Very weak evidence base for antiretrovirals for treatment and prevention of COVID-19, say senior HIV doctors

Rigorous randomised controlled trials and peer review remain essential
Image: Antiretroviral Drugs to Treat HIV Infection. NIAID. Creative Commons licence.

Widely reported claims about the effectiveness of antiretroviral drugs for the treatment of COVID-19 have an extremely poor evidence base, two senior HIV doctors wrote in HIV Medicine last week. The authors’ analysis shows that rigorous clinical trials and peer review remain essential during the current global health emergency.

“We highlight some of the antiretroviral-based treatment and prevention strategies for COVID-19, where hysteria may have trumped objectivity,” write Dr Laura Waters of the Mortimer Market Centre, London, and Professor Jürgen Rockstroh of the University of Bonn. “Pre-publication access, rapid online and social media dissemination of conclusions (valid and otherwise), and the rapid breakneck speed at which national and international bodies include new findings in their guidance, create an environment rife with myth propagation.”

The authors acknowledge that the COVID-19 epidemic necessitates an urgent health response and that the re-purposing of existing drugs to treat emerging infectious diseases is nothing new. However, they caution that “drug repurposing does not negate the need for some preclinical validation, yet despite this, phase 3 trials are underway for drugs that have not yet demonstrated any in vitro [test tube or laboratory] or animal model activity against SARS-CoV-2,” the virus that causes COVID-19 disease.

Glossary

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

syndrome

A group of symptoms and diseases that together are characteristic of a specific condition. AIDS is the characteristic syndrome of HIV.

 

peer review

The process of subjecting a scientist’s research to the scrutiny of other scientists working in the same field. Studies published in medical journals are usually peer reviewed, whereas conference presentations are not.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

standard of care

Treatment that experts agree is appropriate, accepted, and widely used for a given disease or condition. In a clinical trial, one group may receive the experimental intervention and another group may receive the standard of care.

Moreover, Waters and Rockstroh emphasise that premature repurposing can cause very real harm, creating shortages that deny access to treatments for people with conditions for which the drugs have proven efficacy, as well as unforeseen side effects.

The protease inhibitor lopinavir/ritonavir was the first antiretroviral to be proposed as a potential therapy for COVID-19, following its use against Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome (MERS), both also caused by coronaviruses. However, the evidence-base for its use against SARS and MERS is extremely weak. The authors found only ten published studies, six of which were single case reports. The published evidence for the use of lopinavir/ritonavir for COVD-19 wasn’t much better. Waters and Rockstroh identified 14 studies, comprising three single case reports, one small case series, eight retrospective cohort studies (with a total of just 408 individuals and no clear benefits reported) and two randomised controlled trials.

The first randomised trial enrolled patients with mild/moderate disease. The investigators concluded the lopinavir/ritonavir monotherapy provided no additional benefit over standard of care. The second study involved people hospitalised because of severe COVID-19. Lopinavir/ritonavir had no benefit in terms of clinical improvement or viral clearance. However, there has some evidence that the people who received the protease inhibitor had better outcomes, if the treatment was started early (within twelve days of COVID-19 symptoms emerging). This finding was considered worthy of consideration and many more trials looking at the use of lopinavir/ritonavir are currently recruiting or are imminent.

The authors note that there is test-tube evidence of the efficacy of lopinavir/ritonavir against SARS-CoV-2. But the concentration of the drug needed to inhibit the virus is between 4000 and 8000 greater than that needed for HIV. The risk of side effects, including liver toxicities, will limit the use of higher doses of lopinavir/ritonavir to treat COVD-19.

Anecdotal reports circulated about the effectiveness of the protease inhibitor darunavir against COVID-19. This prompted its manufacturer issue a statement saying there was no laboratory evidence supporting activity of the drug against SARS-CoV-2 and that the drug showed no benefit in a small, single-arm study. Nevertheless, there are two phase III studies investigating the use of darunavir for COVID-19 (one underway and one planned).

The protease inhibitor atazanavir does have in vivo activity against SARs-CoV-2, but there are apparently no trials underway exploring its use for COVID-19.

Antiretrovirals are also been explored for COVID-19 prevention. There were anecdotal reports of fewer cases of severe COVID-19 amongst HIV-positive people in Spain. This prompted the design of a large randomised study involving healthcare workers in Spain, exploring the safety and efficacy of tenofovir/emtricitabine with low-dose hydroxychloroquine as COVID-19 prophylaxis.

A study in New York suggested that the number of people with HIV hospitalised because of COVD-19 was lower than expected. However, the difference was small and didn’t take into account factors known to impact on the risk and severity of COVID-19 disease such as age, socio-demographic status and social distancing practices. Moreover, there have been numerous cases of COVID-19 in people with HIV taking tenofovir.

"The concentration of lopinavir/ritonavir needed to inhibit SARS-CoV-2 is between 4000 and 8000 greater than that needed for HIV."

There are no laboratory data to show the activity of tenofovir against SARS-CoV-2. Although the drug does have immune modulatory properties, Waters and Rockstroh caution that these may be detrimental to people with heightened COVID-19 induced inflammatory profiles. They emphasise that the results of clinical trials are needed before tenofovir/emtricitabine can be recommended for COVID-19 prophylaxis.

The anti-malaria drugs chloroquine and hydroxychloroquine also have immune modulatory properties, and have therefore been considered as treatments COVID-19. Previous studies using them to treat viral infections such as HIV and chikungunya showed that their use was associated with harm.

“Unfortunately, a small, poorly designed study with non-clinical end-points and media hysteria have led to hydroxychloroquine and azithromycin (the drug it is partnered with) to be the top two treatments for COVID-19,” note the authors. The rapid inclusion of hydroxychloroquine and azithromycin in COVID-19 treatment guidelines would be “brave enough if the drug combination was harmless,” but they note that it can cause cardiac side effects, and that one recent COVID-19 study was stopped for this reason.

“When dealing with a novel disease, we must not forget the hierarchy of evidence that should guide the interpretation of trials, in particular, drug modelling, as we have outlined, may be a poor predictor of clinical outcome,” conclude Waters and Rockstroh. “While the peer review process may be flawed, it offers a buffer that filters out some of the more ludicrous COVID-19 assertions, and in our view, continues to play an important role.”

References

Waters L and Rockstroh JK. Antiretroviral HIV drugs in COVID-19 research: promises and risks. An opinion piece. HIV Medicine, peer reviewed, published online ahead of print, 16 June 2020 (open access).

https://doi.org/10.1111/hiv.12913

Full image credit: Antiretroviral Drugs to Treat HIV Infection. NIAID. Available at www.flickr.com/photos/niaid/31793869534/in/album-72157625994990013/ under Creative Commons licence CC BY 2.0.