# Presentation: 849377

## 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 

- Subsets of donors or potential donors with an elevated prevalence of the pathogen
- Assays and assay development
- Risk of transmission
- 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 |  |  |
| --- | --- | --- | --- | --- |
| Reference |  | HIV-negative MSM | Blood 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- women |  |  | Blood 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 KS | 80%-100% |
| HIV-positive MSM | 40%-60% |
| HIV-negative MSM | 10%-20% |
| HIV-negative IV drug users or STD clinic attendees | 5%-20% |
| Blood donors | 1%-5% |

## HHV-8 Seroprevalence in Blood Donors†

| Lab | Positive KS controls (%) (n=40) | Positive blood donors (%) (n=1000) |
| --- | --- | --- |
| D | 40 (100) | 5 (0.5) |
| B | 39 (100)* | 17 (1.7) |
| A | 40 (100) | 24 (2.4) |
| C | 40 (100) | 27 (2.7) |
| F | 40 (100) | 37 (3.7) |
| E | 40 (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)* |
| --- | --- | --- | --- |
|   0 | 205‡ | 1 (0.5) | 1 |
|   1-5 | 133 | 30 (23) | 29.8 (3.9-226.5) |
|   6-10 | 80 | 22 (28) | 29.0 (3.7-228.2) |
|   11-50 | 230 | 94 (41) | 46.5 (6.2-351.6) |
|   51-100 | 73 | 34 (47) | 59.5 (7.6-467.2) |
|   101-250 | 40 | 24 (60) | 96.6 (11.4-820.4) |
|   >250 | 26 | 17 (65) | 105.6 (12.5-895.5) |
| *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)* |
| --- | --- | --- | --- |
| Never | 523 | 67 (12.8) | 1 |
| Never during study | 345 | 58 (16.8) | 1.3 (0.9-2.0) |
| Sometimes during study | 294 | 50 (17.0) | 1.3 (0.8-2.0) |
| Every visit, not daily | 104 | 23 (22.1) | 1.8 (1.0-3.2) |
| Every visit, daily | 28 | 10 (35.7) | 3.2 (1.4-7.6) |
| *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 |  |  |  |
|   0-5 | 129 | 13 (10.1) | 1 |
|   >50 | 49 | 9 (18.4) | 2.0 (0.8-5.1) |
| Commercial sex |  |  |  |
|   No | 311 | 30 (9.6) | 1 |
|   Yes | 160 | 30 (18.8) | 2.2 (1.3-3.7) |
| Syphilis |  |  |  |
|   Seronegative | 479 | 56 (11.7) | 1 |
|   Seropositive | 44 | 11 (25.0) | 2.5 (1.2-5.3) |
| *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

- HHV-8 is an example of an emerging pathogen that can be found in persons negative for HIV, HBV, and HCV.
- Screening tests for emerging pathogens need to be developed and approved.
- Precise risk of transmission needs to be estimated.
- 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, 266:1865-9
- Simpson et al., *Lancet* 1996, 348:1133-8
- Lennette et al., *Lancet* 1996, 348:858-61
- Blackbourn et al., *J Infect Dis* 1997, 179:237-9
- Martin et al., *N Engl J Med* 1998, 338:948-54
- Cannon et al., *N Engl J Med* 2001, 344:637-643
- Tabet et al., *AIDS* 1998, 12:2041-8
- Ndimbie et al., *Clin Diagn Lab Immunol* 1995, 2:219-24
- 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

## References (2)

- Chatlynne et al., *Blood* 1998, 92:53-58
- Pau et al., *J Clin Microbiol* 1998, 36:1574-1577
- Zhu et al., *Virology* 1999, 256:381-92
- Pellett et al., *J Clin Microbiol* 1999, 37:1298-1301
- Pauk et al., *N Engl J Med* 2000, 343:1369-77
- Biggar et al., *J Natl Cancer Inst* 1984, 73:89-94
- Penn, *Transplantation* 1997, 64:669-73
- Jones et al., *MMWR CDC Surveill Summ* 1999, 48(SS-2):1-22
- Rezza et al., *Int J Cancer* 1998, 77:361-5
- Jacobson et al., *J Infect Dis* 2000, 181, 1940-9