Thursday 30 April 2020
The first case series of HIV-patients with COVID-19 have been published (1-3). So far there is no evidence for a higher COVID-19 infection rate or different disease course in people living with HIV than in HIV-negative people.
Current evidence indicates that the risk of severe illness increases with age, male sex and with certain chronic medical problems such as cardiovascular disease, chronic lung disease and diabetes. Although people living with HIV who are on treatment with a normal CD4 T-cell count and suppressed viral load may not be at an increased risk of serious illness, many people with HIV have other conditions that increase their risk. Indeed, almost half of people living with HIV in Europe are older than 50 years and chronic medical problems, such as cardiovascular and chronic lung disease, are more common in people living with HIV. Smoking is a risk factor for respiratory infections; smoking cessation should therefore be encouraged for all patients. Influenza and pneumococcal vaccinations should be kept up to date.
It has to be assumed that immune suppression, indicated by a low CD4 T-cell count (<200/µl), or not receiving antiretroviral treatment, will also be associated with an increased risk for a more severe disease presentation. For patients with low CD4-counts (<200/ml), or who experience a CD4-decline during a COVID-19 infection, remember to initiate opportunistic infection (OI) prophylaxis. More information regarding recommendations for prophylaxis and treatment of specific opportunistic infections can be found in the BHIVA/EACS guidelines for HIV/AIDS.
First reports suggest a growing evidence for potential COVID-19 vertical transmission [4-6]. So far clinical outcome of the newborn however, has been very good.
Existing national guidelines should be followed in terms of reducing risk for acquiring a COVID-19 infection and managing symptoms [7-9].
Expedited research and publication are welcomed with the caveat that results may be disseminated pre-publication and/or published without usual peer review. There is ongoing discussion and research around some HIV antiretrovirals which may have some activity against COVID-19. The first randomised clinical trial with lopinavir/ritonavir demonstrated no benefit over standard care in 199 hospitalised adults with severe COVID-19 . There is no evidence to support the use of other antiretrovirals, including protease inhibitors; indeed, structural analysis demonstrates no darunavir binding to COVID-19 protease.
Despite lack of in-vitro data to support antiviral activity of TDF/FTC against CoV-2 , and only molecular docking evidence , which may not be predictive of activity, and limited binding data , a large randomised phase 3 placebo-controlled study in Spain using the HIV PrEP combination TDF/FTC and low-dose hydroxychloroquine (HCQ) as prophylaxis for COVID-19 in health workers is planned . The observation that there have been COVID-19 infections in HIV-patients on TDF or TAF at least speaks against a complete protection from these agents. Clearly, the trial results have to be awaited to shed light on the usefulness of this PEP strategy.
Currently no evidence is available to justify switching a patient from their usual antiretroviral therapy. Additionally there is no evidence to support HIV-negative people taking antiretrovirals outside the context of pre-exposure prophylaxis (PrEP) to prevent HIV acquisition – PrEP should be taken as directed and there is no current evidence that PrEP is effective against COVID-19.
A recent case series on hydrochloroquine, with or without azithromycin, was not able to demonstrate a clear clinical benefit, despite in vitro inhibition of SARS-CoV-2, due to methodological issues ; although the same group has postulated an infection control benefit of more rapid viral clearance there was a lack of control arm for comparison . One small RCT demonstrated trends for reduced time to clinical recovery and short-term radiological improvement for hydroxychloroquine , though another showed no benefit in terms of viral clearance, clinical or radiological endpoints . Despite lack of evidence, indeed no acute viral infection has ever been successfully treated with either product , the FDA has issued an Emergency Use Authorisation to allow hydroxychloroquine and chloroquine products to be used for certain hospitalised patients with COVID-19  while awaiting results from randomised trials. Of great concern are recently published results from a retrospective analysis of data from patients hospitalized with confirmed SARSCoV-2 infection in all United States Veterans Health Administration medical centers which found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19 and even found an association of increased overall mortality in patients treated with hydroxychloroquine alone . As a consequence the FDA now cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems.
A further potential drug candidate for treatment of COVID-19 is remdesivir, originally developed for Ebola therapy. Remdesivir has broad in vitro antiviral activity against SARS-CoV-2 . First cases from the expanded access program using remdesivir for COVID-19 patients suggested potential clinical benefit . More recently however, data published from a first randomized clinical trial from China in adults with severe COVID-19, demonstrated that remdesivir was not associated with statistically significant clinical benefits . Remdesivir was stopped early in 18 (12%) patients because of adverse effects, compared with 4 (5 %) in the control group . Of note, the study was stopped early due to low patient enrollment which may limit its power. Preliminary data on remdesivir was presented recently in an NIAID press release from the Adaptive COVID-19 Treatment Trial (ACTT), in which 1063 hospitalized patients with advanced COVID-19 and lung involvement randomized to remdesivir recovered faster than similar patients who received placebo . Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059) . Meanwhile, Gilead also reported top-line results from their late-stage SIMPLE study, showing that a five-day dosing duration of remdesivir led to "similar improvement in clinical status" as the 10-day treatment course being evaluated in the NIAID study and other ongoing trials. The initial phase of the SIMPLE trial, which is not placebo-controlled, randomised 397 hospitalised patients with severe manifestations of COVID-19 disease to receive intravenous remdesivir until either day five or 10, on top of standard care. An expansion phase of the study has recently been added and will enroll an additional 5600 patients, including patients on mechanical ventilation. The full results from these trials, as well as other ongoing clinical trials especially in early COVID-19 disease, are eagerly awaited.
A COVID-19 drug interactions website (www.covid19-druginteractions.org) has been developed for the experimental drugs being trialed to treat COVID-19 in different parts of the world. EACS and BHIVA are happy to announce that they have agreed to financially support this very useful website.
We would like to highlight two resources for reporting COVID-19 cases:
The NEAT ID Foundation has developed a ‘data dashboard’ to monitor COVID-19 case numbers, hospitalisations and mortality in people with HIV at European and country level. The data will be available for public viewing via www.NEAT-ID.org and if your centre has not signed up, you can do so via this link.
The Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) launched by the German Society for Infectious Diseases (DGI) and ESCMID’s Emerging Infections Task Force (EITaF) an open register based on anonymous questionnaires and they are keen to collaborate with other registries. See https://leoss.net, contact them by email at firstname.lastname@example.org and the register can be accessed here https://leoss.net/statistics
The coronavirus outbreak is rapidly evolving. EACS and BHIVA will continue to share any updates to specific guidance for people with HIV. Wishing you all well. Stay healthy.
1. Blanco JL, Ambrosioni J, Garcia F, Martínez E, Soriano A, Mallolas J, Miro JM; COVID-19 in HIV Investigators. COVID-19 in patients with HIV: clinical case series. Lancet HIV. 2020 Apr 15. pii: S2352-3018(20)30111-9.
2. Härter G et al. Infection (in press).
3. Guo W, Ming F, Dong Y et al. A Survey for COVID-19 among HIV/AIDS Patients in Two Districts of Wuhan, China. Preprint research paper, The Lancet, 2020.
4. Zeng L, et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA Pediatr 2020; DOI: 10.1001/jamapediatrics.2020.0878.
5. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during Pregnancy and Possible Vertical Transmission. Am J Perinatol. 2020 Apr 18. doi: 10.1055/s-0040-1710050. [Epub ahead of print]
6. Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S. Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission. Prenat Diagn. 2020 Apr 17. doi: 10.1002/pd.5713. [Epub ahead of print]
10. Cao B, Wang Y, Wen D et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; doi: 10.1056/NEJMoa2001282.
11. Choy KT, Wong AY, Kaewpreedee P et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020 Apr 3;178:104786. doi: 10.1016/j.antiviral.2020.104786.
12. Wu C, Liu Y, Yang Y et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020 Feb 27. doi: 10.1016/j.apsb.2020.02.008
13. https://www.biorxiv.org/content/10.1101/2020.03.18.997585v1; accessed 26th April 2020
14. https://clinicaltrials.gov/ct2/show/NCT04334928; accessed 26th April 2020
15. Gautret P et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. Int J Antimicrob Agents. 2020 Mar 20:105949. doi:10.1016/j.ijantimicag.2020.105949.
16. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf; accessed 31st March 2020
17. Chen Z, Hu J, Zhang Z et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020.03.22.20040758; doi: https://doi.org/10.1101/2020.03.22.20040758
18. Chen J, Liu D, Li L et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ. 2020; Mar. (DOI 10.3785/j.issn. 1008-9292.2020.03.03
19. Guastalegname M, Vallone A. Could chloroquine /hydroxychloroquine be harmful in Coronavirus Disease 2019 (COVID-19) treatment? Clin Infect Dis. 2020 Mar 24. pii: ciaa321. doi: 10.1093/cid/ciaa321.
20. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-30-2020; accessed 21st March 2020
21. Magagnoli m et al. medRxiv preprint doi: https://doi.org/10.1101/2020.04.16.20065920
22. Wang M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
23. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. doi:10.1056/NEJMoa2007016. [Epub ahead of print]
24. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; Published online April 29, 2020