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Re-Examining Multidrug Resistance in Heavily Pretreated PLWHIV With Few Antiretroviral Therapy Options

  • Authors: Ravindra Gupta, MD; Huldrych Günthard, MD
  • CPD Released: 2/22/2022
  • Valid for credit through: 2/22/2023, 11:59 PM EST
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Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US HIV specialists, primary care physicians, and allergists and clinical immunologists.

The goal of this activity is to understand the mechanisms and implications of multidrug resistance and its impact on antiretroviral therapy (ART).

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • The reasons why individuals develop multidrug-resistant (MDR) HIV 
    • Mechanism of ART resistance conferred by viral mutations
    • Optimization of background regimens for heavily treatment-experienced patients 


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  • Ravindra Gupta, MD

    Professor of Clinical Microbiology
    Cambridge Institute of Therapeutic Immunology & Infectious Disease
    University of Cambridge
    Cambridge, United Kingdom


    Disclosure: Ravindra Gupta, MD, has the following relevant financial relationships:
    Advisor or consultant for: GlaxoSmithKline; Viiv
    Speaker or a member of a speakers bureau for: Johnson & Johnson


  • Huldrych Günthard, MD

    Head of the HIV Research Laboratory
    President of the Swiss HIV Cohort Study
    University Hospital Zurich
    Zurich, Switzerland


    Disclosure: Huldrych Günthard, MD, has the following relevant financial relationships:
    Advisor or consultant for: Gilead Sciences; Merck; Viiv
    Grants for clinical research from: Gilead Sciences


  • Shanthi Voorn, PhD

    Medical Education Director, WebMD Global, LLC


    Disclosure: Shanthi Voorn, PhD, has disclosed no relevant financial relationships.

  • Eloise Ballard, PhD

    Scientific Content Manager, WebMD Global, LLC


    Disclosure: Eloise Ballard, PhD, has disclosed no relevant financial relationships.

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance


    Disclosure: Susan L. Smith, MN, PhD, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

Accreditation Statements

    For Physicians

  • The Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom (FPM) has reviewed and approved the content of this educational activity and allocated it 0.25 continuing professional development credits (CPD).

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Re-Examining Multidrug Resistance in Heavily Pretreated PLWHIV With Few Antiretroviral Therapy Options

Authors: Ravindra Gupta, MD; Huldrych Günthard, MDFaculty and Disclosures

CPD Released: 2/22/2022

Valid for credit through: 2/22/2023, 11:59 PM EST


Activity Transcript

Ravindra Gupta, MD, PhD: Hi, there. I'm Ravi Gupta. I'm a professor of clinical microbiology at the Cambridge Institute of Therapeutic Immunology & Infectious Diseases at the University of Cambridge, United Kingdom. Welcome to this program titled, “Re-Examining Multidrug Resistance in Heavily Treatment Persons Living With HIV With Few ART Options.” Joining me today is Professor Huldrych Günthard, who is head of the HIV Research Laboratory, University Hospital, Zurich in Switzerland. He's also president of the Swiss HIV Cohort Study.

So today we're going to start by discussing the reasons why individuals have multidrug-resistant or MDR HIV, and we're also going to be discussing how we can optimize background regimens for highly treatment-experienced patients. So Huldrych, who experiences multidrug-resistant HIV?

Huldrych Günthard, MD: So, multidrug resistance is a major barrier to a successful treatment. MDR has markedly decreased over time in high-income countries, and the population is small, but the unmet needs are high. So MDR is due to past therapies and potential lengths of HIV infection. For example, men who have sex with men (MSM) who acquired HIV 20 to 30 years ago, hemophiliacs, migrants, patients with inconsistent antiretroviral treatment. MDR has declined over time in Europe significantly, which is great. But there is this remaining fraction of people who we must take care of. So, Ravi, what are the drivers of resistance?

Dr Gupta: Well, despite the advances and revolutionary advances we've made in ARV combinations, MDR HIV remains a concern for people living with HIV. And those contributing factors include suboptimal adherence; it may not always be due to the patient, but also structural factors such as supply, in particular countries. Inadequate pipelines of drugs, highly effective drugs for example, using less potent ARVs compared to the more potent drugs. Transmission of harbored MDR variants and also pharmacokinetic factors and drug-drug interactions that can lower the plasma drug concentrations, allowing virus replication and evolution to occur. So we know that patients with MDR HIV have an increased risk of transmission of a drug-resistant virus. So Huldrych, why does resistance occur in today's landscape? Does HIV actually evolve during ART?

Dr Günthard: So it's widely accepted that drug resistance mutations do not appear during antiretroviral treatment in patients with suppressed viral loads. Studies based on sequence clustering have in fact indicated that at least in developed countries, HIV infected antiretroviral treatment-naive patients are the major source of drug resistant viruses; these kinds of drug-resistant virus have been fixed in those populations and is being transmitted. So, Ravi, what are the genetic mechanisms of resistance?

Dr Gupta: Well, this comes back to some of the biological principles of retroviruses in particular, lentiviruses like HIV. So, HIV has a lack of proofreading, which is found in other viruses, such as SARS-CoV-2 for example, and of course reverse transcriptase does not have a proofreading activity. In other words, it makes a DNA template out of RNA, but it does not have the chance to check whether it's made the right connections. In other words, there is a high capacity to mutate, and we can also see recombination where reverse transcriptase jumps from one RNA template to another, if you have 2 viruses infecting a particular cell. So, this generates virus diversity and selection of drug-resistant mutations, partly contributed to by suboptimal ART.

In this table, we can see some of the key drug classes and the mutations that occur as a result of suboptimal therapy with those regimens and something about the resistance. So, we'll just start with the NRTIs for example; these are competitive inhibitors of viral nucleic acid with reverse transcriptase. They often act as chain terminators. In other words, the nucleoside or nucleotide is incorporated into the growing chain of dNTP. And there is the inability to add further nucleosides onto that backbone because of the fact that it's a modified nucleoside. And the drugs in this class include 3TC or FTC, tenofovir, AZT, and abacavir. So these drugs have a very similar mechanism, and the escape mechanism involves mutations of reverse transcriptase either in the binding site in the case of, for example, K65R or thymidine analog mutations ... enable faster excision of the incorporated nucleotide. In other words, for catalyzing the reaction of removal. So, these are diverse mechanisms of resistance to NRTIs.

Looking at the NNRTIs, these are drugs that actually bind to a hydrophobic pocket in the reverse transcriptase enzyme, and therefore mutations that confer resistance are located in that hydrophobic pocket around positions 182 to 188 in particular. Protease inhibitors affect, of course, the viral cleavage by inhibiting the protease dimer, and this is a 99-amino acid molecule. And the key mutations that confer resistance to protease inhibitors are often located within the active site but can also be found in extended regions of the protease enzyme. Moving on to integrase strand transfer inhibitors -- of course, these are the new game-changing class of drugs. The second-generation integrase inhibitors include dolutegravir and bictegravir, and these drugs are essentially binding the integrase active site and preventing integrase from performing the strand transfer reaction, which involves taking DNA from the reverse transcribed product of HIV and catalyzing that reaction of transfer into host chromosomal DNA through a series of steps. So, if you inhibit that step, obviously HIV cannot integrate, and it's not infectious. Mutations that are key to resistance are located in a diverse array of sites, including positions ranging from something like 148 all the way through to 155. And we think that these mutations decrease binding of the viral DNA to integrase.

Another class of drug is the entry inhibitor group that includes, first of all, the fusion inhibitors, which were described probably a decade or so ago, and these bind to the heptad repeat region and resistance to this group. It's less well understood but essentially means that the drug cannot block the fusion step involved in virus entry. CCL5 antagonists such as maraviroc can be highly effective as an antiretroviral therapy, but on the other hand, drug resistance to maraviroc has been documented through mutations that reduce the affinity of maraviroc for CCR5 or alternatively allow CCR5 to bind maraviroc and perform the entry step efficiently. So Huldrych, how is resistance identified? Are there signature patterns that result in drug resistance to antiretrovirals?

Dr Günthard: I think studying HIV drug resistance is kind of a multi-step process before drugs come to the market that people do a lot of work in vitro passaging of viruses on the different drug concentrations, then site-directed mutagenesis is done. So there is already kind of a signature pattern known before the drug comes to the market, and that is being done for all the drugs, basically. Then one does a comparison of in vitro phenotype testing, which genotypes, what are the mutations and with those, the diagnostic labs can look in vivo in the patients of treatment failures or when drug-naive, whether there are specific signature mutations there for certain drug classes. And then at the end of the day, there are a lot of population studies being done because one often finds additional mutations which have not been found in vitro because if new combinations are being given to patients, there can be the chance that new mutations occur. So it's really a continuous learning by measuring all these different steps. And there is clearly a signature for basically all individual drugs, of course, there are signatures for drug classes, but even among drug classes there are still some signature mutations which occur more frequently, let's say, in the non-nucleoside reverse transcriptase inhibitors that one can differentiate. For example, efavirenz or rilpivirine or delavirdine -- so yeah.

So, Ravi, HIV is very diverse, there are lots of different subtypes. Do you think that resistance patterns differ according to subtypes on antiretroviral treatment?

Dr Gupta: Well, there are some minor differences. For example, there are polymorphisms in gag, which do alter the phenotypic susceptible to protease inhibitors. But I think that in general, these do not have a major impact on the selection of highly active combination therapies for HIV. And that means that all the drugs in the market that work against subtype B, where we have the best knowledge on ARV activity, can also be used against other subtypes. But of course, this does not necessarily extend to HIV-2. So Huldrych, what are the polymorphisms that are found across subtypes? And how does this impact drug resistance?

Dr Günthard: There are different ones which are kind of different. There's I13V, a tipranavir mutation. We don't use this drug much anymore, but that's only prevalent in 13% of the subtype B, but it's highly prevalent in subtype A and G and those such a polymorphism can have some impact in those people if treated. Then there are atazanavir mutations, which are prevalent in different frequencies -- also polymorphisms which can also play a role K20I, and then 36I, and again, they are different. And then the V81I, for example, atazanavir, just 2% in subtype P but 87% in subtype G, and then another polymorphism later on. So in general, there are differences, but again, they do not play a major role in particularly not when a patient is drug-naive because it has been shown that their prevalence in polymorphisms kind of secondary protease inhibitor mutations, they do not play a role in the first place if there are no major protease inhibitor resistant mutations around. So, Ravi, how does it work in the clinic? Do you work with a multidisciplinary team, or what do you do if you have these complex multidrug resistance patterns?

Dr Gupta: Thanks, Huldrych. Well, we do assemble a multidisciplinary team comprised of clinicians and virologists in order to understand the impact of these resistance profiles. Of course your resistance test at a particular time point in plasma only gives you a snapshot of the viral quasi species within the patient. And therefore you should assess drug resistance at intervals. You should take the history of drug resistance into account with multiple resistance tests over time. And if you have access to HIV DNA sequencing, then of course, that is of added benefit even when the viral load is undetectable. So it really does require a complex group of people coming together, if possible. But what are the clinical implications of the same resistance mutation between treatment-naive and suppressed patients who are treated in [your] experience, Huldrych?

Dr Günthard: So thanks, Ravi -- in general, the resistance mutation is of higher relevance in drug-naive patients because the virus is replicating and the drug against which the virus has resistance has no effect. So on the other hand, if full viral suppression has been achieved in the patient, the resistant virus is among many other variants archived in the pro virus and first needs to be activated to breakthrough, meaning that even if the total resistance profile is not favorable to the whole regimen, the relevance of a specific drug resistance mutation is lower. So now Ravi, how does resistance analysis inform the selection of therapies for antiretroviral treatment?

Dr Gupta: Well, thank you for that. So of course one must select drugs against which the virus is not resistant and therefore sensitive and design a regimen with optimal potency. And this requires knowledge of not only sensitivity but also trial data to show whether combinations of ARVs are actually effective against HIV in terms of suppression because you can have drugs that are slightly antagonistic or synergistic against HIV replication, but a general rule is to have at least 2 fully active drugs in regimen. How do physicians deal with intermediate resistance, Huldrych? And what's the best practice when resistance to only 1 agent is detected?

Dr Günthard: I mean, in general, it's the best to change to a regimen that doesn't contain drugs where resistance has been found against. And if this is not possible, then one can kind of combine different, additional drugs that, for example, have some partial activity which is still there, but it's really kind of excluding substances where one has found resistance. I think that's the whole idea. So Ravi, now how do you navigate the treatment options in your MDR HIV patients? Can you talk us through how you optimize treatment? And for example, when would you use therapies that are specifically there to target MDR, for example, substances like ibalizumab or fostemsavir?

Dr Gupta: Well of course when we look at the resistance profiles of particular patients, we identify fully active drugs and where we have difficulty, we now have the option of using these new agents that essentially block viral entry. And for example, fostemsavir a prodrug of temsavir. It's an attachment inhibitor directly binding the HIV GP120 subunit, and that's preventing CD4 attachment and therefore entry. The ongoing phase 3 BRIGHTE study has been assessing the efficacy and safety of fostemsavir in heavily treatment- experienced patients failing ARVs. And in this study by 96 weeks of treatment, 60% of the randomized group had a response, and 30% of the non-randomized cohort had a viral response. So this supports the use of fostemsavir in heavily treatment-experienced patients. The mean change based on CD4 was 205 and 119, respectively. And you can see that in the figure on the right here. So, there's a virological and immunological benefit from adding fostemsavir in heavily treatment-experienced patients.

Looking at ibalizumab in MDR HIV in this study in the New England Journal of Medicine, 31 patients completed the study, and ibalizumab combined with an optimized background regimen, or OBR, significantly reduced the HIV viral load, increased the CD4 count from baseline in patients with HIV that was multi-drug resistant with heavily treatment-experienced histories. And therefore this advocates for the use of ibalizumab in MDR HIV. There was evidence of the emergence of diminished ibalizumab susceptibility in vitro with patients who had experienced virologic failures. So we do need to be careful with these drugs, we do need to combine them with other highly active molecules. So Huldych, what about other new drug classes?

Dr Günthard: There is a new drug class lenacapavir, which is the potent first-in-class inhibitor of the HIV1 capsid, with long-acting properties and the potential for subcutaneous dosing every 3 months or longer in the CAPELLA study. The lenacapavir group had 88% who met the primary endpoint vs only 17% in the control group, with mean decreases in viral load from baseline to day 15 of 1.93 vs 0.29 log. So it's a very potent drug, and there's a lot of hope that this would change many things in HIV treatment, and also in the population with multidrug resistance.

Dr Gupta: So, in summary, HIV drug resistance is declining in incidence in Europe, MDR impacts a small number of patients, but their unmet needs are high. We need to individualize treatments in the event of virologic failure due to drug resistance and to prevent further resistance. And in terms of future directions for MDR resistance, new drug classes for resistance to HIV are needed. We'd like to thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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