Editorial Comment: A Plethora of Options in Multidrug-Resistant HIV-1 Infection

Although more than 20 years of antiretroviral therapy use has resulted in the selection of multidrug-resistant (MDR) HIV-1, new drugs in the traditional and newer antiretroviral drug classes provide an increasing range of options for the effective treatment of HIV-1 infection. While the protease inhibitor (PI) darunavir combined with low-dose ritonavir (DRV/r) appears to be the basis for a very active boosted PI regimen, the best way to combine the additional drugs and classes in treatment regimens for PI- and NNRTI-experienced patients remains poorly defined. The knowledge base of pharmacological interactions between drugs from the NNRTI class and DVR/r is scant. Further analysis of the DUET studies was recently presented at this year's International AIDS Conference.^1,2 The latest results from these pivotal trials continue to demonstrate that an antiretroviral regimen of boosted darunavir given with an optimized background and the second-generation NNRTI etravirine provides new options in the treatment of MDR HIV-1 infection.

Crafting an effective regimen for the treatment of MDR HIV-1 infection including a boosted PI, an NNRTI, and an NRTI combination, such as tenof­ovir/ emtricitabine or abacavir/lamivudine, can be a daunting challenge given the paucity of information on the potential pharmacokinetic drug-drug interactions, adverse effects, and interpretation of drug resistance test results. With respect to new approaches to MDR HIV-1, the DUET genotypic data reported by Haubrich and colleagues1 provide evidence for virological response rates greater than 67% to DRV/r and etravirine among patients with 3 or fewer darunavir or etravirine resis­tance-associated mutations (RAMs) and less consistent but encouraging response rates of 29% to 65% among patients with up to 6 (combined) darunavir or etra­virine RAMs.

Rawizza and Sax³ present current examples of the choices and conundrums in the treatment of patients with high levels of drug resistance after long and checkered histories of antiretroviral therapy. They pose an important question: what is the appropriate dosing of the first-line NNRTIs, efavirenz and nevirapine, when given with DRV/r in persons with MDR HIV-1 infection? To address this issue, they reviewed the data provided from studies of normal volunteers (HIV-1–uninfected persons). Although most of the interactions between DRV/r and efavirenz or nevirapine increase the NNRTI and darunavir plasma drug levels, the data available sound a note of caution in that interactions may also result in a modest increase in efavirenz levels (and hence, a risk of CNS toxicity) as well as a slight decrease in darunavir levels.

Of the 3 cases presented by Rawizza and Sax, their third patient, who was treated with a combination of DRV/r, etravirine, tenofovir/emtricitabine, and the integrase inhibitor raltegravir, provides a glimpse of the future for treating persons with MDR HIV-1 infection.⁴ For patients with successfully suppressed MDR HIV-1 infection who have required the parenterally administered entry inhibitor enfuvirtide to be included in their drug regimen, raltegravir has been successfully substituted with sustained suppression.⁵ The results from community-based studies of patients with MDR infection have demonstrated the potency of the integrase inhibitor class. When this new class of antiretroviral drugs has been incorporated into a drug regimen, patients have achieved greater than 90% virological suppression.⁶ Both elvitegravir,⁷ an investigational integrase inhibitor currently in clinical trials, and raltegravir are very likely to be effectively combined with a boosted PI and an optimal NNRTI to offer a relatively simple oral regimen for patients who have exhausted previous generations of drugs and now have extensive resistance. Understanding and using drug-drug interactions among agents from the traditional and new antiretroviral drug classes can help minimize drug-related toxicity and achieve long-term, tolerable viral suppression in our most drug-experienced patients.

David A. Katzenstein, MD
Professor of Medicine
Division of Infectious Diseases
Stanford University
Stanford, Calif
 

References 1. Haubrich R, Schapiro J, Vingerhoets J, et al. Combined darunavir (DRV) and etravirine (TMC125; ETR) resistance analysis of the pooled DUET trials: when can we spare the other new classes? 17th International AIDS Conference; August 3-8, 2008; Mexico City. Poster TUPE0048.
2. Cahn P, Molina JM, Towner W, et al. 48-week pooled analysis of DUET-1 and DUET-2: the impact of baseline characteristics on virological response to etravirine (TMC125; ETR). 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract TUPE0047.
3. Rawizza HE, Sax PE. Pharmacokinetic interactions between ritonavir-boosted darunavir and NNRTIs: a report of 3 cases. AIDS Reader. 2008;18:466-472, 478-479.
4. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of virologic success with raltegravir plus etravirine and darunavir/ritonavir in treatment-experienced patients with multidrug-resistant virus: results of the ANRS 139 TRIO trial. 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract THAB0406.
5. Talbot A, Machouf N, Thomas R, et al. Retrospective analysis of a switch from enfuvirtide to raltegravir in patients with undetectable viral load: efficacy and safety at 12 weeks in a Montreal Cohort. 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract TUPE0112.
6. Mounzer K, Smith S, Ondercin J, et al. Combination antiretroviral treatment (CART) with darunavir/ritonavir (DRV/r) and raltegravir (RAL) in patients with multidrug resistant (MDR) HIV-1 infection in a community-based setting through an expanded access protocol (EAP). 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract CDB0202.
7. Zolopa AR, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 has potent antiretroviral activity in treatment-experienced patients. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 143LB.

Dr Katzenstein reports receiving research grants and serving on advisory boards for Bristol-Myers Squibb, GlaxoSmithKline, Merck, Abbott, Roche, and Gilead.