An Interview with Shahin Gharakhanian
Doctor Gharakhanian practiced clinical HIV medicine for almost 20 years at AP-HP academic Hospitals in Paris, having trained there in Infectious Diseases / HIV Medicine and been mentored by Willy Rozenbaum, co-discoverer of the HIV virus (Science, 1983). As a clinical practitioner, his principal academic focus was on PCP, Kaposi’s sarcoma and HIV-associated lipodystrophy/metabolic syndrome. He then moved on to R&D in the pharmaceutical industry, were he has worked on opportunistic infections and anti-retrovirals … In Vertex Pharmaceuticals, Inc, he co-led the clinical development & FDA NDA/EMA approval of fosamprenavir for them in collaboration with GSK, and also developed telaprevir in HIV/HCV co-infection. Since 2011, he has been more closely involved in HIV therapeutic vaccines and HIV functional cure research. During the past four years, he has, therefore, been working on two different vaccines and designed/worked with a team to set up a major international phase II clinical trial [NCT 02041247].
How do you see the place of immune-based therapies now that we have single tablet regimens against HIV that are simple and well tolerated?
It is widely acknowledged that advances in antiretroviral therapies have been significant, if not spectacular. Recent progress in tolerance, efficacy and different combinations have broadened the options available to clinicians and improved the quality of life of people living with HIV. While beneficial, and generally well tolerated, ART regimens still have chronic-long term toxicity that can limit their use, as well as present long-term adherence difficulties for many patients. As such, the HIV community has not contented itself with the progress it has achieved and aspires to further innovations and advances. HIV investigators have spawned vaccine research into novel monoclonal antibodies (refer to also to R Weiss, N. Eng. J. Med. 2014; 370: 4). New studies, including some just published in 2015 (for example, M Caskey et al doi:10.1038/nature14411) have indicated that some monoclonal antibodies might be quite therapeutically effective.
We should therefore try not to develop any opposition between these convenient single tablet regimens and immunotherapy and/or vaccines, but rather attempt to design approaches that could be complementary.
Can these approaches help to develop an effective HIV functional cure?
I believe the first step is to reach a consensus on how we define "functional cure". This is not an academic exercise but it is necessary because it conditions clinical trial design and regulatory approval criteria. One review, (from Katlama Ch., Deeks S, Autran et al., Lancet, 2013) has defined functional cure as a host-mediated control of HIV replication, in the absence of ART. A functional cure implies the control of viral replication for a predefined period of time, in the absence of treatment, as well as, a stabilized, effective immune function. It is also considered that HIV-induced inflammation will be at a low level, as will the risk of viral transmission. This is a highly ambitious goal. As a clinical developer, I believe we should start with a pragmatic objective:
(a) let's apply the “Precision Medicine” approach to the HIV functional cure area, or in other words define the sub-group of individuals living with HIV who have characteristics that would allow them to attain a functional cure using current technology, and then,
(b), we need to define what a clinically meaningful period off ART might be (also referred to as VSOT: Viral suppression Off Therapy). Some have argued, and I agree, that 12 months off therapy would be a good starting point. Only then could we attempt to answer your question: “Can these approaches help to develop an effective HIV functional cure ?”. The history of HIV therapeutics has been one of combination therapy. We need to determine what the “cocktail” for functional cure therapy will look like: potent anti-retroviral plus latency activating agents, or agents exerting some control over the reservoirs plus agents acting peripherally to lower HIV RNA to undetectable levels and prevent peripheral HIV reactivation via immunological or other novel mechanisms.
In recent years we have learnt that HDAC inhibitors are too weak to reactivate the reservoir and that HIV strains in the reservoir contain mutants to escape the CTL response. How could we overcome these facts?
Over the past months and years we have learned a great deal about HDAC inhibitors that (a) structurally and functionally they are not all equivalent and have shown differing pharmacologic activity and adverse event profiles, (b) to date, using carefully controlled clinical trial design, they can be safely administered in people living with HIV, and, (c) HDACs can be combined with other agents. I believe that much more clinical research and basic pharmacology is still needed in this area.
We are just now starting to see the first ex vivo results comparing latency activating agents (as an example, see the poster from GM Laird and co-workers, CROI 2015). Different aspects of HDAC pharmacology deserves and requires more work. Careful exploration of the pharmacokinetic - pharmacodynamic relationships of HDAC within the specific context of HIV functional cure is necessary and is currently lacking. We should team up with our HIV clinical pharmacology colleagues, many of whom have accumulated impressive expertise over the years.
Lastly, please let me address the “elephant in the room”, there are many different laboratory methods designed to quantify the reservoir, but their relevance as clinical trial endpoints needs definition and validation. This overall area of so-called “HIV Reservoir” assessment requires a broad consensual methodology that would involve clinical researchers, virologists, biotech and pharmaceutical companies’ clinical development teams working in the functional cure field, and, especially, the regulators (see the comprehensive review of this important area by KM Brunner, NH Hosman and R Siliciano in Trends in Microbiology 2015 http://dx.doi.org/10.1016/j.tim.2015.01.013). It should also be recognized that, in addition to histone deacetylase inhibitors, other pharmacological compounds such as inhibitors of bromodomain, protein kinase C activators (bryostatin and prostratin) and extraterminal proteins could be considered as candidates in functional cure strategies. Furthermore, significant data on a TLR7 agonist were presented earlier this year at the CROI 2015 [Ref. J Whitney et al. CROI 2015]
What kind on “immunogen” should we develop?
We could start off by defining immunogens ! But to move on, generally speaking, several types of immunogens or immmunogen-likes are currently available, for example:
- Biotech companies have been developing - some for more than a decade - therapeutic vaccines that contain one or multiple immunogens. These are currently being evaluated, or have been assessed, during phase I and phase II studies in Europe, Canada and the US.
- New alternative constructs such as that presented by MR Gardner et al., which is a CD4-Ig combination containing both CD4 and a mimetic of CCRS so that it therefore blocks several points of viral binding (ref. doi:10:1038/nature 14264 and CROI 2015)
The question that remains open is to determine which combinations of immunogens should be assessed in the clinic.
What is your timing in terms of clinical trials in humans?
The field of HIV progressed last year with numerous publications of laboratory and some clinical research results allowing us to increase our understanding. Additionally, important initiatives were taken to map out roadmaps, such as the meeting on “regulatory pathways for cure research” organized by the Forum for Collaborative Research in June 2014 in Washington DC .
In 2014, I finalized initiation of a major international phase II clinical trial with the sponsor involving an HIV therapeutic vaccine [NCT 02041247]. I am now working with a new team on a new phase II clinical trial project that is directly related to HIV functional cure research.
* Disclaimer: Opinions stated in this interview are all personal and do not necessarily reflect the positions of companies Shahin Gharakhanian is currently under contract with, nor his past employees nor any other company, organization or entity.
Key words: HIV cure, HIV discovery, HIV immune therapies, HIV reservoirs, HIV vaccine, Shahin Gharakhanian