HIV and COVID-19: A collision of 2 pandemics

COVID-19 remains a significant public health threat even 3 full years into the pandemic. Case volume has been huge, with more than 761.4 million confirmed cases of COVID-19 and more than 6.89 million reported deaths as of April 4, 2023.¹ In addition, HIV has continued to affect an enormous number of individuals, with an estimated 38.4 million people living with HIV worldwide in 2021 and 650,000 people dying of HIV-related illnesses in 2021.² There has never been a pandemic that overlapped on this scale with HIV, and so it is crucial to better understand the interplay between these 2 events.

In this update, we will discuss the evidence for increased COVID-19 severity among people living with HIV. We will discuss the ways that disruptions in care during the COVID-19 pandemic have impacted people with HIV. We will provide an update on COVID-19 vaccines for these patients. Finally, we will discuss therapeutic considerations for people living with HIV who develop COVID-19.

Is HIV infection associated with increased COVID-19 disease severity?

Relatively early in the COVID-19 pandemic, some studies did not establish a clear association between well-controlled HIV infection and increased severity of illness from COVID-19. However, many of these early studies included a relatively small number of patients with HIV and had limited power to detect differences in clinical outcomes.^3-5 Some larger early studies did show an increased risk for mortality from COVID-19 among people with HIV. For example, a large early study in South Africa included 22,308 patients diagnosed with COVID-19 between March and June 2020, of whom 3,978 (18%) had HIV.⁶ This study found that HIV infection was independently associated with COVID-19 mortality, with similar risks independent of HIV RNA level or CD4 cell count.

Given these conflicting early data, larger and more recent studies were crucial to understanding the link between well-controlled HIV and COVID-19 severity. A study by Bertagnolio et al analyzed data from 197,479 patients with COVID-19, of whom 16,955 had HIV.⁷ The study assessed whether people living with HIV were at higher risk for severe illness or mortality from COVID-19 than individuals without HIV. Most of those studied (91%) were on antiretroviral therapy (ART) at the time of COVID-19 diagnosis. When compared with similar individuals without HIV, they found people with HIV had a 15% increased odds of severe or critical presentation with COVID-19 after adjusting for other comorbidities. HIV infection was also associated with a 38% increased likelihood of in-hospital mortality from COVID-19. In addition, several recent meta-analyses found increased risk for mortality due to COVID-19 among people living with HIV compared with HIV-uninfected counterparts.^8-10 With this updated evidence, we can conclude that there is likely an independent association between HIV infection and increased disease severity and mortality from COVID-19, even among people with well-controlled HIV.

In addition to understanding the link between well-controlled HIV and severe COVID-19, it is important to understand the association between uncontrolled or advanced HIV and COVID-19 severity. Multiple studies have found that low CD4 cell count and HIV viremia are substantial risk factors for the development of severe COVID-19 and COVID-19–related mortality. For example, a large South African cohort study found that among people living with HIV, COVID-19 mortality was associated with lower recent CD4 cell count, HIV RNA, and no evidence of a recent antiretroviral prescription.¹¹ A subgroup analysis of the Bertagnolio study discussed above found a strong association between HIV RNA of more than 1,000 copies/mL and CD4 cell count less than 200/mm³ and COVID-19–related mortality.¹² In this study, patients with low CD4 cell counts or HIV viremia had nearly double the risk for in-hospital mortality compared with their counterparts without HIV infection. A US-based study of 649 patients with HIV who were diagnosed with COVID-19 found that CD4 cell count less than 350/mm³ or lowest recorded prior CD4 cell count less than 200/mm³ was associated with increased risk for hospitalization.¹³

Based on the evidence, there is a clear link between HIV infection and increased disease severity and mortality from COVID-19, particularly in individuals with low CD4 counts and high HIV viremia. This association highlights the importance of ensuring adequate funding and support are allocated to vaccination and care for people living with HIV.

What are possible mechanisms linking increased disease severity of COVID-19 and HIV infection?

As discussed above, there is evidence for increased disease severity and mortality from COVID-19 for people living with HIV. Increasing comorbidities in this population and disparities in access to care, discussed further below, likely play a role in this association. However, many of the studies above controlled for comorbidities and other factors, and yet, this association between COVID-19 severity and HIV infection persisted. Both immunodeficiency and immune dysregulation have been posited to contribute to the increased risk for COVID-19 severity among people with HIV.

Immunodeficiency is likely playing a major role in severe COVID-19 outcomes for patients with low CD4 cell counts or HIV viremia. Patients with other immunodeficiencies, such as those who have received an organ transplant, are also at higher risk for severe disease and mortality from COVID-19.¹⁴ HIV pathophysiology is likely also partly responsible for the increased severity of illness related to COVID-19 among those with HIV. Untreated HIV leads to T-cell lymphopenia, which has been shown to be associated with worse outcomes related to COVID-19 among people with and without HIV.^15,16

In patients with well-controlled HIV whose CD4 cell counts are in the normal range, it has been posited that immune dysregulation may be a significant contributing factor. People with HIV have increased chronic inflammation compared with similar age-matched controls, even while on virally suppressive ART. Excessive inflammation has been linked to the increase in other comorbidities among these patients, such as malignancy and cardiovascular disease.^17,18 Similarly, elevated inflammatory markers have been associated with increased severity of COVID-19.¹⁹ However, the impact of this potential mechanism is still somewhat uncertain, and further study is needed to better understand the etiology of the link between well-controlled HIV and severe COVID-19.

How has the COVID-19 pandemic affected the HIV care cascade?

In addition to the direct impact of COVID-19 on people living with HIV, this population has been disproportionately harmed by disruptions in healthcare access and use during the COVID-19 pandemic, compromising overall health outcomes. Early in the COVID-19 pandemic, there were significant disruptions in outpatient medical care for those with HIV infection, including difficulties in accessing testing and laboratory monitoring, ART, and in-person clinic visits. Nationwide sequester in place orders and closures of clinics directly impacted people with HIV. For example, a study in the United States analyzed HIV service interruptions at Ryan White–supported clinics during the initial COVID-19 pandemic and found that nearly 56% were partially interrupted and 26% were completely closed.²⁰ Clinics with a higher percentage of uninsured patients were more likely to see service interruption, highlighting inequities in access to care. A study in Uganda found that during its COVID-19–related national closures, clinic visits by people with HIV decreased 50% and the risk for running out of ART increased from 5% to 25%.²¹ A large international study of people living with HIV found that 1 in 5 reported being unable to reach their provider during the early COVID-19 pandemic and almost half were unable to refill their prescriptions for HIV medications.²² In addition, physicians who typically provided HIV care may have been diverted to COVID-19–related care, particularly early in the pandemic, making it more challenging for patients to access their regular providers.²³

Overall, these disruptions have had a significant negative impact on this patient group in terms of access to care and overall health. A modeling study highlighted that even a temporary disruption in access to ART could lead to a 10% increase in mortality among people with HIV living in low- and middle-income countries.²⁴ Ensuring access to clinicians and antiretroviral medication is crucial for the care of patients with HIV.

Are there specific considerations for COVID-19 vaccination in people with HIV?

Vaccines against COVID-19 are our most effective public health tool for prevention of severe disease related to COVID-19. However, there may be differences in vaccine immunogenicity among people with HIV. For people with well-controlled HIV and normal CD4 cell counts, several studies have confirmed a good response to vaccination based on anti–SARS CoV-2 antibody development.^25,26 This antibody response is similar to that seen for matched controls without HIV infection. However, for those with low CD4 cell counts, multiple studies have shown lower immunologic response to COVID-19 vaccines. For example, one study found significantly lower antibody response in people with HIV whose CD4 counts are less than 250 cells/mm³ and another found significantly lower antibody response in those with CD4 counts less than 500 cells/mm³, with an especially poor response in those with CD4 cell counts less than 200/mm³.^25,27 For people with low CD4 cell counts, although vaccination is still recommended, they may not be getting the same protection as those with more robust immune systems; as a result, they should receive COVID-19 therapies if they develop COVID-19 infection.

Besides the possibility of decreased antibody response for people with HIV, there is evidence that they have an increased risk for breakthrough COVID-19 infections after vaccination. A large cohort study found that the risk for breakthrough infection was 28% higher in people with HIV than in those without HIV.²⁸ In this study, a CD4 cell count of greater than 500/mm³ was associated with a lower rate of breakthrough infections. For those with breakthrough infections, people with HIV with CD4 cell counts less than 350/mm³ had a 59% increased risk for severe illness from COVID-19 compared with individuals without HIV.²⁹

The COVID-19 vaccination schedule is similar for people with and without HIV. For HIV patients who are not significantly immunocompromised, the current recommendation includes a 2-dose primary series for the mRNA vaccines followed by a bivalent booster at least 2 months later. For those with moderate or severe immunocompromise, the current recommendation includes a 3-dose primary series for the mRNA vaccines followed by a bivalent booster at least 2 months later.

Are there any specific treatment considerations for people with HIV?

For high-risk, non-hospitalized patients with mild to moderate COVID-19, the National Institutes of Health and Infectious Diseases Society of America guidelines both recommend treatment with nirmatrelvir/ritonavir (Paxlovid, Pfizer) or IV remdesivir (Veklury, Gilead); if neither is available or appropriate, then molnupiravir (Lagevrio, Merck) is an alternative choice.^30,31

Remdesivir directly inhibits viral replication and is given as an IV infusion over 3 consecutive days. It can be considered particularly for patients on other medications that interact with nirmatrelvir/ritonavir. Management of people with HIV and COVID-19 is the same as management for the general population. Patients on ART that includes ritonavir or cobicistat may receive nirmatrelvir/ritonavir without altering or interrupting their ART.

For hospitalized patients with severe COVID-19, the open-label RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial from the United Kingdom showed that dexamethasone at a dose of 6 mg per day for 10 days provided a 28-day mortality benefit versus the usual-care arm (relative risk, 0.83; 95% CI, 0.75-0.93), with the difference more pronounced in those receiving mechanical ventilation (36% lower risk) than in those receiving supplemental oxygen therapy (18% lower risk).³² This study included a small number of people with HIV, but outcomes were not reported by HIV status. As with the management of COVID-19 in the outpatient setting, management of hospitalized people with HIV with severe COVID-19 is the same as management of patients without HIV. People with HIV should receive steroids if indicated based on COVID-19 severity. However, it is important to assess for drug interactions, as dose adjustments of antiretroviral medications may be needed in some cases.³³

Conclusion

The COVID-19 pandemic has had a huge impact on people living with HIV and led to significant morbidity and mortality. HIV infection is an independent risk factor for increased COVID-19 severity and increased mortality risk, possibly related to HIV-related immunosuppression and immune dysregulation. The COVID-19 pandemic has also impeded access to HIV care and medications for these patients. The collision of these 2 pandemics highlights the need to continue to strengthen health services, preventive care, and treatment for people with HIV around the world.

References

1. World Health Organization. WHO coronavirus (COVID-19) dashboard. Accessed April 4, 2023. https://covid19.who.int/
2. World Health Organization. Summary of the global HIV epidemic 2021. Updated July 2022. Accessed March 24, 2023. https://www.who.int/ data/ gho/ data/ themes/ hiv-aids
3. Lee MJ, Smith C, Fidler S, et al. HIV and COVID-19 inpatient outcomes: a matched retrospective multicentre analysis. Top Antivir Med. 2021:29(1):41.
4. Gervasoni C, Meraviglia P, Riva A, et al. Clinical features and outcomes of HIV patients with coronavirus disease 2019. Clin Infect Dis. 2020 May 14:ciaa579. doi:10.1093/cid/ciaa579
5. Karmen-Tuohy S, Carlucci PM, Zervou FN, et al. Outcomes among HIV-positive patients hospitalized with COVID-19. J Acquir Immune Defic Syndr. 2020;85(1):6-10.
6. Marais F, Mudaly V, Voget J, et al. Risk factors for COVID-19 death in a population cohort study from the Western Cape Province, South Africa. Clin Infect Dis. 2021:73;7:e2005-e2015.
7. Bertagnolio S, Thwin SS, Silva R, et al. Clinical features of, and risk factors for, severe or fatal COVID-19 among people living with HIV admitted to hospital: analysis of data from the WHO Global Clinical Platform of COVID-19. Lancet HIV. 2022 May 10. doi:10.1016/S2352-3018(22)00097-2
8. Mellor MM, Bast AC, Jones NR, et al. Risk of adverse coronavirus disease 2019 outcomes for people living with HIV. AIDS (London, England). 2021;35(4):F1.
9. Hariyanto TI, Rosalind J, Christian K, et al. Human immunodeficiency virus and mortality from coronavirus disease 2019: a systematic review and meta-analysis. South Afr J HIV M. 2021;22(1):1-7.
10. Moradi Y, Soheili M, Dehghanbanadaki H, et al. The effect of HIV/AIDS infection on the clinical outcomes of COVID-19: a meta-analysis. J Pharm Pharm Sci. 2022;25:183-192.
11. Kassanjee R, Davies MA, Ngwenya O, et al. COVID-19 among adults living with HIV: correlates of mortality in a general population in a resource-limited setting. medRxiv. 2022 Jan 1. doi:10.1101/2022.10.17.22281085
12. Bertagnolio S, Silva R, Nagarajan S, et al. Are people living with HIV at higher risk of severe and fatal COVID-19? Presented at: AIDS 2022; July 29-August 2; Montreal, Canada. Abstract OAB0404.
13. Shapiro AE, Ignacio RA, Whitney BM, et al. Factors associated with severity of COVID-19 disease in a multicenter cohort of people with HIV in the United States, March-December 2020. J Acquir Immune Defic Syndr. 2022;90(4):369-376.
14. Raja MA, Mendoza MA, Villavicencio A, et al. COVID-19 in solid organ transplant recipients: a systematic review and meta-analysis of current literature. Transplant Rev (Orlando). 2021;35(1):100588.
15. Zhao Q, Meng M, Kumar R, et al. Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a systemic review and meta-analysis. Int J Infect Dis. 2020;96:131-135.
16. Peng X, Ouyang J, Isnard S, et al. Sharing CD4+ T cell loss: when COVID-19 and HIV collide on immune system. Front Immunol. 2020;11:596631.
17. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51(3):268-273.
18. Peterson TE, Baker JV. Assessing inflammation and its role in comorbidities among persons living with HIV. Curr Opin Infect Dis. 2019;32(1):8-15.
19. Ji P, Zhu J, Zhong Z, et al. Association of elevated inflammatory markers and severe COVID-19: a meta-analysis. Medicine. 2020;99(47):e23315.
20. Qiao S, Li Z, Weissman S, et al. Disparity in HIV service interruption in the outbreak of COVID-19 in South Carolina. AIDS Behav. 2021;25(1):49-57.
21. Wagner Z, Mukasa B, Nakakande J, et al. Impact of the COVID-19 pandemic on use of HIV care, antiretroviral therapy adherence, and viral suppression: an observational cohort study from Uganda. J Acquir Immune Defic Syndr 2021;88(5):448.
22. Rao A, Rucinski K, Jarrett B, et al. Potential interruptions in HIV prevention and treatment services for gay, bisexual, and other men who have sex with men associated with COVID-19. MedRxiv. 2020 Jan 1. doi: 10.1101/2020.08.19.20178285
23. Kowalska JD, Skrzat-Klapaczynska A, Bursa D, et al. HIV care in times of the COVID-19 crisis—where are we now in Central and Eastern Europe? Int J Infect Dis. 2020;96:311-314.
24. Hogan AB, Jewell BL, Sherrard-Smith E, et al. Potential impact of the COVID-19 pandemic on HIV, tuberculosis, and malaria in low-income and middle-income countries: a modelling study. Lancet Global Health. 2020;8(9):e1132-1141.
25. Nault L, Marchitto L, Goyette G, et al. Covid-19 vaccine immunogenicity in people living with HIV-1. Vaccine. 2022;40(26):3633-3637.
26. Liu Y, Han J, Li X, et al. COVID-19 vaccination in people living with HIV (PLWH) in China: a cross sectional study of vaccine hesitancy, safety, and immunogenicity. Vaccines. 2021;9(12):1458.
27. Hassold N, Brichler S, Ouedraogo E, et al. Impaired antibody response to COVID-19 vaccination in advanced HIV infection. AIDS. 2022;36(4):F1-5.
28. Coburn SB, Humes E, Lang R, et al. Analysis of postvaccination breakthrough COVID-19 infections among adults with HIV in the United States. JAMA Netw Open. 2022;5(6):e2215934.
29. Lang R, Humes E, Coburn SB, et al. Analysis of severe illness after postvaccination COVID-19 breakthrough among adults with and without HIV in the US. JAMA Netw Open. 2022;5(10):e2236397.
30. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Infectious Diseases Society of America 2023; Version 10.2.1. Accessed March 24, 2023.
31. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed March 24, 2023.
32. RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704.
33. Jacobs TG, Marzolini C, Back DJ, et al. Dexamethasone is a dose-dependent perpetrator of drug–drug interactions: implications for use in people living with HIV. J Antimicrob Chemother. 2022;77(3):568-573.

By Kathleen W. Miller, MD, and Rajesh T. Gandhi, MD