Important note: Information in this article was accurate in January 2001. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, January 2001
David Gilden
On September 15, the FDA announced approval of a new HIV drug, Abbott Laboratories' new protease inhibitor formulation, Kaletra.
Providentially for Abbott's marketing department, the agency's announcement came the eve of one of the largest biomedical conferences of the year (the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, or ICAAC). But Abbott's promotional drive has hit a snag as doctors, already burnt by drug-resistance and side-effect problems with other protease inhibitors, wonder when to prescribe this new entry in the antiretroviral drug sweepstakes.
Kaletra capsules contain a combination of 133 mg of the new protease inhibitor lopinavir (formerly known as ABT-378) plus 33 mg of Abbott's old protease inhibitor ritonavir. Normally, three capsules are taken twice a day.
One of ritonavir's side effects is to inhibit the breakdown of drugs by liver enzymes. This is its sole function in the Kaletra combination, since the dose of ritonavir is too low to have much of an anti-HIV effect. Kaletra, then, follows in the tradition of other "ritonavir-enhanced" protease inhibitor combinations. The first of these was ritonavir/saquinavir, both taken twice daily at a dose of 400 mg. Four years ago, the introduction of this combination made saquinavir a viable drug despite its very rapid elimination in the liver.
Adding ritonavir to lopinavir transforms it into a twice-a-day drug, whereas lopinavir ordinarily would start to disappear in about four hours. Abbott says that the added ritonavir in the twice-daily regimen also leads to 50 times higher, stable plasma levels of lopinavir, levels that are 75-fold higher than that needed to suppress normal, "wild-type" HIV by 50% (the EC50 level). At those levels, lopinavir would be able to suppress HIV that contains mutations conferring significant resistance to the drug.
Such claims, based on laboratory tests of lopinavir's effectiveness, are immediately challenged by Hoffmann-La Roche, the maker of saquinavir and Abbott's competitor. Dr. Andrew Hill, Roche's Britain-based International Medical Manager for Fortovase, has argued at two recent scientific meetings that Abbott's figures are heavily distorted. He said, "There is no definitive data that any of the ritonavir-boosted PIs is better than another. In viral load, there is a standard way of testing. For in vitro efficacy, there may never be the standard, and a variety of estimates will exist."
One major issue is that most of the protease inhibitor in the body is bound to blood proteins and is unavailable to cells. The exact proportion varies from 60% to over 99%, depending on the drug, and this effect may not be taken into account in lab tests performed on HIV-infected cell cultures. Roche has now started an initiative to get drug companies to standardize the lab assays that gauge drug effectiveness. Uniform testing would allow better comparisons between drugs.
The ultimate test is how well the various regimens perform in humans, and the data from clinical trials are very positive for Kaletra. In persons without prior treatment, a 653-person Phase III trial compared d4T / 3TC / Kaletra to d4T/3TC/nelfinavir (Viracept). At 40 weeks, 70% of those starting in the Kaletra arm had viral loads under 50 copies/mL whereas 54% in the nelfinavir arm did so. 1 (These figures come from an intent-to-treat analysis that counted as treatment failures those who altered their initial therapy.)
The results were almost as favorable in volunteers whose treatment histories included multiple protease inhibitors. One Kaletra salvage therapy trial enrolled 57 such persons with current viral loads over 1,000 copies/mL.( The trial participants had to have a history of more than three months on at least two different protease inhibitors and yet still be naïve to NNRTIs such as efavirenz (Sustiva). They received efavirenz and Kaletra plus two individually selected nucleoside analogs. All started on a Kaletra dosage of three capsules twice daily (400 mg lopinavir/100 mg ritonavir). After the first two weeks, half added an extra Kaletra capsule (for a total twice-daily dosage of 533 mg lopinavir and 133 mg ritonavir). At the end of 24 weeks, 82% of the people on this higher dose had viral loads below 400 copies/mL, compared to 69% of those on the lower dose. (These data were arrived at through the same sort of intent-to-treat analysis as the one above.)
In this trial, 68% of the volunteers had HIV with cross-resistance to three or more protease inhibitors. The results are taken to show that Kaletra is highly effective drug even in situations where protease inhibitor resistance abounds. On the other hand, the use of efavirenz in these NNRTI-naïve volunteers clouds the issue. Perhaps much of the success was due to the two nucleoside analogs plus efavirenz?
Dr. Eugene Sun, director of antiviral research at Abbott Laboratories, has little patience with this line of reasoning. "We've shown that the response rate depends on the amount of lopinavir resistance, so our drug must be central," he commented last June following a contentious Kaletra presentation at the 4th International Workshop on HIV Drug Resistance. This fall, Abbott also presented further data indicating that the response rate to Kaletra depended on the blood levels of lopinavir achieved relative to the lopinavir resistance present in individual trial participants.3 Still, the doubts about the relative roles of efavirenz and Kaletra are hard to resolve because this trial had no comparison arm that did not receive Kaletra.
Many doctors prefer starting therapy with an efavirenz-containing regimen, which is a known quantity, rather than tempt fate with Kaletra, which they regard as uncharted territory. Dr. Mike Para, an HIV researcher at Ohio State University Medical Center in Columbus, said "I prefer to use non-nukes [NNRTIs] in initial therapy because they require fewer pills and are better tolerated. I want to save Kaletra for PI failures and NNRTI failures who also have resistance mutations for nucleoside analogs. Kaletra would be good if you don't feel comfortable that the nukes work as well as they should [in a particular patient]."
Part of doctors' fear of Kaletra is a lack of data about the frequency of the development of Kaletra-resistant HIV and the genetics behind that resistance. For this reason, they tend to look at it as a last-ditch agent to use when other drugs have failed. "Kaletra is a potent drug, but I don't know what I can replace it with if a patient has viral rebound," said Dr. Howard Grossman, an HIV specialist in New York City.
There is little information about lopinavir-resistant HIV in humans. Abbott has documented the development of some sort of drug resistance in 20 Kaletra trial participants who experienced HIV rebound while on Kaletra. (This analysis did not include anyone from the large nelfinavir versus Kaletra trial in treatment-naïve adults.) Of these 20, 15 (including two treatment-naïve individuals) had HIV that acquired resistance mutations to two other drugs in the regimen - 3TC and nevirapine or efavirenz. This development was associated with poor compliance in seven persons and with a high number (six to nine) of baseline protease mutations in the other eight. The protease mutations conferred broad protease inhibitor cross-resistance, including to lopinavir, apparently.4
In just five persons was there any sign of evolving lopinavir resistance during therapy. Four of these five could be further analyzed. The loss of susceptibility to lopinavir was associated with continued or new resistance to indinavir, ritonavir, nelfinavir and, in two of the cases, amprenavir.
When looking at the total pool of 13 persons with either baseline or acquired resistance to lopinavir, Abbott could find no definite pattern here, either. Its researchers associated lopinavir resistance with a number of the standard HIV mutations that confer resistance to other protease inhibitors. The company analysis indicated that lopinavir failure was associated with the total number of mutations in the protease gene as well as with inability to include effective nucleoside analogs that would give lopinavir support in suppressing HIV replication. Based on an analysis of the persons in the multiple-PI failure trial, Abbott says the chance of lopinavir failure reaches 50% when the number of protease mutations is about six.5
Still, certain common single mutations (at protease amino acids 20, 53, 54 and 82) are particularly troubling for lopinavir. A combination of just two of them could confer a ten-fold or more loss in susceptibility to lopinavir. These mutations could also spell broad cross-resistance to succeeding protease inhibitors. In three people with lopinavir-resistant HIV, Abbott researchers did find some continuing viral sensitivity to amprenavir and saquinavir in lab assays. Protease inhibitor rescue after lopinavir failure may require a protease inhibitor of radically different design, such as Boehringer Ingelheim's tipranavir, which is still in Phase I testing.
In the past year, there has been a markedly increasing tendency for doctors to prescribe ritonavir-enhanced regimens that include indinavir, saquinavir or amprenavir. In the past, Abbott has tested and recommended regimens involving 400 mg of ritonavir and 400 mg of either indinavir or saquinavir. Merck and Roche, these latter two drugs' manufacturers, have lately tested reduced doses of ritonavir - 100 or 200 mg - with higher doses of their own drugs - 800 mg for indinavir and up to 1600 mg for saquinavir - in once- or twice-daily regimens. An ongoing French study is comparing a particularly low-dose, inexpensive combination that contains just 400 mg of indinavir and 100 mg of ritonavir taken twice- a-day.
Other researchers have tested 100 mg of ritonavir twice daily in combination with 600 mg of Glaxo's protease inhibitor amprenavir. In all cases, adding the ritonavir stabilizes the other PI in the body to the extent that total pill burdens are reduced as well as dosing schedules. In the case of indinavir/ritonavir, even Abbott agrees that trough levels of indinavir are raised to about 25 times the EC50 for the 800/100 indinavir/ritonavir combination.6
Ritonavir itself has a host of side effects, including increased blood lipids, taste perversion, stomach upset and numbness around the lips and other areas. These days, it is prescribed only occasionally as a single protease inhibitor at the full 600 mg dose. Lowering the traditional 400 mg dose used in ritonavir -enhanced PI regimens to only 100 or 200 mg further reduces ritonavir's toxicities. But Dr. Keith Henry, who heads the HIV salvage therapy clinic of Regions Hospital in St. Paul, MN noted, "People on ritonavir still have some problems with it, but the dose is lower than what they were on. For ritonavir virgins, even the low end is a jolt, but it's not as bad as what used to happen."
With the introduction of the 400 mg lopinavir/100 mg ritonavir combination, Abbott itself seems to have bought into the argument for ritonavir "minidosing." Still, Henry complains, "This is the first time that we've had ritonavir enhancement built in. So the data are cleaner as there is no need to establish intercompany cooperation. But I don't know how unique lopinavir plus ritonavir is. Comparison trials do not seem to be getting done."
Various trials have tested other ritonavir-enhanced regimens through the years. One recent such trial tried saquinavir/ritonavir at a twice-daily dose of 1000 mg/100 mg plus efavirenz and two nucleoside analogs in 32 persons.7 On enrollment, the volunteers were all failing their first protease inhibitor-containing regimen, with baseline viral loads over 5,000 copies/mL. They all also had never taken saquinavir or any NNRTI. At week 48, 56% had viral loads below 50 copies/mL. Last September, preliminary results from an indinavir/ritonavir salvage therapy trial were presented at the ICAAC.8 The 72 trial participants all had previously received indinavir and had "failed" at least one PI-containing regimen. In the trial, they received indinavir/ritonavir twice daily at doses of 800 mg /200 mg (47 volunteers) or 400 mg/400 mg (25 volunteers). They also received supporting nucleoside analogs and, in two-thirds of the cases, NNRTIs. At 12 weeks, 24 of the 44 volunteers (55%) on the 800/200 regimen with results available had viral loads under 400 copies/mL compared to 8 of 24 (33%)on the 400/400 combination.
This indinavir/ritonavir study has the merit of comparing different doses of the combination. Without any agreement on how much ritonavir or the other drugs to use, it is difficult to evaluate any of the results. It is also hard to run the head-to-head trials with Kaletra that doctors are calling for.
Hoffman-La Roche is proceeding with one 300-person, one-year trial comparing 1000 mg saquinavir/100 mg ritonavir, Roche's favorite version of the combination, to 800 mg indinavir/100 mg ritonavir, both twice daily, in treatment-naïve and -experienced volunteers. That trial, with 40 sites in Europe, South America and the United States, is now enrolling. A similar trial testing the same saquinavir/ritonavir regimen against the standard Kaletra dose is in the planning stages.
Abbott does have one cohort of treatment-naïve individuals who have taken Kaletra for two years. The cohort, which started with 100 volunteers and now numbers 86, has been remarkably stable. Nearly all (92%) of the remaining members have viral loads below 50 at week 96, making for a 78% success rate by intent-to-treat standards. Side effects have been low, with loose stools or diarrhea in a quarter of the group being the most common problem. High cholesterol levels occurred in 14 of the 100 and high blood triglycerides in 12.
Trial cohorts frequently do not reflect the population as a whole. Keith Henry worried, "It's just a matter of time to see Kaletra-specific side effects - we don't know what yet." Other doctors are convinced that they are already seeing increases in blood lipids tied to the lopinavir rather than the ritonavir. In the end, "we don't know yet" sums up the medical community's view of Kaletra. Four years ago, Abbott's ritonavir crashed in the real world as a stand-alone protease inhibitor despite impressive trial data. Patients found its gastric and other side effects intolerable. Further experience with Kaletra will decide this drug's ultimate popularity, too.
1. Walmsley S et al. Efficacy of ABT-378/r vs Nelfinavir (NFV) in Antiretroviral (ARV)-Naïve Subjects: Results of a Phase III Blinded Randomized Clinical Trial. 40th ICAAC September 17-20 2000, slide presentation 693.
2. Becker S et al. ICAAC ABT-378/ritonavir (ABT-378/r) and Efavirenz: 24 Week Safety/Efficacy Evaluation in Multiple PI Experienced Patients. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20 2000, slide presentation 697.
3. Hsu A et al. Trough Concentration-EC50 Relationship as a Predictor of Viral Response for ABT-378/Ritonavir (ABT-378/r) in Treatment-Experienced Patients. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20 2000, poster 1660.
4. Kempf DJ et al. Definition of Genotypic Breakpoints for ABT-378/Ritonavir (ABT-378/r) for Use in the Interpretation of HIV Resistance Testing. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20 2000, poster 1264.
5. Kempf D et al. Genotypic Correlates of Reduced In Vitro Susceptibility to ABT-378 in HIV Isolates from Patients Failing Protease Inhibitor Therapy. 4th International Workshop on HIV Drug Resistance and Treatment Strategies, June 16-20 2000, oral presentation 38.
6. Benson C et al. Two Year Follow-Up of ABT-378/Ritonavir (ABT-378/r) in Antiretroviral Naïve HIV+ Patients. 40th ICAAC, September 17-20 2000, poster 546.
7. C. Piketty et al. Phenotypic Resistance to Protease Inhibitors in Patients Who Fail on Highly Active Antiretroviral Therapy Predicts the Outcome at 48 Weeks of a Five-Drug Combination Including Ritonavir, Saquinavir and Efavirenz. AIDS 2000 Mar 31;14(5):626-8.
8. Grossman H et al. Response with Twice Daily (BID) Crixivan® plus Norvir® Based Regimen (IDV-RTV) in Patients (pts) Failing Protease Inhibitor (PI) Therapy. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20 2000, poster 545.
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