key: cord-335038-q32ghvsv authors: Huang, Jiao; Xie, Nianhua; Hu, Xuejiao; Yan, Han; Ding, Jie; Liu, Pulin; Ma, Hongfei; Ruan, Lianguo; Li, Gang; He, Na; Wei, Sheng; Wang, Xia title: Epidemiological, virological and serological features of COVID-19 cases in people living with HIV in Wuhan City: A population-based cohort study date: 2020-08-17 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa1186 sha: doc_id: 335038 cord_uid: q32ghvsv BACKGROUND: We aimed to describe the epidemiological, virological and serological features of coronavirus disease 2019 (COVID-19) cases in people living with HIV (PLWH). METHODS: This population-based cohort study identified all COVID-19 cases among the whole PLWH in Wuhan city, China, by April 16, 2020. The epidemiological, virological and serological features were analyzed based on the demographic data, temporal profile of nucleic acid test for SARS-CoV-2 during the disease, and SARS-CoV-2-specific IgM and IgG after recovery. RESULTS: From January 1 to April 16, 2020, 35 of 6001 PLWH have experienced COVID-19, with the cumulative incidence of COVID-19 to be 0.58% (95%CI: 0.42%-0.81%). Among the COVID-19 cases, 15 (42.86%) had severe illness, with 2 deaths. The incidence, case-severity and case-fatality of COVID-19 in PLWH were comparable to that in the entire population in Wuhan. 197 persons had cART discontinuation, of whom 4 persons experienced COVID-19. Risk factors for COVID-19 were age ≥50 years old and cART discontinuation. The median duration of SARS-CoV-2 viral shedding among confirmed COVID-19 cases in PLWH was 30 (IQR: 20-46) days. Cases with high HIV viral load (≥20 copies/ml) had lower IgM and IgG levels than those with low HIV viral load (<20 copies/ml) (median S/CO for IgM, 0.03 vs. 0.11, P<0.001; median S/CO for IgG, 10.16 vs. 17.04, P=0.069). CONCLUSIONS: Efforts need to maintain the persistent supply of antiretroviral treatment to elderly PLWH aged 50 years or above during the COVID-19 epidemic. The coinfection of HIV and SARS-CoV-2 might change the progression and prognosis of COVID-19 patients in PLWH. Coronavirus disease 2019 (COVID-19) is an emerging infectious disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported in the latterly December 2019 in Wuhan, China [1] . According to the WHO status report, more than 16 million COVID-19 cases have been reported worldwide until July 30 [2] . has emerged as a great challenge to global public health. Since no vaccine and effective drugs are available against this infectious disease, non-pharmaceutical interventions were implemented to slow the spread and flatten the epidemic curve of COVID-19 [3] . Although governments and communities have been dedicated to maintaining HIV service provision for people living with HIV (PLWH), antiretroviral treatment for PLWH may be hindered by the COVID-19 epidemic [4] . Considering the large number of PLWH, it is urgent to evaluate whether the incidence of COVID-19 in PLWH differs from that in the general population. Cases with coinfection of SARS-CoV-2 and HIV have been reported in several countries [5] [6] [7] . But only one study calculated the COVID-19 incidence in PLWH based on HIV patients in a single hospital [8] . The population-based incidence of COVID-19 in PLWH needs to assess this population at risk of SARS-CoV-2 infection comprehensively. Previous studies have found that PLWH with low CD4 cell count, high HIV viral load and not taking antiretroviral treatment have an increased risk of other respiratory infections [9] . However, limited data were available for the risk of SARS-CoV-2 infection in PLWH. Several studies have demonstrated the antibody response to SARS-CoV-2 infection in the general population [10, 11] , which may inform vaccine intervention in the future. Nevertheless, there is no information currently on the antibody against SARS-CoV-2 infection in PLWH. Guidance has been proposed by US Department of Health and Human Services and EACS European AIDS Clinical Society to M a n u s c r i p t 5 provide information about the proper response to COVID-19 in PLWH [12, 13] . But guidance like these needs more evidence to refine their recommendation. In the present study, we performed a population-based cohort study to calculate the cumulative incidence of COVID-19 in PLWH from January 1 to in Wuhan city, China, and compared it with the entire population of Wuhan. Furthermore, we described the virological and serological features of COVID-19 cases in PLWH. All individuals in Wuhan who were tested positive for HIV have been reported to Wuhan Center for Disease Control (CDC) through the China National HIV/AIDS Comprehensive Response Information Management System (CRIMS) [14] . According to CRIMS requirement, a standardized form was used to collect HIV-positive persons' information, including basic demographic characteristics (gender, date of birth, education level), mode of HIV acquisition and baseline CD4 cell count and HIV viral load. The local CDC or designated hospital staff followed up them every year for their CD4 cell count and HIV viral load at least once [15] . HIV-positive persons who met the Chinese national treatment criteria were referred to the China National Free Antiretroviral Treatment Programme (NFATP) to receive combination antiretroviral therapy (cART) [16] . On December 31, 2019, 6001 PLWH resided in Wuhan city had been included in CRIMS. COVID-19 has been listed as a Class B infectious disease on January 20, 2020 in China [17] . All COVID-19 cases must be reported to the National Notifiable Infectious Disease Report System (NNIDRS) within 2 hours after diagnosed [18] . All COVID-19 cases A c c e p t e d M a n u s c r i p t 6 reported to NNIDRS in Wuhan have been rechecked and verified on April 16, 2020[19] . Therefore, the COVID-19 cases in PLWH were identified by linking the individual information from these two systems in Wuhan using the unique ID Number on April 17, 2020 . According to the national guideline, COVID-19 cases were categorized into confirmed cases, clinically diagnosed cases, suspected cases, and asymptomatic cases. And the severity status of COVID-19 cases was categorized as mild, moderate, severe, or critical. The details could be found elsewhere [3, 20] . In this study, COVID-19 cases with severe or critical illness were classified into severe cases group. Otherwise, they were classified into non-severe cases group. Among the 6001 PLWH, 474 (7.90%) persons were not on cART before Dec Demographic characteristics included gender, date of birth, education level, duration of HIV infection, mode of HIV acquisition, cART regimens and treatment status, CD4 cell count and HIV viral load at last routine medical visit within the previous 12 months were obtained from CRIMS. For COVID-19 cases, information including date of onset, date of diagnosis, date of death (if applicable) and case type and clinical severity were extracted from NNIDRS. We also collected temporal profiles of RT-PCR results for testing SARS-CoV-2 in each confirmed case. In addition, we obtained the COVID-19 incidence among the general population by the street where the PLWH's living address located to indicate their chance of infection by SARS-CoV-2. If the COVID-19 incidence among the general population for the street was ≤0.66% (median level of the COVID-19 incidence among all the streets in Wuhan), PLWH located in this street were classified as having low chance, otherwise, they were deemed to have high chance. Serum samples were taken from each alive COVID-19 cases in PLWH on May 18, 2020. SARS-CoV-2-specific IgM and IgG were detected by Magnetic Chemiluminescence Enzyme Immunoassay using commercial kits following the manufacturer's instructions, which have been described elsewhere [10, 22] . The antibody level was expressed as the chemiluminescence signal value divided by the cutoff value (S/CO). IgM or IgG was defined as positive if the S/CO value was higher than 1.0; otherwise, it was regarded to be negative. A c c e p t e d M a n u s c r i p t 8 The COVID-19 incidence was estimated assuming a Poisson distribution and described for the entire PLWH population and subgroups. We used Poisson regression to estimate incidence rate ratios (IRRs) to compare the COVID-19 incidence in subgroups of PLWH. Univariate and multivariate modified Poisson regressions with robust variance were used to evaluate the relationship between characteristics of PLWH with the COVID-19 occurrence [23] . Besides, we imputed the missing data on the basis of multivariable imputation and performed sensitivity analyses retaining all PLWH to explore the risk factors of COVID-19 among PLWH. We used the direct method to calculate the COVID-19 incidence standardized by age and gender for PLWH and to compare the difference in COVID-19 occurrence between PLWH and the general population in Wuhan. We derived standardization weight from the age and gender distribution of the general population of Wuhan in 2018. A similar method was used to calculate case-severity and case-fatality standardized by age and gender for PLWH, with the number of COVID-19 cases in different age groups obtained from the previous study as a standard [3] . All analyses were conducted using SAS statistical software version 9.4 (SAS Institute Inc) and R Project version 3.6.1 (http://cran.r-project.org). A two-sided p value of <0.05 was considered statistically significant. This study was reviewed and approved by the institutional review board of the Wuhan A c c e p t e d M a n u s c r i p t From January 1 to April 16, 2020, 35 (0.58%) PLWH had experienced COVID-19, including 22 (62.86%) confirmed cases, 11 (31.43%) clinical cases and 2 (5.71%) asymptomatic cases. The median age of PLWH (52, IQR: 36-57 years) for COVID-19 cases was higher than that for non-COVID-19 cases (37, IQR: 29-52 years, P=0.004). Most Table 1 ). The cumulative incidence of COVID-19 was 0.58% (95%CI: 0.42%-0.81%). There is no significant difference between the COVID-19 incidence for males (0.61%, 95%CI: 0.43%-0.86%) and females (0.35%, 95%CI: 0.09%-1.39%, P=0.444). COVID-19 incidence among PLWH aged ≥50 years was 1.18%, which was higher than that of PLWH below 50 years Table 2 ). The standardized rates of case-severity and case-fatality of COVID-19 in PLWH were also similar to that in the entire population in Wuhan (Table 2) . We included the 5004 (83.39%) persons with available data for HIV viral load to analyze the risk factors for COVID-19 in PLWH, with 984 (16.49%) and 3 (8.57%) PLWH exclude from non-COVID-19 and COVID-19 cases groups (Supplementary Figure 1) . The multivariate Poisson regression analysis showed positive associations between COVID-19 occurrence and older age and cART discontinuation after adjusting for other variables (Table 3 ). Compared to PLWH aged below 50 years with cART continuation, PLWH aged 50 years or above with cART discontinuation were at sharply increased risk for COVID-19 (adjusted IRR=16.86, 95%CI: 4.71-60.26) ( Table 4 ). The sensitivity analyses results using multivariable imputation of missing data were consistent with the above analyses retaining only patients with complete data (Supplementary Table 3 A c c e p t e d M a n u s c r i p t The temporal profile of RT-PCR results in 22 confirmed COVID-19 cases in PLWH was shown in Figure 2 . Table 7 ). In this cohort study, we reported the COVID-19 incidence among PLWH in Wuhan during the COVID-19 epidemic. The incidence, case-severity and case-fatality of COVID-19 in PLWH were comparable to that in the entire population in Wuhan. The COVID-19 incidence among PLWH aged 50 years or above was twice higher, compared to PLWH below 50 years. The median duration of viral shedding was 30 days for confirmed COVID-19 cases in PLWH. Higher antibody levels were observed in cases with high HIV viral load than those with low HIV viral load. Although several studies recently reported the COVID-19 cases in PLWH in hospitals, there are few population-based studies having focused on COVID-19 of PLWH. Our study showed that PLWH have similar risk of COVID-19 compared to that in the general population during COVID-19 epidemic. The incidence of COVID-19 among PLWH (0.58%) in Wuhan was lower than that in HIV-infected individuals (1.8%) in Madrid [8] . It may be one of the reasons that PLWH in Wuhan (mean age 40.7 years) were much younger than HIV-infected individuals in Madrid (mean age 53.5 years), since old age was found to be positively associated with COVID-19 in PLWH [24] . In spite of the different incidence, the age and case type were similar in the 35 COVID-19 cases (Wuhan, median age 52 years old, 63% confirmed cases) and 51 COVID-19 cases (Madrid, mean age 53.3 years old, 68% confirmed cases) from these two studies. The case-fatality of COVID-19 in PLWH varied 4%-28.6% in different studies [25] [26] [27] [28] , further systematic studies are needed to clarify the disparity. A c c e p t e d M a n u s c r i p t 13 Maintaining antiretroviral therapy during the COVID-19 epidemic is urgent for the health of PLWH, especially in elderly person. Out study firstly suggested that PLWH aged over 50 years with cART discontinuation had over ten times risk of SARS-CoV-2 infection than young PLWH with ART continuation. Similar findings from studies on the coinfection of HIV and tuberculosis demonstrated that antiretroviral therapy for HIV-positive adults could lower the incidence and mortality of people having coinfection of HIV and tuberculosis [29, 30] . Our findings provide the evidence to support the suggestion from NHH Interim Guidance for COVID-19 and Persons with HIV that the elderly persons with HIV are at the highest risk of COVID-19 [12] . Although the supply of antiretroviral drugs against HIV had been disrupted during the "lockdown period" in Wuhan, most of PLWH in Wuhan had antiretroviral drugs supply with the help of the CDC staffs and volunteers from the community based organizations (CBOs) during the COVID-19 epidemic. However, designed hospitals for HIV care services have been closed, which means PLWH may have not proper antiretroviral therapy without any timely examination. The challenge would have been the toughest if the COVID-19 epidemic duration lasts over three months. Therefore, it is critical to make a response policy and strategy to provide a timely ART treatment for PLWH during the COVID-19 epidemic. Our findings suggested that coinfection of HIV and SARS-CoV-2 may change the development and prognosis of COVID-19 in PLWH. The median interval from symptom onset to viral clearance of confirmed COVID-19 cases in PLWH was 30 days in this study, which was longer than that of COVID-19 cases without HIV infection (20 days) [31] . This indicates that COVID-19 cases in PLWH may have delayed viral clearance for SARS-CoV-2 because of immunosuppression, although clinical improvement of COVID-19 in PLWH was not worse than that of individuals without HIV infection as described in the present study and other published studies [25, 32] . Furthermore, our study found that the level of HIV viral load We thank all staff members at municipal and district Center for Disease Control and Prevention and designated hospital for data collection. We acknowledge all medical staff members and community volunteers who are working on the frontline of caring for patients and collecting the data. The views expressed in this study are those of the authors and do not represent the official position of Wuhan Center for Disease Control and Prevention. This work is funded by the Fundamental Research Funds for the Central Universities (2020kfyXGYJ066). All authors declare that they have no conflicts of interest. A c c e p t e d M a n u s c r i p t M a n u s c r i p t M a n u s c r i p t M a n u s c r i p t 25 M a n u s c r i p t 27 The boxplots indicate medians (middle line) and third and first quartiles (boxes), while the whiskers indicate 1.5× the interquartile range (IQR) above and below the box. 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NRTIs: Nucleoside reverse transcriptase inhibitors NNRTIs: Non-Nucleoside reverse transcriptase inhibitors; PIs: Protease Inhibitors; in this study, only Lopinavir/Ritonavir (LPV/r) was in this category of antiretroviral PLWH: people living with human immunodeficiency virus *according to the report from Wuhan Municipal Health Commission on Estimated based with the number of COVID-19 cases in different age and gender groups obtained from the published study as a standard 3 A c c e p t e d M a n u s c r i p t