Guidance offered in drug combination choices
Regimens with few pills making compliance easier
The development of more new antiretrovirals, including two protease inhibitors and a non-nucleoside reverse transcriptase inhibitor, adds to the daunting choices for combination therapy. At the same time, however, clinicians and patients can make wiser treatment decisions by evaluating the most recent comparative trials as well as considering the risks of resistance and noncompliance, say AIDS experts.
"We are beginning to develop data that tells treaters and patients that if you pick a potent set of double nucleosides whether it’s zidovudine [AZT] and lamivudine [3TC], stavudine [d4T] and 3TC, or d4T and didanosine [ddI] and combine it with an active protease inhibitor, you are going to get similar results," says Joseph Eron, MD, assistant director of the HIV/AIDS Research Unit at the University of North Carolina in Chapel Hill. "That gives us some more options and more confidence."
Eron recently joined a panel of experts for a symposium at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto for putting the new federal HIV treatment guidelines into action. He presented preliminary data from the first direct head-to-head comparison studies of triple combinations, prior to which they were compared to monotherapy or two-drug therapy.1,2
The studies enrolled nearly 300 drug-naive patients with CD4 counts of 200 and viral loads of 10,000 cells. After 24 weeks of therapy, the studies showed that the three combinations AZT/3TC/indinavir, d4T/3TC/indinavir, and d4T/ddI/indinavir were equally effective and well-tolerated, Eron tells AIDS Alert.
"We only have data out to 24 weeks, but when you see the curves of the proportion below detectable virus, they are superimposable," he says. "We need to see data over at least a 48-week period to say these medicines actually are comparable, but it gives treaters and patients options."
One of the more interesting findings of the studies was the efficacy of the d4T/ddI/indinavir combination, because it is difficult to take, requiring separate dosing on empty stomach for ddI and indinavir, Eron says. Patients, however, had doses of ddI reduced to once daily a reduction that has been shown in other recent studies of d4T plus ddI to be safe and effective.
The approval of 11 antiretroviral drugs, with more in the pipeline, may be providing too many treatment options, some clinicians say. How to choose among the numerous possible combinations is growing more difficult, they explain, not unlike choosing the best antibiotic. With the lack of hard, long-term data, the deciding factor often becomes marketing, they add. Whatever the initial success of a combination, clinicians and patients should be prepared for drug failure and the need to switch drugs.
"The current triple-drug regimens have been impressive in driving HIV below detectable levels, but the failure rate hovers around 10% to 20% for patients without prior treatment," said Calvin Cohen, MD, research director of the Community Research Initiative of New England during the symposium. "Thus, Plan B’ is essential. In selecting initial and subsequent therapies, the clinician must consider such factors as resistance and the patient’s ability to take medications as prescribed, as the sequencing of antiretroviral therapy can preserve or limit future therapeutic options."
Eron and other AIDS clinicians say most patients place tolerability as a top priority, and note that some regimens are more easy to take than others. The AZT/3TC/indinavir combination, for example, had twice as many patients discontinue the study compared to the other two combinations. Although the AZT/3TC/indinavir combination had slightly more adverse events than the other two combinations, the recent approval of Combivir a single tablet combining AZT and 3TC could be a significant factor in making a decision, Eron adds. For patients taking d4T/ddI/indinavir, the difficult regimen requirement may account for why eight of 156 patients discontinued. D4T/3TC/indinavir is emerging as a popular choice because it has so few side effects, Eron says, but he also notes that d4T can cause neuropathy problems.
Resistance theories remain untested
Resistance is another consideration when choosing among triple-drug combinations. However, the impact of resistance patterns on treatment is theoretical and hasn’t been demonstrated in clinical trials, Eron cautions. Knowledge about resistance profiles suggests, for example, that a patient starting on ddI can receive added benefit after switching to 3TC, but starting with 3TC may diminish the subsequent effectiveness of ddI, panel members noted. The same problem may occur if starting a patient on d4T-combination regimen and, after failure, switching to an AZT-combination regimen. "Because of high-level resistance to AZT, maybe d4T is not quite as good a drug in that situation, but that hypothesis has not been tested," Eron says.
Since the new guidelines were issued this summer, results from studies of ongoing triple-drug combinations have solidified the consensus for offering triple-combination therapy to patients as initial treatment. Evidence of that consensus was illustrated by the symposium audiences’ response to a case study of a 25-year-old, HIV-positive male who was drug-naive. More than three-quarters (77%) of attendees recommended triple-drug therapy. And yet the consensus breaks down when choosing which three drugs. While the most popular combination was AZT and 3TC plus a protease inhibitor, 68% chose other combinations, such as d4T and 3TC plus a PI (26%) and d4T and ddI plus a PI (17%).
Another promising triple-drug combination that complicates the picture is the use of two nucleoside analogues in combination with a on-nucleoside reverse transcriptase inhibitor (NNRTI), such as nevirapine (Viramune), the investigational drug efavirenz, or DMP 266 (Sustiva). In a Phase III study presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection in Hamburg, Germany, researchers reported that a combination of efavirenz plus AZT and 3TC produced significant reductions in HIV RNA. After 16 weeks of therapy, 88% of the 245 patients who took 600 mg doses of efavirenz achieved undetectable viral load. Their CD4 count increase averaged 240 cells.
The drug’s manufacturer, Dupont Merck of Wilmington, DE, announced in September that efavirenz plus indinavir in patients with moderate HIV disease (CD4 counts between 100 and 500, and viral load greater than 20,000) reduced viral load below detectable levels in 68% after 48 weeks of therapy.
"This confirms and extends earlier presentations showing a profound lowering and maintenance of viral load, as well as an elevation of CD4 counts in patients who take this two-drug combination," says Paul Friedman, MD, president of Dupont Merck Research Laboratories, adding that the drug requires only one dose a day.
Recent data on the only FDA-approved NNRTI, nevirapine, showed that combining the drug with AZT and ddI reduced HIV RNA levels below detection in more than 50% of drug-naive patients after 52 weeks of treatment.
With both NNRTIs having good efficacy in triple-drug combinations, the advantage of one over the other may depend on their resistance patterns and side effects. Friedman tells AIDS Alert that efavirenz develops a mutation at K103n when given as monotherapy, even at dosages of 600 mg. However, there was no evidence of a mutation at Y181c, which is the codon at which nevirapine mutates. He also points out that only 2% of patients in the efavirenz study develop skin rashes. Reports of moderate to severe rashes for patients in some nevirapine studies have been more than twice that rate.
Dupont Merck plans to submit the drug for FDA approval this spring for use in combination with protease inhibitors or nucleoside analogues. It has trials planned for combining efavirenz with the protease inhibitor indinavir.
Vertex Pharmaceuticals of Cambridge, MA, also presented data at the Hamburg conference on its new protease inhibitor, 141W94 (VX-478), which is entering Phase III trials. In combination with AZT and 3TC, the drug brought viral loads to undetectable levels (400 copies) in 70% of patients after 12 weeks. The drug is a second-generation protease inhibitor that is being developed worldwide by Glaxo-Wellcome.
Defining failure
As the science of treating patients with the right sequence of combinations becomes perfected, one issue that must be more clearly addressed is how to define drug "failure."
While many researchers have defined it as an increase in viral load of one log or more, others are questioning whether viral load should be the sole criterion, Eron says.
"The word failure’ puts a lot of weight on patients and clinicians," he says. "So I think it’s important we carefully evaluate virologic failure." He mentions at least one prominent AIDS researcher who believes CD4 count should also be figured into the failure equation.
"Someone who has a 200 CD4 cell increase feels clinically better and goes back to work, and then has detectable virus at a low level. Is that failure?" he asks. "It’s virologic failure, but it may be that person had good clinical results."
John Bartlett, MD, chief of infectious disease at Johns Hopkins University, argues that widespread reports that up to half of patients on combination therapy may be failing their regimens are misleading and harmful.
"There is a relatively high rate of failure, but that is being misinterpreted by people as meaning the patients aren’t doing well," he explains. "The patients by and large are doing great; they just haven’t achieved the very rigid criteria we have for success vs. failure. We have put the bar you have to jump over awfully high."
References
1. Gulick R, Santana J, Squires R, et al. A 15-site open-label, randomized, comparative study of stavudine + lamivudine + indinavir versus zidovudine + lamivudine + indinavir in treatment naive HIV-positive patients. Presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV-infection. Abstract # 433. Hamburg, Germany; October 1997.
2. Murphy R, Pottage J, Peterson D, et al. A 15-site open-label, randomized, comparative study of stavudine + didanosine + indinavir versus zidovudine + lamivudine + indinavir in treatment naive HIV-positive patients. Presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV-infection. Abstract # 434. Hamburg, Germany; October 1997.
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