AIDSWEEKLY Plus, Monday, 10 November 1997
Daniel J. DeNoon, Senior Editor
Switching to double-protease-inhibitor therapy with ritonavir (Norvir) and saquinavir (Invirase) does not provide long-term HIV suppression for patients who have failed indinavir (Crixivan) therapy.
Data do not prove conclusively that switching to two new protease inhibitors cannot help patients who fail combination therapy that includes a protease inhibitor. But they provide chilling evidence that patients may have only one chance to benefit from the new protease inhibitors.
"Ritonavir plus saquinavir is not recommended for salvage therapy after indinavir," said Steven Deeks of the University of California, San Francisco, in a presentation to the American Society for Microbiology's 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28 to October 1, 1997, in Toronto, Ontario, Canada.
Deeks defined indinavir failure as an HIV viral load of more than 10,000 copies/mL after more than 24 weeks of indinavir treatment or, after the same length of treatment, two viral load assays detecting virus in patients with previously undetectable viral load (lower limit of detection, 500 copies/mL).
Nineteen patients enrolled in the study. Six of these patients had received prior ritonavir and due to evidence of drug resistance had switched to indinavir. Prior to receiving indinavir, the patients had a median CD4 count of 73 cells/(micro)L and a viral load of 4.93 log[10] copies/mL.
All patients switched from indinavir to ritonavir plus saquinavir (each at 400 mg twice daily) as the protease- inhibitor component of combination therapy with nucleoside- analog reverse-transcriptase inhibitors (RTI). At the time of the switch in protease inhibitors, 11 of the 19 subjects switched from zidovudine (AZT) to stavudine (d4T) as well. At this time the patients had a median CD4 count of 169 cells/(micro)L, a median viral load of 4.5 log[10] copies/mL, and a median 53 months of prior RTI therapy.
Undetectable viral loads (<500 copies/ml) occurred in seven of 19 patients at week 4, in three of 19 patients at week 12, and in two of 15 patients at week 24.
A greater than 1 log[10] decrease in viral load occurred in eight of 14 patients at week 4, in four of 13 patients at week 12, and in two of 13 patients at week 24.
"The only two patients to remain at undetectable viral load levels were those who entered the study with undetectable viral load on indinavir that became detectable two times," Deeks said.
The general pattern seen after switching to the double- protease-inhibitor regimen was an immediate drop in viral load that rebounded within 12 weeks.
Mutational analysis of HIV protease typically showed that the rebound in viral load was associated with a V90M mutation.
"There is a trend for patients, as they fail [ritonavir plus saquinavir] to develop mutations at amino acid positions 48 and 90," Deeks said.
One of the two patients with a durable response to the switch developed G48V and V82A mutations after two years of indinavir therapy. After switching to ritonavir plus saquinavir, his viral load remained undetectable for 52 weeks; at this time, a new I54 mutation appeared. The other patient with a durable response had only the V82A mutation.
During a animated question-and-answer session following Deeks' presentation, Martin Markowitz of the Aaron Diamond AIDS Research Center, New York, suggested that Deeks was too hasty in his conclusions.
"You should change your conclusion to say that the 400/400 dose doesn't work," Markowitz said. "Higher doses may work. Since these are the best drugs available for salvage, we should try to raise patients' ritonavir levels."
Deeks replied that a much earlier switch to ritonavir and saquinavir might be an even better salvage regimen.
Roy Gulick of New York University suggested that Deeks might have obtained different results with a different patient population: "Before making sweeping generalizations, it would be helpful to identify populations in which salvage regimens don't work," he said.
Deeks agreed that careful viral load and mutational analysis with a rapid switch of treatments would increase chances of success.
"But in the clinical setting, that is difficult to achieve," he said.
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