People with HIV and hepatitis C virus (HCV) co-infection who take sofosbuvir/ledipasvir (Harvoni) to treat hepatitis C along with boosted protease inhibitor antiretroviral regimens may experience changes in drugs levels, but these are mostly not considered clinically relevant, according to a drug-drug interaction study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2015) last month in Seattle, USA. However, data on the safety and efficacy of combining sofosbuvir/ledipasvir with boosted protease inhibitors during treatment are lacking, and increased tenofovir exposure may be a concern.
The advent of interferon-free direct-acting antiviral regimens has brought about a revolution in treatment for chronic HCV infection, including for patients who have traditionally been considered 'difficult to treat', such as those with HIV/HCV co-infection. Clinical trials have seen hepatitis C cure rates for people with co-infection equal to those for people with HCV alone, and current treatment guidelines and product labels indicate that people with HIV can be treated with the same recommended regimens as HIV-negative people, taking into account potential interactions with antiretroviral therapy (ART).
Polina German of Gilead Sciences reported findings from a phase 1 study to evaluate interactions between sofosbuvir/ledipasvir and ART regimens containing ritonavir-boosted atazanavir (Reyataz) or darunavir (Prezista) plus tenofovir/emtricitabine (Truvada) in healthy HIV-negative volunteers.
Studies to date have shown that sofosbuvir and ledipasvir have limited potential for clinically significant drug-drug interactions, she noted as background. Sofosbuvir (but not its predominant metabolite GS-331007) and ledipasvir are substrates of P-glycoprotein (Pgp) and BCRP drug transporters, which play a role in drug distribution and elimination; ledipasvir also inhibits the action of Pgp and BCRP. Neither sofosbuvir nor ledipasvir are metabolised by cytochrome P450 enzymes that are inhibited by ritonavir – which is how it raises levels of many medications including HIV protease inhibitors.
Before studying sofosbuvir/ledipasvir in people with HIV and HCV co-infection, Gilead scientists conducted drug-drug interaction studies with commonly used antiretroviral regimens. Early on, regimens containing efavirenz (Sustiva), raltegravir (Isentress) or rilpivirine (Edurant) plus Truvada were found to be safe when combined with sofosbuvir/ledipasvir; participants with HIV and HCV co-infection were limited to these ART regimens in sofosbuvir/ledipasvir trials such as ION-4 and ERADICATE.
Co-administration with ritonavir-boosted HIV protease inhibitors is more challenging because ritonavir interacts with many drugs. Sofosbuvir/ledipasvir did increase tenofovir levels somewhat in NNRTI-containing regimens due to its inhibition of Pgp and BCRP, but not enough to be considered clinically important. However, tenofovir reaches higher levels when taken with ritonavir-boosted protease inhibitors, and when added to the effect of sofosbuvir/ledipasvir this could potentially bring levels high enough to cause kidney toxicity or other side-effects.
German reported findings from a randomised, multiple-dose, cross-over study that included 97 participants without HIV or hepatitis C. About 70% were men, the mean age was 33 years, and whites, black and Hispanics/Latinos were all well represented.
In Part A, participants simultaneously received the fixed-dose sofosbuvir/ledipasvir coformulation (400mg/90mg) with either atazanavir/ritonavir (300mg/100mg) or darunavir/ritonavir (800mg/100mg) plus tenofovir/emtricitabine (300g/200mg) for 10 days. Based on the results from Part A, volunteers in Part B took sofosbuvir/ledipasvir and the antiretrovirals in a staggered fashion, separated by 12 hours, to see how this might change drug interactions.
The researchers measured plasma concentrations of sofosbuvir, its metabolite GS-331007, ledipasvir and all the antiretrovirals over 24 hours and calculated pharmacokinetic (PK) parameters including overall, maximum and minimum concentrations.
Coadministration of sofosbuvir/ledipasvir with the antiretrovirals appeared safe and well-tolerated, with most observed adverse events being mild or moderate. The most commonly reported side-effects across all regimens were headache and nausea. Some people taking atazanavir/ritonavir had yellowing of the eyes and elevated bilirubin; the only serious adverse event was severe abdominal pain in an atazanavir/ritonavir recipient.
The researchers observed modest increases in levels of GS-331007 and ledipasvir when administered simultaneously with atazanavir/ritonavir plus Truvada. German suggested the increase in ledipasvir was likely due to the effect of atazanavir/ritonavir on Pgp and BCRP metabolic pathways, while the reason for the rise in GS-331007 (which is eliminated by the kidneys) is unknown. Conversely, simultaneous administration of sofosbuvir/ledipasvir with darunavir/ritonavir plus Truvada resulted in a small reduction in the level of sofosbuvir. These changes were not deemed clinically relevant based on prior exposure safety evaluations.
Looking at the effect of sofosbuvir/ledipasvir on the antiretrovirals, trough or minimum levels of atazanavir and ritonavir increased when they were taken simultaneously. German suggested that ledipasvir affects clearance of these drugs, perhaps due to Pgp inhibition. These changes did not warrant dose adjustment. Sofosbuvir/ledipasvir had no notable effect on darunavir levels.
Tenofovir levels increased "moderately" – by 30% to 60% – when taken with sofosbuvir/ledipasvir and either atazanavir/ritonavir or darunavir/ritonavir, compared to levels when taken with the boosted protease inhibitors alone. Again, the effect was attributed to ledipasvir's inhibition of the Pgp and BCRP transporters. German noted that in a different study sofosbuvir/ledipasvir had no apparent effect on clearance of tenofovir by the kidneys, so this was probably not the mechanism underlying elevated levels.
These changes in drug levels were similar regardless of whether sofosbuvir/ledipasvir and the antiretrovirals were taken at the same time or 12 hours apart, showing that staggered dosing had no significant benefit.
The researchers stressed that there are currently no available data on the safety and efficacy of sofosbuvir/ledipasvir taken with boosted protease inhibitors in people with HIV and HCV co-infection. In their abstract they added that "the safety of higher tenofovir concentrations in this setting has not been established," and therefore "patients should be monitored for tenofovir-associated adverse reactions if co-administered."
German said that other ongoing studies are evaluating sofosbuvir/ledipasvir with other antiretroviral regimens including dolutegravir (Tivicay) plus Truvada, and an investigational coformulation containing elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (TAF), a new version that has less detrimental effect on the kidneys and bones than the current tenofovir disoproxil fumarate (TDF).