Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy

Abstract

Background Human herpesvirus 8 (HHV-8) replication increases the risk of Kaposi sarcoma (KS). Highly-active antiretroviral therapy (HAART) reduces the incidence of KS, and regimens that contain protease inhibitors (PIs) may be particularly effective. Objective To determine whether PI-based HAART regimens may more effectively inhibit HHV-8 shedding compared to regimens without PIs. Study design Prospective, observational study of 142 HIV-1 and HHV-8 co-infected men conducted in Seattle, Washington. Quantitative HHV-8 PCR testing was performed on daily swabs of the oropharynx, the primary site of HHV-8 replication. Associations between antiretroviral regimen and detection of HHV-8 DNA in swabs were evaluated using generalized estimating equations. Results HHV-8 DNA was detected in 3,016 (26%) of 11,608 specimens collected. PI-based HAART was associated with a statistically significantly lower frequency of detection (RR 0.2; 95% CI 0.1 to 0.5) compared to ART-naïve persons, whereas HAART without a PI was not (RR 0.7; 95% CI 0.4 to 1.3). Compared to ART-naïve persons, there was also a trend toward lower quantities of HHV-8 detected during treatment with HAART regimens that contained a PI. These associations between PIs and measures of HHV-8 shedding could not be attributed to use of nelfinavir, which inhibits HHV-8 replication in vitro, and were independent of CD4 count and HIV plasma viral load (VL). Conclusions HAART regimens that contain PIs appear to decrease HHV-8 shedding compared to NNRTIs. Further study of PI-based HAART is warranted to determine the optimal regimens for prevention and treatment of KS.

Diagnosis and Treatment of Kaposi Sarcoma

“…There are several studies that suggest that HIV protease inhibitors, and in particular nelfinavir, have direct anti-KS activity in addition to their anti-retroviral therapy [88, 92–94]. There are also reports that fail to see a clinical benefit in KS comparing non-protease inhibitor containing regimen to protease inhibitor containing regimen [95].…”

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…This suggests that only a fraction of exposures leads to establishment of latency and eventual disease. Systemically circulating and salivary levels of KSHV in asymptomatic persons are orders of magnitude lower than those of EBV, herpes simplex virus, or human CMV (13,14,200). Evidence of KSHV superinfection in immune-competent persons is limited.…”

“…The majority of primary KSHV infections have no clinical symptoms and, as with other human oncogenic viruses, cancer emerges only after decades of dormancy. KSHV can be transmitted via asymptomatic oral shedding as well as through bodily fluids (12)(13)(14). KSHV can infect many different types of cells including endothelial cells, B lymphocytes, monocytes, dendritic cells (DCs), and epithelial cells.…”

Evolving Paradigms in HIV Malignancies: Review of Ongoing Clinical Trials

“…AMC-098 is studying nelfinavir, an early-generation HIV protease inhibitor once abandoned for its off-target effects, and more recently found to directly inhibit KSHV replication in vitro and in vivo (NCT03077451). 21–23 This trial uses higher-than- standard nelfinavir dosing to parlay the well-known “off-target” effects on NFκ, VEGF, HIF-1-α, and PI3K/Akt pathways. A Mexican government–sponsored study is evaluating the impact of 4 weeks of valganciclovir on KICS in ART- and treatment-naïve persons with limited KS (NCT03296553).…”