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Update on the "cure" and metabolic complications
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Pablo Tebas MD
University of Pennsylvania
This year the CROI meeting took place in Boston. For the clinician, I thought the most interesting part of the meeting related to the discussions around the use of pre-exposure prophylaxis for the prevention of HIV infection and to the presentations about the new treatments for hepatits C with the first preliminary data of early virological responses to telaprevir in patients co infected with HIV and HCV virus, and many interaction studies of both boceprevir and telaprevir with antiretroviral drugs.
The cure
There was a lot of talk about "the cure" and presentations of the first phase 1 clinical trials results of the use of Zn finger nucleases as a gene therapy approach to "remove" the CCR5 co-receptor in circulating CD4 T cells in HIV infected individuals1-2. The idea is simple: take the CD4 cells of well controlled HIV infected individuals, remove the CCR5 of those CD4 cells using Zn finger nucleases using different vectors (adenovirus) and reinfuse the modified cells into the patient. Two small studies, one from UCSF and another from the University of Pennsylvania, presented preliminary data1-2. The genetically modified CD4 cell infusions appear to be safe, the modified CD4 cells persists, they seem to expand, and they even seem to circulate well into the GI mucosa track. No data was presented about how functional these cells are, a key question to answer, but these two proof of concept studies demonstrated that gene therapy approaches to modify the CCR5 co receptor is a doable strategy. It may be even possible to do this in hematopoietic stem cells3, as Paula Cannon showed in an oral presentation, a development that may help reproducing the first case of HIV eradication with an autologous bone marrow transplantation rather the much more toxic allogenic bone marrow transplant. The Berlin patient case4 is the one that generated all this excitement about the possibility of HIV cure in the first place. The Berlin case has recently been updated in Blood 5.
When we think about curing HIV, first it is important to define cure, so everybody is talking about the same thing. Most people would agree that a "functional cure" is having the HIV virus under control in the absence of antiretroviral therapy and without having other side effects of having HIV infection like ongoing inflammation and events associated with it.
Several strategies have been tried to get to the promise land of a "functional cure". First researchers thought that the maintenance and replenishment of the HIV reservoir was a question of ongoing viral replication, and that adding (or intensifying) the treatment will take care of the problem. This strategy has been tried multiple times. Researchers have added abacavir, raltegravir or maraviroc to fully suppressed individuals with the hope that the additional antiviral activity will suppress even further the HIV virus. To the dismay of everybody, nothing really dramatic has been seen, and the HIV reservoir seems to be stable in spite of the extra treament. In this meeting Martin Markowitz6 presented data treating early HIV infection with five drugs belonging to multiple classes of antiretrovirals (nucleosides, protease inhibitors, integrase inhibitors and an entry inhibitor) and compared it to classic triple therapy. Disappointingly there was absolutely no effect on the frequency of suppression or in measurements of the reservoir (single copy assay). To me the idea that we are going to eradicate HIV infection by throwing more antiretrovirals seems dead at this point, and unless new fundamentally different drugs are discovered, I do not think adding more drugs to the treatment is going to be the trick that "cures" HIV patients.
The field suffers from the fundamental problem that we have not agreed yet about what constitutes a good measurement of the HIV viral reservoir. Without a measurement that everybody agrees on (and that correlates with reality) it is very difficult to move forward. Some people have postulated that the single copy assay is a good reflect of the reservoir, and some people have suggested that the only assay that really matters is the very tedious and labor intensive (thus very unpopular) culture assay evaluating replication competent virus from the reservoir done by Silicano's group at Hopkins. A lot of work has to be done in this area before we can evaluate properly the impact of different interventions in the reservoir.
Another approach to get to the "functional cure" has been the use of therapeutic vaccines: the idea is to vaccinate HIV positive individuals that are doing well on antiretroviral therapy, with the hope that after "building their immunity" and stopping antiretroviral treatment, the new, "improved" immune system will take care of the virus. There have been some advances in this regard, with vaccines that decrease the viral setpoint by about half a log7, but there have not been home runs. There was an interesting poster about using an autologous dendritic cell vaccine approach, with autoimmunization, that seems to decrease the viral load after treatment interruption by about half a log8.
The problem for the whole field of therapeutic vaccines is the expectation that a vaccine should control the virus in the absence of antiretroviral therapy, a really dramatic result that is unlikely to happen in the first few tries. It is not reasonable to expect that a therapeutic vaccine alone will control HIV viremia in the absence of antiretroviral treatment, but that has become the bar to overcome for licensing a product, as the expectation is that the vaccine will have to control viral replication in the absence of treatment. In my opinion, the bar has been set too high, making the development of these products unattractive to pharmaceutical companies. I would prefer to consider a therapeutic vaccine as any antiviral that would allow after treatment interruption the use of a more simplified treatment and keep the viral load undetectable with the "extra" help of the vaccine. For example it would be possible to vaccinate individuals while receiving triple therapy, and allow them to simplify the regimen to a single boosted protease inhibitor, with the expectation that viremia will be suppressed because of the additional help of the vaccine.
In any case the whole field of therapeutic vaccines does not seem to have a lot of traction, although I think it will come back in the future.
The last approach that being considered is to reactivate the HIV reservoir (CD4 T cells harboring replication competent HIV virus) using drugs, and to purge the reactivated cells from the system. The area is still in its infancy, because there are some concerns about the safety of the approach (basically drugs may also activate things that have been dormant in the CD4 cells other than HIV itself). A few trials are starting to look at this approach using drugs that have been approved for other indications. A study(clinicaltrials.gov # NCT01286259) usuing disulfiram , a drug that has been used to treat chronic alcoholism, has just started to see if the addition of disulfiram to a stable antiretroviral regimen for two weeks results in a decline in the size of the HIV-1 reservoir,
Metabolic complications
In the metabolic section I think the most interesting results related to bone disease (I have a bias).
Bone disease
First, the 2 PREP studies 9-10 showed the effects of tenofovir in HIV negative individuals. The results were consistent in both studies. The initiation of tenofovir leads to a bone loss of approximately 1% of the total bone mass, which tends to occur early after the initiation of treatment. These findings suggest that tenofovir has direct or indirect bone toxicity that is completely independent of its antiretroviral effect (these were healthy volunteers). This 1 to 2 % bone loss is of questionable significance in the very short follow up of the iPrEx studies, but may become important if pre-exposure prophylaxis has to be taken for several years by large segments of the population. It will also be important to know if this bone loss phenomenon occurs everytime the individual is exposed to tenofovir, or if it is a onetime deal. It is not difficult to envision scenarios in which high risk individuals will use pre-exposure prophylaxis intermittently (a few months each year -when they are more sexually active-) and discontinue it when they are less active. Will repeated exposures lead to repeated decreases of BMD or not? These results should put a word of caution in the early enthusiasm for PREP in HIV uninfected individuals10.
Another interesting finding of these studies is the very high prevalence of low bone mineral density in HIV uninfected individuals; with 33% of them having z-scores less than -1 (expected around 16%). This probably is a manifestation of the not very healthy life style that we all have in this part of the world, with little outdoor exercise, low vitamin D intake, high frequency of smoking, etc. This is also a problem for young HIV positive men. In a poster by Kathy Mulligan et al (ATN study 021b) HIV positive individuals had lower BMD than HIV negatives, particularly if they were receiving protease inhibitor based therapy, a concerning finding, mostly because this population that has not reached peak bone mass11.
The second important study was a presentation that looked at the early bone loss associated with the initiation of antiretroviral therapy. It has become apparent over the last two years that the initation of antiretroviral therapy (any antiretroviral therapy is associated with a bone loss of around 4% of the total bone mass -worse in the case of tenofovir containing regimens- ). Dr. Ofotukun presentation suggested that the initial bone loss is an immune reconstitution phenomenon associated with the rapid reconstitution of the T cells. In this 20 patient na•ve trial, they evaluated the effects on bone markers of the initiation of antiretroviral therapy. The raising CD4 cells secrete RANKL that increases osteoclastic activity and leads to a rapid resorption of bone. The osteblast activity increases subsequently to stabilize the situation. In the most interesting twist, they went back to the lab and to a TCR-ß knock out mouse model and they demonstrated that the reconstitution of the immune system is associated with bone loss that stabilizes overtime12. To me this was one of the highlights of the conference
Link to video presentation:
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13724&mediaType=podiumVideo
Abdominal obesity
Abdominal obesity was another of the themes in the metabolic complications section. The ACTG presented a secondary analysis of the A5224 substudy which compared atazanavir/ritonavir based regimens (with tenofovir or abacavir) to efavirenz based regimens in a factorial design. The use of atazanavir was associated with increased abdominal fat when compared to efavirenz. Approximately 1 kilogram more of trunk fat after 2 years of follow up. Otherwise the regimens were pretty equivalent (except that tenofovir produces more bone loss).
The FRAM studies (2 sequential cross sectional studies, separated by several years) showed that the amount of abdominal fat and the amount of limb muscle mass was associated with mortality after 5 years14. The study shows that, as in the general population15, having an increased abdominal fat is not good. The increase risk in mortality was not dramatic, and the study could not control for HIV viremia and other HIV factors, but confirms what is known: the higher your intra-abdominal fat the more likely you are going to have complications down the road. Several strategies for reducing abdominal fat have been tried, and tesamorelin (Egrifta) was recently approved for that particular indication16, although its price tag is so high and the benefits relatively transient, that in an era of shrinking budgets and growing ADAP waiting lists that its use will be limited.
Abacavir and myocardial infarction
One of the most animated discussions of the meeting occurred around the FDA poster about abacavir use and cardiovascular risk17. The FDA looked at 26 randomized trials of abavacir (16 trials from the drug manufacturer database, 5 from the AIDS Clinical Trials Group (ACTG), and 5 from academic centers) and did not found an association of an increased risk of MI and abacavir. A total of 46 MI events were reported, including 24 MI events from 5028 subjects randomized to an abacavir-containing regimen and 22 MI events from 4840 subjects randomized to a non-abacavir regimen. No statistically significant association between MI and the abacavir-containing regimen was detected (Mantel-Haenszel OR 1.02, 95% CI 0.56 - 1.84). The number of events was small, and Jens Lundgren, the senior author of the DAD study that found that association, was trying to point that out to the presenters of the poster which generated quite a passionate discussion. In any case, the strength of the FDA data comes from the underlying nature of the studies (where individuals were randomly assigned to abacavir or other medications). The DAD is an observational cohort, and treatments are not assigned randomly, providers can select abacavir (or other drugs) based on their preference and perceived risk of toxicities. Although the DAD tried to control for biases, it is very difficult to be certain that they are not present.
Vitamin D
Vitamin D was another star in the metabolic section, as it has been in the last couple of years. There has been suggestions that efavirenz interferes with the metabolism of vitamin D and that individuals receiving efavirenz containing regimens as a group have lower vitamin D levels. David Wohl presented a secondary analysis of the ECHO study, a study that compared the use of efavirenz vs TMC278 (AKA rilpivirine) in antiretroviral naïve individuals. His study showed that the use of TMC278 does not change vitamin D levels whereas there is a significant decrease of those levels in individuals receiving efavirenz. The difference was not very big (6 nmol/L, around 3 ng/ml), but the study confirms that efavirenz is somewhat worse in this regard that other antiretrovirals. To understand the clinical relevance of the findings will require a longer follow up18.
There were two interesting presentations about the role of supplementing vitamin D and its effects on different metabolic complications. A study19 form the Modena cohort (disclaimer I am an author of that study) compared the incidence of diabetes mellitus among the more than 1500 participants in the cohort. The risk of developing diabetes was reduced by a factor of 5 if the participants took consistently vitamin D supplementation (30,000 units per month). Although vitamin D levels did not changed that much (they increased in winter in individuals supplementing) there were less cases of diabetes in that group than among individuals not taking supplementation. These results may represent a real protective effect of vitamin D or a reflection that individuals that take vitamin supplements are healthier as a group (the association remained significant even after controlling for traditional risk factors of DM). This findings need to be validated in a prospective study.
Another poster from Grace McComsey group in Cleveland20 suggested that vitamin D supplementation not only does not improve endothelial function (measured by FMD, flow mediated arterial dilation), but that it was associated with worsening insulin resistance, something that does not match the previous study from the Modena cohort, and the general perception in the field. The changes in HOMA-IR were modest, and the study was a small (45 participants, 30 receiving vitamin D supplementation), so it is difficult to know at this point how clinically relevant the observation is, but it is worth considering it.
I think the question of the long term effects of vitamin D supplementation in the incidence of diabetes and other metabolic complications of HIV will have to be resolved in prospective randomized trial/s that add vitamin D or not to an antiretroviral regimen and monitors for the incidence of diabetes and other problems. I have doubts that an study like that will ever be done, because no funding agency seems to be interested in supporting long term intervention studies with hard clinical endpoints. It would be nice if it could be proven, that by just supplementing the vitamin D intake we may improve clinical outcomes.
One concerning finding of the two studies was that in spite of the vitamin D supplementation with relatively high doses, a significant number of patients did not reach normal vitamin D levels, which may be a reflection of an interference of some of the antiretroviral medications (particularly efavirenz) in the normal vitamin D metabolism.
Tenofovir and hyperparathyroidism.
There were two presentations focused in the increase PTH levels seen in patients receiving tenofovir21-22. Initially I thought that this observation was confounded because of the high prevalence of low vitamin D levels in the HIV infected population and the compensatory secondary hyperparathyroidism that occurs to compensate for that deficit. However several studies have now made and confirm this observation even after controlling for baseline vitamin D levels. The mechanisms underlying the association and the long term clinical relevance of the observation are not clear. We need to learn more about this, but it is another word of caution about giving antiretrovirals massively to prevent HIV infection in HIV uninfected individuals, we should remember the Hippocratic oath: Primum non nocere ("First do no harm")
References
1. Jay Lalezari*, R Mitsuyasu, S Deeks,and others. Successful and Persistent Engraftment of ZFN-M-R5-D Autologous CD4 T Cells (SB-728-T) in Aviremic HIV-infected Subjects on HAART. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 46.
2. P Tebas, B Levine, G Binder, J Hoxie, R Collman, P Gregory, M Holmes, D Ando, and Carl June. Disruption of CCR5 in Zinc Finger Nuclease-treated CD4 T Cells: Phase I Trials. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 165.
3. Paula Cannon*, N Holt, U Hofer, C Exline, J Wang, P Gregory, and M Holmes . CCR5 Knock-out in Hematopoietic Stem Cells. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 164.
4. HŸtter, G., D. Nowak, et al. (2009). "Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation." New England Journal of Medicine 360(7): 692-698.
5. Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5{Delta}32/{Delta}32 stem cell transplantation. Blood 2011;117:2791-9
6. Martin Markowitz*, T Evering, M Caskey, A Figueroa, K Rodriguez, M La Mar, S Palmer, V Sahi, N Prada, and H Mohri. A Randomized Open-label Trial of 5-Drug vs 3-Drug Standard PI-based cART Initiated during Acute and Early HIV-1 Infection: 48-Week Results. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 148LB.
7. Schooley, R. T., J. Spritzler, et al. (2010). "AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein." J Infect Dis 202(5): 705-716.
8. Jean-Pierre Routy*, J Angel, S Vezina, C Tremblay, M Loutfy, J Gill, J-G Baril, F Smaill, R Jain, C Nicolette, and AGS-004-001 Study Group. Final Analysis of a Phase 2 Study of an Autologous DC Immunotherapy (AGS-004) Showed Positive Outcomes in Primary Endpoint of Viral Load Control, and Favorable Safety and Immunogenicity Profile, in Subjects Undergoing Structured Treatment Interruption of ART. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 385.
9. Mulligan K, Glidden D, Gonzales P, et al. Effects of FTC/TDF on bone mineral density in seronegative men from 4 continents: DEXA results of the global iPrEx Study. Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, Massachusetts. Abstract 94LB.
10. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599.
11. Mulligan K, Harris, P Emmanuel, et al. Low Bone Mass in Behaviorally HIV+ Young Men on ART: ATN 021b. Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, Massachusetts. Abstract 705.
12. Ofotukun I, Weitzmann N, Vunnava A, et al. ART-induced immune reconstitution: A driving force behind bone resorption in HIV/AIDS. Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27 - March 2, 2011; Boston, Massachusetts. Abstract 78.
13. Grace McComsey*, D Kitch, P Sax, P Tebas, C Tierney, N Jahed, L Myers, K Melbourne, B Ha, and E Daar. Central Fat Accumulation in ART-naïve Subjects Randomized to ABC/TC or TDF/FTC with ATV/r or EFV: ACTG A5224s, a Substudy of ACTG A5202. Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27 - March 2, 2011; Boston, Massachusetts. Abstract 77.
14. Scherzer R, Heymsfield S, Lee D, et al. Decreased limb muscle and increased central adiposity are associated with 5-year all-cause mortality in HIV infection. Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27 - March 2, 2011; Boston, Massachusetts. Abstract 76.
15. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Decreased muscle mass and increased central adiposity are independently related to mortality in older men. Am J Clin Nutr. 2007;86:1339-1346.
16. Falutz, J., S. Allas, et al. (2007). "Metabolic effects of a growth hormone-releasing factor in patients with HIV." N Engl J Med 357(23): 2359-2370.
17. X Ding, E Andraca-Carrera, C Cooper, and others. No Association of Myocardial Infarction with ABC Use: An FDA Meta-analysis. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 808.
18. David Wohl*, M Doroana, C Orkin, JH Pilotto, S Sungkanuparph, P Yeni, S Vanveggel, H Deckx, and K Boven Change in Vitamin D Levels Smaller and Risk of Development of Severe Vitamin D Deficiency Lower among HIV-1-infected, Treatment-naïve Adults Receiving TMC278 Compared with EFV: 48-Week Results from the Phase III ECHO Trial. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 79LB.
19. G Guaraldi, S Zona, Gabriella Orlando*, F Carli, G Ligabue, C Stentarelli, M Menozzi, E Garlassi, C Giovanardi, and P Tebas. Vitamin D3 Supplementation Decreases the Risk of Diabetes Mellitus among Patients with HIV Infection. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 827.
20. Chris Longenecker*, C Hileman, T Carman, A Ross,, V Tangpricha, S Seydafkan, T Brown, D Labbato, N Storer, and G McComsey1 . Vitamin D Supplementation and Endothelial Function among Vitamin D-deficient HIV-infected Persons: A Randomized Placebo-controlled Trial. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 829.
21. D Pocaterra, L Carenzi, E Ricci,, and others. TDF Therapy Is Independently Associated to Hyperparathyroidism in HIV-infected Treated Patients. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 825.
22. Pablo Labarga*, P Barreiro, L Mart’n-Carboneroand others. Prevalence and Mechanisms of Hyperparathyroidism in HIV+ Patients Treated with TDF. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 824.
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