One way to categorize the large HIV/AIDS conferences is by whether they provided overall bad news (Berlin International, 1993, "resistance to nuke antivirals is a fatal flaw and combination nuke therapy doesn't add much"), good news (Vancouver International, 1996, "protease inhibitor-containing 'cocktails' are dramatic successes at extending and improving life") or not much news. By most accounts, the 9th Retrovirus Conference in Seattle was in the last category.

That's in part because we are in a temporary hiatus between the rollout of new antiviral drugs and also because some large, multi-year clinical trials designed to answer some key questions (like when to start antiviral therapy, how to stimulate the body's own immune system, structured treatment interruptions, control of lipodystrophy) are still underway or even just beginning.

However, there was useful information presented that confirms and clarifies what we already knew, raises a few warnings and casts doubt on some hopes and keeps us waiting expectantly for potential good news on new drugs and treatment strategies in the pipeline. I have highlighted a view of these items below. [Note: I was not able to attend this year's conference and so my comments are gleaned from Web-posted reports of others and conversations with a few friends who attended. I have listed the Web sites I relied upon at the end so that readers may consult them directly for more extensive and first-hand reports.]

New Drugs In Pipeline

New drug developments likely to be most immediately available to persons living with HIV are not actually new drugs at all, but new formulations or clarified indications for the use of many of the 17 currently FDA-approved antivirals, particularly pills that can be taken only once a day. Several new extended-release or otherwise long-acting formulations (such as ZeritXR) should be more widely available later in 2003 and early 2004.

Developing second-generation versions of the existing main drug classes (NRTIs or nukes, NNRTIs or 'non-nukes,' and PIs or protease inhibitors) is one key strategy to increase the potency of HAART regimens, with the intent of more fully suppressing HIV replication and overcoming resistance to earlier drugs. One such drug, a second-generation NNRTI by the Belgian company Tibotec known as TMC125, got a lot of favorable attention, with data showing very dramatic early reductions in viral load both in treatment-naïve patients and those who had become resistant to other NNRTIs. While continuing clinical trials, Tibotec is also working to create a user-friendlier version of its drug (which currently requires 18 pills twice a day!).

Conferees also expressed excitement over some very small and preliminary studies of a new class of drugs, "entry inhibitors," (sometimes referred to as "cytokine inhibitors") that aim to block HIV's binding to one of the co-receptors (CCR5 or CXCR4) on the surface of T-cells that is a necessary stage in HIV infection of each new vulnerable cell. Though these drugs are at least a few years away from large-scale clinical trials, and we all remember the promising candidate drugs that have fallen by the wayside during development, these small trials reported in Seattle represent the first testing (successful as far as it went) of entry inhibitors in humans, a necessary step in proving the efficacy of a whole new class of anti-HIV drugs and one that there is good reason to expect will be less prone to resistance.

There were also reports of further modest development of the first in another new class of anti-HIV drugs, "integrase inhibitors." The Japanese Shionogi Company in collaboration with Glaxo-Smith-Kline is developing the drug, called S-1360 for now. The once-darling fusion inhibitor candidate drugs, T-20 and T-1249, of yet another new class, are farther along in development but have lost some luster in the face of continuing difficulties in drug delivery (requiring frequent injections), safety and considerable variability in efficacy in different people who have taken them.

Lipodystrophy and Reversing Body Shape Changes

This topic combines two key areas of concern: the potential of metabolic side effects of long-term antiretroviral therapy for causing serious cardiovascular illness and the negative effect of changes in body-fat distribution on the quality of life of PWAs and therefore on our willingness to continue taking antiviral medications.

Assessing the causes and risk of metabolic changes on the cardiovascular system remains controversial and full of unknowns. The Conference did not help much in clarifying our understanding of the cause and extent of such risk, in part due to some quite contradictory reports. There was useful discussion of the fact that an aging PWA population has many other ("regular") sources of risk for cardiovascular illness or catastrophe. For instance, a 40-year-old man who smokes cigarettes, is overweight, has elevated cholesterol and triglycerides and doesn't exercise much has a 10% chance of experiencing a serious heart attack or stroke before he reaches 50, even without HIV infection. While we don't yet know how much added risk being on HAART entails for our theoretical man, we do know from some small studies presented that the same methods that are useful for such pre-heart-attack cases who are HIV negative work for those who are HIV-positive to significantly lower risk: stop smoking cigarettes, make and sustain gradual healthy dietary changes and increase regular exercise. Also, HIV docs, and we patients who let them know what we expect of them, should pay increased attention to monitoring, counseling about and pharmacologically treating these non-HIV risk factors for serious chronic disease that we all have to one extent or another.

The other part, the effect of "fat wasting" on appearance, is of serious concern also, independent of the cardiovascular effects of altered metabolism. People living with HIV/AIDS dread the characteristic sunken cheeks, skinny arms, and bloated bellies that are collectively known as lipoatrophy or fat wasting. In a way reminiscent of KS lesions in the past, these physical signs can identify even folks who are doing quite well as a PWA/HS. Not surprisingly, many people are reluctant to start, continue or adhere to medication regimens that potentially cause such side effects.

It is not easy to pinpoint which drug is responsible for fat wasting in individual patients -- both nukes and PIs have been implicated, and it is not clear yet if individual drugs or specific combinations are most likely to cause it. Nevertheless, there have been several "switch" studies to see if changing the constituents in drug cocktails can reverse or at least halt this side effect.

Three such studies were reported at the Conference, all involving switches from d4T (brand name Zerit) to abacavir (Ziagen), and were sponsored by (big surprise) Glaxo Smith Kline, manufacturers of Ziagen. The rationale is that one hypothesized central cause of fat wasting is mitochondrial toxicity, which laboratory studies show abacavir less likely to cause.

None of the three studies showed dramatic improvement, but each showed some modest improvement in arm, leg and butt fat. The changes were greatest in those participants whose former regime included a protease inhibitor as well as d4T and whose regime included an NNRTI as well as abacavir. Unfortunately, the improvement in each study was so modest that it was detected mostly by DEXA machines -- most participants themselves say they did not notice any significant change. At least, however, the fat wasting process was halted. As one participant said, "A 10% increase in fat is better than losing 10% more." The studies are ongoing and the Conference reports were early (only about six months' follow up after the switch), so we may see better results later. It is too bad that none of the studies measured facial fat loss or restoration that is often the greatest concern to PWA/HS. There was no difference in effectiveness of the "switched to" compared to the "switched from" regimen in maintaining low viral loads.

Drug Holidays and Structured Treatment Interruptions (STI)

Overall, we got a mixture of bad news and good news in this domain. Most physicians will continue to recommend against STIs in most cases of "chronic infection" (meaning after the primary phase of HIV infection is passed and the 'viral setpoint' or baseline level has been established). If STI is begun during primary infection, meaning within a few weeks or months of the time or original infection, there is evidence that such a strategy helps maintain the body's own ability to fight HIV that is ordinarily destroyed after making a valiant effort. However, for those who have been infected more than about six months, the hopes of restoring HIV-specific immune function through pulsed or intermittent antiviral therapy have been pretty much dashed. Doesn't happen. Reports from several ongoing studies at the Seattle Conference continued to confirm this widespread finding. Dr. Bernard Hirschel, a Swiss doctor who has conducted the largest and best designed STI study to date, in fact declared the "theory of auto vaccination" dead. That's the bad news.

Other strategies to boost or restore the body's own anti-HIV immune response are currently under study, and may in the end produce better results. These include treatment with various therapeutic vaccines or immune modulators, either together with HAART or in a concentrated burst before each point at which HAART is stopped in STI, or throughout the periods off antiviral. For instance, the ACTG trial 5102 is evaluating the role of interleukin-2 in prolonging periods off therapy and the European Quest trial is evaluating the role of vaccines ALVAC and Remune in prolonging times off antiviral therapy.

However, auto vaccination (or letting one's body immunize itself against HIV by periodically stopping medications and letting the latent or suppressed HIV multiply again) is only one of the reasons for trying to find out if STI or drug holidays are safe and useful. The other two main reasons are to reduce the cost of HAART, especially in resource-limited countries around the world, and to reduce the cumulative side effects and toxicity of HAART, by reducing one's total exposure to these drugs over one's lifetime. For this last reason, we patients continue to take drug holidays on our own or at our own insistence, even if doctors recommend against it.

The good news here is that, at least for most people whose HIV infection has not progressed to an AIDS diagnosis (either by an AIDS-defining illness or a CD4 count under 200), stopping therapy for closely-monitored intervals does not increase resistance to the drugs one was taking, and does not appreciably lessen the ability of the drugs to achieve suppression of HIV once therapy is resumed. These findings would seem to bode well for many people who wish to undertake STI.

However, there were some worrisome findings as well on these questions of safety and continued efficacy. The EuroSIDA cohort study from Europe reported a very much higher rate of new AIDS-defining events or deaths during periods off therapy than in periods on therapy, especially at advanced stage of infection where CD4 count is below 50 (80% off therapy versus 30% on therapy), though also at earlier stages (30% off therapy versus 7% on therapy for those with CD4 between 51 and 199 and 20% off therapy and 5% on therapy for those with CD4 above 200). The study involved several thousand participants, of whom 20% stopped therapy for at least three months and were thus eligible for inclusion in the analysis. A big caution is needed to assess this study because it is observational rather than prospective and randomized, and therefore includes potentially confounding factors besides individual choice that may have been related to the decision to go off therapy. Nevertheless, the differences are great and worrisome.

Finally, a related analysis of people with HIV who are over 50 indicated the need for special caution in people of this age group going off therapy. This was not a study of STI, but rather comparing people who did not choose to go on HAART compared to those who did. Over a three-year period, those patients over 50 were significantly less likely to survive than were younger people who also elected not to go on HAART. Only 13% of those over 50 survived the three years without therapy, despite starting with an average CD4 count of 200, whereas 31% of those younger than 50 survived despite an average lower CD4 count of 130. Both older and younger patients who did go on HAART had the same chances of surviving after three years, 72%. So it seems clear that delaying start of therapy seems riskier for older compared to younger people, and one might thereby infer a likelihood that prolonged interruptions of therapy may also be riskier for older folks.

For More Information

If my schedule permits, I will cover some more topics in the next issue of the Newsletter. In the meantime, check out these Web sites for more [Sites will open in a new browser window]:

• TheBody.COM: http://www.thebody.com/confs/retro2002/retro2002.html
• NATAP: www.natap.org
  • When To Begin Therapy
  • Entry Inhibitors: T-20 and beyond: Chris Pilcher, MD, UNC
  • Opportunistic Conditions in the HAART Era: David Alain Wohl, MD, UNC
  • HIV and Cardiovascular Disease: Judith Aberg, MD, Washington University, St Louis
  • Structured Therapy Interruptions: Mike Youle, MD, Royal Free Clinic, London, UK
  • Primary HIV Infection: Chris Pilcher, MD, UNC
  • New Drugs Reported at 9th Retrovirus Conference (NATAP, Jules Levin; 02-02)
• Medscape: www.medscape.com (register for free if you have never visited before, then go to "Conferences")
• The Official Retrovirus Conference Site (which includes several audio and slide presentations of the sessions themselves, as well as all posters, for the first time): www.retroconference.org