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The End of HIV Drug Development as We Know It?

A Blog Entry From CROI 2010

Feb. 18, 2010; 1:45 p.m. Pacific Time

Gerald Pierone Jr., M.D.

Gerald Pierone Jr., M.D.

While scanning the CROI 2010 abstracts during my six-hour plane ride to San Francisco, the thought occurred to me that we may be witnessing the winding down of the HIV drug development process.

Historically, CROI has been a high-profile event during which pharmaceutical companies would showcase their up-and-coming investigational antiretroviral agents. Not anymore.

At this conference, the number of clinical trials of novel antiretroviral agents could be counted on one hand: Gilead's "quad" tablet, elvucitabine, vicriviroc and the ViiV integrase inhibitor S/GSK1349572. There were a few interesting antiretroviral agents presented, but never has there been such a wide gap between the number of investigational pre-clinical antiretroviral agents and the compounds that are actually moving through clinical development.

There appear to be several reasons for this phenomenon. First and foremost, the bar for antiretroviral drug development has been raised to a very high level. Current combination therapy is not perfect, but about 80% of patients reach an undetectable viral load with minimal or manageable side effects. Furthermore, co-formulation of frontline antiretroviral therapy is becoming the standard, so a promising first-line agent without an already-established potential antiretroviral partner is at a disadvantage.

On the other end of the treatment spectrum, for an investigational agent looking for a niche among treatment-experienced patients, there is not a clear path forward to regulatory approval. For example, as Myles Helfand discussed in his blog, data presented at this meeting detailed the failure of the CCR5 inhibitor vicriviroc to outperform placebo in a salvage trial. The failure was not because of a lack of potency or side effects, but rather was related to the fact that the majority of patients in the placebo arm had more than two active agents in their optimized background regimen.

The misfortune that befell vicriviroc may have a chilling effect on future salvage trials. An ethical study design which would allow a potential salvage drug to demonstrate efficacy has yet to be articulated.

Copyright © 2010 Body Health Resources Corporation. All rights reserved.

See Also
CROI 2010 Wrap-Up: The HIV Drug Development Pipeline
CROI 2010 Wrap-Up: The Evolution of Antiretroviral Therapy
CROI 2010 Wrap-Up: Complications of HIV and Its Treatment

Reader Comments:

Comment by: dr. george pradhan,mb (vskpm,india) Sun., Apr. 11, 2010 at 1:15 pm UTC
becos my small touch w HIV persons ,india,shows not many live to earn their food and keep. can real statistics for the poor countries be accessed? like healthy survival w/o HAART from the time of diagnosis,survival with Rx, survive and back to full work/ half work/ no work ??? this to remove my gloom that all this cld be a waste of such huge effort, diverting funds from the surviving Neg Persons/ families. yes i have seen a policeman go back to his full duties, but how long did he live, lost his follow up? and how many such? and awareness campaigns ! and condoms ! with the infection increasing annually !
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Comment by: Jay (Charleston, S.C) Sat., Mar. 20, 2010 at 8:08 pm UTC
Thanks for that useful information Gerald that is really scary stuff to hear though that the medicine currently being used are starting to gain alot of resistance so that really means that these college professors and microbiologist need to really concentrate all of their efforts on a cure because the virus is just going to keep mutating and mutating until no medication can combat the affects of the disease. Until there is a cure.
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Comment by: sam (New York, N.Y) Mon., Mar. 15, 2010 at 3:21 am UTC
i strongly believe that a cure is obtainable but lets face,it's bad for business.
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Comment by: stan (United Kingdom) Sun., Mar. 7, 2010 at 12:31 pm UTC
I think that this is a sign of things to come ARVs will eventualy be a thing of the past as new treatments emerge such as gene therapy and eventually eradication we need to invest more in therapeutic vaccines and eradication ARVs have been a remarkable advance in modern medicine but the treatment of hiv has to move in other directions
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Comment by: Anthony (Long Island, NY) Mon., Mar. 1, 2010 at 8:52 pm UTC
It is time for drug companies to invest in a cure rather than dependency-maintenance-drugs, whoever happens to come up with the long-term solution can be sure of guaranteed returns.
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Comment by: Daniel (San Francisco) Mon., Mar. 1, 2010 at 8:26 pm UTC
tic, tic, tic - just wait. HIV will mutate. In the USA when straight, white people under 35 start getting HIV - a flood of new drugs will be developed so fast your head will spin.
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Comment by: Fiona (UK) Sat., Feb. 27, 2010 at 6:53 am UTC
As a long term survivor, with extensive drug resistance and having used up nearly all medications, this is disturbing news.
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Comment by: Stanley Lewis (Houston, TX) Fri., Feb. 26, 2010 at 10:57 am UTC
"Objects in this mirror may be closer than they appear". Clinician, pharmaceutical, and regulatory postures of late suggest that our recent success has caused us to lose some of our respect for just how vicious HIV is as a pathogen. Clinical gains are the result of diligent and aggressive research, development, and deployment of ARVs. If we take our foot off the gas (as Eddie alludes), I'm afraid that the horrors of a virus that we lack drugs to treat will not be a thing of the past, but real possibility for our future. Mark is right right now and perhaps for the near future. But Gerald's view forcasts a gloomy day ahead if we allow ourselves to become complacent.
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Comment by: Florence ngobeni Allen (Johanneburg, South Africa) Fri., Feb. 26, 2010 at 4:46 am UTC
The new guidelines are recommending putting everyone on ARV's; I believe this is very good accept that for most developing countries this is still a dream. Many people in my country have developed resistance and they have less and less chance of living longer if they are receiving their medication from the public health institutions. Some of the new drugs are not even heard of in Africa. We need more more clinical trials and access to the approved drugs/ARV's for all. Drug development must continue.
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Comment by: Mark Harrington (New York, NY) Thu., Feb. 25, 2010 at 4:08 pm UTC
I disagree. We have just come off a peak of 25 years of drug development efforts with the approval in 2008 of two new classes, the integrase inhibitors and CCR5 receptor blockers. It's not clear yet what the role of the latter will be but with the new DHHS ART guidelines moving raltegravir to a preferred recommended first-line therapy it's clear that Merck has the potential to make lot of money on their 20+ years of investment in HIV research - certainly it is likely to be as much as if not more than they made on indinavir, which was third in class (after saquinavir and ritonavir) but which led them in sales for part of the mid-90s. Since raltegravir is first in class it has the field to itself for a bit and then will have to measure up against elvitegravir, et al.; but its rapid (within 2 years) movement from FDA approval to DHHS guidelines first-line recommendation shows that with the right new agent (or class) you can still make a lot of money by innovating in the HIV therapeutic space. And with the need to start people earlier on therapy, the NNRTIs we have today are not necessarily the best global first-line anchor drugs. So there is a clear need for a new first-line NNRTI which lacks the toxicities of NVP and EFV and which is cheap. And there's a clear need for second-line drugs which are cheaper than boosted PIs, and for novel non-cross resistant NRTIs.

So while I believe it's possible that industry will start to pull away, I think with good basic science and the discovery of new targets, work on some of which was clear at last week's CROI, there is still a potential for the emergence of strong new drugs within existing as well as new classes -- not to mention the possibility of entirely new approaches to curative therapy or a functional cure.


- Mark
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Comment by: David (Raleigh, NC) Thu., Feb. 25, 2010 at 3:42 pm UTC
Not good. I wish this would be a part of the health care reform discussions currently ongoing in Washington. Are we a nation which cares little for those who need our help most, or are we a nation which helps our neighbors and believes in the sanctity of life?
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Comment by: bash (nigeria) Sat., Feb. 20, 2010 at 11:01 pm UTC
This issue of ARV resistance,is an issue that needs serious consideration by the CROI and the agents responsible in the development of these ARVs
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Comment by: Eddie (Houston, Tx) Fri., Feb. 19, 2010 at 3:40 pm UTC
Scary. I believe scientists should fully steer the boat toward gene therapy or stem cell research and microbacides. The majority of HIV+ people are doing just fine, but this is a crucial time when everyone, I mean, everyone should press the pedal to the metal, if you will. The drugs only allow people to buy time till HIV develops resistance and comes back with full force.researchers need to speed up the process in developing new strategies or alternatives in controlling the virus because If HiV develops resistant to the latest drugs,everyone will be done.
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Comment by: Eddie (Jacksonville, FL) Thu., Feb. 18, 2010 at 6:34 pm UTC
Interesting observation, and i would agree with everything. What however is the take away?

Perhaps with the lack of novel agents , we need to be very selective and cautious utilizing medications currently available in order to prevent ARV resistance.

Patients have been fortunate to have late stage meds to rely on. Caution in selection of initial therapies should be the norm to avoid losing future options.
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