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Letters to the Editor

The Unpredictable Outcome of SARS-CoV-2 in Kidney Transplant Recipients With HIV-infection

de Sandes-Freitas, Tainá Veras MD, PhD1,2; Cristelli, Marina Pontello MD, PhD3; Neri, Beatriz de Oliveira MD2; Guedes, Andreza Liara Machado de Oliveira MD2; Esmeraldo, Ronaldo de Matos MD2; Garcia, Valter Duro MD, PhD4; Dal Prá, Ronivan Luis PharmD4; Suassuna, José Hermógenes Rocco MD, PhD5; Rioja, Suzimar da Silveira MD, PhD5; Zanocco, Juliana Aparecida MD6; Claudino, Auro Buffani MD6; Medina-Pestana, José Osmar MD, PhD3,7; Tedesco-Silva, Hélio MD, PhD3,7

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doi: 10.1097/TP.0000000000003529
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To the Editor:

It remains unclear the clinical presentation and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in HIV-infected kidney transplant (KT) recipients receiving immunosuppressive drugs and highly active antiretroviral therapy (HAART). To date, there are only 2 reports, one in kidney and one in liver HIV-infected transplant recipients, both with favorable outcomes.1,2

Here, we report a series of 8 HIV-infected KT recipients who developed coronavirus 2019 (COVID-19), among 893 patients included in a national registry, from Mach 1 to July 17, 2020 (Clinical trials no.: 30631820.0.1001.8098).

Demographics, clinical, and laboratory characteristics, and outcomes are summarized in Table 1. All but one patient had comorbidities. All patients were receiving HAART, but one patient had detectable HIV viral load and 2 had <400 CD4 cells/µL. All patients were receiving calcineurin inhibitor-based immunosuppressive therapy. Six had a community-acquired and 2 nosocomial-acquired COVID-19 infections (#1 and #5), one of them (#1) during the hospitalization for kidney transplantation. The main clinical symptoms were fever and dyspnea. Ground-glass opacity was the main radiological finding. Two patients had lymphopenia (defined as lymphocytes count <1000 cells/m3). From the 6 patients with community COVID-19 acquisition, 5 required hospitalization. Patient management evolved over time based on current knowledge. Immunosuppression was withdrawn in five patients but HAART was unchanged. Four patients were admitted to the intensive care unit, received mechanical ventilation, and developed acute kidney injury requiring hemodialysis. Three of them died, all due to sepsis, and one lost the graft. Another patient without severe disease lost the graft secondary to nonimmune interstitial fibrosis/tubular atrophy.

TABLE 1. - Baseline demographic and clinical characteristics and COVID-19 outcomes
#1 #2 #3 #4 #5 #6 #7 #8
Gender, age (y) Male, 63 Female, 52 Male, 40 Male, 57 Male, 76 Male, 50 Female, 56 Male, 37
Comorbidities DM, HT DM, HT DM, HT DM, HT, HCV DM, HT, COPD, CAD PKD, HT, CAD DM, HT, CAD None
Donor type, date DD, Februaruy 20, 2020 DD, August 25, 2019 SKPT, February 8, 2013 DD, December 26, 2015 DD, June 02, 2016 LD, April 01, 2013 DD, October 14, 2015 LD, August 13, 1998
HAARTa DTG,3TC, DRV, RTV ABC, 3TC, DTG ABC, 3TC, DRV, RTV ABC, 3TC, DTG ABC, 3TC, DRV, RTV ABC, 3TC, EFV AB3, 3TC, DTG ABC, 3TC, DTG
HIV viral load (copies/mL)b Undetectable Undetectable Undetectable Undetectable Undetectable Undetectable Undetectable 223
CD4 (cells/µL)b 471 234 >500 699 272 400 NI 1172
COVID-19 treatment High-dose ST, HCQ, AZI, OSE, full-dose heparin AZI, OSE, prophylactic heparin, ATB HCQ, AZI, OSE, ATB NI ATB High-dose ST, prophylactic enoxaparin AZI, ATB Prophylactic heparin
IS regimena TAC-ST-MPS TAC-ST TAC-SRL TAC-ST-MPS TAC-MPS TAC-ST-MPS TAC-ST-AZA CsA-ST-MPS
IS changes Withdrawal Withdrawal Withdrawal Withdrawal None None Withdrawal None
Hospitalization NAc Yes Yes Yes NAf No Yes Yes
ICU Yes Yes No Yes No No Yes No
MV Yes Yes No Yes No No Yes No
Baseline SCr (mg/dL) 6.19 3.0 0.9 1.48 2.5 1.2 2.3 3.0
AKI-HD NAd Yes No Yes No No Yes Yes
Graft loss No Yese No No No No No Yesg
Death Yes No No Yes No No Yes No
ABC, abacavir; AKI, acute kidney injury; ATB, antibiotics; AZI, azithromycin; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus 2019; CsA, cyclosporine; DD, deceased donor; DM, diabetes mellitus; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; HAART, highly active antiretroviral therapy; HCQ, hydroxychloroquine; HCV, hepatitis C virus; HT, hypertension; ICU, intensive care unit; IS, immunosuppressive therapy; LV, living donor; MPS, mycophenolate sodium; MV, mechanical ventilation; NA, not applicable; NI, information not available; OSE, oseltamivir; PKD, polycystic kidney disease; RTV, ritonavir; SCr, serum creatinine; SKPT, simultaneous pancreas-kidney transplant; SRL, sirolimus; ST, steroid; TAC, tacrolimus; 3TC, lamivudine.
aAt COVID-19 diagnosis.
bLast available test before COVID-19 diagnosis.
cPatient admitted on February 20, 2020 for kidney transplant surgery.
dPatient with delayed graft function when COVID-19 was diagnosed.
ede novo glomerulonephritis.
fPatient admitted on April 16, 2020 to treat urinary tract infection.
gNonimmune interstitial fibrosis/tubular atrophy.

This case series suggests that HAART does not mitigate the poor outcomes of COVID-19 in HIV-infected KT recipients. In vitro studies demonstrated that nucleoside and nucleotide reverse transcriptase inhibitors might be effective against SARS-CoV-2 by inhibiting RNAdRNAp.3 Furthermore, a multicenter Spanish cohort analysis including 236 HIV-positive patients with COVID-19 demonstrated that those receiving tenofovir disoproxil fumarate/emtricitabine had lower COVID-19-related hospitalization risk than those receiving other therapies.4

The hypothesis that drug-induced immunosuppression could prevent the cytokine storm, attenuating COVID-19 complications, has not been confirmed in solid organ transplant recipients, as the lethality rates are higher than that of the general population.5 In our cohort, immunosuppressive drugs were completely withdrawal in 5 of the 8 patients, and 4 of them presented severe COVID-19 disease. It is not possible to ensure whether this strategy was an unsuccessful attempt to enable clinical recovery of critically ill patients, or conversely if it precluded the attenuation of cytokine storm. It is still under debate whether this poor prognosis is related to the impaired cellular and humoral responses, to the commonly associated comorbidities, or both.5 Furthermore, regardless of the viral load control, HIV-infection is associated with a pro-inflammatory and prothrombotic state that might be detrimental for the course of COVID-19.

These data should prompt further studies to define optimal management strategies of COVID-19 in solid organ transplant recipients with HIV infection.

REFERENCES

1. Kumar RN, Tanna SD, Shetty AA, et al. COVID-19 in an HIV-positive kidney transplant recipient. Transpl Infect Dis. 2020e13338Epub ahead of print
2. Modi AR, Koval CE, Taege AJ, et al. Coronavirus disease 2019 in an orthotopic liver transplant recipient living with human immunodeficiency virus. Transpl Infect Dis. 2020e13351Epub ahead of print
3. Elfiky AA. Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;253:117592
4. Del Amo J, Polo R, Moreno S, et al. Incidence and severity of COVID-19in HIV-positive persons receiving antiretroviral therapy: a cohort study. Ann Intern Med. 2020;173:536–541.
5. Chaudhry ZS, Williams JD, Vahia A, et al. Clinical characteristics and outcomes of COVID-19 in solid organ transplant recipients: a case-control study. Am J Transplant. 2020. Epub ahead of print
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