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Impressions from CROI
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Pablo Tebas, MD
University of Pennsylvania.
Every year, in the middle of the winter, HIV researchers around the world get together, usually in a cold city in the northern United States where hotel prices are cheap (HIV specialists are not the richest crowd) to talk about advances in their field and plot directions for the future. We were blessed with unseasonably mild weather to the delight of the organizers, who probably made special offers to the Climate Change Gods. Boston was beautiful and the meeting, as usual, was great.
The opening ceremony set the tone for CROI with Bruce walker giving an overview of hyper-acute infection treatment and the role of the T cell responses against HIV infection. He is a great researcher and speaker but most of the talk sounded familiar and stuck on themes that we have tried to tackle for more than a decade now. Gerald H. Friedlander form Yale gave ...... http://www.croiwebcasts.org/console/player/29436?mediaType=audio& .........a fantastic talk about the environment (the soil), the virus (the seed) and the wind (social conditions) that drove the epidemic. He drew parallelisms between HIV and Tuberculosis. A memorable plenary for the ages. The whole session ended with Kenneth Cole (yes, the shoe designer) who said, among many things, that dressing well the crowd was going to be more difficult that curing HIV (which is probably true) and gave a prolonged add for AmfAR that was received with mixed opinions from the audience............... I liked it, and I always have enjoyed the non-scientific component of the opening ceremony at CROI. HIV is a disease that affects the public in many different ways and it is important to be reminded that we are part of a community, that HIV is important not because of us, but because of the people that live with it and what it does to them, even if we think we are important and we like to talk about the HIV reservoir in the Central Memory cell compartment.
The conference was full of interesting data and I will organize my impressions around what I thought were the main themes:
PREP
PREP was the area with the most exciting new data. Several important studies were presented.
To great expectation and fanfare, given the simultaneous publication in the New England Journal of Medicine of the ASPIRE trial, the two studies evaluating the use of ring microbicides (1-2) were presented: the ASPIRE and the Ring Study. The results were incredibly consistent. In the ASPIRE trial, conducted by the microbicide trials network, more than 2600 women were randomized to receive the dapivirine ring vs placebo. The Ring study was conducted by the International Partnership for Microbicides (IPM) and enrolled close to 2000 women. Both studies showed that the dapavirine ring was moderately successful in preventing HIV infection (around 30%), but the results came as a little disappointment for most of the audience, which felt that this is not good enough. Both teams deserve credit for completing these very expensive and massive trials, but I think the success of oral TDF/FTC has set the bar higher, much higher. Objectively speaking, the results are not really not much better than the CAPRISA 004 tenofovir gel that was presented many years ago, that subsequently could not confirmed in subsequent studies, and tenofovir gel has gone nowhere...
The issue, as it is always the case with PREP, is adherence. Any PREP that is used consistently works, as it has been proven over and over again to nobody surprise (medicines only work if you take them as Everett Koop would say). The problem is that patients can not adhere well, despite the massive support provided in a clinical trial, and that is basically it. It is predictable that in the "real world" the efficacy of these interventions will be lower. Both studies did the typical slicing of the data, looking for populations in which the success rate is a little bit better, and again, there were no surprises: older women used the ring more consistently (where did the "intent to treat" dogma when analyzing randomized trials go?). The intervention unfortunately does not work in the most important population that it needs to be effective, the population at the highest risk behaviors and risk of HIV acquisition: young women.
What can we do to make it work? It is difficult to think of adherence improvement interventions that will bring the effectiveness of topical microbicides to the level that we need, well above 90%... So, in all honesty I do not know what is the path forward of topical microbicides. I do not see a viable product at the present time, although I am sure that there will be a filling for approval. But those were not the only news from the meeting regarding PREP.
Maraviroc, the only antiretroviral that is active before the HIV virus infects the cells, and that has a very good bio distribution in genital tissues has always been an attractive drug for use in PREP. Trip Gulick presented the data from HPTN 069/ACTG 5305 study (3). This was a large study patients were randomized to receive maraviroc alone or with FTC or tenofovir and TDF/FTC. Approximately 100 participants in each arm. The regimens were well tolerated. Adherence, not surprisingly tended to go down as the study progressed for 48 weeks. There were a lot of STDs in this study (21% of the patients had them at one point or another), despite the counseling and promotion of condoms and safe sex, which tells you a lot about the behavioral risk of participants in this study. Although this was not an efficacy study, the most intriguing finding was that there were five new HIV infections during the follow-up: 4 of them occurred in patients receiving maraviroc alone and 1 in somebody on maraviroc and FTC. The study was not powered to evaluate the efficacy but these findings are quite concerning and they suggest to me that maraviroc was underdosed in the trial. Maraviroc for the treatment of HIV is a twice a day drug and in this study was used once a day.
The most promising way to remove adherence from the PREP equation is directly observed therapy. The only the only way to do that is by the administration of long-acting antiertroviral therapy (4). Cabotegravir, a long acting integrase inhibitor drug allows administration every 8 to 12 weeks. Results of ECLAIR, a PREP trial using cabotegravir were presented by M. Markowitz. In this study 127 patients were randomized 5:1 to receive 800 mg every three months of cabotegravir or placebo. Drug levels were low at the end of the dosing interval in a significant proportion of patients (around 15%), what suggests that this drug will have to be administered every eight weeks to maintain levels that would be protective. In general cabotegravir was well tolerated although local reactions are common because of the significant amount of volume of the injection. It is obvious that the drug is not perfect but I think this is also a clear step in the right direction: until we create an effective vaccine, the periodic administration of parenteral antiretroviral therapy to prevent infection is an alternative that might prove effective to curb the epidemic, particularly in high risk populations. A phase 3 trial of parenteral cabotegravir is starting at the HPTN. We will definitely hear more about this type of intervention in future years.
NEW AND NO SO NEW ANTIRETROVIRALS
More data was presented about doravirine (5), a Merck new NNRTI that does not have the neurologic side effects of efavirenz and can be given once a day. In this Phase II trial, 132 patients were randomized to receive doravirine or efevirenz with TDF/3TC and they were followed for 48 weeks. The proportion of individuals with undetectable viral load was similar between the two groups. Using the ACTG criteria of less than 200 copies/mL around 85% of the participants in both groups had undetectable viral loads at the end of the year. The participants randomized to receive this new NNRTI had less neurological side effects than those receiving efavirenz. This compound would be a nice addition to our therapeutic armamentarium, as at the present time we do not have an NNRTI as one of the preferred regimens in the DHHS treatment guidelines. One of the most interesting twists with this compound is that it is being co-formulated with generic tenofovir and 3TC both of them manufactured by Merck, so if the single tablet regimen makes it, it will hopefully decrease the significant cost of initial treatment..., but that might be wishful thinking knowing how the pricing of drugs work in this country...
Antiretroviral treatment during pregnancy is always complicated as the PK of antiretrovirals is uncertain. It would be nice to have more information about the use of integrase inhibitors during pregnancy, as the information about PK is somewhat limited, except for raltegravir. In IMPAACT P1026s (6) 21 women received a dolutegravir-containing regimen in combination with other antiretrovirals and they had PK parameters evaluated during the second, third trimester and postpartum. Although this study was small and the concentrations of dolutegravir tended to be a little bit lower than in non-pregnant adults, the results of the study suggest that no adjustment in the dose of dolutegravir is needed during pregnancy.
The first randomized trial about the use of long-acting intramuscular cabotegravir and rilpivirine (7) as maintenance therapy in patients chronically infected with HIV, the LATTE-2 study, was presented. In this study, 309 patients received cabotegravir with rilpivirine every four or eight weeks and were compared to a control group that received oral cabotegravir with 2 nucelosides. The drugs were well tolerated and the frequency of viral suppression at 32 weeks after the initiation of the parenteral administration was similar in all the arms of the study. There were only 2 cases of virological failure: one in the oral arm and the other in the q8 week dosing that had low rilpivirine levels. Although local reactions were common, for most patients this was not a deal breaker and they generally liked the freedom of not having to take HIV medicines every day. Obviously this intervention was tried with very adherent participants which is not the group that most clinicians will think to use parenteral therapy. It is still a little bit early to know exactly how we will use these long acting antiretrovirals in clinical practice both therapeutically and in prevention.
Now I will comment two studies that I found interesting because they relate more to the delivery of care rather than drugs themselves.
A study from South Africa (the RapIT trial –best acronym of the year-(8)) suggests that starting therapy immediately, on the first clinic visit, was more effective at one year than going through multiple education and laboratory testing visits that delayed the initiation of antiretroviral therapy for up to six weeks. We tend to think that more education and "readiness" helps maintaining patients on therapy, and that patients need to "prove" that they can maintain adherence before receiving treatment, and to some degree is true, but we should not overdo it: there is a sweet spot. When you "overcook it" patients get tired and move on. We do it with good intentions, we like "holding the hand of our patients" and we think that we make a difference for patients when we do so, but in fact, in many cases less is better. Many patients just want to take the medicines and move on with their lives. Think about yourself when you go to see the doctor: you want a quick, complete and efficient visit and move on. Our patients are not different, and that is true whether they live in the US or in Africa. This study clearly demonstrated that. We should not create artificial barriers to the initiation of antiretroviral therapy. I'm looking forward to studies that try to make HIV care more efficient and simple for patients. We may be able to use new technologies with less physical visits. We just need to figure out a way to get paid for doing so. This was an eye opening and refreshing study.
The second study I want to highlight evaluated the use of economic incentives (Navigation/contingency Management ACT) (9) in patients very difficult to treat. You know the phenotype if you work in a hospital: the patient that despite being diagnosed with HIV infection for many years is still not taking antiretroviral therapy, does not come to his or her clinic appointments and has problems with substance abuse. If you work in HIV you know who I am talking about.... Those patients were randomized to receive economic incentives to show up to the clinic and maintain undetectable viral loads or general education and standard of care. The economic incentives, and they were significant, worked a little bit while they were maintained for 6 months, but unfortunately the benefits disappear immediately after discontinuation. This is not the first study to show that economic incentives offer only transient benefits, but I think it is the first study that applied them to this very challenging population. We need better techniques to engage these patients in care, but is not going to be very easy to do so. Sometimes money does not solve everything.
INFLAMMATION, COMPLICATIONS AND OPPORTUNISTIC INFECTIONS
Everybody knows, and if you did not know, you will know soon because TDF is becoming generic, and Gilead will remind all of us that TAF is a better formulation of tenofovir than TDF because it is associated with less bone mineral density loss and better kidney profile.
Several studies along those lines were presented: In a sub-study of IPREX (10)(a PREP study that gave TDF) bone loss was reversible after switching off TDF. This is important for young patients considering PREP, as they will be taking tenofovir only temporally. And it seems that the modest bone loss associated with TDF as PREP is reversible. There was also an update on prior TAF studies (101/111) the demonstrated that after three years of treatment the bone mineral density losses and the kidney function are better with TAF than with TDF (11). And the third one was a switch TAF study (12) that revealed that switching to TAF from TDF maintains viral suppression and to no surprise improves slightly the BMD and the kidney function.
Obviously the question is if these differences justify using always TAF instead of TDF. At the present time, given that the price of the fixed dose combination Stribild is similar to Genvoya, this is nothing more than an academic discussion; however next year when TDF becomes generic it can become and economic issue as the old TDF may be much cheaper. We will see what happens. Unfortunately in medicine, if you have to bet, you should bet for the most expensive drug, they tend to win...
The initiation of antiretroviral therapy is associated with significant bone loss that is greater when you start an antiretroviral regimen that includes tenofovir (the old formulation). Last year we learned that giving vitamin D and calcium supplementation can prevent the initial bone loss associated with antiretroviral therapy. This year, a very interesting study evaluated the administration of a single dose of zoledronic acid (13)to prevent the initial bone loss. Not surprisingly it was successful. Whether this should become the standard of care for all patients receiving antiretroviral therapy needs to be proved in a larger trial. The long term safety of drugs as potent as zoledronic acid, in young patients without a clear indication for it is also another question that will need to be resolved in the future.
A large study run by the ACTG (A5298) evaluated the use of the HPV vaccine (14) in HIV-infected individuals older than 26 to see if it could stop the progression of the rectal precancerous HPV lesions and prevent anal cancer. The study was stopped by the DSMB because of futility, meaning that it was going to be impossible to see a difference between vaccinating or not vaccinating. There was a slight decrease in the persistence of oral HPV, but I would be careful over interpreting this sub analysis. The bottom line is that at the present time it does not seem to be a justification to vaccinate against HPV in patients co-infected with HIV outside the current clinical indications in men and women younger than 26.
Another important study by the AIDS clinical trial group evaluated the use of aspirin as an anti-inflammatory drug (15) in patients chronically suppressed with HIV infection. Aspirin used at doses of 100 mg or 300 mg a day did not have significant anti-inflammatory properties over the course of the 12 weeks of therapy. It was sobering that another therapeutic intervention targeting the persistent ongoing inflammation seen in some patients with HIV infection was negative (and we have had a bunch of these studies over the years). This does not mean that aspirin is useless in patients with HIV infection. Aspirin should be used for secondary prevention in patients who have had myocardial infarctions or cardiovascular disease and also when it is indicated as primary prevention in patients with high-cardio vascular risk, but this indication is not because of its anti-inflammatory properties it is because of its antiplatelet properties.
CURE
We are still early in the clinical evaluations of strategies to attain cure. In the basic science/animal models side of it there was an interesting study evaluating the use of a TLR7 agonist in monkeys (16). In this study rhesus macaques were infected with SHIV and treated with antiretroviral therapy, and while they were suppressed they also received GS-9620, an investigational toll -like receptor agonist developed by Gilead. While the monkeys were receiving this drug they had transient blips of viremia. After several cycles of treatment there was an analytical treatment interruption. The monkeys that had received the TLR7 agonist had a lower level of viremia and two monkeys maintained viral suppression for three months. This is very preliminary, but also very tantalizing, we will hear more about these compounds in the future. Studies in humans are planned soon...
The ACTG evaluated VRC01, a broadly neutralizing antibody against the CD4 binding site of gp120, in A5340. I am a little bit bias with this study as I am an author of it. Broadly neutralizing antibodies (17) is one of the hottest areas in HIV research at the present time. They are being used both for prevention of HIV acquisition and the treatment of HIV infection. In this study we evaluated if the passive administration of a broadly neutralizing antibody could prevent the rebound of viremia after an analytical treatment interruption. If that is the case it would suggest a pathway to attain a functional cure of HIV, by passively administering these antibodies, or delivering them with a therapeutic vaccine or gene therapy. However, in A5340, most of the 13 participants had a quick rebound of viremia after the discontinuation of antiretroviral therapy in the presence of high levels of the antibody, most likely because of preexisting resistance. Nevertheless there were two signals that were promising: two participants had a very late rebound of viremia associated with declining levels of the broadly neutralizing antibodies and there was evidence of significant pressure of the broadly neutralizing antibodies in the virus as it rebounded from the reservoir. These findings suggest the antibody is putting pressure on the virus and that better antibodies or a combination of them may be more effective. Studies like this clearly pave the way for future studies. As it frequently happens in this type of the studies not everybody agreed: some people think this was a complete failure and some people think (like me) that it was a necessary study that will move us one step forward to control of HIV infection in the absence of antiretroviral therapy.
References
1. Baeten JM, Palanee-Phillips T, Brown ER, et al. A phase III trial of the dapivirine vaginal ring for HIV-1 prevention in women. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 109LB.
2. Kapiga, S; Bekker, LG; Brid Devlin, B. et al. Safety and Efficacy of Dapivirine Vaginal Ring for HIV-1 Prevention in African Women. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 110LB.
3. Gulick R, Wilkin TJ, Chen Y, et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 103.
4. Markowitz M, Frank I, Grant RM, et al. ECLAIR: phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 106.
5. Gatell JM, Raffi F, Plettenberg A, et al. Doravirine 100mg QD vs efavirenz +TDF/FTC in ART-naive HIV+ Patients: week 48 results. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 470.
6. Mulligan N, Best BM, Capparelli E, et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 438.
7. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 31LB
8. Rosen S, Maskew M, Fox MP, et al. Initiating ART at a Patient's First Clinic Visit: The RapIT Randomized Trial. Abstract 28
9. Metsch L, Feaster D, Gooden L et al. A Patient Navigation/Contingency Management RCT for Hospitalized HIV+ Substance Users. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 27
10. Grant R, Mulligan K, McMahan V, et al. Recovery of bone mineral density after stopping oral HIV preexposure prophylaxis. Program and abstracts of the 2016 Conference on retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 48LB.
11. Wohl D, Thalme A, Finlayson R, et al. Renal safety of tenofovir alafenamide in patients at high risk of kidney disease. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 681.
12. Gallant J, Daar E, Raffi F, et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 29.
13. Ofotokun I, Kehmia Titanji K, Vunnava A et al. A Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 47.
14. TJ Wilkin, H Chen, M Cespedes, et al. ACTG A5298: A Phase 3 Trial of the Quadrivalent HPV Vaccine in Older HIV+ Adults. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 161.
15. O'Brien M, Kitch D, Peter W. Hunt P et al. Aspirin Fails to Impact Immune Activation or Endothelial Function in Treated HIV. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 44LB.
16. JB Whitney, S-Y Lin, CE Osuna, et al. Repeated TLR7 Agonist Treatment of SIV+ Monkeys on ART Can Lead to Viral Remission. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 95LB.
17. Bar K, Harrison L, Overton T et al. ACTG 5340:The Effect of VRC01 on Viral Kinetics After Analytic Treatment Interruption. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 32LB
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