Clinical Research in Practice: The Journal of Clinical Research in Practice: The Journal of Team Hippocrates Team Hippocrates Does HIV status confer a higher risk of acquiring COVID-19? Using Does HIV status confer a higher risk of acquiring COVID-19? Using Clinical Decision Science to combat patients’ anxiety Clinical Decision Science to combat patients’ anxiety

A clinical decision report using: del Amo J, Polo R, Moreno S, et al. Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving Antiretroviral Therapy. Annals of Internal Medicine . 2020;173(7):536-541. for a patient with HIV and concerns about COVID-19 for immunocompromised individuals.

Does HIV status confer a higher risk of acquiring COVID-19? Using Clinical Does HIV status confer a higher risk of acquiring COVID-19? Using Clinical Decision Science to combat patients' anxiety Decision Science to combat patients' anxiety Cover Page Footnote Cover Page Footnote I would like to thank Dr. Norman Markowitz for productive discussions and mentorship throughout the entire writing process.
Mr. Lopez (pseudonym) is a 57-year-old Hispanic man with a past medical history of generalized anxiety disorder and hyperlipidemia who presented in August 2020 for his biannual chronic Human Immunodeficiency Virus (HIV) visit. During the visit, Mr. Lopez reported full adherence to Biktarvy® (bictegravir, emtricitabine, and tenofovir alafenamide) without any issues obtaining the medication or any noticeable side effects. A basic metabolic panel and lipid panel revealed no abnormalities, and his HIV viral load was at the lower limit (<20 HIV1 copies/mL) with a total helper CD4 count of 653 cells/uL. Thus, Mr. Lopez was encouraged to continue the same regimen.
Though Mr. Lopez was encouraged to hear that there were no new health concerns, he expressed concerns surrounding the ongoing COVID-19 pandemic. While he was grateful to keep his job and therefore his medical insurance, he was struggling with 'work from home.' He worked as a social worker and felt he could not communicate effectively with clients through virtual interactions. Additionally, he was concerned that the immunocompromise associated with HIV diagnosis could increase susceptibility to COVID-19, not only for his own sake but also for the sake of his partner, who had both HIV and early-stage Parkinson's Disease. They had both been proactive and diligent in achieving control of their illness and were fearful at the prospect of infection with another potentially lethal virus. Furthermore, if one of them did become ill, it would introduce multiple uncertainties into their household, as standard 'isolate at home' protocols might not suffice for someone with an immunocompromised partner.
More broadly, Mr. Lopez was also heavily involved in the HIV community, both through his employment and social life, as he had lived with the virus for over 30 years. He had been a participant in the earliest HIV drug trials and knew all too well what it was like to watch a virus devastate his loved ones and his community. Due to these additional stressors, Mr. Lopez had increased his consumption of alprazolam from once to twice per week.
At the time of the appointment, the scientific community was struggling to understand a virus that was equally confusing as it was devastating. Just one month prior, the World Health Organization had finally announced that COVID-19 can be airborne, while simultaneously, the total cases in the United States (US) surpassed three million. As such, we asked Mr. Lopez for some time to investigate this question that carried such crucial implications for him.

Description of Related Literature
On August 30, 2020, the search engines Google Scholar and PubMed were used for the search terms "Incidence of COVID-19 in HIV" and "Prevalence of COVID-19 in HIV." Though the research question is primarily concerned with COVID-19 incidence (i.e. likelihood of acquiring the virus), the virus was first discovered just eight months before the clinical encounter, making these two terms virtually synonymous. PubMed yielded 184 and 185 results for these terms, respectively, while Google Scholar yielded 30,800 and 34,500 results. Only the first 100 results from these four searches were examined further with respect to the inclusion criteria, as results past this mark became irrelevant for the question.
The inclusion criteria were any cohort, cross-sectional or case-control studies that compared the incidence or prevalence of COVID-19 infection between HIV-negative and HIV-positive individuals. In total, seven studies met these criteria, and they are examined below in order of increasing relevance for the clinical question.
Various studies were discarded due to their relatively small PLWH sample sizes (i.e. 200 2 , 116 3 , 2873 4 , 5683 5 and 6001 6 ). These studies had wildly conflicting results, perhaps due to their small samples, varying definitions (e.g. symptom-based characterizations of COVID-19 2 vs. positive PCR 3-6 with additional radiologic evidence of pneumonia 3 ) and different geographic locations (i.e. Iran 2 , South Africa 3 , Spain 4-5 and China 6 ). To summarize, one study found a higher prevalence of COVID-19 in PLWHs 3 , two found a lower prevalence 2, 5 , one found no difference 6 and to further complicate matters, one had opposite results when comparing suspected COVID-19 cases with confirmed cases. 4 Three of these studies examined the role of demographic factors and ART regimen on COVID-19 prevalence. [4][5][6] Of these, two found no significant association with demographic factors 4,5 while one found a higher prevalence in older participants 6 , though it only described two categories of age (<50 and ≥50). Only one study found an association with ART regimen 4 , as tenofovir-based regimens were more prevalent in PLWHs who acquired COVID-19. However, other studies also accounted for all these variables while involving a much greater sample, thus increasing our confidence in the validity of their results.
For example, Boulle et al. 7 used public sector data in Western Cape, South Africa, to derive a cohort of over 500,000 PLWHs. The study focused on predictors of mortality from COVID-19 rather than incidence rate of the infection. However, the data can be used to derive risk ratios for the variables of interest as they pertain to COVID-19 incidence. As such, HIV status has a risk ratio of 1.17 (P <0.0001), male sex has 0.56 (P <0.0001) and the age group 50-59 has 1.05 (P = 0.36) when compared to all other age groups cumulatively. However, the data provided is not sufficient to perform this calculation for ART regimens. The study ultimately selected for critical appraisal was del Amo et al. 1 , a prospective cohort study in Spain that followed a cohort of PLWHs to calculate the incidence of COVID-19 and examined how epidemiological and therapeutic factors influenced this outcome variable. By addressing these factors, the study accounted for various of Mr. Lopez's social factors. Furthermore, its PLWH cohort of 77,590 encompassed 65% of all PWLHs in Spain, and it was the second-largest PLWH cohort of all studies that met the inclusion criteria.
Though Boulle et al. had a larger PLWH cohort, it did not describe the effect of ART on COVID-19 incidence. This was an essential aspect of the research question because there is speculation that ART can protect against COVID-19 infection, as it was previously suggested to protect against SARS. 8 Additionally, previous in-vitro studies showed that ARTs could inhibit RNA-dependent RNA polymerase 9,10 , and current clinical trials are examining the efficacy of ARTs against COVID-19 e.g. RECOVERY (ClinicalTrials.gov: NCT04381936) and SOLIDARITY (ISRCTN83971151).
As the virus struck the Americas after Asia and Europe, no studies involved a Hispanic sample, and no studies were located in the US. Seeing as how COVID-19 incidence is highly dependent on spatial 11 and socioeconomic 12 factors, comparing an urban Hispanic male in the US with nation-wide Spanish participants carries significant limitations. On the other hand, of all the study locations above (i.e. Iran, South Africa, China, Spain), Spain is the most similar to the US. For instance, it ranks 25th in Human Development Index, compared with 17th for the US and 114th for South Africa. 13 As such, luxuries like avoiding public transit and having access to infectious disease specialists are most applicable in a country like Spain. Similarly, being a service-driven economy, Spanish participants were most likely able to 'work from home,' as Mr. Lopez could. Furthermore, the COVID-19 incidence was similar when comparing Spain during the study period (~1/16,000 per day) with the local incidence surrounding Mr. Lopez in August. 14 Lastly, many Hispanics have ancestries that can be partly traced back to Spain, which indeed manifests as high concordance at a genetic level. 15 Thus, though by no means an exact comparison, the external validity was greatest with the Spanish sample.
No studies matched Mr. Lopez's timeline adequately. The studies occurred from February to June, whereas Mr. Lopez posed his question in August. Notably, del Amo was the earliest of the studies, taking place from February to April. Though COVID-19 has a relatively low mutation rate 16 , multiple variants have emerged with different infectivity, and extrapolating data from six months in the past is therefore a significant limitation. On the other hand, improving the match by 1-2 months was not sufficient rationale for altering the study of choice in light of the multiple advantages mentioned above.
Overall, by accounting for most of the variables in the research question while involving a large sample from a comparable population, del Amo was chosen for critical appraisal.

Critical Appraisal
Del If instead of calculating risk per 10,000 people, the data from del Amo et al. is used to calculate risk ratios for each of the four variables, one could derive a cumulative risk ratio that accounts for all of the variables. As such, the COVID-19 risk ratio calculation gives 0.72 for HIV-positive status, 2.14 for male sex, 0.78 for age 50-59 (compared to all other age groups cumulatively) and 1.50 for tenofovir alafenamide/emtricitabine (compared to all other regimens cumulatively). Age, sex, and HIV-status are not amenable to change, and this information was shared with Mr. Lopez.