 |
|
|
| |
Lopinavir/Ritonavir Monotherapy as an Antiretroviral Stopping Strategy
|
| |
| |
10th International Workshop on Clinical Pharmacology of HIV Therapy
April 15-17, 2009
Amsterdam
Mark Mascolini
Several trials have scrutinized lopinavir/ritonavir monotherapy as a simple maintenance or first-line antiretroviral regimen [1]. Now British clinicians and pharmacologists proffer a different reason for giving lopinavir/ritonavir with no other antiretrovirals--as a way to take people off their antiretroviral regimen without running the risk of resistance [2]. Steve Taylor (Birmingham Heartlands Hospital) and colleagues at other centers call it "a universal ART stopping strategy."
Stopping all antiretrovirals in a regimen at the same time can be risky when some of the constituent drugs have substantially longer half-lives than others. With nonnucleosides, tenofovir, and emtricitabine in wide use, Taylor observed, chances are good that many current regimens are unbalanced when the half-lives of their individual drugs are compared. When a person stops all drugs in an "unbalanced" regimen at the same time, levels of a drug with a long half-life can persist in the circulation and result in functional monotherapy. Stopping a regimen completely may be necessary because of toxicity or development of a non-HIV illness. Women who took antiretrovirals during pregnancy to avoid transmitting the virus to their newborns may want to stop after delivery if they don't need to continue treatment for their own health.
To avoid the risk of resistance with functional monotherapy, Taylor proposes switching everyone to twice-daily lopinavir/ritonavir for 4 weeks after they stop their regimen. The rationale for substituting lopinavir/ritonavir monotherapy is the same with this strategy as it is for lopinavir/ritonavir monotherapy for maintenance: The two drugs potently inhibit HIV replication in people whose virus is susceptible to these PIs, and they have a high barrier to resistance [1].
This pilot study involves 20 people so far, 12 of them taking regimens whose elements had "unbalanced" half-lives. Everyone replaced their current regimen with two lopinavir/ritonavir tablets twice daily, aiming to continue for 4 weeks. Taylor measured blood levels of drugs in the stopped regimen weekly until they were undetectable and measured lopinavir concentrations at weeks 1 and 4. He monitored viral load 1, 2, 3, 4, and 8 weeks after stopping the original regimen.
Among 17 people with a viral load below 200 copies when they started lopinavir/ritonavir, 14 were under 40 copies/mL after taking 4 weeks of monotherapy with the protease inhibitors (PIs). Three people had a viral load above 200 copies when they started lopinavir/ritonavir--at 353, 90,288, and 128,789 copies. After 4 weeks of lopinavir/ritonavir, those loads stood at 131, 1263, and 282 copies/mL. Viral load rebounded in all 12 people who have stopped their lopinavir/ritonavir after 4 weeks.
Median lopinavir concentrations remained above 1000 ng/mL in all but 2 measurements in 2 people with suspected nonadherence.
⋅ Week 1: 7368 ng/mL (range 227 to 14,152)
⋅ Week 2: 7324 ng/mL (range 733 to 14,049)
⋅ Week 3: 6996 ng/mL (range 2080 to 11,989)
⋅ Week 4: 6334 ng/mL (range 1231 to 13202)
At the time of this report, 7 of 12 people who swapped an "unbalanced" regimen for lopinavir/ritonavir had detectable levels of one or more drugs in their discontinued regimen more than 1 week after stopping it. No new resistance mutations have evolved in any patient, probably because lopinavir/ritonavir is controlling viral replication--often better than the replaced regimen.
Taylor proposed that "the pharmacological protection provided by a drug [lopinavir/ritonavir] with a high genetic barrier to resistance should prevent the development of resistant viruses at a time when the stopped drug concentrations fall through the zone of resistance selection."
Of course this strategy is feasible only for people with virus susceptible to lopinavir/ritonavir, and it would not be an option for people who have to stop all antiretrovirals immediately.
References
1. Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. 2009;23:279-291.
2. Taylor S, Fisher M, Jayasuriya A, et al. Kaletra single agent therapy as a universal ART stopping strategy: the STOP 2 study. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_17.
|
| |
|
|
|
|
|
