Expert Opinion on Pharmacotherapy ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20 Pharmacological considerations for the treatment of COVID-19 in people living with HIV (PLWH) María Del Mar Gutierrez, Isabel Mur, María Gracia Mateo, Francesc Vidal & Pere Domingo To cite this article: María Del Mar Gutierrez, Isabel Mur, María Gracia Mateo, Francesc Vidal & Pere Domingo (2021) Pharmacological considerations for the treatment of COVID-19 in people living with HIV (PLWH), Expert Opinion on Pharmacotherapy, 22:9, 1127-1141, DOI: 10.1080/14656566.2021.1887140 To link to this article: https://doi.org/10.1080/14656566.2021.1887140 © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 26 Feb 2021. Submit your article to this journal Article views: 2060 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ieop20 EXPERT OPINION ON PHARMACOTHERAPY 2021, VOL. 22, NO. 9, 1127–1141 https://doi.org/10.1080/14656566.2021.1887140 SPECIAL REPORT Pharmacological considerations for the treatment of COVID-19 in people living with HIV (PLWH) María Del Mar Gutierreza, Isabel Mur a , María Gracia Mateoa, Francesc Vidal b and Pere Domingo a a Infectious Diseases Unit. Hospital De La Santa Creu I Sant Pau, Institut De Recerca Del Hospital De La Santa Creu I Sant Pau, Barcelona, Spain; b Infectious Diseases Unit. Hospital Universitari Joan XXIII, Universitat Rovira I Virgili, Tarragona, Spain ABSTRACT ARTICLE HISTORY Introduction: When coronavirus infectious disease-2019 (COVID-19) blew up, ill-fated auguries on the Received 17 October 2020 collision between COVID-19 and the human immunodeficiency virus (HIV) epidemics loomed. Accepted 3 February 2021 Areas covered: Data from observational studies suggest similar incidence attacks of SARS-CoV-2 KEYWORDS infection in people living with HIV (PLWH) and HIV-uninfected populations. The mortality rate of COVID-19; SARS-CoV-2; COVID-19 is similar in both populations too. The authors discuss the role of combination antiretroviral cART; remdesivir; therapy (cART) in preventing infection or reducing COVID-19 severity. They also discuss the pharmaco­ dexamethasone; interferon; logical interventions for COVID-19 in PLWH. IL-6 antagonists; LPV/r; DRV; Expert opinion: Management of COVID-19 in PLWH is no different from the general population. It TDF; FTC should be based on careful supportive care, emphasizing lung-protective ventilation, and wise phar­ macological interventions. The antiviral drug remdesivir and dexamethasone are the only pharmacolo­ gical interventions with clinical benefit for COVID-19, whereas anticoagulation may prevent thrombotic complications. The experience with using these drugs in PLWH is limited, which prevents from render­ ing well-founded conclusions. Until more data on COVID-19 in PLWH become available, the best weapons within our reach are sound supportive care and sensible use of RDV and dexamethasone, bearing in mind the potential for drug–drug interactions of most corticosteroids and antiretroviral drugs. 1. Introduction respiratory distress syndrome (ARDS) from the illness onset Since first being reported in December 2019 in Wuhan, China, ranged from 8 to 15 days [5]. Eleven percent of patients severe acute respiratory syndrome coronavirus-2 (SARS-CoV need intensive care unit (ICU) admission, usually because of -2), causing the coronavirus disease of 2019 (COVID-19), has ARDS (18.4%), with a mortality rate of 4.3% [6]. Mortality is spread around the world, becoming a pandemic, affecting higher in ICU patients [4] and those requiring mechanical more than 31 million people with almost one million deaths ventilation (MV) [7]. Increased biomarker and proinflammatory in 9 months [1]. cytokines, as high-sensitivity cardiac troponin I, D-dimer, The pathogenesis of COVID-19 has been envisaged as the serum ferritin, interleukin (IL)-6, IL-8 and tumor necrosis factor dynamic interaction between four feedback loops, including (TNF)-α, are associated with worse outcomes [5,8–10]. Severe the viral loop, the hyperinflammatory loop, the non-canonical cases have lower lymphocyte, monocyte, eosinophil, and renin-angiotensin system (RAS) axis loop, and the hypercoa­ basophil counts, higher leukocyte count and neutrophil–lym­ gulation loop [2]. Therefore, comprehensive COVID-19 man­ phocyte ratio (NLR), and lower levels of both helper T (Th) cells agement may need pharmacological measures addressed to and suppressor T cells [11]. counteract these disturbances. Staged therapeutic management has been proposed early The clinical stages of SARS-CoV-2 infection range from during the pandemic according to the different clinical phases absent or minimal symptoms to severe respiratory failure of COVID-19 [3]. In the initial (mild) stage, in addition to with multiple organ failure [3]. About 80% of the people symptomatic relief, early treatment with antiviral agents have SARS-CoV-2 infection asymptomatic, or with mild to could play a role in reducing the duration of symptoms, mini­ moderate illness (mild symptoms up to mild pneumonia), mize contagiousness, and prevent progression to severity. In 15% have severe symptoms (dyspnea, hypoxia, or >50% lung the second stage (moderate), when inflammation in the lung involvement), and 5% have a critical illness with respiratory and hypoxemia is present, corticosteroids may be useful. failure, shock, or multiorgan system dysfunction [4]. Finally, in the third and most severe stage of the illness, the The most common symptoms are fever, shortness of use of immunomodulatory agents, such as corticosteroids, breath, cough, fatigue/malaise, headache, and confusion [5]. cytokine inhibitors, and intravenous immune globulin, has Among patients with severe disease, the median time to acute been proposed to reduce systemic inflammation before CONTACT Pere Domingo pdomingo@santpau.cat Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Avgda. Sant Antoni Mª Claret, 167.08025 Barcelona, Spain © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 1128 M. D. M. GUTIERREZ ET AL. syndrome (MERS) coronaviruses on the susceptibility and severity disease in PLWH is scarce [20]. People living with HIV (PLWH) could Article highlights potentially be at increased risk of developing severe COVID-19 ● Incidence of SARS-CoV-2 infection and mortality from COVID-19 are disease for various reasons. First, immunosuppression or not similar to those of the HIV-uninfected population receiving combination antiretroviral treatment (cART) and compli­ ● Combination antiretroviral therapy (cART) does not prevent SARS-Cov _2 infection neither decreases COVID-19 severity cations from added opportunistic infections could play a negative ● Careful supportive care and the wise use of remdesivir, dexametha­ role. HIV infection remained a significant risk for infectious respira­ sone, and anticoagulation therapy are the mainstays of COVID-19 tory diseases (both opportunistic infections and non-acquired management ● There is limited experience with the use of these drugs in PLWH with immunodeficiency syndrome (AIDS) infections) after the introduc­ COVID-19 tion of highly active ART (HAART) [21]. Some of these infections ● A careful acquaintance of the potential interaction between corticos­ may be even more severe in PLWH [22] and their management teroids and antiretroviral drugs remains a large component of HIV healthcare [23]. Persistent risk of respiratory infections in PLWH may be in part due to incomplete penetrance or ART coverage [24]. Even on cART, many PLWH have incomplete immune reconstitution and persistent immune activa­ tion [25], which would support a theoretical risk of worse COVID- multiorgan dysfunction develops [3]. More recently, World 19 outcomes. HIV infection is also an independent risk factor for Health Organization (WHO) guidelines recommend corticoster­ other noninfectious pulmonary complications, including chronic oids for the treatment of patients with severe and critical obstructive pulmonary disease (COPD), diffusing capacity impair­ COVID-19 [12]. ment, asthma, and pulmonary hypertension [24]. Both infectious Current evidence indicates that the risk of severe illness and noninfectious respiratory diseases were associated with an and worse outcomes increases with age, male gender, and increased risk of mortality [21,24]. Moreover, PLWH are aging [26], comorbidities, such as hypertension, diabetes, cardiovascular have a higher prevalence of comorbidities [27], and other risk disease, chronic lung disease, chronic kidney disease, cancer, factors for respiratory infections, such as smoking [28], all known and obesity [4,5,8,13–17]. The role of immunosuppression, conditions associated with increased COVID-19 severity. caused by solid organ transplantation, cancer, immunodefi­ Since the beginning of the COVID-19 epidemic, case ciency, or medication-induced, is controversial. There is evi­ reports, case series, and cohorts of PLWH with COVID-19 dence that patients with solid organ cancer and have been published worldwide [29–45]. A systematic review transplantation have more severe disease [17,18]. But gener­ summarized the evidence on the earliest PLWH with COVID-19 ally speaking, there are few immunosuppressed patients with [46] to provide updated information and advice to healthcare COVID-19, and they present a favorable outcome compared to professionals about emerging patterns. The results of exten­ other comorbidities [19]. A possible explanation for the sive population studies comparing COVID-19 outcomes in hypothetical protective role of a weaker immune response is patients with and without HIV infection have recently been that an exuberant cytokine release is essential in inducing presented [47–49]. immune-mediated damage. 2.1. Prevalence, risk factors, and disease severity 2. COVID-19 in PLWH The prevalence of SARS-CoV-2 infection in PLWH ranges from The experience from previous coronaviruses outbreaks like severe 0.3% to 0.8% [31,34,36,50] and is similar to that in the general acute respiratory syndrome (SARS) and the Middle East respiratory population [31,34], or even lower when including suspected Table 1. Drug interactions between antiretroviral treatment and proposed treatments for COVID-19. DTG BIC RAL EVG/c DOR RPV EFV ETR ATV/r o c DRV/r o c LPV/r FTC 3TC ABC TDF TAF MVC Tocilizumab Sarilumab Siltuximab Ruxolitinib Baricitinib Anakinra Bevacizumab Infliximab Adalimumab Interferon beta-1a Interferon alpha-2b Dexamethasone Methylprenisolone Chloroquine Hydroxychloroquine Azithromycin Remdesivir DTG: dolutegravir. BIC: bictegravir. RAL: raltegravir. EVG/c: elvitegravir/cobicistat. DOR: doravirine. RPV: rilpivirine. EFV: efavirenz. ETR: etravirine. ATV/r o c: atazanavir/ritonavir o cobicistat. DRV/r o c: darunavir/ritonavir o cobicistat. LPV/r: opinavir/ritonavir. FTC: emtricitabine. 3TC: lamivudine. ABC: abacavir. TDF: tenofovir disoproxil. TAF: tenofovir alafenamida. MVC: maraviroc. Do not coadminister Potential interaction Not interaction expected EXPERT OPINION ON PHARMACOTHERAPY 1129 cases [33]. Among patients who required hospital admission, people. Chest imaging abnormalities were more frequent in prevalence ranges from 0.8% to 2% [16,32,41,42,50], which PLWH than in uninfected patients [40]. does not suggest increased hospitalization rates among PLWH [41]. As in uninfected people [4,5,7,13–16], PLWH have higher 2.4. Outcome morbidity and mortality among male patients, and mortality increases with multimorbidity [46]. The risk for SARS-CoV-2 infec­ Hospitalization, ICU admission, and case-fatality rates in PLWH tion and hospitalization is greatest in men older than 70 years with COVID-19 are 64.7%, 16.8%, and 14.3%, respectively [46]. [34]. Duration of HIV infection [33], CD4 nadir [33] and recent CD4 However, there are confounding factors such as older age and count [33,40,42], CD4/CD8 ratio [33] and HIV viral load on or prior a higher prevalence of comorbidities. Furthermore, there might to admission [42] are unrelated to COVID-19 severity. The mild also be higher hospitalization rates among PLWH due to safety CD4 percentage decrease observed in hospitalized PLWH is not reasons. Most studies have included only symptomatic patients, associated with worse COVID-19 outcomes [42]. A population- thus overestimating morbidity and mortality. Matched cohorts based study in South Africa found a two-fold increased risk of found no significant differences in adverse outcomes in PLWH COVID-19 death in hospitalized PLWH with CD4 < 200 cells at for hospitalized COVID-19 patients compared to uninfected diagnosis or admission, while the previous immuno-virological patients [40,42]. status did not influence mortality [49]. Comorbidities, such as A larger prospective cohort in Spain found greater age- and organ transplant, diabetes, and obesity, carried a poor prognosis sex-standardized mortality from COVID-19 in PLWH (3.7 per in some studies [42,47], while not in others [33]. 10.000) than in the general population (2.1 per 10.000) [34]. High C reactive protein (CRP) [42,47], procalcitonin [42], IL6 Recently, three population studies from the UK and South [42], white blood cell (WBC) counts [47] are signals of dismal Africa concluded that living with HIV raises the risk of dying prognosis. Lower lymphocyte counts and higher lactate dehy­ from COVID-19 (from 1.63 to 2.3-fold increased risk), after drogenase concentrations are markers of severe COVID-19 in adjusting for age and other factors [47–49]. This increased PLWH [33]. Distinct therapies resulted in no difference in mortality risk was similar in PLWH irrespective of viremia and COVID-19-associated mortality [42]. CD4 count, although there was little representation of virolo­ gically uncontrolled and immunosuppressed patients [49]. 2.2. Demographics and clinical characteristics 3. The potential role of antiretroviral therapy (cART) Most PLWH with COVID-19 were males; their mean age was in preventing COVID-19 53 years [46], which is nearly ten years lower than that observed in uninfected patients [7,16]. In a large population- Regarding the possible beneficial role of antiretroviral use in based study, the age difference between the two populations preventing COVID-19, the observational design and lack of was even greater [47]. Some authors found that PLWH were appropriate control of many studies do not permit us to more likely to be of black ethnicity [47,48] and from socially reach reliable conclusions [46]. Larger cohorts and population- deprived areas [48]. Comorbidity has been reported in nearly based studies in PLWH have demonstrated some evidence of two-thirds of PLWH with COVID-19 [46], a higher proportion a potential effect of nucleoside reverse transcriptase inhibitors than in the general population [5,7,13]. The most common (NRTI) against SARS-CoV-2 infection, finding no benefit of clinical symptoms of COVID-19 in PLWH were fever (74%) and other antiretroviral drugs. A Spanish observational study cough (58.3%) [46], as in uninfected patients [6,7,13]. PLWH found lower risk for COVID-19 diagnosis and hospitalization were more likely to present with systemic symptoms and signs in PLWH receiving tenofovir disoproxil fumarate (TDF)/emtri­ and have a longer duration of symptoms [47]. The severity of citabine (FTC)-based cART versus those receiving other regi­ the COVID-19 disease was mild in most cases (66.5%) [46], with mens [34]. Moreover, none of the TDF/FTC recipients died or no significant difference in supplemental oxygen requirement was admitted to the ICU. In a recently published further by HIV status [40,42,47]. analysis, the authors suggest that the association observed is not explained by confounding due to unmeasured clinical characteristics [52]. 2.3. Viro-immunological features, biomarkers and Other studies found an adjusted association between NRTI imaging use [42], and specifically TDF-based cART [40], with lower Most PLWH with COVID-19 were cART-treated with suppressed COVID-19-related mortality in PLWH. However, the analysis HIV viral load and relatively preserved immunity [46]. Since was not subject to correction for multiple statistical tests and patients with low CD4 counts are often underrepresented, it could have been confounded by other factors. Results of could be that uncontrolled HIV infection and poor CD4 + T-cell a retrospective observational study in Lyon evaluating the function may limit SARS-CoV-2–related immune dysregulation attack rate of COVID-19 infection in PLWH on cART, including and cytokine release. The absence of T-cell activation has been TDF or TAF/FTC-based cART, are still unsettled [53]. hypothesized to mitigate the severe immunopathological phe­ No difference has been found in PLWH COVID-19 incidence nomena in COVID-19 [51]. There was CD4 decline (median: 4%, concerning the other components of cART. Small case-series in IQR 0%-9%) [42], consistent with lymphopenia, during COVID- PLWH with COVID-19 showed that non-nucleoside reverse 19 [11]. Ferritin [42], total white blood cell [42,47] and platelet transcriptase inhibitors (NNRTI) [31] and darunavir (DRV)- counts [47], and CRP were higher whereas absolute lympho­ based regimens [35] did not prevent SARS-CoV-2 infection or cyte count [40,47] was lower in PLWH than in uninfected protect against worsening respiratory function. Other studies 1130 M. D. M. GUTIERREZ ET AL. also found no association between previous NNRTI-, protease with interferon-alpha 2b) showed no evidence of benefit in inhibitor (PI)- or integrase strand transfer inhibitor (INSTI)- terms of SARS-CoV-2 clearance rate or clinical improvement in based regimens and COVID-19 diagnosis [33], severity [33] or patients with mild COVID-19 [68]. Notwithstanding that, mortality [42,49]. An observational study is assessing the pos­ ongoing trials investigate DRV as a therapeutic option for sible impact of ritonavir-boosted lopinavir (LPV/r)-based cART COVID-19, one of them comparing DRV vs. LPV/r [69]. on the attack rate of SARS-CoV-2 infection in PLWH [53]. Currently, the lack of in vitro and in vivo efficacy does not Until robust evidence from randomized clinical trials support DRV use in COVID-19 treatment. (RCTs) becomes available, switching PLWH from their usual Data regarding tenofovir use against SARS CoV-2 are con­ cART is not currently recommended. Besides, there is no flicting. A molecular docking study indicated that tenofovir evidence to support HIV-uninfected people taking antiretro­ tightly binds to SARS-CoV-2 RNA-dependent RNA polymerase viral drugs to prevent SARS-CoV-2 infection, except in the (RdRp), suggesting that it may inhibit this enzyme [70]. context of pre-exposure prophylaxis to prevent HIV acquisi­ A recent in vitro study found that both the active triphosphate tion or an RCT [54]. form of tenofovir (TDF, tenofovir alafenamide (TAF)), and FTC act as terminators of the RdRp-catalyzed reaction and inhibit this enzyme [71]. Moreover, treatment with TDF plus FTC 4. Pharmacological management of COVID-19 showed a reduction in severity scores, duration of clinical Potential therapies for COVID-19 can be classified into at least four symptoms, and nasal SARS-CoV-2 titers in infected ferrets categories depending on the target addressed. The direct-active [72]. On the contrary, other studies have failed to demonstrate antivirals target coronavirus components and block its replication. any tenofovir or FTC in vitro activity against SARS-CoV-2 Other drugs may interfere with host factors crucially required for [60,73]. Tenofovir has immunomodulatory effects, including viral infection and replication. Adjunctive therapy modulates the reducing inflammatory cytokines IL-8, IL-10, and monocyte exacerbated host immune response, thereby reducing inflamma­ tion and limiting immune-mediated damage. Some drugs exert chemoattractant protein 1 (MCP-1), but also in IL-12. As IL-10 more than one mode of action [55]. Additional interventions with inhibits and IL-12 regulates the inflammatory and immune clinical benefit are those directed to avoid the excess thrombotic responses to viral infections, these results suggest a potential risk associated with COVID-19. beneficial effect of tenofovir in COVID-19 [74]. There are cur­ rently three RCTs investigating FTC plus TDF [75,76] or TAF [77] as prophylaxis for COVID-19 in healthcare workers, one 4.1. Antiviral agents still recruiting [75]. Moreover, as TDF, TAF and FTC (with The SARS-CoV-2 lifecycle steps provide potential therapeutic tar­ suggested molecular basis to prevent SARS-CoV-2 infection gets, including viral entry, RNA synthesis, replication, and assembly [70,71,74]) are components of the two approved medications process pathways [55–58]. for use as HIV pre-exposure prophylaxis (PrEP), their effect on the risk of COVID-19 is being evaluated in PrEP users [53]. 4.1.1. Antiretroviral drugs Recently, an observational descriptive study conducted in Several antiretroviral drugs used for the treatment of HIV Madrid found that users of PrEP presented a higher seropre­ infection have been considered for use in the treatment of valence to SARS-CoV-2 than the control group, with no statis­ COVID-19, LPV/r being the most frequently studied. LPV/r is tically significant differences in relation to COVID-19 clinical active against HIV and SARS and MERS coronaviruses [59]. LPV/ manifestations [78]. r also has in vitro antiviral activity against SARS-CoV-2 [60]. C–C chemokine receptor type 5 (CCR5) receptor antagonist However, the concentration of LPV/r required to inhibit SARS- maraviroc (MVC) has been suggested as a potential drug CoV-2 is 4000- to 8000-fold higher than that required to inhibit candidate for COVID-19. MVC binds to the substrate-binding HIV [61], which may carry unbearable toxicity. Early in the pocket of SARS-CoV-2 main protease and forms a significant COVID-19 pandemic, some national guidelines suggested number of non-covalent interactions, resulting in potent inhi­ treatment with LPV/r. bition and infection prevention [79]. Besides, by inhibiting Two RCTs on the efficacy of LPV/r in COVID-19 hospitalized CCR5, a receptor for molecules that mediate inflammation, patients have been published to date. They found no clinical MVC could play a beneficial role in treating the inflammatory benefit of LPV/r therapy over symptomatic or supportive care phase of the COVID-19. A clinical trial evaluating the efficacy [62,63]. Data from a retrospective analysis of hospitalized and safety of MVC in SARS-CoV-2 infection is currently recruit­ COVID-19 patients suggested that early administration ing patients in Spain [80]. (≤10 days from disease onset) of LPV/r was associated with a shorter duration of virus shedding [64]. Accordingly, the 4.1.2. Type I and III interferons RECOVERY and the WHO-sponsored SOLIDARITY trials discon­ Type I Interferon (IFN) α/β are broad-spectrum antivirals, exhi­ tinued LPV/r arms in late June and early July 2020, respectively biting direct inhibitory effects on viral replication and inducing [65,66]. an immune response against viruses [81]. During the 2003 Given the structural similarity with LPV, DRV, boosted with SARS-CoV-1 outbreak in Toronto, Canada, treatment of hospi­ ritonavir or cobicistat, was suggested as a candidate drug for talized SARS patients with IFN-α, resulted in accelerated reso­ the treatment of SARS-CoV-2 infection. However, DRV has no lution of lung abnormalities [82]. IFN-β-1a inhibits replication in vitro antiviral activity against SARS-CoV-2 at clinically rele­ of SARS-CoV-2 in vitro [83]. IFN-β-1a has been used in the vant concentrations [67]. Moreover, DRV (alone or combined treatment of COVID-19, in conjunction with other treatment EXPERT OPINION ON PHARMACOTHERAPY 1131 regimens, with decreased virologic clearance [84]. The first and no longer requiring ongoing medical care. Overall, the clinical trial conducted with IFN-β-1a in severe COVID-19 did study showed that patients treated with RDV recovered after not find statistically significant differences between the two 11 days, compared with 15 days for placebo-treated patients. groups in time to clinical response. The discharge rate This effect was not observed in patients with mild to moderate increased significantly on day 14 and 28-day mortality disease. For patients with severe disease, approximately 90% decreased, especially when patients received IFN-β-1a early of the study population, time to recovery was 12 and 18 days in the disease [85]. Regarding IFN-α-2b, a retrospective study in the RDV and placebo group, respectively. However, no showed significantly reduced detectable virus shedding from difference was seen in time to recovery in patients on the upper respiratory tract [86]. Currently, there is a study with mechanical ventilation or extracorporeal membrane oxygena­ rintatolimod and IFN-α-2b for the treatment of mild or mod­ tion. In a post-hoc death analysis at day 14, there was no erate COVID-19 infection in cancer patients [87]. evidence that RDV impacted the mortality rate in this sub­ Type III interferon (IFN-λ) also acts as an antiviral, but group (HR 1.06; 95% CI, 0.59–1.92). Recent data report that the produces a local response because it is expressed in epithelial estimates of mortality by day 29 were 11.4% in the RDV group cells and a subset of immune cells, including neutrophils [88]. and 15.2% in the placebo group (hazard ratio, 0.73; 95% CI, This minimizes systemic inflammation contrary to IFN type 0.52 to 1.03) [96–98]. I and causes less adverse effects [89]. Currently, there are five Gilead presented new findings in July on a comparative ongoing clinical trials with IFN-λ for the treatment or preven­ analysis of Phase 3 SIMPLE-Severe trial and a real-world retro­ tion of COVID-19 [87]. spective cohort of patients with severe COVID-19. In this ana­ There are no known interactions between IFN – 1a and lysis, RDV was associated with an improvement in clinical IFN – 2b and cART components. Although co-administration recovery and a 62% reduction in mortality risk compared with TDF or TAF has not been studied, a pharmacokinetic with standard of care [99]. However, the results of interaction is unlikely to occur. It should be noted that liver SOLIDARITY study, a mortality trial recommended by WHO decompensation has occurred in HIV/HCV co-infected cirrhotic expert groups in hospitalized COVID-19 of four re-purposed patients receiving NRTI, interferon, and ribavirin. Therefore, antiviral drugs (RDV, hydroxychloroquine, LPV/r, and IFN-β-1a) these patients need close monitoring [90]. showed that no study drug reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitaliza­ tion duration [100]. Specifically, this preprint included a meta- 4.1.3. Remdesivir analysis of mortality of four trials that have compared RDV Remdesivir (RDV) is an intravenous nucleotide prodrug of an with control: the Solidarity trial (604 deaths in 5451 randomly adenosine analog. RDV binds to the viral RNA-dependent RNA assigned patients), the ACTT-1 (136 deaths in 1062 patients; polymerase, inhibiting viral replication through premature ter­ mortality was a secondary outcome), and two smaller trials mination of RNA transcription. It has a potent in vitro antiviral [101,102] (41 deaths). Summation of these trials showed a rate activity against a diverse panel of RNA viruses such as Ebola, ratio for death (RDV vs. control) of 0.91 (95% CI, 0.79 to 1.05) Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus, [100]. Due to the results from these trials, the WHO guidelines Nipah virus (NiV), and Hendra virus [91]. It has demonstrated on drugs for COVID-19 suggest against administering remde­ in vitro activity against SARS-CoV-2 [92]. In a rhesus macaque sivir in addition to usual care for the treatment of patients model of SARS-CoV-2 infection, RDV treatment was initiated hospitalized with COVID-19 regardless of disease severity soon after inoculation, and RDV-treated animals had lower (weak or conditional recommendation) [103]. lung virus levels and less lung damage than controls [93]. Treatment starts with a 200-mg infusion on the first day, RDV improves pulmonary function, reduces lung viral load, followed by one 100-mg infusion a day for at least 4 days, and and severe lung pathology in mice [94]. no more than 9 days. A multinational, open-label trial of RDV has been studied in several RCTs. In June 2020, the hospitalized patients with severe COVID-19 showed that RDV EMA’s human medicines committee (CHMP) recommended treatment for 5 or 10 days had similar clinical benefits granting conditional marketing authorization for the treat­ [96,97,104]. RDV is a safe drug but can cause gastrointestinal ment of COVID-19 in adults and adolescents older than symptoms, elevated transaminase levels, and increased pro­ 12 years with pneumonia who require supplemental oxygen, thrombin time. RDV is not recommended in patients with but who do not require oxygen delivery through a high-flow eGFR < 30 ml/min [105,106]. RDV has no relevant pharmaco­ device, noninvasive ventilation, invasive mechanical ventila­ kinetic interactions with almost any medication [90,106,107]. tion, or extracorporeal membrane oxygenation [95,96]. The However, the use of RDV with strong CYP3A4 inducers (e.g. dossier’s assessment was mainly based on data from NIAID- rifampicin) is not recommended since it may modestly reduce ACTT-11, a multinational, randomized, placebo-controlled trial RDV levels. Other drugs used for COVID-19 such as chloro­ sponsored by the US National Institute of Allergy and quine or hydroxychloroquine may decrease the antiviral activ­ Infectious Diseases, plus supporting data from other studies. ity of RDV, and co-administration is not recommended [108]. NIAID-ACTT-1 evaluated the effectiveness of a planned 10- Experience with RDV in PLWH is limited and comes from day course of RDV in over 1000 hospitalized patients with PLWH included in RCT or expanded access programs. The COVID-19 compared with placebo. The primary measure of reports range from a single patient to four receiving, more­ effectiveness was patients’ time to recovery, defined as no over, other expanded access drugs such as sarilumab and longer being hospitalized and/or requiring home oxygen or anakinra [33,41,42]. Co-administration with antiretrovirals has being hospitalized but not requiring supplemental oxygen not been studied, but RDV is a substrate of CYP2C8, CYP2D6, 1132 M. D. M. GUTIERREZ ET AL. CYP3A4, OATP1B1, and P-gp. Therefore, based on metabolism, (50%). No effect on chloroquine or HCQ levels by antiretrovir­ clearance, and toxicity profiles, a clinically significant interac­ als is expected. Bictegravir levels may increase due to tion is unlikely [90,107]. P-glycoprotein inhibition by chloroquine or HCQ, but this is unlikely to be clinically significant as clinical data have shown 4.1.4. Mixed action mechanism drugs (chloroquine, a good safety profile up to a 2.4-fold increase in bictegravir hydroxychloroquine, and azithromycin) area under the curve. Concentrations of tenofovir may also Chloroquine and hydroxychloroquine (HCQ) are antimalarial increase, and the recommended dose of 10 mg TAF with P-gp drugs. HCQ is also used to treat autoimmune diseases. Both inhibitors is not possible with Biktarvy, which is only available increase the endosomal pH, inhibiting the fusion of SARS-CoV as a fixed-dose combination containing 25 mg of TAF. -2 with the host cell membranes and also have immunomo­ Thankfully, TAF has an excellent clinical safety profile. No dulatory effects. Due to these effects, it has been hypothesized effect on FTC is expected [90,107]. Some PI could potentially that they may be useful in the treatment of COVID-19 [92,109]. increase chloroquine and AZR exposure. There is no dosage Azithromycin (AZR) is a macrolide antibiotic that, in vitro, adjustment recommended for chloroquine, but toxicity mon­ might decrease viral load and might exert immunomodulatory itoring is advisable. Rilpivirine may lengthen QTc, and when effects [110,111]. An in vitro study showed synergistic activity co-administered with these drugs, ECG monitoring is sug­ of the combination of HCQ and AZR against SARS-CoV-2 [112], gested [90,107]. and a small non-randomized, open-label trial from France reported decreased viral load when AZR was added to HCQ 4.2. Immunomodulatory agents in patients with non-severe COVID-19 [113]. Nevertheless, these drugs might increase the risk of ventricular arrhythmias In patients infected with SARS-CoV-2, there is an increase in or cardiac arrest due to corrected QT (QTc) interval prolonga­ pro-inflammatory cytokines (IL-6, IL-1, IFN-γ, TNF-α), probably tion, especially when co-administered with other drugs that because of activated T-helper-1 cell response [134] and macro­ prolong the QTc interval [114,115]. phages [135,136]. There is evidence that some COVID-19 Most preclinical drug efficacy studies to help guide deci­ patients respond to infection with an exacerbated cytokine sions for COVID-19 treatment have shown the lack of antiviral release, similar to that seen in bacterial septic processes, which activity of HCQ in animal models (macaque, hamster) [116–­ has been associated with the severity of the disease [137]. 116–118] and in human cell lines [119]. However, cytokines that suppress inflammation (IL-4 and IL- The safety and efficacy of chloroquine and HCQ with or 10) have also been observed by increased T-helper-2 secretion without AZR were evaluated in RCTs [120–124] and observa­ [5]. Some scores have been evaluated that relate levels of tional studies [125,126]. These studies showed no evidence of cytokines with severity and outcome of SARS-CoV-2 infection, benefit and risk of QTc lengthening. Therefore, these drugs are especially IL-6 and IL-10 [10,138]. Therefore, immunomodula­ not recommended for the treatment of COVID-19, outside of tory agents have been proposed as a treatment for COVID-19- RCT [107,127]. However, a multi-center retrospective observa­ associated ARDS. tional study conducted in Michigan reported a survival benefit among hospitalized patients who received either HCQ alone 4.2.1. Interleukin-6 inhibitors or HCQ + AZR [128]. A higher percentage of patients in the IL-6, a pleiotropic cytokine released by T-cells, endothelial HCQ arms also received corticosteroids compared with the cells, fibroblasts, macrophages, and monocytes during acute control arm (77.1% vs. 36.5%), and thus, the imbalance in and chronic inflammatory disease, regulates the immune sys­ corticosteroid use confounded the results in this study. As tem [139,140]. High levels of IL-6 correlated with prognosis of well, some authors suggest that anti-inflammatory action of COVID-19, providing the rationale for targeting IL-6 pathway HCQ should not be discarded due to the results observed in with monoclonal antibodies [141]. Currently, there are 3 some observational studies with early HCQ treatment and low monoclonal antibodies capable of inhibiting IL-6 signaling: doses that shows lower risk of admission in intensive care unit tocilizumab, sarilumab, and siltuximab [142–144]. [129,130] and lower mortality rate in patients exposed to HCQ Tocilizumab was the first IL-6 inhibitor used in the treatment therapy compared to no or other treatment [129,131–133] of COVID-19 in critically ill patients, resulting in decreased There are no data from RCT on chloroquine, and HCQ + oxygen need and decreased pulmonary opacities in lung CT AZR, in treating COVID-19 in PLWH. The scarce data come scan [141]. Multiple observational studies have been published from case series in which most PLWH received HCQ + AZR. describing clinical and laboratory outcomes in COVID-19 In these retrospective studies, between 17% and 77% of PLWH patients treated with tocilizumab [145–147]. One of the largest received HCQ whereas between 15% and 75% were treated observational studies published to date shows that tocilizu­ with AZR [33,36,41,42]. There were no differences in COVID-19- mab is associated with a lower risk of death or ICU need in associated mortality in patients treated with HCQ, AZR, and patients with high levels of CRP (>150 mg/L) [148]. other expanded access agents [42]. There are several ongoing RCTs with tocilizumab, sarilu­ Co-administration of these drugs with cART components mab, and siltuximab, alone or in combination. Three RCTs has not been studied but based on drug metabolism and about tocilizumab use in COVID-19 have been published clearance, a clinically significant interaction is unlikely. recently [149–151]. CORIMUNO-TOCI-1 [149] is a RCT in Chloroquine and HCQ undergo metabolism by CYPs 2 C8, patients with COVID-19 and pneumonia requiring oxygen sup­ 3A4, and 2D6, and are eliminated unchanged via the kidney port but not admitted to the intensive care unit in France. This EXPERT OPINION ON PHARMACOTHERAPY 1133 study, with 130 patients, concluded that tocilizumab did not Baricitinib and ruxolitinib are the only JAK inhibitors being reach the primary outcome, reduce WHO-CPS scores lower studied in COVID-19 [158,159]. A pilot study with 12 patients than 5 at day 4. But might have reduced the risk of noninva­ treated with baricitinib (BARI-COVID) showed improvement in sive ventilation, mechanical ventilation, or death by day 14. symptoms and oxygenation compared to the control group, Although no difference on day 28 mortality was found. Other without serious adverse reactions [158]. A study with ruxoliti­ RCT was carried out in Italy [150], with 126 patients hospita­ nib was unassociated with accelerated clinical improvement in lized with COVID-19 pneumonia and PaO2/FIO2 ratio between severe COVID-19 [159]. 200 and 300 mm Hg. Twenty-eight percent of patients in the There are 18 ongoing studies with ruxolitinib and 13 with tocilizumab arm showed clinical worsening vs 27% in standard baricitinib [160]. Possible adverse effects should be considered, of care group. The trial was prematurely interrupted after an and risks versus benefits carefully weighed before considering interim analysis for futility. The third [151] is a double-blind, their use. There is no experience with the use of JAK inhibitors placebo-controlled trial involving patients with confirmed in PLWH infected by COVID-19. severe acute respiratory syndrome SARS-CoV-2 infection. There are no known interactions between baricitinib and Primary outcome was not achieved with 243 patients. The cART components. Atazanavir, DRV, cobicistat, ritonavir and hazard ratio for intubation or death in the tocilizumab group lopinavir, which are CYP3A4 inhibitors, may increase the as compared with the placebo group was 0.83 (95% confi­ serum concentrations of ruxolitinib, and dose reduction is dence interval, 0.38 to 1.81; P = 0.64). Therefore, tocilizumab advisable [154]. There are no data on the doses used for was not effective for preventing intubation or death. COVID-19. A clinical trial with sarilumab showed that there were no differences in general clinical improvement and mortality 4.2.3. IL-1 receptor antagonists: anakinra compared to standard treatment [152]. In its preliminary ana­ Anakinra, a recombinant, non-glycosylated IL-1RA (IL-1 recep­ lysis, a study with siltuximab, SISCO (siltuximab in severe tor antagonist), has been evaluated as a method to counteract COVID-19), has reported that it reduces the need for ventila­ the cytokine release observed in severe sepsis and septic tion [153]. There is scarce experience on the use of tocilizumab shock [161]. Because IL-1β serum concentrations were signifi­ in PLWH, only 8 patients reported to date [33,36,41]. cantly increased in COVID-19 patients compared with healthy Tocilizumab, sarilumab, and siltuximab may decrease serum controls, it is thought that anakinra may block the activity of concentrations of CYP3A4 substrates such as atazanavir, DRV, IL-1β in these patients [137]. In a retrospective cohort study of ritonavir, cobicistat, elvitegravir, rilpivirine, efavirenz, etravir­ patients with COVID-19 and ARDS managed with noninvasive ine, doravirine, and MVC [154]. In 12 rheumatoid arthritis (RA) ventilation outside the ICU, treatment with high-dose anakinra patients receiving a single dose of simvastatin (CYP3A4 sub­ was safe and associated with clinical improvement [162]. strate), the AUC of simvastatin and its -hydroxy metabolite There are RCT pending results. Limited data are available were reduced by 57% and 39%, respectively, 1 week following describing the tolerability and toxicity of high dose anakinra tocilizumab compared to simvastatin without tocilizumab. [157]. There is no experience of using anakinra in PLWH Five weeks after tocilizumab infusion, reduced systemic expo­ infected by COVID-19. No known interaction exists between sure was still evident [155]. Therefore, it is recommended to IL-1 receptor antagonists and cART components. monitor the effects of antiretroviral drugs if patients receive concomitant treatment with tocilizumab. Regarding sarilumab, the technical data sheet recommends caution when combin­ 4.2.4. VEGF inhibitors: bevacizumab ing sarilumab and CYP3A4 substrates with narrow therapeutic Vascular endothelial growth factor (VEGF) is a potent vascular indexes where a decrease in exposure and effectiveness is permeability inducer. Bevacizumab, a recombinant monoclo­ undesirable [143]. With siltuximab treatment, the decrease in nal antibody that binds to and neutralizes VEGF, was found to levels of CYP3A4 substrates should be monitored. Once siltux­ inhibit pulmonary edema in a VEGF overexpression model. In imab is discontinued, the rise in CYP3A4 substrates should comparison to healthy controls, VEGF serum concentrations also be monitored because restoring CYP3A4 activity may were significantly increased in patients with COVID-19 [137]. increase the metabolism of CYP3A4 substrates. This effect There are 3 RCTs assessing the efficacy and safety of bev­ may persist several weeks after discontinuation due to siltux­ acizumab, one of them with recruitment completed [160]. imab long half-life [156]. Considerations regarding the risk of serious adverse effects, including myocardial ischemia, cerebral thrombosis, and gas­ trointestinal perforation, are important in determining 4.2.2. JAK inhibitors whether targeting VEGF is a viable option [163]. There is no Janus kinase (JAK) mediates the release of proinflammatory known interaction between bevacizumab and cART cytokines leading to increased inflammatory processes [157]. components. The mechanism of JAK inhibitors, sunitinib, erlotinib, ruxoliti­ nib, fedratinib, and baricitinib, is inhibition of cytokine signal­ 4.2.5. TNF-α inhibitors: infliximab and adalimumab ing, thereby downregulating the immune response. The doses TNF-α is a proinflammatory cytokine primarily produced by of sunitinib and erlotinib needed to inhibit AP2-associated monocytes and macrophages that induce the production of kinase 1 and cyclin G-associated kinase are significantly higher other cytokines and promote inflammation [164]. The hyper­ than those used for anticancer treatment, which may result in inflammatory response in COVID-19 is characterized by ele­ unbearable adverse effects [157]. vated concentrations of serum TNF-, IL-6, IL-8 and to a lesser 1134 M. D. M. GUTIERREZ ET AL. extent IL-1 [9]. Administration of anti-TNF to patients for treat­ sheet [172] does not recommend co-administration, whereas ment of autoimmune disease leads to reductions in all these the ritonavir data sheet [173] recommends avoiding futica­ key inflammatory cytokines [165]. This is the rationale that sone, budesonide, or triamcinolone and caution with dexa­ anti-TNF- therapy can decrease inflammation in COVID-19 methasone and prednisolone/prednisone use. and have a major impact on the need for ventilation and Dexamethasone can be used in single doses, but Cushing mortality. syndrome has been described in multiple doses, even with There are a small number of case reports on the use of anti- eye drops together with RTV-boosted PI. If these associations TNF therapy in acute COVID-19. Currently, there is a clinical must be used, careful monitoring of therapeutic effects and trial assessing the efficacy of infliximab in hospitalized adult adverse reactions is warranted. In the event of glucocorticoid patients with severe or critical COVID-19 [166]. withdrawal, a progressive reduction of the dose may be There is no known interaction between adalimumab and required over a longer period. Dexamethasone interacts with cART components. Co-administration of Infliximab and etravir­ all PI, not recommended according to the data sheet [174]. ine may increase the risk of peripheral neuropathy, especially High doses of dexamethasone can also decrease plasma con­ in patients with diabetes or older than 60 years. They should centrations of DRV/c due to CYP3A4 induction with the possi­ be administered with caution and neurological symptoms ble loss of therapeutic effect and induction of resistance. monitored. Co-administration of efavirenz with infliximab Similarly, it also interacts with elvitegravir. No interactions may potentiate the risk of liver injury. It is recommended to have been described with dolutegravir and raltegravir. The co- monitor liver function during treatment [107]. administration of bictegravir and dexamethasone has not been studied. However, caution is required as bictegravir is (1) Corticosteroids metabolized by CYP3A4 and UGT1A and co-administration may potentially decrease bictegravir concentration [90]. The Systemic corticosteroid treatment is controversial in severe use of dexamethasone with rilpivirine is contraindicated [175] ARDS; however, it is used in patients with severe viral ARDS because it can significantly decrease plasma concentrations of [167]. Given the large number of cytokines induced by COVID- rilpivirine. It is dose dependent, so a single dose could be 19 infection, corticosteroids may help to reduce the inflamma­ used, but long-term use alternatives should be considered. tion that causes lung damage, especially in patients with Its use with efavirenz or etravirine is not recommended severe disease [137]. A meta-analysis published in April 2020, because of a decrease in antiretroviral drug level. in which the studies evaluated were mainly in SARS-CoV and Dexamethasone is a substrate of CYP3A4 and a moderate MERS-CoV, and only 2 in SARS-CoV-2, suggested that corticos­ inducer of CYP3A4 and therefore can decrease doravirine teroid use is associated with increased mortality in patients exposure and efficacy [90]. If co-administration cannot be with coronavirus pneumonia [168]. Different corticosteroids avoided, doravirine should be administered 100 mg twice are currently being evaluated for the treatment of COVID-19. daily (based on the interaction study with rifabutin, another Methylprednisolone and dexamethasone are the most fre­ moderate inducer) and maintained at this dose for at least quently used because of high lung bioavailability. another two weeks following dexamethasone discontinuation. Limitations of most of the methylprednisolone studies At least a 4-week cessation period is recommended prior to include the small cohort size and the lack of follow-up data, initiation of doravirine due to the persistent inducing effect as far as the resolution of lung injury is concerned [169]. upon discontinuation. The same is true for MVC. In contrast, Nevertheless, the most robust data came with dexamethasone interactions between dexamethasone and NRTI have not been in the RECOVERY trial [170]. It is the only randomized con­ evidenced. trolled study, carried out in the UK, where 2104 patients were Methylprednisolone is also metabolized by CYP3A4. Co- randomized to dexamethasone 6 mg per day (oral or intrave­ administration of methylprednisolone with DRV, ritonavir, ata­ nous) for 10 days and compared to 4321 patients receiving zanavir, cobicistat, efavirenz, etravirine or elvitegravir can usual care. The trial showed a significant reduction of death by potentially increase methylprednisolone concentration and 35% in ventilated patients and by 20% amongst patients on increase the risk of steroid side effects [154]. Rilpivirine at supplemental oxygen therapy, although no benefit was a dose of 25 mg once daily is unlikely to have a clinically observed in mild cases or moderate cases not requiring oxy­ relevant effect on the exposure of medicinal products meta­ gen support. bolized by CYP enzymes [90]. When the use of corticosteroids A prospective meta-analysis of clinical trials of critically ill is greatly needed, it is recommended to use the lowest possi­ patients with COVID-19 has recently been published [171]. It ble dose and to monitor the adverse effects together with concludes that administration of systemic corticosteroids, com­ antiretroviral drug levels [90]. pared with usual care or placebo, was associated with lower 28- day all-cause mortality. There are few published studies of corticosteroid treatment of COVID-19 infection in PLWH. In the 5. Anticoagulant therapy literature, only 21 PLWH with COVID-19 received corticosteroids COVID-19 infection can induce a prothrombotic state, due to without assessment on the impact on their outcome [33,41]. the pro-inflammatory state and endothelial dysfunction, with Corticosteroids are mainly metabolized by CYP3A4, and a high risk of arterial and venous thrombosis [176]. The inci­ therefore their concentrations may increase in the presence dence of pulmonary thromboembolism (PTE) in critically ill of inhibitors such as ritonavir or cobicistat. The cobicistat data COVID-19 patients is significantly higher than in patients EXPERT OPINION ON PHARMACOTHERAPY 1135 with ARDS due to other diseases [177]. Besides, patients who the main target of SARS-CoV-2 is the lung where acute lung develop a PTE have a worse prognosis [178]. Recent evidence injury, diffuse alveolar damage, and eventually ARDS are the suggests that pulmonary thrombosis originates in situ, due to leading causes of death. Why some patients develop acute the low incidence of deep vein thrombosis evidenced [179]. respiratory failure, while others remain asymptomatic or have Studies indicate that anticoagulant therapy with low molecu­ minimal symptoms, has not been fully untangled. Severe lar weight heparin (LMWH) in patients with severe COVID-19 COVID-19 is frequently associated with ARDS, and since there decreases mortality [180,181]. The latest recommendations is no specific pharmacologic therapy for ARDS, painstaking suggest that all patients hospitalized should receive thrombo­ supportive care with the premise of lung-protective ventila­ prophylaxis or full therapeutic-intensity anticoagulation if such tion associates with a better outcome. On the other hand, an an indication is present [182]. D-dimer could aid in the early unequivocal principle in ARDS management is that the treat­ recognition of high-risk patients [183]. No interactions have ment of its underlying roots is crucial to upgrade outcomes. been found between LMWH and cART components. Based on the knowledge gathered about the pathogenesis of COVID-19, combination therapy with antivirals with immunomo­ dulating agents has been proposed. Among the myriad of 6. Expert opinion pharmacological interventions tested during the pandemic’s When two epidemics collide, such as COVID-19 and HIV infec­ heroic times, only two have shown clinical benefit. RDV is the tion, some questions unavoidably arise. While engrossed by the only antiviral associated with an inconspicuous clinical benefit, pandemic, HIV clinicians soon noticed the disproportionately since it shortened the time to recovery in hospitalized patients. low number of COVID-19 cases amongst PLWH. This finding As of 22 October 2020, the Food and Drug Administration (FDA) prompted lucubration about the presumptive protective role has approved Veklury (remdesivir), as the only antiviral drug for of cART on SARS-CoV-2 infection incidence. This speculation the treatment of COVID-19 disease. However, inquiries remain was fed by knowledge gathered from the SARS-CoV-1 and about its efficacy, such as the optimal patient population, the MERS-CoV epidemics, showing the sensitivity of these viruses optimal duration of therapy, and the unclear effect on discrete to LPV/r. Given the genetic analogy and the shared pathogenic outcomes. In a large open-label and non-randomized clinical mechanisms between the three coronaviruses, LPV/r was pro­ trial, dexamethasone decreased the mortality in patients who moted as a potentially useful therapy for COVID-19. Without needed mechanical ventilatory support or had high oxygen question, the colliding epidemics may modify each other, but therapy requirements. There are limited data, and indeed, not we do not yet know to what extent the presumed changes will a single RCT to date indicating the presumptive benefit of affect PLWH. Nevertheless, what most HIV physicians are cur­ cytokine or chemokine blockade in COVID-19. Handling rently asking themselves can be summarized in three questions: a system as intricate, redundant, overlapping, and full of alter­ 1.- Is SARS-CoV-2 infection incidence lower or higher in nate pathways as the immunologic system may prove a massive PLWH? task for single molecule targeting, and it may sometimes hap­ Current evidence indicates that PLWH have a roughly similar pen to be hazardous. It is worth recollecting that patients who incidence of SARS-CoV-2 infection to the non-HIV-infected did not need oxygen therapy but received dexamethasone had population. However, hospitalization rates are lower for PLWH, an excess mortality rate. In addition, corticosteroids inhibit sig­ but information from observational studies in this respect is very naling of endogenous type I interferon, a first line of defense biased, since a major problem of this kind of studies is the bias against respiratory viral infections. for indication. Therefore, to draw reliable conclusions is difficult. There is a low number of PLWH with COVID-19 treated, and Besides, there is no proof of a protective role of cART or com­ therefore, no conclusion can be drawn. Hopefully, both RDV and ponents thereof against the risk of acquiring SARS-CoV-2 infec­ dexamethasone have a good safety profile. However, there is tion, despite data from observational studies involving TDF/FTC a risk of drug–drug interactions of most antiretroviral drugs with in such a role. PrEP studies’ data may offer a new insight into this dexamethasone, whereas the likelihood of such an interaction is issue soon, since evidence from RCT is not expected. almost negligible with RDV. The pharmacological management 2.- Is COVID-19 severity comparable between PLWH and of COVID-19 in PLWH shall not be different from that in the the uninfected population? general population except for increased awareness about phar­ PLWH have a higher prevalence of comorbid conditions asso­ macokinetic interactions, especially with corticosteroids. ciated with a poor prognosis in COVID-19, which may harm all- Indeed, for most of the drugs discussed above, there is no cause mortality [27]. Lately, data from observational studies sug­ evidence from RCT of beneficial effects for COVID-19 patients, gest higher mortality rates in PLWH after adjusting for age and either uninfected or PLWH, but with some potentially jeopardiz­ other confounding factors. Notwithstanding that, other matched ing side effects. In an emergency setting such as that presented studies suggest similar adverse outcomes to those of the unin­ by the COVID-19 pandemic, it is useful to recall Milton Friedman’s fected population. Combination antiretroviral therapy does not message, ‘The power to do good is also the power to harm.’ play a protective role related to COVID-19 outcomes in PLWH. 3.- Shall the management of COVID-19 be different in Funding PLWH? With the incidence, presentation, and evolving trend of This work has been partially funded by the Fondo de Investigaciones COVID-19 in PLWH being roughly like those of the general Sanitarias (PI14/0700, PI14/0063, PI016/0503, PI17/0420, PI17/0498 and PI19/01337), the SPANISH AIDS Research Network ‘RD16/0025/0006’ (Co- population, there are no features for a different management funded by European Regional Development Fund/European Social Fund; approach in PLWH. Although COVID-19 is a systemic disease, 1136 M. D. M. GUTIERREZ ET AL. ‘A way to make Europe’/”Investing in your future”) and the Programa de 5. Zhou F, Yu T, Du R. Clinical course and risk factors for mortality of Suport als Grups de Recerca AGAUR (2014 SGR 250, 2017 SGR 948). adult inpatients with COVID-19 in Wuhan, China: a retrospective Furthermore, this work was supported by the Gilead Fellowship Program cohort study. Lancet. 2020;395(10229):1054–1062. GLD14/293, and GLD17/00299, and GLD19/00008. Additionally, this work 6. Zhang JJY, Lee KS, Ang LW. Risk factors of severe disease and efficacy was supported by grant COV20/00070 (to P Domingo), from the Instituto of treatment in patients infected with COVID-19: a systematic review, de Salud Carlos III, Madrid, Spain (ISCIII) and by grant COVID19 617 (to meta-analysis and metaregression analysis. Clinl Infect Dis. 2020;(16). F Vidal) from the Departament de Salut and BIOCET, Generalitat de 10.1093/cid/ciaa576. ciaa576. Published online 14 May 2020. Catalunya. P Domingo and F Vidal are also supported by grants from 7. Yang X, Yu Y, Xu J. Clinical course and outcomes of critically ill the Programa de Intensificación de Investigadores (INT19/00036 and patients with SARS-CoV-2 pneumonia in Wuhan, China: a INT20/00031, respectively) from the ISCIII. single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–481. 8. Li X, Xu S, Yu M. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020;146(1):110–118. Author Contributions 9. Del Valle DM, Kim-Schulze S, Huang HH. An inflammatory cytokine PD devised the concept and developed the idea. MMG, IM and GMM signature predicts COVID-19 severity and survival. Nat Med. performed bibliographic research. All authors coordinated and oversaw 2020;26(10):1636–1643. the development of the manuscript. All authors participated in data 10. Nagant C, Ponthieux F, Smet J. A score combining early detection interpretation. 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