A High Percentage of People With Human Immunodeficiency Virus (HIV) on Antiretroviral Therapy Experience Detectable Low-Level Plasma HIV-1 RNA Following Coronavirus Disease 2019 (COVID-19).

To the Editor—We read with interest the recent article by Geretti et al in which, among adults <60 years of age with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, human immunodeficiency virus (HIV) seropositivity was shown to be significantly associated with 28-day mortality, even when adjusted for age and other potentially important factors [1]. As the authors discuss in detail, these data contrast with a study recently published in Clinical Infectious Diseases by Sigel et al of people with HIV (PWH) who were hospitalized for acute SARS-CoV-2; in that study, there were no differences in adverse outcomes compared to a demographically similar HIV-seronegative group [2]. While a number of case series and retrospective studies have also shown no differences in coronavirus disease 2019 (COVID-19) mortality or severity in PWH [3-8], there is emerging evidence for exacerbations of lymphocyte dysfunction and aberrant immune activation in the setting of SARS-CoV-2/HIV coinfection [9]. Furthermore, COVID-19 often leads to increased markers of immune activation, inflammation, and immune dysregulation, regardless of concomitant chronic infections [10]. It is therefore plausible that, in addition to HIV modulating SARS-CoV-2 infection, COVID-19 may have a short- or longer-term impact on HIV disease following acute SARS-CoV-2 infection in PWH on effective antiretroviral therapy (ART). As a result, we sought to identify if SARS-CoV-2/HIV-1 coinfection may lead to an increase in the frequency of detectable, but low-level plasma HIV-1 RNA levels that would not necessarily be detected by clinical viral load assays.

We tested large volumes of plasma for HIV-1 RNA using a highly sensitive single copy assay (SCA) from 12 PWH on ART using a replicate (9×) technology as previously described [11] with polymerase chain reaction–confirmed, convalescent SARS-CoV-2 infection a median of 37 days since onset of COVID-19 symptoms, and from 17 PWH on ART with plasma collection prior to COVID-19 (March 2018–October 2019). Table 1 summarizes participant demographics, ART use, and low-level residual HIV-1 RNA. Whereas 83.3% of PWH had detectable HIV-1 RNA by SCA, only 58.8% of PWH had detectable HIV-1 RNA prior to the COVID-19 pandemic despite similar input plasma volumes. The median HIV-1 RNA level was 1.59 copies/mL in PWH with recent COVID-19 compared with 0.38 in the pre–COVID-19 group. Four COVID-19–positive participants who all had detectable blips had subsequent testing a median of 75 days after onset of symptoms (interquartile range [IQR], 58–90 days); 3 had persistence of detectable HIV-1 plasma RNA (median, 1.95 [IQR, 0.1–14.53] copies/mL).

Table 1.

Characteristics of People With Human Immunodeficiency Virus on Antiretroviral Therapy With Recent Coronavirus Disease 2019 (COVID-19) and Prior to COVID-19 Including Detectable Low-Level Plasma HIV-1 RNA

Characteristic	PCR+ COVID-19	Pre–COVID-19
No. of patients	12	17
Time from onset of COVID-19 symptoms to initial sampling, days, median (IQR)	37 (29–62)	NA
Hospitalized for COVID-19	2 (16.7)	NA
Median age, y (IQR)	57 (53–64)	63 (57–69)
Male sex	12 (100)	16 (94)
Race
White	10 (83.3)	14 (82.3)
Black/African American	1 (8.3)	3 (17.6)
Asian/Pacific Islander	1 (8.3)	…
ART
INSTI use	11 (91.7)	12 (70.6)
NNRTI use	1 (8.3)	3 (17.6)
PI use	2 (16.7)	2 (11.8)
Leronlimab use	0 (0)	2 (11.8)
CD4 count, cells/µL, median (IQR)	658 (540–804)	537 (457–827)
Detectable plasma HIV-1 RNA (SCA positive)a	10 (83.3)	10 (58.8)
No detectable plasma HIV-1 RNA (SCA negative)b	2 (16.7)	7 (41.2)
Plasma HIV-1 RNA, copies/mL, median (IQR)	1.59 (0.39–6.95)	0.38 (0.0–5.67)

Data are presented as No. (%) unless otherwise indicated.

Abbreviations: ART, antiretroviral therapy; COVID-19, coronavirus disease 2019; HIV-1, human immunodeficiency virus type 1; INSTI, integrase strand transfer inhibitor; IQR, interquartile range; NA, not applicable; NNRTI, nonnucleoside reverse transcriptase inhibitor; PCR, polymerase chain reaction; PI,  protease inhibitor; SCA, HIV-1 single copy assay (plasma RNA).

aNo significant difference between recent COVID-19–positive and COVID-19–negative participants using Fisher exact test (P = .23).

bNo significant difference between recent COVID-19–positive and COVID-19–negative participants using Mann-Whitney test (P = .36).

Although sample sizes were modest and there were no significant differences between the COVID-19–positive and pre–COVID-19 groups, the above results suggest that lasting perturbations of immune function and systemic inflammation may impact the natural course of HIV infection, potentially months following SARS-CoV-2 infection. Whereas these low-level viremic episodes are unlikely to have direct clinical implications for patients, larger, prospective studies will be needed to fully understand the long-term impact of COVID-19 on HIV dynamics and viral immune responses.