Tune in for a quick and easy primer on how to recognize key populations who may present with multidrug-resistant HIV, identify underlying reasons for regimen failure, and evaluate resistance profiles to construct new ART regimens.
Tune in as Dr Daniel R. Kuritzkes presents a quick and easy primer on managing multidrug resistant HIV.
Topics covered include:
Presenters:
Daniel R. Kuritzkes, MD
Chief, Division of Infectious Diseases
Brigham and Women's Hospital
Harriet Ryan Albee Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Link to full program:
https://bit.ly/4oiYxEx
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My name is Daniel Kuritzkes, and I am the Chief of the Division of Infectious Diseases at Brigham and Women's Hospital and the Harriet Ryan Albee Professor of Medicine at Harvard Medical School in Boston, Massachusetts.
This is part one of a four-part program, HIV care for Treatment Experienced People: Optimizing ART and Improving Outcomes. I invite you to view the medical minutes and the accompanying slide sets for this program on the Clinical Care Options website.
This program is supported by an educational grant from ViiV.
Factors Contributing to Incomplete Suppression of HIV Virus Replication
There are numerous factors that may contribute to incomplete suppression of HIV virus replication. These include:
Key Populations Who May Present With Multidrug-Resistant HIV
There are key populations who may present with multidrug-resistant HIV. These include persons with a long treatment history who may have had periods of incomplete viral suppression, even while on antiretroviral therapy. This could be due to the use of regimens that were not fully suppressive, especially people who started therapy in the late 1980s and early 1990s. Those who had a history of treatment with one or just two nucleoside RT inhibitors, people who were treated with first-generation non-nucleoside RT inhibitors, or unboosted first generation protease inhibitors, and those who received sequential functional monotherapy with new drugs. That refers to the use - the addition of just a single new drug as new agents became available, without being able to construct a fully suppressive regimen of leaving the single new drug at risk for acquisition of resistance.
In addition, people who acquired HIV by mother to child transmission may be at risk for multidrug resistant HIV, largely because of the challenges of maintaining effective therapy in infancy, early childhood and adolescence.
And then people with past or current adherence challenges. And of course, as mentioned previously, people who acquired a multi-resistant - a multidrug resistant virus through transmission.
DHHS Guidelines: Managing Persons With HIV With Virologic Failure on ART
Treatment goals for reestablishing virologic suppression in persons with HIV with virologic failure on antiretroviral therapy have been established by the DHHS guidelines for the use of antiretroviral treatment in adults and adolescents. These include:
In addition to performing drug-resistance testing, drug resistance testing ideally should be performed while the person is still on a failing regimen or within four weeks of discontinuation in order to identify fully active and partially active agents.
The reason it is important to test while someone is still on a failing regimen is that there is the possibility that wild-type viruses may re-emerge, and you could fail to detect resistance that is actually present.
Resistance Testing in the Setting of Virologic Failure
In addition, it is important to try to gather as much information as you can about previous and current treatment regimens, because that may provide important information about possible resistance that could have existed in the past, and to review all previous and current drug resistance test results whenever available.
In the majority of cases, genotypic testing is preferred while the person is on the first or second-line regimen, and when resistance mutation patterns are expected to be relatively straightforward.
In rare circumstances, phenotypic testing may be needed as an adjunct to genotypic testing, particularly when you suspect complex drug resistance patterns may be present or when found by genotyping, making the interpretation of the genotype more challenging. This is particularly the case when there are multiple drug resistance mutations for the protease inhibitors, and to some extent, when there are multiple mutations for the various integrase strand transfer inhibitors.
Interpreting the resistance test results can be guided by the use of the Stanford HIV Drug Resistance Database. It is important to keep in mind the option to consult an expert on antiretroviral resistance whenever you have questions about how to proceed with a particular patient.
DHHS: Selection of ARVs With a Failing Regimen
The DHHS guidelines also provide guidance on selecting antiretroviral drugs for people with a failing regimen. What you do not want to do is add only a single new drug to a failing regimen. That is because the failing drugs will not protect the new drug from the development of resistance, and may lead to the emergence of resistance to that new drug. What I alluded to previously as functional monotherapy.
What works for the majority of patients on a failing regimen is to identify two fully active drugs, particularly if one of those has a high barrier to resistance. That would include drugs like dolutegravir or boosted darunavir and possibly bictegravir. And in some instances, we can consider the use of one fully active agent that has a high resistance barrier with two partially active nucleoside RT inhibitors.
Although bictegravir and dolutegravir really have very similar patterns of resistance, the only reason we say possibly bictegravir here is that there is simply no large clinical trials of bictegravir as second-line or third-line therapy in people with a virologic failure.
Then if two drugs can be found according to this outline here, then the third option is to use three fully active antiretroviral agents when none of them has a high intrinsic resistance barrier.
The definition of fully active is that there is no predicted resistance based on treatment history or the results of resistance testing. The drug works by a novel mechanism of action compared to drugs that the patient has previously received, and it may include newer members of existing drug classes that remain fully active against isolates resistance to previous members of the class. For example, drugs like etravirine, darunavir and dolutegravir, as well as possibly doravirine or bictegravir are all members of the existing classes that were these newer drugs may have activity despite resistance to earlier members of the class.
CNICS: Decline in Prevalence of Highly Treatment‒Experienced Pts With HIV With Limited Treatment Options
The CNICS study, which is a retrospective chart analysis of a large US cohort of more than 27,000 persons, followed those individuals over a 17-year period and documented a substantial decline in the prevalence of people with limited treatment options beginning in the mid-2000s, and it has remained below 1% since 2012.
This is largely because of two factors. One, our first-line regimens are now so much better that people are much less likely to develop resistance at the time of initial treatment failure. Secondly, our newer drugs are so potent that they are able to overcome resistance to earlier generations of drugs so that only a small proportion of people in the United States with HIV now fall into this group who are searching for treatment options.
Conclusions
In conclusion, although the prevalence of drug-resistant HIV has decreased over the years, new treatment options are still needed for those with multidrug-resistant HIV or people who are intolerant of currently available antiretroviral drugs.
New regimens should include at least two fully active drugs, ideally including at least one drug with a high barrier to resistance.
Consider consultation with an expert when faced with a challenging or complicated case to help you make the best decisions for your patient.