As at most medical conferences, outside of the hushed meeting rooms more festive attractions await, including a forest of posters and a colorful exhibition hall where pharmaceutical companies set up tents to woo doctors who wander into camp. This is the village marketplace, a swirling festival of lights and video screens where the throng mingles beneath giant logos amid laughter and the hiss of espresso makers.
At EACS, though, more than any conference I've been to, it is the pharmaceutical company-sponsored satellite session that seems to be the central attraction. Not exactly an official part of the scientific program, satellite sessions are granted to the drug makers in return for significant financial support of the conference. Not surprisingly the companies use these events to feature their latest products and to promote recent data that has appeared in proper science sessions. In Dublin, nine companies held satellite sessions over a three day span, beginning at 7:30 in the morning and ending well after dark.
These sessions began to feel a bit like church services, packed with pilgrims come to witness eminent doctors uphold enduring truths and argue the nuances of contending theologies. In honor of the tenth anniversary of the advent of truly effective HIV treatment, almost every company's satellite presentation began with a ritual recitation of the miracle of HAART. In Dublin we gathered to hear the ancient faith affirmed: "The goal of antiretroviral therapy is to achieve maximum virologic suppression."
The topics of these sessions are like parables that reveal the patron's underlying message. If the theme is lipoatrophy and how to avoid it, you know you are in the church of Gilead to learn about the demons of thymidine analog NRTIs. The sermon is subtle and you may hear the virtues of Viread invoked only once or twice during the hour; yet to those with eyes that can see, the path is clear: Truvada will set you free. If the devil is lurking in the lipids, then this morality play is about the evil Kaletra, and rescue by good King Reyataz or Sir Viramune is certain. But if you are called to worship time and tradition by the old sage Abbott, then it's mighty Kaletra reciting the ancient mystery of virologic failure without PI resistance.
In a kind of communion ritual, attendees sometimes receive small devices that allow them to register their opinions on formal questions posed by the presenters. Within seconds the collective responses are displayed on the big screen for all to behold and wonder at. In these moments the secret heart of the congregation is revealed. Often responses seem preordained, such as when a question points to an obvious choice that reinforces the sponsor's message. This is a pedagogic exercise and seems very effective. But the beliefs of the mob can be frightening too. In a catechism sponsored by the makers of efavirenz (Sustiva, Stocrin), the limits and dangers of nevirapine were drilled unmercifully, yet a sizeable minority of respondents never quite seemed to grasp that they risked a case of liver failure by prescribing nevirapine to a woman with more than 250 T cells (over 400 for men).
These errant answers are a sobering reminder of why satellite sessions are so useful. Despite how complex treating HIV can be in day-to-day practice, the dos and don'ts must be made sufficiently simple so that garden variety doctors -- the parish priests of medicine -- can keep the message straight and tend their flocks without losing any sheep to the wolves of toxicity, resistance, or lipodystrophy. When the guidelines are made clear, adherence to the faith is more likely.
There were no apostates or freethinkers in the big hall. No heretics hailing hydroxyurea, immune modulation, or other theories that stray from the central doctrine of everlasting viral suppression. Although Merck allowed a peak behind the veil to suggest a coming paradise of therapeutic vaccines and integrase inhibitors, most companies offered redemption here on earth, available now (or soon) at your local pharmacy. The sponsors' prize for mounting this pageant is a buttressed position in the minds of Europe's doctors -- and a possible up-tick in market share. The doctors get a renewed awareness of the complexities of treating HIV and some measure of comfort knowing they are in touch with the mainstream.
Truly, Schapiro said, sounding a universal theme, AIDS treatments have gotten better, with around 77% of patients achieving virologic suppression within the first year. But this still leaves many who are not undetectable, and as resistance mutations accumulate over time eventually all treatment options will be exhausted. The sad fact is that people are still dying of AIDS in the US and Europe. Patients with multiclass-resistant HIV are especially hard to treat and transmitted drug resistance in newly infected people is a continuing problem.
Schapiro invoked the well-known limitations of the current classes of drugs: non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a relatively low barrier to resistance, there are few choices, and cross resistance is common. There are many nucleoside reverse transcriptase inhibitors (NRTIs), but again cross resistance limits the number of effective options. Even among the protease inhibitors (PIs) with higher barriers to resistance, cross resistance can limit selection. The choices shrink further when tolerability and toxicity are factored in. Once resistance to the most tolerable regimen has developed then second- and third-line choices begin to put a greater burden on the patient in terms of increased toxicity and diminished convenience. The cycle of treatment failure is accelerated as adherence to a suboptimal regimen declines. Fuzeon (T-20, enfuvirtide) is available to help these patients, but it comes with the millstone of twice-daily injection. New drugs in the three main classes are on the way, but at best they offer incremental improvements or are intended to patch over resistance problems after treatment failure has occurred.
At this point it should be clear to all that we need a new drug from a new class with a new mechanism of action that is free from the old toxicity and resistance problems. So what would a truly new drug look like? First it must reduce viral load as well or better than drugs from the current classes. Then it must have no -- or at least manageable -- tolerability issues and minimal long-term toxicity. It should have a unique resistance profile and pose a high barrier to developing resistance in the first place. Finally, it should be an oral drug, ideally taken only once a day. Shapiro's presentation didn't reveal the identity of this savior drug, but it did create a hunger in the hearts of the audience for what was to come.
Daniel Kuritzkes from the USA next reviewed the process of HIV entry, paying particular attention to the role of the human CCR5 receptor, how HIV uses this cellular protein to infect target cells, and what happens when HIV switches from using CCR5 and starts using a similar receptor called CXCR4, an event associated with more rapid disease progression. There has been concern that if the CCR5-using form of HIV is blocked then the virus will start using CXCR4 to gain entry to cells, and some worry this might speed up the pace of immune damage, although in clinical trials to date this hasn't been reported.
Finally Graeme Moyle from the UK took the stage to survey what we currently know about the drugs that deny HIV entry into virginal lymphocytes. Until recently, three companies were developing competing versions of CCR5 antagonists, although in the weeks before this conference one competitor had been swallowed by the whale of toxicity and another had been lured astray by the glittering temptation of once-a-day dosing. All studies of aplaviroc, GSK's CCR5 candidate, were terminated after several cases of severe liver toxicity began to appear among study subjects. Fortunately, the liver problems abated when the drug was removed but this unforeseen safety problem proved fatal to the drug's future and it was dropped. A few weeks later, Schering announced that it was canceling clinical trials of its CCR5 blocker in treatment-naive patients due to low potency and an inability to compete with efavirenz in reducing viral load. Schering's drug, called vicriviroc, benefits from boosting with ritonavir, and trials of the drug in treatment-experienced patients who are taking it in combination with boosted protease inhibitors will continue. It appears likely that blood levels of unboosted vicriviroc, especially when dosed once per day, were not reliable in all patients. This study seems to have been a gamble on Schering's part, since it did not test the once-a-day dose in the initial trial that proved that vicriviroc worked. It's possible that the temptation of achieving the holy grail of one-pill-a-day led to a leap of faith that vicriviroc's long half-life in the blood could carry it through. Alas, whether precipitated by greed or by pride, expectations for vicriviroc have been diminished.
Later in the conference fears about the viability of this entire class of compounds were heightened when word came that there had been a case of serious liver toxicity in a patient taking Pfizer's maraviroc. After the aplaviroc experience, some wondered if this was a problem with all CCR5 blockers. But as details filtered out, it appeared likely that other liver-toxic drugs were responsible for this incident and no other cases involving maraviroc have been reported. Still, this one case, coming on the heels of the other disasters, has put everything to do with vicriviroc and maraviroc under closer scrutiny.
Nevirapine, he reminded his audience, has good efficacy but its safety issues require physicians to learn how to use it correctly. The drug should not be initiated in women with more than 250 CD4+ T cells/mm3 or in men with over 400 CD4+ T cells/mm3. All patients should be instructed to be watchful for signs or symptoms of rash and hepatitis during the first six weeks after starting nevirapine. Once nevirapine has been successfully initiated, CD4 counts that rise above these levels are not a problem.
Results from the Boehringer-sponsored 2NN study, which demonstrated statistical equivalence between nevirapine and efavirenz, have never seemed as compelling as the company would like because of a five percentage point gap between the drugs in the main efficacy result. A presentation in one of Dublin's scientific sessions might help explain this gap. Storfer et al reported on the high rate of liver toxicity seen in 2NN subjects from Thailand who received once-daily nevirapine. The association between higher CD4 counts and liver toxicity was not understood at the time 2NN was designed. When patients with CD4 counts exceeding the current cutoffs were excluded from the 2NN analysis, not only were adverse event rates comparable between the twice-daily nevirapine and efavirenz groups, but the efficacy gap narrowed as well.
Another important use for nevirapine is to help prevent mother-to-child HIV transmission during childbirth. In resource-poor settings the use of a single dose of the drug at the time of delivery had been advocated until evidence began to accumulate that nevirapine resistance was common in mothers when they subsequently began continuous therapy. The very long half-life of the drug in the blood after a single dose allows HIV to replicate and select a nevirapine-resistant strain, which persists. A solution, now being tested, is to cover this "tail" of dwindling nevirapine concentration with a few days of Combivir to keep HIV down until the nevirapine is gone.
Tipranavir (Aptivus) is a recently US-approved protease inhibitor that has been targeted for salvage therapy. Jurgen Rockstroh from Germany reviewed the results from the RESIST studies of tipranavir versus best available therapy in highly treatment-experienced individuals. At 24 weeks, 34% of patients in the tipranavir group had HIV RNA below 400 copies/mL compared to only 15% of those in the comparison group. Subsequently, during a scientific session at the conference, 48 week RESIST results were reported that continued this theme, with about 30% of the tipranavir group below 400 copies versus 13.8% in the comparison group. Clearly there is an advantage to having tipranavir on board, but these low numbers speak to the pressing need for overall improvements in salvage therapy. For patients who included Fuzeon in their regimens, the prospect of success was brighter, with 50% of those on tipranavir having a protocol-defined treatment response. This demonstrates the importance of including at least two active drugs when constructing a salvage regimen; if only one active drug is added to a failing regimen, then the benefit will likely be short lived.
Most dropouts in this study were due to viral failure in the comparison arm and were switched to tipranavir after 8 weeks, which necessarily limits any comparative safety data after that point. The selection of Jurgen Rockstroh, widely known as a hepatitis expert, to present the tipranavir data speaks to concerns about the drug's potential for liver toxicity. In the 24-week RESIST data, grade 3 or 4 ALT elevations were reported in 5.9% of those receiving tipranavir and in 1.8% of those in the comparison arm. Rockstroh acknowledged that the risk of liver toxicity is higher in patients receiving tipranavir, especially those with HBV or HCV coinfection. He recommends routine monitoring and discontinuation if elevated liver enzymes are accompanied by symptoms. Aside from this issue, Rockstroh said, the safety profile of tipranavir was comparable to other PIs used in RESIST.
David Back from the UK addressed one of the other difficulties with boosted tipranavir: how to use it in combination with other drugs. An early study of tipranavir in combination with several protease inhibitors revealed that it could dramatically lower the levels of saquinavir, amprenavir, and Kaletra, which effectively ruled it out for use in a dual boosted-PI strategy. Back, one of the world's experts in drug interactions walked through what else is known about how tipranavir interacts with others. There seems to be no relevant interaction between tipranavir and efavirenz or nevirapine or with the NRTIs, including tenofovir. Coadministration with the PIs, of course, is not recommended. There are also likely significant interactions with certain TB drugs, some statins, some antifungals, and probably other drugs. The bottom line is that the net effect of tipranavir is difficult to predict and clinicians should be mindful of other, unrecognized potential interactions.
Christine Katlama from France then took the podium to implore the audience to never give in to viral replication. There are risks to allowing HIV to run free at every stage of the disease, she said. The accumulation of resistance mutations can affect future treatment options and this means that even patients with high CD4 counts and moderate viral loads are at risk when virologic failure is allowed to occur. One blessing: The availability of new drugs means that no one should go unsuppressed.
She recommends that patients invite Fuzeon into their lives for three months to see if it works for them. Results are seen quickly, she said, and this often motivates patients to keep going, especially when they become undetectable for the first time ever. Katlama also reviewed a study on the acceptability of injectable ARVs that found patients were much more willing to try Fuzeon than their doctors thought they were. At this point she could have called for converts to come forward and be anointed, but she didn't.
Sharon Walmsley of Canada next sang the praises of Roche's boosted Invirase (saquinavir), which in the odd play of history was first-born among protease inhibitors, then exiled to wander in the wilderness, but is now born again in a convenient new 500 mg tablet. Ten years ago, when Invirase became the first PI approved in the US, it seemed miraculous that an effective treatment for AIDS had finally been found. But a high pill burden and poor efficacy meant Invirase was soon eclipsed by other PIs and even a new formulation of saquinavir. Eventually, as ritonavir boosting of PIs became standard, Invirase was rediscovered as a highly effective and quite tolerable alternative to Kaletra. Roche hopes that the new 500 mg tablet removes one of the remaining barriers to its wider use. While older studies show acceptable efficacy compared to its rivals, a study of the new formulation versus Kaletra now in progress in France may help clarify the issue. Importantly, Walmsley noted, is that, similar to Kaletra, no significant PI mutations are found after virologic failure on Invirase, thus leaving future treatment options relatively intact. Invirase does affect blood lipid levels, although differently from Kaletra, tending toward lower triglycerides and higher total cholesterol, according to one study. Another study found its lipid profile similar to that of efavirenz.
At this point Marta Boffito of the UK jumped into to discuss what is known about drug interactions with Invirase, focusing on a significant increase in saquinavir exposure when used with omeprazole. Finally, Mike Youle of the UK presented some clinical data on the new formulation and suggested that once-daily saquinavir/ritonavir at a dose of 2000/100 mg may be equivalent to twice daily 1000/100 mg.
Roche followed its HIV satellite with another session dedicated to treating HIV/HCV coinfected patients, but we shall not stray into such esoteric knowledge here.
Next, Margaret Johnson from the UK broke out the electronic confessionals and took the congregation down a rocky path of clinical quandaries where all roads seemed to lead to efavirenz. This was the session in which 10% to 20% of responders voted to prescribe nevirapine to women with CD4 counts above the recommended range. Merck was the discoverer of efavirenz and licensed it to Bristol Myers-Squibb for the US market and a few other places where it is sold as Sustiva. It may sound odd to American ears, but in much of the rest of the world efavirenz is known as Stocrin and is marketed by Merck.
David Cooper of Australia presented a familiar sounding, but no doubt useful session on factors to consider when choosing between an NNRTI and a PI for an initial drug regimen. Since there is not a lot of comparative data, Cooper reprised the main considerations: PIs are attractive for being slow to allow resistance and NNRTIs have a relatively low barrier to resistance. PIs avoid the risk of initial toxicity to nevirapine, and PIs may also be a better choice for women of child bearing age. On the other hand, NNRTIs are easy to use, avoid the long term toxicity of PIs, are highly potent, and are cheaper.
BMS gains a bit of credibility for promoting the concept of switching because the only evidence that switching can be beneficial comes from studies that switched Zerit (stavudine, d4T) to either AZT or tenofovir to prevent body fat wasting. Of course BMS makes Zerit, and although they have all but abandoned efforts to market the drug, it is still useful as a sacrificial lamb. If switching from d4T minimizes toxicity, then wouldn't switching from Kaletra to Reyataz also be a good idea? As panel members admitted, there is not yet enough evidence to support voicing that strategy but the group did seem to agree that atazanavir has a neutral effect on lipids. One panel member raised the interesting question of whether the 100 mg boosting dose of ritonavir used with atazanavir could be responsible for lingering metabolic problems after the switch. Another considered it possible, but thought it risky to use atazanavir unboosted unless he was able to monitor the drug's levels in the blood. Worries about Kaletra-associated increases in lipids have apparently touched a nerve in many physicians, if not in patients, and sales of Reyataz in the US are said to have nearly caught up to those of Kaletra.
Fiona Mulcahy, one of the conference's Irish hosts, opened this symposium by polling the audience via the electronic butter boxes about their goals and experiences with antiretroviral therapy. To the question of what characteristic was most important for an ARV regimen, 59% answered immune recovery; 21% thought a high barrier to resistance was supreme; and 18% selected tolerability. Only 1.4% thought lack of cross-resistance was most important. Asked if they noticed a plateau in immune recovery in their patients after three or four years on treatment, 52% said this was common and 34% said they see it sometimes. Only 8% said they never saw such a plateau and 5% said it was rare.
Joep Lange from the Netherlands then took the stage to describe results from the Kaletra 720 study, which has now reached seven years and is the longest running prospective study of an ARV regimen. To date, viral suppression below 50 copies/mL has been sustained in 59% of the original participants. He did not dwell on the 41% who didn't fare so well. Building on the question asked earlier, Lange reviewed results from two observational studies that found a "plateau" in CD4 count benefits after three or four years of therapy. In contrast, the Kaletra 720 study shows CD4 counts increasing steadily over the seven year period for all patients, regardless of at what stage they started. At seven years, the mean CD4 cell count increase was +501 cells/mm3. Evidence is accumulating that maintaining a higher CD4 count can help avoid disease progression, improve the tolerability of therapy, and possibly minimize long-term side effects such as lipoatrophy. To address concerns about Kaletra-associated increases in cholesterol and triglycerides, Lange showed a slide that suggested patients in the 720 study who switched from d4T to tenofovir (d4T was state of the art seven years ago) experienced significant decreases in lipid values while remaining on Kaletra.
Jose Arribas from Spain covered several issues concerning drug resistance in current HIV therapy including transmitted drug resistance, which appeared in 10-20% of newly infected people in several studies. But mainly he was there to distinguish between the resistance profiles of the NNRTI class and the PIs, and to guide our attention to the resistance benefits offered by Kaletra. To date, no primary Kaletra resistance mutation has been detected in trials, possibly, Arribas says, because the drug is so rapidly cleared from the blood after a missed dose, thus avoiding putting the virus under pressure to replicate in the presence of subtherapeutic concentrations of the drug.
With the audience softened up by Lange and Arribas, Barry Peters of the UK took on the great looming unknown about Kaletra: Will Kaletra-associated lipid increases eventually translate into an increased risk for cardiovascular disease? First he reviewed the known CVD risk factors; including male sex and older age, then went on to high blood pressure, insulin resistance, smoking, and HIV itself. There is no clear cut answer at this point and the one large study that found an increased risk of CVD in people with HIV on therapy is contradicted by another large study that did not. This is all enough to muddy the waters around Kaletra and conclude that the benefits of an efficacious ARV regimen are so great that the potential CVD risk should not cause an ill-considered switch. Besides, if you want to dramatically lower your risk of heart and vascular problems, then you really should stop smoking. You know who you are.
Finally, George Hanna of Abbott introduced the audience to the new tablet formulation of Kaletra that offers a lighter pill burden, no food restrictions, and requires no refrigeration. In healthy subjects, a lower rate of diarrhea was reported than had been seen in historical studies of the old Kaletra. Whether this benefit will be seen in HIV-positive patients with touchy GI tracts remains to be seen.
Schlomo Staszewski from Germany reviewed the treatment options for patients with multi-drug resistance. It is generally accepted that simply adding one new drug to a failing regimen is a recipe for failure and that at least two drugs with activity against an individual's virus should be added if a switch is to be made. For some patients, sticking with a failing regimen, particularly one containing lamivudine, may help minimize viral replication capacity and thus be preferable to stopping all drugs. Of course for many, toxicity and tolerability problems are responsible for the need to switch or stop therapy. There is increasing evidence that NRTI resistance mutations can be managed to reawaken sensitivity to previously used drugs, such as zidovudine, and sequencing of NRTIs should be considered. For protease inhibitors, although there is a high initial barrier to resistance, once PI mutations have started to accumulate, even double-boosted PIs can be unsatisfactory. This background set up the undeniable need for new drugs with activity against HIV that has lost susceptibility to the existing PIs. Tipranavir is one newly approved drug that attempts to address this problem, although there are concerns with tolerability. TMC114, though not yet approved, has performed well in the limited data shown so far and initial reports say it is well tolerated.
Paul Stoffels of Tibotec reviewed the discovery and development of TMC114. He said the company's criteria required that any successful drug must be active against existing drug-resistant HIV, be resistant to the development of resistance itself, and be as good as or better than the competition in terms of tolerability, toxicity, and convenience. That Tibotec has been successful, he said, is demonstrated by the extraordinary decision of the US FDA to allow the company to file for new drug approval based upon Phase II data -- before the large Phase III trials are completed. Approval in the US could be seen by June 2006.
Christine Katlama from France reviewed 24-week results of the 318-person Phase IIb POWER 1 study that compared several doses of TMC114 plus optimized background therapy (OBT) to OBT alone in highly treatment-experienced patients. In the 600 mg dose that was selected for further study, 59% of patients with more than three primary PI mutations who received TMC114 had viral load below 50 copies/mL compared to only 9% of those on OBT alone. Overall, 53% of the TMC patients versus 18% of the controls achieved viral load below 50 copies/mL. Mean CD4 counts increased by 124 cells/mm3 in the TMC group compared to 20 cells/mm3 in the comparison group. Discontinuations due to adverse events and the incidence of serious adverse events were similar between the groups. These results are impressive and they certainly impressed the FDA, but whether TMC114 can produce a shift in the treatment paradigm remains to be seen. (Efficacy results from the POWER 2 study presented at the ICAAC conference the following month generally supported what was seen in this study, although safety and tolerability results from that trial were not as rosy.)
Conference host Bill Powderly introduced the session by reviewing the range of possible risk factors for lipodystrophy before zeroing in on thymidine analogs and how they may be causing mitochondrial toxicity in fat cells that leads to depletion of fat tissue.
Peter Reiss from the Netherlands sharpened the attack on thymidine analogs by reviewing clinical data on fat loss under different NRTI regimens. The detrimental role of stavudine (d4T) is now widely accepted but it increasingly seems that over a longer time period, zidovudine (AZT) can eventually cause many of the same problems. The non-thymidine NRTIs, which include tenofovir, ddI, and abacavir, have not been shown to significantly affect limb fat or total body fat when compared to thymidine analogs. Although facial fat loss is the most visible and most psychologically damaging manifestation of lipoatrophy, accurate facial fat measurements are difficult to perform and limb fat is generally considered a surrogate.
Finally, Joel Gallant of the USA reviewed the range of treatments for existing fat wasting and concluded that the best strategy is to prevent it from happening in the first place by avoiding thymidine NRTIs. In a hopeful note, there is now some evidence that fat repletion can occur naturally, albeit very slowly, once the offending thymidine analogs have been removed.
Vincent Calvez from France offered a presentation designed to position abacavir as a more logical first choice over GSK's arch foe, Gilead's tenofovir. The strategy is to sequence abacavir before tenofovir to minimize potential resistance issues. All three available dual NRTI combos (based on abacavir, tenofovir, or AZT) also contain either lamivudine or emtricitabine, similar drugs that lose potency when faced with the fairly easy-to-get M184V resistance mutation. Resistance to abacavir or tenofovir is more difficult to produce and generally only occurs after M184V has appeared. Calvez argued that abacavir is a more rational choice for first-line therapy because L74V, the most common abacavir-associated resistance mutation, when it occurs in combination with M184V, actually tends to boost the virus's sensitivity to subsequent use of tenofovir, whereas M184V in combination with the K65R mutation that can cause tenofovir resistance prevents subsequent use of abacavir. The message: To keep your options open, use abacavir first. Um, it's a lot to digest, but it might tip the balance for some doctors.
Simon Mallal from Australia then addressed the abacavir hypersensitivity issue with a discussion of a possible genetic marker that may one day identify individuals most likely to be affected. But the real key to identifying abacavir HSR is clinical vigilance, which means distinguishing it from a reaction to another drug, an unrelated illness, or symptoms of immune reconstitution disease. If a true HSR to abacavir has occurred, the drug must be stopped and never taken again to avoid severe and possibly fatal consequences. It's this last bit that no doubt tempers physician enthusiasm for using abacavir. But for those concerned about long-term mitochondrial toxicity associated with other NRTIs, the extra vigilance at the outset may be worth the effort.
Finally Lynn Marks of GSK addressed the perception that the company's pipeline is sputtering and focused on the pressing need for better therapies in both the developed and developing worlds. As the creator of the world's first AIDS drug in 1987 and the maker of treatment guidelines mainstay, Combivir, GSK has come to seem like a permanent fixture in HIV therapy. But the bar for safety, efficacy, and convenience has been set higher in recent years and it will take a stunningly effective and problem-free new drug from GSK, or indeed any of these companies, to capture an honored spot in the HIV therapeutic pantheon. (The following month at the ICAAC conference in Washington, DC, GSK gave an impressive first look at their new PI candidate, brecanavir, which they hope will return them to greatness.)
Go in peace.