Impact of HIV infection and Kaposi sarcoma on human herpesvirus-8 mucosal replication and dissemination in Uganda

Abstract

Introduction: Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.

Methods: Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).

Results: 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7-6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7-9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0-2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8-5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs).

Conclusions: HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.

Figure 1. Enrollment and follow-up of participants in HHV-8 replication study.

Figure 2. Correlation between HHV-8 detection in participant- and clinician- collected oral swabs.

The quantity of HHV-8 DNA detected in oral swabs collected at home by participants was compared to those collected in clinic by trained clinicians. R = Spearman correlation coefficient.

Figure 3. Proportion of participants with HHV-8 detected, by anatomic site and HIV and KS status.

Percentage of participants with HHV-8 detected from oral swabs, genital swabs, or plasma samples. Participants collected a median of 29 oral swabs, 4 genital swabs, and 5 plasma samples. *p<0.05 for the comparison of the proportion of KS positive to KS negative participants with detectable HHV-8, using chi-square test.

Figure 4. Rate of HHV-8 detection from oral swabs and plasma samples in individual participants, by HIV and KS status.

Participants are numbered in ascending order according to oral shedding rate in each group. The participants collected a median of 29 oral swabs, 4 genital swabs, and 5 plasma samples per person.