Grazoprevir (MK-5172) + Elbasvir (MK-8742) for the treatment of ACUTE hepatitis C genotype 1/4. The Dutch Acute HCV in HIV Study (DAHHS-2)

A newly acquired HCV infection is mostly asymptomatic. Therefore, if liver
enzymes are not measured in the context of medical care for another disease,
the new HCV infection remains undiagnosed for years or decades in most patients
(ref1). Since 2004, a new epidemic of sexually transmitted HCV infections among
HIV positive men who have sex with men (HIV+MSM) emerged in Europe (ref2a 2b).
This new epidemic was rapidly identified because regular liver enzyme testing
is a standard procedure to look for liver injury induced by combination
antiretroviral therapy (cART). In 2014, a prospective observational study in 18
Dutch HIV treatment centers showed that this HCV epidemic is now well
established throughout the Netherlands. During the 12 months of the study, 91
acute HCV infections were diagnosed among 8723 HIV positive MSM in care in
these centers. The incidence of acute HCV was therefore 11/1000 patient years,
which means that 1.1% of Dutch HIV+MSM acquired a new HCV infection in 2014
alone. This is 100-1000 fold higher than what can be expected in the general
Dutch population. Of these acute HCV infections, 74% were genotype 1 (n=71) and
16% genotype 4 (n=15). Other genotypes were rarely seen (genotype 2 in 2 and
genotype 3 in 3 patients respectively) (ref.3).

Until recently, acute hepatitis C infections were almost exclusively seen in
HIV-positive patients because only this risk was screened several times a year
for hepatitis during their HIV control. London was the first increase of acute
hepatitis C in HIV-negative gay men seen. In the Netherlands last year,
however, was rolled out PrEP (pre exposure prophylaxis) implementation program
in Amsterdam. In this program HIV negative gay men at risk for HIV take drug
that protects them against HIV. In this context, they are tested for HIV
several times a year but also hepatitis. As a result, it is now also possible
to detect acute HCV infections in HIV-negative patients, because it can be
proved in this setting that it is a recent infection (on the basis of a
preliminary negative hepatitis test).

Recently 2 interferon-free single tablet HCV therapies, sofosbuvir/ledipasvir
and dasabuvir/ombitasvir/ paritaprevir/ritonavir received European Medicines
Agency approval for the treatment of genotype 1 and 4. In patients with chronic
HCV but without cirrhosis, both regimens cure >95% of the patients. Previously,
sofosbuvir, simeprevir and daclatasvir received EMA approval for the treatment
of chronic HCV. The current medication costs for a 12-week treatment with e.g.
sofosbuvir/ledipasvir is 94500 USD (approximately 81000 euro). This very high
cost per treatment and therefore major impact on national health-care budgets
has resulted in a restrictive reimbursement policy in most European countries.
In the Netherlands, only patients with chronic HCV and documented severe liver
fibrosis or cirrhosis get their treatment reimbursed by the health insurance.

None of these new HCV therapies have been well studied for the treatment of
acute HCV and are therefore not registered for this indication. The only
treatment for acute HCV that is currently reimbursed in most countries is
pegylated or unpegylated interferon. Interferon based therapy for the treatment
of HCV has been shown to be much more effective when given during the acute
phase of the HCV infection than at a time when the infection has become
chronic. Based on our own review of studies published as a full paper or a
conference report, acute HCV infections can be cured with interferon-based
therapy in 542 of 711 (76%) HIV negative patients with an acute HCV. In HIV+
patients the cure rates were somewhat lower at 310/467 or 66%. These responses
of 66-76% are in sharp contrast with cure rates of only +- 35-45% for chronic
HCV genotype 1/4 with pegylated interferon and ribavirin. A likely explanation
for this difference in success for acute versus chronic HCV therapy is a
substantial immune response that is present during the acute phase of HCV
infection, but becomes exhausted during chronic infection (ref4). This potent
immune response is broadly targeted against various HCV epitopes and eradicates
approximately 20% of HCV infections within the first 12 to 18 months of
infection. However, spontaneous cure of HCV becomes very rare after the first
12 to 18 months of infection due to immune exhaustion. It is likely that the
synergistic effect of the host's immune response and antiviral therapy when
given during the first 6 months of HCV infection makes antiviral therapy during
acute HCV infection more effective.

A the end of 2013, the investigator initiated Dutch Acute HCV in HIV Study
(DAHHS) started to recruit acute HCV genotype 1 infected patients in 10 Dutch
HIV treatment centers. In 14 months, 65 patients were included (out of the >100
acute genotype 1 and 4 infections that were diagnosed in these 14 months).
After spontaneous clearance was observed in 8 patients, the 57 remaining
patients started treatment with 12 weeks of boceprevir peginterferon and
ribavirin. We observed that the vigorous immune response during the acute phase
of HCV, together with the addition of a single first-generation DAA to the
peginterferon ribavirin therapy, cured 85% of the patients with only 12 weeks
of treatment. We were therefore able to shorten peginterferon therapy with 50%
without loss of efficacy. In the subset of patients with a rapid viral response
at week 4, 98% reached SVR12 (study results as of 10/JUN/2015, Bart Rijnders).
It became clear that the DAHHS network is able to recruit a very significant
number of acute HCV infected patients in a short time without any patients
being lost-to-follow up. Another relevant observation in the DAHH-study was
that, with all patients being on cART, their median CD4 count was very high at
660/mm3. This is substantially higher than the median CD4 count seen in
patients with HIV and chronic HCV. Therefore, from an immunological point of
view HIV+MSM diagnosed with an acute HCV are comparable to HIV negative
patients.

Two recent phase II and 1 phase III clinical trial showed that chronic HCV
genotype 1 can be cured with 12 weeks of combination therapy with grazoprevir
(MK-5172) and elbasvir (MK-8742) in 95% of HCV mono-infected and 87% (without
ribavirin) to 97% (with ribavirin) of HIV-HCV co-infected patients.
Furthermore, all 18 patients with genotype 4 infection that were treated for 12
weeks in the C-EDGE study were cured. Larger clinical trials for the treatment
of chronic HCV genotype 4 are ongoing but the in vitro potency of MK-8742 and
MK-5172 against HCV genotype 4 is very high with an EC50 of 0.003-0.0003 nM and
0.062 nM respectively.

The long-term goal of policy makers, healthcare providers and the
pharmaceutical industry should be to reduce the number of new HCV infections in
a substantial way. Ultimately, the eradication of HCV may be possible in
certain countries and patient populations. The first patient population for
which HCV eradication may become a realistic future perspective is the easy to
reach population of HIV+MSM. To make this happen, health care providers should
be able to treat newly diagnosed acute HCV infections as soon as they are
diagnosed to prevent ongoing sexual HCV transmission. If patiens are only
treated years later, at a time when fibrosis has been documented they will
remain a significant source of new sexually tranmitted HCV infections for
years. Treatment as prevention as soon as an acute HCV infection is diagnoses
could therefore be an important measure to halt the spread of HCV among HIV+MSM
just as treatment as prevention works to prevent HIV transmission.

HCV treatment as prevention, is currently not possible because DAA are not
registered for the treatment of acute HCV because their effectivity in the
context of acute HCV has not been shown.

The goal of this study is to document the efficacy of a shortened 8-week
therapy with grazoprevir and elbasvir in patients with acute HCV genotype 1 or
4 infection.

Single arm open label multicenter study
Treatment duration of 8 weeks
Treatment: grazoprevir (MK-5172) 100mg QD + elbasvir (MK-8742) 50mg QD given as
a fixed drug combination tablet

Sample size: n=80 patients, genotype 1 or 4
At least 55 but not more than 65 patients will be infected with genotype 1
At least 15 but not more than 25 of the 80 patients will be genotype 4
Therefore, the inclusion of genotype 1 will end when 65 patients with genotype
1 are included and the inclusion of genotype 4 will end after 21 genotype 4
patients have been included. The study inclusion will end when in total 80
patients are included.

Day 1-56: All patients will receive grazoprevir/elbasvir fixed dose combination
oral tablet consisting of 100/50mg per tablet.

Burden en risks associated with treatment are estimations based on phase 1/2
trials in hiv positive patients and mainly associated with Headache, nausea,
sleeplesness and diarrea. However this burden is anticipated to be much less
than standard treatment with peginterferon. As there are limited phase 3 data
en none phase 4 data, rare adverse events could not have been occured yet.
Thus, patients have to be informed about this level of knowledge of the
treatment regimen. The burden of blood, taken by venapuncture for the research
is considered to be very low for non-Erasmus MC patients (additional 14 ml per
study visit), for Erasmus MC patients this is considered moderate, maximum
additional 54 mL per visit.
All blood drawal will be together with regular venous puncture, so there is no
additional risk for hematomas.