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Too Many Options?

We asked three experts which antiretroviral regimen they would recommend next for a patient with triple-class resistance and low-level viremia — and got three different answers.

A 45-year-old man with long-standing HIV infection was referred for a second opinion about antiretroviral therapy options. For the previous 5 years, he had been taking abacavir, 3TC, and lopinavir/ritonavir. Despite viral loads between 200 and 1000 copies/mL, he had remained clinically stable, with a CD4 count of 500 to 600 cells/mm³. Before starting this regimen, he had a resistance test that demonstrated NRTI, NNRTI, and PI resistance. On several occasions since then, his viral load has been too low to allow for additional resistance testing. Most recently, however, his viral load increased to 1100 copies/mL, and a specimen was sent for phenotype, genotype, and tropism testing. The following results returned.

NRTI genotype: 41L, 67N, 210W, 215Y, 219E, M184V

Phenotype: sensitive to abacavir (4-fold change in susceptibility, compared with wild-type virus), ddI (1.2-fold change), d4T (1.4-fold change), and tenofovir (1.3-fold change)

NNRTI genotype: 103N, 108I

Phenotype: sensitive only to etravirine (0.5-fold change)

PI genotype: 10F, 20M, 24I, 33F, 36I, 46I, 54V, 63P, 71V, 84V

Phenotype: sensitive only to darunavir (8-fold change)

Tropism testing: CCR5-tropic virus

The patient has never taken enfuvirtide, darunavir, maraviroc, raltegravir, or etravirine; he took tenofovir (with other agents) for 2 years between 2001 and 2003. His medication adherence has been excellent. His CD4 count is currently 490 cells/mm³.

How many active drugs would you prescribe? Which specific agents would you use, and why? Would you include NRTIs? Why or why not?

Response 1

— Sharon Walmsley, MD

Current guidelines indicate that the goal of HIV treatment is viral suppression to <50 copies/mL, even in patients with extensive antiretroviral experience. For this particular patient, achieving that goal will require at least two active drugs. Beyond that, the number of drugs is not as important as the selection of a maximally suppressive regimen.

Given the multiple NRTI mutations seen in this patient’s virus, NRTIs are unlikely to contribute significant antiviral activity to his next regimen and would likely contribute only to toxicity. The first-line NNRTIs nevirapine and efavirenz also would not be active, but the second-line NNRTI etravirine should be, because this drug is only minimally impaired in the presence of the K103N mutation. The PI-associated mutations observed will compromise most of the first-line agents in this class, leaving ritonavir-boosted darunavir as the optimal choice. This drug is likely to be fully active, given that the phenotype shows only an 8-fold change in susceptibility relative to wild-type virus, and the genotype shows only two resistance-associated mutations. Among the newer drug classes, maraviroc should be fully active (given the tropism test results) and so should enfuvirtide and raltegravir (because this patient has never received either).

I would begin constructing this patient’s next regimen with ritonavir-boosted darunavir + etravirine, a combination that worked well in the DUET trial against drug-resistant virus (AIDS Clin Care Jul 30 2007). Although these two drugs alone would likely be adequate, they might not maximally and durably suppress viral replication (Abstract TUPE0048, XVII International AIDS Conference, 2008). Therefore, I would add another active drug — either raltegravir or maraviroc. (Enfuvirtide is also an option but is less preferable because of the requirement for subcutaneous injection.) The combination of ritonavir-boosted darunavir + etravirine + raltegravir was successful in suppressing viral replication in most patients with multidrug-resistant virus in the ARNS 139 TRIO trial (Abstract THAB0406, XVII International AIDS Conference, 2008). However, at this stage of the patient’s disease, I would rather use maraviroc than raltegravir because, as disease progresses, the virus will likely shift from CCR5-tropic to CXCR4-using, and maraviroc will no longer be an effective option.

Final choice: ritonavir-boosted darunavir + etravirine + maraviroc. This choice would preserve the use of raltegravir and enfuvirtide for future combinations, if necessary. Some physicians would also include 3TC to maintain mutational pressure on the virus, thereby decreasing fitness, but it is unclear whether this drug would offer any additional benefit in the setting of maximal virologic suppression.

Response 2

— Timothy Wilkin, MD, MPH

The goal of the next antiretroviral regimen is to suppress the viral load to undetectable levels. Many combinations are likely to be effective if the patient continues to demonstrate excellent adherence. Here are the questions that I would consider when constructing a new regimen.

1. How many active drugs (other than NRTIs)? Given the patient’s viral load, he might not need more than two drugs to achieve complete virologic suppression. However, recent studies of etravirine, maraviroc, and raltegravir suggest that three active drugs might lead to better suppression than two in highly treatment-experienced patients. Subgroup analyses from phase III raltegravir trials suggest that using more than three drugs is unlikely to provide additional benefit. Choice: three active drugs

2. PI or no PI? PI-containing regimens were the mainstays of the phase III etravirine, raltegravir, and maraviroc trials. Based on these data, I would choose a PI-based regimen, unless the patient has a contraindication (e.g., hypercholesterolemia or ritonavir intolerance). The clear choice, based on phenotype, is ritonavir-boosted darunavir, which falls within the range of full sensitivity (<10-fold change). Choice: ritonavir-boosted darunavir

3. Which of the newer agents? Raltegravir, maraviroc, and etravirine all have good potency and reassuring safety profiles, making them excellent options for this patient. I would definitely choose raltegravir because there is no concern for archived resistance to this drug. Assuming a phenotypic tropism test was used rather than a genotypic one (which has less sensitivity to detect minor CXCR4-using variants), I would also choose maraviroc. If the patient experiences virologic failure on the new regimen, CXCR4-using HIV may emerge with subsequent regimens, and maraviroc would not be an option. I would reserve etravirine for use in a subsequent regimen. Choice: raltegravir and maraviroc

4. NRTIs or no NRTIs? Almost no data exist on NRTI-sparing regimens for patients with extensive drug resistance. I would therefore refer this patient to ACTG 5241, a trial designed to evaluate whether adding NRTIs to a novel regimen is beneficial in individuals with extensive treatment experience. If the clinical trial is not an option, I would prescribe tenofovir/FTC, provided that the patient does not have significant renal disease. Abacavir is an alternative option, but it is already being used in the patient’s current regimen and has been associated with cardiovascular disease. Choice: tenofovir/FTC

Final choice: ritonavir-boosted darunavir + raltegravir + maraviroc + tenofovir/FTC. The patient should understand that the goal of this regimen is long-term virologic suppression (i.e., for decades) and should be ready to commit fully with excellent adherence. Should virologic failure occur, he would still have both enfuvirtide and etravirine available for a future regimen.

Response 3

— Graeme Moyle, MD

This gentleman is experiencing triple-class failure, most likely because of a suboptimal regimen received during the formative years of antiretroviral therapy. Nonetheless, some discussion around other possible reasons for failure, such as medication adherence and superinfection, is warranted. Assuming good adherence, I would evaluate the best new regimen for him, using newer therapeutic options. I would change his regimen sooner rather than later, before further mutations accumulate or tropism shifts. The integrase inhibitor raltegravir and the CCR5 antagonist maraviroc would be the core of my new regimen because his virus is apparently susceptible to both. (He has never used integrase inhibitors, and his virus is CCR5-tropic.) The question then is whether just one additional agent is necessary or two. The answer depends on whether the extra agent is likely to be fully active.

Given the mutations observed, NRTIs are likely to have limited activity against this patient’s virus, and they may add toxicity. For these reasons, I would not include them in the new regimen. Among NNRTIs, the only agent that might be active against this patient’s virus, given the resistance report, is etravirine. Although the particular mutations found during resistance testing are not thought to contribute to loss of etravirine susceptibility (Abstract 24, XVII International HIV Drug Resistance Workshop, 2008), the assessment may not fully represent all accumulated NNRTI mutations, given that the patient has not received NNRTIs recently. The presence of additional, undetected mutations could reduce the likelihood of etravirine response. This concern alone would not be enough to keep me from recommending etravirine, but darunavir seems to be a better option in this case. The patient has only two darunavir resistance-associated mutations (33F, 84V) and a fold-change in darunavir susceptibility that is consistent with (near) full activity (<10-fold shift). This agent would therefore be my preferred partner for raltegravir and maraviroc, providing significant activity, an extra genetic barrier, and a useful ritonavir boost to maraviroc. In BENCHMRK 1 and 2, 89% of patients using both raltegravir and darunavir for the first time, plus an entry inhibitor, achieved viral loads <50 copies/mL by week 48 (N Engl J Med 2008; 359:355). Although the entry inhibitor in these studies was enfuvirtide, maraviroc should have at least similar activity.

Final choice: raltegravir + maraviroc + ritonavir-boosted darunavir. This regimen would offer fairly simple dosing (5 pills twice daily) with a low risk of important adverse events.

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Dr. Walmsley is Professor of Medicine at the University of Toronto and Director of HIV Clinical Research at the Toronto Hospital Immunodeficiency Clinic. She has served on advisory boards and spoken at symposia or local meetings for Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, Roche, and Tibotec.

Dr. Wilkin is Assistant Professor of Medicine in the Division of Infectious Diseases at Weill Cornell Medical College in New York City. He has received research grants (through Weill Medical College) from Tibotec and Merck. He has also served as an ad hoc consultant to Tibotec and Pfizer.

Dr. Moyle is Director of HIV Research Strategy and Associate Specialist in HIV/GU Medicine at Chelsea and Westminster Hospital in London. He has received research grants and has advisory and speaker relationships with Merck, Pfizer, and Tibotec.

Published in Journal Watch HIV/AIDS Clinical Care January 12, 2009

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