HIV and ID Observations

Fresh back from lovely Montreal, where the temperature (I’m glad to report) climbed into the balmy 40’s …

Here’s a rapid-fire listing of the Greatest Hits.  As I’m sure to be leaving something off this list, happy to accept other suggestions:

1. Interleukin-2 does not work.  The ESPRIT and SILCAAT studies are over. Yes, the CD4’s increase, but compared to antiretroviral therapy alone, there’s absolutely no clinical benefit, and plenty of side effects.
2. Should we be starting antiretroviral therapy at even higher CD4s? At ICAAC, the NA-ACCORD group said starting before 350 improved survival; here they said it was 500!  The ART-CC disagreed, slightly (their estimate was around 350).
3. Switching from lopinavir/r to raltegravir increases the risk of virologic failure in suppressed patients. Likely explanation:  undetected NRTI resistance at baseline.  This study should have no bearing on the use of raltegravir in either treatment-naive or treatment-experienced patients — essentially, the drug must be used with at least one other fully active agent.  (Oh yeah, the lipids improved, not surprisingly.)
4. Treating HIV during TB treatment increases survival compared with waiting until TB therapy is completed. One of the most interesting things about this study is that TB treatment outcomes were similar — but those who delayed therapy obviously had HIV disease progression.  By contrast, a small study of cryptococcal meningitis from Zambia suggested that early ART was harmful — the first time early ART has been associated with worse outcomes.
5. Treating HIV significantly reduces the risk of HIV transmission to a seronegative partner. This study from Zambia and Uganda involved nearly 3000 discordant couples (!), and the effect was dramatic — especially when one considers that HIV therapy was only given if clinically indicated (i.e., not to prevent transmission).
6. …But the risk of transmission is not zero. Some studies showed persistent HIV shedding in semen despite effective antiretroviral therapy.  No surprise — but this doesn’t diminish my enthusiasm for #5 above, as the reduction in risk from treatment is huge.
7. Antivirals and cardiovascular disease. D:A:D is updated, and continues to implicate abacavir, and a French Hospital Database study does the same — and both now cite lopinavir/r as associated with increased risk as well.  An ACTG database study does not find an association with abacavir, but a prospective randomized switch trial (to ABC/3TC or TDF/FTC) does — in the updated analysis, the difference was statistically significant.  Regarding abacavir, pathogenesis studies were all over the place — split about evenly whether positive or negative.  Peter Reiss gave a sensational summary on this complex issue — web cast highly recommended if you have 15 minutes to spare.
8. Lopinavir/r is better than nevirapine for women who previously received single-dose nevirapine. This might seem intuitively obvious, but it answers an important question that has generated enormous controversy over the years.  (Plus the first author is a beloved colleague.)
9. Two non-ritonavir boosters are introduced. (Details here and here.)  Yes, data are early, but something without the GI and lipid effects would be welcome indeed.  Whether we really will need PK boosters at all remains an open question, but for now they clearly are needed for PIs and the investigational integrase inhibitor elvitegravir.
10. A microbicide works.  Sort of.

So what’s missing?  Not a single phase III study of a novel agent, nor a phase IV comparative trial of existing drugs done in the developed world.

Yes, it’s a very “quiet” phase in HIV drug development — too quiet.  If this poster is a harbinger of what’s coming with integrase resistance, let’s hope it’s not quiet for long.

Happy New Year!

In the spirit of list-making that seems to permeate the world right about this time, we’ve just published our own list over at AIDS Clinical Care.  Check it out — our editorial board this year did a superb job of summarizing the field.

I have a strong feeling that next year’s version will have some much more hopeful news on prevention, perhaps through pre-exposure prophylaxis (PrEP), or treatment as prevention, or both.

As for advances in vaccines, um … perhaps the less said the better?

The FDA has issued one of its new “early communications” indicating that it has opened an investigation into the safety of abacavir and didanosine based on analyses showing higher rates of myocardial infarction with these drugs than with other NRTIs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study.

The pace of our field is sometimes remarkably fast: Immersed in HIV care or research or policy, we think of this as old news — after all, it was presented over a month ago at the Retrovirus Conference. These D:A:D results linking abacavir and ddI to increased MI risk have already been the subject of extensive discussions in clinics, conference rooms, and meetings. But I have to remind myself that no, it’s not old news at all — the full paper has not yet been published, although it will be soon — and that we still need some time to process the data, and to consider the questions raised by the findings. Is this a causal relationship, or just an association? Why has it not been seen in other studies? What is the mechanism? Would it still be the case with HLA-B*5701 screening? Why is the risk not cumulative? When will we be seeing data on tenofovir? (I suspect soon, given when tenofovir was approved.) What do abacavir and ddI have in common that would cause this? What should we be doing with our patients on abacavir who are doing well? I confess my answer to all of these questions is the same: I just don’t know.

D:A:D is an extremely important study that has already provided enormous insight into HIV treatment. But as the D:A:D investigators no doubt would agree, there are limitations to ascribing toxicities to treatment based on observational data. So I guess I’m proposing that as of today (March 31, 2008) we view these results as suggestive, and hypothesis-generating, rather than defining standard of care right now.

UPDATE

The D:A:D data have now been published in the Lancet. There is also an accompanying editorial here (subscription required).