key: cord-355439-eqtk51q3
authors: Lesko, Catherine R; Bengtson, Angela M
title: HIV and SARS-CoV-2: Intersecting Epidemics with Many Unknowns
date: 2020-07-22
journal: Am J Epidemiol
DOI: 10.1093/aje/kwaa158
sha: 
doc_id: 355439
cord_uid: eqtk51q3

As of July 2020, approximately 6 months into the pandemic of novel coronavirus disease 2019 (COVID-19), whether people living with HIV (PLWH) are disproportionately affected remains an unanswered question. Thus far, risk of COVID-19 in people with and without HIV appears similar but data are sometimes contradictory. Some uncertainty is due to the recency of the emergence of COVID-19 and sparsity of data; some is due to imprecision about what it means for HIV to be a “risk factor” for COVID-19. Forthcoming studies on the risk of COVID-19 to PLWH should differentiate between 1) the unadjusted, excess burden of disease among PLWH to inform surveillance efforts; and 2) any excess risk of COVID-19 among PLWH due to biological effects of HIV, independent of comorbidities that confound rather than mediate this effect. PLWH bear a disproportionate burden of alcohol, other drug use, mental health disorders, and other structural vulnerabilities, which may increase their risk of COVID-19. In addition to any direct effects of COVID-19 on the health of PLWH, we need to understand how physical distancing restrictions impact secondary health outcomes, and the need for, accessibility of, and impact of alternative modalities of providing ongoing medical, mental health, and substance use treatment that comply with physical distancing restrictions (e.g., telemedicine).

CoV-2 epidemic. It is critical that we understand these risks to modify ongoing HIV care accordingly, and to update future pandemic preparedness plans. Herein, we outline several research questions to frame this research agenda, and we highlight existing data and future opportunities to answer these questions. We focus mainly on the intersecting epidemics of SARS-CoV-2 and HIV in the United States of America (USA), but many of the questions we pose apply to other settings as well.

It is unclear whether or not PLWH are at higher risk for infection with SARS-CoV-2 or for poor clinical outcomes subsequent to infection. There are reasons to hypothesize that PLWH are a high-risk group: antibody responses to an immune system challenge are impaired in PLWH, and PLWH have high prevalence of risk factors for severe SARS-CoV-2 infection including hypertension, diabetes, cardiovascular disease, obesity, lung disease and smoking, male sex, and older age (1, 2) . Alternatively, worse COVID-19 outcomes may be due to immune (over)activation, and thus PLWH might actually be at lower risk for poor outcomes following SARS-CoV-2 infection due to their reduced immune response (3) . However, there are not yet sufficient data to support or refute either of these hypotheses.

Early in the course of an epidemic of a novel pathogen, evidence is scarce and the most practical or indeed the only epidemiologic study design available to us is the case report or case series (4) (5) (6) (7) (8) . Early case reports and case series of COVID-19 in PLWH told of an occasionally atypical, but not more severe, disease course, relative to people living without HIV (7) (8) (9) (10) (11) (12) (13) . Some case series suggested that PLWH with COVID-19 may be younger than persons with COVID-19

in the general population (11, 12). However, incidence and mortality rates for COVID-19 will be a function of the age structure of the underlying populations of people with versus without HIV, thus it is difficult to compare rates without age-standardization.

Data on the incidence of COVID-19 in PLWH is slowly amassing from population-(i.e., surveillance) and clinic-based cohorts of PLWH. While important, absolute risk estimates will 

Illinois, USA (15%) was comparable to the positivity rate among people without HIV (19%) (16) . In contrast to these cohorts suggesting similar infection rates in people with and without HIV, unpublished surveillance data from South Africa's Western Cape province through June 9, 2020 suggest that PLWH were 2.3 times as likely to die from COVID-19 as people without HIV, after age and sex standardization (17) .

Certainly, more information is needed. Surveillance data, such as those available from South Africa or Wuhan, will provide the most complete picture of COVID-19 risk among PLWH (e.g., by not restricting to PLWH who are in care and who are more likely to have wellcontrolled HIV disease); however clinical data, such as those from Madrid, may provide the most depth (e.g., by allowing examination of the role of comorbidities, medications, and COVID-19 treatments) as long as potential selection bias is considered. Perhaps the most fruitful investigation would be one that merged clinical and surveillance data.

Strict initial guidelines for testing for SARS-CoV-2 infection that restricted testing to people with a history of travel to Wuhan, and then to China, or to people with a known epidemiologic connection to a confirmed case limits our ability to accurately describe incidence of SARS-CoV-2 in PLWH. Even if testing were widely available, incidence estimates would be plagued by non-randomly missing data from people with poor access to health care, people who are avoiding healthcare settings for fear of contracting or transmitting SARS-CoV-2, and people who don't believe themselves to be infected.

New serologic assays for past exposure to SARS-CoV-2 are rapidly becoming available (18) . Sensitivity of serologic tests in PLWH with compromised immune systems who may not

mount a vigorous antibody response may be lower than the nominal sensitivity; unless test and patient characteristics are taken into account, serosurveys of PLWH may underestimate the true burden of SARS-CoV-2 infection. As with estimation of incidence, attempts to estimate prevalence of past SARS-CoV-2 infection in PLWH must take into account who is and is not included in any serosurvey. Some states are randomly sampling residents for serosurveys (19) ; if sampling strategies considered groups of special interest, including PLWH, these serosurveys may be an opportunity to get estimates of prior SARS-CoV-2 infection in PLWH.

Useful epidemiologic investigations into the impact of COVID-19 on PLWH will need to carefully consider the research question of interest and how results will be used. There is justified concern about labeling HIV as an -independent risk factor‖ for poor COVID-19

outcomes based on an arbitrary multivariable model as it may then be inappropriately used to ration care or guide treatment decisions. Ambiguity about the meaning of the term -independent risk factor‖ make it highly likely that results will be misinterpreted and misapplied (20, 21) . If interest is in identifying groups that should be monitored more closely for SARS-CoV-2 infection, this is a descriptive epidemiology question and crude analyses (or perhaps age-and sex-adjusted analyses) may be sufficient (22) . While the most appropriate adjustment set for descriptive epidemiology is an unresolved question, associations from a multivariable model are Matching factors included some confounders of the effect of HIV, such as admission date, age, gender, and tobacco history, but also included variables that might be considered mediators, such as body mass index, and history of chronic kidney disease, hypertension, asthma, chronic obstructive pulmonary disease, and heart failure (23) . In another matched cohort in New York, outcomes of people with and without HIV hospitalized for COVID-19 were similar even without adjusting for higher prevalence of chronic obstructive pulmonary disease, prior cancer, cirrhosis, and current smoking in PLWH (24) . in the data.

Certain antiretroviral medications, such as lopinavir-ritonavir (a protease inhibitor), were proposed and partially evaluated as treatments for other, similar coronaviruses (25) . However, a trial of 199 patients randomized to lopinavir-ritonavir versus standard of care found only small differences in time to clinical improvement (hazard ratio: 1.24, 95% confidence interval: 0.90, 1.72) and 28-day mortality (risk difference: -5.8%, 95% confidence interval: -17.3%, 5.7%).

There was some hint that the impact of lopinavir-ritonavir on mortality was stronger if treatment was administered closer to symptom onset, although results were imprecise. Results were reported as indicative of -no benefit‖ of lopinavir-ritonavir, although associations were suggestive of a potentially protective effect (26) . While these results do not support initiating

treatment with lopinavir-ritonavir in patients with SARS-CoV-2, they might suggest some benefit to PLWH on a lopinavir-ritonavir-containing antiretroviral therapy (ART) regimen who continue on treatment while infected with SARS-CoV-2.

Darunavir (another protease inhibitor) has also been hypothesized to potentially have therapeutic action against SARS-CoV-2, however no trial results are yet available.

Thus far, in cohort studies of COVID-19 among PLWH, ART regimen has not been consistently associated with disease incidence or severity. In a small cohort (n=88) of PLWH hospitalized with COVID-19 in New York City, New York, USA, being on a nucleoside reverse transcriptase inhibitor was protective against death (24) . In a cohort of over 77,000 PLWH receiving ART in Spain, being on a regimen containing tenofovir/emtricitabine (a nucleotide reverse transcriptase inhibitor and a nucleoside reverse transcriptase inhibitor, respectively) was protective against COVID-19 diagnosis and hospitalization (27) . Data on the association between ART regimen and COVID-19 outcomes are still too limited as to support or exclude an effect of any particular regimen.

Engagement in ongoing care is essential to the health of PLWH. HIV viral load and CD4 cell count should be monitored every 3-6 months (28) . In light of the risk of SARS-CoV-2 transmission associated with face-to-face contact, particularly in medical settings, many clinical encounters (for all people, including for PLWH) were rapidly changed to telehealth visits starting in March 2020 as SARS-CoV-2 cases started increasing rapidly (29) .

While telehealth visits eliminate the potential exposure to SARS-CoV-2 and thus may be necessary for some period, the costs and benefits associated with telemedicine need to be

enumerated and weighed. Prior to the SARS-CoV-2 outbreak, telehealth was studied as a potential intervention to increase access to care (30) particularly for PLWH with transportation difficulties and those living in rural settings (31) . However, offering telehealth to persons who opt-in is a different intervention than requiring telehealth visits to all persons in the midst of a pandemic, and may result in different outcomes.

There is, as yet, little data on the short and long-term impacts of the transition to telehealth on engagement in care and ART adherence for PLWH. In a narrative report, >90% of patients in a Missouri HIV clinic (presumably among those who successfully completed a telehealth visit) reported their telehealth visit during COVID-19 physical distancing restrictions was as good as or better than a traditional in-clinic visit (29) . Not provided was the number of patients who failed to complete a telehealth visit. At a clinic in Chicago, from late-March to mid-April, only 21% of scheduled visits were carried out virtually; 31% were rescheduled, 2% occurred in person, and 46% were not attended (16) . The impact of telehealth on high-need patients and new patients who have not yet established rapport with their providers has yet to be described (7).

Despite some good telehealth outcomes for some PLWH, telehealth has the potential to exacerbate disparities in care for people with lower socio-economic status: lack of necessary technology and services, technology literacy, and safe, confidential surroundings to participate fully in telehealth may be barriers to engagement in care (32 distancing restrictions if they need to go outside their homes to access alcohol or other drugs, or critically, medication assisted treatments (such as methadone or buprenorphine).

Poor baseline mental health is likely to be exacerbated by physical distancing restrictions (42) . PLWH, particularly older PLWH, are already at high risk of social isolation (43, 44) , and social structures and creative outlets that have helped people cope in the past may be dismantled under physical distancing restrictions. Breaking with physical distancing policy to seek out these coping outlets may be associated with additional stress due to fears of SARS-CoV-2 exposure or stigma. Accurate estimates of the risk associated with such activities for PLWH are critical to help individuals weigh the risk and benefits of participating in them, but are not currently available. People able to shelter in place in their homes, may face additional stressors at home, if they are alone in their home, if being at home imposes additional caregiving responsibilities, or if they live with someone who poses a physical or emotional threat.

For persons with diagnosed mental health disorders, physical distancing restrictions and the transition to telehealth may lead to difficulty receiving or fully engaging in behavioral treatments for those disorders. Indeed, while delivery of mental health counseling may be one of the medical services most amenable to delivery via video conferencing, it may also serve as a ‗canary in the coal mine' for emergent disparities due to access to technology and private, safe spaces to participate in counseling (30, 45) . For example, one HIV clinic in Chicago, Illinois, USA reported some patients who had been receiving mental health counseling prior to the institution of physical distancing measures temporarily discontinued services when they were offered via telehealth, but other patients engaged in tele-counseling for the first time.

Engagement in tele-counseling was universal among patients with stable income and housing, but entirely absent among patients who were unstably housed with no steady source of income;

in lieu of tele-counseling, the latter group of patients received peer counseling, which was more flexible with respect to the time and locations in which it could occur (16) . In addition to exacerbated mental health symptoms as a result of physical distancing, persons with severe mental health symptoms may be at higher risk for SARS-CoV-2 infection if their understanding of public health messaging is impaired, and if they do not understand their risk and how to mitigate it (46) .

The HIV epidemic has disproportionately impacted marginalized communities: people belonging to minority racial or ethnic groups, and in particular women of color, young men of color who have sex with men, people who inject drugs, transgender individuals, and people with a history of incarceration. The same structures that placed these groups at higher risk for HIV, including racism, stigmatization, limited economic opportunities, oppression, also place them at higher risk for SARS-CoV-2, such that the term syndemic has been used to describe these overlapping epidemics and vulnerabilities (47, 48) . Less than 6 months into the COVID-19

pandemic, we are already seeing staggering disparities in the proportion of confirmed SARS-CoV-2 infections and COVID-19 deaths in Black Americans, and persons in homeless shelters and prisons (49) (50) (51) (52) . Persons with limited income are likely to be able to take some precautions that require financial resources, such as driving in lieu of taking public transportation (53), stockpiling groceries, or paying for grocery delivery. Indeed, even in the first two weeks of implementation of physical distancing regulations in Alabama, USA, there was increased need for wrap-around social services such as provision of nutritional and personal care items (54) .

There is likely to be increased need for services among PLWH who were already receiving such services, and also increasing number of people in need of services.

Data that can help answer many of these questions are already being collected (or their collection is planned), but not yet available for analyses. Because many cohorts of PLWH pre- around HIV provides many opportunities to answer some of these outstanding questions, as long as we adhere to good epidemiologic principles with regards to asking well-defined questions.

Leveraging these opportunities to inform public health practice, requires that the specific research question being addressed is clearly stated, and appropriate analyses for answering that questions are applied. 

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