 years and find progress in most areas to be very slow. To their credit the ACTG has created a Liver Disease Focus Group which plans and conducts studies in coinfected patients. But government agencies, State and local Departments of Health, Ryan White Councils, ADAPs, and community organizations have been very slow in recognizing and starting programs to address the coinfection problems. In addition, there are significant gaps in reimbursement for diagnostics and therapy in ADAPs. Due to budget constraints in ADAP, Federal and most State funding is not supporting ADAP reimbursement for HCV therapy. With the availability of the new pegylated interferon therapy used in combination with ribavirin therapy for HCV, treatment will become more widely used for coinfected patients. Unfortunately, many HIV doctors are not trained and prepared for treating their coinfected patients. In addition, HCV treating physicians, such as hepatologists, are not prepared in general to treat HIV+ patients. Hepatitis doctors are often themselves overwhelmed with high numbers of patients and may not feel able to treat patients coinfected with HIV.
HIV/HCV coinfection is in many ways very different than HCV. HIV appears to impair the immune response to HCV. Preliminary study results find coinfected patients show lower response rates to pegylated interferpn plus ribavirin. This could be due to several reasons, but we are not yet sure why. HIV+ patients may have more difficulty in tolerating HCV therapy. HIV+ patients may experience increased incidence and severity of side effects. As I said above HIV may impair the immune response to HCV and may impair the response to therapy. In addition, a high number of coinfected patients in the US are African-American and Hispanic. Studies show that African-Americans have a lower response rate to therapy. Although fewer studies have been conducted in Hispanics it appears as if they may not respond as well to therapy either.
The NIH Consensus Development Conference Statement, which is available on the NATAP website in full, says the following on sexual transmission of HCV:
"HCV-infected individuals with multiple sexual partners or in short-term relationships should be advised to use condoms to prevent transmission of HCV and other sexually transmitted diseases. Sharing common household items that may be contaminated with blood, such as razors and toothbrushes, is another potential source of transmission of HCV that should be avoided. There is no evidence that kissing, hugging, sneezing, coughing, food, water, sharing eating utensils or drinking glasses, casual contact, or other contact without exposure to blood is associated with HCV transmission."
The sexual transmission of hepatitis C: has the risk been underestimated? - Risk among men who sex with men
Reprinted from the NAM Aids Treatment Update newsletter; September 2002.
available at www.aidsmap.com
Last month the Government published its Hepatitis C Strategy for England ,a plan intended to raise the profile of this blood-borne virus amongst health professionals and those at risk,and to improve NHS prevention,diagnosis and treatment facilities. The threat to both individual and public health is significant: it's estimated around 200,000 people are infected in England alone,and Scottish figures indicate that over 13,000 diagnoses have already been made there. In short, though hepatitis C (HCV) was identified several years later than HIV, the numbers of people affected in the UK are comparable, and in terms of undiagnosed cases, many more Britons have yet to discover they have HCV. When it comes to public profile, service provision and access to licensed treatments, the association swiftly ends. In relation to HCV therapy, not only is the Postcode Lottery alive and well, but has been given an improved prognosis since the allocation of health commissioning responsibility to Primary Care Trusts - in many regions you (and your doctor) may struggle to identify your HCV treatment commissioner. If you find them before we do, you might consider passing them a copy of the article over the page. Though the Government Hepatitis C Strategy rightly concentrates on improving drugs education and services (people who inject drugs are by far the worst hit by HCV), we've been aware of rumbling concern over the spread of HCV through sex - particularly amongst gay men - for some time. In our lead article this month, Edwin J Bernard speaks to two British doctors who have seen a rising number of new cases of HCV in people attending their HIV clinics. They are in no doubt that these individuals acquired HCV not through injecting drugs, but through their sexual behaviour.
Sexual Transmission of Hep C
As UK doctors admit concern about rising numbers of people contracting hepatitis C through sex, we ask who is most at risk and how people with HIV may be affected. Written by Edwin J Bernard
Coinfection with HIV and the hepatitis C virus (HCV) has increased in the past few years, as reported in the May 2002 issue of AIDS Treatment Update . Until very recently, the major risk factors for acquiring HCV were thought to be injection drug use (IDU), haemophilia and blood transfusion; sexual transmission was considered to be theoretical but insignificant. Now, however, there is new evidence that sexual transmission of HCV is on the rise, particularly amongst gay men with HIV. Recent studies suggest that not only is sexual transmission of HCV possible, but that being infected with HIV, and/or having certain kinds of sex, are major risk factors for transmission of the virus. In June 2002, the US government's National Institutes of Health issued a consensus statement by an independent panel of clinicians, researchers and community groups with expert knowledge of HCV. For the first time, they added sexual transmission to the list of exposure risks for HCV. Although they continued to say that the risk was extremely low for heterosexual monogamous couples, they added that "HCV-infected individuals with multiple sexual partners or in short-term relationships should be advised to use condoms to prevent transmission of HCV and other sexually transmitted diseases."
Last month the UK Department of Health issued their Hepatitis C Strategy for England . The approach of the DoH is similar to that of their US equivalent. "There is evidence that both homosexual and heterosexual transmission of hepatitis C may occasionally occur," the report states, before offering the somewhat contradictory advice to people with HCV to discuss the use of condoms with regular partners and practice safer sex with new partners. Two large HIV clinics in London have seen an increase in new HCV infections over the past six months, causing concern that the risks of sexual transmission for gay men with HIV in particular have been underplayed. Is it possible that just like the delay that occurred over public health messages about the current syphilis outbreak amongst gay men, not enough people are taking the sexual HCV threat seriously?" I hope it isn't going to take us two years to realise that yes, it's here, and it's being sexually transmitted," says Dr. Sanjay Bhagani,specialist registrar in infectious diseases and HIV at London's Royal Free Hospital.
Early evidence on HCV transmission
HCV was first identified in 1989 and although studies as far back as 1993 pointed to sexual transmission as a probable risk factor amongst gay men, the information did not translate into a public health message. This is likely because many more studies showed that the risk of sexual transmission was seen to be extremely low in the general population, and there may also have been an assumption that safer sex messages relating to HIV would also implicitly cover HCV transmission. In these earlier studies, published between 1993-1996, data on three different cohorts of gay men without a history of IDU in the US showed that between 3-5% were infected with HCV. Osmond found that HCV infection was marginally associated with more than 50 sex partners a year; or more than 25 oral receptive partners; or more than 25 anal receptive partners
Buchbinder found that sexual risk factors for HCV infection included receptive anal intercourse, fisting, having a sexual partner with a history of IDU, a self-reported history of genital herpes and being HIV-positive
Ndimbie found that whilst the number of sexual partners was not a significant risk factor, a history of syphilis, rectal gonorrhoea, insertive anal intercourse with ejaculation, and douche or enema use before anal receptive intercourse were statistically significant sexual risk factors
When Rooney undertook a 1998 review of the literature into sexual trans-mission of HCV amongst the general population, he concluded that there was "a small but definite risk of sexual transmission of hepatitis C " of between 1-3%. Rooney did not look at the difference between heterosexual and gay sex transmission risks, however. Since 1998, there have been many studies looking for a heterosexual transmission risk of HCV in monogamous couples that have found there is little to none. For example, Sciacca's Turin Study found that only three out of 196 long-term heterosexual spouses were infected with the same HCV viral genotype, and concluded that while sexual transmission of HCV was a possibility, "this method of transmission does not appear to be important if compared with that of other viruses (hepatitis B virus and HIV)".
Similar conclusions were drawn by Garcia at the recent International AIDS Conference in Barcelona. However, not all heterosexual transmission studies have come to the same conclusion, particularly those that include casual partners. Tenegan looked at the sexual partners of HCV- positive blood donors in Brazil from January 1992 to July 1996 and found that 11.76% were HCV-positive. Sexually transmitted infections (STIs) were found to be more prevalent among partners with HCV infection, suggesting that the high prevalence of HCV infection seen here may be attributed at least partially to sexual transmission because they put themselves at risk of other STIs. HCV, HIV and sex.
Though it has been suspected since 1994 that coinfection with HIV/HCV contributed to a higher risk of HCV transmission than being singularly infected with HCV (since HCV viral load was shown to be significantly higher in those coinfected with HIV/HCV, it was only towards the end of last year that a study confirmed that HIV/HCV coinfection magnified the risk of sexual transmission of HCV to both heterosexuals and gay men. Researchers from Naples found that HCV infection was almost three times higher in those who were HIV-positive compared to HIV-negative controls (15.1% versus 5.2%). Significantly, 18.7%of those who had regular heterosexual or gay sex with an HIV-positive partner were HCV-positive, compared with only 1.6% for partners of HIV-negative controls. The authors concluded therefore, that "in subjects who had only a sexual risk factor for parenterally transmitted infections, HIV may enhance the sexual transmission of HCV."
At the same time, another study found that HIV, certain sexual acts, and multiple sexual partners, correlated with a higher risk of sexually transmitted HCV amongst gay men.
Here, 662 HIV-positive and HIV-negative men in the Vancouver Lymphadenopathy Cohort were investigated for HCV. 8.8%of HIV- positive men were HCV-positive compared with 2.6%of the HIV-negative men. Almost half (49%)of HCV-positive men reported never injecting drugs. The HCV-positive men were more likely to report the following: more than 20 sexual partners in the last year; more than 100 lifetime partners; practicing insertive fisting; practicing receptive anal sex, and practicing insertive oral-anal sex (rimming). A comparison of the non-IDU HCV-positive group with the non-IDU HCV-negative group found insertive rimming and insertive fisting associated with HCV infection. Multivariate analysis showed three factors independently associated with HCV infection: injecting drug use; HIV infection and more than 20 male partners in the last year
Three further studies confirming HIV as a cofactor for sexual HCV infection were reported at the recent International AIDS Conference in Barcelona. Risbud from India found that HIV infection was independently associated with more than a three-fold increased likelihood of HCV infection amongst STI clinic attendees11.
Mendes-Correa from Brazil found that independent risk factors of HIV/HCV co-infection amongst male and female AIDS Outpatient Clinic attendees were (highest risk first):injecting drug use; a sexual partner with past history of chronic hepatic disease; a sexual partner who had received a transfusion; age above 30; anal intercourse; use of inhaled illicit drugs; and a history of an IDU sexual partner12.
Finally, Abresica from Italy found that 20% of women who had been infected with HIV by HIV/HCV coinfected partners were also infected with HCV, leading the co-authors to conclude: "It's probable that HIV and its related opportunistic infections of the female genital tract could strongly facilitate HCV sexual transmission "13.
Increasing UK cases
Mark Nelson, consultant in HIV at the Chelsea &Westminster Hospital, London, has been convinced for a long time that HCV is sexually transmitted. "What we've seen recently is an outbreak of syphilis (amongst gay men)," says Dr. Nelson, who also runs the HIV/HCV coinfection clinic, "and with the outbreak, what we've noted in the HIV clinic are small but increasing numbers of people seroconverting for HCV. Approximately a quarter of those have picked up syphilis at the same time, suggesting that HCV is sexually transmitted."
Dr. Sanjay Bhagani has been running the Royal Free's HIV/HCV coinfection clinic since last October. "In the last six months we have picked up six patients who have seroconverted for HCV," he says."We've been through all of them with a fine tooth comb in terms of risk factors and it seems that they have none of the other risk factors for HCV transmission," leading him to conclude that sexual transmission was the most likely route. "Two have an HCV- positive partner, and one had a gonorrhea coinfection," he adds, "leaving me in no doubt that these were due to sexual transmission." Both clinics only found these new HCV infections because of abnormal liver function tests (LFTs)since most acute HCV infections are clinically asymptomatic. "If we weren't doing the LFTs we wouldn't pick up (the acute infections)," says Dr. Nelson. This is because although most HIV clinics test for HCV during intake, regular screening is not commonplace. "Part of the problem is, once you've been tested you tend not to test again, so we're now promoting yearly testing for HCV," he adds.
"At the Royal Free we screen first for antibodies and do LFTs," says Dr. Bhagani. "If you have persistently abnormal LFTs, you're antibody negative for HCV, and your index of suspicion is high, we do an HCV PCR [viral load test ]." The most common way to measure HCV infection is the ELISA-2 anti-HCV (antibody) test. However, HIV infection can make the diagnosis of HCV more difficult since in a small minority, HCV infection may not show up on antibody tests in HIV-infected people. Last year, Bonacini found that 5.5%of people with HIV tested negative for HCV antibodies but were positive on the Amplicor PCR test for HCV viral load14. (ed note: studies suggest patients with low CD4 counts may be at risk for showing a false negative HCV antibody test).
Dr. Nelson estimates that around 7% of HIV- positive patients at Chelsea & Westminster are coinfected with HCV.(ed note: bear in mind that his patient population is likely largely composed of gay men with HIV not injection drug users where the prevalence rate would be expected to be higher). "A lot of them have none of the major risk factors of IDU or blood transfusion," he says. "Clearly a lot of people have tattoos, so you can't say it didn't come from tattooing, but when we screened individuals in the GU clinic, a history of tattooing was not a significant risk factor for HCV. And of course you can't exclude toothbrushes and razors. But I think the majority is sexually transmitted."
"There is a strong biological probability as to why coinfected men should be at higher risk of transmitting HCV," continues Dr. Bhagani."If you look at the HCV viral loads in people who are coinfected with HIV, as compared to singularly infected HCV patients, they are much, much higher. And the higher the viral load, the higher the risk of transmission." The jury is still out, however, on the actual mechanism of HCV infection during sex. Nelson points to a recent study that found that the higher the HCV viral load, the higher the level of HCV in saliva15,"although we don't really know what that means," he admits. Many of the studies reviewed here point to fisting, rimming, and unprotected anal intercourse as being associated with a greater risk, leading Dr. Bhagani to speculate that "practices that involve blood may be more high risk."
Safer sex, screening, treatment Drs.Nelson and Bhagani both believe that people with HIV can best protect themselves from acquiring HCV sexually by continuing to practice protected anal intercourse, rimming and fisting."Like everything, you're better off not getting it, and since there is no vaccine available, taking precautions is the only way," says Dr. Nelson.
They also strongly suggest that yearly screening for HCV should become the norm in all UK HIV clinics. "The first thing we really need to know in this country is what is the true prevalence of HCV in the HIV population," continues Dr. Nelson. "It is clearly something that people who have got HIV have put themselves at risk of. We need to make sure that everyone is screened for HCV. The advantage of picking it up early means you are much more likely to eradicate it." Although similar evidence is lacking in those who are HIV/HCV coinfected, last year, Jaeckel showed that HCV can be eradicated in HIV-negative people during acute HCV infection after 24 weeks treatment with interferon alpha. The average time from infection until the start of therapy was 89 days, suggesting that screening every three to six months might be optimum for those who believe they are at the greatest risk of acquiring HCV sexually. In this trial, at the end of both therapy and follow-up,98%had undetectable levels of HCV and normal LFTs16.
"The data for treating acute HCV from the Jaeckel paper is using just interferon alone," says Dr. Bhagani. "At the Royal Free we use pegylated interferon and ribavirin since we feel we should be giving these people the best standard of care that we can." Eradicating HCV during the acute stage "may be very important when you look at the data on HIV/HCV coinfection and higher rates of progression to end-stage liver disease," concurs Dr. Nelson. Many recent studies have confirmed the link between HIV/HCV coinfection and accelerated progression to fibrosis, cirrhosis, liver cancer and liver failure (including those by Martin-Carbonero17, Bica18 ,Monga19, Hatzakis20, Soto21 and Garcia-Samaniego22).
"Before HAART, everyone was saying you're going to die of your HIV, don't worry about your hepatitis C," continues Dr. Nelson. "Now suddenly people are living, and hepatitis is a major cause of morbidity and death in many people with HIV worldwide. It's something that we can't ignore anymore, and it's something that we've got to be much more proactive about."
Take home messages
"I think the take home messages are that HCV is sexually transmissible amongst gay men and it may be more so than with heterosexual," concludes Dr. Bhagani. "So gay men and people with HIV should always practice safer sex. In coinfected patients, HCV is a particular concern because of the propensity for faster progression to end stage liver disease and complications with drug- related toxicity. We know from singularly infected patients that HCV is potentially curable if caught early. And so we should be making an effort to try and detect and treat early HCV seroconversion."
Except where stated, references are from XIV International AIDS Conference, Barcelona, 2002.
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