COVID-19 TREATMENT GUIDELINES

  it's pleasure to be here today thank you for joining my name is Raj Gandhi i'm at mass general hospital i'min the infectious diseases division i'm alsoprofessor of medicine at harvard medical schoolso this is meant to be interactive so what i thought i would do isjust give a brief overview of a few topics that i'm particularly involvedwith with covid but then leave the majority of the time for forquestions and discussion um just as a road map what i'm going totalk about in the next 20 minutes roughly is one or two words ontransmission of covert 19. one word on diagnosis but i'll spend thebulk of my time on treatment guidelines and the reason isthat's been the area of covert i've been most involved with but happy todiscuss broader topics as well for those of you who are involved in theentire course and i hope that's most if not all of you on wednesdayafternoon i think in the last session of thecourse i'm going to be talking about covet againbut the emphasis on that wednesday talk will be on clinical manifestations ofcovid i'll spend a little bit of time ontreatment since that'll be a larger group so i'll come back totreatment but then i'll have a section on covet and hivand so um please join again on wednesday and we'll talkabout some of the similar topics but also things that i won't cover todayuh unless we get into them in the clinical manifestation or and and thediscussion so with that i am going to i'm justlooking around to see it looks like a good number of people are onum um why don't i start with some prepared remarks and then as i saidthere'll be plenty of time for questions you're welcome to put questions into thechat you're welcome to turn on your video and um and askquestions as we get into it so let me try to sharemy screen certainly recognize a few friendly nameson the screen and hope to see the rest of you okay let's see here there's always a little bit of suspensewhen i share my screen hopefully you're about to see my uh powerpoint as opposed to my emailsand um sam can you tell me if i'm on my uhpowerpoint and um does it look like it's the fullscreen or your album okay okay so let me try to move myvideo aside okay so these this is a talk i gave notlong ago for the cdc idsa clinicians forum um which some ofyou may have joined this is on treatment guidelines um i did it alongwith a colleague named jason gallagher a number of people to acknowledge shownhere and so i'll spend about 15 minutes or so on these these arerelatively recent updates and then i'm happy to talk more broadlyso um before we get into treatment i'm goingto just say two words on one word on transmission one word on diagnosis toset the stage so transmission transmission of cover 19 appears toprimarily be through respiratory dropletsan area of discussion is the fact the virus may be aerosolized and transmittedduring certain activities for example singing and clearly during certainprocedures such as intubation or the use of nebulizersi'm sure as you well know the role of aerosols and transmission is underactive discussion happy to come back to that when weget to the open discussion point part the other point that is notcontroversial though is that asymptomatic and presymptomatic peopleare infectious a pre-symptomatic is prior to the onset of symptomsasymptomatic are people who remain without symptoms they are infectious andin some series may account for about forty tofifty percent of cases of code and there are recent data in factincluding this week um that high nasopharyngeal viral levelsappear just before or perhaps soon after symptom onset there was a study out ofkorea i think it was day before yesterday thatsuggested that during that asymptomatic phase the viral levels are really quitehigh incubation period this hasn't changedtoo much in the last few months the incubation period is a median of aboutfour to five days and one question that we often get askedis what's the outer range of the incubation period and it appearsthat about 98 of people will develop symptoms withinabout 11 to 12 days so really by by two weeks um that seems to be theouter range of the incubation period at leastyou know for the vast majority one word on diagnosis um where i am pcrtesting is still the most common way to diagnose cova-19it's still most commonly the nasopharyngeal swab pcr although thereare others um swabs anti-urinaries or apharyngeal swabs as well there's a lot of discussion recentlyabout cheaper less sensitive tests as to whetherthey might have an important role in ruling out infectiveinfectious people we um there are data that sars kobe 2 rna levels peak justbefore symptom onset and then remain detectablefor weeks if not months we've all seen um and i suspect you have as well peoplewhose pcr stays positive stay positive forfor many many weeks after symptom onset and and i've seen it up to abouttwo or three months uh the viral rna appears to be detectable long after uhwe're able to culture infectious virus and a number ofstudies including studies cited by the cdc in the last two weeksindicate that it's really not um common to be able toculture virus after eight to nine days uh following symptom onset at least inimmunocompetent patients so without his background let's talkabout the treatment guidelines these are the two main us-based guidelines i'm amember of both of these treatment guidelines panels on your left is thenih treatment guidelines panel it's 55 people from a variety of differentspecialties infectious diseases as you might expectbut also pulmonology hematology critical care ob pediatrics so it's abroad group and the other main guideline in theunited states is the infectious disease society of americathey have three such guidelines and i recommend them all one is on diagnosisone is on prevention and then um or infection control and then the one thati'm most involved with is the is the treatment one which is the onei'll be talking about okay so this is a framework um that ilike to put this problem of treatment in andthe framework is the following one is knowing the host what are their clinicalmanifestations but then and i'll come back to that but then theother framework is the stage and severity of disease andhere is just a little bit about what we think about the pathogenesisand i put it in this framework because i think different interventions are likelyto work differently depending on where you arein the stage of disease so asymptomatic presymptomatic covate19is having a positive test but no symptoms some estimates as that's about 40 to 50percent of people um but it's that's a somewhat harder oneto to get a firm answer on although people are moving towards getting anestimate once you're symptomatic 80 percent ofillness is either mild or moderate what do we mean by mild well that's mildsymptoms uh things like fever cough taste smell changesno shortness of breath moderate illness traditionally and some of this has comefrom clinical trials is defined as having a normal oxygen saturationbut now having some evidence of lower respiratory tract disease now it isprobably the case that if you were to ct everyone with coping 19 you would findsome ct findings and there are some data on this even earlier in diseasebut for example the trial one of the trials i'll talk aboutuse moderate and severe as their as their criteriasevere illness is when you have someone who's oxygen saturation is over 94under 94 percent has tachypnea has extensive andlung infiltrates and then critical illness of course is respiratory failureshock multi-organ dysfunction and multi-organ failure we think the viralreplication is particularly prominent in the earlier stages of disease and wethink that inflammation becomes substantial during the moderate tosevere to critical stages of disease so i'm going to group treatments intothese three categories of antiviral small molecule antiviralsprobably going to work best in early stages of diseaseantibody therapies convalescent plasma monoclonal antibodiesi think also will probably work best in early stages of disease and thenanti-inflammatories of which dexamethasone is the best examplei'm going to pause for one second and actually ask our umtechnical support for a second are you able to umdo one of those impromptu polls uh sam are you still onyes can you do an impromptu poll to give me a sense of umhow many people in the in the zoom room um are umeither treating or um let's say treating hospitalized patients with coven-19 umcould you do um are you treating hospitalized patientswith coven-19 number one yes number two no and let's see what people are doingi'm curious yeah so if you're trading hospitalizedpatients with coven 19 in your practice or involved in that um go aheadand vote yes and if you're not go ahead and vote no a lot of peoplevoting that's great okay looks like um the majority are nottreating hospitalized patients with copenhagen so that's that's good for meto know and one thing i'll say now but i'll repeat lateris most of the trials we have to date are on uh treatment of hospitalizedpatients and that's i think going to need tochange since 80 as i mentioned of cover 19 is in is inoutpatients um let me flip the question let's doanother one and say are you involved in treating um oradvising or caring for outpatients with copa19 sonot hospitalized but if it's yes go let's put up another oneso if you're treating or advising or caring for outpatients with coven19 sayyes and if you're not treating outpatientsay no i guess i didn't give you the option ofsaying you're not treating anybody with kelvin 19 butso it looks like the majority of this group is treating outpatients withcovert 19 and so i will um observe that much of what i'mgoing to talk about in the next few minutesis inpatient treatment so you know and that reflects i think where we arewith cover 19 treatment but near the end i'll umpoint to at least and in the discussion i'm happy to point to some thingsthat are coming down the pipe for for outpatientsokay so let's go on okay so let's start with so there are two drugs that are nowendorsed by both guidelines committees the first is therem deserver these are the two guidelines that imentioned at the outset the nih and the idsathey both recommend the antiviral redeserver inpeople who are hospitalized with severe copin 19.one point i want to make here and i'll repeat it in a moment the data forremdezavir is strongest for severe covet 19but not yet critically ill that's where the data shows the greatest benefit orit shows evidence of the clearest benefitso the nih recently i would say in the last two weeksrevised their guidelines random deserve to say that there's uncertaintyregarding whether rem desevere in people who are on high flow oxygen ormechanically ventilated or on ecmo whether rem deserve confers benefit inthese groups of patients and and that's a revision from theiroriginal guideline both guidelines or at least the nhguidelines um right now do not endorse the use ofrendezvous for mild or moderate cobit 19.and the last point i'll observe on the nh guidelines is they setbased on limited supplies of rem deserve they feel likepeople who are in that first box the people are on supplementaloxygen but not yet critically ill that's where the drug should be prioritized ifyou have a limited supply so these are the data for remdezavirthis is a nucleotide pro drug it inhibits the viral rna polymerase itacts as a chain terminator in an animal model and i think this isreally interesting remdezavir reduces the sars cov2 levelsin the lung but not in the upper respiratory tractof these animals so just keep that in mind um in animals what thedrug is doing is reducing levels in the in the deep tissues and amelioratesdisease i suspect many of you have seen the datafrom the nh trial called act this is a preliminary analysisthey're still following up and going to publish a final analysisbut the preliminary analysis showed that recovery was more rapid and those whogot rimdesevere than in those who got placebo11 days in the rendezvous group 15 days in the placebo groupthe mortality was lower in the rim deserve group seven percent risk isabout twelve percent but the um that that was not statisticallysignificant at least the hazard ratio crossed oneas i mentioned just now the benefit of rendezvous and the act study wasclearest and those who were on oxygen supplementation but weren't yetcritically ill the theory may be here that once you're critically ill thatyou're further on in the stage of disease andmaybe viral replication is less of the driver at that pointand then in a separate manufacturer funded study sponsored study calledsimple that trial found that in an act peoplegot 10 days of room desevere in the simple trial which wasa duration of therapy trial five days was as good as 10 days for severe covert19 and so the treatment guidelines of largely in doseendorsed five days for most people with severe coping 19. steroids this is the next drug for whichthere are clinical trials evidence that supportin this case a mortality benefit so both guidelines committees the nihand the idsa endorse dexamethasone for mechanicallyventilated patients i'll show you some datathey also endorse it with a little bit weaker recommendation for supplementaloxygen not yet mechanically ventilated and both of themand this is important um for those especially since themajority of the of the group here treats outpatients bothrecommend against the use of corticosteroids against and people whoare not on supplemental oxygen and by extension those who are outpatientsand i'll show you why there's an against recommendation thereon one point kind of a subtle one but i'll just mention if you arehaving shortages of dexamethasone for the 25 or 30 percent who are treatinginpatients the idea say lists a couple of otheralternatives and what the dosing is so these are the data from therecovery trial that support dexamethasonethe recovery trial was done in the uk for years there's been controversyregarding the use of steroids in viral pneumonia and in acute respiratorydistress syndrome but given that hyperinflammatory statein coba 19 that i started off this conversation withsteroids were evaluated as a potential interventionrecovery was an open label trial that's important it randomizeduh hospitalized patients no outpatients 2100 in the um dexamethasone group alittle over 4 300 in the usual care groupand here are the mortality benefits you might be able to see my cursor on onthe right-hand side of the screen so among all comers all participants andthey enrolled something like 40 of people in the uk got enrolled inrecovery it was a very high proportion so a 17 reduction in mortality but whenyou broke it down it was mostly amongst peoplewho were mechanically ventilated there there was a 36now these numbers were updated in the publication a week or two agoa 36 reduction in um in mortality there was also a reductionin mortality among those on supplemental oxygen alonebut there was no benefit in mortality and maybe even potential harmin people who were hospitalized but were not require oxygen people who wereearlier in the course of disease and that'sthat's critical okay i'm going to just fill in a coupleof more agents uh famotidine has gotten a lot ofpress the idsa recommends uh that uh it not be used for treating copa19outside of the context of a clinical trialthis is the this one of the studies that got it some umnotoriety the proposed mechanism of famotidine is that it can bind andinhibit the protease of chronovirus at least invitro or actually in silico it's predicted youknow based on on some other um evidence that it mightbend bind but as to whether it does it in people is still an open questionthere were anecdotal reports from china suggesting that people receivingfamotidine had improved survival compared to those who got a proton pumpinhibitor and then there was a cohort study among 84 people who got famotidineover 1500 who did not and you can see that the group that got promoted in inthis trial really a case cohort study had a lowermortality and a lower rate of intubation than those who didnot get famotidine but and this is what the idea say i've gotnice point out critically ill patients may be morelikely to receive ppi's than famotidine and there really could be somesubstantial confounding going on here there is a randomized trial and that'simportant that's ongoing at northwell and i think i wouldpersonally wait for the results of that trial before endorsingformodidine um there's not enough good evidence andand as we all know there's been things that have looked promising that haven'tbeen worn out so i've more or less said this alreadylet's talk about hydroxychloroquine a topic of um greatdiscussion over the last five months or so both guidelines panelsrecommend against hydroxychloroquine except in a clinical trialsimilarly they recommend against hydroxychloroquine plus a zithroexcept in the clinical trial so um i think we've all gone throughthis this time together basically in march aprilmay most of the data we saw in hydroxychloroquine was coming fromsingle arm studies or coming from observational studies butreally starting in june we started to see the results ofrandomized trials and now there's five randomized trials i'm just going to showthree of them and they span the range frompost-exposure prophylaxis to hospitalized patientsso here's one randomized trial from david beware and university of minnesotalooking at post-exposure prophylaxis no differencebetween hydroxychloroquine and placebo and pep there are limitations tothis study it was an internet-based study at a time whena lot of testing was not available so only a small proportion of people inthis pep study had a confirmed serous cov2infection diagnosis there are other trials ongoing includingone in spain which is given the similar resulthere's an early treatment trial people here were had a median of aboutthree to four days of symptoms again no difference between placebo andhydroxychloroquine in this randomized trialand there are some limitations happening to talk about it but certainly nosupport and then finally the same recovery groupthat studied dexamethasone studied hydroxychloroquine this time inhospitalized patients and again they found no clinical benefitof that drug in hospitalized patients compared to usualcare there's a separate study from brazil also randomizedthat was in the new england journal about two weeks ago that came to asimilar conclusion okay i'm going to finish up in a fewminutes i think we're doing okay on time so convalescentplasma both guidelines committees say that convalescent plasma reallyshould be limited to the context of the clinical trial now that is notthere are many people who've gotten convalescent plasma outside of a trialand we'll talk about that but both guidelines committees say thatto date at least there's insufficient dataso what are what is convalescent plasma and what are theseantibodies therapy so it's passive transfer of neutralizing antibodiesprobably working as an antiviral we thinkum so convalescent plasma taken from people who've recovereduh several um groups have isolated monoclonal antibodiesum which are a more defined way to give antibody therapy andsome of those trials have launched as well convalescent plasma had been hasbeen used in the past and even now to treat other viral infectionsand as i mentioned there are ongoing trials of both convalescent plasma andmonoclonal antibodies here's one trial that was at that is out of chinait was an open label randomized trial looking at convalescent plasma plusstandard of care versus standard of care alonethey only had 103 participants they had aimed to have many morebut because the pandemic came under control in china they stopped earlybefore the target enrollment was reached if you look at the left-handpart of this graphic um that's all participants there wasreally no difference between convalescent plasma and um usualcare similarly and those people who arecritically ill no difference but there was a suggestion that there might be abenefit in severe disease but it was a subgroup analysis and andit was underpowered or it was stopped earlyand the last point about this and the reason why this is not definitive datais it was started really quite late uh in the course it was about 30 days aftersymptom onset and as i mentioned before if this isgoing to work i suspect it's going to workearlier in the disease course by um but convalescent plasma has beengiven to way more than twenty thousand americansat this point um this was a preprint from a few weeks ago looking atthe first twenty thousand people what these um authors could say is thatand this is given under an fda expanded access program oremergency use authorization um transfusion reactions were really quiterare less than one percent and then othercomplications were also very rare and the vastmajority were unrelated to plasma transfusionso i think what we can say is that it's safe it appears to be safebut we don't yet know if it's efficacious and there are a number ofgroups that are working hard to try to get a firm answer on convalescent plasma last last couple of slides interleukin-6inhibitors have been in the news a lot we know from the work of a number ofinvestigators that elevated interleukin-6 levels in covet19 are associated with worst clinical outcomes and we thinkthat it may be part of the cytokine storm thathyperinflammatory state that occurs in severe covenant 19.there were some early non-randomized studies suggesting a possible benefitbut two press releases that have come out bythe makers of two of these aisle six receptor antibodies cyrillumand tocilizumab indicated that these drugsin hospitalized patients failed to demonstrate efficacymore details will come these are just the headline results fromsurulumab and tosalisma but something to delve intoand and watch out for but so far the data hasn't supportedthese these drugs so for those of you who take care of outpatients which isthe majority of you a lot of what i've spent time on in thelast 25 20 minutes or so is on the right hand side of your screen which arethings like recovery act um aisle six inhibition basically drugsfor people who are hospitalized or critically illbut i think and i think a number of us think that earlier treatment mayactually give us a bigger bang for the buck we may actually have more of animpact if we can treat earlier and prevent progressionprevent complications prevent death hopefullyand then as we've learned from the hiv world treatment is preventionin hiv treatment equals prevention we we don't know that yet for coca-19 but it'sdefinitely something that that is a potential benefit of early treatment andsomething we should um try to assess so what we'll see i think in the nextmonths is um um now i'm departing from my scienceantibody studies i've done earlier on the aids clinical trials group andothers are doing antibody studies early onin this kind of um early symptomatic phasethere's still some prep trials going on pre-exposure prophylaxis amonghealthcare workers there's some promising small moleculesthat are coming down the pike antivirals so i think you're going to see a lotmore activity in that early kind of a green part of this curvethis is just a summary slide saying where the idsa guidelines camecame around came about when it first started and umi think it was in april nothing was recommended and now we have severalthings recommended the last thing i'll say and i'll repeatthis in my main talk in wednesday for those of us who've been doing hivfor most of our career you know there's a lot of lessons one ofwhich is you make iterative process uh progresswith hiv you know it took one drug after another until we got to a tipping pointand in 1996 that tipping point happened and andnow we've seen the consequences and cover 19 i think we'll get to thattipping point but it'll be through the samemechanism of one drug after another perhaps combinationsand hopefully we'll get there a lot quicker i think we will than we did inhiv so that's all i've prepared for forcomments i think we have 35 minutes for discussion so thathopefully will be a good amount of time i'm gonnastop sharing my screen and that way i canlook at all of you and and happy to take any questions or comments don is encouraging encouraging you tofeel free to turn on your video thank you laura for turning on your videoi can see you and steve as well but yes any questionscomments you know disagreements orthings you want to just hear more about or talk about let's so this is laura i have a questionso um in a couple of scenarios that i'veheard about in terms of how they're managing going back to school and thatsort of thing they're saying that that uh someone willbe tested and that they'll remain quarantined until they have the firstnegative test so for some people that could bethree months i mean for the on the outliers like howdoes that play out or how do you rationalize thatyeah that's a critical question and i think has been really challenging theselast few months for hospitals and school nursingfacilities et cetera et cetera and it's in schools as well i think what we'removing towards and the cdc made this adjustment to their um guidance just inthe last two or three weeks is that this um and i'm just looking tosee if there's anyone from the cdc on who's and you're welcome to comment ifyou are but um what they put out guidance around isbased on the data i just touched on briefly that infectiousvirus really seems to go away after eight to nine daysthey're saying that if you've had a positive covet test within the last 90days that you should not have a repeat testand actually this came up with one of my infection controlpractitioners david hooper if by some reason you have a positive testthat within that 90 days that you're essentially to ignorethe positive test because there's enough data in immunocompetent peoplethat they're not infectious and then there's contact tracing data from koreaand other places saying that people aren't transmittingbut the cdc took took that fairly important step just in the last two orthree weeks so this came up with a patient um i'llgive you a general scenario one of my colleagues who's quite elderlyand has wanted to go visit his daughter who is anurse in arizona he wasn't going to arizona she had cometo massachusetts she had had cover 19 two months ago but prior to travel hadbeen tested and came up positive even though she wasasymptomatic came a positive you know two monthsafter her covet so i called my infection controlprovider because this is one of my treasure colleagues can you go down andvisit his daughter on cape cod and he said yes the cdc really feelslike once you're that far out that even first you shouldn't test but if you aretested and she was tested for travel related reasons thatis required to come into massachusetts that you get a testor you quarantined for two weeks but where to ignore that so i i told themyou can go and visit your daughter so yeah and sofor for schools i i don't know how the schools preciselywill handle it i would say probably they should follow that cdcguidance around not retesting and can i just see if anyone from the cdc is onand wants to comment um i don't recognize anybody but if youare and you want to comment you're more thanwelcome to or anyone else who's dealing with thisat their local level with schools or anyone elsei'm happy to hear your thoughts i'm seeing a bunch of questions but ifyou want to unmute your microphone and comment on theschools in particular before we move on to something else i'm happy totake your comments one comment i'm seeing on the chat aboutum well let's stay on the topic of schoolson advising regarding school mitigation matters whatdo you advise do you advise on quarantining students since i think the question does have to dowith the same issue of um if someone gets sick um you if you wantto say your question i'm not quite following it in the chat but you're morethan welcome to unmute and and say that okay maybe i'll go on and we'll we'llcome back to uh schools in a minute post-exposure prophylaxis usinghydroxychloroquine vitamin c and zinc any data supporting thisit's a good question these are this has gotten a lot of also interest umum there's a new section on both vitamin c and on zincin the nih guidelines not yet in the idsa guidelinesum the data for zinc and for vitamin c thus far haven't reallybeen conclusive in a in a positive way so even though they've been talked abouta lot they really haven't the studies thathave done to date haven't really supported thatparticular combination now one of the reasons might be at least for mostpeople zinc levels in the body are really quitehigh and so the extra levels you get from exogenoussink and most individuals aren't reallymaking a substantive difference it's not a field ithat i've closely delved into myself but two of my colleagues sue swindells andum susan davis um reviewed that verycarefully and i really wouldn't um suggest that read the part in the nhguidelines on scene because i think they gave it a a fairlook and they kind of summarized the data today but that's my takeaway onseeing vitamin c is um so far not enough datato really think that those in combination wouldhave a would have a benefit um art treatment let me um comment on thatand as i mentioned just at the beginningbefore some of you joined i'm going to be speaking again onwednesday and my focus on wednesday and also on cover 19 will be on clinicalmanifestations i'll i'll touch again on treatmentbut then i'll have an entire section on covet and hiv so this is kind of apreview to well uh say uh in more depth on wednesday but with some data and withsome slides but so where this started with art and andcovet is um so with sarsko v1 you know the originalsars back in um back in 2003there were some in vitro data suggesting that la pinavir ratanovir might have aneffect and there was a non-randomized studydone with soros kovi just the original sarscompared to historical controls that that ledto some people thinking there might be an effect of la pinovirtanavirthat subsequently led in mers you know in adifferent human coronavirus but but also a serious human coronavirus to arandomized trial that's still going on it's called the miracle trialof la pinavir retinovir versus um no le pen ver retanovir in mers and wechecked in back in march when we were grapplingwith these issues with the with the principal investigator of themers trial to see if they had data with mers and and it was still ongoing theydidn't have data so what do we know about lupinvilleretinovir and by extension other protease inhibitors for for sores cov2so there are some data that lapinope retinovir in vitro andcell cultures can affect sars kobe 2. but and this is a really reallyimportant caveat this is incredibly important the levelsthat you need to inhibit sars kobe 2 areway more than the levels that you need to inhibit um hivso there was a study that's in annals it's one of my favorite studies of uhin the coba era looked at trough levels and eight people in austriaand it measured the trough levels and these were people with covidwho were given lepinoviritonovir and the levels they were gettingwere 60 to 120 fold lower than the in vitro level that you need toinhibit stars kobe 2 that is you would have to swallow60 to 120 um la pinova retinovirus um to get to the level that you need toinhibit sars kobe 2. and i think all of you on who've evergiven up innovative retirement know that that's that's just notpossible so um so the there's been two trials that havelooked at la pinavirtanovir in humans one is out of chinait was one of the first published randomized trials in in kova 19. itlooked at about 200 people lupine rotanovir versus usual care umdone quickly and and there was really noeffect of la pinovir ratanavir and people with code but these are peoplewithout hiv all of these trials and that was in thenew england journal and then more recently therecovery trial the one that i keep coming back to in the ukhas a press release saying that in several thousand people that they lookedat lupine bear versus usual care no effect oflupine retinovir no difference in mortality at all at day28 and no other hint of clinical benefitand then finally the who which is running a trial calledsolidarity they actually closed their la pinovir batanovirarm um recently so i think the the i don't think that drug is going to workand by extension i don't think boosted roonever or some of these other proteusinhibitors will work the other drug that you've i'm sureheard about is you know how i mentioned remdezavir is a nucleotide analog wellso is um tenofovir and so there was aninteresting study out of spain that is a lot of my patients have askedme about because it's it's obviously gotten into the umyou know the general press this looked at about 77 000 people in spainthis time with hiv okay all of these people had hivthey looked at the regimens they were on and then they looked at the rate ofhospitalizations of with covet and they found that peoplewho were on tenofovir disopproximal fumarate tdf ftchad half the rate of um hospitalization uh for covid uh compared to people whowere on a baccavir or people who are on tapbut and this is a big but again big caveatas best i can tell we don't have adjustment for things like age or othercomorbidities and we know that people who have renalinsufficiency people who perhaps are older might be less likely to be giventdf and so it's possible that that signalwas was due to confounding and so i have been telling my patientsand i'm really interested i love it if steve johnson or anyone elsewho would like to comment what they tell their patients or lauraor alice anyone who'd like to come in but i've been telling my patients idon't think you're at more risk by virtue of your hiv of gavin covenantwe can we can talk about that if you'd like and i'll certainly talk about it onwednesday but i i also don't think that yourantiretrovirals are in any way protective and i certainly don't thinkthat you should change your antiretrovirals i think that would be abad idea to try to prevent covet 19. does anyone else wantto comment on this well i think of course the advantage ofantiretroviral therapy and the fact that most of our patientsare on it is that they come in with you know viral suppressionand a reasonably normal immune system and so it kind ofi think levels the playing field with you know other types ofpatients so um but yeah i don't i i've not seen any benefit i think the southafrican study also um may have shown a a trend towardsimprovement with tdf but uh has the same kind of set of issues in terms ofnot really controlling for uh confoundersthere is a trial being done in spain among healthcare workers ofpre-exposure prophylaxis with tdf ftc i i don't think that's reported out yetso something to watch out for but um certainly right now i don't think wehave data supporting the use ofantiretrovirals um anyone else want to comment umyeah raj um thanks um so i've been getting a few of mypatients that have become positive for covid um but one ofthe things which is a little different than whatyou're asking that i've been struck by is just how vigilant my hiv patientshave been they have drunk the kool-aid from thecdc and from id providers and they arestaying in they are distancing they are wearingmasks and i think when you face death with the diagnosis of hiv oraids it gives you a different perspective anda few of them have asked you know do my antiretrovirals protectme and i've told them it doesn't look like it buthaving you know having a reconstitution immune systemis helping you and um a few of my patients that have gottenadmitted they've been the spectrum a one is a hemodialysis patient who feels hecaught it on the what i call the medicare busfrom another hemodialysis patient and amazinglyhe did great then my other patient um was a course carebranch worker and his roommate had it and he masked up and actually waspermitted to still go to work because he wasessential of course farming is so important here in kentuckyso he was listed as an essential worker by the health department was allowed towork and um then he um contacted me we testedhim he actually was positive and there were quite a few exposureswith him with the mask on and co-workers with mask on and there was zerotransmission that i found between him and people wereexposed sort of tongue-in-cheek the only personthat did not wear their mask even though he had a mask on was the veterinarianand the veterinarian because it was outside i suppose did not get itso i think the good news for our patients and thatat least my patient population has been doing a great jobuh following directions you know alice i i think you're right and actually i'llsay i think one other reason not only what they experience with their hiv buti think it's their relationship to their doctorsalso i i've really um you know by definition people in care with hiv havea relationship with their clinician their provider and i thinktherefore they they i don't they trust the medicalassessment that may be taken too far but i think they have a relationship with usand i think that has helped i i think my wife is a primarycare doctor and and the patients that she has arelationship with i think they really um trust trust her and i think that's ourrole is to be that trusted provider that canreally you know counsel our patients and i think that's what my sense is aswell after talking to people usually on telehealthi think a lot of times they i get the same message and i think it'sperhaps because of that love other comments on this topic imaybe i should i put hiv in the main talk um you know on wednesday but ii obviously um it's a topic that we're all passionate about so happy to talkabout it here as well i didn't bring slides today i broughtthem for wednesday but it's it's sometimes better to talk without sliceraj steve johnson i did put a question in the chat box but just wording aboutwhen our patients are on a rt or no hospitalized where there aredrug interaction concerns we should think about witheither rem desevere or dexamethasone yeah it's a good questionum so for remdezavir i'm not aware steve or anyone of anyinteractions between um art and umand remdezavir with um dexamethasone we know that with other steroids there isan interaction between cobasisthat and batonvir containingproteus inhibitors and um and i think that probably mightextend the dexamethasone although i'd love it if an id pharmacistor a pharmacist could confirm do you know steve is thataccurate with excellence yeah i think so and and i think that's reflected in theart guidelines that yeah there could be some induction yeah sowhat a couple of dexamethasone interactions to be awareof one is rifampin you know obviously we don't always usethat but rifampin does interact with steroids and then i think umsteve was leading us towards the sip c3a4 inhibitors the cobasis statsand the rotonovers something to check on so beyond thatintegrase inhibitors i think we're on safe ground with umdexamethasone a good number of questions um let metackle one about hepatitis c daas directly actingantivirals and covet so this year at the age 2020conference there was a day called virtual covetwhich is the friday after age 2020. and there was a presentationby some investigators from iran and from the ukandy hill was one of the authors and he recently spoke to our group about thesedata so what they were looking at is acombination of cephospha there and the cladosphere these are two hepatitis cdrugs um in vitro they too have activity against stars kobe 2. so therewas a couple of uh smallish trials done in iranamong people with copenhagen with hiv not with with hep cto look at um cephosphere the cladosphere andone of the trials was with 66 people about 33 people gotum hep c drugs 33 people got a mix of other drugs including lupine andviratanavir and there looked to be a clinicalbenefit of the sophosphere the cladospherenow just i i've said the word caveat a little bit too manytimes but i think it's just true of some of these datait was a pretty small study there was a meta-analysis of some other studies fromiran that that also pointed in the same directionbut um they did say and they're careful to say this they're doing a 600 personstudy in iran with that particular combination to seeif it has a benefit in a larger group of people ithink it was just too small to to hang your head onone question i asked andy hill um when he presented to our group about a monthago about suffolk severed the cladosphere isprotein binding so with lapinova retinovir um one reasonit's really hard to get to levels that inhibit stars kobe 2 is because mostlepinove retinovir is protein-bound so that's where youyou get get that you need to swallow 60 to 120 pills to get above thatprotein binding for um lupinville retinovirand so the same issue may i don't know enough about sulphosphere decline aswell to know what its protein binding is but justbecause you can inhibit something in vitro doesn't mean you can get to thelevels in a person and so we'll just have towait and see in terms of effect i wouldn't um endorse it right now soum question about the blood clots um and whether we should be givingmildly ill outpatients aspirin even after the course of disease toprevent late small blood clots it's a good question i mean certainlyamong people with severe covingting we saw a fair amount of thromboembolicdisease um i learned a term calledthromboinflammation so in severe covid if you look at someof those inflammatory markers there's a very tight connection betweeninflammatory markers and and poor outcome but there's also aconnection between things like the dimer which is a coagulation marker andpoor outcome this is among severe covet not not mildand when you look at autopsies of people who have severe covet and have died ofcovet you'll find not only thrombosis but you'll find evidence ofendothelial injury and other things that make it seem like theinflammatory response is leading to to thromboembolism and we've seen peoplewith pulmonary emboli and myocardial infarctions mostly amongthe you know essentially among the severe diseaseum that has led to a lot of interest in anticoagulationwe and i think most in the dhhs added a section on anticoagulation so i wouldrefer you there as well but they essentiallyendorse prophylactic doses of anticoagulationbut not yet therapeutic levels of anticoagulation unless you have someother kind of indicator you have evidence of a pe or youhave strong clinical suspicion and in terms of aspirin once you get beyondthe um either before or after a course of severe coping 19i don't think there was enough data for them to say that that would make adifference um so i think right now i wouldn't go thereunless there's some other reason why someone should be on an aspirini will say parenthetically that we've seen a lot of thromboembolism but we'vealso seen a fair amount of bleeding and in fact in our own series sevenpercent of people in with severe copper 19 had thromboembolic disease but sevenpercent had serious bleeding so that that's really kind of atwo-edged sword right now so so yeah right now i wouldn'ti wouldn't do aspirin unless i have some other reason to be honestum colchicine um culture saying i'm aware ofa study out of greece that suggested colchicine perhaps through itsanti-inflammatory effects maybe other cleotropic effects might bebeneficial but and i am aware of a randomized trialbeing done but i haven't seen data enough tosay whether it's ready for prime time i think thedata out of greece was um suggestive but not definitive enough to to useand in terms of the rationale i think it's both anti-inflammatory and maybesome other cleotropic effects on the virus but i don't knowtoo much more about about that um does anyone want to unmute theirmicrophone and make a comment or ask a question will itry to catch up on these there's a lot of good questions here i think one of the things i can say rajis um and you sort of alluded to this is of course we've had more emphasis onour inpatient because obviously these peopleare dying right now yeah but i think in keeping with what you're talking aboutprevention um even just doing telehealth withpeople or telephones with people i think makes a huge difference i'mseeing lots and lots of anxiety and i've just found it amazingly calmingfor people when i say oh yeah many of my patients have mentioned that you getnight sweats at night oh yeah many of my patientstell me that night is the worst time and they're like reallyokay i thought it was just me yeah and sobecause none of us really know this when people hearokay this is sort of the natural course of the disease that we're seeingthey feel this huge uh relief yeah and and i'm i'm gonna like continue totry to push that that you know you know yes the firstinitial consult or discussion with that personmay take 30 minutes it's definitely not my usual hour that i have with a newpatient and then my follow-ups depending on howthe person is doing can be 15 or 30 minutes you know 15 minutes orif they're sick longer and i've done about three direct admits fromtelemedicine something i thought i would never dobut um i really think that should be emphasized moreyeah you know the point about long-lasting symptoms is a is a good oneand um and the symptoms what to expect there was a study that came out recentlysaying that even after two months after having coveted 86or so of people 87 still have some symptoms so itit lasts a long can last a really long timeand um i so i think for those who think it's really a mild disease i mean it canbe mild but it but even but we i mean i think we've allseen too many people especially at one point we had 450 people in ourhospital with kobe 19 of whom 250 were in the icu i mean reallyreally really sick people and i know that's going on in other parts of thecountry but it can be very severe and it can belong lasting let me take another testing questionthis issue of less accurate but more rapid tests is areally good question home tests um how many people have heard of somethingcalled twiv i guess i can't really take a poll heretwiv is a podcast um that stands for this week in virologyand it's a really good podcast that some of my friends had told me about it ijust started listening to it but check out 12 this week in virology butthey had a speaker a few weeks ago named michael mina who's um a really thoughtful person and he made acouple of points and a few other people on twitter havereiterated this you know our pcr tests especially the umum kind of the gold standard pcr test the tech down to about 80 copies or solet's say 80 to 100 copies per ml of sars kobe 2.but he made the point that people really don't get infectious until they'recloser to about a million copies so in some instances really having supersensitive tests and one instance where it's a problem isafter a covet as we talked about that so sensitive that people stay positive fora long time what he's arguing for is less sensitivebut rapid cheap tests and and something that we could doyou know he wants us to do it on a daily basis there's a paper-based test thathe's been trying to develop and and the idea hereis that if you can test frequently even if it'sless accurate you can find out if someone is positivebefore they get to that infectious part when they get to about a millioncopies and then you could isolate people and so i think that's a reallyinteresting idea and a number of people are nowstarting to talk about this idea of um less sensitive becauseyou don't necessarily need to know someone has 80 copies in terms ofeffectiveness you need to know if they come up to the hospital and you'retrying to figure out do they have cover 19um or is it something else is it nema pneumonia you know you need to know ifthey have it but for infection prevention maybe aless accurate but very rapid uh test mightmight kind of change the the curve so if you want to if you have amicrophone and want to comment yourself um on this you'rewelcome to unmute yourself and comment further aska follow-up i'm getting a five-minute warning eightminute warning here hi raj it's jeannie so i i have a i havea question regarding that for serial testing and soyou know it just your your it gets reported as negative or positive but ifthere are copies there so if somebody is testing positive for alonger period of time but let's say it's 100 copies yeahthat would uh instead of just saying well the cdc says you knowafter eight weeks you know or you know aftera couple of weeks you could return to work i mean somebody that hasa positive test result if you actually really knew what the copy level waswouldn't it help in being able to describe to a patientwhat represents like with viral hiv viral load blipsi mean in the same way i mean this negative and positive and the testhow how good the test is it's you know if we have the datawhy wouldn't we use it in that way i'd like to hear itit's a good question so we all remember or not all of us butin the early days of hiv viral load testing there used to be somethingcalled cts and now it's back so cts is cycle thresholds andthankfully genie we got away from pretty quicklyfrom those in hiv but it's how many cycles of pcr do youneed to get to before you get to a detectable value and and thankfully wegot two copies per mill you know thousand copies 400 copies 50copies 20 copies but those ct values are wherethings are unfortunately at right now with a lot of the umsoros kobe 2 testing the trouble is um they're not generally reportedand so i'm not in my lab and maybe if someone has access to a quantitativecopies per mil test could you it'd be great if you spoke up but right now thebest word most of our labs are doing is they havethese ct values where the higher the ct is more cycles it takes to get to apositive value the lower the viral load and so people are coming up with thesenumbers like if your ct value is um below 24 that's a high viral load youknow for ct um and then if you're above 34 it takesa lot more cycles and so it's a low viral load so some of those numbers iwas throwing around before um a millioncopies 80 copies those are coming you know fromthat that type of data but you know i agree with you iwish we had a quantitative rlo test that we could tell people okay you're you'reat 80 copies it's probably dead virus that you had and it's on the way downnothing to worry about or you had a million copies stay homeyou know and um i does anyone have access to that i'm now looking around umum you know testing i think we should do a wholething on testing i think testing is getting a lot ofappropriate questions okay i'm being warned that i have five more minutes andi think they cut off the um zoom at 110 so we can't stay even if wewant to it's gonna like turn black in about four minutes so umanagen testing um i think it's in the same vein as some of the otherum more rapid somewhat cheaper tests you know this paper-based test that michaelmeena is talking about is a couple of dollars per test the antigentesting i think is in that same direction that it's not assensitive but it might um tell us about you know if someone is positive or notand so i i don't have as much personal experience with antigen testing i thinkum it's something that some centers are using and it's probably in that samevein it may not be as sensitive but it may get you information about infectioninfectiousness in fact and infectiousness infectivity the other question in that vein sorry i'm just scanning here are there other questions there there'sa lot of them that i think we might have many of them we've done but if you wantto unmute your microphone and ask one you'remore than welcome to the neres one um instead of the the one where that goesdown back to your brain you know vanessa franchisei think the nares one um probably is not as sensitive but it mayget to where we need to go around um you know someone infectious or noti've seen some data supporting anterinaries but unfortunately a lot ofthe clinical trials are still using the the nasopharyngeal swab i think peopleare working hard on switching over to less invasive testsbut um can't say much more about that maybesomeone else can hi there could you speak touh returning to work for um in the outpatient world i guess we'retrying to deal with uh people getting exposed at home thatthey are keep having ongoing exposureand trying to bring them back versus the folks that might have haduh exposure a while with a cloth mask on and the cdc is still saying six feetapart in 15 minutes but the cloth mask is not measured they'renoted there so these are people who they haven't had kova they're justrecently been exposed is that the questioncorrect yes that's a good question i um i don't that's a good question i thinkhere we've been um for return to work for someone who hashad it we've not been using testing for people who'vejust been exposed that's i don't know off the top of myhead maybe someone else can comment i do i'm a little less on the infectioncontrol side steve or analyst you want to comment how you'rehandling it in colorado or in kentucky i'm not quite sureyeah i can't answer either i'd have to review i mean we unfortunately you almost end up havingto look at each case individually and we're following the cdcrecommendations yeah um that's kind of how we're handling it yeah mywife had an exposure recently and she's a physician but she um i thinkshe didn't have symptoms and so they did allow her to return to work buti'm sorry this is one that's a really good one i think alex is right it's caseby case maybe in a future one we can tackle testing and return to work umit's i know a little less about it than i do about some other parts ofamazing thing about covert write is um it's so vast already that you knowit covers just a range of things and we're all doing our best to keep up soi see 109 so maybe um there's any last points or commentsquestions otherwise we'll close and look forward to talking again on wednesdayabout covet that was good great session okaythank you all for joining talk to you more on wednesday hope you enjoyed thecourse and really appreciate you joining usthank you raj thank you