Human Herpesvirus 8 (HHV-8) as an Emerging Pathogen: Relevance to Semen Donation Michael J. Cannon, Ph.D. Centers for Disease Control and Prevention

Issues Relevant to Emerging Pathogens and Donation Deferral Policies 1.Subsets of donors or potential donors with an elevated prevalence of the pathogen 2.Assays and assay development 3.Risk of transmission 4.Disease burden attributable to donation-related transmission

Human Herpesvirus 8 (HHV-8) Discovered in 1994 (Chang et al., 1994) Enveloped DNA virus Closest human herpesvirus relative is Epstein- Barr virus Strong evidence that HHV-8 has a causal role in: –Kaposi’s sarcoma (KS) –Primary effusion lymphomas –Multicentric Castleman’s disease

HHV-8 Seroprevalence in Selected Populations vs. Blood Donors/US Population HHV-8 seroprevalence ReferenceHIV-negative MSMBlood donors/US pop. Simpson et al. (1996)12%0% Lennette et al. (1996); Blackbourn et al. (1999) 43%20% Martin et al. (1998)17%0% HIV-, HBV-, HCV- womenBlood donors Cannon et al. (2001)10%*3% *Data not shown in article

Issue 1—Population Subsets at Risk HHV-8 is more common in HIV-negative MSM than in blood donors/US population. There are no data on HHV-8 prevalence in MSM who are negative for HIV, HBV, and HCV. However, many HIV-negative MSM are also negative for pathogens such as HBV and HCV (Tabet et al., 1998; Ndimbie et al., 1995). Thus, testing for HIV, HBV, and HCV may not eliminate all MSM donors who are positive for HHV-8.

HHV-8 Serologic Assays Latent antigens targeted –Major latent nuclear antigen encoded by open reading frame 73 Lytic antigens targeted –Virion glycoprotein encoded by open reading frame K8.1 –Capsid protein encoded by open reading frame 65 Assay formats –Immunofluorescence assays (IFA) (Gao et al., 1996; Lennette et al., 1996; Smith et al., 1997; Whitby et al., 1998) –Enzyme immunoassays (EIA) (Simpson et al.,1996; Chatlynne et al., 1998; Pau et al., 1998) –Immunoblot assays (Zhu et al., 1999) No FDA-approved assays

HHV-8 Seroprevalence in Different Population Groups in the US Population group Prevalence of HHV-8 antibody Persons with KS80%-100% HIV-positive MSM40%-60% HIV-negative MSM10%-20% HIV-negative IV drug users or STD clinic attendees 5%-20% Blood donors1%-5%

HHV-8 Seroprevalence in Blood Donors † LabPositive KS controls (%) (n=40) Positive blood donors (%) (n=1000) D40 (100)5 (0.5) B39 (100)*17 (1.7) A40 (100)24 (2.4) C40 (100)27 (2.7) F40 (100)37 (3.7) E40 (100)51 (5.1) * Tested only 39 of 40 controls. † Pellett et al., unpublished data

Issue 2—Screening Tests PCR detection of HHV-8 DNA is not a sensitive testing method. HHV-8 serological assays are: –Adequate for epidemiologic studies –Not sufficiently reliable for individual testing in low prevalence populations HHV-8 serologic assays need to be improved and FDA approved.

HHV-8 Transmission In the US, having multiple male homosexual partners carries the highest transmission risk. Some transmission may occur via heterosexual sex and needle sharing. In Africa, there is evidence that HHV-8 is transmitted via close, non-sexual contact. Low HHV-8 seroprevalence in healthy persons suggests that transmission via close, non-sexual contact is rare in the US.

Relationship between Male Sex Partners and HHV-8 Seroprevalence † No. of male sex partners in previous 2 yrs. No. of men No. HHV-8 pos. (%) Multivariate OR (95% CI)* 0205‡1 (0.5) (23)29.8 ( ) (28)29.0 ( ) (41)46.5 ( ) (47)59.5 ( ) (60)96.6 ( ) > (65)105.6 ( ) *Adjusting for HIV infection, needle sharing, transfusion history, CD4 count. ‡95% were exclusively heterosexual. † Martin et al., 1998

HHV-8 Transmission via Injection Drug Use † Injection drug use No. of women No. HHV-8 pos. (%) Multivariate OR (95% CI)* Never52367 (12.8)1 Never during study34558 (16.8)1.3 ( ) Sometimes during study29450 (17.0)1.3 ( ) Every visit, not daily10423 (22.1)1.8 ( ) Every visit, daily2810 (35.7)3.2 ( ) *Adjusting for race/ethnicity, study site, education, HIV infection, syphilis infection. † Cannon et al., 2001

HHV-8 Transmission via Heterosexual Sex † Variable No. of women* No. HHV-8 pos. (%) Univariate OR (95% CI) Lifetime male sex partners (10.1)1 >50499 (18.4)2.0 ( ) Commercial sex No31130 (9.6)1 Yes16030 (18.8)2.2 ( ) Syphilis Seronegative47956 (11.7)1 Seropositive4411 (25.0)2.5 ( ) *These women did not use injection drugs. † Cannon et al., 2001

Prevalence of HHV-8 DNA in US Studies

Issue 3—Transmission Risk In the US the highest risk for HHV-8 transmission is through intimate contact with male homosexual sex partners. However, HHV-8 is not commonly found in semen. There are no studies measuring risk of HHV-8 transmission via semen donation. HHV-8 transmission via donated semen is probably rare but the precise risk is unknown.

Estimated Annual Risk of Developing KS 1 in 1,000,000 in healthy persons (Biggar et al.,1984) 1 in 80 in organ transplant recipients (Penn, 1997) 1 in 50 in persons with HIV (Jones et al., 1999) 1 in 20 in persons seropositive for both HIV and HHV-8 (Martin et al., 1998; Rezza et al., 1998; Jacobson et al., 2000).

Issue 4—HHV-8 Disease Burden HHV-8 is uncommon in semen. Even if a person becomes infected with HHV-8, additional factors (usually immunosuppression) are required for disease to occur. Thus, the burden of disease associated with semen-donation acquired HHV-8 is probably very low. However, the precise burden is unknown.

HHV-8 Dichotomies HHV-8 is more common in HIV-negative MSM than in others. However, HIV-negative MSM donors could not be screened for HHV-8 because there is no FDA-approved test. HHV-8 is transmitted through intimate contact between male homosexual sex partners. However, HHV-8 is rarely detected in semen. The risk of disease caused by semen donation-acquired HHV- 8 is probably very low. However, the precise risk is unknown, and with blood donation, considerable dollars and effort are spent to lower the already low risks due to HIV, HCV, etc.

Conclusions 1.HHV-8 is an example of an emerging pathogen that can be found in persons negative for HIV, HBV, and HCV. 2.Screening tests for emerging pathogens need to be developed and approved. 3.Precise risk of transmission needs to be estimated. 4.Disease burden attributable to the practice in question needs to be estimated. If steps 2-4 are in place, a scale will exist upon which we can weigh the risks and benefits of different courses of action.

References Chang et al., Science 1994, 266: Simpson et al., Lancet 1996, 348: Lennette et al., Lancet 1996, 348: Blackbourn et al., J Infect Dis 1997, 179:237-9 Martin et al., N Engl J Med 1998, 338: Cannon et al., N Engl J Med 2001, 344: Tabet et al., AIDS 1998, 12: Ndimbie et al., Clin Diagn Lab Immunol 1995, 2: Gao et al., Nat Med 1996, 2:925-8 Smith et al., J Infect Dis 1997, 176:84-93 Whitby et al., J Natl Cancer Inst 1998, 90:395-7

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