DAWNING Study Casts New Light on the Details of Resistance

As 2019 draws to a close, TheBodyPro takes stock of the year's most noteworthy developments in HIV. And not just any developments: We're looking specifically at those with the largest impact for people who provide HIV care and services in the U.S. In this series, veteran clinician-researcher David Alain Wohl, M.D., guides us through the new research and other important moments of 2019 that have the greatest potential to alter the HIV clinical landscape in the months and years to come.

The DAWNING study may be one of the most significant recent clinical trials that you have probably never heard of. This may be because the trial was conducted mostly in resource-limited countries, leading to it not getting as much interest in the U.S. as it deserved. Or it could be that the study's message was hard to hear above the din of the other integrase inhibitor studies I've covered in this year's Top 10.

Presented first in 2017, these findings are nonetheless important not only for revealing the advantages of integrase inhibitors over protease inhibitors, but also for clarifying the number of active meds that are really needed to treat HIV infection. Oh, and also for how to deal with that pesky M184 mutation.

DAWNING enrolled patients with a viral load of 400 copies/mL or higher who were taking an NNRTI-based regimen and had predicted activity with at least one NRTI, according genotypic resistance testing at the time of study screening. These participants were randomized to receive either lopinavir/ritonavir (LPV/r, Kaletra) or dolutegravir (DTG, Tivicay) in addition to two NRTIs that were selected based on study-performed resistance testing.

Of the 968 people screened for the study, 627 became randomized participants; exclusions were mostly due to a lack of any active NRTI on resistance testing. At entry, over 75% of participants were taking efavirenz (EFV, Sustiva) and about 60% were on tenofovir disoproxil fumarate (TDF, Viread). After randomization, the NRTIs selected by clinicians were predominantly lamivudine (3TC, Epivir) plus zidovudine (AZT, Retrovir), 3TC plus TDF, or emtricitabine (FTC, Emtriva) plus TDF.

The study was stopped early by a Data Safety and Monitoring Board (DSMB) when there was clear evidence of excess virologic failure in the lopinavir/ritonavir (i.e., the boosted protease inhibitor) arm. At 48 weeks, 84% in the dolutegravir arm and 70% in the lopinavir/ritonavir arm had a viral load below 50 copies/mL, a difference that qualified as a demonstration of superiority of the dolutegravir arm.

Since the first presentation of DAWNING's results at CROI 2017, more data from the trial have slowly become available. At CROI 2019, we learned more about the responses of those with various drug resistance mutations at baseline -- all of whom, remember, were failing their prior regimen. As expected, there was a lot of M184V/I present at the start of this trial: 84% in the dolutegravir arm and 81% in the lopinavir/ritonavir arm had this FTC or 3TC (i.e., XTC)-associated resistance mutation. Despite this, roughly 70% of participants had FTC or 3TC included in their study regimen.

Regardless of whether there was M184V/I present at baseline -- or even whether XTC was used in the study regimen despite M184V/I being detected -- not only did dolutegravir perform better than lopinavir/ritonavir, but there was no indication of reduced efficacy when this mutation was present. In other words, the resistance mutation really did not matter: The active NRTI, along with the protease inhibitor or integrase inhibitor, were able to do all of the heavy lifting.

Remarkably, the same was true for the 90 or so people in each arm with a baseline K65R mutation, even when TDF was used in the study regimen. Even more notable was that the same was true for the many participants who had M184V/I and one or more NRTI resistance mutations. How cool is that?

The Bottom Line on Drug Resistance and Integrase vs. Protease

It is not a great surprise that dolutegravir beat lopinavir/ritonavir in a study of viremic patients. After all, the FLAMINGO study previously showed similar dominance. What is unexpected is how little pre-switch/salvage drug resistance impacted responses in both of DAWNING's study arms.

Clearly, only having M184V/I present at baseline could be understood to be fairly inconsequential provided the anchor (be it an integrase inhibitor or protease inhibitor) plus an NRTI were active. But in DAWNING, even in those with M184V/I knocking out XTC and thymidine analog-associated mutations (TAMs) knocking out some or all of their NRTI activity, virologic responses were preserved. This is really informative.

Many times we grapple with what to do with folks who have known or potential resistance to NRTIs, but who we want to place on a simplified regimen, such as emtricitabine/tenofovir alafenamide (Descovy) plus dolutegravir, or bictegravir/emtricitabine/tenofovir alafenamide (Biktravy). The DAWNING data suggest we should not be too worried, especially given that, unlike these study participants, our switch patients would have suppressed viremia.

One can assume from DAWNING, at least to some extent, that there remains some activity of the NRTIs, or some hit to viral fitness. This is because the response rates to what was effectively monotherapy were a bit higher than one would expect with actual use of dolutegravir alone. A separate analysis of an Italian database of virologically suppressed patients also found that switching to two NRTIs plus an integrase inhibitor was successful, regardless of any prior known NRTI mutations. By contrast, one factor was independently associated with virologic failure: less time with a suppressed viral load before the switch.

Understanding the ramifications (or lack thereof) of prior resistance mutations can help us craft regimens that are not excessive. Certainly, when we use a newer integrase inhibitor or boosted protease inhibitor with a higher barrier to resistance, the M184V/I mutation will not be too concerning -- and DAWNING suggests that even when TAMs are present, we should not get overly concerned.

By comparison, we know much less about the impact of such pre-existing resistance for regimens composed of antiretrovirals such as NNRTIs and older integrase inhibitors. Caution in such cases is advised.

Read More From This Series

• Introduction: The Top 10 HIV Clinical Developments of 2019
• #1: Weight Gain and HIV Antiretrovirals -- Lipodystrophy for the Integrase Era
• #2: TANGO, the Most Relevant Two-Drug Antiretroviral Therapy Trial of the Year
• #3: And Then There Were Two -- FTC/TAF Is Also PrEP
• #4: Tsepamo Study Provides Critical Update on Neural Tube Defects and Dolutegravir
• #5: ATLAS, FLAIR, and the Upcoming Arrival of Long-Acting Injectable HIV Treatment
• #6: Islatravir Is Potent and Long-Lasting -- and May Be Having an Identity Crisis
• #7: DAWNING Study Casts New Light on the Details of Resistance
• #8: Doxycycline for Bacterial STI Prevention -- A Different Type of PrEP
• #9: The Tangled Knot of Suicide Rates Among People Living With HIV
• #10: The Ironies of a New Plan to End the U.S. HIV Epidemic
• Epilogue: A Final Tribute to Charles van der Horst