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9/19/2019 - Michael Kozal, MD

September 27, 2019
"HIV in 2019: What does an Internist Need to Know"
ID
4502

Transcript

  • 00:01Good morning in. Welcome to medical grand rounds.
  • 00:04Couple of announcements point in Jerusalem in speaker.
  • 00:09Next week will be a talk by James Freeman from Cardiology contemporary advances in the management of issue fibrillation.
  • 00:17And the week after next would be bought. Murcia Mecca from geriatrics complex medication management in the older adults.
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  • 01:34We have no commercial support for grand rounds in the conflicts of interest.
  • 01:38And for the case of Dubnyk Hannah, we present the case. Hannah. Welcome.
  • 01:46Morning for this week's case of the week comes to us from Verde 5 N on the SRC campus. We have a 6 year old woman who came in with confusion and falls. She had a history of congenital structural brain abnormality, alcohol use disorder in remission, history of psychosis, hypertension and she presented with weakness, confusion unsteady gait with numerous falls for several days.
  • 02:07Her initial physical exam was significant for normal vitals. She was chronically ill appearing in her neurological exam was significant for uncoordinated Hill to shin an unsteady gait.
  • 02:18Her initial labs in the emergency Department showed a elevated calcium of 15.7.
  • 02:23She was subsequently admitted to 35 N after 2 liters of normal Saline in the emergency Department and for hypercalcemia crisis. The team manager with aggressive fluids and subcutaneous calcitonin.
  • 02:34Overnight they ordered some additional labs including repeat calcium, ionized, calcium PTH, vitamin D parathyroid, related protein and 24 hour urinary calcium level to work up the elevated calcium.
  • 02:47By the morning her EP calcium had come down, but it was still elevated on her. Parathyroid hormone had come back elevated at 401.6 and some other labs or still pending.
  • 02:58With this elevated hormone, that team was concerned for primary hyperparathyroidism and ordered Image Ng.
  • 03:03An ultrasound next showed a probable parathyroid adenoma. Vala Byassee Teaneck that showed corresponding ultrasound finding soft tissue density posterior then fair poll that measured 1.6 centimeters seen here.
  • 03:21Here's another view of her image Ng.
  • 03:25The team diagnose the patient with hypercalcemia crisis secondary to primary hyperparathyroidism and managed her medically with improvement in her calcium endocrinology and surgery or consulted and she was transferred to York Street Farm in Lane base of parathyroidectomy. The patient did very well and she went back to her baseline mental status without further weakness. She would seem to be able to ambulate independently and discharged home with supper mentation of calcium and vitamin D.
  • 03:53And her final pathology showed an enlarged in cellular parathyroid gland.
  • 03:59For excellent teamwork, careful lab interpretation and great management. The case of the week goes to the Verde Fed N night and day. Teams doctor Nathan would doctor Noreen and sorry doctor Lindsey Archaon Doctor Christina Johns.
  • 04:16Thank you.
  • 04:17So now for for speaker today my causal is going to be a speaker. Mike is a professor of Medicine in the sectional infectious disease. His chair medicine at the VA and is the service line director for vision one. So visit one for you. For those of you not familiar with, the VA consists of Connecticut, Rhode Island, Massachusetts, Vermont, Maine and New Hampshire. So it's a really big job.
  • 04:44So Mike is a physician scientist. Those clinical research with transitional research in over his career. He's been involved in the genetic basis of drug resistance for HIV and hepatitis C his develop new molecular methods to actually detect viral mutations. And for that work is with patterns for it is recognized for this work is conducted many, many trials over 30 trials will last 20 years related to the treatment.
  • 05:14HIV and HCV.
  • 05:17So and is well funded, highly recognized for his work. Participate in a lot of panels that decide how you treat HIV and HCV.
  • 05:27He is a graduate of Creighton University degree in chemistry Magna Coomb Laudy where to Med school in Nebraska trained at Nebraska, then Sanford and then came here after a few stops elsewhere and it's been here since it's really a pleasure to be here. As a faculty member is an extraordinary leader, quick clinician and there is no one else knows as much about HIV than micros. Perhaps there are.
  • 05:57But.
  • 05:59For today, he'll defer to my welcome.
  • 06:08Well that was great. Make sure they have that on tape, so I'm going to what I hope to do today is actually really I'm directing this at internists and residents so.
  • 06:22So first my disclosures. I am a member of that. NIH panel for guidelines and although I'm going to talk about their recommendations. Today I'm my opinions are mine alone here today. I'm altorfer up-to-date. I receive grants support from even Gilead, an I have received patent royalties from some of the tests all show today. But they have sunsetted so it really is not there and they were licensed by a number of companies and I did help start a couple of biotech companies that were eventually purchased but those are I no longer have any.
  • 06:54Support with him and the reason why I mentioned those is because I'm employee of the federal government and I want you to know my prior history.
  • 07:01So here's the outline for today's talk. I'm going to give you data from the CDC WHL, the United States Preventive Services Task Force in the NIH, and we're going to talk about screening treatment. And then I'm going to talk about the United States planned and the HIV epidemic. And then we have time new therapies.
  • 07:21So I'm really glad you came today. I'm sure everybody. When you look at that grand rounds title you'll say should I even go to this talk? And I'm hoping that you're glad you did at the end, 'cause I'm hoping you'll see that you can play an important role in ending the HIV epidemic.
  • 07:36So I'd like to start with the case. This patient with this refer to me for a clinical trial.
  • 07:41And I anonymized that a little bit before confidentiality miss you is a black woman in her 20s who developed fever, rash and abdominal pain. And after a week of symptoms, she was admitted to be evaluated and she was diagnosed with an adnexal hemorrhagic cyst.
  • 07:58Their social history. She's married to a woman and they invite male partners into their relationship to the 3 male partners per month. She uses protection but does not use with partners she knows and her last HIV test was negative.
  • 08:11So in HIV screening test was done the HSV 1 and 2 antibodies are negative, but the Anagen is positive.
  • 08:18Now I'd like you to engage in a thought experiment.
  • 08:22Many clinicians interviewed or about her sexual history ID physicians, general Internist OBGYN, clinical trial specialists, and this is a summation of all those sexual histories, each one with a little bit different. Not surprisingly, that this is sort of a summation of those so patient a had a sexual risk event with their two months prior to her diagnosis, patient B had one three weeks prior to your diagnosis and patients eat. Had one less than 3 days prior to your diagnosis.
  • 08:51So ask yourself these questions when she infected and doesn't matter. Should she be started on treatment? And what should we do about her partners?
  • 09:02So in the United States about 1,000,000 people are living with HIV and about 39,000 new diagnosis occured in 2017, reporting is usually about 2 years in arrears and at that in 2017, anyone percent were Mail in 19% were female.
  • 09:17In Connecticut, 10,500 people are living with HIV and importantly about 1000 or undiagnosed.
  • 09:25And what do you notice about this map?
  • 09:28You see the different color shades of blue and you see how the S there is actually a little bit darker. When I was a resident in when the epidemic occured, it was on the coast and it was mainly in the major cities, but now.
  • 09:43The epidemic is migrated into the SE 52% of the new infections occur in SE.
  • 09:49And it disproportionately effects African Americans accounted. They accounted for 43% of the new diagnosis, but only 13% of the population. Similarly for Hispanic Poppin Latino populations.
  • 10:03So this is the classical way you normally see risk behavior and incidence of new HIV infections. and I wanted to show you in reverse order just so you could see how geographically and also by race and ethnicity. It actually changed and I want to point out heterosexuals 24% of the new diagnosis are in heterosexuals and in Connecticut. In 2017, the only demographic group that had an increase in HIV where heavily sexually active black females.
  • 10:32So this is HIV diagnosis by age and you can see as you would guess, most of them occur in the younger age. But people over the age of 4525% of the new diagnosis occur in that age. So you age group. So you should consider HIV at any age.
  • 10:48Now for your first board question for the residents who do you actually test for HIV? So this is from the task force us task force and they came out with these. Recommend updated recommendations in June and they recommended test every adolescent and adult age 15 to 65 years of age and they gave that a grade six grade.
  • 11:10And you should be assured that these are incredibly accurate tests. They probably had some of the best sensitivity and specificity of any of the screening. Test your order.
  • 11:20So how well are we doing screening everybody for HIV fewer than 40% of US adults have ever had an HIV test.
  • 11:29Everyone should be tested and the reason why we actually have 160 estimated 165 thousand people in the United States that are HIV infected and they don't know they're infected and we can't treat them if they don't know they're infected.
  • 11:42So what about globally?
  • 11:45This is the number of people living with HIV. The graft on the left is in Orange Is the number of new infections.
  • 11:52And the Gray is the number of people dying from HIV aids overtime and I think you can see right away. There's a difference between new infections and deaths.
  • 12:02And because of this, we actually having an increasing number of people living with HIV around 37,000,000 people are living with HIV globally.
  • 12:13So this is a really interesting graph, so this is the trends in annual rates of death due to the 6th leading causes among persons 25 to 44 years old.
  • 12:23An it's really an amazing graph. When you look at it. I just want to point out to the training. This is where I did medical school residency in ID fellowship.
  • 12:33And it seemed like every other patient was admitted to hospital. Was HIV related?
  • 12:37And that's why many of us decided to treat people with HIV and I dedicate our lives to actually doing it. 'cause at that point in time it was decimating populations.
  • 12:47Unfortunately, HIV infection still is among the 10 leading causes of death among persons 25 to 44 years old. And increasingly it consists of black EFC, Americans, residents of the South and women.
  • 13:03But we have incredible therapies. This is a slide from the UN aids and it shows the expected survival of a 20 year old if they come into a high income country and go on to therapy.
  • 13:16In our patient who's in her 20s, if she takes a RT, we can tell her she can live approximately 50 more years.
  • 13:25So this is the drugs we have to treat HIV. There's 7 drug classes, 29 agents and more than 20 fixed dose combinations. I can't go through all these today now even debated presenting this light 'cause it can overwhelm.
  • 13:40But we usually put three of these drugs together to treat somebody, and so instead of showing all the drugs and make everybody feel little bit anxious.
  • 13:49Want to do another thought experiment? Choose 3 desserts from a menu of 10. This is Union Lee Arrow. This is union, so you already know what you want.
  • 14:01Well, imagine you're at a table with your family of 6 and 7 and had a huge dinner and somebody says let's just order three desserts and share. Everybody is great, but then the waiter says I'll come back. Why does he have to come back? It used to be a former waiter, so I know this.
  • 14:17The number of possible 8 possible combinations. There are enormous. There's over 120 possible combinations. You can do that. So imagine if these were HIV drugs and why that's important. We don't test all these possible combinations, but we actually use them and patients.
  • 14:33And for those of you that deal with HIV drug resistance, some of you in the audience we usually use about 20 to mix and match and put together to treat somebody. And there's over 1000 possible combinations you can do for that. But what do I want you to remember today? Just three drugs. Doggy Taggart enough of your FTC and for the others, we have the guidelines.
  • 14:54So the HIV guidelines were started in the 1990s by the NIH and they did this to help clinicians because the data was coming out and people wanted access to see how you treat people.
  • 15:06If you take anything from this download this app. This is a free app from the NIH and it actually has the guidelines on at the guidelines for about 350 pages, but it's very nicely ordered. Then you could just touch and go to where you want to go. These are living guidelines. We have calls monthly to decide if we should update them and if there is a new finding we can actually push it right through the app or put it on the website. So instead of going to a Journal have to pay Journal fees, the NH thought this was the best way to disseminate this information.
  • 15:36And I think it's been a huge success. This is the guideline page views last year around 900,000 pageviews. These are these guidelines are used internationally and I think it's an incredible valuable service resource.
  • 15:50To download that app.
  • 15:52So this is now for your second board question. Who do you treat?
  • 15:56ART is recommended for all individuals with HIV. Why? Because it decreases death.
  • 16:03Also it prevents transmission.
  • 16:06And when should the person be started as soon as possible?
  • 16:10So our patient at the time of her diagnosis, she had a CD 4 count of 758 which is normal.
  • 16:16However, no matter the value, she should be started on treatment.
  • 16:20Why is that so? This is a Kaplan Meier from the start study. We did this start study here. Juries. The Pi. We still patients on on it long term and evaluate patients that had high CD 4 counts 500 or higher and they either sort of the patients on therapy immediately or wait until the CD 4 count got down to 350, which many of the lower resource countries were using at the time. But the study was stopped early because starting HIV medications above 500 significantly.
  • 16:52Had a greater health benefit, decreased morbidity and death. So that's why we treat everybody irregardless of CD 4. So.
  • 17:01So.
  • 17:02I actually going to go through a couple of these assays here because you might need to order these when you go out in clinical practice and you have an HIV patient on your panel or if their patients on the inpatient. You might actually be asked to order these test so I thought they would be helpful to understand.
  • 17:18So first diagnosis.
  • 17:20How do we diagnose HIV in the 1980s? The initial antibody tests had a 50 day window where we couldn't diagnose a patient.
  • 17:28These have gotten progressively better now that the CDC that blue line there represents a 4th generation asset.
  • 17:36And by the addition of adding P 24 antigens HIV antigen, we can actually diagnose a patient after about 14 days after infection.
  • 17:47This is exactly where our patient is. Antibody negative antigen positive.
  • 17:52So how do you confirm a diagnosis when you can't use antibodies in a person with acute HIV infection? Which this woman meets that criteria, you confirm with an HIV viral load and her viral load was greater than 4,000,000 copies. Now she's very infectious at this time. One of our loads very high and she doesn't know she's infected.
  • 18:15So are currently the Eclipse period. The time after an infection until we can diagnosis about 10 days. So we still can't diagnose somebody right after infection. It takes about 10 days.
  • 18:25So back to our thought experiment.
  • 18:28Now patient a here.
  • 18:30The patient, actually, after her diagnosis, she reached out to all of her own context.
  • 18:36And patient a when she called him. He said he had recently just been diagnosed with being HIV positive.
  • 18:43So could patient AB the source.
  • 18:45Well, if she if patient a was the source, she would be 60 days into her infection and you would expect her to be antibody positive which she is not.
  • 18:55So he's unlikely to source.
  • 18:58What about patient be when she calls him up? He says I'm not a I'm not surprised by your diagnosis, but he doesn't admit to being HIV positive.
  • 19:09Patient B actually fits the criteria. The patient is Arnie positive energy and positive positive. An antibody negative fitting there right in that window.
  • 19:19Patient be subsequently tested and he is also HIV positive.
  • 19:24What about patient? See.
  • 19:26Well patient sees risk event occured right during her prodromal phase.
  • 19:31Will go back to patients in a minute.
  • 19:35So.
  • 19:36We used quantitative PCR to actually quantitate the virus in the patient's plasma and with effective therapy we want to try the viral load down to 0. We can't say 0, so we say less than 50 or less than 20 'cause you can't optimize an asset to that level.
  • 19:51Viral load levels should be monitored every 3 to 6 months after a person has viral suppression and that this depends on how well the patient is doing. But at least every 3 to 6 months. So for our patients whose viral load is greater than four million, we want to drive it down to less than 40 copies.
  • 20:08What about drug assistance? Well, this is data from the CDC and Unfortunately about 19% of newly infected patients in the United States are infected with drug resistant strains.
  • 20:20And our patient was no different. Her virus had a K 103 N Mutation which confers resistance to nucleus. Nucleoside reverse transcriptase inhibitors, and she had a 41 Ellen 215 L which confer resistance to the nucleoside drugs.
  • 20:34And secondary transmission of drug resistance is actually a big in many cohort studies have shown to be a problem, so persons has drug resistant virus infect somebody else person doesn't know they're infected and they can infect somebody else with services strings, but I do want to point out that integrates inhibitors have one of the lowest rates of transmitted drug resistance and This is why we actually use these drugs first line.
  • 20:57So how do we test virus for drug resistance? Is recommended for everybody after a new diagnosis. Well, we amplify gene regions that encode the viral proteins that are the drug targets and we look for mutations and we use standard Sanger sequencing to determine what the mutations. By doing this we don't have to culture the virus.
  • 21:17So every drug that's approved by the FDA, they actually have to submit. What are the mutations that cause drug resistance for their drug?
  • 21:24And these limitations that are patient had a 41 L 215 K, 103 N.
  • 21:30Now these mutations have different weights and we use weights if they cause a lot of drug resistance is given a higher weight. If it's a lower only a little, give the lower number and we use the algorithms to determine the drug susceptibility. And why do we use algorithms?
  • 21:47Well, there's over 100 possible mutations currently that we used to follow. I used to know all these, but now I don't. I can't do that 'cause That's factorial but.
  • 21:58These algorithms are updated every time a new drug comes out.
  • 22:02So this is a figure that we did in one of our reviews and it represents a person that's infected with drug resistant virus and they don't go on therapy. What actually happens to them? So this is exactly with our patient.
  • 22:15So these red squiggles here are supposed to represent drug resistant virus.
  • 22:20She had a K103 on this one has a K103 as well, but this is not our patient but overtime. If the person is not an therapy, the virus will actually back mutate to a more wild type virus because these mutations helped the virus in the presence of drug that actually cause decrease replication capacity. In the absence of drug. So overtime, the virus will actually change in a patient.
  • 22:43To become more and more wild type and that means the resistant variants actually fall down in the percentages. And when they fall below 20% Sanger based population sequencing which are acids are based on cannot detect them.
  • 22:56And then if a person is put on those drugs.
  • 22:59The virus can rapidly re emerge and cost therapy failure, and Interestingly our patient had a 215 L and this is a known revert. So this is capturing the virus. Reverting back to a wild type with this mutation.
  • 23:15And so it's likely are patient. Be actually was not an therapy because he was able to transmit this virus. We don't know. You can't tell talk about directionality, but it's just very suggestive of it.
  • 23:27So how do we detect these low level variants when they get below 20%? This is a singer sequencing file, a standard DNA sequencing file and you can see the computers reading that it's wild type. But you see this little peek here that actually represents 5% mutant virus in a patient. And if you use deep sequencing, you can actually quantitate the number of mutant variants in a person's blood sample.
  • 23:54And we actually have optimized these assets where you can get down to about 1 to 2%.
  • 23:59And 8 years ago when I gave grand rounds.
  • 24:04I presented these data and we use deep sequencing in. This was the first study where he had subjects from twenty five US cities and we basically showed that transmitted drug resistance increased basically doubled when you use these new technologies and the graph on the right here shows that if you have this is working with colleagues at Harvard and John Lee. We put all our data together and we could show that minor variants. If you are infected with a minor variant and you're put on therapy, that variant is resistant to you're more likely to fail pretty standard infectious disease.
  • 24:35So currently I've been working with an international group evaluating the drug resistance in the start study that when I mentioned earlier.
  • 24:42This is we're looking at all the patients that around 4000 patients enrolled in this trial and doing deep sequencing. We showed again that doubling the prevalence of drug resistance almost 20% in this population.
  • 24:56And this is data from UNH skews me WHL that came out this summer. These are load in middle income countries to your left here and this dotted line is if you have prevalence of pre-treatment drug resistance in your population greater than 10% and you can see most of the countries do.
  • 25:15And Unfortunately among women in these countries, 14 of 18 countries had pre existing drug resistance greater than 10%. And why that's important. This drug class in an RTS is what we is used to prevent mother to child transmission in those countries. And so what's the take away from those 3 quick studies?
  • 25:37Pretreatment drug resistance is a problem globally.
  • 25:40But it informs aren't decision on how we should treat people first link there with the first line therapy.
  • 25:46So what should you start in a patient and for boards? I think the only thing you would ever need to know is that it integrates based with two nucleoside drugs, at least for the next 2 years.
  • 25:56In the United States, you can choose from one of these 4 combinations and it's not important for you guys to know these. But the patient is started on this regiment.
  • 26:06So where do these drugs work? This is the viral lifecycle.
  • 26:12And I only think you need to know to reverse transcriptase. We take two drugs to block the HIV reverse transcriptase and we take one drug and integrates inhibitor to block into Grace.
  • 26:25And these drugs are actually Co formulated 3 drugs in one. So you can take one pill once a day.
  • 26:31How old are these drugs work? Really want. This is the FDA licensing study it compared two of those regiments against one another and you can see by per protocol 99% of the subjects were suppressed at Week 48 or about one year, but intent to treat a little bit lower. But this is the reason why that is is in the FDA snapshot analysis. If a person doesn't come in around Week 48, they're considered a failure, but they might come in 2 weeks later and they're still suppressed.
  • 27:01And they're successful. So all HIV trials usually reported by intent to treat and by per protocol. So you can actually see how it's really working in the field.
  • 27:12So our case continues. She started on this regimen for viral load becomes non detectable. CD 4 counts 800.
  • 27:19But after 6 months, she wonders about becoming pregnant.
  • 27:23But then she heard. But the issue with Dolly Teddy Bear, which will touch on an shell. She switched to a protease inhibitor based regimen.
  • 27:30So in the guy thinks we have nice tables that you can say Oh, the person has sarot sis. What should I use? And we can tell you which regiments to use.
  • 27:37But what she had heard about and this came out 2 weeks ago in New England Journal about the neural tube defects that there's a slight signal that maybe W tag if you're actually has a higher incidence of neural tube defects, and there's an important caveat with this.
  • 27:53This study was done in Botswana, where they don't do fully self limitation. So the fields really wants to wait to see what happens when they initially reported this a year ago is .9% and as they followed patients that keeps on falling. Now it's down 2.3%.
  • 28:09But because that we switched it to produce an amateur.
  • 28:13Now these are data from the WHL. They were ready to roll out value, tag River to everybody. But then that information came out. But then finally, this summer, even knowing that point 3%, they decided to recommend value Tiger for all populations.
  • 28:32For those of you, they want to learn more about this. There's a nice editorial 2 weeks ago from Bob Redfield and the National Center for birth defects and the CDC where they actually talk about this. A woman can actually be involved in her decision, making a point, 3% incidents or 20% incidents of drug resistance. And they may not.
  • 28:52Respond in transmit to their child. A woman should be involved in a country. Shouldn't be saying You have to use this or that and it's really nice. So basically the CDC came out in support of The Who guidelines.
  • 29:06So again, 2 nucleoside drugs in an integration hitter Tanaff very FTC and W Tiger Bear.
  • 29:13So how? Well, how well does this generic combination work? This is data that was published in August 29th just couple weeks ago. This is the first line regimen right here.
  • 29:25This was done in South Africa. 99% of the patients were black and 59% were female. This is really important. Most of studies in United States so usually in white men. But this shows that these drugs actually work very very well.
  • 29:40And that's important is we have 37,000,000 people living with HIV.
  • 29:44And 59% are currently receiving a RT more than twenty one million. So how do you treat twenty one million people?
  • 29:51Well, the median price of this value tag very containing regimen is about $80.00 a year and with economies of scale you can get it down to about $20 a year.
  • 30:01Anybody want to guess with that same regiment? Cost United States.
  • 30:05The wholesale price is $40,000 a year and our patients new regiment is $50,000 a year and she's very stressed because she has a high deductible and it's really stressing her out.
  • 30:19The US government spends 20 billion in annual direct care for patients and so I'll let you guys do the math about how many more people we could treat if we. If we use that.
  • 30:30So undetectable equals untranslatable.
  • 30:34Stand firm and gave us a lecture last year about if your patient is HIV positive and they go on therapy and their viral loads. Non detectable.
  • 30:43They cannot transmit to their partner know transmissions were observed in these studies and it's because of this interesting data. I don't want to go into the studies consist ended at last last year.
  • 30:54The US came out with a plan to end the HIV epidemic and this is a collaboration between the CDC, NIH, HHS, Hersa, an Indian health service.
  • 31:05What is their plan? They want to decrease new infections by 90% by 2030 and how are they going to do that? Well, they're going to focus on specific high intensity error areas initially.
  • 31:19And you remember when I showed you the chart about the SE.
  • 31:27They're going to focus on the South and in major cities where there has a high impact. We have 3000 counties in United States. 48 of the counties account for over 50% of the new diagnosis. So they're going to focus on that.
  • 31:40And how they're going to do it? There's 4 pillars.
  • 31:43They want to diagnose everybody. That's HIV positive as early as possible. Treat everybody effectively and rapidly. Did reducer viral load prevent at risk individuals by using prep and will talk about Prof in a minute?
  • 31:57And rapidly detect and respond to clusters of HIV infection.
  • 32:01And you should treat each new diagnosis as a Sentinel event. So let's go back to our patients cluster here.
  • 32:08Just remember it.
  • 32:10So this is data from Tony fact for all you skeptics in the audience arrow.
  • 32:17I apologize. He told me he was going to fall asleep, so I want to make sure these are data from Tony Fouchy at the recent Croix and this is the incidence of new infections in New York City, San Francisco in Washington, DC, and they each these cities implemented these 4 similar to these 4 pillars so it can work.
  • 32:40And they're going to funnel money into the Ryan White programs. the NIH is because they do some of the best work didace is leading the P of the Brian White for Connecticut does amazing job. The suppressions of viral load in this area are amazing and they want to try to do this nationally to drive down the viral load of the population.
  • 33:02So what can you do? You take a good sexual history and drug use history. So this is our patient cluster and just to remind everybody our patient turns out to be HIV positive with a resistant strain.
  • 33:14Our partner, a actually has HIV partner B is HIV positive with resistance partner. See Unfortunately it turns out to be HIV positive. We don't know because he's not under care for us, but we don't know if he has resistance or not, but because she reached out to him within 3 weeks. He was on therapy and doing Kerry needed.
  • 33:37So 15 years ago Jerry and I did a series of studies about risk behavior and I just want to show you some of these. So a patient would come in for these studies and they would answer anonymously on the computer about their risk behaviors and in my lab would do HIV genotyping on the blood sample and then researchers remote researchers under a certificate of confidentiality would put those two data together and we could actually see how many risk events the patients were having that involve drug resistance. and I can't show you all these today, but I just want to show you 3 representative patients.
  • 34:09These are all HIV positive patients. One patient had one partner in one sexual risk event.
  • 34:15One patient had 15 partners in 55 sexual risk events.
  • 34:19Another patient had 4 partners, 95 sexual risk events, but 80 of them with exposure to drug resistant virus. Why am I showing you these data first? Because 15 years ago I got a terrible question from the audience. We said what can you do about?
  • 34:35Well now we can do something about it.
  • 34:38Everybody in this group should either be on ART or prep.
  • 34:43What is prep?
  • 34:45Prep is one pill once a day. It's to not fear an FTC. It can reduce the risk of HIV infection by 97% in some studies. It's up to 99% and we have 3 prep clinics here on Iama. Who's the leader locally and prep studies and also in the prep planks? Michael Virado runs that prep clinic at Saint Ray fields and Sandy Springer runs the one at the VA but Sandy's already transitioned this. The primary care physicians can do this on their own and CPRS has a nice template on how to ask patients and actually start start therapy.
  • 35:17So you say Oh good. I can just refer my patient to prop clinic. However, this summer the US preventive task list comes out and says all clinicians.
  • 35:25Should actually discuss with their patients about their risk and prescribe prep indicated.
  • 35:32So of course I can't go through all this today, but I do want to bring out our patient.
  • 35:37These are the indications for starting prep. If you're heterosexual man or woman and you have a serodiscordant partner or inconsistent use during sex with a partner whose HIV status is unknown. Or is that high risk such as injects drugs or a man have sex with men and women or recent STI syphilis gonorrhea in the last 6 months.
  • 35:59So the CDC came out and says by routinely testing patients for HIV, assessing HIV negative patients for risk behaviors and prescribing prep is needed. Providers can play a critical role in ending HIV epidemic.
  • 36:13So the CDC estimates. There's over a million prep candidates.
  • 36:1762600 thousand heterosexuals about half a million MSMS and over 100,000 people inject drugs and how well are we doing well half a million black and African American candidates offer prep and only one percent prescribed prepped in 2016. And by 2017 it still remains very low and not meeting the incidents of other populations.
  • 36:40So I'm going to take a brief survey break. I asked. I asked a bunch of people at the VA. Have you ever seen an attending obtaining sexual history from location?
  • 36:52I don't think so. We do it. The attending will only do it if they think it's clinically indicated.
  • 36:58I've seen in attending take a sexual history once. I think it was an awesome. Actually. I had multiple people answer that way. So Yay Donaldson.
  • 37:08Only when the patient brings up the issue more reactively not proactively. and I think that's where a lot of us fall.
  • 37:15Most attendance won't ask anymore questions after patient says they're married and I also think a lot of it.
  • 37:21Do that and my favorite answer.
  • 37:24Who's my attention?
  • 37:27That person was post call, so we'll give him. Give him a break.
  • 37:31So I know taking a sexual history can be hard.
  • 37:34The CDC has a great resource that you can actually use it. It's a starter script and you can just say I ask all my patients these same questions. I'd like to ask you these questions, and you can say, do you have sex with a man woman or both? And you can go through it. So reach out. I don't have time to go through that today, but that's a great resource.
  • 37:51So now hope new agents.
  • 37:53Before talk about these, I do want to emphasize Yale has really been a leader in the treatment of HIV, especially for multi drug resistant virus.
  • 38:03And this study by Brenda.
  • 38:06It was published last year in New England Journal. This was an evolution map. Is a post attachment inhibitor that it's none immunosuppressive monoclonal antibody that binds to the CD 4 cell receptor and Blacks viral entry. And in those heavily treatment experience patients, 43% of the participants had an HIV RNA below 50 copies at Week 24 and that's all you really need. FDA approval when you're actually looking at this population.
  • 38:34So I had the the nice honor of being deleted. This study this is false temps. If you're in heavily treatment experienced patients.
  • 38:42This drug act, the pro drugs ostensibly attempts if you're actually binds to GP 120 blocks, the virus from engaging the C4. So now this study is at 108 sites in 23 countries across 6 continents and randomized very experienced patients to treatment. And importantly, we had 99 patients that were non randomized. These were patients that had no treatment options and so we were able to get the drug to them and this drug met primary end point being superior to placebo.
  • 39:11And then at Week 24.
  • 39:14Over 70% of the patients had a viral load lesson 200 copies. So it really looks a promising and this is under review at a current Journal right now and so hopefully they'll accept it and.
  • 39:26Patients that were not had no other treatment options. 41% of them actually went to non detect balls with 24.
  • 39:33So this drug is sort of unique in that there seems to be really robust. CD 4 cell responses. These are patients that enter the trial with a CD 4 count less than 20 very advanced aids and over a 2 year time period you can see those. It remained on study, have increase over 200 cells.
  • 39:53So I want to show you a couple of patients here at Yale. This is one of our patients that came in for CD. 4 count was 2. She goes on therapy bar logos, the non detectable and after 3 years sort of CD 4 count has risen to 729 really incredible rise.
  • 40:08This is another patient that many of you might have taken care of in the hospital. He was a 52 year old with multi drug resistant HIV. Had PML VZV of the pallet is all resistant handed Asafa Gitis he goes on therapy this CD 4 count has gone from 2 to 197 but it's viral load has never gone to non detect.
  • 40:27Which is really unusual.
  • 40:29And we've been funded by the company to actually investigate these.
  • 40:36Patients on this trial and this is a research collaboration with the but Walter moths, Richard Sutton, Pretty Kumar and myself were were working with the company to really try to investigate what's actually happening with this drug in these in these patients.
  • 40:49So.
  • 40:51Back to treatment naive patients you'll say. Well, I'm never going to have to treat anybody. I'll refer to an HIV clinic.
  • 40:57These are this is a drug that's an injectable drug. It's cabotegravir and repairing these drugs can be given once a month by injection. I am the FDA licensing study. They were found to be similar to drugs. The standard of care taken by mouth.
  • 41:15And just couple weeks ago announced positive phase 3 results for this drug. These 2 drugs given every 2 months by injection.
  • 41:24And so there's a lot of Hope in the field that maybe in the future we will just be able to give patients injections.
  • 41:30And obviously you can. Both of you are there doing the quick calculation about prep.
  • 41:36You could use these drugs for prep and so the NIH has lost a very large trial. Bought 4500 patients internationally and they're going to compare IM injections every 2 months versus daily oral prep and this the results should come out in 20 twenty one less. It stopped early.
  • 41:54So tools to evaluate tropism I have to talk to you a little bit about this. I know it can be a little bit confusing, but because I'm going to talk about cure, I want you guys to understand this. So we want a virus comes in to bind to a CD4 cell, engages the CD 4 cell receptor and then it can use either you CCR 5.
  • 42:14Or can you see X CR4 to actually engage in into the cell?
  • 42:19And we can determine which receptor virus uses either through a recombinant virus asset or we sequence the V3 region of the envelopes.
  • 42:29Why that's important is we have Co receptor antagonist that can block the coreceptor.
  • 42:34But when I talk about HIV cure.
  • 42:37And I say Delta 32 this receptor does not come to the surface.
  • 42:43So all those that are HIV providers always get this question with our patients. One of the in the 1st question she asked me when I sat down with robotic trial. She says, what about HIV cure?
  • 42:54Well, many of you might have seen the paper in the New England nature. Madison in April, a second patient has been cured of HIV or in Virologic permission and he was transplanted similar to the first patient with a donor that had the Delta 32 mutations. There's a 32 base pair deletion and CCR 5 that makes the receptor not be able to come to the surface.
  • 43:18So there's been a lot of research. Then let's use zinc finger nucleases or crisper to try to knockout that. And maybe we can cure everybody and there's a nice editorial. New England Journal this week about this and Richard Sutton, who's hopefully watching will be is on he's attending right now. He's going to be discussing both these papers that editorial an appointment today at Journal Club. So if you want some pizza, just come listen to Richard.
  • 43:48So if you want to learn anything about Delta 32, I really would start with Alison Galvani's paper. She's endowed professor at Yale and school public health and this is an old paper 2003, but this is where she was arguing is that plague or smallpox that actually cause this pressure on the human genome that make this Delta 32 present? And she argues in favor of smallpox. Nobody really knows, but smallpox also uses a kema kind of Receptor, Andrew itself and so she was suggesting that is.
  • 44:19And so.
  • 44:21Who has Delta 32 northern Europeans about 10% of northern Europeans have hetero Sigusr Delta 32 in about 1% are homeless I guess.
  • 44:34And with this they were saying all these, if everybody has this, why this might not cause any problems and so there's Chinese researchers actually edited.
  • 44:45The germline embryos and actually created crisper babies. Basically, they knocked out the CCR 5 in these children.
  • 44:53Unfortunately there's there was a report in nature. Madison, just a couple months ago.
  • 45:00Suggesting that if your homozygous for Delta 32, you might actually have a decrease increase risk of all cause mortality and what this is based off of is Delta 32. Although it might reduce life expectancy in a modern cohort, it can protect against HIV. But people have shown that maybe influenza and other viruses can actually can have worst disease with that. And don't ask me any questions about this.
  • 45:25Because you can ask Ruth Montgomery, she did a nice analysis looking at the different genetic variants in the incidence of severe infections with Danny and West Nile and she actually talks about CCR 5 in that paper.
  • 45:38So profile DNA testing. I'm just going to rapidly run through this. We can actually evaluate proviral DNA in a CD4 cell and we need this 'cause we want to try to purge that. If we're going to cure somebody.
  • 45:51And this is just a cartoon of.
  • 45:55How we can order this? You guys can order this test right now on a patient. They'll send 4 blood Mills and blood. You isolate the purple bloodbound nuclear cells. We want to focus on the CD 4 cells, but in a virally suppressed patient like our patient. You might only be able to evaluate 440 pro viruses and the reason why that is is replication competent in a patient on therapy. There's very few cells that have that maybe one out of a million cells has that if you're only drawing formulas of blood, you really are getting unrepresentative sample.
  • 46:27So for this patient, when I saw her, she wanted to volunteer for one of our functional cure research studies. In this study was in Valuating the envelope sequence in late in the latently infected reservoir in patients. And because we couldn't draw full meals of blood, she volunteered very altruistic Lee volunteered to undergo 4 hours of local pheresis so we could isolate a lot of purple bug nuclear cells to evaluate the replication competent HIV and why are we doing this while they're being broadly neutralizing antibody combinations that are being developed to directly and kill latently infected cells.
  • 47:01And the NIH is launched. The trial that it's actually comparing two of these for this to try to purchase, and so patients are patient is doing very well and she wants to help find a cure for HIV. Most of our patients are extremely altruistic and they volunteer for many, many studies to help research.
  • 47:18So In summary, HIV prevalence is increasing. People are living longer and there's a demographic shift in the US.
  • 47:25Screen everyone between the ages of 15 to 65 and if you think they're acutely infected, order a plasma viral load.
  • 47:32You treat everyone when ASAP within integrates inhibitor 'cause it treats drug transmitted drug resistance and they're very potent and why survival benefit and you equals you. We actually have the tools to stop the epidemic right now if we apply them appropriately. And what can you do about it? Take a good sexual history and consider prep for your patients.
  • 47:55And there's a lot of hope on the horizon's we're going to be using injectable agents very soon, I think.
  • 48:00And so acknowledgements. I want to think about all the clinical trial group. Folks are all here. Specifically think this group of people because they actually see all the patients and do all the hard work. Cindy and Laurie and Jackie and Susie and Frances and Jen, who probably deep sequence a couple thousand patient couple thousand samples for me want to thank all the investigators and all the patients in the bright study.
  • 48:24And I also want to thank Max lots. EOD Max was a fellow in my lab about 10 years ago. He get turned on to HIV research. Really want. Is passion about developing drugs for patients with drug resistant virus and now is a big wig at a company. Vice president global now clinical development.
  • 48:41And so I'll answer any questions.