Factors affecting Kaposi's sarcoma-associated herpesvirus transmission in rural Ugandan households, a longitudinal study

Abstract

Background: We report the impact of HIV infection within a household on oral Kaposi's sarcoma-associated herpesvirus (KSHV) shedding.

Methods: We enrolled 469 individuals from 90 households. Mouthwash rinse samples collected at three monthly visits, were analyzed for KSHV DNA using quantitative polymerase chain reaction (qPCR). Generalized linear mixed effects logistic models were applied to analyze factors associated with KSHV ever shedding, and among shedders, always versus intermittent shedding. Linear mixed effects models were applied to models of KSHV viral loads. Intraclass correlation coefficients (ICCs) were calculated to assess the contribution of household-level factors to variations in shedding probabilities. Hotspot analyses of geospatial feature clusters were calculated using Getis-Ord Gi* statistic and visualized using inverse distance weighted interpolation.

Results: Analyses included 340 KSHV seropositive individuals, aged 3 + years, with qPCR results from 89 households. Forty households had 1 + persons living with HIV (PLWH), while 49 had none. Among participants, 149(44%) were KSHV ever shedders. Of 140 who shed KSHV at two or more visits, 34(24%) were always shedders. Increasing number of KSHV seropositive household members was significantly associated with ever shedding [Odds ratio(OR) (95% Confidence Interval(95%CI)):1.14(1.03,1.26);p = 0.013]. Among KSHV shedders, a statistically significant age-related trend was identified with 10-19 years being more likely to be always shedders (type III test p = 0.039) and to have higher viral loads (type III test p = 0.027). In addition, higher viral loads were significantly associated with increasing number of household members [coefficient(95%CI):0.06(0.01,0.12);p = 0.042], increasing number of KSHV seropositive members [coefficient(95%CI):0.08(0.01,0.15);p = 0.021], and living in households with 1 + PLWH [coefficient(95%CI):0.51(0.04,0.98);p = 0.033]. Always shedders exhibited higher viral loads than intermittent shedders [coefficient(95%CI):1.62(1.19,2.05);p < 0.001], and viral loads increased with the number of visits where KSHV DNA was detected in saliva (type III test p < 0.001). Household-level factors attributed for 19% of the variability in KSHV shedding (ICC:0.191;p = 0.010). Geospatial analysis indicated overlapping hotspots of households with more KSHV seropositive individuals and KSHV shedders, distinct from areas where PLWH were clustered.

Discussion: KSHV oral shedding is influenced by multiple factors at the individual, household, and regional levels. To mitigate ongoing KSHV transmission a comprehensive understanding of factors contributing to oral KSHV reactivation and transmission within households is needed.

Keywords: HHV-8; HIV; Household cohort; KSHV; Kaposi’s sarcoma-associated herpesvirus; Longitudinal Follow-up; Saliva; Shedding; Transmission; sub-Saharan Africa.

Figure 1. Geospatial Distribution of Households.

A) Number of individuals per household B) Number of PLWH per household; C) Number of KSHV seropositive individuals per household; D) Number of KSHV shedders per household; E) Number of KSHV shedders who always had KSHV detected in saliva per household (always shedders); F) Number of KSHV shedders who had at least one visit with and one visit without KSHV detected in saliva per household (intermittent shedders); G) Proportion of a household who are KSHV seropositive; H) Proportion of shedders among KSHV seropositive individuals tested in a household; I) Proportion of household shedders who were always shedders.

Figure 2. Hotspot analysis of HIV, KSHV seropositivity, and KSHV shedding by geographic location.

Filled circles represent statistically significant hotspots and coldspots. From Left to Right: A) Number of individuals per household; B) Number of PLWH per household; C) Number of KSHV seropositive individuals per household; D) Number of KSHV shedders per household; E) Number of KSHV shedders who always had KSHV detected in saliva per household.