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ART Safety: FAQ
ART Safety and Tolerability: Questions, Answers, and More Questions

Released: December 07, 2020

Expiration: December 06, 2021

Danielle Roman
Danielle Roman, PharmD, BCOP
Brian Wood
Brian Wood, MD
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Editorial Note: The DHHS guidelines on ART in pregnant women have been updated since this commentary was written. Please refer to the new guidelines here for updated recommendations for this population.

Based on the latest Tsepamo data, would you recommend ART modification for a woman virologically suppressed on dolutegravir (DTG) who wishes to conceive?

Brian Wood, MD:
In the updated Tsepamo analysis presented at AIDS 2020, the prevalence of neural tube defects (NTDs) with DTG at conception was 0.19 vs 0.11 for non-DTG ART, and the difference was no longer statistically significant. I think these updated data are very reassuring that DTG taken at the time of conception does not increase risk of NTDs compared with efavirenz (EFV). I would counsel a woman about what we know and what we do not know based on the latest data. If she were doing well with a suppressed viral load and preferred to stay on DTG, I would support that. However, I would highly encourage folate supplementation, beginning before conception, to reduce the likelihood of NTDs.

Daniel R. Kuritzkes, MD:
I think that as long as the risks and benefits are discussed in the context of shared decision-making with the patient, DTG can be continued in a woman who wishes to conceive, and that is certainly the current WHO recommendation. The DHHS guidelines, which have not been updated to reflect the latest Tsepamo data, indicate DTG as an alternative regimen for women trying to conceive, so continuing DTG would also be in alignment with those guidelines.

If a woman becomes pregnant while receiving tenofovir alafenamide (TAF), would you recommend a switch?

Brian Wood, MD:
The FDA package insert and DHHS guidelines still state that there are insufficient data for TAF in pregnancy, but the guidelines have not been updated since the IMPAACT 2010 study provided very reassuring data about TAF use in the second or third trimester. The study enrolled women after 14 weeks of gestation and demonstrated fewer adverse pregnancy outcomes with DTG plus emtricitabine (FTC)/TAF compared with DTG plus FTC/tenofovir disoproxil fumarate (TDF) or EFV/FTC/TDF. However, there are still insufficient data with TAF use during conception and the first trimester. Again, I think this becomes a one-on-one decision with the patient, with some shared decision-making about what we know and what we do not know. If this were a woman who had been receiving TAF for a very long time, with a suppressed viral load, tolerating it well, and taking it with a potent anchor drug with a high barrier to resistance, I would not say the patient necessarily should switch and would support continuing the regimen if she preferred. If this were a patient who had more recently started receiving TAF, with nothing prohibiting a switch to TDF, or not taking a very potent anchor drug, I might be more conservative and switch to TDF.

What are the underlying mechanisms of weight gain with INSTIs or TAF?

Brian Wood, MD:
When the association between specific ARVs with weight gain was first presented, I think what crossed everyone’s mind was that maybe we were seeing some new adverse event of DTG or TAF. There are in vitro data suggesting that DTG might stimulate appetite through some complicated mechanisms, but there is no clinical confirmation of that. I think what we have seen in the past 6-12 months suggests that the mechanism is potentially not a direct off-target effect of DTG or bictegravir with TAF but weight suppression with TDF and EFV. For example, a study presented at IDWeek 2020 by McComsey demonstrated an increased risk of weight gain with a TDF to TAF switch vs an abacavir to TAF switch. I think that more and more data suggest that the difference may be driven by appetite suppression or adverse events of the older agents as opposed to adverse events of the newer agents. However, this has yet to be confirmed.

Does the weight gain observed with INSTIs or TAF contribute to increased cardiovascular risk?

Brian Wood, MD:
This is a million-dollar question that I have not seen answered. Most individuals, when they start ART, do gain some weight, and many individuals gain weight when they switch ART, mostly in the 9-12 months after the switch, as we saw in the OPERA study. For most individuals, the weight gain is minor, but for 20% to 30% of people, it could be considered an excessive amount of weight gain that may increase risk of metabolic syndrome or cardiovascular risk. However, we do not yet know how much the weight gain contributes to cardiovascular risk and if there are any differences in long-term clinical outcomes. I hope we see more long-term outcomes data soon.

Daniel R. Kuritzkes, MD:
You could certainly predict based on the magnitude of weight gain and the association with hyperlipidemia or increasing abdominal girth that the individual may be at risk for insulin resistance and for metabolic syndrome. However, an increase in adverse clinical outcomes in terms of myocardial infarction, renal failure, or stroke has not been demonstrated.

What lifestyle and diet advice have had the most meaningful impact for patients with HIV in your experience?

Daniel R. Kuritzkes, MD:
I think the interventions that best support weight loss in patients with HIV who are receiving ART are similar to what we would expect to work in the general population: exercise, modifying diet to match caloric intake to caloric expenditure, or reducing caloric intake to below expenditure if the person is already overweight. In addition, I recommend a well-balanced diet with fewer carbohydrates to prevent storage of fat. The challenge, of course, is helping people adhere consistently to weight loss programs. We know how difficult it is for people—no matter how badly they want to lose weight—to actually successfully lose the weight.

Join the Discussion
What do we still need to know about ARV-associated weight gain and ART safety in women of childbearing potential? How are the latest data affecting your recommendations in clinical practice? Please share your thoughts in the comment section.

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How often do you recommend that women currently receiving DTG-based ART switch to a non-DTG ART regimen prior to trying to conceive?
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