HIV and antiretrovirals

Coronavirus disease (COVID-19):
HIV and antiretrovirals
29 November 2020
Q&A

Are people living with HIV at increased risk of being infected with the virus that causes COVID-19?
People living with HIV (PLHIV) who are not taking antiretroviral treatment (ART) and have a low CD4 cell count, particularly those with advanced HIV disease, are at increased risk of opportunistic infections and AIDS related complications.
However, there is evolving and conflicting evidence whether people living with HIV have an increased risk of acquisition of SARS-CoV-2 infection and and/or COVID-19 clinical complications in PLHIV compared to the general population.
PLHIV can have a greater prevalence of the known risk factors for COVID-19 acquisition and complications, such as heart disease, kidney disease, diabetes, chronic pulmonary disease, obesity, as well as, other comorbidities and co-infections, like tuberculosis.
Several case report series and small cohort studies among hospitalized PLHIV with COVID-19 have shown comparable clinical outcomes and similar risk of SARS CoV2 infection when compared with general population, particularly in those with well controlled HIV infection (on ART and with a CD4 count > 200 cells/mm3 and supressed viral load).
These limited clinical data suggest the mortality risk in PLHIV is associated with known COVID-19 factors such as older age and presence of comorbidities including cardiovascular disease, diabetes, chronic respiratory disease and obesity [1-3].
There have been several systematic and non-systematic reviews that evaluated COVID-19 outcomes among PLHIV; most have found comparable outcomes of mortality and morbidity when compared with HIV negative patients [4-8].
Methods did not always include assessment of outcomes while controlling for known COVID-19 risk factors [4].
There is also limited data in patients with advanced HIV disease (i.e. low CD4 cell count). 
One systematic review, notably published as a pre-print, found of 144,795 hospitalized COVID-19 patients in North America, Europe, and Asia the pooled prevalence of HIV in COVID-19 patients was 1.22% [95% (CI): 0.61%-2.43%)] translating to a 2-fold increase compared to the respective local-level pooled HIV prevalence in the general population of 0.65% (95% CI: 0.48%-0.89%) – which hinted at a potential susceptibility among PLHIV [9]. 
Additional data on this topic come from several cohort studies from South Africa, the USA and the UK [10-12] have reported a moderate increased risk of death directly attributed to HIV infection after adjustments for age, sex, ethnicity and presence of comorbidities; an unpublished meta-analysis including these studies found that the risk of death was almost double that of HIV-negative patients; however, confounding by comorbidities associated with increased risk of severe COVID-19 cannot be ruled out [13].
Protecting people living with HIV during the COVID-19 pandemic, and ensuring they can maintain treatment, is critical.
Researchers are currently investigating whether people with HIV have an increased risk of poor outcomes with COVID-19.
Preliminary evidence of moderate increased vulnerability of people with HIV makes it even more urgent that people with HIV have access to ARVs and treatments for co-morbidities – such as treatment for hypertension, cardiovascular disease, chronic pulmonary disease, diabetes, tuberculosis, and maintenance of a healthy body weight. 
A larger dataset from a broader geographical representation is required to expand understanding of how SARS-CoV-2 co-infection with HIV impacts the severity of illness, disease progression and outcomes from hospitalization with COVID-19.
For this purpose, WHO has established a Global COVID-19 Clinical Platform.
As of 4 November 2020, WHO has received clinical data from 79 000 patients hospitalised with confirmed or suspected COVID-19, including from 5 291 hospitalised patients living with HIV, from over 30 countries around the world.
The platform is open to all Member States and health facilities to contribute data and inclusion will help inform future guidance on how best to ensure PLHIV are well protected during the COVID-19 pandemic.
PLHIV are advised to take the same COVID-19 precautions as recommended for the general population [14-15]: wash hands often; practice cough etiquette; ensure physical distancing; wear masks when appropriate and according to local regulations; seek medical care if symptomatic; self-isolate if one develops symptoms or has contact with a positive  COVID-19 case; and other actions per the local and government response. 
It is important to ensure that PLHIV have access to antiretroviral drugs for longer periods (3-6 month supply); and that programmes practice multi-month dispensing (MMD) of ARVs, as well as, other necessary medications, such as, opiate substitution therapy (OST), TB preventative therapy (TPT) and treatments for comorbidities.
It is also important to ensure that some vaccinations are up to date (influenza and pneumococcal vaccines) and there is access to adequate supplies of medicines to treat or prevent co-infections and comorbidities.



Can antiretrovirals or direct-acting antivirals against hepatitis C virus be used to treat COVID-19?
Antiretrovirals drugs were initially considered for use in the treatment of COVID-19 based on virtual screening and in vitro studies.
Published data indicate that most of patients infected with the virus causing COVID-19 have mild to moderate symptoms, have good clinical outcomes and do not require hospitalization.
In some cases, patients admitted to the hospital were given an antiretroviral drug, most often lopinavir boosted with ritonavir (LPV/r) or, less frequently, darunavir boosted with ritonavir (DRV/r).
Studies assessing the potential benefit of an antiretroviral drug on COVID-19 were mostly carried out in HIV-negative individuals.
A systematic review on use of antiretrovirals in patients with coronaviruses, conducted in March 2020 identified two randomized trials and 21 observational studies provided clinical outcome data on the use of LPV/r for the treatment of COVID‐19, SARS and MERS [16].
The randomized trials showed no clinical benefit, the observational studies were inconclusive, and the certainty of the body of evidence across all important outcomes was low or very low quality.
A living systematic review and network meta-analysis on the efficacy and safety of drug treatments for COVID-19 published in September 2020 did not find any convincing evidence that antiretrovirals drugs such as lopinavir/ritonavir reduced the mortality or increased the rate of viral clearance [17].
More recently, two additional randomized studies confirmed these findings and didn't support the use of LPV/r for treatment of hospitalized patients with COVID-19.
A recently published clinical trial showed that in patients admitted to hospital with COVID-19, LPV/r was not associated with reductions in mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death [18].  
Similarly, in the WHO-coordinated Solidarity Trial recently published, LPV/r appears to have little or no effect on hospitalized COVID-19 patients, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. [19].
Based on available evidence, the use of LPV/r and other antiretrovirals are not likely to improve clinical outcomes in hospitalized individuals with COVID-19.
Several randomized and nonrandomized studies have evaluated anti-hepatitis C drugs including sofosbuvir and daclatasvir for treating of SARS-CoV-2 and while these preliminary results suggested benefit in terms of clinical recovery, this evidence is insufficient (small sample size, inclusion of a nonrandomized study) to be able to recommend using these antivirals for treating SARS-CoV-2. [20]



Can antiretrovirals be used to prevent COVID-19 infection?
A number of small studies have assessed whether antiretrovirals can be used to prevent infection from SARS-CoV2, often with discordant results.
A recent study suggests that people living with HIV who were using tenofovir disoproxil fumarate (TDF) were less likely to contract SARS-CoV-2.
However, other studies indicate that tenofovir-based HIV pre-exposure prophylaxis (PrEP) does not provide protection against infection with the new coronavirus, nor does it ameliorate the course of COVID-19 disease [21].
In this study, prevalence of SARS-CoV-2 was actually higher among people taking PrEP compared to individuals who were not.
Taken together, the available literature does not provide conclusive evidence that antiretrovirals could protect individuals from SARS-CoV-2 infection or from becoming seriously ill with the virus.
However, the certainty of the evidence is very low due to small sample size, and uncertainty regarding intensity of exposure.
People taking PrEP or who are taking ARVs with the hopes of preventing COVID-19 need to adopt the same COVID-19 prevention measures as recommended for people in the general population.



What is WHO’s position on the use of antiretrovirals for the treatment or prevention of COVID-19?
WHO does not currently recommend the use of antiretrovirals as treatment or prevention of COVID-19, outside of the context of clinical trials.
Existing published literature on antiretrovirals is mostly observational in nature, with few clinical trials; and does not provide good quality evidence in favour of these agents for these purposes.
The current body of evidence does not show benefit of using LPV/r and other antiretrovirals reduce the risk of new coronavirus infection or improve clinical outcomes in symptomatic disease among patients with COVID‐19.

More recently, two additional randomized studies confirmed these findings and didn't support the use of LPV/r for treatment of hospitalized patients with COVID-19.
The Recovery trial showed that LPV/r was not associated with reduction in mortality, time of hospitalisation stay and risk of progressing to invasive mechanical ventilation or death. [18] The interim results of the WHO multicounty adaptative trial (Solidarity trial) also found that LPV/r had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients with COVID-19 [19].



How do we ensure human rights and reduce stigma and discrimination?
As the world scales up public health responses to the COVID19 pandemic, countries are being urged to take decisive action to control the epidemic.
WHO has urged all countries to ensure an appropriate balance between protecting health, preventing economic and social disruption, and respecting human rights.
WHO is working with partners including the UNAIDS Joint Programme and the Global Network of People Living with HIV to ensure that human rights are not eroded in the response to COVID-19 and to ensure that people living with, or affected by, HIV are offered the same access to services as others and to ensure HIV-related services continue without disruption.
To mitigate potential prison outbreaks of COVID-19 and reduce morbidity and mortality among people in prisons and other closed settings, it is crucial that prisons and immigration detention centres are embedded within the broader public health response.
This requires close collaboration between health and justice ministries and includes protocols for entry screening, personal protection measures, physical distancing, environmental cleaning and disinfection, and restriction of movement, including limitation of transfers and access for non-essential staff and visitors.  
In the current context it is of critical importance that countries work toward developing non-custodial strategies to prevent overcrowding in closed settings [22].
Governance of prison health by a ministry of health, rather than a ministry of justice or similar, is likely to facilitate this approach [23].  



How can programmes assure continued access to HIV services?
Continuous access to essential HIV prevention, testing and treatment services must be assured, including in settings where measurements of confinement are implemented within the public health response to the COVID-19 pandemic.
Adapted and evidence-based measures to reduce possible transmission should be considered and implemented. These include [24]:
    Applying standard precautions for all patients (including ensuring that all patients cover their nose and mouth with a tissue or elbow when coughing or sneezing, offering a medical mask to patients with suspected COVID-19 infection while they are in waiting in the service, perform hand hygiene etc.)
    Health care and outreach workers, as well as peer educators and clients should apply hand hygiene and other protective measures
    Ensuring triage, early recognition, and source control (isolating patients with suspected COVID-19 infection)
    Ensure there is adequate ventilation in all areas in the healthcare facility
    Spatial distance between 1 and 2 meters should ideally be maintained between all patients within all types of services
    Cleaning and disinfection procedures should be followed consistently and correctly
    Dispensing medicines (for treatment of HIV, TB and other chronic conditions such as opioid dependence) for longer periods allowing reduced frequency of patient visits
    Consider reduction of services to the most critical ones (provision of essential treatment and prevention services; services such as counselling sessions may be reduced or adapted)
    Many countries have developed virtual ways of delivering services and supporting people to reduce clinic attendance.
    Countries have also increased self-care options, for example HIV self-testing, often in combination with virtual support to keep services going.  
    There are many examples of innovations being used to support the continuation of PrEP services including virtual support, community and home distribution and using HIVST for monitoring during periods when clinic services have been suspended.  
Learning from these may help guide future implementation in the post-COVID-9 era.  
Generally, vulnerable populations, including members of key populations (men who have sex with men, sex workers, people who use drugs, transgender people and people in prisons) as well as homeless and/or displaced people may be at increased risk of infection – because of additional comorbidities impacting on their immune system, reduced ability to apply measures of confinement and social distancing, as well as generally limited access to health services.
It is critical that services that reach these populations such as community-based services, drop-in centres and outreach services can continue providing life-saving HIV prevention (distribution of condoms, PrEP, needles and syringes), testing and treatment while securing safety of staff and clients.
Services can be adapted according to above considerations where applicable.  
Some prevention services, such as voluntary medical male circumcision (VMMC), which require clinic attendance, were initially suspended in the early phases of the response to the COVID-19 epidemic.
Some countries, following assessing the covid situation, have adjusted their responses and are restating VMMC services with additional COVID-19 prevention measures.



What is WHO’s position on use of corticosteroids for the treatment of COVID-19?
The current interim guidance from WHO on clinical management of severe acute respiratory infection when COVID-19 infection is suspected advises against the use of corticosteroids unless indicated for another reason.[8]
This guidance is based on several systematic reviews that cite lack of effectiveness and possible harm from routine treatment with corticosteroids for viral pneumonia or acute respiratory distress syndrome.[9]



What is the role of multi-month prescriptions and dispensing for antiretrovirals and other medicines?
All PLHIV doing well on ART can benefit from simplified antiretroviral therapy delivery models which include multi-month prescriptions and dispensing (3-6 month supply) which will reduce the frequency of visits to clinical settings and ensures continuity of treatment during possible disruption of movements during the coronavirus outbreak.  
Similar consideration should be given to providing people who are clinically stable on methadone or buprenorphine substitution therapy with an increased possibility for take-home medications to reduce additional burden on the health sector.
Many countries have now implemented the provision of take-home dosages for stable patients on opioid substitution therapy as recommended by WHO [25].
As is common practice, experienced preexposure prophylaxis (PrEP) users may be given multi-month prescriptions according to national guidance which may include regular STI testing.
Individuals initiating PrEP should continue to return for a 1-month follow-up HIV testing and clinic visit before receiving multi-month prescriptions.
This is to rule out acute HIV infection, assess adverse effects and determine intention to continue PrEP use.
However, flexibility for the 1-month visit can be considered for motivated clients who have not had a recent (in the past 3 weeks) potential exposure to HIV.
These decisions could be made on a case-by-case basis between providers and clients initiating PrEP for the first time.
Telehealth and community dispensing can be considered for follow up.
Quality-assured HIV self-testing can be considered for maintenance.



Can pregnant or postpartum women living with HIV transmit the COVID-19 virus to their unborn child or infant?
There are few data on the clinical presentation of COVID-19 in specific populations, such as children, pregnant and breastfeeding women [26] but findings from a small published study suggest that there is currently no evidence for intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy, nor are data sufficient to conclude vertical transmission through breastfeeding [27].
Although no vertical transmission has been documented, transmission after birth via contact with infectious respiratory secretions is a concern.
Infants born to mothers with suspected, probable, or confirmed COVID-19 should be fed according to standard infant feeding guidelines [28], while applying necessary precautions for infection prevention and control (IPC).
As with all confirmed or suspected COVID-19 cases, symptomatic mothers who are breastfeeding or practicing skin-to-skin contact or kangaroo mother care should practice respiratory hygiene, including during feeding (for example, use of a medical mask when near a child if the mother has respiratory symptoms), perform hand hygiene before and after contact with the child, and routinely clean and disinfect surfaces with which the symptomatic mother has been in contact [29].   
Q&A on COVID-19, pregnancy, childbirth and breastfeeding



Should pregnant and breastfeeding women living with HIV with COVID-19 and their newborns be managed differently?
There is currently no well-established difference between the clinical manifestations of COVID-19 or risk of severe illness or foetal compromise for pregnant and non-pregnant women with HIV.
However, a recent large database study conducted by US-CDC suggested that pregnant women with COVID-19 are more likely to need intensive care due an increased relative risk of developing severe disease [30].
Pregnant women with suspected or confirmed COVID-19 should be treated with supportive and management therapies, considering the immunologic and physiologic adaptations during and after pregnancy which may overlap with COVID-19 symptoms.
Data are limited but, until the evidence base provides clearer information, special consideration should be given to pregnant women with concomitant medical illnesses who could be infected with COVID-19.
There are no reported deaths in pregnant women at time of publishing this information [31].
However, COVID-19 testing of symptomatic pregnant women may need to be prioritized to enable access to specialized care.  
All recently pregnant women with COVID-19 or who have recovered from COVID-19 should be provided with information and counselling on safe infant feeding and appropriate IPC measures to prevent COVID-19 virus transmission [32].
With confirmed disease or under investigation, management is similar to non-pregnant women, with appropriate isolation of confirmed or under investigation.  
Obstetric facilities must be notified and prepared, noting that each infant born to any mother with confirmed COVID-19 should be considered a ‘person under investigation’ and should be isolated according to the IPC guidance.  
Currently, it is unknown whether newborns with COVID-19 are at increased risk for severe complications.
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[2] 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.

[3] Gudipati, S, Brar I, Murray S, McKinnon JE, Yared, N, Markowitz N. Descriptive Analysis of Patients Living with HIV Affected by COVID-19. J Acquir Immune Defic Syndr 2020;85:123–126.

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[12] Geretti AM, Stockdale AJ, Kelly SH, Cevik M, Collins S, et al. Outcomes of COVID-19 related hospitalization among people with HIV in the ISARIC WHO Clinical Characterization Protocol (UK): a prospective observational study. Clin Inf Dis (2020), ciaa1605.

[13] Mellor M, Bast A, Jones N, Roberts N, Ordóñez-Mena J, Reith A, Butler C, Matthews P, Dorward J. Risk of adverse COVID-19 outcomes for people living with HIV: a rapid review and meta-analysis Running head: HIV & COVID-19 outcomes: review & meta-analysis. https://www.medrxiv.org/content/10.1101/2020.09.22.20199661v1.full.pdf .

[14] Coronavirus disease (COVID-19) pandemic. World Health Organization, 2020 (available at (https://www.who.int/emergencies/diseases/novel-coronavirus-2019).

[15] Country & technical guidance -Coronavirus disease (COVID-19) pandemic. World Health Organization, 2020 (available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance).

[16] Ford N, Vitoria M, Rangaraj A, Norris SL, Calmy A, Doherty M. Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID‐19: initial assessment J Int AIDS Soc. 2020 Apr; 23(4): e25489. Published online 2020 Apr 1. doi: 10.1002/jia2.25489.

[17] Reed AC Siemieniuk et al. Living systematic review and network meta-analysis. BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2980).

[18] RECOVERY collaborative Group. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial Recovery trial, Lancet 2020; 396: 1345–52).

[19] WHO Solidarity trial consortium. Repurposed antiviral drugs for COVID-19 – interim WHO SOLIDARITY trial results. medRxiv 2020.10.15.20209817; doi: https://doi.org/10.1101/2020.10.15.20209817.

[20] Simmons B; Wentzel H; MobarakS Eslami G; Sadeghi A; et al., Sofosbuvir/daclatasvir regimens for the treatment of COVID-19: an individual patient data meta-analysis.J Antimicrob Chemother (2020) dkaa418, https://doi.org/10.1093/jac/dkaa418.

[21] Ayerdi O et al. Preventive efficacy of tenofovir/emtricitabine against SARS-CoV-2 among PrEP users. Open Forum Infectious Diseases, ofaa455, published online ahead of print, 25 September 2020.

[22] Effectiveness of interventions to address HIV in prisons. Geneva, World Health Organization, 2007(Evidence for Action Technical Papers) http://whqlibdoc.who.int/publications/2007/9789241596190_eng.pdf?ua=1.

[23] Kinner S. Jesse T. Snow K. Southalan L. et al. Prisons and custodial settings are part of a comprehensive response to COVID-19.  The Lancet Public Health. Published: March 17,2020; DOI:https://doi.org/10.1016/S2468-2667(20)30058-X.

[24]. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected Interim guidance, World Health Organization, 13 March 2020 (available at: https://apps.who.int/iris/handle/10665/331446).

[25] WHO Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. World Health Organization, 2009 (available at:  https://www.who.int/publications/i/item/9789241547543).

[26] Huijun Chen, Juanjuan Guo et al, Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.  Published Online February 12, 2020 https://doi.org/10.1016/S0140-6736(20)30360-3.

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[30] Centres for Disease Control.  Interim Considerations for Infection Prevention and Control of Coronavirus Disease 2019 (COVID-19) in Inpatient Obstetric Healthcare Settings, 6 April 2020 (available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcare-guidance.html).

[31] Royal College of Obstetricians and Gynaecologists.  Corona virus (COVID - 19) infection in Pregnancy.  Information for healthcare professionals Version 12, 14 October 2020. (available at: https://www.rcog.org.uk/coronavirus-pregnancy).

[32] Caring for pregnant women with COVID-19 Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance, World Health Organization, 27 May 2020.
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