Editorial Comment: Impact of Darunavir for Salvage Therapy

Most HIV clinicians can easily recall the frustration and dismay they felt when trying to construct a salvage antiretroviral regimen for a patient with significant antiretroviral resistance. Such a regimen was essential to stave off HIV disease progression and death, but the cross-resistance associated with the antiretroviral agents usually used in salvage regimens meant that complete suppression of viral replication was close to impossible to reestablish. The best hope was only for a modest degree of viral suppression brought about through some limited drug activity and the presence of antiretroviral resistance mutations associated with reduced fitness.

When successful, these partially suppressive salvage regimens would result in a stabilization of the patient's falling CD4⁺ cell count or, at times, a gain in CD4⁺ cells that pulled the patient out of a high-risk category. Unfortunately, however, these regimens proved to be either unsuccessful or not durable in many patients and, even in those with persistent CD4⁺ stabilization or recovery, often led to a further accumulation of resistance mutations, making the construction of a subsequent active regimen even more difficult, if not impossible.^1,2

The excellent review article by Taiwo and Hicks³ discusses the most recently approved protease inhibitor (PI) darunavir, an important new drug in the treatment of highly antiretroviral-experienced patients. As these authors point out, darunavir has some unique characteristics that allow it to be active in patients with significant resistance to other PIs. As demonstrated in the POWER studies, the availability of darunavir should allow for the construction of an effective antiretroviral regimen for many patients
despite extended periods of antiretroviral exposure and high-grade antiretroviral resistance.^4,5 With the introduction of antiretrovirals such as darunavir, complete viral suppression is now a plausible treatment goal for all persons with HIV infection, even for those who harbor highly drug-resistant virus.

Of course, there are some caveats. First, some patients with very high-grade PI resistance (ie, 9 or more PI mutations or, of more consequence, 4 or more darunavir-specific mutations) may have minimal response to darunavir.⁶ Fortunately, there is sufficient understanding of the predictors of response to darunavir that the selection of this PI can be appropriately made on the basis of resistance testing, which will indicate when darunavir is likely to be effective.

Second, darunavir should be combined with at least 1 other active antiretroviral agent to be the most effective. The robust genetic barrier of this PI, when boosted with ritonavir, to maintain partial viral suppression is an impressive and important feature, but even though the POWER studies have shown boosted darunavir to be effective in some patients who had no other active drugs in their antiretroviral regimen, the best results have been obtained when this boosted PI is used in combination with other active agents, especially when it is combined with enfuvirtide in enfuvirtide-naive patients.^4,5,7

Fortunately, even if the patient now has no active drug options among the currently FDA-approved agents, the list of possible agents to combine with darunavir continues to expand, with a number of drugs in or approaching expanded access, including the CCR5 antagonist maraviroc, the integrase inhibitor MK-0518, and the second-generation NNRTI etravirine (also known as TMC125), in addition to other drugs available through clinical trial enrollment.

Encouraging preliminary data indicate that a regimen containing both darunavir and etravirine in heavily antiretroviral-resistant patients is particularly effective. In a pilot study, 10 patients with substantial resistance to all 3 traditional antiretroviral classes were treated with a regimen of darunavir, etravirine, and 2 or more NRTIs.⁸ At 12 weeks, all patients had achieved an HIV RNA level below 400 copies/mL and a decrease of at least 2 log10 copies/mL, with 8 of the patients achieving an HIV RNA level below 40 copies/mL. This strategy is currently being explored in larger trials.

Finally, it is important to be aware of a few other aspects of darunavir. As discussed by Taiwo and Hicks, in addition to its activity, darunavir appears to be very well tolerated and to have limited toxicity-characteristics that are critical for patients to maximize and maintain their adherence to treatment. Second, the risk of hepatotoxicity and lipid disturbances with darunavir appears to be less than that associated with many of the first-generation PIs as well as with tipranavir.^4,5 Third, while darunavir is currently indicated in patients with high-level antiretroviral resistance, the characteristics of darunavir suggest that it may also have a potential use in initial therapy, and studies are ongoing to evaluate this strategy.

In summary, the availability of darunavir and other new antiretrovirals is likely to lead to a paradigm shift in the treatment approaches of most clinicians. As recently stated in the Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, "The goal of treatment for patients with prior drug exposure and drug resistance is to re-establish maximal virologic suppression."9 The days of routinely accepting the presence of viremia in heavily treatment-experienced patients are increasingly behind us, at least for our patients who are able to take and tolerate ritonavir-boosted darunavir.

Brian A. Boyle, MD
Associate Professor, Department of International Medicine and Infectious Diseases (Courtesy)
New York Presbyterian Hospital-Weill Medical College of Cornell University, New York

Calvin J. Cohen, MD
Research Director, Community Research Initiative of New England, Springfield, Mass
Clinical Instructor, Harvard Medical School, Boston

Dr Boyle reports having received grant or research support from Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Tibotec; speaking fees from Bristol-Myers Squibb and Gilead Sciences; and honoraria from Bristol-Myers Squibb and Gilead Sciences. Dr Cohen reports having received grant or research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Roche Laboratories, and Virco Laboratories; speaking and consulting fees from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Roche Laboratories, and Virco Laboratories; and honoraria from all of the above. No other potential conflicts of interest relevant to this editorial comment were reported.

References:

References1. Deeks SG, Barbour JD, Grant RM, Martin JN. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS. 2002;16:201-207.
2. Hatano H, Hunt P, Weidler J, et al. Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen. Clin Infect Dis. 2006;43:1329-1336.
3. Taiwo BO, Hicks CB. Darunavir: an overview of an HIV protease inhibitor developed to overcome drug resistance. AIDS Reader. 2007;17:151-156, 159-161.
4. Katlama C, Carvalho M, Cooper D, et al. TMC 114.r outperforms investigator selected PIs in 3-class-experienced patients: week 24 primary analysis of POWER 1 (TMC 114-C213). 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro. Abstract WeOaLB0102.
5. Wilkin T, Haubrich R, Steinhart CR, et al. TMC114/r superior to standard of care in 3-class–experienced patients: 24-wks primary analysis of the Power 2 study (C202). 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2005; Washington, DC. Abstract H-413.
6. De Meyer S, Vangeneugden T, Lefebvre E, et al. Phenotype and genotype determinants of resistance to TMC114: pooled analysis of POWER 1, 2, and 3. XV International HIV Drug Resistance Workshop; July 13-17, 2006; Sitges, Spain. Abstract 73.
7. Hill A, Moyle G. Relative week 48 antiviral efficacy of TMC114/r and tipranavir/r versus control PI in the POWER and RESIST trials. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco. Abstract H-1386.
8. Boffito M, Winston A, Fletcher C, et al. Pharmacokinetics and ART response to TMC114/r and TMC125 combination in patients with high-level viral resistance. 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver. Abstract 575c.
9. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Revised October 10, 2006. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 12, 2007.