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Less Is More: 2-Drug ART Options for People With HIV Experiencing Toxicity

Pedro Cahn, MD, PhD

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.

View ClinicalThoughts from this Author

Released: September 28, 2021

Several years ago, I was happy to have any combination of drugs that was effective enough to control HIV replication in my patients. Today, we can select among many regimens to individualize treatment for our patients. With this richness of antiretroviral therapy (ART), I am more keen to look beyond HIV-1 RNA and CD4+ cell count to see if my patients are receiving the best treatment available. With new 2-drug regimens, we can further improve tolerability while maintaining virologic efficacy.

Assessing Tolerability
When thinking about ART tolerability, the most important part of the medical consultation is to have a conversation with your patients and ask how they are feeling. As healthcare professionals, we are sometimes pressed for time, and we look only at HIV-1 RNA and CD4+ cell count without paying enough attention to the patient’s experience with therapy.

For example, if you ask a patient who is receiving an efavirenz-based regimen, he or she may say, “I’m okay—my viral load is below 50 copies/mL and my CD4+ cell counts are above 200 cells/mm3,” But if you dig deeper, you will find many patients who report trouble sleeping, who experience nightmares and dizziness, and so on. These accounts should not be ignored given the plethora of effective agents from which we now have to choose.

We must also consider other laboratory results as they can signal toxicity that is unnoticed by the patient. Indeed, elevated creatinine levels, triglycerides, and blood glucose are all unwanted results and may warrant a change in therapy. We should monitor these parameters and make changes where needed in order to find the most efficacious regimen with the lowest rate of adverse events.

Switching to 2 Drugs
We have seen a recent focus on switch strategies involving 2-drug regimens that aim to maintain virologic suppression while minimizing adverse events and maximizing tolerability. New clinical trial data have highlighted the utility of 2 of these regimens: dolutegravir (DTG)/lamivudine (3TC) and long-acting cabotegravir (CAB)/rilpivirine (RPV).

The phase III TANGO and SALSA studies evaluated a switch to DTG/3TC vs continuing a ≥3-drug ART regimen in patients with HIV who were stably suppressed. In TANGO, participants were receiving a tenofovir alafenamide–based regimen at baseline; in SALSA, the baseline regimen could consist of 2 nucleos(t)ide reverse transcriptase inhibitors plus an integrase inhibitor, a nonnucleos(t)ide reverse transcriptase inhibitor, or a boosted protease inhibitor.

The good news is that we have 144 weeks (TANGO) and 48 weeks (SALSA) of analysis demonstrating that switching to DTG/3TC is noninferior to continuing on the ≥3-drug ART regimen in terms of virologic efficacy.

In terms of overall adverse events, in the SALSA study, there were slightly more among participants who switched vs those who continued the baseline regimen (73% vs 70%), but there were very few withdrawals due to adverse events (2% vs 1%). The mean change in BMI from baseline to Week 48 was similar for both arms, and the mean weight change was minimal: 2.1 kg in the switch arm vs 0.6 kg in the control arm. Moreover, a recent metabolic analysis of the TANGO study demonstrated that changes in lipids at Week 144 were more favorable for those who switched to DTG/3TC vs those who did not switch.

Based on these studies, I think we need to consider that 2-drug ART may help address tolerability issues in our patients and may have substantial long-term benefits for the overall health of our patients.

CAB/RPV is another 2-drug regimen that has demonstrated noninferior efficacy in patients with HIV switching from 3-drug ART in the phase III FLAIR trial. Of note, this regimen is a game-changer in terms of ART delivery. For the first time, we have a long-acting injectable regimen we can offer to patients, which is extremely important for the many patients who experience treatment fatigue (ie, they are no longer happy taking a pill every day), as well as those who struggle with daily adherence.

In terms of safety, CAB/RPV has been shown to be extremely well tolerated out to 124 weeks, except for injection-site reactions, which are the most common adverse event. Although very frequent with the first injection, most injection-site reactions were grade 1, however, and the frequency slowed progressively with further injections. Of importance, only 2% of FLAIR participants discontinued because of these injection-site reactions. Of course, we have to consider that this is a highly motivated population who volunteered to be part of a study exploring injectable ART. Nevertheless, in my practice, many patients are very keen to have the chance to switch from daily oral to every-other-month injectable ART.

With CAB/RPV, we have a new weapon in our armamentarium to help address tolerability issues in our patients receiving 3-drug regimens. It will also be a refreshing option for patients who are tired of daily pills.

Beyond Viral Suppression
Once patients stably suppressed with healthy CD4+ cell counts, what else can we do for them? If my patient is young with no other health issues, partakes in regular exercise, eats a healthy diet, does not smoke, and has no other risk factors for cardiovascular or neurological disease, then I can wait and monitor him or her before considering an ART switch.

But if my patient is older than 50 years of age, is overweight or obese, smokes, does not exercise, and/or has other cardiovascular or metabolic risks (the majority of the patients we see in our clinics), we need to be very careful and understand that ART is not only about HIV-1 RNA. HIV medicine is about the overall health of our patients, and certain ART regimens may help minimize the risks of other health problems.

My best advice to my colleagues is to counsel patients about healthy lifestyle and review how they are tolerating treatment. Laboratory values can only tell use so much, and it is important to uncover how they are feeling and what else are they experiencing.

Encouragingly, to minimize adverse events and maximize adherence, we may be able to now treat our patients with regimens using only 2 drugs vs 3. This option is now reflected in several international guidelines, solidifying that we are in a new era in which less can be more.

Your Thoughts?
When managing patients with HIV who are stably suppressed, do you review treatment tolerability at every appointment? Answer the polling question and join the conversation by posting in the discussion section.

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