Advances in HCV Treatment Volume 20 Issue 1 April/May 2012
Antivir Med. 2012;20(1):5-10 ©2012, IAS–USA
Perspective
Advances in HCV Treatment Volume 20 Issue 1 April/May 2012
Since 2007, the annual age-adjusted mortality rate in HIV disease in the United
States has been surpassed by that of hepatitis C virus (HCV) disease,
reflecting the continuing decline in HIV-related mortality and the continuing
increase in HCV-related mortality.1 The prevalence of HCV-related cirrhosis is
projected to continue to increase until it reaches a peak around 2020,
reflecting what is commonly a 20- to 40-year period between HCV acquisition and
the later-stage manifestations of cirrhosis, end-stage liver disease, and liver
cancer. These projections assumed no changes in our ability to treat HCV
infection. The rate of sustained virologic response (SVR; ie, absence of HCV
RNA in blood for 6 months after the end of treatment) with what has been the
standard treatment of peginterferon alfa plus ribavirin is approximately 40% in
patients with HCV genotype 1 Dr Thomas is Professor of Medicine and Director of
the Division of Infectious Diseases at The Johns Hopkins University in
Baltimore, MD. Since 2007, the annual age-adjusted mortality rate in hepatitis
C virus (HCV) infection in the United States has been greater than that in HIV
disease, reflecting the continuing decline in HIV-related mortality and the
continuing increase in HCV-related mortality. The approval of 2 new
direct-acting antivirals within the past year, as well as the promise offered
by numerous other direct-acting agents in development, provides hope that we
will be able to markedly improve our ability to cure HCV disease. The addition
of a protease inhibitor (PI) to what has been the standard HCV therapy of
peginterferon alfa and ribavirin dramatically improves sustained virologic
response rates in treatment-naive patients with genotype 1 infection. Similar
results have been observed in some treatment-experienced patients in whom prior
peginterferon alfa/ribavirin therapy has failed. The use of these new agents
has also permitted response-guided therapy, wherein early sustained virologic
response to treatment allows for a shortened treatment duration. However, these
new PIs add cost and adverse effects to HCV therapy. Boceprevir is associated
with increased risk of anemia and dysgeusia, and telaprevir is associated with
increased risk of anemia and skin and gastrointestinal adverse effects. Early
studies indicate that the addition of PIs results in high response rates in
patients with HCV/HIV coinfection. Other studies suggest that combinations of
PIs and other direct-acting antivirals may ultimately permit cure when used in
interferon sparing regimens. This article summarizes a presentation by David L.
Thomas, MD, MPH, at the IAS–USA live continuing medical education course held
in New York City in October 2011.
Since 2007, the annual age-adjusted mortality rate in HIV
disease in the United States has been surpassed by that of hepatitis C virus
(HCV) disease, reflecting the continuing decline in HIV-related mortality and
the continuing increase in HCV-related mortality.1 The prevalence of
HCV-related cirrhosis is projected to continue to increase until it reaches a
peak around 2020, reflecting what is commonly a 20- to 40-year period between
HCV acquisition and the later-stage manifestations of cirrhosis, end-stage
liver disease, and liver cancer. These projections assumed no changes in our
ability to treat HCV infection.
The rate of sustained virologic response (SVR; ie, absence
of HCV RNA in blood for 6 months after the end of treatment) with what has been
the standard treatment of peginterferon alfa plus ribavirin is approximately
40% in patients with HCV genotype 1 infection, the predominant type of
infection in the United States. The rate is less than 30% in HIV/HCV-coinfected
patients with HCV genotype 1. However, the past year has brought the approval
of 2 new drugs for treating HCV infection—the HCV protease inhibitors
boceprevir and telaprevir— and numerous new drugs are in advanced stages of
development. It is hoped that these new weapons will allow us to improve the
projections for HCV disease outcomes.
Treatment Outcomes With Telaprevir and Boceprevir Treatment-Naive Patients
In the trial supporting approval of telaprevir, more than
1000 treatment-naive patients with HCV genotype 1 infection were randomly
assigned to receive telaprevir for 8 weeks or 12 weeks plus concurrent standard
peginterferon alfa/ribavirin therapy for up to 48 weeks, or peginterferon
alfa/ribavirin alone for 48 weeks.2 Patients receiving telaprevir who achieved
a virologic response that was sustained between weeks 8 and 12 were further
randomly assigned to stop peginterferon alfa/ribavirin after week 24 or
continue for the full 48 weeks. Overall, cure (ie, SVR) was achieved in 69% of
patients receiving 8 weeks of telaprevir and 75% of those receiving 12 weeks of
telaprevir, compared with 44% of those receiving peginterferon alfa/ribavirin
alone. In black patients, who are known to have lower rates of response to
peginterferon alfa/ribavirin, SVR rates were 25% with standard therapy, versus
58% and 62% with 8 weeks and 12 weeks of telaprevir, respectively. Among
nonblack patients, SVR rates were 48% with peginterferon alfa/ribavirin,
compared with 73% and 79% with the addition of telaprevir for 8 weeks and 12
weeks, respectively.
Patients who stopped therapy at 24 weeks after an early
response to telaprevir-containing therapy had outcomes similar to those who
continued to receive peginterferon alfa/ribavirin for the full 48-week course.
The 12-week course of telaprevir was approved in 2011 by the US Food and Drug
Administration (FDA) for use in combination with peginterferon alfa/ ribavirin,
as was the shortened treatment duration in patients with early sustained response to treatment.
With regard to the ability to abbreviate therapy based on
early response to treatment, Sherman and colleagues performed a study in
treatment-naive, genotype 1–infected patients.3 Patients who achieved early
rapid virologic response (eRVR; defined as undetectable HCV RNA at week 4 and
week 12) with telaprevir plus peginterferon alfa/ribavirin therapy were
randomly assigned to continue receiving peginterferon alfa/ribavirin for the
full 48 weeks or to stop treatment after a total of 24 weeks. The overall SVR
rate was 72%, with 65% of the total of 540 patients achieving eRVR. SVR rates
were 92% among those stopping treatment after 24 weeks and 88% among those
receiving 48 weeks of treatment. Among those who did not achieve eRVR, the SVR
rate was 64%.
In the pivotal boceprevir trial, approximately 1100
treatment-naive patients with genotype 1 infection received a lead-in of
peginterferon alfa/ ribavirin for 4 weeks.4 This was followed by either
continuation of peginterferon alfa/ribavirin treatment for 44 weeks (total of
48 weeks); addition of boceprevir for 44 weeks (fixed-duration group); or
addition of boceprevir for 24 weeks followed by treatment discontinuation if
virus was undetectable from 8 weeks to 24 weeks or treatment continuation with
peginterferon alfa/ribavirin alone for 20 weeks if virus was detectable
(responseguided therapy group). Overall, SVR rates were 63% in the
response-guided therapy boceprevir group and 66% in the fixed-duration
boceprevir group, compared with 38% in the peginterferon alfa/ribavirin
treatment group. SVR rates were improved with the addition of boceprevir in
black patients (42% in the response-guided therapy group and 53% in the
fixed-duration group vs 23% in the standard treatment group) and nonblack
patients (67% and 69% vs 41%, respectively). Boceprevir was approved by the FDA
in 2011 for use in combination with peginterferon alfa/ribavirin, including a
shortened response-guided course of therapy in treatment-naive patients.
Treatment-Experienced Patients
Telaprevir and boceprevir have each been shown to achieve
cure in a substantial proportion of HCV-infected patients in whom prior
peginterferon alfa/ribavirin therapy had failed. In a study of more than 600
treatmentexperienced patients, Zeuzem and colleagues found SVR rates of 64%
with the combination of 12 weeks of telaprevir plus 48 weeks of peginterferon
alfa/ribavirin; 66% with a 4-week lead-in regimen of peginterferon alfa/
ribavirin followed by 12 weeks of telaprevir and 44 weeks of peginterferon
alfa/ribavirin; and 17% with retreatment with 48 weeks of peginterferon
alfa/ribavirin.5 Among patients with relapse (ie, those who relapsed after
having undetectable virus at the end of prior treatment) SVR rates were 83%,
88%, and 24%, respectively. Among those who had shown a partial virologic
response to prior treatment, SVR rates were 59%, 54%, and 15%, respectively.
For those with no virologic response to prior treatment (null responders), SVR
rates were 29%, 33%, and 5%, respectively.
In a trial in approximately 400 treatment-experienced
patients conducted by Bacon and colleagues, overall SVR rates were 66% in
patients receiving boceprevir and 48 weeks of peginterferon alfa/ribavirin, 59%
in those receiving boceprevir with response-guided therapy, and 21% in those
receiving standard peginterferon alfa/ribavirin.6 SVR rates were 75%, 69%, and
29%, respectively, among patients who had relapsed after prior therapy and 52%,
40%, and 7%, respectively, among those who had partial response to prior treatment.
Increased Toxic Effects With Addition of Telaprevir or Boceprevir \
Jacobson and colleagues reported that adverse events
occurred more frequently in telaprevir-containing study arms than in the
peginterferon alfa/ribavirin alone arm. Adverse effects included pruritus
(45%-50% with telaprevir vs 36% with peginterferon alfa/ribavirin), nausea
(40%-43% vs 31%), rash (35%-37% vs 24%), anemia (37%-39% vs 19%), and diarrhea
(28%-32% vs 22%). In the boceprevir trial conducted by Poordad and colleagues,
anemia (49% in the boceprevir group vs 29% in standard treatment group) and
dysgeusia (37%-43% vs 18%, respectively) were more common in
boceprevircontaining study arms.
Resistance to HCV Protease Inhibitors
Because neither interferon alfa nor ribavirin is a
direct-acting antiviral agent, viral resistance is a new phenomenon in HCV
treatment. Resistance to the protease inhibitors (PIs) telaprevir and
boceprevir is detected in approximately 50% of patients in whom therapy
containing these agents fails.7,8 To date, there is no evidence that resistant
variants have greater replicative fitness or pathogenicity than wild-type
virus. As has been observed with HIV, there is a return to predominance of
wild-type virus generally within 18 months of stopping HCV PI treatment.9
However, unlike HIV, there is no biologic basis for archiving of PI-resistant
variants in the body.
Table 1. Sustained
Virologic Response Rates According to Patient and Disease Characteristics in
Treatment-Naive Patients Receiving Telaprevir or Boceprevir plus Peginterferon
Alfa/Ribavirin Compared with Peginterferon Alfa/Ribavirin Alone
TPV 12 indicates patients receiving telaprevir for 12 weeks; Peg/RBV 24-48, peginterferon alfa and ribavirin for 24
to 48 weeks; Peg/RBV 48, peginterferon alfa and ribavirin for 48 weeks; BOC 44, boceprevir for 44 weeks. Adapted from Jacobson et al2 and Poordad et al.4
The long-term consequences of selecting for HCV PI resistance are unclear at this time.
Investigations are currently underway on whether emergence of resistance will result
in poorer response to subsequent treatment containing a PI.
There are no convincing data thus far that baseline
resistance to HCV PIs affects response to treatment. Thus, although there is a
commercially available assay for testing for HCV resistance, for now there is
no indication for testing to guide immediate treatment decisions. However, it
may be prudent to document resistant variants in case the information becomes
useful in the future.
More Potent Therapy Reduces Predictive Value of Some Risk Factors for Poor Response
More potent anti-HCV therapy reduces the value of some of
the traditional factors predictive of poor response to peginterferon
alfa/ribavirin therapy. This is a good thing, however, because the loss of
predictive value is the result of higher cure rates in subgroups of patients
with traditionally greater risk of poor response. Most notable is the
diminished effect of higher HCV viral load in predicting poorer treatment
outcome with peginterferon alfa/ribavirin (see Table 1). For example, in the
pivotal telaprevir trial, SVR rates were similar among telaprevir-receiving
patients with baseline HCV RNA viral load 800,000 IU/mL or higher and those
with viral load less than 800,000 IU/mL (74% and 78%, respectively).2 The SVR
rate in those with elevated viral load receiving telaprevir represents a
striking improvement over the response rate among patients with high viral load
receiving peginterferon alfa/ ribavirin alone (36%). In the pivotal boceprevir
trial, the SVR rate among boceprevir recipients with elevated baseline viral
load was 63%, compared with 33% among patients with elevated baseline viral
load receiving peginterferon alfa/ribavirin alone.4
As noted previously, black race is also a risk factor for
poorer response to peginterferon alfa/ribavirin. The difference in the
frequency of the unfavorable interleukin-28B genotype explains about half of
the difference in treatment response between black and nonblack patients.
Although there was still a difference in SVR rates between black patients and
white patients receiving telaprevir (62% and 75%, respectively), the SVR rate
in black patients represents a striking improvement over that achieved with
peginterferon alfa/ribavirin alone (25%).2 Similarly, black patients receiving
boceprevir had a lower SVR rate than white patients, but the high cure rate in
black patients receiving boceprevir compared with those receiving peginterferon
alfa/ribavirin alone is another striking improvement—53% versus 23%,
respectively.4 Some of the differences observed between the telaprevir and
boceprevir studies, with regard to response rates in patient subgroups, likely
reflect the fact that the post hoc analyses were performed in different patient
populations.
Comparison of Telaprevir and Boceprevir-Containing Regimens
Table 2 provides an overview of characteristics of HCV
treatment with telaprevir- and boceprevir-containing regimens. A 4-week lead-in
period with peginterferon alfa/ribavirin is recommended before adding
boceprevir and no lead-in is recommended for patients receiving telaprevir,8,10
reflecting the way the drugs were developed in phase II and, especially, phase
III studies. Boceprevir is administered for 24 weeks or 44 weeks in
treatment-naive patients and for 32 weeks or 44 weeks in treatment-experienced
patients, depending on early virologic response, whereas telaprevir is
administered for 12 weeks in both treatment-naive and treatment–experienced
patients.
Table 2. Selected Characteristics of Boceprevir and Telaprevir
to 48 weeks; Peg/RBV 48, peginterferon alfa and ribavirin for 48 weeks; BOC 44, boceprevir for 44 weeks. Adapted from Jacobson et al2 and Poordad et al.4
The long-term consequences of selecting for HCV PI resistance are unclear at this time.
Investigations are currently underway on whether emergence of resistance will result
in poorer response to subsequent treatment containing a PI.
There are no convincing data thus far that baseline
resistance to HCV PIs affects response to treatment. Thus, although there is a
commercially available assay for testing for HCV resistance, for now there is
no indication for testing to guide immediate treatment decisions. However, it
may be prudent to document resistant variants in case the information becomes
useful in the future.
More Potent Therapy Reduces Predictive Value of Some Risk Factors for Poor Response
More potent anti-HCV therapy reduces the value of some of
the traditional factors predictive of poor response to peginterferon
alfa/ribavirin therapy. This is a good thing, however, because the loss of
predictive value is the result of higher cure rates in subgroups of patients
with traditionally greater risk of poor response. Most notable is the
diminished effect of higher HCV viral load in predicting poorer treatment
outcome with peginterferon alfa/ribavirin (see Table 1). For example, in the
pivotal telaprevir trial, SVR rates were similar among telaprevir-receiving
patients with baseline HCV RNA viral load 800,000 IU/mL or higher and those
with viral load less than 800,000 IU/mL (74% and 78%, respectively).2 The SVR
rate in those with elevated viral load receiving telaprevir represents a
striking improvement over the response rate among patients with high viral load
receiving peginterferon alfa/ ribavirin alone (36%). In the pivotal boceprevir
trial, the SVR rate among boceprevir recipients with elevated baseline viral
load was 63%, compared with 33% among patients with elevated baseline viral
load receiving peginterferon alfa/ribavirin alone.4
As noted previously, black race is also a risk factor for
poorer response to peginterferon alfa/ribavirin. The difference in the
frequency of the unfavorable interleukin-28B genotype explains about half of
the difference in treatment response between black and nonblack patients.
Although there was still a difference in SVR rates between black patients and
white patients receiving telaprevir (62% and 75%, respectively), the SVR rate
in black patients represents a striking improvement over that achieved with
peginterferon alfa/ribavirin alone (25%).2 Similarly, black patients receiving
boceprevir had a lower SVR rate than white patients, but the high cure rate in
black patients receiving boceprevir compared with those receiving peginterferon
alfa/ribavirin alone is another striking improvement—53% versus 23%,
respectively.4 Some of the differences observed between the telaprevir and
boceprevir studies, with regard to response rates in patient subgroups, likely
reflect the fact that the post hoc analyses were performed in different patient
populations.
Comparison of Telaprevir and Boceprevir-Containing Regimens
Table 2 provides an overview of characteristics of HCV
treatment with telaprevir- and boceprevir-containing regimens. A 4-week lead-in
period with peginterferon alfa/ribavirin is recommended before adding
boceprevir and no lead-in is recommended for patients receiving telaprevir,8,10
reflecting the way the drugs were developed in phase II and, especially, phase
III studies. Boceprevir is administered for 24 weeks or 44 weeks in
treatment-naive patients and for 32 weeks or 44 weeks in treatment-experienced
patients, depending on early virologic response, whereas telaprevir is
administered for 12 weeks in both treatment-naive and treatment–experienced
patients.
Table 2. Selected Characteristics of Boceprevir and Telaprevir
*RGT indicates response-guided therapy; PI, protease inhibitor; eRVR, early rapid virologic response. RGT is
not recommended in patients with cirrhosis or HIV coinfection.
Response-guided therapy is not recommended in patients
with cirrhosis or in HIV-coinfected patients. Responseguided therapy in
HIV-seronegative, noncirrhotic, treatment-naive patients is permitted based on
an HCV RNAnegative response during weeks 8 to 24 with boceprevir treatment and
at weeks 4 and 12 with telaprevir treatment. Based on clinical trial data, it
is estimated that 44% of treatment-naive patients receiving boceprevir and 58%
to 65% of treatment-naive patients receiving telaprevir are eligible for
response-guided therapy. The total duration of anti-HCV treatment in treatment-
naive patients, depending on presence or absence of early virologic response,
is 28 weeks or 48 weeks for boceprevir, and 24 weeks or 48 weeks for
telaprevir.
Response-guided therapy in treatment- experienced patients
is not recommended for patients receiving boceprevir who were null responders
to prior treatment or for patients receiving telaprevir who were partial or
null responders. For treatment-experienced patients receiving boceprevir, total
anti-HCV treatment duration is 36 weeks (for those with eRVR) or 48 weeks.
Total treatment duration is 24 weeks or 48 weeks for patients receiving
telaprevir. Anti-HCV therapy with boceprevir should be stopped due to futility
if HCV RNA level is greater than 100 IU/mL at week 12 or if there is detectable
HCV RNA at week 24. The recommended stopping rule for telaprevir- containing
therapy is a viral load of greater than 1000 IU/mL at week 4 or 12, or
detectable virus at week 24.
As noted previously, there are added adverse effects with
the addition of either of the PIs to peginterferon alfa/ ribavirin. There is an
increased risk of anemia with boceprevir compared with peginterferon
alfa/ribavirin therapy alone, and telaprevir is associated with increased risk
of anemia and skin and gastrointestinal side effects. Pill burdens differ
between the two treatments, with boceprevir requiring four 200 mg pills every 8
hours and telaprevir requiring two 375 mg pills every 8 hours. There is also a
difference in food requirements: boceprevir needs to be taken with some food,
whereas each dose of telaprevir needs to be taken with a meal containing at
least 20 g of fat.
The addition of a new agent to HCV treatment regimens
increases cost as well as cure rates. A 48-week course of peginterferon
alfa/ribavirin costs approximately $38,000. Full courses of telaprevir (12
weeks) and boceprevir (up to 44 weeks) cost approximately $50,000.
Ongoing Studies of HCV PIs
Patients with HCV infection in whom PI treatment has yet
to be fully evaluated are those with more advanced disease (eg, patients with
decompensated cirrhosis and transplant patients), those with HBV coinfection,
and those with HIV coinfection. In addition, safety and efficacy of these drugs
have not been established in patients with HCV genotype 2 or 3 infection.
Genotype 2 infection is responsive to peginterferon alfa/ribavirin in most
patients, and there is some indication that cure rates are improved with the
addition of a PI. Genotype 3 infection is more difficult to treat in many
cases, and there is some evidence indicating that response rates are not
improved with the addition of a PI.
Studies in HIV Coinfection
In a small study by Sulkowski and colleagues, patients
with HCV/HIV coinfection received a full 48-week course of anti-HCV therapy
with telaprevir plus peginterferon alfa/ribavirin or peginterferon
alfa/ribavirin alone with or without antiretroviral therapy.11 The group
receiving peginterferon alfa/ribavirin without antiretroviral therapy included
patients with high CD4+ cell counts who did not meet current guidelines for
initiation of antiretroviral therapy. Patients who received antiretroviral
therapy took efavirenz/tenofovir/emtricitabine, or ritonavir-boosted atazanavir
with tenofovir/emtricitabine or tenofovir/lamivudine. Patients who received the
efavirenz-containing regimen received an additional telaprevir pill with each
dose to compensate for lowered blood levels due to pharmacokinetic interaction
with efavirenz. As shown in Figure 1, the telaprevir-containing regimen
markedly improved week 4 and week 12 virologic responses in patients receiving
and not receiving antiretroviral therapy. These promising findings need to be
confirmed in larger studies.
not recommended in patients with cirrhosis or HIV coinfection.
Response-guided therapy is not recommended in patients
with cirrhosis or in HIV-coinfected patients. Responseguided therapy in
HIV-seronegative, noncirrhotic, treatment-naive patients is permitted based on
an HCV RNAnegative response during weeks 8 to 24 with boceprevir treatment and
at weeks 4 and 12 with telaprevir treatment. Based on clinical trial data, it
is estimated that 44% of treatment-naive patients receiving boceprevir and 58%
to 65% of treatment-naive patients receiving telaprevir are eligible for
response-guided therapy. The total duration of anti-HCV treatment in treatment-
naive patients, depending on presence or absence of early virologic response,
is 28 weeks or 48 weeks for boceprevir, and 24 weeks or 48 weeks for
telaprevir.
Response-guided therapy in treatment- experienced patients
is not recommended for patients receiving boceprevir who were null responders
to prior treatment or for patients receiving telaprevir who were partial or
null responders. For treatment-experienced patients receiving boceprevir, total
anti-HCV treatment duration is 36 weeks (for those with eRVR) or 48 weeks.
Total treatment duration is 24 weeks or 48 weeks for patients receiving
telaprevir. Anti-HCV therapy with boceprevir should be stopped due to futility
if HCV RNA level is greater than 100 IU/mL at week 12 or if there is detectable
HCV RNA at week 24. The recommended stopping rule for telaprevir- containing
therapy is a viral load of greater than 1000 IU/mL at week 4 or 12, or
detectable virus at week 24.
As noted previously, there are added adverse effects with
the addition of either of the PIs to peginterferon alfa/ ribavirin. There is an
increased risk of anemia with boceprevir compared with peginterferon
alfa/ribavirin therapy alone, and telaprevir is associated with increased risk
of anemia and skin and gastrointestinal side effects. Pill burdens differ
between the two treatments, with boceprevir requiring four 200 mg pills every 8
hours and telaprevir requiring two 375 mg pills every 8 hours. There is also a
difference in food requirements: boceprevir needs to be taken with some food,
whereas each dose of telaprevir needs to be taken with a meal containing at
least 20 g of fat.
The addition of a new agent to HCV treatment regimens
increases cost as well as cure rates. A 48-week course of peginterferon
alfa/ribavirin costs approximately $38,000. Full courses of telaprevir (12
weeks) and boceprevir (up to 44 weeks) cost approximately $50,000.
Ongoing Studies of HCV PIs
Patients with HCV infection in whom PI treatment has yet
to be fully evaluated are those with more advanced disease (eg, patients with
decompensated cirrhosis and transplant patients), those with HBV coinfection,
and those with HIV coinfection. In addition, safety and efficacy of these drugs
have not been established in patients with HCV genotype 2 or 3 infection.
Genotype 2 infection is responsive to peginterferon alfa/ribavirin in most
patients, and there is some indication that cure rates are improved with the
addition of a PI. Genotype 3 infection is more difficult to treat in many
cases, and there is some evidence indicating that response rates are not
improved with the addition of a PI.
Studies in HIV Coinfection
In a small study by Sulkowski and colleagues, patients
with HCV/HIV coinfection received a full 48-week course of anti-HCV therapy
with telaprevir plus peginterferon alfa/ribavirin or peginterferon
alfa/ribavirin alone with or without antiretroviral therapy.11 The group
receiving peginterferon alfa/ribavirin without antiretroviral therapy included
patients with high CD4+ cell counts who did not meet current guidelines for
initiation of antiretroviral therapy. Patients who received antiretroviral
therapy took efavirenz/tenofovir/emtricitabine, or ritonavir-boosted atazanavir
with tenofovir/emtricitabine or tenofovir/lamivudine. Patients who received the
efavirenz-containing regimen received an additional telaprevir pill with each
dose to compensate for lowered blood levels due to pharmacokinetic interaction
with efavirenz. As shown in Figure 1, the telaprevir-containing regimen
markedly improved week 4 and week 12 virologic responses in patients receiving
and not receiving antiretroviral therapy. These promising findings need to be
confirmed in larger studies.
Figure 1. Hepatitis C virus (HCV) virologic responses to telaprevir-containing therapy at week 4
(left) and week 12 (right) in patients with HCV/HIV coinfection, according to
antiretroviral regimen. Numerals in bars show total number of patients in
treatment group. EFV indicates efavirenz/tenofovir/emtricitabine; ATV/r,
ritonavir-boosted atazanavir with tenofovir/emtricitabine or
tenofovir/lamivudine. Adapted from Sulkowski et al.11
A phase II trial of boceprevir with peginterferon
alfa/ribavirin in HIV/ HCV-coinfected patients is ongoing. A total of 99
coinfected patients with stable HIV disease are being treated with a lead-in of
4 weeks of peginterferon alfa plus weight-based ribavirin, then randomly
assigned to add boceprevir (800 mg every 7-9 hours) or placebo for an
additional 44 weeks. Subjects were allowed into the study if they were on
raltegravir or ritonavirboosted PIs. Baseline HCV RNA level was above 800,000
IU/mL for 88% of subjects; 82% were white, and 5% had cirrhosis.12
The proportion of patients with undetectable HCV RNA at
week 8 was higher in the group receiving boceprevir (24 of 64 [37.5%] with
undetectable HCV RNA) than in the group receiving placebo (5 of 34 [14.7%]). At
week 24, HCV RNA was undetectable in 43 of 61 patients (70.5%) in the
boceprevir arm and undetectable in 11 of 32 (34.4%) in the placebo arm.
Treatment was discontinued in 3 (9%) and 9 (14%) of the patients in the placebo
and boceprevir arms, respectively, because of adverse events.
Updates on the trials described above were presented at
the 19th Conference on Retroviruses and Opportunistic Infections in March 2012.
In the telaprevir trial in HIV/HCV-coinfected patients, 28 of 38 patients (74%)
receiving telaprevir plus peginterferon alfa/ribavirin had undetectable levels
of HCV RNA at week 24 (end of treatment), compared with 12 of 22 patients (55%)
in the peginterferon alfa/ribavirin–only control group.13 Twelve weeks after
stopping therapy, all 28 of the 38 (74%) who had undetectable levels of HCV RNA
at the end of telaprevir treatment had sustained virologic response. In the
control group, 10 of 22 patients (45%) had sustained virologic response.
In the boceprevir trial, 39 of 61 coinfected patients
(63.9%) receiving boceprevir plus peginterferon alfa/ribavirin had undetectable
HCV RNA at week 48 (end of treatment), compared with 10 of 34 (29.4%) receiving
peginterferon/ alfa alone.14 Twelve weeks after stopping therapy, 37 of 61
patients (60.7%) who had received boceprevir had sustained virologic response,
compared with 9 of 34 (26.5%) in the peginterferon alfa/ribavirin–only group.
These results in coinfected patients are notable because
in both studies, virologic response was substantially better than with
interferon alfa/ribavirin alone. Virologic response rates were also nearly as
high as those in monoinfected patients.
Potential for Cure Without Interferon Alfa
Peginterferon alfa therapy is associated with considerable
toxicity, and there is intense interest in developing treatments that would
spare patients from the rigors of such therapy. An example of studies assessing
this possibility was reported by Lok and colleagues.15 Patients who were prior
null responders to peginterferon alfa/ribavirin therapy received a combination
of an HCV PI and an HCV nonstructural protein 5A (NS5A) inhibitor (which is
active at different steps of the viral replication process than PIs), with or
without peginterferon alfa/ribavirin.
Four of 11 patients receiving the PI and NS5A inhibitors
without peginterferon alfa/ribavirin had viral loads that fell below the limit
of quantitation at week 12 and remained undetectable after stopping therapy,
showing in principle that cure is achievable without interferon alfa therapy.
Six of the 11 patients exhibited viral breakthrough. It is also noteworthy that
all 10 patients receiving the 2 direct-acting antivirals in combination with
peginterferon alfa/ribavirin had undetectable virus at week 12, a remarkable
outcome of treatment in prior null responders. There is considerable excitement
over what might be achieved with multidrug combinations of the numerous
investigational direct-acting agents.
Although formal guidelines for treatment of
HIV/HCV-coinfected persons are being planned, at this time treatment should be
prioritized for those with advanced liver fibrosis (cirrhosis and bridging
fibrosis). When possible, coinfected patients should be enrolled in clinical
trials to expand the available information on optimal HCV treatments in that setting.
Summary
The current era in HCV treatment is reminiscent of the
transformation of HIV treatment that occurred in the mid-1990s. With the new
HCV treatments, cure and complications occur more frequently. We can make smart
applications of the treatments available to us right now in some patients, and
we await tomorrow’s treatments for other patients. As with the first wave of
HIV medications in the potent antiretroviral era, the new HCV drugs offer huge
advantages but also present substantial challenges.
Presented by Dr Thomas in October 2011. First draft prepared from transcripts by Matthew Stenger.
Reviewed and edited by Dr Thomas in February 2012.
Dr Thomas has received grants and research support from Gilead Sciences, Inc,
and Merck & Co, Inc. He has served as a consultant to Merck & Co, Inc.
References
1. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg
SD. The increasing burden of mortality from viral hepatitis in the United
States between 1999 and 2007. Ann Intern Med. 2012;156:271-278.
2. Jacobson IM, McHutchison JG, Dusheiko G, et al.
Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl
J Med. 2011;364:2405-2416.
3. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided
telaprevir combination treatment for hepatitis C virus infection. N Engl J Med.
2011;365:1014-1024.
4. Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir
for untreated chronic HCV genotype 1 infection. N Engl J Med.
2011;364:1195-1206.
5. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for
retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
6. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for
previously treated chronic HCV genotype 1 infection. N Engl J Med.
2011;364:1207-1217.
7. Vierling JM, Kwo PY, Lawitz E, et al. Frequencies of
resistance-associated amino acid variants following combination treatment with
boceprevir plus PEGINTRON (peginterferon alfa-2b)/ribavirin in patients with
chronic hepatitis C (CHC), genotype 1 (G1). Hepatology. 2010;52(Suppl
S1):702A-703A.
8. Telaprevir [package insert]. Cambridge, MA: Vertex
Pharmaceuticals; 2011.
9. Zeuzem S, Sulkowski M, Zoulim F, et al. Long-term
follow-up of patients with chronic hepatitis C treated with telaprevir in
combination with peginterferon alfa- 2a and ribavirin: interim analysis of the
Extend study. Hepatology. 2010;52(Suppl S1):436A.
10. Boceprevir [package insert]. Whitehouse Station, NJ:
Merck & Co, Inc; 2011.
11. Sulkowski M, Dieterich D, Sherman K, et al. Interim
analysis of a phase 2a doubleblind study of TVR in combination with
pegIFN-alfa2a and RBV in HIV/HCV coinfected patients. [Abstract 146LB.] 18th
Conference on Retroviruses and Op- portunistic Infections (CROI). February
27-March 2, 2011; Boston, MA.
12. Sulkowski M, Pol S, Cooper C, et al. Boceprevir plus
peginterferon/ribavirin for the treatment of HCV/HIV co-infected patients:
interim on-treatment results. [Abstract LB-37.] 49th Annual Meeting of the
Infectious Diseases Society of America (IDSA). October 20-23, 2011; Boston, MA.
13. Dieterich D, Soriano V, Sherman K, et al. Telaprevir
in combination with pegylated ininterferon- a-2a+RBV in HCV/HIV-co-infected
patients: a 24-week treatment interim analysis. [Abstract 46.] 19th Conference
on Retroviruses and Opportunistic Infections (CROI). March 5-8, 2012; Seattle,
WA.
14. Sulkowski M, Pol S, Cooper C, et al. Boceprevir +
pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected
patients: end of treatment (week-48) interim results. [Abstract 47.]
Proceedings from the 19th Conference on Retroviruses and Opportunistic
infections (CROI). March 5-8, 2012; Seattle, WA. 15. Lok AS, Gardiner DF,
Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C
genotype 1. N Engl J Med. 2012;366:216-224.
(left) and week 12 (right) in patients with HCV/HIV coinfection, according to
antiretroviral regimen. Numerals in bars show total number of patients in
treatment group. EFV indicates efavirenz/tenofovir/emtricitabine; ATV/r,
ritonavir-boosted atazanavir with tenofovir/emtricitabine or
tenofovir/lamivudine. Adapted from Sulkowski et al.11
A phase II trial of boceprevir with peginterferon
alfa/ribavirin in HIV/ HCV-coinfected patients is ongoing. A total of 99
coinfected patients with stable HIV disease are being treated with a lead-in of
4 weeks of peginterferon alfa plus weight-based ribavirin, then randomly
assigned to add boceprevir (800 mg every 7-9 hours) or placebo for an
additional 44 weeks. Subjects were allowed into the study if they were on
raltegravir or ritonavirboosted PIs. Baseline HCV RNA level was above 800,000
IU/mL for 88% of subjects; 82% were white, and 5% had cirrhosis.12
The proportion of patients with undetectable HCV RNA at
week 8 was higher in the group receiving boceprevir (24 of 64 [37.5%] with
undetectable HCV RNA) than in the group receiving placebo (5 of 34 [14.7%]). At
week 24, HCV RNA was undetectable in 43 of 61 patients (70.5%) in the
boceprevir arm and undetectable in 11 of 32 (34.4%) in the placebo arm.
Treatment was discontinued in 3 (9%) and 9 (14%) of the patients in the placebo
and boceprevir arms, respectively, because of adverse events.
Updates on the trials described above were presented at
the 19th Conference on Retroviruses and Opportunistic Infections in March 2012.
In the telaprevir trial in HIV/HCV-coinfected patients, 28 of 38 patients (74%)
receiving telaprevir plus peginterferon alfa/ribavirin had undetectable levels
of HCV RNA at week 24 (end of treatment), compared with 12 of 22 patients (55%)
in the peginterferon alfa/ribavirin–only control group.13 Twelve weeks after
stopping therapy, all 28 of the 38 (74%) who had undetectable levels of HCV RNA
at the end of telaprevir treatment had sustained virologic response. In the
control group, 10 of 22 patients (45%) had sustained virologic response.
In the boceprevir trial, 39 of 61 coinfected patients
(63.9%) receiving boceprevir plus peginterferon alfa/ribavirin had undetectable
HCV RNA at week 48 (end of treatment), compared with 10 of 34 (29.4%) receiving
peginterferon/ alfa alone.14 Twelve weeks after stopping therapy, 37 of 61
patients (60.7%) who had received boceprevir had sustained virologic response,
compared with 9 of 34 (26.5%) in the peginterferon alfa/ribavirin–only group.
These results in coinfected patients are notable because
in both studies, virologic response was substantially better than with
interferon alfa/ribavirin alone. Virologic response rates were also nearly as
high as those in monoinfected patients.
Potential for Cure Without Interferon Alfa
Peginterferon alfa therapy is associated with considerable
toxicity, and there is intense interest in developing treatments that would
spare patients from the rigors of such therapy. An example of studies assessing
this possibility was reported by Lok and colleagues.15 Patients who were prior
null responders to peginterferon alfa/ribavirin therapy received a combination
of an HCV PI and an HCV nonstructural protein 5A (NS5A) inhibitor (which is
active at different steps of the viral replication process than PIs), with or
without peginterferon alfa/ribavirin.
Four of 11 patients receiving the PI and NS5A inhibitors
without peginterferon alfa/ribavirin had viral loads that fell below the limit
of quantitation at week 12 and remained undetectable after stopping therapy,
showing in principle that cure is achievable without interferon alfa therapy.
Six of the 11 patients exhibited viral breakthrough. It is also noteworthy that
all 10 patients receiving the 2 direct-acting antivirals in combination with
peginterferon alfa/ribavirin had undetectable virus at week 12, a remarkable
outcome of treatment in prior null responders. There is considerable excitement
over what might be achieved with multidrug combinations of the numerous
investigational direct-acting agents.
Although formal guidelines for treatment of
HIV/HCV-coinfected persons are being planned, at this time treatment should be
prioritized for those with advanced liver fibrosis (cirrhosis and bridging
fibrosis). When possible, coinfected patients should be enrolled in clinical
trials to expand the available information on optimal HCV treatments in that setting.
Summary
The current era in HCV treatment is reminiscent of the
transformation of HIV treatment that occurred in the mid-1990s. With the new
HCV treatments, cure and complications occur more frequently. We can make smart
applications of the treatments available to us right now in some patients, and
we await tomorrow’s treatments for other patients. As with the first wave of
HIV medications in the potent antiretroviral era, the new HCV drugs offer huge
advantages but also present substantial challenges.
Presented by Dr Thomas in October 2011. First draft prepared from transcripts by Matthew Stenger.
Reviewed and edited by Dr Thomas in February 2012.
Dr Thomas has received grants and research support from Gilead Sciences, Inc,
and Merck & Co, Inc. He has served as a consultant to Merck & Co, Inc.
References
1. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg
SD. The increasing burden of mortality from viral hepatitis in the United
States between 1999 and 2007. Ann Intern Med. 2012;156:271-278.
2. Jacobson IM, McHutchison JG, Dusheiko G, et al.
Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl
J Med. 2011;364:2405-2416.
3. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided
telaprevir combination treatment for hepatitis C virus infection. N Engl J Med.
2011;365:1014-1024.
4. Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir
for untreated chronic HCV genotype 1 infection. N Engl J Med.
2011;364:1195-1206.
5. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for
retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
6. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for
previously treated chronic HCV genotype 1 infection. N Engl J Med.
2011;364:1207-1217.
7. Vierling JM, Kwo PY, Lawitz E, et al. Frequencies of
resistance-associated amino acid variants following combination treatment with
boceprevir plus PEGINTRON (peginterferon alfa-2b)/ribavirin in patients with
chronic hepatitis C (CHC), genotype 1 (G1). Hepatology. 2010;52(Suppl
S1):702A-703A.
8. Telaprevir [package insert]. Cambridge, MA: Vertex
Pharmaceuticals; 2011.
9. Zeuzem S, Sulkowski M, Zoulim F, et al. Long-term
follow-up of patients with chronic hepatitis C treated with telaprevir in
combination with peginterferon alfa- 2a and ribavirin: interim analysis of the
Extend study. Hepatology. 2010;52(Suppl S1):436A.
10. Boceprevir [package insert]. Whitehouse Station, NJ:
Merck & Co, Inc; 2011.
11. Sulkowski M, Dieterich D, Sherman K, et al. Interim
analysis of a phase 2a doubleblind study of TVR in combination with
pegIFN-alfa2a and RBV in HIV/HCV coinfected patients. [Abstract 146LB.] 18th
Conference on Retroviruses and Op- portunistic Infections (CROI). February
27-March 2, 2011; Boston, MA.
12. Sulkowski M, Pol S, Cooper C, et al. Boceprevir plus
peginterferon/ribavirin for the treatment of HCV/HIV co-infected patients:
interim on-treatment results. [Abstract LB-37.] 49th Annual Meeting of the
Infectious Diseases Society of America (IDSA). October 20-23, 2011; Boston, MA.
13. Dieterich D, Soriano V, Sherman K, et al. Telaprevir
in combination with pegylated ininterferon- a-2a+RBV in HCV/HIV-co-infected
patients: a 24-week treatment interim analysis. [Abstract 46.] 19th Conference
on Retroviruses and Opportunistic Infections (CROI). March 5-8, 2012; Seattle,
WA.
14. Sulkowski M, Pol S, Cooper C, et al. Boceprevir +
pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected
patients: end of treatment (week-48) interim results. [Abstract 47.]
Proceedings from the 19th Conference on Retroviruses and Opportunistic
infections (CROI). March 5-8, 2012; Seattle, WA. 15. Lok AS, Gardiner DF,
Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C
genotype 1. N Engl J Med. 2012;366:216-224.