Feature

Much Ado About (Almost) Nothing: The Impact of PPIs and DAAs

Amid the overwhelmingly positive response to direct-acting antivirals post-2011 came a handful of data sets suggesting a negative drug–drug interaction with proton pump inhibitors. However, the studies were, at best, moderately conclusive.

They demonstrated an association with slightly reduced response rates, but the researchers in each of these data sets concluded that the situation was manageable. The association appeared only to exist with sofosbuvir/ledipasvir (Harvoni, Gilead), and was tenuous at best. But questions remained. As new therapies and combinations undergo testing, a potential interaction with PPIs must be accounted for, at least to some degree.

Mitchell L. Shiffman

“In general, the concerns about PPIs and the most common regimen, Harvoni, created a lot of anxiety,” Elliott Benjamin Tapper, MD, of the Division of Gastroenterology and Hepatology at the University of Michigan, told HCV Next in an interview. “A lot of the concerns among clinicians and counseling in clinic relates to whether patients can be on PPIs.”

Mitchell L. Shiffman, MD, of the Liver Institute of Virginia, spoke plainly and broadly on the topic. “This does not apply to all DAAs,” he said. “Sofosbuvir-based regimens have a problem.” He noted that the package insert for sofosbuvir/velpatasvir (Epclusa, Gilead) contains stricter recommendations regarding PPI use. “The question, for all of these sofosbuvir-based regimens, is: How significant is the association and how much will this impact SVR? We don’t really know for sure. But it does seem to be more of a limitation for Epclusa.”

The point of concern is the mechanisms of action of the respective drugs. Specifically, the way PPIs impact the absorption of the DAA. While researchers seem to have gained a handle on dosing strategies to minimize this effect with sofosbuvir-based regimens, it remains to be seen whether it will be a problem for future therapies. For example, Shiffman said PPI use is not an issue for grazoprevir/elbasvir (Zepatier, Merck) or ombitasvir, paritaprevir and ritonavir with dasabuvir (Viekira Pak, AbbVie) and does not appear to be a problem for glecaprevir/pibrentasvir (Abbvie), which is anticipated to be approved by the FDA this summer.

Mechanism of Interaction

Three studies were published in 2016 that elucidated the issue with absorption. Tapper and colleagues cited data from the HCV-TARGET study suggesting that concomitant use of PPIs with ledipasvir/sofosbuvir yielded reduced SVR12 rates. They aimed to determine the impact of PPIs on SVR12 in a real-world cohort of 1,979 patients who underwent therapy with this drug combination.

Eligible participants had record of treatment with the combination with or without ribavirin for 8, 12 or 24 weeks. SVR12 in a per-protocol basis served as the primary endpoint. Among patients who completed therapy, the SVR12 rates were 97.1% among PPI recipients and 98.2% among those who did not receive PPIs (P = .19). Decreased SVR12 did not occur in patients who had received low or high doses of PPI. However, the SVR12 rate was lower in patients receiving PPIs twice daily (91.2%; 95% CI, 77-97). In a propensity-matched analysis, no significant association was observed between SVR12 and any dose or frequency of PPI therapy, according to the findings. Results of a sensitivity analysis, however, indicated that in cirrhotics, the twice-daily PPI regimen yielded reduced SVR12 (OR = 0.11; 95% CI, 0.02-0.59).

“These data from a cohort of real-world patients receiving hepatitis C antibody therapy with [ledipasvir/sofosbuvir with or without ribavirin] support the prescription labeling suggesting that patients take no more than low-dose (20-mg omeprazole equivalents) PPI daily,” the researchers concluded.

“The key fact is that ledipasvir, like the newer NS5A inhibitor velpatasvir, requires an acidic (low pH) environment for absorption,” Tapper said. “That is something that was shown in a pharmacokinetic study where they just looked at blood levels of the drug on or off PPI.”

The purpose of PPI therapy is to make the stomach less acidic, according to Tapper. “This can theoretically decrease the amount of the DAA drug that gets into the system,” he said. “But we don’t know if it decreases it enough to reduce efficacy.”

Shiffman suggested that this issue is manageable with attention to the timing and dosing. “If you give a low dose of the PPI once a day, you should be fine,” he said. “Importantly, the PPI should be given first thing in the morning at the same time as Harvoni. That maximizes the absorption of sofosbuvir and ledipasvir.”

The FDA recommends that a PPI should not be taken at more than 20 mg, according to Tapper. “What we found is that in patients taking a PPI, we didn’t see a lower cure rate,” he said “We also saw that people with a higher dose of PPI had a similar cure rate.”

Naoky Tsai, MD, clinical professor of Medicine at the John A. Burns School of Medicine at the University of Hawaii, Manoa, and medical director of the Liver Transplant Program at Queen’s Medical Center in Honolulu, echoed this point. He was a researcher in the Tapper study.

“We take the conservative approach to recommend that if a PPI is taken as recommended as in the prescription information put out by FDA, one can ascertain that there will be no influence on the outcome of SVR rate,” he said.

It may be worth noting that in this particular data set, in a sensitivity analysis where patients were matched for their propensity to research twice daily PPI, the twice daily regimen reduced SVR rates among cirrhotic PPI users. Tsai explained this discrepancy. “The propensity score matching is an attempt to make two populations as similar as possible for the known characteristics, such as patient, disease and treatment characteristics captured in the data set,” he said. “The sensitivity analyses are asking the question: what happens to the outcome if we change one of the variables?”

Tsai pointed out that the two sensitivity analyses occurred after propensity score matching. “The first is in all patients with cirrhosis, where we found that twice-daily PPI impacted outcomes,” he said. “The disclaimer here is that while significant, the sample is small and not powered to detect differences in dosing frequency. So, at best, this is not proof, but it does raise a concern.”

Tapper put the findings into broader context. “What these results tell us is that if you are dosing twice daily, you may see reduced efficacy,” he said. “However, I’m not so sure you could generalize these results. Nevertheless, if your patient is cirrhotic, you really want them to be cured, so you do what you can to improve their chances and that may mean avoiding twice-daily PPIs.”

Elliot Benjamin Tapper

He added that a high dose of PPI did not change SVR. “I’m not saying you should treat your patient with a high-dose PPI,” he said. “But I would not be afraid to use a high dose of a PPI if it was clinically indicated. That being said, I am not so sure that the data that we produced changed practice. The PPI issue is still an uncomfortable one.”

Other Data Sets

The HCV-TARGET study was an important set of findings in this discussion. Terrault and colleagues collected data for 2,099 patients to determine factors associated with treatment failure with regimens containing ledipasvir/sofosbuvir. The data set comprised 1,788 patients treated without ribavirin, including 282 patients treated for 8 weeks, 910 for 12 weeks, 510 for 24 weeks and 86 patients treated for a different duration. Among 311 patients treated with ribavirin, 212 were treated for 12 weeks, 81 were treated for 24 weeks and 18 were treated for another duration.

Results indicated that absence of PPIs was one of the factors that predicted SVR12. “Modification of proton pump inhibitor use may increase rates of SVR,” the researchers concluded.

Afdhal and colleagues “An incomplete report from the HCV TARGET network suggested that PPI use at baseline was associated with a 5% reduction in SVR12; however, data regarding the actual PPI, duration of use and dosage was not available.”

In the current study, they aimed to evaluate the type of PPI used, along with the dose and duration of those drugs, and how they impacted SVR12 in a cohort of 2,034 patients being treated with LDV/SOF. Eligible participants had been treated for 8, 12 or 24 weeks with or without ribavirin between October 2014 and March 2015. Daily PPIs were being used by 468 patients in the cohort, with 63% of those receiving omeprazole, 17% pantoprazole and 11% esomeprazole. High-dose, twice-daily PPIs were used in 120 patients, or just over one-quarter of the cohort.

The overall SVR12 rate was 95% in the intention-to-treat analysis and 98% in the per-protocol analysis. The SVR12 rate for PPI users was 97%. Results of a matched propensity analysis comparing PPI use to non-PPI use indicated no impact of those drugs on response.

“Daily PPI did not have an effect on SVR in a heterogeneous real-world U.S. population and suggests that [ledipasvir/sofosbuvir] can be safely used in HCV genotype 1 patients according to current prescribing information,” the researchers concluded.

Naoky Tsai

For Shiffman, part of the reason for this ongoing research is because so many people take PPIs. “These drugs are among the most prescribed medications in the U.S.,” he said. “At least half of our patients are on a PPI. Sometimes the indication is not very strong and so when it is interfering with HCV therapy, it’s easy to stop. But sometimes a patient will have debilitating acid reflux or gastric ulcers, so it makes sense that people need the medications. Clinically, you have to make that decision: Stop the PPI and switch to an alternative acid suppression medication or use an alternate DAA, such as Zepetier or Viekira Pak. More research helps inform those decisions.”

Other Therapies, Future Research

Shiffman acknowledged that this is a niche area of research. “We are likely to see more studies with velpatasvir, but we might not see much more after that,” he said. “The reality is that that we have several DAAs that are all highly effective in curing HCV and we can simply pick an alternative agent for patients taking a PPI if the PPI cannot be stopped.”

Regarding velpatasvir, Tapper agreed that more real-world data could be justified. “As far as we know now, if you want to use a PPI with this drug, you should use a minimum dose of 20 mg and it should be 4 hours after the velpatasvir dose,” he said. “Until then, the package insert does not recommend coadministration of PPI with velpatasvir

There is unlikely to be any research about grazoprevir/elbasvir, according to most experts. “We haven’t seen any suggestion that PPIs affect the absorption of this product,” Shiffman said.

Despite the increasing body of knowledge and the relative safety of PPIs with most DAA combinations, many clinicians remain nervous, according to Tapper. “It remains to be seen how much this matters for velpatasvir,” he said. “We haven’t had this drug around long enough to generate a real-world data set. Even though many of the data are reassuring, physicians understandably want to do everything they can to maximize cure.”

Shiffman added that with so many therapeutic options available, the stakes have increased. “Patients are expecting a cure,” he said. “There is the perception that combining a DAA with a PPI is taking a chance, and so people might not want to do it.”

Tsai offered some practical thoughts to sum up those concerns: “Read the prescribing information carefully before starting DAA therapies,” he said. — by Rob Volansky

Disclosures: Tapper reports no relevant financial disclosures. Shiffman reports being an advisor, speaker and receiving research funding from AbbVie, Gilead and Merck. Tsai reports receiving research grants, being a member of the speaker’s bureau and serving on the advisory board of AbbVie, Beckman, Bristol-Myers Squibb, Genfit, Gilead, Intercept, Merck, Roche Diagnostic and Shire.

Amid the overwhelmingly positive response to direct-acting antivirals post-2011 came a handful of data sets suggesting a negative drug–drug interaction with proton pump inhibitors. However, the studies were, at best, moderately conclusive.

They demonstrated an association with slightly reduced response rates, but the researchers in each of these data sets concluded that the situation was manageable. The association appeared only to exist with sofosbuvir/ledipasvir (Harvoni, Gilead), and was tenuous at best. But questions remained. As new therapies and combinations undergo testing, a potential interaction with PPIs must be accounted for, at least to some degree.

Mitchell L. Shiffman

“In general, the concerns about PPIs and the most common regimen, Harvoni, created a lot of anxiety,” Elliott Benjamin Tapper, MD, of the Division of Gastroenterology and Hepatology at the University of Michigan, told HCV Next in an interview. “A lot of the concerns among clinicians and counseling in clinic relates to whether patients can be on PPIs.”

Mitchell L. Shiffman, MD, of the Liver Institute of Virginia, spoke plainly and broadly on the topic. “This does not apply to all DAAs,” he said. “Sofosbuvir-based regimens have a problem.” He noted that the package insert for sofosbuvir/velpatasvir (Epclusa, Gilead) contains stricter recommendations regarding PPI use. “The question, for all of these sofosbuvir-based regimens, is: How significant is the association and how much will this impact SVR? We don’t really know for sure. But it does seem to be more of a limitation for Epclusa.”

The point of concern is the mechanisms of action of the respective drugs. Specifically, the way PPIs impact the absorption of the DAA. While researchers seem to have gained a handle on dosing strategies to minimize this effect with sofosbuvir-based regimens, it remains to be seen whether it will be a problem for future therapies. For example, Shiffman said PPI use is not an issue for grazoprevir/elbasvir (Zepatier, Merck) or ombitasvir, paritaprevir and ritonavir with dasabuvir (Viekira Pak, AbbVie) and does not appear to be a problem for glecaprevir/pibrentasvir (Abbvie), which is anticipated to be approved by the FDA this summer.

Mechanism of Interaction

Three studies were published in 2016 that elucidated the issue with absorption. Tapper and colleagues cited data from the HCV-TARGET study suggesting that concomitant use of PPIs with ledipasvir/sofosbuvir yielded reduced SVR12 rates. They aimed to determine the impact of PPIs on SVR12 in a real-world cohort of 1,979 patients who underwent therapy with this drug combination.

Eligible participants had record of treatment with the combination with or without ribavirin for 8, 12 or 24 weeks. SVR12 in a per-protocol basis served as the primary endpoint. Among patients who completed therapy, the SVR12 rates were 97.1% among PPI recipients and 98.2% among those who did not receive PPIs (P = .19). Decreased SVR12 did not occur in patients who had received low or high doses of PPI. However, the SVR12 rate was lower in patients receiving PPIs twice daily (91.2%; 95% CI, 77-97). In a propensity-matched analysis, no significant association was observed between SVR12 and any dose or frequency of PPI therapy, according to the findings. Results of a sensitivity analysis, however, indicated that in cirrhotics, the twice-daily PPI regimen yielded reduced SVR12 (OR = 0.11; 95% CI, 0.02-0.59).

“These data from a cohort of real-world patients receiving hepatitis C antibody therapy with [ledipasvir/sofosbuvir with or without ribavirin] support the prescription labeling suggesting that patients take no more than low-dose (20-mg omeprazole equivalents) PPI daily,” the researchers concluded.

“The key fact is that ledipasvir, like the newer NS5A inhibitor velpatasvir, requires an acidic (low pH) environment for absorption,” Tapper said. “That is something that was shown in a pharmacokinetic study where they just looked at blood levels of the drug on or off PPI.”

PAGE BREAK

The purpose of PPI therapy is to make the stomach less acidic, according to Tapper. “This can theoretically decrease the amount of the DAA drug that gets into the system,” he said. “But we don’t know if it decreases it enough to reduce efficacy.”

Shiffman suggested that this issue is manageable with attention to the timing and dosing. “If you give a low dose of the PPI once a day, you should be fine,” he said. “Importantly, the PPI should be given first thing in the morning at the same time as Harvoni. That maximizes the absorption of sofosbuvir and ledipasvir.”

The FDA recommends that a PPI should not be taken at more than 20 mg, according to Tapper. “What we found is that in patients taking a PPI, we didn’t see a lower cure rate,” he said “We also saw that people with a higher dose of PPI had a similar cure rate.”

Naoky Tsai, MD, clinical professor of Medicine at the John A. Burns School of Medicine at the University of Hawaii, Manoa, and medical director of the Liver Transplant Program at Queen’s Medical Center in Honolulu, echoed this point. He was a researcher in the Tapper study.

“We take the conservative approach to recommend that if a PPI is taken as recommended as in the prescription information put out by FDA, one can ascertain that there will be no influence on the outcome of SVR rate,” he said.

It may be worth noting that in this particular data set, in a sensitivity analysis where patients were matched for their propensity to research twice daily PPI, the twice daily regimen reduced SVR rates among cirrhotic PPI users. Tsai explained this discrepancy. “The propensity score matching is an attempt to make two populations as similar as possible for the known characteristics, such as patient, disease and treatment characteristics captured in the data set,” he said. “The sensitivity analyses are asking the question: what happens to the outcome if we change one of the variables?”

Tsai pointed out that the two sensitivity analyses occurred after propensity score matching. “The first is in all patients with cirrhosis, where we found that twice-daily PPI impacted outcomes,” he said. “The disclaimer here is that while significant, the sample is small and not powered to detect differences in dosing frequency. So, at best, this is not proof, but it does raise a concern.”

Tapper put the findings into broader context. “What these results tell us is that if you are dosing twice daily, you may see reduced efficacy,” he said. “However, I’m not so sure you could generalize these results. Nevertheless, if your patient is cirrhotic, you really want them to be cured, so you do what you can to improve their chances and that may mean avoiding twice-daily PPIs.”

Elliot Benjamin Tapper

He added that a high dose of PPI did not change SVR. “I’m not saying you should treat your patient with a high-dose PPI,” he said. “But I would not be afraid to use a high dose of a PPI if it was clinically indicated. That being said, I am not so sure that the data that we produced changed practice. The PPI issue is still an uncomfortable one.”

Other Data Sets

The HCV-TARGET study was an important set of findings in this discussion. Terrault and colleagues collected data for 2,099 patients to determine factors associated with treatment failure with regimens containing ledipasvir/sofosbuvir. The data set comprised 1,788 patients treated without ribavirin, including 282 patients treated for 8 weeks, 910 for 12 weeks, 510 for 24 weeks and 86 patients treated for a different duration. Among 311 patients treated with ribavirin, 212 were treated for 12 weeks, 81 were treated for 24 weeks and 18 were treated for another duration.

PAGE BREAK

Results indicated that absence of PPIs was one of the factors that predicted SVR12. “Modification of proton pump inhibitor use may increase rates of SVR,” the researchers concluded.

Afdhal and colleagues “An incomplete report from the HCV TARGET network suggested that PPI use at baseline was associated with a 5% reduction in SVR12; however, data regarding the actual PPI, duration of use and dosage was not available.”

In the current study, they aimed to evaluate the type of PPI used, along with the dose and duration of those drugs, and how they impacted SVR12 in a cohort of 2,034 patients being treated with LDV/SOF. Eligible participants had been treated for 8, 12 or 24 weeks with or without ribavirin between October 2014 and March 2015. Daily PPIs were being used by 468 patients in the cohort, with 63% of those receiving omeprazole, 17% pantoprazole and 11% esomeprazole. High-dose, twice-daily PPIs were used in 120 patients, or just over one-quarter of the cohort.

The overall SVR12 rate was 95% in the intention-to-treat analysis and 98% in the per-protocol analysis. The SVR12 rate for PPI users was 97%. Results of a matched propensity analysis comparing PPI use to non-PPI use indicated no impact of those drugs on response.

“Daily PPI did not have an effect on SVR in a heterogeneous real-world U.S. population and suggests that [ledipasvir/sofosbuvir] can be safely used in HCV genotype 1 patients according to current prescribing information,” the researchers concluded.

Naoky Tsai

For Shiffman, part of the reason for this ongoing research is because so many people take PPIs. “These drugs are among the most prescribed medications in the U.S.,” he said. “At least half of our patients are on a PPI. Sometimes the indication is not very strong and so when it is interfering with HCV therapy, it’s easy to stop. But sometimes a patient will have debilitating acid reflux or gastric ulcers, so it makes sense that people need the medications. Clinically, you have to make that decision: Stop the PPI and switch to an alternative acid suppression medication or use an alternate DAA, such as Zepetier or Viekira Pak. More research helps inform those decisions.”

Other Therapies, Future Research

Shiffman acknowledged that this is a niche area of research. “We are likely to see more studies with velpatasvir, but we might not see much more after that,” he said. “The reality is that that we have several DAAs that are all highly effective in curing HCV and we can simply pick an alternative agent for patients taking a PPI if the PPI cannot be stopped.”

Regarding velpatasvir, Tapper agreed that more real-world data could be justified. “As far as we know now, if you want to use a PPI with this drug, you should use a minimum dose of 20 mg and it should be 4 hours after the velpatasvir dose,” he said. “Until then, the package insert does not recommend coadministration of PPI with velpatasvir

There is unlikely to be any research about grazoprevir/elbasvir, according to most experts. “We haven’t seen any suggestion that PPIs affect the absorption of this product,” Shiffman said.

Despite the increasing body of knowledge and the relative safety of PPIs with most DAA combinations, many clinicians remain nervous, according to Tapper. “It remains to be seen how much this matters for velpatasvir,” he said. “We haven’t had this drug around long enough to generate a real-world data set. Even though many of the data are reassuring, physicians understandably want to do everything they can to maximize cure.”

Shiffman added that with so many therapeutic options available, the stakes have increased. “Patients are expecting a cure,” he said. “There is the perception that combining a DAA with a PPI is taking a chance, and so people might not want to do it.”

Tsai offered some practical thoughts to sum up those concerns: “Read the prescribing information carefully before starting DAA therapies,” he said. — by Rob Volansky

Disclosures: Tapper reports no relevant financial disclosures. Shiffman reports being an advisor, speaker and receiving research funding from AbbVie, Gilead and Merck. Tsai reports receiving research grants, being a member of the speaker’s bureau and serving on the advisory board of AbbVie, Beckman, Bristol-Myers Squibb, Genfit, Gilead, Intercept, Merck, Roche Diagnostic and Shire.