Annual Retrovirus Conference
This year a number of research/doctors are contributing extensive conference coverage to NATAP. These reports are forthcoming and some have been reported. All Conference reports are posted at the NATAP web site. The NATAP Reports newsletter summarizing conference proceedings is forthcoming and can be ordered (firstname.lastname@example.org, or by tel. 212 219-0106, 888-natap-26).
Hope From This
Year's 8th Retrovirus Conference: new drugs in development
Reported by Jules Levin
At the end of this report is a discussion of a new NRTI ACH-126,433 which has very interesting potential for resistant virus, long half-life, and potentially no or little mitochondrial toxicity.
Some reports from this conference will tell you of incremental progress and limited new information reported here. I disagree. Sure there are no spellbinding breakthroughs like there was for protease inhibitors 6 years ago at the World AIDS Conference in Vancouver. But as we look back, the promises from Vancouver were overreaching and made a big splash because for the first time we had an effective HIV treatment. The introduction of protease inhibitors marked the era of HIV treatment where deaths & clinical progression was tremendously impacted. Of course, the excitement of these breakthroughs are diminished by the toxicities and side effects now emerging and because the hope & promise for eradication is an unlikely goal as it appears today. The emergence of HCV/HIV coinfection presents quite a disheartening challenge for individuals infected with both diseases. Although several small studies suggest coinfected persons may respond to interferon+ribivarin as well as HCV alone infected persons, there are doubts about these findings. We need more data to establish this. For many individuals HIV is already or will become a chronic manageable disease not much unlike diabetes. HIV related complications and therapy is more complicated. But, we have come a long way since AZT monotherapy, and I think we are going to go a lot further. There is no telling where research will take us--possibly to once a week or once a month nontoxic easy to take therapy.
But, we are on the brink of a number of major breakthroughs including the development of a new class of drugs--entry inhibitors and a number of new antiretroviral drugs for resistant HIV many of which are presented at this conference. Let's not forget the ongoing vaccine and immune based therapy research. Vaccine research proceeds in the search for both a preventative and therapeutic vaccine. A therapeutic vaccine, if developed, would be helpful for people with HIV. Merck is in early pre-clinical development of such a vaccine. They have two candidates in such early studies. The goal and hope for this research is twofold. The vaccine could be used in combination with HAART to improve the durability and overall effectiveness of HAART, or it could be used to stimulate control of HIV by the immune system so you could take a therapy interruption from HAART. Of course, this needs to be confirmed in human studies.
There are quite a number of new drugs discussed and presented on at this Conference. Tibotec Pharma has several protease & NNRTI drug candidates for resistant virus with their lead PI being TMC-126. It appears to have potent antiviral activity against viruses with extensive resistance to all protease inhibitors. There is new data on T-20 in a salvage study which looks good. T-1249 is the 2nd fusion inhibitor from Trimeris/Roche and 14-day data here shows promising antiviral activity. The Schering Plough entry inhibitors were discussed by Gregory Reyes, MD with Schering who focused on what appears to be their lead drug, SHC-C, a CCR5 antagonist (it interferes with entry at this site). Much ongoing data on entry inhibitors was presented here and will be reviewed in a forthcoming NATAP report. Although progress on bringing entry inhibitors to the clinic and human studies appears slow, except for T-20 & T-1249, progress is being made. Much research attention is being paid to developing this new class of drugs. I believe it's possible we will have an entire treatment regimen composed of only entry inhibitors. There was an interesting abstract from Mark Wainberg et al on the combination of interferon+ribivarin+ddI as an anti-HIV therapy. The 3 drugs offer a synergy which takes advantage of ribivarin's affect on ddI. The activity of ddI in this combination is greatly enhanced by ribivarin. The activity of ddi exceeds by 80 times the IC50 of wild-type HIV. This means that ribivarin greatly increases the drug exposure of ddi much like the affect of hydroxyurea on ddi In theory, less ddi could be used to achieve the antiviral activity & potency it currently achieves, or the exposure or amount of ddi on board could be greatly increased to overcome resistant viral strains. Of course, let's not underestimate the potential for toxicity & side effects. So, this combination will have to be scrutinized for safety.
Although not entirely utilizing new drug, several once per day therapy approaches were reported on here at this Conference: once a day protease inhibitors--amprenavir+ritonavir (1200/200), indinavir+ritonavir (1200/200 or 1200/400), BMS-232632; once per day regimens 3TC 300mg or FTC plus efavirenz+ddi Abacavir & d4T are being explored for once per day administration. In some cases, twice per day may be safer in terms of missing doses. There were adherence problems reported in the 303 FTC study presented at this conference. The data from study 303 suggests one of two hypothesis--taking a once per day drug such as FTC in combination with drugs that are twice per day may create an adherence problem, or individuals may be more likely to forget a dose if it's only once per day, and possibly missing a dose that's once per day may be more harmful in creating resistance than missing a dose of a drug that's taken twice per day. Margaret Fischl from the University of Miami and an ACTG researcher reported a follow-up on the direct observed therapy (DOT) study she reported at last year's Retrovirus Conference. She created quite a stir by showing that DOT in a prison setting achieved a significantly better antiviral response to HAART than self-administered treatment (SAT) HAART in her clinic. Amazingly, at week 24 and at week 88 the DOT group had 100% <400 copies/ml. This was compared to 80% <400 copies/ml in the SAT group. When looking at proportions <50 copies/ml, at weeks 64 and 88 90% or better in the DOT group had <50 copies/ml compared to 70% at week 88 in the SAT group. More details on this study will be in forthcoming NATAP report.
As you may know, I host a weekly radio show in New York City on WOR 710 AM every Sunday 11pm to 12 Midnight. After this Conference the next month's shows will be devoted to this Conference. We will have very interesting researchers on as guests, discussing and dissecting developments and new information reported at this conference. Free tapes are available from our shows and can be ordered online at the NATAP web site at www.natap.org or by calling our offices at 212 219-0106 (888-natap-26).
ACH-126,443: new NRTI that may not cause or might reverse mitochondrial activity, may be active against HIV resistant virus and has 24 hour intracellular half-life
Lisa Dunkle formerly with Bristol Myers & now with Achillion Pharmaceuticals reported for the first time that I've seen on a new nucleoside analogue with interesting characteristics. ACH-126,443 (from here on in called ACH) is a L-nucleoside analogue designed to improve on earlier analogues by providing potent anti-HIV and anti-HBV activity while avoiding mitochondrial toxicity. Dunkle reported that early in vitro work with this drug demonstrated anti-HIV and anti-HBV activity 10-20 fold greater than 3TC, excellent bioavailability in two animal species and an intracellular half-life exceeding 24 hours. The long half-life will permit once per day dosing with a buffer. Dunkle reported that in vitro studies showed no reduction in mitochondrial DNA (toxicity) following cellular exposure to ACH alone, and amelioration of DNA loss die to d4T when the two drugs were combined.
Of course, this remains to be established in humans. Dunkle also reported preliminary resistance data showing ACH's antiviral activity against NRTI resistant viruses. ACH appeared to show good activity against viruses with multi-nucleoside resistant mutations 69S and 151M, as well as against viruses with limited 3TC resistance and AZT/3TC dual resistance. Of course this also will have to be confirmed in human studies.