People with HIV are more likely to experience ‘long COVID’ symptoms and to experience serious cardiovascular and metabolic disorders and cancers after being diagnosed with COVID-19, a large US study has found. Two US researchers involved in long COVID research say there is an urgent need to understand why people with HIV are more vulnerable to long COVID and to include them in clinical trials of potential long COVID treatments.
‘Long COVID’ is the label given to a range of symptoms that linger or appear after an acute episode of COVID-19. The most common long COVID symptoms are fatigue, weakness, joint and muscle pain, loss of smell, shortness of breath, cognitive dysfunction and loss of concentration. A large UK study found that three to four months after developing COVID, around 5% of people still had symptoms.
Several small studies have shown an increased risk of long COVID symptoms in people with HIV. A University of California San Francisco study compared immune system markers and symptoms in 39 people with HIV recovering from COVID-19 contracted prior to vaccination and an HIV-negative control group of 43 people. The study found that four months after being diagnosed with COVID-19, people with HIV were approximately twice as likely to report new or worsening symptoms including fatigue, muscle pain, concentration problems, vision problems and trouble sleeping.
The same research group looked at risk factors for long COVID symptoms in 280 people with a COVID-19 diagnosis, 208 of whom had post-COVID-19 symptoms. Of those with post-COVID symptoms, 97 had more than five symptoms. Twenty per cent of those with post-COVID symptoms were living with HIV and neurocognitive and gastrointestinal symptoms were more than twice as common in people living with HIV. The study found that among all participants, recent Epstein-Barr virus reactivation was associated with a higher likelihood of reporting fatigue.
A third study, still undergoing peer review and issued as a pre-print, looked at the incidence of severe post-COVID events and prolonged symptoms in 3,048,792 people who tested positive for SARS-CoV-2 at 69 health care organisations in the United States up to September 2022. One per cent (28,904) were living with HIV. People with HIV were significantly more likely to have an underlying health condition associated with increased risk of severe COVID-19, as well as having a higher prevalence of elevated lipid levels and statin use. The median CD4 count was high (573) and 29% were taking tenofovir, which has been shown to reduce the risk of severe COVID outcomes in some studies.
The study found that after matching for demographic factors and underlying health conditions, people with HIV had a moderately increased risk of developing new-onset diabetes, heart disease, thrombosis or any cancer more than 28 days after COVID-19 diagnosis. HIV raised the risk of being newly diagnosed with diabetes, heart disease or thrombosis by approximately a quarter and raised the risk of a new cancer diagnosis by two-thirds compared to people without HIV. For people with HIV, the risk of severe post-COVID events was between two and three times higher in the pre-Delta variant period (before July 2021) than later, with the greatest difference in risk noted for malignancy (odds ratio 2.88).
The study also found that people with HIV were approximately 30-80% more likely to experience the persistence of several COVID-related symptoms depending on the symptom, including respiratory (cough, shortness of breath), headache, fatigue, gastrointestinal, cognitive impairment or body aches. For people with HIV, the odds of experiencing persistent symptoms after a COVID-19 diagnosis were two to two-and-a-half times higher in the pre-Delta period.
Nine per cent of people with HIV diagnosed with COVID-19 had been vaccinated against the virus (vaccination began in the United States in December 2020 and the authors do not specify what proportion of COVID-19 diagnoses occurred before this time). COVID-19 vaccination was associated with a significantly reduced risk of death and serious events, as well as a 40-50% reduction in the risk of persistent symptoms.
Although the risk of serious events and long COVID symptoms was higher in people with HIV, there was no correlation between CD4 count or viral load and risk.
Why might people with HIV be at higher risk of serious post-COVID events and persistent long COVID symptoms? In a recent review article, Dr Michael Peluso at University of California San Francisco and Dr Annukka Antar at Johns Hopkins University Medical School explore several mechanisms and outline research questions:
- Inflammation: People with HIV have higher levels of inflammation – does this exacerbate inflammation caused by acute COVID-19 that contributes to post-COVID health problems?
- SARS-CoV-2 binds to the ACE-2 receptor on human cells, activating the renin-angiotensin pathway, a regulator of blood pressure and cardiovascular function. Does this lead to the increased frequency of these events in people with HIV, who already have a higher cardiovascular risk due to HIV, treatment-related factors and comorbidities?
- Persistence of SARS-CoV-2 antigen due to impaired immune functions and incomplete clearance from tissue reservoirs: might HIV-related immune dysregulation further impair the immune system’s ability to clear SARS-CoV-2 after acute illness?
- Exacerbation of endothelial dysfunction by SARS-CoV-2: Endothelial dysfunction leads to narrowing of the arteries and is more common in people with HIV. Does this contribute to the higher rate of serious post-COVID cardiovascular events in people with HIV?
- Exacerbation of microbial translocation due to ‘leaky gut’ and major imbalances in the microbiome: some long COVID symptoms may be due to loss of gut wall integrity due to SARS-CoV-2 infection, or to changes in the bacterial population in the gut. Again, HIV causes microbial translocation and affects the microbiome. Might it exacerbate these long COVID pathways?
- Epstein-Barr virus reactivation due to impaired CD8+ cell responses: Epstein-Barr virus is more common in people with HIV. If acute COVID-19 can trigger reactivation of this virus, do defects in cellular immunity caused by HIV, especially the loss of CD8 T-cells which clear virus-infected cells, contribute to this pathway?
"People with HIV need to be included in clinical trials of interventions to manage long COVID."
The researchers say that more intensive research is needed to investigate the burden of long COVID in people with HIV, as well as to understand whether HIV-related mechanisms are contributing to the increased risk of serious clinical events and long-term COVID symptoms in people with HIV. Critically, people with HIV need to be included in clinical trials of interventions to manage long COVID.
But the researchers say that long COVID symptoms in people with HIV need to be thoroughly investigated to rule out other causes, including antiretroviral side-effects, comorbid conditions and psychosocial conditions.
Peluso MJ, Antar A. Long COVID in people living with HIV. Current Opinion in HIV/AIDS, 18(3):126-134, 2023.
Yedewa GA et al. HIV infection is associated with higher risk of Post-Acute Sequelae of SARS-CoV-2 (PASC) however vaccination is protective. SSRN pre-print, 15 November 2022 (open access).