Coinfection with HIV and the hepatitis C virus (HCV) has increased in the past few years. 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 U.S. 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."1
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.
In these earlier studies, published between 1993-1996, data on three different cohorts of gay men without a history of IDU in the U.S. showed that between 3-5 percent 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.2 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.3 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.4
When Rooney5 undertook a 1998 review of the literature into sexual transmission 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 percent. 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)."6 Similar conclusions were drawn by Garcia7 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 percent 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.
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 percent versus 5.2 percent). Significantly, 18.7 percent of those who had regular heterosexual or gay sex with an HIV-positive partner were HCV-positive, compared with only 1.6 percent 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."9
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. Nearly 9 percent of HIV-positive men were HCV-positive compared with 2.6 percent of the HIV-negative men. Almost half (49 percent) 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.10
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 attendees.11 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 partner.12 Finally, Abresica from Italy found that 20 percent 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
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 percent of people with HIV tested negative for HCV antibodies but were positive on the Amplicor(TM) PCR test for HCV viral load.14
Dr. Nelson estimates that around seven percent of HIV-positive patients at Chelsea & Westminster are coinfected with HCV. "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 saliva,"15 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."
They also strongly suggest that yearly screening for HCV should become the norm in all U.K. 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 percent had undetectable levels of HCV and normal LFTs.16 "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-Carbonero,17 Bica,18 Monga,19 Hatzakis,20 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."
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