As Two-Drug HIV Treatment Rises, Long-Term Inflammation Becomes a Potential Concern

People who switch from three-drug HIV treatment regimens to two-drug regimens are able to safely maintain virologic suppression at similar rates to people who don’t switch—but potentially at the cost of increased long-term systemic inflammation, a new study indicates. The findings were presented at the 23rd International AIDS Conference (AIDS 2020) in early July.

Background: The Rise of Dual-Drug HIV Antiretroviral Therapy

Triple-drug regimens have been the undisputed heavyweight champions of antiretroviral therapy since protease inhibitors and NNRTIs stormed the HIV treatment arena in 1996. But as the potency, lack of toxicity, and favorable drug resistance profiles of newer medications make them more dominant over HIV than ever, two-drug regimens have gained a reputation as an increasingly plausible option.

The breakthrough moment for two-drug HIV treatment regimens came in December 2019, when dolutegravir/lamivudine (sold under the brand name Dovato)—which had been approved by the U.S. Food and Drug Administration (FDA) just eight months earlier—was added to the list of recommended first-line treatment regimens in the well-regarded U.S. Department of Health and Human Services (HHS) antiretroviral guidelines.

U.S. and European HIV treatment guidelines also indicate that a number of other two-drug regimens may be successful options for patients who want to simplify their therapy, including dolutegravir plus rilpivirine, or a ritonavir-boosted protease inhibitor (e.g., atazanavir, darunavir, or lopinavir) plus lamivudine. Meanwhile, research continues to explore the potential for other two-drug regimens, such as the investigational drug islatravir plus doravirine.

Two-drug regimens have become a new reality, not just a passing trend—and with that, interest in their long-term viability has grown.

Study Construction: Inflammation in People Who Switch to Simplified Therapy

To seek answers regarding that long-term viability, Sergio Serrano-Villar, M.D., Ph.D., of the University Hospital Ramón y Cajal in Madrid, Spain, and colleagues conducted a long-term simplification study of 8,416 participants in the Spanish AIDS Cohort.

These individuals all started HIV treatment within the cohort between 2004 and 2018, utilizing a three-drug regimen (two NRTIs plus a boosted protease inhibitor, integrase inhibitor, or NNRTI), and had achieved (and maintained) viral suppression within a year.

The researchers compared outcomes among those who continued to take their three-drug regimens (91% of the cohort) to those who switched to regimens with fewer drugs, which included several two-drug regimens:

• Dolutegravir plus rilpivirine (34% of all two-drug regimen users).
• Boosted darunavir plus lamivudine (25%).
• Boosted atazanavir plus lamivudine (18%).
• Dolutegravir/lamivudine (13%).
• Lopinavir/ritonavir plus lamivudine (5%).

In total, 5% of the cohort switched to a two-drug regimen. An additional 4% switched to a single-drug regimen (either boosted darunavir or lopinavir/ritonavir).

The average time between the participants’ initial achievement of viral suppression on their three-drug regimen and their switch to a simplified regimen was 3.4 years.

Study Findings: Similar Efficacy and Overall Safety, but Emerging Signs of Inflammation

Major clinical outcomes—virologic failure risk through and after the first 24 months; serious non-AIDS adverse events or deaths; and deaths from any cause—were similar between people who continued their three-drug regimen or switched to a two-drug regimen. The single-drug regimens weren’t as hardy: After holding their own virologically through the first 24 months post-switch, single-drug regimens became roughly three times as likely to fail beyond the 24-month mark relative to triple-drug regimens.

Serrano-Villar and colleagues then conducted a nested study exploring inflammatory markers among 180 study participants for whom longer-term blood samples were prospectively taken. These participants were stratified 3:2:1 by drug regimen: 90 had continued their three-drug therapy, 60 had switched to two-drug therapy, and 30 had switched to single-drug therapy.

In this deeper dive into signs of inflammation among study participants, the researchers found signs of emerging systemic inflammation as time wore on among people who switched to two- or single-drug regimens. (This recap will focus specifically on the two-drug regimens, since the single-drug regimens didn’t pass muster virologically.)

Although there were no initial indications of inflammation, beginning roughly two years post-switch, IL-6, c-reactive protein (CRP), and D-dimer concentrations began to increase in blood samples taken from people who switched to two-drug regimens, compared to a decrease over time among people who did not. At three years post-switch, this difference reached statistical significance for all three inflammatory markers. (An analysis of intestinal fatty-acid binding protein [I-FABP] concentrations over time did not find a significant difference.)

These differences in inflammation appeared to be largely similar across two-drug regimens. IL-6 and D-dimer concentration trajectories remained significantly different three years post-switch regardless of whether the person was taking a boosted protease inhibitor or dolutegravir. For CRP concentrations, only dolutegravir-based regimens remained statistically significant, with boosted protease inhibitor–based treatment showing a non-significant trend.

After adjusting for multiple variables (including age, sex, nadir CD4 count, and viral load peak, among others), the researchers determined that switching to a two-drug regimen ultimately conferred a two- to three-times greater risk of a full quartile increase in CRP and D-dimer concentrations after three years. (IL-6 and IFABP did not carry a risk in this regression analysis.)

It’s worth noting that this was a relatively small substudy, and the number of individual participants with long-term follow-up data was even smaller: The median post-switch follow-up period was only a year among people who moved to a two-drug regimen. Nonetheless, there were clear indications of emerging inflammation as the follow-up period extended.

Of course, the real question surrounding these findings is whether these inflammatory signals actually result in a greater risk to the long-term health of people taking simplified HIV treatment regimens. For that answer, we’ll need to wait for additional research: “The potential clinical implications of these findings on the development of non-AIDS events deserve further investigation,” Serrano-Villar said.

Other Dolutegravir/Lamivudine Findings Presented at AIDS 2020

Serrano-Villar’s presentation floated amidst a sea of other research presented at AIDS 2020 regarding two-drug therapy, most of it encouraging—although unlike this study, most of these other findings were presented or partly conducted by researchers working for the pharmaceutical companies that are developing the regimens, and none focused on inflammation. For example:

• New 48-week findings from the TANGO study revealed that switching from a tenofovir alafenamide–based regimen to dolutegravir/lamivudine yielded significant improvements in total cholesterol, LDL cholesterol, triglycerides, fasting insulin, and insulin resistance—with an especially pronounced benefit when switching from a baseline regimen that included a boosted protease inhibitor.

• A meta-analysis of real-world studies involving treatment-experienced people with viral suppression who switched to dolutegravir/lamivudine found a high rate of maintained viral suppression at 96 weeks (86%), as well as an extremely low rate of virologic failure (2%), with treatment discontinuations accounting for much of the difference between the two.

• A meta-analysis of studies comparing three-drug regimens to dolutegravir/lamivudine in treatment-naive people found similar rates of viral suppression and adverse event rates between the two at 96 weeks—as well as a trend toward higher increases in CD4 count among people on the two-drug regimen.

• An open-label, randomized, controlled trial conducted in Spain among people who were virally suppressed on triple-drug therapy found that those who were switched to dolutegravir/lamivudine had nearly identical rates of viral suppression and adverse events after 48 weeks compared to those who were not—but that people who switched gained an average of 1.5 kg relative to those who didn’t (although no similar changes were seen in limb or trunk fat).

Two-Drug Treatment in the Works: Islatravir Plus Doravirine

Meanwhile, AIDS 2020 also brought a couple of new developments regarding islatravir, an investigational antiretroviral with long-acting potential. Prior research has shown the potential of islatravir plus doravirine as a first-line regimen when compared to doravirine/emtricitabine/tenofovir disoproxil fumarate (TDF), and the drug is also being explored as a potential long-acting pre-exposure prophylaxis (PrEP) option.

(Islatravir is classified as a nucleoside reverse transcriptase translocation inhibitor, or NRTTI; should it ultimately gain FDA approval, it would be the first approved HIV drug in that class.)

During this meeting, Chloe Orkin, a professor of medicine at Queen Mary University of London and former chair of the British HIV Association, presented a deep dive into the relatively small number of virologic failures experienced by people taking islatravir plus doravirine in the Phase 2 study that pitted three different doses of the duo against doravirine/emtricitabine/TDF. Efficacy data at 48 weeks from that clinical trial were initially presented at the International AIDS Society conference last summer, generating speculation about islatravir’s future place in the HIV treatment armamentarium.

Orkin et al found that even among study participants who discontinued the islatravir combo due to protocol-defined virologic failure, their viral load still never exceeded 200 copies/mL—and, in fact, never even crossed the 80 copies/mL threshold in a confirmed viral load test result. Orkin also noted that low-level viremia persisted through 42 days of follow-up among half the people who switched off the islatravir combo because of protocol-defined virologic failure, suggesting that the study drug had not been the primary cause of the failure.

Another islatravir substudy presented at AIDS 2020 focused on adverse events in the same Phase 2 first-line treatment trial on which Orkin et al based their virologic failure analysis. Presented by Edwin DeJesus, M.D., the medical director of the Orlando Immunology Center, the analysis found that islatravir plus doravirine appeared to have a similar adverse event profile compared to doravirine/emtricitabine/TDF through 48 weeks.

Adverse events were extremely common among both study arms through the first 24 weeks, with roughly two-thirds of participants across all arms reporting at least one event. (Of note, the islatravir arm also received lamivudine through the first 24 weeks to accelerate viral suppression.) Adverse events attributed specifically to the study drugs appeared to occur less frequently in the islatravir arms relative to the doravirine/emtricitabine/TDF arm, however. Virtually all events were classified as minor, with no adverse event–related treatment discontinuations.

By week 48, adverse event rates had dropped somewhat (to less than 60% in both arms) and drug-attributed events evened out between the study arms, though moderate adverse events appeared to occur more frequently in the triple-drug arm than the islatravir arms.

Severe adverse events remained extremely rare, as were treatment discontinuations due to adverse events. (Two people receiving high-dose islatravir discontinued, one due to gastrointestinal distress and the other to reactivation of hepatitis B infection. One person receiving the triple-drug regimen discontinued, due to a worsening of their preexisting long QT syndrome.)

DeJesus et al found that the most commonly occurring adverse events were consistent across all study arms, but that the incidence rates sometimes differed by study drug:

• Diarrhea was reported by 7% of islatravir recipients, compared to 16% of triple-drug recipients.
• Headache was reported by 11% of islatravir recipients, compared to 7% of triple-drug recipients.
• Nausea was reported by 9% of islatravir recipients and 10% of triple-drug recipients.

In most cases, these events were mild and tended to be transient, usually lasting no more than a few days at most.

Several other events were reported with some frequency within study arms, including arthralgia (7% of islatravir recipients), bronchitis (7%), nasopharyngitis (7%), syphilis coinfection (8%), and vitamin D deficiency (7%).

Lab abnormalities (e.g., ALT levels, creatine kinase levels, and triglycerides) were relatively similar across study arms, as were changes in total cholesterol:HDL cholesterol ratio and fasting glucose levels (the latter of which rose slightly in the islatravir arms and dropped slightly in the triple-drug arm, though the difference fell well short of significance).

Some weight gain was seen in all study arms and appeared to show a trend toward greater frequency in the islatravir arms, particularly during the first 24 weeks of therapy. Overall, a 5% or greater increase in body weight was seen at the 48-week mark among 33% of islatravir recipients at week 24 and 38% at week 48; by contrast, in triple-drug recipients, the same level of weight increase occurred 16% of the time at week 24 and 23% of the time at week 48. DeJesus et al posited that this may be a “return to health” phenomenon, but the definitive cause is unknown.

The islatravir plus doravirine combination continues to make its way through a range of clinical trials, with Phase 3 studies underway exploring the two-drug regimen in treatment-naive people, virologically suppressed people, and people with significant prior HIV treatment experience.