CATIE News – Leading Canadian researcher calls for inclusion of co-infected people in large HCV clinical trials

CATIELogoColHepatitis C virus (HCV) infects the liver. Chronic infection with HCV causes inflammation in this vital organ and slowly degrades it as healthy tissue is replaced with scar tissue. This ongoing injury to the liver results in complications, including bacterial infections, internal bleeding and liver, kidney and brain dysfunction. If left untreated, HCV infection can cause severe liver injury, the liver can stop working and death can occur. HCV infection also increases the risk for developing liver cancer.

Impact of HIV co-infection

Co-infection with HCV and HIV is relatively common, as both viruses have shared routes of infection. HIV-HCV co-infection accelerates the pace of HCV-related liver injury.

Historically, co-infected people have had increased rates of illness and death compared to people with HCV infection alone (mono-infection). There are at least two reasons for this, as follows:

  • only a relatively small proportion of co-infected people have received treatment for HCV
  • rates of recovery from HCV infection in people with HIV have been low

As a result, manufacturers of therapies for HCV have excluded co-infected patients from large phase III clinical trials. These trials are called registration trials because they are the final phase of clinical research before a drug is registered and licensed for sale by regulatory authorities.

Focus on research

Until 2011, the standard treatment for HCV was a combination of the following two medicines:

  • interferon-alpha – a chemical produced by the immune system that helps the body resist some viral infections
  • ribavirin – a broad-spectrum antiviral agent

These drugs were only modestly successful, particularly in co-infected patients.

In the past several years new drugs designed specifically to attack HCV have successfully completed phase III studies and have been granted regulatory approval. These therapies, called DAAs (direct-acting antivirals), are very potent and generally safe. The most powerful DAAs have resulted in high cure rates in HCV-mono-infected people: In most registration trials of the more powerful DAAs, between 95% and 100% of participants have been cured.

DAAs can be divided into several groups, or classes, such as the following:

  • protease inhibitors
  • NS5A inhibitors
  • nucleoside analogues
  • non-nucleoside analogues (non-nukes)

A matter of size

After the completion of phase III trials, manufacturers of DAAs conducted studies in co-infected people. For the most part, these subsequent studies enrolled relatively small numbers of participants. Due to the small numbers enrolled, such studies have not yielded sufficient data to make statistical comparisons among the different DAAs tested. Furthermore, some of these studies excluded participation by people whose previous anti-HCV therapy failed.

These small clinical trials have led to delays in getting DAAs onto lists of subsidized drug plans for co-infected people by some regional authorities, at least in Canada.

A call for change

In an important scientific paper soon to be published in the journal Clinical Infectious Diseases, professor Stephen Shafran, MD, from the University of Alberta, performed a major review of clinical trials of many DAA-containing HCV therapies used for the treatment of HCV mono-infection as well as HIV-HCV co-infection. His analysis found that cure rates of HCV, also called sustained virological response (SVR), are “remarkably similar” in HCV mono-infected and co-infected participants who were treated with the same regimen and who have the same strain (genotype) of HCV.

Professor Shafran makes a powerful argument, backed by available clinical data, that co-infected people should be enrolled in large trials of DAAs alongside mono-infected people. If implemented, such a policy should speed the subsequent licensure and approval of these drugs for treating HIV-HCV co-infected patients so they are approved at the same time as for mono-infected patients. By agreeing to such an inclusionary practice, pharmaceutical companies can also play a role in helping to remove barriers to future treatment access for co-infected people.

Key findings

Professor Shafran reviewed many clinical trials, from the first licensed DAAs to more recent regimens. We cannot list all of the trials he reviewed but will mention just a few summaries of key results with powerful combinations of DAAs. For this purpose we focus mainly on clinical trials that enrolled participants with the most common HCV genotype in Canada, genotype 1:

Harvoni (a fixed-dose combination of sofosbuvir + ledipasvir) for 12 weeks:

  • cure rates in HCV mono-infection – between 94% and 99%
  • cure rates in HIV-HCV co-infection – between 96% and 99%

Holkira Pak (a combination of paritaprevir + ombitasvir + dasabuvir + ritonavir) with ribavirin for 12 weeks:

  • cure rates in HCV mono-infection – between 92% and 99%
  • cure rates in HIV-HCV co-infection – 94%

Sofosbuvir (Sovaldi) + daclatasvir with or without ribavirin:

  • cure rates in HCV mono-infection – 100%
  • cure rates in HIV-HCV co-infection – 97%

In the cases of HCV genotypes 2 and 3, cure rates of trials reviewed for both co-infection and mono-infection were slightly lower than for genotype 1 but were similar (generally between 83% and 94%) between mono-infection and co-infection.

Compare and contrast

As mentioned earlier, treatment for HCV infection in the time before DAAs was usually a combination of interferon and ribavirin. In the present era, now that powerful combinations of DAAs are licensed, HCV cure rates are high and, according to professor Shafran, “virtually identical” among mono-infected and co-infected patients who have the same genotype and who are treated with the same regimen.

Furthermore, professor Shafran adds, “there is no evidence” that side effects from HCV therapy, including the most potent DAAs, are more common or more severe in co-infected people compared to mono-infected people. An important point that he raises is that in clinical trials, co-infected people who receive DAAs continue to maintain suppression of HIV while they also take their anti-HIV meds.

Moving forward

Taking many of these points into consideration, Shafran states: “The time has come to stop considering HIV-HCV co-infection as a unique subpopulation of HCV infection, requiring dedicated anti-HCV clinical trials.” Instead, he proposes, “HIV infection should be considered as a comorbidity that occurs in a small proportion of HCV-infected persons, similar to [type 2 diabetes].”

Shafran notes that diabetes occurs in about 10% of HCV-infected people. Diabetic HCV-infected people are allowed into HCV clinical trials provided that their diabetes is under “reasonable control,” Shafran says.

Comorbidities are common in HCV

People who seek to enter clinical trials of DAAs can have a range of comorbidities, including the following:

  • asthma
  • abnormal levels of cholesterol in the blood
  • coronary artery disease
  • chronic obstructive pulmonary disease

Shafran points out that people with these comorbidities are allowed to enter HCV clinical trials “as long as these medical conditions are controlled.”

Therefore, he argues, when it comes to HIV-HCV co-infected people and phase III clinical trials of DAAs, “HIV should be considered yet another permissible comorbidity.” As such, as with other permissible comorbidities, HIV infection should be well controlled with treatment, and drug interactions with HCV medicines should be avoided or, if they occur, “appropriately managed.”

In cases of co-infection, significant drug interactions can occur when HCV protease inhibitors are taken by people who are taking HIV protease inhibitors. Shafran states that such interactions are “usually manageable, in many cases by avoiding the use of HIV protease inhibitors.”

Including HIV-HCV co-infected people in phase III trials of DAAs helps to make such trials more representative of the real world. Ultimately, by doing so, data are collected that can help hasten the approval of DAAs for this population and therefore their access to these therapies.

Furthermore, Shafran notes, “arguably, denying patients access to HCV clinical trials for which they meet all study criteria, except for being [HIV-positive], is discriminatory and could conceivably be challenged legally.”

A possible future

Shafran envisions a future where all phase III trials of DAAs have co-infected participants. He encourages regulatory agencies and research ethics committees to “challenge pharmaceutical companies and/or researchers who propose to exclude [HIV-positive] participants to provide a valid scientific reason for their exclusion and to simultaneously explain why a myriad of other comorbidities can be included.”

Shafran ends his article with the following statement:

“The time to ‘mainstream’ HIV-infected persons into HCV clinical trials is now. It is ‘the right thing to do,’ both scientifically and ethically.”

Resources

CATIE’s hepatitis  C information

Harvoni fact sheet

Holkira Pak fact sheet

—Sean R. Hosein