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Impressions of CROI 2017.
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Pablo Tebas, MD
University of Pennsylvania.
Again, as a winter pilgrimage, the HIV docs and investigators across the world converged at CROI. This year was the turn of Seattle, which lately alternates with Boston for the honors. You can almost classify the jet-lagged faces depending on the origin of the people. "Early morning happy" faces from the east coasters, "Where the heck I am" faces from the Europeans/Australians/Asians, and "Why everybody looks bad?" faces from the West coasters.
As usual, and that is also becoming a tradition..., the weather was unseasonably mild. While people in Boston were getting their customary foot of snow on Sunday that would have brought Armageddon to the meeting, we enjoyed a mostly dry and sunny Seattle. My theory now is that the organizers make special offerings to the God of Weather for beautiful days. In exchange (and this is an empirical rule), the local team loses the Super Bowl the year that CROI is in town. To make my point -we are all scientists here- since 2005 CROI has been in Boston on 08, 11, 14 and 16. The Patriots won the Super Bowl in 15 and 17 (both CROIs at Seattle) and lost in 08 (CROI in Boston) and 12. Seattle hosted CROI in 12, 15 and 17, won the Super Bowl in 14 (CROI at Boston) and lost in 15 (CROI in Seattle). So if my theory is correct... do not bet for the Patriots next year, as the CROI 2018 will be, again, in Boston. You can bet that the weather will be nice.
Congratulations Sea Hawks 2018!
Opening Lectures
Jeff Lifson gave the the Bernard Fields lecture ( http://www.croiwebcasts.org/console/player/33335), that is usually a more basic science lecture and talked about the non-human primate models of HIV and how they have contributed to improve our understanding of HIV pathogenesis, and how, if used properly can be useful to understand human disease. It was a passionate defense and a good overview lecture about the field. People during these talks tend to talk about their own research, which can be overwhelming for an audience that may not be that interested in a narrow field. He avoided that and made the case for the continued use of the non-human primate model in HIV pathogenesis and now cure research and inflammation. The problem, as it happens with every in vitro and animal model, is that sometimes we do not know if a model is correct or not until we do the experiment in humans.
The N'Galy Mann lecture, which in general has a more global view of HIV, was given by James Hakim from Zimbabwe who highlighted how much has been done to contain the scourges of this terrible disease and how Zimbabwe has been in the front lines of clinical research in studies of prevention, treatment and implementation in this filed ( http://www.croiwebcasts.org/console/player/33336). To me the most inspiring message was how a good clinical trials unit, with well done research can drive improvements in care and health systems in a country and around the world. This has happened in many places and has contributed to the real feat of having 20 million people on treatment across the globe. I hope our new administration realize the importance of research in the developing world, how powerful tool it is to improve the health of people and does not take a "contemplate your own American navel" approach to HIV research.
Oliver Tuku, a well-known Zimbabwean musician with a very "Southern African" sound and also a philanthropist and HIV activist received the CROI foundation special award. He was brief, humble, and did what he does best: sang a song "what shall we do? The lyrics (which may have been lost to many in the audience) (http://www.croiwebcasts.org/console/player/33337)
What shall we do?. That was the whole purpose of the meeting and a wonderful beginning.
(if you want to hear more of Oliver Tuku listen to: http://www.npr.org/event/music/224419551/oliver-tuku-mtukudzi-tiny-desk-concert)
Cure Research
Cure was one of the main themes of the conference, and I am sure that over time will become even greater. We still spent an inordinate amount of time discussing what we are talking about: from a functional cure (not having to take antiretrovirals regularly) to the holy grail of a sterilizing cure, not everybody agrees in what a cure is. In my opinion, it really does not matter: there is a continuum between long acting antiretroviral therapy (which is where the therapeutics field is going) with sparser dosing of antiretrovirals to a functional cure and eventually a sterilizing cure. We will probably achieve these goals sequentially and I am pretty sure that we will learn things from each one of those aspects on the way.
These are the themes that DAIDS wants to put the taxpayer money to work in the next few years and they will be the main subjects of this conference in the future.
Tuesday plenaries appropriately focused on cure research. Jintanat Ananworanich (http://www.croiwebcasts.org/console/player/33338) from the MRCP made the best case I have ever seen for cure research. She gave a powerful talk that also gave voice to some of her patients. I think that anybody that has doubts why we should invest in curing HIV should see her talk. Antiretroviral treatment is just not enough. She has a calm and precise demeanor that is extremely powerful. Carl June (http://www.croiwebcasts.org/console/player/33339) talked how advances in HIV and Oncology has always gone together. From the beginning of the epidemic, when patients were dying of Kaposi sarcoma, to the utilization of lentiviral vectors (modified HIV) to deliver gene therapy interventions to cure some leukemias (CAR19 cures otherwise refractory B cell leukemias). There was a long video in his talk that was a little distracting, but HIV has had a major impact on cancer therapy, and now is coming back. His talk clearly made an important point: research is not a silo. The benefits and findings in one field affect others and ultimately improves the health of people in others. Research spent on HIV improves the life of people with cancer and other diseases. This is a talk that people against the so called "AIDS exceptionalism" should see. Both talks were very powerful and made their points.
It is difficult to select the posters and presentations that are more relevant in this area. These are the ones that cached my eye and I will follow the typical order (Kick, Kill and protect):
Looking for "kickers", drugs that activate the reservoir has been the first step in cure research. The goal is to reactivate the mostly quiet HIV from its reservoir and make it start making protein that is expressed in the surface of the cell, so the immune system can "see" the infected cells and eliminate them, or if the activation process kills the infected cell even better.... All of this sounds great in theory, but is more complicated in practice. The "activators" are not specific for HIV and they activate other things that millions of year of evolution have been kept quiet for a reason or they are simply too toxic. Over the last few years there was a lot of hope on histone deacetylators, like vorinostat, romidepsin or panobinostat. They proved that is possible to reactivate HIV, but they do not reduce the reservoir in the process, and may affect the function of the immune system....
Protein kinase C agonists (PKCa) are potent in vitro latency reversing agents. There had been hopes that they may work and be more potent. Glaxo has been working with them for a while. Ingenol (GSK445A) was developed and tested in vitro and in the non-human primate model (1). There were good news (sort of) and very bad news: the drug reactivates HIV in in vitro model, but the toxicity in monkeys is really scary: the effective dose and the lethal dose are way too close. So I think this compound is done, as Glaxo is not planning to develop it further. There is still some hope for TLR7 and 9 antagonists. They have been in humans and seem better tolerated. ( http://www.croiwebcasts.org/console/player/33580?mediaType=slideVideo&)
There were more things about improving the killing, boosting the immune system to control HIV in the absence of therapy.
The MHRP group presented data on viral rebound during an ATI in 8 patients treated during Fiebig 1 stage (when they still have not developed antibodies) (2). These patients have very small reservoirs. All of them rebounded with a median time of 26 days, a little longer than chronically infected individuals, but certainly not a very impressive number. There were no clear predictors of a longer time to rebound and everybody seroconverted. The good news is that all participants re-suppressed very quickly with ART and that the size of the reservoir did not really changed after the interruption, the bad news is that treating very, very early, although leads to a very small size of the reservoir is not going to cure anybody, something that we already knew.
There was an interesting case of a patient from the Mayo clinic that received an allogenic bone marrow transplant for acute lymphoblastic leukemia with a donor that was HLA matched and wild type CCR5 (3). The patient had aggressive chemotherapy, and graft vs host disease. After two years of virological control with ART the patient had an undetectable viral reservoir and he underwent a treatment interruption and stayed undetectable for approximately 9 months. This is a similar case to the Boston patients presented before by Tim Hendrich and shows the limits of curing HIV by eliminating the reservoir. It is difficult to think of an intervention more aggressive than chemotherapy with myeloablation plus graft vs host disease. What these cases tell us is that we are going to need a very powerful killing and protection of uninfected cells if we want to "sterilize" the blood.
There has been an enormous amount of interest in alpha 4 beta 7 inhibition in early infection since the publication of the Science paper that suggested that treatment with alpha 4 beta 7 antibodies controls SIV (4). HIV, particularly early after infection (when is replicating in the gut) maintains in its membrane Alpha 4 beta 7 and this tends to "trap" the virus in the GI track (5) (http://www.croiwebcasts.org/console/player/33472?mediaType=slideVideo&). This may be important for pathogenesis, as it is well known that the HIV virus mainly replicates in the gut during the initial stages of infection (the incorporation of this protein to the virion can contribute to that process). It is possible that this is relevant in the macaque study, as the alpha 4 beta 7 antibody (equivalent to vedolizumab in humans) may have direct antiviral activity (behaving like a broadly neutralizing antibody), however, the antibody alone does not seem to have antiviral activity, at least in advanced disease. We will hear more about this..., a lot of people are still trying to figure out the results of the Science paper, and this presentation was one to pay attention too.
We have put a lot of faith on a new CMV based HIV vaccine that the group of Lous J. Picker has developed and that has shown a lot of promise in preventing SIV infection in non-human primate models. Picker presented data of the therapeutic trial in macaques as part of his plenary (19) (http://www.croiwebcasts.org/console/player/33440?mediaType=slideVideo&). It was surprising not to see this data as a regular presentation. The results were disappointing when the vaccine is used therapeutically early after infection: It really did not matter if the macaques received a tuberculosis vaccine or the HIV vaccine.... the only animals that controlled the infection were the ones that were treated with antiretrovirals very early, only 4 days after the infection. Animals treated later, even a single day later, did not control viremia after treatment interruption. He postulated that there is an unstable reservoir early after infection and that if the reservoir is established the vaccine does not work. Bad news... It is not realistic to think that we are going to be able to find individuals infected that early. In any case the vaccine did not work in the therapeutic setting. Hopefully the results will be better in prevention.
Another vaccine trial from Barcelona was interesting (BCN02-Romi (NCT02616874). Participants received a chimp adenovirus vaccine that was boosted with an MVA vaccine during acute infection, after that, they maintained full virological suppression for years and then received two doses of a different MVA vaccine, 3 cycles of romidepsin and two more doses of the MVA vaccine again (if you are getting confused, you are not the only one...). Five of the 13 participants that interrupted therapy have maintained low level viremia or undetectable viral loads for several months. An unexpected result on a very complicated study. It is difficult to know what the most critical component was.... but in any case gives hopes to the field of therapeutic vaccines (20).
ACTG 5342 gave VRC01 (a broadly neutralizing antibody that binds to the CD4 binding site of the virus) to participants fully suppressed in the hope that it will decrease the reservoir, or at least decrease any remaining viral replication measured by the single copy assay (21). It did not. This finding suggest that we ae going to need to activate the reservoir in a meaningful way if we want these interventions to work. Full circle then....
New drugs. New formulations
Whoever thought that the field was dying (me) could not have been more wrong: there were numerous presentations with new drugs, new ideas and new delivery systems for HIV antiretrovirals.
Gilead presented some data about a new capsid formation inhibitor (GS-CA1), a total new drug class that looks incredibly powerful in vitro (6) [ CROI: Discovery of Novel Potent HIV Capsid Inhibitors with Long-Acting Potential.] These compounds block the capsid formation during maturation and early after entry. They do not have cross resistance with other antiretrovirals. Concentrations in the picogram range inhibited HIV (that is 100s times less than concentrations that we usually use). There is a long pathway form the test tube to clinical use, but this new class of medicines look really promising, both in the therapeutic setting and as PREP.
Bictegravir is a new, very potent integrase inhibitor that does not require boosting. This compound is already in phase 3 clinical trials. Bictegravir looks really good (7). In a phase 2b study 100 participants were randomized to TAF/FTC with dolutegravir or bictegravir. They were pretty much equivalent (in the 95% range of suppression at week 48). Obviously the study was not powered to compare effectiveness between the two drugs, but it seems that the new combination is in the same ballpark of dolutegravir, which is a good thing. Will see what the phase 3 studies show. [CROI: Randomized Trial of Bictegravir or Dolutegravir with FTC/TAF for Initial HIV Therapy ]
Merck presented data on doravirine (8). A phase 3 study that compared this drug with TDF/3TC vs darunavir/ritonavir with the same nucleosides. The combinations were equivalent ("non-inferior" in the statistical lingo we like to use), which is good news for doravirine as darunavir is a powerful PI. There was a significant amount of dropouts in the trial making the efficacy numbers to look a little lower that what we are accustomed to see. The most likely explanation is that because of the blinding all participants had to take 4 tablets daily, which in the current era is too much for a naïve study. Doravirine does not have the neurological side effects of efavirenz, and it seems to me that in the near future we will have a new NNRTI that is well tolerated. What place will have in therapy and when it will be used (earlier like an integrase inhibitor, or later) remains to be seen. [CROI: Doravirine in Non-Inferior To Darunavir+Ritonavir in Phase 3 Treatment-Naive Trial at Week 48 ]
Dolutegravir plus rilpivirine seems to be a good, simple combination when the use of nucleosides is problematic. The results of the SWORD trials were presented (9). In these two phase 3 trials, that enrolled more than 1000 participants with undetectable viral loads for a year and no history of virologic failure, switching to a regimen of once daily DTG+RPV was equivalent to maintaining the triple ART combination for 48 weeks. The regimen improved bone markers and some renal markers too. The regimen is simple (2 tablets a day with food) and is a good alternative when you want to avoid Abacavir and tenofovir for whatever reason. As Jose Arribas joked with me: TAF reduces your systemic levels of tenofovir by 90%, but if you do not take TAF your levels are down 100%....[ CROI: SWORD 1 & 2: Switch to DTG + RPV Maintains Virologic Suppression Through 48 Weeks, a Phase III Study ]
Finally, the 24 week data of Ibalizumab, a monoclonal antibody against CD4 was presented. 40 patients with very resistant virus received a loading dose of 2 grams and 800 mg every 2 weeks with an optimized background regimen for 24 weeks. For the first 2 weeks of monotherapy with the drug more than 60% had a decrease of viral load greater than 1 log. At week 24 around 50% of the patients had an undetectable viral loads. This is an option, although not a very convenient one, for patients with multidrug resistant HIV. Nobody developed antibodies against ibalizumab, which was reassuring. There were 10% deaths, which is a reminder of how bad this disease can be. Maybe the FDA will use this trial to approve this compound that has been in development for more than a decade. Some patients need it. [CROI: PRO 140 Single-Agent Maintenance Therapy for HIV-1 Infection: A 2-Year Update ]
There is a lot of excitement about the use of long acting agents like cabotegravir, broadly neutralizing antibodies with modifications in the FC fragment with very long half-lives, nano formulations etc. that can be administered every few weeks or months. It is worth watching the plenary by Charlie Flexner for a good overview of where the field is going (11) (http://www.croiwebcasts.org/p/2017croi/croi33659). It is not very far-fetched to imagine a day in the next few years when patients with HIV will have an injection every few months and will not have to take daily medications. These long acting agents will also have an important role in preventing HIV infection.
Metabolic complications
The DAD cohort analyzed the use of "modern" protease inhibitors (atazanavir and darunavir) and cardiovascular risk (12). In their analysis the use of boosted darunavir was associated with an increased cardiovascular risk overtime, while atazanavir was not (in fact another presentation suggested that having high bilirubin levels is cardio protective, as it happens in individuals with a genetic mutation that decreases the elimination of bilirubin (Gilbert disease)(13). Darunavir was associated with an increased cardiac and stroke events of 1.53 [1.28-1.84] times. I am not a big fan of this type of studies as I am always very worried about persistent channeling bias. There are reasons why clinicians use a drug versus another. Darunavir tends (and tended even more in the past, when we were less familiar with integrase inhibitors) to be used in people with more advanced disease, with more concerns about adherence, as part of rescue regimens. The D:A:D tried to control for all of that and the association still persisted. However, they did not use more sophisticated statistical methods like inverse probability weighting and structural modeling that statisticians think are more powerful to control for bias. In any case, the data is there. The absolute risk is relatively small (somewhere between 0.5 and 1% per year), but that risk is greater with darunavir (1.4%). The whole presentation had a deja vu to it. This data is in agreement with a field that has evolved beyond protease inhibitors as first line therapy. C'est la vie....[CROI: Association between Cardiovascular Disease & Contemporarily Used Protease Inhibitors - D:A:D ].
We know that patients with HIV have an increased cardiovascular risk than the general population. What can we do about it, beyond picking more cardiovascular friendly drugs? The answer to that question is to pay attention to traditional risk factors. A study (14) evaluated the contributors to myocardial infarctions among HIV infected patients and to no surprise found that smoking, hypertension and hyperlipidemia are the main contributors to cardiovascular problems in this population, much bigger than HIV related factors. Dah?
An NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) study showed that the "statin gap" is large in the United States. The GAP is the difference between people that should be receiving statins and those who actually have a prescription. Since the 2000 the gap has decreased, but is still 50%, e.g., only half of the patients that should be on a statin are really receiving it. That number is really astonishing, particularly when HIV patients have medical interactions with providers 3-4 times a year on average. We do not like to talk about it, but in some cases the increase cardiovascular and other events seen in HIV infected patients when compared to the general population may be related to the care that we provide (or we do not...). We should be paying more attention, and at the very least follow general recommendations for the general population. The study focused on the period of 2001 to 2013. Since the 2013 ACVDS guidelines probably the gap has become bigger. Statins may have an additional benefit of reducing the risk of virological failure when you are suppressed, as a study from the VA cohort suggested (16). The REPRIEVE study is evaluating if all patients with HIV would benefit from receive a statin even if their cardiovascular risk is small. It has enrolled almost 3000 participants across the globe, still another half to go (https://clinicaltrials.gov/ct2/show/NCT02344290).
Regarding bone disease, there was a talk and a poster about the value of TBS (trabecular bone score), a new methodology that uses DEXA scans to evaluate the microarchitecture of the bone. Patients living with HIV have an increased risk of bone fractures over the general population, a combination of the contributions of the HIV infection itself, the bone losses associated with the initiation of treatment (all treatments) and the even greater loss associated with the use of tenofovir. For unclear reasons patients infected with HCV has even greater risk despite the fact that their bone mineral density is similar to mono-infected patients with HIV. It turns out that they have worse microarchitecture of the bone (as measured by TBS) and that may explain that increased risk. The addition of TBS to the FRAX calculation score probably gives a more accurate prediction of the real fracture risk among HIV infected patients, particularly those who are infected with HCCV (17-18) [http://www.croiwebcasts.org/console/player/33603?mediaType=slideVideo& ]
Prevention
There were also incredible presentations about PREP and preventing HIV, but I will leave to others summarize them. The plenary of Demetre Daskalakis from New York on how he and his team is going to put all of us out of business because he is going to prevent new infections in NYC was a real tour de force and worth watching CROI: Ending HIV Epidemic in NYC - Plan/Strategy IF YOU CAN MAKE IT THERE: ENDING THE HIV EPIDEMIC IN NEW YORK
Conclusions
This was an outstanding CROI, one of the best of the last few years... with lots of new information, much of it in the posters sessions and superb plenaries, worth watching online. Well organized and relatively compact, more difficult to get lost than in other gargantuan venues... This is a rapidly evolving field that is still fascinating and challenging.... Hopefully our patients living with HIV, and those not living with HIV too, will benefit from all these advances.
References
1. Jessica Brehm et al. Development of a PKC agonist derived from Ingenol for HIV latency disruption in vivo. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 123.
2. Donn Colby et al. HIV RNA rebound postinterruption in persons suppressed in Fiebig i acute HIV. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 124.
(http://www.natap.org/2017/CROI/croi_51.htm)
3. Nathan Cummins et al. Two Hundred Eighty-Eight–Day Drug-Free Remission From HIV Rebound by Allogeneic PBSCT. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 319. (CROI: 288 Day Drug-Free Remission From HIV Rebound by Allogeneic PBSCTK)
4. Byrareddy SN et al. Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy. Science. 2016 Oct 14;354(6309):197-202.
5. Christina Guzzo et al. Virion Incorporation of Integrin Α4β7: Implications For HIV-1 Pathogenesis. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 64LB.
6. Winston C. Tse et al. Discovery of Novel Potent HIV Capsid Inhibitors With Long-Acting Potential. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 38
7. Paul E. Sax et al. Randomized Trial Of Bictegravir Or Dolutegravir With FTC/TAF For Initial HIV Therapy. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 41
8. Jean-Michel Molina et al. Doravirine Is Non-Inferior To Darunavir/R In Phase 3 Treatment-Naïve Trial At Week 48. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 45LB.
9. Josep M. Llibre et al. Phase III SWORD 1&2: Switch To DTG+RPV Maintains Virologic Suppression Through 48 Wks. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 44LB.
10. Stanley Lewis et al. Long-Acting Ibalizumab in Patients with Multi-Drug Resistant HIV-1: A 24-Week Study. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 449LB.
11. Charles W. Flexner. Long-Acting Antiretroviral Therapy: A Shot In The Dark Or A Paradigm Shift?. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 147.
12. Lene Ryom et al. Association Between Cardiovascular Disease & Contemporarily Used Protease Inhibitors. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 128LB.
13. Vincent C. Marconi et al. Hyperbilirubinemia Prevents Cardiovascular Disease For HIV+ And HIIV- Individuals. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 127.
14. Keri N. Althoff et al. Impact of Smoking, Hypertension & Cholesterol On Myocardial Infarction In HIV+ Adults. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 130.
15. Keri N. Althoff et al. The Large Gap between Statin Eligibility and Prescription Among HIV+ In North America. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 619.
16. Henning J. Drechsler et al. Current Statin Use Reduces Risk Of Viral Rebound On Suppressive Cart. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 468.
17. Jingyan Yang et al. Bone Density and Trabecular Bone Score Improve Fracture Prediction In HIV+ Women. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 132.
18. Roger Bedimo et al. Bone Microarchitectural Changes And Fracture-Risk Prediction In HIV and HCV. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 677.
19. Louis J. Picker. Therapeutic Vaccination for HIV/SIV: What Will It Take For Cure?. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 48.
20. Beatriz Mothe et al. Viral Control Induced By HIVconsv Vaccines & Romidepsin In Early Treated Individuals. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 119LB. (http://www.croiwebcasts.org/console/player/33576?mediaType=slideVideo&)
21. Sharon Riddler et al. VRC01 Infusion Has No Effect On HIV-1 Persistance In Art-Suppressed Chronic Infection. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 330LB.
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