KA: What about the antiretroviral studies presented today? Have you seen anything today that is likely to change your clinical practice or any compounds on the horizon that you think are particularly interesting?
MF: The interesting compounds were the Dupont compounds, DPC 681 and 683, both protease inhibitors, but clearly they are all at early stages of development [abstract 11]. And the somewhat disappointing data for FTC and the BMS protease makes one less enthusiastic about such preliminary findings. The AI424-007 study showed equivalence between various doses of BMS 232632 and nelfinavir, with around 60% in each arm below 400 copies at 24 weeks [abstract 15].
MJ: The thing about the BMS data was that even in comparison with nelfinavir, the percentage of patients with a viral load response below 50 copies was very low, around 30-35% at 24 weeks, and I don’t quite know why but it was....
MF: Surprisingly poor.
MJ: ....surprisingly low even given we’ve seen nelfinavir shown to be less effective lately in a head to head study with Kaletra.
KA: And in the Combine study comparing nelfinavir and nevirapine as well.
MJ: Yes. That sort of surprised me about the BMS 232632 study.
MF: And it was three times daily nelfinavir dosing versus once daily BMS 232632 dosing. And clearly, therefore, once daily dosing may not be as a good as we all want it to be and I think there’s a danger that we all want it to be simple when perhaps it ain’t going to be, and similarly with the FTC simplification data – it’s not the finding everybody expected to see [abstract 8].
Editorial note: Data from two randomised studies of 150 mg 3TC BID compared with 200 mg FTC once daily in triple therapy combination regimens were reported.
In study FTC-303, 440 individuals with viral load below 400 copies/mL on a 3TC-containing regimen were randomized to switch to FTC or continue on 3TC. No differences in the rate of viral rebound was observed between the two arms up to week 48 (8% in each arm).
However, a second study, FTC-302, showed more disappointing results. This study was a randomized, double blind comparison of FTC and 3TC in 468 treatment naïve patients also receiving d4T and either nevirapine (if viral load below 100,000 copies/mL) or efavirenz (if viral load above 100,000 copies/mL). Viral rebound after initial suppression below 400 copies occurred in 12% of the FTC recipients compared to 6% of 3TC recipients (p<0.05). adherence has been proposed as the cause of this difference, since 60% of those who experienced viral load rebound on ftc had wild type virus, compared to 23% of the 3tc group, and only 15% had the 184v mutation compared to 54% of the 3tc group (p=0.03).
MF: The result was partly driven by the toxicity but overall... it was a bit of a hotch potch of two different studies actually looking at quite different things. One was a naive study comparing FTC and 3TC and the other was a 3TC to FTC switch. And in the switch study, like most of the switch studies, there was an increased drop out rate in the switch arm due to new toxicity. So again, moving to a once daily dosing regimen may not be the right thing to do in somebody who is otherwise well.
MJ: And the liver toxicity in the FTC study, although it was all put down to nevirapine, clearly that was also concerning [abstract 19].
MF: Yes, the actual rate of hepatotoxicity was similar to the bulk of other nevirapine studies with the exception of the 1090 study (which always stands out in numerous analyses looking at different questions - one wonders how neutral that data is). Again, the explanation was put down to the fact that it was largely a population of black women - both of which [geneder and ethnicity] are known to be risk factors for nevirapine toxicity. Where I don’t entirely follow the logic is the recommendation for very intensive monitoring of liver function tests which covers everybody’s backs but it doesn’t seem to predict who is going develop severe hepatotoxicity and who won’t.
MJ: And then there was the switch study for patients undetectable on a protease inhibitor, randomised to either continue their protease inhibitor or switching to efavirenz and showing better outcomes for those switched to efavirenz in terms of ongoing viral control [abstract 20].
KA: And that was 48 week follow-up.
MJ: Yes it was. So, I think, again, that that’s important. And most of that was actually down to adherence and raises the question of continuing to think about adherence with every patient even when they’re undetectable. It really is important to say ‘look there are other things we can do if adherence is a problem, perhaps we think about a simpler regimen’, in order to try to avoid failure. Do you feel that, Martin?
MF: Yes, obviously with the switch studies what one is looking for is better or at least equal virological suppression without a big drop out due to toxicity and the efavirenz study appeared to achieve both. So it was notable that there were 25% with CNS toxicity. And if we believe the Australian data, then maybe 48 weeks isn’t the right time to be looking at the long-term significance of that.
MJ: I am always very sceptical about CNS toxicity with efavirenz and I don’t think any study properly defines what CNS toxicity is. I mean, how do you measure depression, are they using validated methodologies? It’s not my clinical experience that 25% of patients have significant CNS toxicities that I need to do anything about. Do you think that’s the case Martin?
MF: I agree with you that there is no validated measure. It’s disappointing we have come this far and we are using so much of the drug without really knowing what we are all talking about.
MJ: Absolutely.
MF: That being said, it’s rather coincidental that so many patients report remarkably similar complaints for it to be nothing real. That being said, most people seem to be able to put up with it, at least in the short to medium term.
MJ: There was also T1249, another entry inhibitor from Trimeris/Roche in phase II studies in humans - fourteen day data. It appears to be a once daily dose and seems to have less of an injection site reaction than T20, and is active against T-20 resistant virus in the test tube. About 1.2 log viral load reduction at 14 days [abstract 14].
MF: And the possible synergy with other entry inhibitors looks very exciting.
MJ: And that was backed up also by our State of the Art lecture by Robert Doms of the University of Pennsylvania. He talked about CCR4 and CCR5 antagonists, entry inhibitors and other strategies for preventing HIV entry and fusion, and the way in which a CCR5 inhibitor may improve the ability of entry inhibitors like T-20 to inhibit gp41 by reducing the amount of CCR5 expression on cells and thus increasing the amount of time that HIV must hang around, exposing gp41 regions while it looks for extra CD4 receptors to bind to, in the absence of CCR5 co-receptors. Several combinations are already being looked at and this is clearly a very promising area.
CS: Were you interested in cyclophosphamide? [a study which looked at the utility of the cancer drug in purging reservoirs of latently infected cells][abstract 16].
MF: It was a disproof of concept study. It fits with previous interleukin-2 data. It looks like you can’t purge latent reservoirs – they’re here to stay and we’ve got to live with it and adapt. It’s so important that people present negative results. They are so often hidden away at the back of the hall.
MJ: - and presented in a positive light. And I thought that was quite refreshing to see that.