CROI 2012: Studies Look at Interactions Between New Hepatitis C Drugs and HIV Antiretrovirals

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Drug-drug interactions between direct-acting antiviral agents for hepatitis C and some antiretroviral medications used to treat HIV are common, but are often modest and can be managed with dose adjustments when treating people with HIV/HCV coinfection, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last week in Seattle.

Approximately one-third of HIV-positive people are coinfected with hepatitis C virus (HCV). Last year's approval of the first direct-acting antivirals (DAAs) for hepatitis C has ushered in a new era of treatment, but these drugs are not yet approved for coinfected patients, a group that urgently needs better treatment options.

One factor that slows development of therapies for the coinfected population is concern about drug-drug interactions (DDIs). Some drugs can raise or lower concentrations of other medications, leading to elevated levels that can cause worse side effects, or conversely, reduced levels that can allow viral breakthrough and treatment failure. Ideally, drug interactions should be assessed in laboratory studies and healthy volunteers before new drugs are tested in coinfected patients, but this does not always happen.

Boceprevir

Ellen Hulskotte from Merck and colleagues presented a poster (abstract 771LB) looking at drug-drug interactions between the HCV protease inhibitor boceprevir (Victrelis) -- 1 of the first 2 approved hepatitis C DAAs -- and the widely used ritonavir-boosted HIV protease inhibitors, atazanavir (Reyataz), darunavir (Prezista) and lopinavir/ritonavir (Kaletra).

In this study 39 healthy adult volunteers with neither HCV nor HIV first received 800 mg 3-times-daily boceprevir for 6 days. They then took 300/100 mg once-daily atazanavir/ritonavir, 600/100 mg twice-daily darunavir/ritonavir, or 400/100 mg twice-daily lopinavir/ritonavir for about 2 weeks, adding boceprevir during the last 5 days.

Results

These drug-drug interactions had already come to light in February when Merck issued a Dear Health Care Professional letter describing the findings and stating that the company "does not recommend" co-administration of boceprevir with ritonavir-boosted HIV protease inhibitors.

However, as described in another presentation at CROI, boceprevir combined with pegylated interferon and ribavirin appeared safe and effective for HIV/HCV coinfected people taking boosted HIV protease inhibitors. A small number of participants experienced HIV viral breakthrough -- which could be a consequence of reduced antiretroviral drug levels -- but this occurred in both the boceprevir arm (three of 64 patients) and the group receiving pegylated interferon/ribavirin alone (four of 34 patients).

These conflicting results make it difficult to know how to manage HIV/HCV-coinfected patients today. At a CROI symposium on this topic, Jürgen Rockstroh from University of Bonn said, "For now the only recommendation we can give is that patients not newly start boceprevir-based therapy with any of the listed HIV protease inhibitors."

However, Douglas Dieterich from Mt Sinai Medical Center suggested in an interview that "it's perfectly appropriate to use either boceprevir or telaprevir as long as you're cognizant of drug-drug interactions" and frequently monitor both HIV and HCV viral load.

Another option, favored by both Rockstroh and Dieterich, would be to use boceprevir with the HIV integrase inhibitor raltegravir (Isentress).

In another poster at CROI (abstract 772LB), Clara de Kanter and colleagues from University of Nijmege in the Netherlands reported findings from a drug-drug interaction study of 24 healthy volunteers who either received 800 mg 3-times-daily boceprevir for 10 days then added 400 mg raltegravir once-daily, or else took the same drugs in the reverse order.

No interactions were expected based on how the drugs are process in the body, and concentrations of raltegravir fell within normal range, leading the researchers to conclude that boceprevir has "no clinically meaningful effect" on raltegravir pharmacokinetics.

"Due to the absence of a clinically significant drug interaction," they continued, "raltegravir can be recommended for combined HIV/HCV treatment including boceprevir."

TMC435

In a related study (abstract 49) presented during an oral session on breakthroughs in hepatitis, Sivi Ouwerkerk-Mahadevan from Janssen present drug-drug interaction findings for Janssen/Tibotec/Medivir's next-generation HCV protease inhibitor TMC435.

Researchers performed 2 open-label cross-over studies of healthy volunteers to investigate pharmacokinetic interactions between TMC435 and the antiretrovirals rilpivirine (Edurant), tenofovir (Viread), efavirenz (Sustiva), and raltegravir.

A totally of 48 healthy adult volunteers with neither HIV nor HCV were randomly assigned to receive 150 mg TMC435 once-daily, followed by an antiretroviral alone (25 mg rilpivirine once-daily, 300 mg tenofovir once-daily, 600 mg efavirenz once-daily, or 400 mg raltegravir twice-daily), followed by TMC435 combined with an antiretroviral. Dosing periods ranged from 7 to 14 days.

Results

The researchers concluded that no dose adjustments are required when combining TMC435 with rilpivirine, raltegravir, or tenofovir, but co-administration of TMC435 and efavirenz is not recommended.

"If efficacy and safety are confirmed," they suggested, "these combinations may provide convenient treatment options for HCV/HIV-coinfected patients."

Daclatasvir

Finally, in another poster presentation (abstract 618), Marc Bifano from Bristol-Myers Squibb conducted pharmacokinetic studies in healthy volunteers to look for drug-drug interactions between the investigational HCV NS5A inhibitor daclatasvir (formerly BMS-790052) and antiretrovirals from 3 classes.

In 2 studies, a total of 29 participants first received 60 mg daclatasvir once-daily for 4 days, then added either 300/100 mg atazanavir/ritonavir once-daily or 600 mg efavirenz once-daily for up to 18 days. In the third study, 20 participants took the same dose of daclatasvir or 300 mg tenofovir once-daily or both for 7 days in a cross-over design.

Results

The researchers concluded that, "no clinically relevant drug-drug interactions" occurred between daclatasvir and tenofovir, and daclatasvir "did not appear to have any clinically significant effects" on efavirenz or atazanavir/ritonavir.

However, daclatasvir levels were altered when co-administered with atazanavir/ritonavir or efavirenz. The researchers calculated that lowering the daclatasvir dose to 30 mg once-daily when given with atazanavir/ritonavir, or raising it to 90 mg once-daily when used with efavirenz, "are expected to provide daclatasvir exposure similar to that for 60 mg daclatasvir administered alone."

Taken together, these findings suggest that most HIV/HCV coinfected people should be able to find an antiretroviral regimen that can be safely and effectively used with new hepatitis C drugs.

However, they also show that clinically important drug-drug interactions can and do occur with some specific combinations, underscoring the demand from community advocates that pharmaceutical companies must perform drug-drug interaction studies in the laboratory and in healthy volunteers before moving into clinical trials of coinfected patients.

3/15/12

References

E Hulskotte, H-P Feng, F Xuan,et al. Pharmacokinetic Interaction Between the HCV Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Lopinavir, and Darunavir. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 771LB.

C De Kanter, M Blonk, A Colbers, et al. The Influence of the HCV Protease Inhibitor Boceprevir on the Pharmacokinetics of the HIV Integrase Inhibitor Raltegravir. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 772LB.

S Ouwerkerk-Mahadevan, V Sekar, M Peeters, et al. The Pharmokinetic Interactions of HCV Protease Inhibitor TMC435 with RPV, TDF, EFV, or RAL in Healthy Volunteers. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 49.

M Bifano, C Hwang, B Oosterhuis, et al. Assessment of HIV ARV Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile Which Supports Co-administration with Tenofovir Disoproxil Fumarate, Efavirenz, and Atazanavir/Ritonavir. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 618.