A correlation analysis of HHV infection and its predictive factors in an HIV‐seropositive population in Yunnan, China

Abstract Human herpesviruses (HHVs) have a particularly high prevalence in certain high‐risk populations and cause increased morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). Screening and treating subclinical HHV infections reduce human immunodeficiency virus (HIV) infection incidence, disease progression, and transmission. However, there are few studies on HHVs, HIV coinfection rates, and their related risk factors. We aimed to clarify the prevalence of all eight HHVs in peripheral blood samples collected from HIV‐positive patients, and explore the association of HHV infection in HIV‐positive patients in an HIV‐seropositive population in Yunnan. We recruited 121 HIV‐positive patients with highly active antiretroviral therapy (HAART) and 45 healthy individuals. All the eight HHVs were detected using polymerase chain reaction and their epidemiological information and clinical data were collected and statistically analyzed. A high prevalence of HHVs (89.3%) was observed in individuals with HIV infections and with herpes simplex virus (HSV)‐2 (65.3%), and HSV‐1 (59.5%) being the most common. Coinfection with more than two different HHVs was more common in patients with HIV infections receiving HAART (72.7%) than in healthy controls. Older age, being married, higher HIV‐1 plasma viral loads, and use of antiviral protease inhibitors were independently correlated with an increased frequency of HHVs, but we found no association with CD4 count, WHO HIV clinical stage, and HIV infection duration. Our findings are of great significance for the prevention of HHV opportunistic infection in patients with AIDS and their clinical treatment.

immunodeficiency syndrome (AIDS). 1 HIV infection is becoming a global health issue due to high morbidity and mortality, and comparatively the situation may be worse in Yunnan. By the end of 2016, approximately 93 437 people were estimated to be living with HIV in Yunnan. This province has been considered the epicenter of HIV-1 in China, and was the first to conduct highly active antiretroviral therapy (HARRT) in China. 2 The course of infection of HIV-1 is characterized by a long interval between initial infection and the onset of serious symptoms as T cell numbers are gradually reduced. HIV infection is associated with an increased risk for human herpesviruses (HHVs) and related diseases, such as AIDS-associated oral lymphoma and oral hairy leukoplakia. 3 HHVs belong to the Herpesviridae family and are widely distributed viruses that cause benign and malignant disease in animals and humans. They are ubiquitous and have a particularly high prevalence in certain high-risk populations, causing increased morbidity and mortality in patients with AIDS. 4  Normal host immune response may control and limit HHV replication, but reactivation of latent infection can result in severe opportunistic infections with high morbidity and mortality in immunocompromised subjects. 7,8 Furthermore, some HHVs might interact with HIV-1 or have a role as a cofactor for HIV-1 progression, accelerating the replication of HIV-1. 9 At the same time, HIV-1 can facilitate acquisition and reactivation of HHVs as HIV-1 and HHVs are involved in a vicious cycle. 10 Prevalence rates and viral loads are influenced by the biological properties of the virus, method of detection, frequency of sampling, whether symptomatic or not, social behaviors, and immunological status of the patient. 11 Detection using polymerase chain reaction (PCR) assay shows that the frequencies of these viruses are wide-ranging across a variety of clinical samples [12][13][14] and are influenced by the degree of immunodepression, 15

| Epidemiological information and clinical data
Data on the social-demographic characteristics of these participants as well as the informed consent to participate in this study were obtained from the enrolled participants during the face-to-face interview by the outpatient doctor. Clinical data were also collected from the hospital laboratory information system, including a blood biochemical analytical index and CD4 lymphocyte count.
The number of double and triple HHV infections were 33 and 30 in HIV-positive group, respectively, higher than a single infection.
Three cases were found to have six HHV infections (one was negative for VZV and EBV and two showed failure to detect VZV and HCMV).
Coinfection with multiple HHVs was more likely to occur in the HIV group than in the control group, especially coinfection with more than two different HHVs (P < .001), and this difference was found to be statistically significant. However, the control group was more likely to be coinfected with only one HHV (P < .01) ( Figure 1B). Age was the most relevant factor for single HHV infections in the HIV group and significant differences were observed for the risk of infection by HHV-1 (P < .001), HSV-2 (P = .049), HHV-6 (P < .01), and HHV-8 (P = .001) at different age stages ( Table 1). The infection rates among those older than 31 years were especially higher than among others. Marital status was another leading risk for HHV; infections

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The prevalence of HHVs was higher in the peripheral blood of HIV-positive individuals than in that of the control group. This finding is in accordance with those of other studies, likely because of the high sensitivity of our PCR assay. 21 The eight HHVs except VZV were more prevalent in HIV-positive patients than in the control group. The consequences of universal access to HAART include a reduction in the number of deaths by AIDS and a reduction of the incidence of opportunistic diseases. 28 However, in this study, HHV incidence appeared to persist at a higher frequency. Regarding the impact of current HAART regimens for HHV infections, we can conclude that patients treated with PIs instead of NNRTIs were at the highest risk of HHV-6 infection. As a second-line treatment, PIs instead of NNRTIs have been included in the HAART regimen for patients with side effects or drug resistance. 29 These findings suggest that no single type of therapy is likely to reduce reactivation rates among all classes of herpesviruses. 25