John Martin: [00:00:00] Okay, well, I also have to thank Bob [Gallo] for the invitation and the team that put together the conference. Bob suggests this title, said you can talk about what you want to talk about. I can honestly talk about how we make nucleotides come forward to be the backbone of a single tablet regimens. It's a really fun meeting. I think just about everyone in this room has somehow interacted with things I've done during my career, even if I'm not aware of it, it's just [00:00:30] such a group of people work together. Some of you I know very well, I see all the time. Some I know you well but haven't seen you in a while. The chair of the previous session, John Mellors, he could give my talk even though he hasn't seen the slides, because we've discussed and argued about this stuff all these years.
To get into it, [chuckles] this is a picture from four years ago. Tony [Fauci] showed a picture of Mitch [Mitsuya], Bob [Yarchoan] and [00:01:00] Sam [Broder] from about 30 years ago. This is just an example how we still get together, the three of us got to know each other in the '80s, we collaborated on dideoxynucleosides. We've talked about chemists, so two other chemists in that group too that I became quite familiar with, John Driscoll and Victor Marquez who were part of the NCI effort. This as you can recognize, by up at the top, it's one of Raymond [Schinazi's] HIV DART meetings. Doug Richman took this picture because this is his side restaurant. [00:01:30] A small group of us got together to talk about old times. Lady in front is Mitch's daughter who at that time was at Oakland Children's Hospital. Now she's at Stanford. It's a group of people, we known each other all these years and really have a lot of respect [for], that goes really broadly for people in this room.
I’ll divide this in two parts, nucleotide antivirals to go into single tablet regiments, and how the simplified therapy has helped impact low [00:02:00] income countries.
We all had careers, almost all of us had careers before we realized what AIDS was in 1981. I was an organic and medicinal chemist. I took great pride in sometimes making molecules that are just complicated and had no use. That's what young people do. But then, around late '70s into 1980, I start to work on antivirals. I was the only person and the first molecule I made was [00:02:30] ganciclovir. (1, 2) That sort of put me on the focus of trying to have impact on human health.
You can see ganciclovir is a little bit closer to 2′-deoxy-guanosine than acyclovir. That leads to quite a bit of toxicity, Ganciclovir’s 3’-OH gets incorporated in DNA and it's very, very toxic. I don't think it ever would have been a drug except what sometime after synthesizing it, we had HIV and AIDS patients and CMV (cytomegalovirus) [00:03:00] retinitis. Ganciclovir's first approval was for CMV retinitis, that was in 1989.
This was a time—Marty [St. Clair] talked about it, Raymond talked about it—where there was a lot of optimism about nucleosides for antivirals. Bill Prusoff (1920–2011) had introduced IDUR (idoxuridine) in the '50s, and then trifluorothymidine, but there were limit use toxic, and aciclovir was the first [00:03:30] really potent safe drug for the treatment of a viral infection. It has the mechanism that’s already been talked about, going to a monophosphate and on to the triphosphate inhibit the polymerase.
At the time that we were all excited about this and the work Trudy [Elion] (1918–1999) and Marty [St. Clair] and others did, we were thinking, "What if we can make analogs of the monophosphate there stable?" (3) If you just give monophosphate, it falls off, it just metabolizes. It's a soluble form of nucleoside [00:04:00] but it's not a nucleotide. But if you could make this metabolically stable, would it work? Up until then, nothing has worked. There been nucleotides made for instance, a phosphonate analog of AMP, which you would think would be active, because an AMP is in everything, but it had no biological activity. So it was thought that these molecules are too polar to get into cells, when in fact, that was not the case. It's just that once they’re made, they’re inactive: a little bit gets into cells and a little bit that gets into cells persists [00:04:30] for a long period of time.
What we found, the advantage of bypassing the first phosphorylation step means it's activated in all cells, and the little bit gets in and being retained, allows for extended intra-cell retention and easy once-daily dosing. A simple experiment has been done that you can think about: if you incubate cells with something like acyclovir, and take off the supernatant, put [00:05:00] in drug free supernatant, add virus, you can infect the cells. But you do that same experiment with a nucleotide, those cells are protected for about two days. So nucleotides get in and behave differently.
The first one we made, I believe it's the first nucleotide ever to have biological activity against a virus, was just replacing the oxygen—I think everyone knows oxygen, but I’ll point at it—with a carbon to have a phosphonate[00:05:30] analog, that's stable and that molecule has the same potency in tissue culture and in animals as ganciclovir itself has against CMV.
About this time—well, this was published in 1986. In 1984, I moved to Bristol-Myers. Obviously, when you change companies, most of the times the intellectual property stays behind. I started the collaboration before they published with Erik De Clercq (b. 1941) and Tony Holý (1936–2012) [00:06:00] whose names have come up. They developed a very, very—this is Tony's work to come up with this, there we go. This is an unstable phosphate, here's the carbon phosphorus bond, the oxygen at this position makes the phosphonate more electronically similar to a phosphate. And so, within that class there are a lot of biological molecules, it's just how [00:06:30] biological active just how to identify the one for the right profile.
The two in the paper were PMEA and HPMPA. (5) We embarked on a lifelong collaboration that I've been to Leuven and Prague probably 25 times each in the last 30 years, and we'd meet frequently at scientific conferences. This is a conference in 1987, Ron Burkhardt gave me this picture. He just [00:07:00] retired from University of Kansas last year and has been, very active medicinal chemist. I don't have a copy of it, so he gave me a copy of his. You see Erik De Clercq, Tony Holý, and Bill Prusoff, who Raymond [Schinazi] talked about. Raymond collaborated with Bill on d4T, I collaborated with Bill on d4T, I was the project team leader at Bristol-Myers. Eric, a student, Jan Balzarini was the one Sam mentioned that came to [00:07:30] his lab and collaborated on d4T. Bill's been at the center of a lot of these types of activities.
And Bob [Gallo], I remember you gave a talk at this meeting, but I couldn't find you in the picture, but I'm sure you were there. That was that meeting in Italy at Il Ciocco (resort in Tuscany)
John: Yes. [chuckles]
Bob: I came [unintelligible 00:07:50]
John: Yes, it was a two-week meeting, I probably took…
Bob: No, I just came for [unintelligible 00:07:55]
John: Yes. That's why Bob Gallo's name is [00:08:00] up there without an arrow. [chuckles]
So the three nucleotides that made it as drugs, cidofovir for CMV retinitis—it's never had much use because it was approved right after we had HAART therapy and CMV retinitis wasn't that important of a disease. Then prodrugs of PMEA and PMPA, adefovir and tenofovir (TDF, Viread). The adefovir prodrug is the dipivoxil, [00:08:30] it was approved for hepatitis B in 2002. It never got approved for HIV because the dose needed for HIV was kidney-toxic. We had an FDA panel meeting in 1999, where the FDA asked for more clinical studies. However, we already had phase II data on TDF (tenofovir) or Viread that showed it was far safer and much better. (6, 7)
We switched the development program [00:09:00] to TDF, but adefovir played a really important role there—about lower [than] 10,000 patients that had compassionate adefovir when there weren't treatment options in the late '90s. Doctors who treat HIV patients from then and still treating today, had patients that were kept alive on adefovir even though it never became a drug.
Tenofovir has better designed prodrug function, but the main difference on [00:09:30] the nucleotide is a methyl group. That methyl group is—we put methyl groups all around these molecules and that methyl group is the one position that allows—that reduces the affinity of this for human mitochondrial DNA polymerase. That methyl group, although a very simple modification, really changed the future.
The study that lead for the initial TDF [00:10:00] approval was done—remember it was approved in 2001 so this is late '90s and 2000—it was a study that defied the guidelines and how we felt we should treat patients. But because tenofovir is a unique molecule and, with the help of many people in this room, we were able to convince FDA to accept this design. (8) That is take patients who, according to guidelines are failing and should get three new drugs [00:10:30] but have run out of treatment options, and randomize them to either additional tenofovir or placebo on top of their background regimen and allow everyone that's on placebo to switch to TDF after six months.
As you can see what we thought would be the case turned out to be the case that we didn't have too many, patients failed from what could be called in effect functional monotherapy, and that patients on placebo [00:11:00] benefit when they switched. This simple design led to approval of the drug in 2001. We've also done head to head naive studies against AZT and d4T and that's how TDF became the backbone of therapy because it has a better safety profile.
So we're sitting there with the approval of Viread, and what's the next thing to do? Of course, what we wanted to do was come up with a single tablet [00:11:30] regimen. The question is, how do you do that? We just knew it'd be important to single-tablet regimens; you could treat more people and have better health outcomes. We knew we had a safe backbone for that. The good thing about a single-tablet regimen is not just improving compliance, but you take all or nothing. So people are taking all these pills, they may think that one pill makes them feel bad, or they don't want to take it after dinner or whatever, and so they wouldn't take a complete regimen. Take a [00:12:00] partial regimen during a day after day. That's when you're going to fail fairly rapidly because you won't be fully suppressed. Then we thought even back then, if we have a well-tolerated single-tablet regimen without a lot of resistance, then we can treat more people and reduce the burden of infection.
The obvious candidate was emtricitabine (FTC)—and Raymond already talked about that, if you notice, Raymond and my life's keeps intersecting. (9, 10) [00:12:30] We've been friends for most of our professional careers—emtricitabine compared to lamivudine (3TC) had favorable properties and the most important one is the long intracellular half-life.
You can see on this slide: if you want to make a single-tablet regimen as we did, TDF, FTC, and efavirenz have the long intracellular half-life. (11, 12, 13, 14, 15, 16) Lamivudine doesn't quite get there and that is a real [00:13:00]difference in the pharmacology of those two drugs. We were able to acquire Triangle [Pharmaceuticals] and combine the products together. That combination was—FTC still was on the market. Yet we initially got FTC approved. Then we got Truvada (emtricitabine+tenofovir) approved in 2004. That simplified two drugs into a single pill, but we still needed the third one and that was [00:13:30] efavirenz (EFV).
It was complicated. I'm sure Emilio [Emini] remembers this, that Merck and Bristol Myers had a collaboration on efavirenz where the different companies sold it in different markets. When you negotiate a deal, you have to worry about, what are the rules in certain countries. Then it's a three-way collaboration between companies. At Gilead, we did the [00:14:00] work at risk. Merck gave us a bunch of Efavirenz and as we negotiated the deal, we worked on forming a tablet that'd be bioequivalent.
It's a good thing we did that at risk because it was our fifth tablet before we had something that's bioequivalent. People typically think you just mix the three drugs together and press a pill and give it to someone it's going to be bioequivalent, but that's not the case. In fact, we can never formulate efavirenz mixed [00:14:30] with Truvada. We ended up having to make a bilayer where it's one pill, but on one side is TDF and FTC, and on the other side is Efavirenz
That work—technology evolves, and we actually can produce that pretty efficiently now. This shows how TDF, FTC goes through one supply to be granulated and be put into the pill machine and [00:15:00] efavirenz on the other side, and they have completely different methods of formulation to get to granulation. That machine at the lower right is a very, very complicated piece of equipment, but it has 59 stations. Presses 59 pills at a time, each time it presses pills and it can do over a thousand tablets a minute. It's really allows for large scale production of these bilayer [00:15:30] type products. We have about three of them scattered around the world.
We continue to work to come up with other single-tablet regimens. I think everyone knows this. We've had a very fruitful collaboration with Johnson & Johnson to date. They have rilpivirine to make Complera (TDF+FTC+rilpivirine) which is broadly available around the world. Then Stribild (elvitegravir (EVG)+cobicistat+FTC (emtricitabine)+tenofovir) more recently—JT (Japan Tobacco) sells our HIV products in Japan [00:16:00] and so we've had a long collaboration with them. They came up with an integrase inhibitor in early clinical studies, which we took over. (15) It needed to be boosted. Fortunately, we had a boosting agent that was designed, unlike ritonavir, to have no activity for HIV and that was a critical thing for regulatory bodies. They didn't want us to use ritonavir as a booster because they were worried about suboptimal protease inhibitor dosing. I don't know how big [00:16:30] of a concern that would be, but we had already come up with cobicistat. And so we did this four drug formulation, Stribild.
I do want to make a point that, well, I've found all these years, working on these products with FDA, is FDA's been a partner in the work we do to address HIV and have been always engaged and always very helpful to find a way. The rapid development of Stribid to its [00:17:00] approval overtook elvitegravir and cobicistat, so Stribild was approved by FDA before the individual components. The other thing, just on the topic of single-tablet regimens, Atripla (efaviranz+emtricitabine+tenofovir), the first single-tablet regimen, FDA approved that in only 10-week review, because they recognized what an advance a single tablet regimen would be.
Okay, moving on. During this time, Doug [Richman] showed data like this. (16, 17) [00:17:30] I probably should show Doug's data, I pulled something from the British Columbia cohort—how the percent below 50 grew, the number of patients shown in blue increased, patient months of treatment increase and the resistance mutations dropped. That just has continued on with simplification and better-tolerated therapies.
HPTN Protocol 052 (2005–2015) has been mentioned already. [00:18:00] This worked in 2000. In fact, someone showed this, that may have been Tony [Fauci]—okay. That as we treat people, we prevent new infections. That treating early leads to a reduction in death, and age-related illness and START (2011–2016) and TEMPRANO (2008–2015), that's mentioned, and these better outcomes benefit patients and society by reducing [00:18:30] the number of new infections. I was working on a project with Joep [Lange] (1954–2014), who Doug brought up, and Joep coined this term in my presence, but I bet it's other people use that may be a generalized type thing, but I like it: "Early Treatment Initiation to Prevent Transmission and Preserve Health" is what this is all about. (18, 19, 20, 21)
We're also involved in PrEP, and PrEP is an important component, but you'd have to imagine that we've already averted [00:19:00] millions of new infections by treating patients with HIV, to have them undetectable and not transmit the virus.
Our latest innovation is TAF. TAF is a more potent prodrug of tenofovir, here's, tenofovir, here's TDF. This prodrug and TAF is a more stable prodrug that better targets lymphocytes. In cells, [00:19:30] it's a substrate for cathepsin and goes to tenofovir. As a result, it creates a downhill gradient, so more and more drug gets into the cell. (22, 23)
I can show you that on this slide, you can see that on the left panel, 25 milligrams of TAF in monotherapy appears to be a little bit more potent than TDF. (24) That's one 10th disposure of tenofovir with at least [00:20:00] as good a potency. Then, in the bloodstream, in the plasma, obviously, you are going to have a lot less tenofovir and as a result of that, we see a lot less toxicity on biomarkers for bone and kidney and then in lymphocytes or PBMCs you can see that TAF delivers more tenofovir diphosphate than TDF does. This [00:20:30] product we've studied extensively in phase three studies and understand its safety profile pretty well.
This is in our elvitegravir+cobicistat+FTC+TAF versus the TDF one that's upwards on the market in 2012. You can see retention in the study was high in both arms. (25) Efficacy in terms are below 150 copies, it is pretty much the same. [00:21:00] Discontinuation to AEs and to renal events in 96—the renal events is starting to become significant 960week data.
We do long-term studies on all our HIV drugs, for instance Viread, we continued naive treatment studies up to ten years to have long-term safety. Patients now are averaging 50 who are on treatment for AIDS, they have decades of therapy and this type of difference becomes [00:21:30] meaningful in long-term therapy.
In less than last year, there have been three products with TAF approved for the market, the one I showed on the previous slide, then one that's in collaboration with Johnson & Johnson again, and then two drug tablets for use with other third agents FTC/TAF. TAF for hepatitis B is under review and [00:21:59] we have in phase 3 [clinical trial] bictegravir in combination with FTC and TAF. That will be our next single tablet regimen for HIV. The desire for this product can be demonstrated that Genvoya in its second quarter on the market became the number one prescribed regimen for naive patients.
I’m going to quickly finish with the— [00:22:30] what we are doing to create access and that's in partnership with many, many people. When we brought TDF to the market, we are a biotech company, US-based, very limited employees or footprint in other parts of the world, so we didn't have an organization to do work in middle and low-income countries and we developed a different model where we would work with regional partners [00:23:00] and we have 20 regional partners for 130 countries. You still have to do country by country registration and you still have to do clinical studies in the country. What we did is come up with a tiered pricing mechanism depending upon the GDP of the country and the burden of disease.
We just made the decision that we do non-exclusive licenses to Indian pharmaceutical companies that can make generic drugs [00:23:30] and do a full technology transfer. For a company in India to come up with a drug that would be approved by PEPFAR or WHO prequalification takes a couple of years, but if we transfer the technology, that can happen in five months, so it lowers their upfront investment. That has really transformed what has happened.
Of course, there are many other factors going on at this time. [00:24:00] We were starting this in this timeframe, you can see initially it was just our brand of product, but then the licensed generics started coming in in a very big way and our brand has declined somewhat and this is a huge volume because this is pills every day, year in and year out. It's over 10 million people now using TDF in the lower-income countries, and with that huge volume, that's what allows that price to go down that [00:24:30]dramatically.
It's been very interesting to be a part of this, just as an anecdote, right about in this timeframe, Bob Redfield understood all of this. He asked me to join him on [unintelligible 00:24:46] he's been a part of advocating this. Also, when Tony [Fauci] mentioned that delegation with Tommy Thompson going to Africa, I was part of that trip to Africa. It's been very gratifying to see [00:25:00] that by having a scheme like this and also the Global Fund and PEPFAR investing that, there has been this big increase which Doug already talked about in excess.
It's been an interesting timeline. The Nature paper on nucleotides that Tony [Holý] and Erik [De Clercq] published was in 1986. (5) That's one year before AZT came about, but [00:25:30] we've really moved a little bit slowly initially, as Sam was talking about, before the time for the dideoxies to get on the market, but things are really accelerated. A really important thing was three years ago, WHO making a single tablet regiments as the first-line agent for the treatment of HIV.
There are so many stakeholders in this for the developing world, [00:26:00] they are involved in procurement, we talked about PEPFAR, the Global Fund, FDA's tentative approval to allow these products to ensure the quality which WHO does too. The groups that are involved in improving access, UNAIDS plays a very, very big role there. Clinical studies, it's NIAID, is listed first but I guess that's because I'm American, [00:26:30] there is MRC (Medical Research Council), and ANRS (Agence nationale de recherches sur le sida) has been involved, Gates [Foundation] has funded a lot of this stuff including some work on PrEP, and of course the CDC has played a really big role in understanding how to tackle HIV. Guidelines are very important, I mentioned WHO guidelines, and of course, IAS (International AIDS Society) guidelines are important too. With that, that's my last slide, thank you very much.
Sandra Lehrman (Moderator): Thank you, John. Questions for John.
Elena [Llinas]: Actually, I have a question. Hi, my name is Elena, and we do work in Mexico and one of the things that we've learned is that AZT was being produced in Mexico and came to the United States obviously, sometimes illegally, my question to you is, currently, they do not have Stribild in Mexico, do you know the timeline [00:27:30] between you manufacture medicine and the time it actually arrives to the developing world?
John: It varies a lot, I don't know the specifics of Mexico, I can look into it for you but I don't know, but some of the middle-income countries, for instance, don't use single-tablet regimens which is very, very surprising because it's become, WHO recommended for years [00:28:00] but two of the largest middle-income countries in the world still don't have, that's not Mexico, don't have single-tablet regimens yet.
Elena: Would it be because the price is so high because that's one thing that we've learned that the price of the medication in the United States it's really high and when it gets to the developing world is obviously inaccessible to most people, do you think that would be [crosstalk]
John: I showed you the price, there is well over [00:28:30] maybe 70% of people taking HIV medications in the developing world are on generic TDF through this program we have.
Bob Gallo: John, I just started to ask Bob Redfield who seems never to comment, publicly, but he comments a lot within the Institute [of Human Virology], so if you would like to make a comment relative to what you thought and some of the things in Africa et cetera? I like putting him on the spot and he doesn't like to be on the spot but so what? [00:29:00]
Robert Redfield: Well, I was going to comment a little tomorrow since I was asked to talk a little bit about it, but I do, and I was going to acknowledge this tomorrow, I think one of the reasons that Bob and the institute gave John the Lifetime Achievement Award for Public Service is that he did work aggressively, not just to help us with parallel pricing, not just to help us with conditional approval, but the real long-term sustainability is to [00:29:30] transfer the technology to generic companies both in Africa and India which he aggressively did. When I started treating in Malawi, it was $15,000 to secure drugs for a patient, and today in our program we pay less than $100 per year and we are getting a high-quality drug that we know is quality controlled. I think John did an outstanding job in leading that and I was fortunate to have him on the policy group of the [00:30:00] President's Commission because it helped facilitate that to actually happen.
John: Yes, thank you. I think you've been whispering in my ear—Yes, yes. Thank you.
Sandra: Question over there. Mike.
Mike Gottlieb: Thanks. John, is there a good rationale for country by country registration and in-country studies, does that delay access?
John: Yes. I think we've all had that experience. US approval is just for HIV [00:30:30] products. We know what FDA has done. They've been terrific. Europe works very well because European common market there's only one registration. For any application, two European countries carry the burden. One’s assigned to be the rapporteur and one's a co-rapporteur, and it's a very efficient process and it's very scientifically based, and they depend upon the experts in their countries to determine [00:31:00] what the label is. We find that works very well too. There's no common registration scheme in Africa. There's over 50 countries and it's country by country and some of them they can take years. Sometimes it goes faster and it's different. It's really different everywhere.
Mike: Is there any hope for some standardization or someone developing a system like they have in Europe?
John: We've been trying it [chuckles] Everyone's been trying it.
Sandra: John Mellors. [00:31:30]
John Mellors: John, the tech transfer program is just fabulous. It's had a huge impact. You and your company and the industry is maligned a lot, but this is just fabulous.
John Martin: Thank you.
John Mellors: SO I'm going to throw you a soft pitch. What's the future? What's the future of antiretrovirals? Are our single tablets enough? Do we need depots? Do we need long acting? Are there more potent molecules for treatment and prevention? [00:32:00] Is there further simplification? What's going on inside that head of yours?
John: Okay. Well, you know two years ago, actually I don't know how many people—because I've talked to people about TAF. Two years ago, even people at Gilead, "Oh, we need TAF. We already have TDF." The fact it's pretty clear now that that's the future. We're also, like everyone else, and [00:32:30] as you know we're working on a variety of approaches to HIV cure, a variety of approaches as to what Daria [Hazuda] you've talked about being able to give very infrequent doses to people.
Audience 6: I have a similar question. When malaria, Plasmodium drugs were taken through same process that current HIV drugs are being taken through by licensing them to generics, one component that was actually [00:33:00]left out was the monitoring and evaluation process. What that did was that over a very short period, a lot of either counterfeit or poorly-bioavailable drugs were circulated all over the place and that led quickly to resistance, resurgence. I'm wondering whether in this program you have already built in certain quality [00:33:30] criteria and have monitoring processes that are able to monitor these things, to make sure that we don't have such issues pretty soon.
John: All those are really important points and they're even important points for the United States. You know about this, how often in manufacturing, you have to do investigation because there's some sort of counterfeitor tampering with products. If that's a problem in United States, you know it's a problem elsewhere too. A lot of the [00:34:00] mechanisms are put and held in place by WHO and PEPFAR goes a long way to securing the supply chain, but you still have to be forever vigilant. Another thing with manufacturing, the world we live in is becoming more and more disciplined about making sure if someone's qualified to manufacture they make a batch and looks good, but you could come back a year later on their 20th batch, and it may not be good anymore. [00:34:30]
How do you have these good manufacturing practices that regulatory bodies inspect, to make sure that the quality of the work is there? One of the things that's helping with that a lot is the evolution to electronic and data control process so that there's an electronic record that you can't tamper with. It is what it is, so that we have certainty at the source of what's being made, and certainty from the source that the product's getting where it [00:35:00] should be. That's an evolution that I've experienced going on the last few years just for my own business.
Sandra: Thanks John. I think seeing no more questions, Val any housekeeping or Bruce? Any housekeeping?
[00:35:17] [END OF AUDIO]
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Schinazi, Raymond F., Chung K. Chu, Annette Peck, Angela McMillan, Rodney Mathis, Deborah Cannon, Lak-Shin Jeong, et al. “Activities of the Four Optical Isomers of 2’,3’-Dideoxy-3’-Thiacytidine (BCH-189) against Human Immunodeficiency Virus Type 1 in Human Lymphocytes.” Antimicrobial Agents and Chemotherapy 36, no. 3 (March 1992): 672–76. doi:10.1128/AAC.36.3.672.
Choi, Woo-Baeg, Lawrence J. Wilson, Suresh Yeola, Dennis C. Liotta, and Raymond F. Schinazi. “In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the Synthesis of Thialanyl and Dioxolanyl Nucleoside Analogs.” Journal of the American Chemical Society 113, no. 24 (November 1991): 9377–79. doi:10.1021/ja00024a058.
- Anderson, Peter L., Thomas N. Kakuda, Sagar Kawle, and Courtney V. Fletcher. “Antiviral Dynamics and Sex Differences of Zidovudine and Lamivudine Triphosphate Concentrations in HIV-Infected Individuals.” AIDS 17, no. 15 (October 17, 2003): 2159–2168.
- Bristol-Myers Squibb. “Sustiva (Efavirenz) US Prescribing Information.” Labeling-Package Insert. US FDA, March 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021360s024lbl.pdf.
- Dybul, Mark, Anthony S. Fauci, John G. Bartlett, Jonathan E. Kaplan, Alice K. Pau, and Panel on Clinical Practices for the Treatment of HIV. “Guidelines for Using Antiretroviral Agents among HIV-Infected Adults and Adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV.” MMWR Recommendations and Reports 51, no. RR-7 (May 17, 2002): 1–55.
- Hawkins, Trevor, Wenoah Veikley, Robert L. III St. Claire, Bill Guyer, Nicole Clark, and Brian P. Kearney. “Intracellular Pharmacokinetics of Tenofovir Diphosphate, Carbovir Triphosphate, and Lamivudine Triphosphate in Patients Receiving Triple-Nucleoside Regimens.” JAIDS Journal of Acquired Immune Deficiency Syndromes 39, no. 4 (August 1, 2005): 406–411. doi:10.1097/01.qai.0000167155.44980.e8.
- Piliero, P., A. D. Shachoy-Clark, M. Para, and et al. “A Study Examining the Pharmacokinetics of Abacavir and the Intracellular Carbovir Triphosphate (GSK Protocol CNA10905).” Chicago, 2003.
- Wang, Laurene H., J. Begley, Joy Y. Feng, J. Quinn, Franck Rousseau, and Triangle Pharmaceuticals, Inc. “Pharmacokinetic and Pharmacodynamic Characteristics of Emtricitabine Support Its Once Daily Dosing.” Poster presented at the 14th International AIDS Conference, Barcelona, July 2002.
- Xu, Lianhong, Hongtao Liu, Bernard P. Murray, Christian Callebaut, Melody S. Lee, Allen Hong, Robert G. Strickley, et al. “Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer.” ACS Medicinal Chemistry Letters 1, no. 5 (August 12, 2010): 209–13. doi:10.1021/ml1000257.
- Gill, Vikram S., Viviane D. Lima, Wen Zhang, Brian Wynhoven, Benita Yip, Robert S. Hogg, Julio S. G. Montaner, and P. Richard Harrigan. “Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection.” Clinical Infectious Diseases 50, no. 1 (January 1, 2010): 98–105. doi:10.1086/648729.
- Montaner, Julio SG, Viviane D Lima, Rolando Barrios, Benita Yip, Evan Wood, Thomas Kerr, Kate Shannon, et al. “Association of Highly Active Antiretroviral Therapy Coverage, Population Viral Load, and Yearly New HIV Diagnoses in British Columbia, Canada: A Population-Based Study.” The Lancet 376, no. 9740 (August 14, 2010): 532–39. doi:10.1016/S0140-6736(10)60936-1.
- The INSIGHT START Study Group. “Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection.” New England Journal of Medicine 373, no. 9 (August 27, 2015): 795–807. doi:10.1056/NEJMoa1506816.
- The TEMPRANO ANRS 12136 Study Group. “A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa.” New England Journal of Medicine 373, no. 9 (August 27, 2015): 808–22. doi:10.1056/NEJMoa1507198.
- Cohen, Myron S., Ying Q. Chen, Marybeth McCauley, Theresa Gamble, Mina C. Hosseinipour, Nagalingeswaran Kumarasamy, James G. Hakim, et al. “Prevention of HIV-1 Infection with Early Antiretroviral Therapy.” New England Journal of Medicine 365, no. 6 (August 11, 2011): 493–505. doi:10.1056/NEJMoa1105243.
- Cohen, Myron S., Ying Q. Chen, Marybeth McCauley, Theresa Gamble, Mina C. Hosseinipour, Nagalingeswaran Kumarasamy, James G. Hakim, et al. “Antiretroviral Therapy for the Prevention of HIV-1 Transmission.” New England Journal of Medicine 375, no. 9 (September 1, 2016): 830–39. doi:10.1056/NEJMoa1600693.
- Lee, William A., Gong-Xin He, Eugene Eisenberg, Tomas Cihlar, Swami Swaminathan, Andrew Mulato, and Kenneth C. Cundy. “Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue.” Antimicrobial Agents and Chemotherapy 49, no. 5 (May 1, 2005): 1898–1906. doi:10.1128/AAC.49.5.1898-1906.2005.
- Lee, William A., and John C. Martin. “Perspectives on the Development of Acyclic Nucleotide Analogs as Antiviral Drugs.” Antiviral Research, Special Issue To Honour Professor Erik De Clercq, 71, no. 2 (September 1, 2006): 254–59. doi:10.1016/j.antiviral.2006.05.020.
- Ruane, Peter J., Edwin DeJesus, Daniel Berger, Martin Markowitz, U. Fritz Bredeek, Christian Callebaut, Lijie Zhong, et al. “Antiviral Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir Alafenamide as 10-Day Monotherapy in HIV-1–Positive Adults.” JAIDS Journal of Acquired Immune Deficiency Syndromes 63, no. 4 (August 1, 2013): 449–455. doi:10.1097/QAI.0b013e3182965d45.
- Wohl, David, Shinichi Oka, Nathan Clumeck, Amanda Clarke, Cynthia Brinson, Jeffrey Stephens, Karen Tashima, et al. “Brief Report: A Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results.” JAIDS Journal of Acquired Immune Deficiency Syndromes 72, no. 1 (May 1, 2016): 58–64. doi:10.1097/QAI.0000000000000940.
- 2.0 Michael Gottlieb — Introduction to Session 2
- 2.4 Robert Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents & Preparation for the Future
- 3.1 Marty St. Clair: Discovery of AZT as the First Anti-HIV Drug
- 3.2 Samuel Broder: The First Clinical Trials of Antiretroviral Drugs
- 3.3 Douglas Richman: Antiviral Drug Resistance and Combination ART
- 3.4 Raymond Schinazi — Discovery and Development of Novel NRTIs
- 3.5 Daria Hazuda: Discovery and Development of Integrase Inhibitors
- 6.5 Emilio Emini — Issues in HIV Vaccine Development: Will the Future be any Easier than the Past?
- 6.6 Robert Redfield — The PEPFAR Program to Treat HIV in Africa
- 8.1 John Mellors — MACS and Beyond: Epidemiology, Viremia and Pathogenesis
- 3TC (lamivudine)
- aciclovir (ACV)
- adherence, patient compliance
- ANRS (Agence nationale de recherches sur le sida et les hépatites virales)
- AZT (azidothymidine)
- Balzarini, Jan
- Bill & Melinda Gates Foundation
- blood — banks, donors, plasma, screening, transfusions, clotting factors (factor VIII), PBMCs
- Bristol-Myers Squibb
- CDC (Centers for Disease Control and Prevention, US)
- cell culture, tissue culture, immortalized cell line
- chemistry, chemists
- Children's Hospital Oakland
- clinical trials (phases of clinical research)
- cobicistat (Tybost)
- cohort study
- compassionate use (Emergency Use IND)
- cure vs. remission of HIV/AIDS
- cytomegalovirus (CMV)
- d4T (stavudine, Zerit)
- De Clercq, Erik (b. 1941)
- Driscoll, John S.
- drug safety
- EFV (efavirenz)
- Elion, Gertrude B. "Trudy" (1918–1999)
- elvitegravir (EVG)
- European Union
- FDA (US Food and Drug Administration)
- FTC (emtricitabine, Emtriva, Coviracil)
- generic drug
- Global Fund to Fight AIDS, Tuberculosis and Malaria
- highly active antiretroviral therapy (HAART), combination antiretroviral therapy (cART)
- Holý, Antonín (1936–2012)
- HPTN Study 052 (2005–2015)
- idoxuridine (5-iododeoxyuridine)
- Institute of Human Virology, UMD
- integrase inhibitors
- International AIDS Society (IAS)
- Japan Tobacco (JT)
- Johnson & Johnson
- Katholieke Universiteit te Leuven
- Lange, Joep M. A. (1954–2014)
- Llinas, Elena
- Marquez, Victor E.
- Medical Research Council (MRC)
- Merck & Co., Inc. (Merck Sharp & Dohme)
- Mitsuya, Hiroaki "Mitch" (b. 1950, 満屋 裕明)
- National Cancer Institute (NCI)
- National Institute of Allergy and Infectious Diseases (NIAID)
- Nature (journal)
- nucleosides, nucleotides, nucleoside analogues, nucleoside reverse transcriptase inhibitors (NRTIs), nucs
- patents and intellectual property (IP)
- PEPFAR (President's Emergency Plan For AIDS Relief)
- pre-exposure prophylaxis (PrEP)
- prevention of HIV/AIDS
- protease inhibitors
- Prusoff, William H. (1920–2011)
- rilpivirine (Edurant)
- RTV (ritonavir, Norvir)
- scale, scaling
- scientific competition and collaboration
- Session 3: Antiretroviral Therapy
- Stanford University, Stanford University School of Medicine, Stanford University Medical Center
- START (Strategic Timing of Antiretroviral Treatment) study, 2011–2016
- tablet press
- TEMPRANO study (2008–2015)
- tenofovir (TDF, Viread)
- Thompson, Tommy (b. 1941)
- Triangle Pharmaceuticals
- trifluorothymidine (TFT)
- United States
- World Health Organization (WHO)
- Yarchoan, Robert (b. 1950)
Found 6 search result(s) for "John Martin".
... preclinical drug programs targeting any major disease. I think that maybe John Martin will get into this, but virtually any pharmaceutical program that starts out in a preclinical contest is going ... ...
Apr 27, 2021
... fact, there's only, I think, two bonafide chemists with PhDs in the room, John Martin and myself, 00:03:30 but we worked initially on several drugs, which ... ...
Apr 27, 2021
... nonsuccesses. The true success rate in astreated is just absolutely remarkable with the current regimens and John Martin will tell you more about it. #Malaysia Airlines Flight 17 (July 24 ... therapy. In the early '90s, I think it may have been '93 or so, ...
Apr 27, 2021
... began to teach me because I immediately wanted to go to people like John Martin, get some therapy, and start getting treating people. He said, "Professor ... ...
Apr 27, 2021
... historic development of antiHIV drugs, and I refer you to the talks of Sam Broder, John Martin, and Ray Schinazi. When therapy became available, we could determine who ... ...
Apr 27, 2021
... What this says is that all of the remarkable improvements in antiretroviral therapy as a result of the work from John Martin and Daria Hazuda and many others have really dramatically changed treatment to the point ... virus. Now, another thing that became clear very early on from the work of ...
Apr 27, 2021
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