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Chief Operating Officer
Desmond Tutu HIV Foundation
Desmond Tutu HIV Centre
Immediate Past President
International AIDS Society
Faculty of Health Sciences
University of Cape Town,
Cape Town, South Africa
Linda-Gail Bekker, FCP(SA), PhD, has no relevant conflicts of interest to report.
Senior Consultant, Infectious Diseases
Hospital Juan Fernández
Director, Fundación Huesped
Professor of Infectious Diseases
Buenos Aires University Medical School
Buenos Aires, Argentina
Pedro Cahn, MD, PhD, has disclosed that he has received funds for research support and consulting fees from Merck and ViiV Healthcare and fees for non-CME/CE services from Gilead Sciences, Merck, and ViiV Healthcare.
Professor of Medicine
Division of HIV, Infectious Diseases, and Global Medicine
University of California, San Francisco
Ward 86 HIV Clinic
San Francisco General Hospital
San Francisco, California
Monica Gandhi, MD, MPH, has no relevant conflicts of interest to report.
Consultant Physician, HIV/GU Medicine
Mortimer Market Centre
CNWL NHS Trust
London, United Kingdom
Laura Waters, FRCP, MD, has disclosed that she has received consulting fees from Cipla, Gilead Sciences, Janssen, MSD, Mylan, and ViiV Healthcare.
This commentary features select questions posed to expert faculty during the multipart CME/CPE-certified satellite symposium, “What’s Hot in HIV Treatment,” which was held during AIDS 2020: Virtual and will soon be available on demand. The session focused on key areas of HIV management: optimal use of newer ARV agents and strategies, individualizing ART for women of childbearing potential and during pregnancy, the impact of evolving data on adverse events during ART, and the anticipated roles of emerging and investigational novel ART strategies.
If you have a patient virologically suppressed on efavirenz (EFV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) who is experiencing depression and prefers a single-tablet regimen, what do you consider when determining which regimen to recommend?
Laura Waters, FRCP, MD: I begin by exploring lifestyle issues such as food requirements, drug interactions, and adverse events to determine what is important to the patient. Neuropsychiatric adverse events that occur with dolutegravir (DTG)/rilpivirine (RPV), and the need to take RPV-containing ART or darunavir (DRV)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) with food should be considered.
I would also be cautious about using bictegravir (BIC)/FTC/TAF if the patient is older and/or has a glucose level indicating that he or she may be diabetic or borderline diabetic because of reported weight gain and the possible metabolic signals. If any of these considerations are relevant, my recommendation would be narrowed down to doravirine (DOR)/lamivudine (3TC)/TDF or DTG/3TC dual therapy.
Linda-Gail Bekker, FCP(SA), PhD: One or 2 years ago, BIC/TAF/FTC would have been considered a go-to switch option for a patient like this. I think additional emerging data, including what we have seen at AIDS 2020: Virtual, about TAF and the concerns for metabolic syndrome and weight gain is making any TAF-containing regimen less desirable, which would eliminate BIC/TAF/FTC and DRV/COBI/FTC/TAF.
If the patient does not have previous resistance, he or she would be eligible for DTG/3TC, but he or she must be really adherent to a 2-drug regimen.
What are your recommendations for ART management and counseling of women currently receiving DTG who wish to conceive?
Monica Gandhi, MD, MPH: After the release of the latest Tsepamo cohort data at AIDS 2020: Virtual, I believe this 2-year debate regarding the safety of DTG during conception has ended. I would recommend not switching back and forth between ART regimens just because a woman wishes to conceive and is receiving DTG. The other important issue is to ensure that women are being recommended to take folate supplementation. The results of the Tsepamo study have taught us that we should give folate to people for neural tube defect prevention worldwide.
Laura Waters, FRCP, MD: Even if there were a higher signal for neural tube defects—which now the new data suggest there is not—there was also a higher risk of failure in women receiving EFV vs DTG. I think these findings have opened more of a dialogue between women and their HIV care providers, and more women are choosing to stay on DTG during conception. These new data from AIDS 2020: Virtual are further reassuring. However, the choice remains with the woman and if she wanted to switch, I would support that, of course.
Linda-Gail Bekker, FCP(SA), PhD: I also hope that we will continue discussing contraceptive choice with women of childbearing potential. I think that there needs to be a discussion about reproductive choice and contraceptive choices at every single clinic visit.
What potential safety and tolerability concerns do you take into account when considering between TDF and TAF or between triple and dual therapy as first-line ART?
Pedro Cahn, MD, PhD: I would begin by asking the patients if they were taking any mineral supplements containing bivalent cations such as calcium, iron, or zinc. The mineral supplements can hamper the patients’ ability to absorb DTG. Also, if patients do not want to gain weight, then I do not think TAF would be a good choice.
DTG/3TC was evaluated in the GEMINI studies, which demonstrated that if patients are adherent, dual therapy works as well as 3 drugs. For physicians who are hesitant to start patients on dual therapy, a short, 3-month course of triple therapy can be initiated before switching them to dual therapy thereafter. I am a fan of dual therapy when possible, and because DTG/RPV has not been tested as first-line therapy and is indicated only for suppressed patients switching ART, DTG/3TC is a good first-line option.
Laura Waters, FRCP, MD: One thing to consider with dual therapy may be the CD4+ cell count. I have always been cautious about the CD4 signal in GEMINI that suggested a higher rate of virologic nonresponse in patients with a baseline CD4+ cell count ≤ 200 cells/mm3. However, I would worry less about this in a newly diagnosed patient because I think someone with a low CD4+ cell count due to recent diagnosis is actually very different from someone with a low CD4+ cell count who is unwell with an opportunistic illness and with whom I would be more cautious.
Monica Gandhi, MD, MPH: I have also had patients on DTG/3TC who remained unsuppressed with HIV-1 RNA > 200 copies/mL because they were not careful about avoiding cations. My final consideration would be whether or not to recommend TAF for a newly diagnosed patient given the weight gain data and clinical consequences of weight gain presented at AIDS 2020: Virtual. The ADVANCE study showed significantly greater weight gain at 96 weeks in patients receiving DTG plus FTC/TAF vs EFV/FTC/TDF. The weight gain continued beyond 96 weeks and treatment-emergent metabolic syndrome was also increased in the DTG plus FTC/TAF arm.
Are you switching people who gained weight on a given regimen to a different ART regimen?
Pedro Cahn, MD, PhD: In my practice, patients are mainly white men who have sex with men, so few have gained weight. If a patient does gain weight, I consider all reasons for the potential weight gain. Is it weight gain that signifies a return to health or is it weight gain that increases his or her BMI to an unhealthy level? In the case of a clinically meaningful increase in BMI, I would consider changing regimens and discuss this with the patient.
Linda-Gail Bekker, FCP(SA), PhD: I view the weight gain data with trepidation, as in South Africa, we are switching to DTG/3TC/TDF as the preferred regimen. We do not have access to TAF yet, but I think it raises a huge question mark about where we go in terms of TAF. We already have a population that has a really high BMI, particularly among women. Therefore, weight gain is a large concern for us, and I think the weight gain data should be considered as international guidelines are revised.
Monica Gandhi, MD, MPH: There is an upcoming ACTG trial that will assess if a patient can lose the weight gained on an INSTI after switching to DOR. The results of this study should be very helpful because, to date, NNRTIs have been associated with lower weight gain.
Laura Waters, FRCP, MD: While we are continuing to learn about weight and obesity with ART, we may find that drug-induced weight gain does not disappear when you stop taking the drug, as we are often genetically programmed to hold onto weight that we gain. I think that it is going to require hard work by the patient to lose extra weight, even after he or she has switched to a drug associated with less weight gain.
Who do you think will benefit most from long-acting ART? What challenges do you foresee in implementing it?
Linda-Gail Bekker, FCP(SA), PhD: I know that adolescents around the world are awaiting long-acting ART to avoid the stigma of taking pills. However, I wonder whether they will be okay receiving large volume injections every 8 weeks. The need for feasibility studies in the younger populations is urgent. We are still waiting for data to determine the dosage for the lower weight adolescents and in the 18- to 25-year-old age group. However, I think feasibility and acceptability studies must be done as soon as possible.
Laura Waters, FRCP, MD: I also think adolescents are a key population. We have a small cohort of adolescents, and most of them have vertically acquired HIV. When you look at their legacy of treatments and suboptimal suppression in the past, they are a group that, on average, have more resistance. However, my fear with the injectables is that, although they are highly effective, you do see some patients with resistance in the trials. Even with 100% adherence, a few people who are suppressed at entry are failing with resistance. I am not saying the failure rate was any greater than any other suppressed switch study. When we look at switching to DTG/RPV in the SWORD studies, we also see failures, but we can say that it is due to adherence based on lower drug levels in those individuals. However, we cannot say that about the injectables because adherence is not the problem here. The concern I have regarding the risk of virologic failure is the potential for developing dual class resistance, for example, in a younger patient who may not come back for his or her injection. I agree that more studies on feasibility and real-life implementation will be crucial.
I also think poorly adherent people fall into 2 different categories: 1) people who do not come to clinic and do not take their pills (those in whom attendance behavior matches pill-taking behavior), and 2) people who come to clinic regularly but for whatever reason, they are not able or willing to take their pills in between. I think that the latter group, those who attend appointments but do not necessarily adhere to pill taking, would be ideal for injectables.
Monica Gandhi, MD, MPH: In the light of the emergence of INSTI resistance in some cases of virologic failure reported with long-acting injectable cabotegravir (CAB), I am also concerned that it may not have the same genetic barrier to resistance as daily oral BIC and DTG. I think that the forthcoming resistance data from HPTN 083 will be very helpful as we know that CAB has a long half-life with a long pharmacokinetic tail. Any failure of people who broke through and acquired HIV should be checked for CAB resistance. These results will give us more data on where injectable CAB falls in terms of the hierarchy of genetic barriers to resistance for INSTIs, with raltegravir and elvitegravir being lower barrier and DTG and BIC being higher barrier. I agree that we cannot lose the option of treating with INSTIs, which would be the case if patients acquire treatment-emergent resistance to CAB.
Pedro Cahn, MD, PhD: Long-acting ART that is given intramuscularly could be lifesaving for patients with a chaotic lifestyle because of dementia or problematic drug use and for patients who cannot swallow pills due to infections or neurologic issues. I think it is a very useful advance for our armamentarium.