Merck’s Cavalier Attitude Towards the Welfare of HIV/HCV Coinfected Patients

What You Don’t Know, You Can Sell

tagline Spring 2012<http://www.treatmentactiongroup.org/tagline/2012/spring/tagline/2012/spring>



by Tracy Swan

In places where access to antiretroviral therapy is widespread, people
living with HIV are now dying from a common and curable coinfection:
hepatitis C virus (HCV). HIV increases the risk for, and accelerates the
rate of, liver disease from hepatitis C. Pegylated interferon and
ribavirin, medications used to treat HCV, are less effective in people with
HIV than in their HCV-monoinfected counterparts.

In 2011, the first hepatitis C protease inhibitors, Merck’s boceprevir and
Vertex’s telaprevir, were approved based on trials in people with hepatitis
C monoinfection. Both drugs are being studied in coinfected people, thanks
to pressure from the international HIV/HCV community and encouragement from
regulatory agencies.

Despite outrage from activists, Merck refused to study drug-drug
interactions (DDIs) between boceprevir (Victrelis), their HCV protease
inhibitor, and drugs commonly used to treat HIV, putting coinfected study
volunteers at risk for drug-drug interactions in their own clinical trial.

Drug-drug interactions can have serious consequences for HIV/HCV-coinfected
people, who risk forfeiting current and future treatment options for HIV
and possibly HCV as well. DDIs can lower drug concentrations to an
ineffective level, leading to drug resistance, or increase drug
concentrations, worsening side effects and leading to treatment
discontinuation; they can even be life-threatening, as was the case with
ribavirin and didanosine (DDI; Videx).

The boceprevir coinfection study opened in mid-2009, before Merck had
performed drug-drug interaction studies with HIV protease inhibitors in
healthy volunteers, a common step in drug development. Nonetheless,
coinfected study volunteers were allowed to use them; in fact, by default,
HIV protease inhibitors— or Merck’s own integrase inhibitor, raltegravir
(Isentress)—were the only HIV treatment options for study volunteers, since
non-nucleoside reverse transcriptase inhibitors were not allowed. Activists
kept asking Merck to perform DDIs throughout boceprevir’s development, but
Merck’s attitude remained cavalier; they did not launch key drug-drug
interaction studies until two years later, months after boceprevir was
approved.

The results of DDI studies with three ritonavir-boosted HIV protease
inhibitors, atazanavir/r (Reyataz), darunavir/r (Prezista), and lopinavir/r
(Kaletra) in healthy volunteers (rather than the actual trial participants
who were using boceprevir with HIV protease drugs for almost a year) were
presented in March at the 19th Conference on Retroviruses and Opportunistic
Infections (CROI) in Seattle. The news was not good. Combining boceprevir
with these HIV protease inhibitors lowered concentrations of each HIV
protease inhibitor, at both the highest and lowest (peak and trough) levels.

Boceprevir lowered the peak concentration of atazanavir/r by 25 percent,
and the trough by 49 percent; darunavir/r peak decreased by 36 percent and
trough by 59 percent; for lopinavir/r, coadministration with boceprevir
dropped the peak concentration by 30 percent and trough by 43 percent. In
turn, boceprevir levels dropped by 45 percent when coadministered with
lopinavir/r and by 32 percent when administered with daruanvir/r; only
atazanavir/r had no effect on the concentration of boceprevir.

Failure to characterize these drug-drug interactions put study
participants—and coinfected patients— at an unacceptable level of risk,
although clinical implications—or real-life impact on HIV and hepatitis C
treatment outcomes—of these drug interactions are not clear. Nonetheless,
the U.S. Food and Drug Administration warned that “drug interactions
between the hepatitis C virus (HCV) protease inhibitor Victrelis
(boceprevir) and certain ritonavir-boosted human immunodeficiency virus
(HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can
potentially reduce the effectiveness of these medicines when they are used
together.”

Regulators from the European Medicines Agency’s (EMA) Committee for
Medicinal Products for Human Use (CHMP) went a step further, recommending
that “doctors treating patients co-infected with hepatitis C and HIV should
be aware of the findings of the drug interaction study. They should not
co-administer Victrelis with ritonavir-boosted darunavir or lopinavir in
HIV and hepatitis C co-infected patients. Co-administration of Victrelis
with ritonavir-boosted atazanavir may be considered on a case-by-case basis
if deemed necessary in patients with suppressed HIV viral loads and with an
HIV strain without any suspected resistance to the HIV regimen. Increased
clinical and laboratory monitoring is warranted.”

Vertex’s rival protease inhibitor, telaprevir (Incivek) has outsold
boceprevir: in the fourth quarter of 2011, telaprevir trounced boceprevir
$456.8 million to $87 million. The opportunity to capture the coinfection
market share may have motivated Merck’s decision to delay drug-drug
interaction studies. HCV is more likely to be diagnosed and treated in
HIV-positive people than people with HCV alone, for several reasons. HIV
treatment guidelines recommend HCV testing for all HIV-positive people; the
infrastructure to deliver treatment is already in place; and hepatitis C is
known to be more aggressive in people with HIV, so physicians and patients
are more game to try for a cure.

After Vertex reported drug interactions between telaprevir and ritonavir
boosted HIV protease inhibitors, boceprevir became a more attractive option
for co-infected people. Merck’s vice president of clinical research, Robin
Issacs, alluded to off-label use in the company’s February 8 press release.
“Though VICTRELIS is not indicated for the treatment of chronic HCV in
those who are also infected with HIV, we recognize that some physicians
have prescribed or may be considering prescribing VICTRELIS for patients
taking ritonavir-boosted HIV protease inhibitors. We felt it was important
to share these data as part of our commitment to patient safety and
transparency.”

*Where was Merck’s commitment to safety during boceprevir’s development? We
can only hope that no patients have been harmed.*

The boceprevir experience underscores the importance of timely DDI studies.
There are other medications used by people with hepatitis C—whether or not
they are coinfected with HIV—that warrant study, such as methadone,
buprenorphine, and commonly prescribed psychiatric medications. Merck
representatives have stated that the company will be more proactive with
their promising second-generation hepatitis C protease inhibitor, MK-5172.

Activists have released a
statement<http://www.treatmentactiongroup.org/hcv/2012/hepatitis-c-drug-development-and-drug-drug-interaction-studies>
calling
on regulatory agencies and pharmaceutical companies to study DDIs between
experimental HCV drugs that are broken down by the body in a similar way
with hormonal contraceptives, methadone, buprenorphine, lipid lowering
agents, immunosuppressive drugs, herbal remedies, and commonly prescribed
psychiatric medications in addition to HIV medications. •

THE FAIR PRICING COALITION EXPRESSES DISMAY AT THE PRICE OF MERCK’S NEWLY APPROVED HEPATITIS C DRUG

May 17, 2011—On May 13, 2011, the FDA approved Merck’s Victrelis (boceprevir), the first new drug for the treatment of hepatitis C virus (HCV) infection to come to market in almost ten years. The United States Department of Health and Human Services estimates that there are between 2.7 to 3.9 million people in the United States living with HCV and that approximately 20,000 people are newly infected with HCV every year.

“While this new drug approval is a very exciting development for the HCV community, the Fair Pricing Coalition (FPC) is very disappointed at the price set by Merck for Victrelis,” said FPC member Lynda Dee. “The FPC is concerned that the exorbitant wholesale acquisition cost (WAC) of $1,100 per week will adversely affect the ability of people with HCV to access Victrelis and that it will also set an excessively unreasonable future price point for the many HCV drugs in the pipeline. You can bet that no future HCV drugs will be priced less than Victrelis. This is a very bad start.”

Victrelis is a drug from the protease inhibitor family that is relatively easy and uncomplicated to make. “We understand that drug development costs a lot of money, but there is no reason for a drug from the protease inhibitor class to be so expensive,” said Dee.

Two other drugs, pegylated interferon and ribavirin must be taken with Victrelis, and the WAC price for HCV treatment with these two drugs is approximately $30,000. The FDA label recommends that Victrelis be taken with pegylated interferon and ribavirin for either 24, 32 or 48 weeks, depending on a patient’s response to the regimen. The WAC price for Victrelis is $26,400 for 24 weeks, $35,200 for 32 weeks and $48,400 for 48 weeks of treatment.

“These amounts added to the already high $30,000 cost of pegylated interferon and ribavirin make the cost of the new Victrelis containing regimen astronomical,” said Dee. “Although the addition of Victrelis to pegylated interferon and ribavirin should significantly increase the HCV cure rate, it will be impossible to sustain these prices in light of the current US healthcare crisis.”

“The HCV community is anxiously awaiting interferon-sparing regimens because of the terrible side effects caused by interferon as well as ribavirin,” said FPC member Murray Penner. “An encouraging number of these drugs are currently in development. It will take three and maybe even four of these new drugs in a combination regimen to effectively cure HCV in the future. Future HCV drugs will invariably be more expensive than Victrelis. If each of the new drugs costs approximately $50,000, we are looking at regimens that will ultimately cost between $150,000 and $200,000 in the very near future. This is unsustainable and will unacceptably limit access to the regimens.”

A recent paper presented at the American Society of Liver Diseases conference indicates that there will be a 30% increase in the cost of treating side effects caused by use of the new HCV protease inhibitor drugs. “These increased costs must also be considered in the equation,” said Penner. “Many people with HIV are also co-infected with HCV,” said Bill Arnold of the FPC. “The cost of HIV drugs which must be taken over the entire course of a patient’s life, plus a course of this new HCV treatment is unreasonably excessive. At this time, there are over 8,100 people on waiting lists for federally funded AIDS Drug Assistance Programs (ADAPs). I am very concerned that these people will never gain access to promising new HCV therapies. Many may die as a result.”

Many individuals with HCV also have other medical conditions such as diabetes and bleeding disorders, and people with bleeding disorders pay as much as $150,000 each year for their clotting factor drugs alone. While many do have private insurance, the cost of co-pays and caps on insurance coverage may make these promising new therapies unaffordable for many people with private insurance, resulting in the inability of even people with insurance to access promising new HCV therapies.

“We are very disappointed by the cost set by Merck for Victrelis and are even more concerned that Vertex’s Incivek (telapravir) which will probably be approved by the FDA later this month may be even more expensive,” said Dee. “How will this all end? We fear it will end in a lack of patient access to promising new HCV treatments that will result in morbidity and mortality for hundreds of thousands of Americans.

“Both Merck and Vertex have pledged to make their new drugs available to patients who cannot afford these exorbitant prices through their co-pay and patient assistance programs,” Dee pointed out. “The FPC will continue to advocate for people with HCV to ensure that both companies keep their word. We have kept a tight watch on HIV drug manufacturers in this regard. We intend to do the same thing in the viral hepatitis arena.”
http://fairpricingcoalition.org/