American Foundation for AIDS Research, February 2004
Kristen Kresge

December 2003 — By location alone, the 9th European AIDS Conference (EACS) in Warsaw, Poland instantly set itself apart from other HIV/AIDS conferences this year. Dr. Andrzej Horban — co-chair of the conference and director of the Hospital of Infectious Diseases in Warsaw — delivered the opening comments and welcomed delegates from around the world to the first AIDS conference ever to be held in Eastern Europe.

Eastern Europe has experienced a burgeoning HIV/AIDS epidemic in recent years. In countries like Russia and the Ukraine, HIV has quickly exploded among young intravenous drug users. The Ukraine, Poland's neighbor to the east, has the highest prevalence of HIV among adults in all of Europe — a staggering 1% when compared with large countries like France, which have a prevalence of only 0.4%. The countries of Eastern Europe, along with central Asia, are experiencing the fastest growing epidemic in the world, making Warsaw an appropriate location for researchers to gather and discuss the latest research on HIV.

Even more significantly, Poland was hosting the meeting on the eve of its entrance into the European Union. Far in advance of the International AIDS Conference in Thailand, EACS was east meets west on European ground. Ideas and trends in treating and managing HIV infection became the focus. The conference at times succeeded in challenging some of the basic dogmas of therapy and brought some fringe ideas to the forefront of debate.

More Isn't Always Better
You might say that it has been a tough year for Trizivir. The one tablet combination of three nucleoside analogs (zidovudine [AZT], lamivudine [3TC], and abacavir) is a simple and attractive option for doctors seeking to avoid the side effects involved in combining drugs from different classes, and it is the only way that some patients will agree to take any medication. But Trizivir's role as a sole treatment for HIV has been seriously questioned. Earlier this year the ACTG 5095 study, comparing Trizivir alone with the combination of Trizivir and the potent non-nucleoside efavirenz (Sustiva), found that adding efavirenz was much more effective than Trizivir alone. Fewer people taking Trizivir by itself were able to suppress the virus, and this group failed therapy earlier than the participants who were also taking efavirenz. Twice as many people taking Trizivir alone had detectable viral loads within eight months of starting therapy.

These results led the National Institutes of Health, the sponsors of the study, to discontinue the Trizivir-only arm. Soon after the initial reports of this trial garnered attention, another study involving a triple nucleoside regimen met a similar demise. In October, Gilead Sciences (tenofovir's manufacturer) announced high failure rates in people receiving the triple NRTI regimen of didanosine (ddI), 3TC, and tenofovir. In a 24-week, Gilead-sponsored trial, 24 people naive to HIV therapy were given this drug combination and 91% of them were classified as failures because they did not have substantial reductions in viral load by the twelfth week. Gilead issued a letter to physicians recommending that tenofovir, in combination with ddI and 3TC alone, not be used in patients with HIV.

An additional report at EACS only added to questions about the role of Trizivir in HIV treatment. Dr. Schlomo Staszewski of Goethe University in Frankfurt presented the interim results from the QUAD study (abstract F1/1), which compared Trizivir with Combivir when either was taken with a ritonavir-boosted protease inhibitor. The goal of this study was to match a three-drug regimen of Combivir (AZT and 3TC) and boosted saquinavir against a four-drug regimen of Trizivir and boosted saquinavir. By boosting saquinavir with small amounts of ritonavir, the level of saquinavir in the body increases and the drug becomes more potent.

The QUAD study included 59 people who had no prior exposure to HIV drugs but had high viral loads (an average 300,000 copies/mL) and low CD4 counts (between 22 and 31 cells/mm³) at the start of the study. After 24 weeks both groups had made similar progress, experiencing declines in viral load and higher CD4 cell counts. In each group 60% of volunteers had undetectable viral loads. No significant differences of any kind occurred between Trizivir and Combivir. Staszewski concluded that there was no benefit to having four drugs instead of three. This led him to ask what Trizivir is worth — since it cannot be used alone and is not any better than Combivir when the latter is used in combination with another drug.

Dr. Myrto Astriti of Hôpital Pitié-Salpétrière in Paris, whose oral abstract followed Staszewski's, attempted to answer this question. Speaking in Trizivir's defense, Astriti presented a retrospective study of 120 patients who received Trizivir as their initial HIV therapy (abstract F1/2). At the start of treatment, volunteers had an average viral load of approximately 83,000 copies/mL. After two years on Trizivir alone, 58% of participants had viral loads below 200 copies/mL. Only 15% of the people evaluated were considered Trizivir failures, and most of these people reportedly did not take their prescribed medicine. Astriti's data argued against rushing to judgment on Trizivir.

“Fifty percent of patients are on over two years of treatment and still doing well,” said Astriti. “This is something we shouldn't forget.”

But Is Only One Enough?
While doubts about Trizivir persisted, research continued to support the value of Kaletra, a protease inhibitor that boosts the drug lopinavir with ritonavir. In a study [quote]comparing once-daily Kaletra with twice-daily Kaletra, in combination with tenofovir and emtricitabine (FTC), Dr. Daniel Podzamczer of Hospital de Bellvitge in Barcelona reported that there was no difference between doses at 24 weeks (abstract F1/3). Of 190 volunteers, 115 received 800 mg of lopinavir with 200 mg of ritonavir, or eight pills, once daily. The remainder received 400 mg and 100 mg respectively, or four pills, taken twice daily. After six months, 57% had undetectable viral loads in both groups. The rate of adverse events was higher in the once-a-day group, perhaps due to the high peak concentration of drug in the blood. But the level of adherence was lower in the twice-a-day group.

The significance of this study extended beyond Kaletra. These were the first clinical results for Gilead's fixed-dose combination of tenofovir and FTC. In addition to Kaletra, volunteers in this study received the double NRTI combination, which Gilead is currently developing as a single pill. This combination is expected to provide stiff competition for Combivir and another much anticipated combination containing abacavir and 3TC. Though the tenofovir/FTC duo will be the last to hit the market, it will be the only one available as one pill, once a day.

Researchers continue to focus on simpler drug regimens like fixed-dose combinations. Interest is growing in Kaletra as a potential single therapy for people reluctant to take on complex regimens, but willing to accept one medication. Dr. Joe Gathe presented a poster at the Interscience Conference on Antimicrobial Agents and Chemotherapy earlier this fall that reported results from a small group of patients at his private clinic who were taking only Kaletra and doing well (see the December 2003 Treatment Insider, “A Mishmash of Data at ICAAC”). EACS offered more new data on Kaletra monotherapy, in the form of an oral presentation entitled “Lopinavir/r as Sole Therapy for HIV Infection.”

The presentation by Dr. Gerald Pierone, of the AIDS Research and Treatment Center of the Treasure Coast in Florida, focused on a retrospective analysis of 15 people who had received Kaletra monotherapy for at least eight weeks at his clinic (abstract F1/5). In this small cohort, 13 people continued to receive Kaletra as their only therapy for an average of 68 weeks (the range was 39 to 104 weeks). In fact, 12 of the 15 people, or 80%, had viral loads below 400 copies/mL. The majority of this group (10 of 12) was below 75 copies/mL.

For the three patients whose viral loads did not decline to at least 400 copies/mL, resistance data are available. One person had the L63C mutation, while the other two had the L63A and V77I mutations. One person with double mutations was known to be non-adherent to the medication. There is still no evidence of resistance in the group that has successfully stayed on only Kaletra for as long as two years.

Although Dr. Pierone is enthusiastic about these data, he warns against making any presumptions about Kaletra's use as a monotherapy. “We have to be careful when drawing conclusions from small, retrospective studies with fifteen people. We need large, prospective studies with 100 or 200 people,” said Pierone.

And Pierone will get his wish. Abbott, the company that manufactures the drug, is initiating a large study of Kaletra monotherapy. This trial will explore what is called an induction/maintenance approach to Kaletra use. Volunteers will begin by taking Combivir and Kaletra. Once they have sufficiently suppressed their viral loads (to less than 50 copies/mL for three consecutive months), they will be taken off of Combivir and remain on only Kaletra. If at any time they are failing Kaletra monotherapy, another drug will be added to maintain a suppressed viral load.

The study is designed to follow volunteers for up to 96 weeks and will include 150 people from sites around the world. The Kaletra monotherapy group will be compared with a separate reference group who will receive Combivir and efavirenz, a combination therapy that excludes protease inhibitors, for the duration of the study. Abbott is excited about the recent results and is hoping that this larger trial will reach the same conclusions, but they are careful with their recommendations.

“The monotherapy results from Gathe and Pierone are very promising. We now have a protocol and we're looking to initiate sites globally. We're encouraged that there's a good chance for success, but by no means would I endorse this as a wholesale clinical method,” said Scott Brun, global project head of antiviral development at Abbott Laboratories.

The risk with using only Kaletra is the potential for developing resistance. According to Mike Youle, a physician at the Royal Free Hospital in London, it would be “very unwise” to consider this strategy with the limited data that are currently available. He warns that HIV may become resistant to Kaletra more slowly than other drugs, but that resistance is still possible. Volunteers taking Kaletra as monotherapy therefore need to be monitored very closely for signs of virologic failure, so that they do not develop resistance to the entire class of protease inhibitors.

But if there ever were a drug that could be used as monotherapy, it would be Kaletra, according to Youle. HIV must undergo several mutations before developing resistance to Kaletra, posing a high barrier for the virus to surmount. This is not true for all antiretrovirals. A single mutation can confer resistance to efavirenz, resulting in virus resistant to the entire non-nucleoside class.

“In our clinical trials we haven't seen resistance [to Kaletra] develop. That's not to say that it never will,” said Brun of Abbott. “It's not something you want to go out and do unless you have a really good understanding of the drug,” he added, referring to the monotherapy trial.

Abbott feels confident in its understanding of Kaletra after presenting long-term results of the drug in 100 treatment-naive volunteers. In a poster at EACS (abstract 7.3/16), Abbott reported that after five years, 64% of people taking Kaletra along with stavudine (d4T) and 3TC had undetectable viral loads. Through 252 weeks of follow-up in people whose viral loads rebounded on Kaletra, no protease inhibitor resistance was seen.

Continuing on the road to simplifying the treatment of HIV infection, the 9th EACS highlighted not only new combinations of drugs, but also the reversal of an ideology that has existed since the introduction of HAART. Doctors are now looking at using fewer drugs, instead of adding more drugs on to existing regimens. “The best therapy is less or no therapy,” said Dr. Jose Gatell from the Hospital Clinic in Barcelona.

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