February 28, 2007
The last few years have been very good for patients harboring multidrug-resistant HIV. A flurry of new drugs has been developed for this subset of patients. During the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007), we heard results from many studies involving new antiretrovirals targeted at the multidrug-resistant patient, including studies of the new integrase inhibitor MK-0518 (raltegravir, Isentress) from Merck,1,2 the CCR5 antagonist maraviroc (UK-427,857, Celsentri) from Pfizer3,4 and many other drugs that have recently been approved or are in the process of initiating trials.
Tipranavir (TPV, Aptivus) is a new protease inhibitor (PI) that was approved in June 2005. It is very active against HIV with a significant amount of PI resistance. The Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir (RESIST) trials5 demonstrated that when tipranavir was added to an optimized background regimen, a patient's viral load was more likely to become undetectable.
Unusual pharmacokinetics require that tipranavir be administered with a relatively high dose of ritonavir (RTV, Norvir): 200 mg twice a day. This high dose of ritonavir decreases tolerability to tipranavir, worsens its lipid profile, and multiplies its drug interactions. Other boosted PIs require lower doses of ritonavir. On the other hand, ritonavir-boosted tipranavir is highly active against multidrug-resistant HIV.
Several studies were presented during CROI 2007 that addressed various aspects of tipranavir use.
Anne-Geneviève Marcelin6 presented a study on behalf of the French ANRS Tipranavir Study Group that looked at the mutations associated with protease resistance and subsequent response to tipranavir. The study looked at 143 patients and their antiretroviral response after the initiation of tipranavir in France. The authors developed a new tipranavir score to define resistance to this compound. The new score would consider the presence of any resistance mutations in positions 36, 53, 58, 69 and 89 of the protease gene as indicative of resistance to tipranavir. The authors claim that this score is better than the old one in predicting the response to treatment with tipranavir. However, the main limitation of this study is its retrospective nature and the lack of validation of this score in another cohort of individuals or in the RESIST database. As the use of tipranavir increases, we will be able to better understand the factors that predict its activity against drug-resistant mutants. The key to treating patients with multidrug resistance is the use of at least two new drugs with activity against the virus (by genotype or phenotype characterization).
Juan C. Salazar7 presented results from another tipranavir study -- one that looked at its effects in pediatric patients. Unfortunately, it always takes time to study new antiretrovirals in children. Both investigators and pharmaceutical companies generally feel a little bit leery about using potentially toxic products in kids. This fact leads to significant delays in knowing how to use HIV medications in the pediatric population. Fortunately, during the last few years, the number of new cases of children with HIV in the developed has decreased. However, the surviving children and adolescents who acquired HIV infection vertically usually have a significant amount of antiretroviral resistance.
In this open-label, Pediatric AIDS Clinical Trials Group (PACTG) study, a total of 115 children and adolescents (2 to 18 years old) were randomized to receive high- and low-dose tipranavir for 48 weeks. A total of 26 study sites participated: 10 in the United States, one in Argentina, two in Brazil, two in Canada, three in France, three in Germany, two in Italy, one in Mexico and two in Spain. HIV-infected children and adolescents were enrolled, regardless of prior antiretroviral therapy or HIV resistance status.
In general, tipranavir was well tolerated and exhibited significant antiviral activity in these children. The predictors to get an undetectable HIV viral load by week 48 were the genotypic inhibitory quotient, adherence and baseline viral load.
Tipranavir has very significant interactions with other PIs, and therefore there is a recommendation not to use it in combination with them. In another study on tipranavir that was also presented at CROI 2007, Manoli Vourvahis from the University of North Carolina at Chapel Hill et al8 evaluated the effects of ritonavir-boosted tipranavir on the P450 and P-glycoprotein systems. Ritonavir-boosted tipranavir inhibited P450, especially in the bowel. This inhibition might help us better understand the interaction between tipranavir and other PIs. This was a complicated and, at points, difficult-to-follow study.
In another study, this one presented by Daniel Kuritzkes et al,9 the researchers looked at the issue of sequencing PIs. As antiretroviral regimens become better tolerated and more potent, pharmaceutical companies seem to want their particular product to be used as early as possible. Nobody wants to be the treatment of "last resort."
In this study, the investigators looked at the effects of a particular mutation, V82L/T, on susceptibility to darunavir (TMC114, Prezista), another PI, which was approved in June 2006. Virological rebound on a tipranavir-based regimen has been most commonly associated with the development of the V82L or V82T mutation. Darunavir, like tipranavir, is active against very resistant HIV. Patients who have failed tipranavir often have had genotypic changes that make their virus susceptible to other PIs, including darunavir. Studies like this are extremely important in helping health care providers optimize the sequencing of drugs when treating individuals with multidrug-resistant HIV.
Tipranavir is an important agent for use in the management of patients with multidrug resistance, even if it is not the easiest drug to use and has to be used with caution or not at all in patients who have liver disease. In addition, because tipranavir must be taken with a relatively high dose of ritonavir (200 mg BID) it has been more frequently associated with elevated lipid levels. There have been some reports of intracranial bleeding, but the degree to which tipranavir is responsible for this adverse effect is unknown. A study presented at CROI 200710 looking into this was unable to clarify the issue.
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