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COVID-19 death in people with HIV: interpret cautiously - Comment
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Jan 2021 Lancet HIV - *Laura J Waters, Anton L Pozniak
Since the start of the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we have sought to understand the predictors of severe COVID-19 and mortality. Data show that age and chronic comorbidities are major risk factors, but what about immunosuppression? Patients with malignant disease and recipients of solid-organ transplants might be at increased risk, but evidence is less clear for people with other types of immunocompromise, including HIV.1 Are people with HIV, even those with well controlled viraemia and immune reconstitution, at risk of more severe COVID-19 and death or is the risk associated with overlapping demographic and comorbidity characteristics?
In The Lancet HIV, Khrishnan Bhaskaran and colleagues2 have analysed COVID-19 deaths in people with HIV from OpenSAFELY, a UK primary care database of 17⋅3 million adults. Mortality among the 27 480 people with HIV (0⋅16% of the study population) was higher than the general population with an adjusted hazard ratio of 2⋅59 (95% CI 1⋅74-3⋅84; p<0⋅0001). Unfortunately, due to lack of SARS-CoV-2 testing in the UK at the time of the study, there is no denominator of people with infection or people with symptoms but no confirmatory test. London, which has almost half of the UK's HIV cases, was under-represented, and missing data for ethnicity was generated by multiple imputations.
An analysis of people hospitalised with COVID-19 in the UK (ISARIC)3 also found a higher risk of mortality among people with HIV, albeit to a lesser degree, with an adjusted hazard ratio of 1⋅69 (95% CI 1⋅15-2⋅48; p=0⋅008). Neither study was able to fully adjust for confounders, and Bhaskaran and colleagues excluded people with missing age, sex, or index of multiple deprivation.
The "particularly marked" HIV association with COVID-19 death in people of Black ethnicity (HR 4⋅31 [95% CI 42-7⋅65] vs1⋅84 [1⋅03-3⋅26] in non-Black individuals) is in discord with the Public Health England data, which suggest a much smaller excess mortality among Black ethnic groups.4 Some key occupations seem to be at higher risk of COVID-19 in the UK5 and have a high proportion of workers from Black and minority ethnic groups,6 but Bhaskaran and colleagues could not adjust for occupation. This could account for some of the apparent mortality risk associated with ethnicity and is a potential confounder for the association between mortality and HIV.
People with HIV and no comorbidities might be less likely to be registered or to have shared their HIV status with their general practitioner, meaning those who are included in this analysis are more likely to have comorbidities and, thus, already at greater risk of worse COVID-19 outcomes. The role of comorbidities is further highlighted by this study's finding that there was no increased risk of COVID-19 death among people with HIV but no additional comorbidities, a crucial result in our view. The attenuation of effect when restricting the analysis with known, as opposed to imputed, body-mass index and smoking data shows that people with HIV might disproportionately have negative prognostic features.
Additionally, there is uncertainty as to the role of severe immunosuppression or uncontrolled viraemia in the risk for severe COVID-19 and death. A study from the Western Cape, South Africa,7 found an association, but data were not complete, because many participants had no recent viral load or CD4 count. Similar to ISARIC,3 the analysis of OpenSAFELY could not adjust for HIV treatment or surrogate markers of HIV control, which is a major limitation. Although the authors claim that research is hampered by policy guidance that restricts the flow of HIV data, we are not aware of any policy guidance that cautions against sharing HIV-associated information in primary care. On the contrary, there is referenced guidance that encourages data sharing.8
Understanding who is at high risk of worse COVID-19 outcomes, and why, is essential to guiding advice and prevention efforts. Bhaskaran and colleagues have brought important findings into the public domain about the risk of death from COVID-19 in people with HIV and are frank about the strengths and weaknesses of their study. Nevertheless, they draw a strong conclusion on risk, stating that HIV was associated with increased risk of COVID-19 death. This statement might overshadow their other findings of a low absolute mortality of less than 0⋅1% and that 23 (92%) of 25 people with HIV who died had comorbidities and the remaining two (8%) were not of increased risk of death. An interpretation of this study that might better serve people living with HIV in the UK and the clinicians that treat them is that their findings are important, but their conclusion should be taken with caution until we have more specific controlled data to assess the effects of HIV on COVID-19 outcomes.
HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform Jan 2021 Lancet HIV
People with HIV in the UK seem to be at increased risk of COVID-19 mortality. Targeted policies should be considered to address this raised risk as the pandemic response evolves.
17 282 905 adults were included; 27 480 (0⋅16%) were living with HIV and 17 255 425 (99⋅84%) did not have HIV (figure 1). People with HIV had similar median age, but a narrower age distribution overall, compared with those without HIV; there was a substantially lower proportion of people older than 70 years in the HIV group (1146 [4⋅2%] in those with vs 3 070 564 [17⋅8%] in those without HIV; table 1). People living with HIV were more likely to be male, of Black ethnicity, and from a more deprived area. 921 (3⋅4%) individuals with HIV had chronic liver disease, compared with 99 214 (0⋅6%) of those in the comparison group.
There were 25 COVID-19 deaths among people with HIV during 10 680 person-years of follow-up and 14 857 COVID-19 deaths among those without HIV during 6⋅70 million person-years of follow-up (table 2). 68 638 individuals (0⋅4%) died from non-COVID-19 causes and were censored. Between Feb 1 and June 22, 2020, estimated cumulative COVID-19 mortality among all study participants, standardised to the covariate distribution of the HIV group, was 0⋅087% (95% CI 0⋅056-0⋅134) in people with HIV and 0⋅038% (0⋅036-0⋅040) in people without HIV (figure 2).
In this large population-based study using data from the OpenSAFELY platform in England, we found people with HIV to be at more than twice the risk of COVID-19 death compared with people without HIV, after accounting for demographic characteristics and lifestyle-associated factors. Absolute cumulative COVID-19 mortality was low, with less than 0⋅1% of people with HIV dying with COVID-19 as a cause during the study period, reflecting the young age profile of this population. The association between HIV and COVID-19 mortality seemed to be particularly pronounced among people of Black ethnicity, with HIV associated with a 4⋅3-fold higher risk of COVID-19 death in this group.

Whether HIV infection is associated with risk of death due to COVID-19 is unclear. We aimed to investigate this association in a large-scale population-based study in England.
We did a retrospective cohort study. Working on behalf of NHS England, we used the OpenSAFELY platform to analyse routinely collected electronic primary care data linked to national death registrations. We included all adults (aged ≥18 years) alive and in follow-up on Feb 1, 2020, and with at least 1 year of continuous registration with a general practitioner before this date. People with a primary care record for HIV infection were compared with people without HIV. The outcome was COVID-19 death, defined as the presence of International Classification of Diseases 10 codes U07.1 or U07.2 anywhere on the death certificate. Cox regression models were used to estimate the association between HIV infection and COVID-19 death; they were initially adjusted for age and sex, then we added adjustment for index of multiple deprivation and ethnicity, and then for a broad range of comorbidities. Interaction terms were added to assess effect modification by age, sex, ethnicity, comorbidities, and calendar time.
17 282 905 adults were included, of whom 27 480 (0⋅16%) had HIV recorded. People living with HIV were more likely to be male, of Black ethnicity, and from a more deprived geographical area than the general population. 14 882 COVID-19 deaths occurred during the study period, with 25 among people with HIV. People living with HIV had higher risk of COVID-19 death than those without HIV after adjusting for age and sex: hazard ratio (HR) 2⋅90 (95% CI 1⋅96-4⋅30; p<0⋅0001). The association was attenuated, but risk remained high, after adjustment for deprivation, ethnicity, smoking and obesity: adjusted HR 2⋅59 (95% CI 1⋅74-3⋅84; p<0⋅0001). There was some evidence that the association was larger among people of Black ethnicity: HR 4⋅31 (95% CI 2⋅42-7⋅65) versus 1⋅84 (1⋅03-3⋅26) in non-Black individuals (p-interaction=0⋅044).

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