One of the latest FDA-approved drugs is Delstrigo, a single-tablet regimen containing doravirine, lamivudine, and tenofovir disoproxil fumarate. Made by Merck, it is designed to treat HIV in adults who have never taken HIV medication before.
The drug’s approval was a direct result of two randomized, double-blind, active-controlled phase 3 trials called DRIVE-AHEAD and DRIVE-FORWARD. These studies are notable because not only did researchers see a lower discontinuation rate with Delstrigo (3 percent, compared to the 6 percent taking a different treatment), but also a higher percentage showed viral suppression after 48 weeks of treatment with Delstrigo versus the alternative treatment option.
Researchers also found that Delstrigo can be co-administered with a wide range of nonantiretroviral agents. However, it cannot be co-administered with enzalutamide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, mitotane, or St. John’s wort.
In light of the FDA approval of both Delstrigo and Pifeltro (below), Dr. George Hanna, vice president and therapeutic area head of infectious diseases at Merck, said in a statement: “As part of Merck’s 30-year commitment to the care of people with HIV, we are pleased to now bring forward these two new antiretroviral treatment options, Delstrigo and Pifeltro, which we believe offer a compelling clinical profile for clinicians and people living with HIV. We are thankful to the researchers as well as those living with HIV and their communities for the collaboration that made today’s approval possible.”
In April, the Food and Drug Administration approved ViiV Healthcare’s Dovato, a single-tablet regimen of 50 mg dolutegravir and 300 mg lamivudine for treatment of HIV in adults with no antiretroviral treatment history and with no known resistance to either component.
As a two-drug regimen, Dovato reduces exposure to the number of antiretrovirals from the start of treatment while maintaining the effectiveness and high barrier to resistance of traditional three-drug dolutegravir regimens. Because it contains only two drugs (dolutegravir and lamivudine), rather than a traditional three, there is one less drug to worry about — while seeing the same viral load control and reduction. That’s an added bonus for people worried about or experiencing side effects or long-term toxicity from multiple drugs. Like a typical three-drug regimen, Dovato uses its component drugs to inhibit the viral cycle at different sites. Integrase inhibitors, like dolutegravir, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T cells), according to a press release from ViiV Healthcare. This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Lamivudine is a nucleoside reverse-transcriptase inhibitor that works by interfering with the conversion of viral RNA into DNA, which in turn stops the virus from multiplying.
Dovato’s approval was supported by the landmark studies GEMINI 1 and GEMINI 2, which included over 1,400 people living with HIV.
“One thing that surprised us in a very pleasant way was really how well it performed in individuals with high viral loads,” Kimberly Smith, head of global research and medical strategy for ViiV Healthcare, told Plus. “We made a point of enrolling individuals with viral loads above 100,000, and it ended up being that around 20 percent of the individuals in the trial were above 100,000. And when you looked at those individuals on D3 compared to the three-drug regimen, dolutegravir with Truvada, there was no difference in the outcomes in the high viral loads. And that was really exciting for us because I think a lot of folks had speculated that maybe a two-drug regimen wouldn’t do as well in individuals who had high viral loads, but this shows quite clearly that that’s not the case.”
The benefits of a two-drug regimen rather than three-drug regimen, Smith explains, go beyond adherence. It’s also bringing hope for fewer side effects in the long term.
“That’s where some of your kidney troubles and your bone trouble, those types of things, can come up after being on medicine for a long time,” Smith says. “And so what was done with Dovato is taking away one drug, and in particular we took away in comparison to the three-drug regimen that we looked at here in the GEMINI study, which was tenofovir, FDC, and dolutegravir, we took away the tenofovir basically. Tenofovir is the drug that has been associated with bone damage and renal disease, so we’ve taken that out of the picture altogether. It’s one less thing for patients to have to worry about down the road.”
Merck’s newest nonnucleoside reverse transcriptase inhibitor (NNRTI), Pifeltro is a single 100 mg tablet of doravorine, which is to be used in combination with other antiretroviral medications. Pifeltro has several advantages over existing NNRTIs on the market. Clinical studies have shown it to have few drug interactions (particularly with acid-reducing agents), can be taken with or without food, has a more favorable lipid profile, and has lower incidence of rash.
“A new HIV medication that is effective and well-tolerated and has a relatively high barrier to resistance and can be co-formulated with other HIV medications is to be welcomed,” David Alain Wohl, M.D., a professor in the Division of Infectious Disease at the University of North Carolina at Chapel Hill and site leader of the university’s AIDS Clinical Trials Unit, told Infectious Disease News. “Doravirine is a nice addition to the nonnucleoside class, and it is active even against virus that is resistant to older agents in this class. The coformulation with TDF and 3TC may allow some people on two or more pills to switch to a single tablet a day.”
When tested in clinical trials, researchers found that people demonstrated sustained viral suppression after 48 weeks of being on Pifeltro. The drug also met its primary endpoint of non-inferior efficacy as those taking alternate treatment options.
“As a result of the remarkable strides made in the fight against HIV, clinicians and their patients have the opportunity to work together to identify treatment regimens that may be best for each individual, taking into account other aspects of that person’s health, including other medicines they may be taking,” Wohl noted.