key: cord-0783831-jm7c0joa
authors: Liu, Jia; Zeng, Wenjuan; Cao, Yukun; Cui, Yue; Li, Yumin; Yao, Sheng; Alwalid, Osamah; Yang, Fan; Fan, Yanqing; Shi, Heshui
title: Effect of a Previous History of Antiretroviral Treatment on Clinical Picture of Patients with Co-infection of SARS-CoV-2 and HIV: A Preliminary Study
date: 2020-08-20
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.08.045
sha: 5a79c608b815d06636d0f9d0f3bef0df3625db23
doc_id: 783831
cord_uid: jm7c0joa

OBJECTIVES: We aimed to explore the effect of antiretroviral treatment (ART) history on clinical characteristics of patients with co-infection of SARS-CoV-2 and HIV. METHODS: We retrospectively reviewed 20 patients with laboratory-confirmed co-infection of SARS-CoV-2 and HIV in a designated hospital. Patients were divided into medicine group (n = 12) and non-medicine group (n = 8) according to previous ART history before SARS-CoV-2 infection. RESULTS: The median age was 46.5 years and 15 (75%) were female. Ten patients had initial negative RT-PCR on admission, 5 of which had normal CT appearance and 4 were asymptomatic. Lymphocytes were low in 9 patients (45%), CD4 cell count and CD4/CD8 were low in all patients. The predominant CT features in 19 patients were multiple (42%) ground-glass opacities (58%) and consolidations (32%). Erythrocyte sedimentation rate (ESR) in the medicine group was significantly lower than that in the non-medicine group [median (interquartile range, IQR):14.0 (10.0–34.0) vs. 51.0 (35.8–62.0), P = 0.005]. Nineteen patients (95%) were discharged with a median hospital stay of 30 days (IQR, 26–30). CONCLUSIONS: Most patients with SARS-CoV-2 and HIV co-infection exhibited mild to moderate symptoms. The milder extent of inflammatory response to SARS-CoV-2 infection might be associated with a previous history of ART in HIV-infected patients.

The outbreak of coronavirus disease 2019 was caused by a type of beta coronavirus , named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on February 11, 2020. The disease quickly spread across China and beyond. As of July 31, 2020, over 17.1 million confirmed cases including 668,910deaths were reported worldwide (World Health Organization, 2020a) . At helpful to the diagnosis.

The respiratory system is one of the most frequently affected organ systems in HIVinfected patients (Benito et al., 2020) . HIV patients with immunocompromised status seem to be more susceptible to viral infection than healthy individuals. Several reports on co-infection of SARS-CoV-2 and HIV have been published, therefore the public had some initial understanding about the clinical manifestation of this population (Blanco et al., 2012 , Gervasoni et al., 2020 , Harter et al., 2020 , Maggiolo et al., 2020 , Vizcarra et al., 2020 , Zhu et al.,2020 . It remains controversial whether HIV patients are at higher risk of severe disease or death (Gervasoni et al., 2020 , Maggiolo et al., 2020 .

The aim of this retrospective study was to report the clinical characteristics of a case series of HIV and SARS-CoV-2 co-infected patients in Wuhan, and to explore the effect of previous antiretroviral therapy (ART) before SARS-CoV-2 infection on clinical manifestation.

Between February 25, and April 4, 2020, we have retrospectively reviewed 20 patients with laboratory-confirmed co-infection of SARS-CoV-2 and HIV from Jinyintan hospital, a designated hospital specializing in infectious diseases. All patients included were diagnosed with COVID-19 according to the interim guidance from the World Health Organization and the guidelines for the diagnosis and treatment of COVID-19 (seventh edition) published by China National Health Commission (General Office of the National Health Committee of China, 2020a, World Health Organization, J o u r n a l P r e -p r o o f 2020b). The IgM and IgG antibodies against SARS-CoV-2 were also tested on admission. One patient with negative RT-PCR but positive IgM and IgG, as well as another patient with typical symptoms (fever and cough) lasting for 29 days and a positive IgG result were diagnosed according to the seventh edition of China National Health Commission guidelines.

Demographics and epidemiological data, symptoms and signs, laboratory results, medical treatment of HIV infection before admission, as well as COVID-19 treatment and outcome data were obtained from the electronic medical records of the patients.

The clinical endpoint in this study was death or discharge. The severity of the disease was classified into 2 categories (non-severe and severe) at the time of admission as used in a previous study published by China Medical Treatment Expert Group for COVID-19 . Patients were discharged from hospital once the results of RT-PCR tests for SARS-CoV-2 turned negative for two times (at least 24 hours apart) (General Office of the National Health Committee of China, 2020a).

As for chest CT data, one 77-year-old severe patient underwent a chest CT scan in another hospital and died the day after admission, so we failed to obtain his CT data.

All remaining patients underwent non-contrast enhanced chest CT in Jinyintan hospital.

All images were analyzed independently by two chest radiologists (J.L and YK.C) with 5-7 years of experience, and final decisions were reached by consensus. The imaging analysis mainly focused on the lesion features of each patient, such as distribution pattern and important CT signs of COVID-19 pneumonia. The extent of lesion J o u r n a l P r e -p r o o f involvement was categorized as focal, multifocal, or diffuse. The location of the lesion was categorized as peripheral, central, or peripheral and central. We also quantified the CT images with a previously published method (Ooi et al., 2004) . We defined the evolution of lesions as an increase in size or density, and the improvement as decrease in lesion size or resorption of the ground-glass opacities and consolidation.

This was a retrospective, single-center case series study and no patients were involved in the study design. This study was approved by the institutional review board of Wuhan Jinyintan Hospital. All participants remained anonymous and written informed content was waived by the ethics commission for rapid emerging infectious diseases.

We presented the continuous measurements as median (interquartile range, IQR) and categorical variables as frequency (percentage). For laboratory results, we assessed whether the measurements were within or outside the normal range. According to the history of ART before SARS-CoV-2 infection, we have divided the patients into medicine group and non-medicine group. Laboratory results and radiologic features were compared between the two groups using Mann-Whitney U test for continuous variables and chi-squared test for categorical data. Here, we need to point out that when comparing radiologic features between two groups, the non-medicine group only contained 7 patients. The data were analyzed using IBM SPSS, version 22 (SPSS Inc, Chicago, IL) and GraphPad Prism version 7.00 (GraphPad Software, La Jolla).

Demographics, baseline characteristics, treatment and outcomes of the patients are shown in Table 1 . Twenty patients were included in the study with a median age of 46.5 (IQR, 39.3-50.5) and most cases were female (15 [75%]). Twelve of 20 patients were on ART at the time of COVID-19 diagnosis. Antiretroviral regimens included nucleoside reverse transcriptase inhibitors (NRTIs, n=12), protease inhibitors (PI, n=8) and Non-NRTIs (n=6). NRTIs were mainly lamivudine (n=12), tenofovir disoproxil fumarate (n=9) and zidovudine (n=2). PI was mainly kaletra (lopinavir/ritonavir) and

Non-NRTI was mainly efavirenz.

The clinical course of the patients as well as the results of IgM/IgG antibodies obtained on admission are shown in Figure 1 . On admission, the total seropositive rate for IgM and IgG was 20% (4/20) and 55% (11/20), respectively. Ten patients had initial negative RT-PCR on admission, of whom 8 patients showed positive results of RT-PCR four days later, 5 showed normal CT appearance, and 4 were asymptomatic cases. After admission, one severe patient, a 77-year-old male with several combined diseases (COPD, and alcoholic liver disease), died the day after admission due to septic shock and multiple organ failure. The rest of the patients all received antiviral treatment and ART after admission, and were discharged with a median hospital stay of 30 days (IQR, (26) (27) (28) (29) (30) . None of the patients were admitted to intensive care units (ICU).

Laboratory and radiologic findings are summarized in Table 2 and Table 3, respectively. On admission, leukocytes were below the normal range in five patients J o u r n a l P r e -p r o o f (25%). Lymphocytes were low in 9 patients (45%). Only one of the severe patients had high serum levels of myoglobin (786 ng/mL), procalcitonin (31.8 ng/mL) and highsensitivity C-reactive protein (hsCRP > 160.0 mg/L).

The mean interval from symptom onset to the first CT scan was 25.8 days (SD, 21.8). Of 19 patients with chest CT scans, 8 non-severe patients showed normal chest CT appearance of both lungs. As shown in Figure 2 , the predominant CT features were multiple [8 (42%)] ground-glass opacities [11 (58%)] and consolidations [6 (32%)].

Fibrotic streaks were seen in 5 patients (26%). Pleural effusion and enlarged lymph nodes were not present.

ESR in the medicine group was significantly lower than that in the non-medicine group (P = 0.005). hsCRP was also lower in the medicine group compared with that in the mon-medicine group [Median (IQR): 0.5 (0.2-1.3) vs. 2.1 (0.4-5.9)], but the difference was not statistically significant (P = 0.074). Other laboratory parameters and all CT features showed no statistical difference (P > 0.05) between the two groups.

Seventeen patients underwent several follow-up CT scans with a median of 2 times.

The median interval between the initial and second CT scans was 20 days (IQR, (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) .

Five patients (26%) showed improvement on the second CT scan, while 2 patients (11%) showed worsening (Figure 3 ). Eight patients with initial normal CT scan remained normal on the follow-up chest CT scans.

COVID-19 is a severe infectious disease with a capability of human-to-human J o u r n a l P r e -p r o o f transmission , Lu et al., 2020 , which caused a large number of deaths around the world. Patients included in our study were diagnosed using a combination of viral RNA RT-PCR and IgM/IgG antibody test according to the seventh edition of China National Health Commission guidelines for diagnosis and treatment of COVID-19 pneumonia (General Office of the National Health Committee of China, 2020a). As previously reported, the test of IgM/IgG antibodies against SARS-CoV-2 provides important immunological evidence and can be an effective supplementary indicator in diagnosing the suspected cases with no detectable viral RNA (Gao et al., 2020) .

In our study, some patients were tested negative for RT-PCR nucleic acid and IgM/IgG antibodies on admission, while the results of viral RNA test turned positive a few days later. Several reasons may contribute to this phenomenon. Firstly, some of the patients were initially isolated in the compartment hospital, and when admitted to Jinyintan hospital, they were at a stage with a low RNA positive rate, and a high IgM negative and IgG positive rate indicating a late stage of the infection. Secondly, some asymptomatic cases sought medical treatment in the early stage due to a history of close contact with infected patients, in whom temporal negative results may present because of a low viral load.

Our study showed that the predominant gender was female (75%), contradicting with the findings in previous studies (Gervasoni et al., 2020 , Harter et al., 2020 , Vizcarra et al., 2020 . Such a discrepancy may be due to the different risk behavior between study populations. As the priority was to initiate a timely treatment for COVID-19 patients, clinicians were not aware of the risk behavior concerning HIV J o u r n a l P r e -p r o o f infection. Most patients (75%) were infected by close contact with confirmed patients, which is reported to be the current main source of infection . The clinical characteristics in patients co-infected with SARS-CoV-2 and HIV are similar to those in the general population. Except for three severe cases, the rest of the patients (17/20) exhibited mild or moderate symptoms, with predominant presentation of cough and fever. Laboratory tests revealed low peripheral blood leukocytes (25%) and lymphocytes (45%) counts. This finding is consistent with previous studies , which suggests that COVID-19 mainly acts on lymphocytes, especially T lymphocytes. But the extent of lymphocytes decrease in our study (Mean, 1.3; SD, 0.6) was relatively small compared with a previous study published by China Medical Treatment Expert Group for COVID-19 (Median, 1.0; IQR, 0.7-1.3) .

In terms of radiologic findings, we summarized the features of 19 patients who underwent chest CT scans after admission. The predominant CT findings on the first scan were multifocal ground-glass opacities, which were linked to variable histopathologic changes, such as diffuse alveolar damage or interstitial inflammatory cell infiltration (Kanne et al., 2007) . Consolidation was also a typical finding in our case series, occasionally combined with air bronchogram. Fibrotic changes were shown in 5 patients, which is often seen as a form of chronic change during the remission stage.

Ying Xiong et al reported that most patients (83%) exhibited a progressive process on the follow-up CT scans (Xiong et al., 2020) . In our study, abnormal CT appearance in most of the patients remained unchanged or improved on the second scan. Normal CT J o u r n a l P r e -p r o o f appearance was seen in 8 patients, which accounted for nearly half of the patients.

Previous studies also reported cases with normal CT scans (Chung et al., 2020 , which may be related to the relatively weak immune response in HIV patients.

Besides, it suggests that we cannot reliably fully exclude cases by normal imaging studies. Patients showing initially negative for SARS-CoV-2 nucleic acid test can also have abnormal CT findings (Ai et al., 2020) . Given the sensitivity of chest CT, a clinical diagnostic standard based on typical CT characteristics was adopted in the revised 5th edition of the Guideline of Diagnosis and Treatment, which was only applicable in Hubei Province, China (General office of the National Health Committee of China, 2020b). Therefore, chest imaging still plays an important role in the diagnosis and assessment of the patient's condition.

In our study, ESR of patients who have received ART before SARS-CoV-2 infection was significantly lower than that of patients without ART (P = 0.005). Besides, hsCRP was also lower in patients with a previous history of ART than that in patients without ART history [Median (IQR): 0.5 (0.2-1.3) vs. 2.1 (0.4-5.9)], but the difference was not statistically significant (P = 0.074). Another important inflammatory marker;

Interleukin-6 (IL-6); showed no difference between the two groups. A previous study revealed that ART can reduce the systemic inflammation and immune activation in HIV patients (Hileman and Funderburg, 2017) . We propose that the inflammatory response The laboratory test results and radiologic findings both showed that most patients experienced mild illness. As reported, in immunocompromised population, the host response to the virus may be an important contributor to the disease process (D'Antiga., 2020). When infection occurrs in immunocompromised population who have some persistent immune activity, they may be protected by a weaker immune response against the pathogen. As a result, the evolution of SARS-CoV-2 infection may not progress to a severe cytokine storm in this population (Hileman and Funderburg, 2017) .

In the last two outbreaks of coronavirus (SARS and MERS), patients with immunocompromised status were not found to have an increased risk of severe pulmonary involvement, complications, or a poorer prognosis (Hui et al., 2018 , D'Antiga, 2020 . Another possibility of mild manifestation of symptoms, laboratory results and chest CT scans in our study could be related to the early admission and early intervention. Some asymptomatic patients sought medical advice once they were aware of a suspicious contact history. HIV patients might have a higher opportunity for being tested for SARS-CoV-2 infection even in mild or moderate cases, given that they are usually considered at high risk of infection, especially in an epidemic outbreak.

In our study, one severe patient (a 77-year-old male with several comorbidities) died the day after admission due to septic shock and multiple organ failure. Other 19 patients were discharged after corresponding treatment. Up to now, no specific drug has been J o u r n a l P r e -p r o o f confirmed effective for the treatment of patients with COVID-19. Due to the unique sample, except for one severe case which deceased after admission, all of the patients received ART during the hospitalization (they had their usual ART, and some of them modified the regimen to include lopinavir/ritonavir), therefore expecting both antiretroviral and anti-SARS-CoV-2 effects (Choy et al., 2020) . Our study showed low proportion of individuals with severe diseases (n=3) and ICU admission (n=0), which were lower than previous studies (Harter et al., 2020 , Vizcarra et al., 2020 . Vizcarra and colleagues pointed out that in HIV population, severe COVID-19 disease, ICU admission, low nadir CD4 cell counts, and comorbidities could help identify individuals with delayed viral clearance even after clinical improvement (Vizcarra et al., 2020) .

Current data suggest that the main mortality risk factors are still linked to older age and multimorbidity, not particularly to HIV (Mirzaei et al., 2020 , World Health Organization, 2020b .

Our study had some limitations. This single-center study was limited by its retrospective nature and small sample size. HIV viral load was not measured because of the great pressure on the medical supplies and staff regarding COVID-19 treatment at that time, and the dynamic changes of IgM/IgG antibodies during hospitalization was not evaluated due to the limited number of patients with multiple tests of antibodies.

In conclusion, compared with SARS-CoV-2 infected general population, patients with Financial support. This work was supported by Zhejiang University special scientific research fund for COVID-19 prevention and control, the HUST COVID-19 Rapid Response Call (grant number 2020kfyXGYJ019). The funders only provided funding and had no influence on the study design, data collection, analysis, or interpretation, the decision to publish, or preparation of the manuscript.

Ethics approval and consent to participate. This study was approved by the institutional review board of Wuhan Jinyintan Hospital. All participants remained anonymous and written informed content was waived by the ethics commission for 

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