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Managing Heavily Treatment–Experienced Patients With HIV: Questions and Answers

Roger Bedimo, MD, MS, FACP

Professor of Medicine
Division of Infectious Diseases
University of Texas Southwestern Medical Center
Section Chief
Division of Infectious Diseases
Department of Internal Medicine
VA North Texas Health Care System
Dallas, Texas

Roger Bedimo MD, MS, FACP, has disclosed that he has received funds for research support from ViiV and consulting fees from Merck, Theratechnologies, and ViiV.

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Princy N. Kumar, MD, FIDSA, MACP

Professor of Medicine and Microbiology
Division of Infectious Diseases and Travel Medicine
Senior Associate Dean of Students
Georgetown University School of Medicine
Washington, DC

Princy N. Kumar, MD, FIDSA, MACP, has disclosed that she has received consulting fees from Amgen, Gilead Sciences, GlaxoSmithKline, Merck, and Theratechnologies; has received funds for research support from Gilead Sciences, GlaxoSmithKline, Merck, and Theratechnologies; and has ownership interest in Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, Merck, and Pfizer.

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Brian Wood, MD

Associate Professor of Medicine
Division of Allergy and Infectious Diseases
University of Washington
Seattle, Washington

Brian Wood, MD, has no relevant conflicts of interest to report.

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Released: June 2, 2021

What assessments do you perform for patients experiencing virologic failure on their current antiretroviral therapy (ART) regimen and how do you interpret resistance tests to make treatment decisions?

Brian Wood, MD:
Guidelines on resistance testing from the DHHS recommend genotypic testing over use of phenotypic testing in patients with virologic failure or suboptimal response on first-line or second-line ART, or where mutational patterns are not expected to be complex.

In my experience, phenotypic testing is rarely needed, and I often manage heavily treatment–experienced patients with genotypic testing alone. I always try to review a composite of all past genotypes to give a full picture, and I make sure I have an integrase inhibitor (INSTI) genotype available if the person is receiving or has failed an INSTI. In many laboratories, testing for INSTI resistance is ordered separately, and this can be easy to miss. I also rely on tools like the Stanford University HIV Drug Resistance Database, which allows you to input the patient’s genotypic resistance mutations and receive a report of predicted phenotypic resistance.

I find phenotypic testing to be most useful in a person with complex protease inhibitor (PI) class resistance where I need to know which PI is anticipated to be most active, or occasionally a person with complex nonnucleoside reverse transcriptase inhibitors or other class resistance. There are limitations to the use of phenotypic assays in clinical practice compared with the use of genotypic tests—phenotypic tests are more expensive, they take longer to deliver results, and they may be less sensitive for detecting mixtures of resistant and wild-type virus.

Princy N. Kumar, MD, FIDSA, MACP:
Obtaining a drug history from the patient is one of the most important steps in assessing drug resistance in a patient failing ART, but that is often the most difficult because many patients will not recall the names of the medicines they have used. Some laboratories will be able to provide a report of previous genotypes for a given patient, and I have found that to be exceptionally useful.

Roger Bedimo, MD, MS, FACP:
In the United States, we have fewer and fewer patients who are heavily treatment–experienced who are failing with multidrug resistance in our practices. Data from clinical trials exploring strategies for managing such patients are now usually conducted in resource-limited settings. Extrapolating from those data can be challenging, but we can say that patients with virologic failure who switch to agents with a relatively high genetic barrier, such as a boosted PI, generally do well. Some patients who have failed on a PI may not have a resistance mutation to show for it. It is important to emphasize the need for optimal adherence in such patients before making any rash move to switch regimens.

Would you consider switching virologically suppressed patients receiving ibalizumab to fostemsavir?

Princy N. Kumar, MD, FIDSA, MACP:
Ibalizumab is given by infusion every 2 weeks. It is well tolerated, and the logistics of the infusion can be readily managed. However, given its parenteral route, it may prompt consideration as to whether ibalizumab can be substituted with fostemsavir in a patient with virologic suppression. The key when switching any ART regimen is to maintain virologic suppression. So, I would want to be sure that the patient has complete and stable virologic suppression and that there will be other active agents in the new regimen as well as fostemsavir. There are no data from patients who have undergone this switch, and it would be outside the FDA-approved indication for fostemsavir, which is approved for use in combination with other antiretrovirals for heavily treatment–experienced adults with multidrug-resistant HIV infection who are experiencing failure of their current regimen.

When I have undertaken this switch with a patient, my approach was to discontinue ibalizumab and start the patient immediately on fostemsavir 600 mg twice daily. I then make sure the patient returns to see me 2 weeks later, and again 2 weeks after that, to check that his or her HIV-1 RNA is still undetectable. If it remains undetectable, then I am comfortable with that initial response. I have found that preauthorization for fostemsavir may be needed, and so I would check with the pharmacy that the patient will be able to get access to fostemsavir before making changes to his or her regimen.

Are there any drug–drug interactions to consider when recommending fostemsavir?

Brian Wood, MD:
There are no known interactions between fostemsavir and other antiretrovirals, but there are known interactions with other medications. The androgen receptor inhibitor enzalutamide, the anticonvulsants carbamazepine and phenytoin, as well as rifampin, mitotane, and St John’s wort are all contraindicated in people receiving fostemsavir due to reduced fostemsavir exposure with coadministration. Fostemsavir raises levels of statins, including rosuvastatin, atorvastatin, fluvastatin, pitavastatin, and simvastatin. The lowest possible dose of the statin should be used with monitoring for adverse events. Ethinyl estradiol exposure is increased with fostemsavir, and therefore, the daily dose of this contraceptive should not exceed 30 mcg if the two are coadministered. Finally, grazoprevir and voxilaprevir levels may be increased by fostemsavir, and so a hepatitis C antiviral regimen that does not include these agents should be selected for patients receiving fostemsavir if possible.

What do you consider an “undetectable” HIV-1 RNA?

Roger Bedimo, MD, MS, FACP:
The lower limit of detection on HIV-1 RNA assays has been reduced over time from fewer than 500 copies/mL to fewer than 50 or 20 copies/mL on current assays. Several studies have shown that patients with viremia <200 copies/mL on ART but who are not undetectable are not more likely to develop treatment failure than people who maintain an undetectable HIV-1 RNA.

Patients whose HIV-1 RNA moves from being <200 copies/mL to 1000 copies/mL often develop drug resistance and should be considered to be experiencing virologic failure according to the DHHS guidelines. Current guidelines state that patients with viremia that remains <200 copies/mL do not usually need to change treatment.

Brian Wood, MD:
I agree with that approach and consider patients with viremia at this level equivalent to being undetectable. I do not change or add anything to their treatment.

Princy N. Kumar, MD, FIDSA, MACP:
I agree and I think that providing reassurance to such patients goes a long way. Some patients can now look up their blood test results online and see their numbers. They may misinterpret those numbers, so it is important to explain these nuances.

Join the Discussion
What do we still need to know about the management of heavily treatment–experienced patients? How are the latest data affecting your recommendations in clinical practice? Please share your thoughts in the comment section.

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