July 22, 2011
In the United States, an estimated 3.2 million persons are living with hepatitis C virus (HCV) infection.1 HCV transmission occurs primarily through percutaneous exposure to blood, and persons who inject drugs are at greatest risk for infection. The role of sexual transmission of HCV has not been well defined. However, reports over the past decade, mainly from Europe, have implicated sexual transmission of HCV among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). In late 2005, two HIV-infected MSM, each with acute HCV infection that was suspected to have been acquired sexually, were evaluated at Mount Sinai Medical Center in New York City, prompting Mount Sinai to request referrals of similar patients.2 During 2005-2010, a total of 74 HIV-infected MSM with recently acquired HCV infection and no reported history of injection-drug use were evaluated. To examine the role of sexual transmission, a matched case-control study and viral analysis were conducted. Results from the case-control study showed that high-risk sexual behavior was the most likely mode of transmission among these men. Phylogenetic analyses revealed five clusters of closely related HCV variants, suggesting networks of transmission among these men. The findings underscore the importance of screening HIV-infected MSM for HCV, particularly those engaged in high-risk sexual behavior.
For this study, a case-patient was defined as an HIV-infected MSM examined at Mount Sinai during October 2005 - December 2010 who had 1) a newly elevated alanine transferase (ALT) level, 2) a newly positive HCV-antibody test result, and 3) no other evident cause of the newly elevated ALT level. To the extent possible, positive HCV-antibody results were confirmed by HCV RNA testing. If no record was found of a previous negative HCV-antibody test, a finding of jaundice or an ALT elevation of more than 15-fold above the upper limit of normal (i.e., >450 U/L) also was required. To assess whether patients might have had a previous positive HCV test result unknown to the referring physicians, the date of the first positive HCV-antibody test of a subset of patients (24 men) was confirmed by the New York City Department of Health and Mental Hygiene through review of the hepatitis registry of HCV surveillance data. Providers of primary care to HIV-infected MSM in New York City (who, as part of care, routinely obtain ALT levels on their patients during HIV monitoring visits) were contacted by the lead investigator and asked to refer patients with newly elevated ALT levels to Mount Sinai as soon as possible. Reminders were provided periodically throughout the study period. A total of 35 HIV-care providers contributed information on their patients to this study.
During October 2005 - December 2010, Mount Sinai evaluated 74 HIV-infected MSM who reported no injection-drug use and had newly elevated ALT levels and a positive HCV antibody test result; 73 of 74 also had documented HCV viremia. Median age of the 74 patients was 39 years; 41 were non-Hispanic white, 14 non-Hispanic black, 18 Hispanic, and one Asian (Table 1). Median CD4+ cell count for the patients was 483 cells/µL (range: 66-1,258 cells/µL). Sixty patients (81%) were asymptomatic, and new HCV infection was detected solely because of new ALT elevation; 14 (19%) had jaundice at presentation. Median peak ALT level was 665 U/L (range: 72-5,291 U/L). No other cause for the patients' elevated ALT levels was found (e.g., no new infection with hepatitis A or B virus and no new drug therapy). Of the 74 patients, 65 (91%) had a previous negative HCV-antibody test result before detection of hepatitis (median: 12 months; range: 0-110 months).
To assess the role of sexual transmission of HCV, a matched case-control study was conducted beginning in July 2007. HIV-infected MSM examined at Mount Sinai during July 2007-December 2010 who were within 12 months of clinical onset of HCV infection and who reported no injection-drug use were recruited as case-patients. For each case-patient, 1-10 controls (i.e., HIV-infected MSM who did not have HCV infection, reported no injection-drug use, and matched by age [±5 years] and race/ethnicity) were recruited by Mount Sinai staff members from among the practices that referred case-patients during the enrollment period. In all, 22 case-patients and 53 control subjects were enrolled in the study.
All participants were asked to complete self-administered questionnaires regarding their sexual practices and drug-use behaviors during the 12 months preceding diagnosis (for case-patients) or preceding the questionnaire (for matched controls). To conduct a matched analysis, a conditional logistic regression of each variable (i.e., sexual practice or drug use behavior) was performed. Those variables that had a p value of ≤0.20 in the univariable analysis, as well as those previously associated with sexual transmission,3 were entered into a model and analyzed using multivariable conditional logistic regression (i.e., forward, backward, and stepwise) to determine which variables were independently associated with HCV infection.
Univariable analyses indicated that the HIV-infected MSM newly infected with HCV (case-patients) were significantly more likely than the HIV-infected MSM without HCV infection (matched controls) to have had receptive (matched odds ratio [mOR] = 24.87) or insertive (mOR = 2.62) anal intercourse with no condom and with ejaculation, practiced receptive (mOR = 10.08) or insertive (mOR = 7.90) fisting, used sex toys (mOR = 4.38), engaged in group sex (mOR = 19.28), engaged in sex while high on drugs (mOR = 11.37), previously had syphilis (mOR = 8.80) or gonorrhea (mOR = 5.02), and had sex while high on methamphetamine (mOR = 26.80) (Table 2). Because three variables (receptive anal intercourse, no condom, no ejaculation; sex while high on gamma hydroxybutyrate [GHB]; and sex while high on ketamine) yielded undefined ORs, the data were analyzed further using exact conditional logistic regression. Results showed that case-patients were significantly more likely than controls to report receptive anal intercourse with no condom and no ejaculation (mOR = 24.26) and sex while high on GHB (mOR = 16.34).
Results from the multivariable analyses showed that receptive anal intercourse with no condom and with ejaculation of the partner (adjusted odds ratio [AOR] = 23.00) and sex while high on methamphetamine (AOR = 28.56) were both significantly related to acquiring HCV infection. Of all the practices and behaviors, having sex while using methamphetamine was most strongly associated with HCV infection (Table 2).
Polymerase chain reaction and sequencing of a 470 base-pair region of NS5B from HCV strains recovered from 50 of the 74 men were conducted using methods described previously.4 Forty-seven of the 50 were genotype 1a, and three were genotype 1b. A maximum-likelihood phylogenetic tree was then created.5* These analyses identified five clusters of closely related HCV variants from 26 (55%) of the 47 men with genotype 1a infections.
Reported by: Daniel S. Fierer, M.D., Stephanie H. Factor, M.D., Alison J. Uriel, M.B.B.S., Damaris C. Carriero, M.S., Douglas T. Dieterich, M.D., Michael P. Mullen, M.D., Arielle Klepper, Wouter van Seggelen, M.Sc., Kathryn Childs, M.B.B.S., Andrea D. Branch, Ph.D., Dept of Medicine, Mount Sinai School of Medicine, New York, New York. Deborah Holtzman, Ph.D., John W. Ward, M.D., Yury Khudyakov, Ph.D., Scott D. Holmberg, M.D., Div of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC. Corresponding contributor: Deborah Holtzman, email@example.com, 404-718-8555.
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