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Immunomodulating Drugs for the Treatment of HIV, Costermano 2004
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Conference on Immunotherapy & Immunopathogenesis,
Lago Guarda, Italy
Michael Youle, MD
Royal Free Hospital, HIV Clinic, London, UK
Following a very successful meeting last year in Stresa Franco Lori and the group from the RIGHT Foundation in conjunction with the University of Pavia repeated their success in Costermano on Lago Guarda, Italy. Experts in Immunotherapy and Immunopathogenesis once again came to the meeting to discuss the effects that HIV has on host immunity but this year focussed on how this can be harnessed to improve therapeutic options in the era of HAART.
Professor Lorenzo Minoli from the University of Pavia welcomed the delegates to the two-day meeting, which started with a presentation by Professor Mario Stevenson on the role of positive and negative factors in HIV-Host cell interplay. He started by re-jigging the notion that the virus as shown in many schematics is reasonably large compared to the cell. In fact the relationship is more like a football to a football pitch and so for the virus to be passed through the cell undergoing changes as it goes to be finally presented to the nuclear membrane requires a number of cellular "road-signs". Some studies undertaken recently indicate that HIV infects the nucleus when the nuclear membrane is intact (unlike some other viruses e.g. MLV) but surprisingly does not infect cells undergoing mitotic change. There is a suggestion that proteins on the inner surface of the nuclear membrane are required for HIV integration and their absence or suppression leads to an increase in non-integrated episomal forms of virus. It would appear that these episomal forms are a surrogate for ongoing viral replication. These inner nuclear membrane proteins may give another target for HIV therapy.
Next Franco Lori of RIGHT, Pavia opened his talk on virustatics which he described as drugs that carry antiviral as well as cytostatic effects acting directly and indirectly through immunocompetant cells. He discussed the long running debate of whether it is possible to find a balance between the cytotoxicity of hydroxyurea which accounted for high rates of symptoms in the large ACTG 5025 study where a dose of 1200mg daily was used and efficacy in reducing viral load and viral rebound seen in several other trials. He showed the results from the RIGHT 117 study where reduced doses of 900mg or 600mg were used in a factorial design compared to 1200mg. It appeared that the optimal dose was 600mg with a viral load reduction of 1.95log10copies/mL and a rise of CD4 count of 65. Marc Wainberg commented on the results that it appeared that the 900mg was worst and there is some data suggesting that hydroxyurea can affect erythropoietin (red cell production) in a bimodal way. Later on in the meeting Pablo Barreiro presented the results of a simplification study from successful HAART to DDI and hydroxyurea which has been published in the Journal of Clinical Microbiology 2004, 44:862-6 The viral response in the study was unsurprisingly predicted by a low viral load at baseline and high nadir CD4 count. In the 25 subjects who failed 16% were wild type, 40% had L74V and the remaining 56% had greater than three thymidine analogue mutations. In the age of complete HIV suppression the idea that a holding pattern using less therapy is acceptable has gone through a phase of being attractive but with other data from Antonella Castagna from Rome showing 3TC monotherapy may maintain CD4 cell counts for a significant period of time between HAART regimens it may be time to rethink the approach again. Steve Miller from Johannesburg discussed his 8 year cohort of subjects just on DDI plus hydroxyurea where a significant proportion (96) of 160 subjects have maintained their viral load at least 1 log below baseline and 32% are <400copies/mL with a persistent 10% reduction in CD38 activation. Whilst 65% developed some hyperpigmentation (a common phenomenon in black subjects) only 11% developed peripheral neuropathy and 9% gastrointestinal side-effects. Generally well-tolerated most were lost to this study when the negative results of ACTG5025 were published several years ago. For a setting where access to therapy has been and remains limited these cohort data once again speak to the relative benefit of this approach and he should be applauded for this work in the face of the negative first world (mainly US) view of suppressive HAART or be damned.
Guiseppe Panteleo gave a talk on the further work that he and his group have conducted on other cytostatic agents such as cyclosporin and mycophenylate mofetil (MMF), mainly in primary HIV infection, entitled "Can immunomodulating agents complement antiviral therapy in HIV infection?" Currently there is an Italian study of this approach using MMF in conjunction with 3 months of HAART after seroconversion and then stopping all therapy to evaluate rebound. This study is under evaluation but data presented by Jose Gatell seemed to suggest that the agent may be beneficial but only if a higher dose of 500mg bid was used. In his small pilot study the plasma levels of MMF correlated with outcome, 5/6 subjects with good levels maintaining suppression after interruption of HAART versus 1/9 who did not receive the MMF or in whom plasma levels were low (p<0.01).
Panteleo showed long term follow-up on his cyclosporin study, published in Journal of Clinical Investigation. 9 patients at seroconversion (2 women) were treated with HAART and cyclosporine 0.7-1.2mg/kg bid for 8 weeks, a drug which can cause serious renal problems. Now with over 120 weeks of follow-up those patients remain with a 150 CD4 cell advantage over a historical control group treated with HAART alone. The T cell rise was inversely proportional to the baseline viral load but this seems to me to be a study, which is crying out to be repeated in a controlled manner. However the new European Directive on Clinical Trials would seem designed to reduce the likelihood of these types of studies from being conducted where no commercial sponsor is likely. Following these presentations and others of interruption Jan van Lunzen from Hamburg asked the question, which seems to be in most peoples minds "is it really safe to interrupt effective HIV therapy?" Perhaps studies such as the large randomised SMART study of CD4 guided interruption will help to answer this.
The science took a more hopeful if far off turn with a talk from Judy Lieberman of Harvard Medical School on the potential of short interfering RNA's (siRNA's) to be used as a therapy in HIV disease. She showed work conducted in a mouse herpes model of the use of siRNA's to target cellular and viral genes which act synergistically to completely abrogate the effects of HSV in macrophages. She noted that receptors such as CCR5 are ideal as an HIV suppressive target and that in her mouse microbicide model a single application resulted in long lasting (weeks) suppression of the virus. It appears that siRNA delivery and silencing can be achieved in the mouse vagina and thus opens the door for more work on other viruses. When questioned by Marc Wainberg, Montreal, about potential cost for these approaches she said "I can't give you a quote, but they should be very cheap". One potential issue is the development of escape and the use of siRNA's against multiple targets is probably what will be required. This area seems to be moving very rapidly and the potential of these agents to provide safe effective and even potentially sterilising therapy seems high.
Michael Lederman gave an elegant lecture on the mechanism of immune dysfunction in HIV infection. He started by trying to align himself with the madness of President Mbeki by saying he would "convince us that HIV was not the cause of AIDS". He first showed that the baseline absolute HIV RNA values from the long term follow-up of the MACS explains only about 6% of the change over time. So what is the reason? Is it a difference in the pathogenicity of the virus or due to the host response to HIV RNA? Several immunological markers exist which predict progression, CD38 and CD70, the latter is even a positive predictor prior to seroconversion. He posed the question of whether the pathogenic process in HIV is immune activation or lymphopoenia and showed a model in which the highly activated T cells in lymph node tissue may be selectively destroyed where as the introduction of HAART reduces this which may explain the relative success of the intervention using cyclosporin.
On the second day David Cooper from Sydney reviewed the issues around clinical trial design for therapeutic vaccine studies and painted a relatively bleak picture of the hurdles, which exist before these immunomodulatory agents may be moved forward into the clinic. There is currently no precedent for their development, no regulatory framework, there may be immune reactivity to the vectors used, there may be immune escape which could develop quite rapidly, unknown and potentially negative immunomodulatory effects could occur and injectable agents have their own problems as has been seen with T20 use. He presented data on the Quest study, later shown more fully by Sabine Kinloch, and the Virax fowl-pox (FP) study, both of which showed some immunological benefit and tin the latter a benefit of the recombinant FP gag/pol construct given with interferon-_ in a time weighted mean change from baseline analysis after stopping HAART. He also reviewed the result of the ANRS study of ALVAC 1433 plus IL-2 cycles before stopping where a significant benefit was seen in time to viral load rebound. So why haven't they worked? He surmised that it is a combination of a lack of potency, the unclear role of innate immunity and uncertain role of adjuvant cytotoxicity. He then listed the regulatory needs which exist, do we assess acute infection or chronic; based on clinical stage or CD4 nadir; on or off suppressive HAART; full or partial suppression. Do we assess, single vaccine versus prime-boost; which order of vaccination; which timing of vaccine and how do we evaluate the safety of the construct and the adjuvant? Which endpoints will regulators require? Safety, control of viral load, delayed or reduced use of HAART, change in CD4 slope but hopefully not clinical endpoints, in addition how should one deal with the non-completers or the timing of re-initiation of therapy and finally what are the public health issues regarding interruption of drug treatment. All in all a very tall order and one which requires a huge investment which many pharmaceutical sponsors may be unwilling to embark on without quite rightly a promise of a protection of future uncertain profits.
Andrew Bradley next gave a synopsis on the potential use of TNF-related apoptosis-inducing ligand (TRAIL) as a therapeutic agent in HIV disease. It appears that TRAIL is inherently involved in immune surveillance since TRAIL knock-out mice appear normal but have increased rates of malignancy and inflammatory disease. In addition TRAIL causes apoptosis through a death cascade after linking to an extra-cellular TRAIL receptor in transformed or CMV infected cells. Thus a recombinant TRAIL, TRAIL agonist or the cytokines known to increase TRAIL expression such as IL-7 or IL-15 may effectively eradicate HIV infected cells. It is known that gp120 up-regulates TRAIL receptor expression in lymphocytes and that TRAIL reduces viral burden, specifically proviral DNA in resting memory cells but what is a s yet uncertain is whether this would be a safe intervention in view of it's potential to destroy large numbers of infected cells.
So if the aim of the meeting was to highlight new and exciting immunotherapeutics then it succeeded. A wide range of interventions were discussed and once again the potential for vaccine development seemed to slip somewhat compared to other more novel approaches. What does remain clear is that the regulatory and administrative hurdles being erected against conducting ethical and scientifically valid studies are getting ever higher and having a hugely negative effect in terms of advancing basic and clinical science. Every individual I spoke to at the meeting harboured some concerns over this issue. Soon we may have many valid agents to assess but no one interested in developing them due to the complexity of the process, a sad situation indeed.
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