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

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 Immunosuppression was withdrawn in five patients but HAART was unchanged.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.