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Best Practices in the Management of HCV/HIV Coinfection.Optimizing Treatment Success.2014
1. Jürgen K. Rockstroh, MD
Professor of Medicine
University of Bonn
Bonn, Germany
Best Practices in the Management
of HCV/HIV Coinfection:
Optimizing Treatment Success
This program is supported by an educational grant from
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Best Practices in the Management of HCV/HIV Coinfection
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Best Practices in the Management of HCV/HIV Coinfection
Disclosures
Jürgen K. Rockstroh, MD, has disclosed that he has received
consulting fees from AbbVie, Bionor, Bristol-Myers Squibb,
Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline,
Merck Sharp & Dohme, Novartis, Pfizer, Roche,
Tibotec/Janssen, Tobira, and ViiV. He has also received
research support from AbbVie and Merck.
The following planners and managers, Edward King, MA;
Jenny Schulz, PhD; and Michael Westhafer, MD, hereby
state that they or their spouse/life partner do not have any
financial relationships or relationships to products or devices
with any commercial interest related to the content of this
activity of any amount during the past 12 months.
5. Please review the slide notes
for a discussion by Jürgen K.
Rockstroh, MD
7. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Background and Epidemiology
HIV accelerates the natural course of hepatitis C[1]
Successful antiretroviral therapy can slow fibrosis progression but not
back to the rate in HCV monoinfection[2]
Liver disease associated with HCV infection has become a leading
cause of morbidity and mortality among HCV/HIV-coinfected patients[3]
HIV/HCV epidemiology[4]
– Approximately 25% of HIV+ patients are coinfected with HCV
– Approximately 80% of HIV+ patients who inject drugs are coinfected with
HCV
– All patients with HIV infection should be tested for HCV
HIV+ patients are at 4.1 times the risk of HCV as HIV- patients[5]
1. Rockstroh JK, et al. Am J Gastroenterol. 1996;91:2563-2568. 2. Graham CS, et al. Clin Infect Dis.
2001;33:562-569. 3. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 4. CDC. HIV and viral
hepatitis. May 2013. 5. Yaphe S, et al. Sex Transm Infect. 2012;88:558-564.
8. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Sexual Transmission of HCV Among
HIV+ MSM: An Emerging Population
Reports of epidemic of sexually transmitted HCV among HIV+ MSM
– United States: 6-fold higher incidence rate in HIV+ vs HIV- MSM[6]
– Swiss HIV Cohort Study: HCV incidence increased 18-fold from
1998 to 2011[7]
– Sydney, Australia: 9% of HIV+ MSM coinfected with HCV vs 1.9%
HIV- MSM[8]
– Amsterdam, Netherlands: HIV/HCV coinfection prevalence
increased from 14.6% to 20.9% from 2000-2007[9]
Phylogenic analysis indicates HCV transmission clusters in some
areas[9,10]
6. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 7. Wandeler G, et al. Clin Infect Dis. 2012;55:1408-1416.
8. Lea T, et al. Sexual Health. 2013;10:448-451. 9. Urbanus AT, et al. AIDS. 2009;23:F1-F7.
10. MMWR. 2011;60:945-950.
9. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Risk Factors for Sexual HCV Transmission
Among HIV+ MSM
Multiple factors associated with HCV transmission[11,12]
– Unprotected receptive anal intercourse
– Online casual sexual partners
– Sex at sex venues
– Older age
– Syphilis
– Recreational drug use
– Drinking > 13 alcoholic drinks per week
11. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 12. Larsen C, et al. PLoS ONE. 2011;6:e29322.
11. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Screening, Surveillance, Treatment
Initiation for HCV in HIV+ Patients
US and international treatment guidelines recommend[13-16]
:
– HCV screening at HIV diagnosis, then annually and as
indicated
– More frequent surveillance if ongoing risk (eg, MSM, IDU)
– HCV RNA if HCV Ab+ or suspected acute infection
13. EACS Guidelines, Version 7.0. October 2013. 14. DHHS Antiretroviral Guidelines for Adults and
Adolescents. February 2013. 15. Brook G, et al. HIV Med. 2010;11:1-30. 16. Ghany MG, et al.
Hepatology. 2009;49:1335-1374.
13. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Why Is HCV Therapy Deferred in Many
HIV/HCV-Coinfected Patients?
Challenges with interferon- and/or ribavirin-based regimen
Anticipated approval of new agents
– Greater efficacy
– All-oral regimens
– Shorter duration
– Improved tolerability
– Fewer drug-drug interactions
14. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Challenges With Telaprevir- or Boceprevir-
Based HCV Therapy in Coinfected Patients
Regimen complexity[17,18]
– High pill burden
– Long duration, complex RGT rules
– Multiple drug-drug interactions
– Overlapping toxicities
– With/without food dosing requirements
Tolerability
– Additional AEs beyond peginterferon/ribavirin
17. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1):S33-S42. 18. DHHS Antiretroviral Guidelines for
Adults and Adolescents. February 2013.
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Best Practices in the Management of HCV/HIV Coinfection
Specific Risks of Deferring Therapy in
HIV/HCV-Coinfected Patients
Accelerated rate of HCV-related hepatic fibrosis
progression in coinfected patients with increasing immune
deficiency[19-22]
– Progression to cirrhosis risk 3-fold higher in coinfected vs
HCV-monoinfected patients[20]
– Relative risk of decompensated liver disease 6-fold higher in
coinfected vs HCV-monoinfected patients[21]
Coinfected patients have reduced access to liver
transplantation and reduced survival
19. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1:S33-42). 20. DHHS Antiretroviral Guidelines for
Adults and Adolescents. February 2013. 21. Naggie S, et al. Gastroenterology. 2012;142:1324-1334.
22. Macías J, et al. Clin Infect Dis. 2013;57:1401-1408.
16. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
HCV Coinfection vs Monoinfection:
Cumulative Incidence of Decompensation
10-year hepatic decompensation risk 83% higher in coinfected
patients
– Adjusted HR 1.83 (95% CI: 1.54-2.18)
P < .001
HIV/HCV coinfected
HCV monoinfected
0.074
0.048
23. Lo Re V, et al. IAC 2012. Abstract WEAB0102.
0
0.1
0.2
0 1 2 3 4 5 6 7 8 9 10
Yrs to Hepatic Decompensation
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Best Practices in the Management of HCV/HIV Coinfection
Importance of Informed Deferral:
Know What You Are Waiting for
Need for individualized decision-making and informed
consent
Stepwise progress in HCV therapy anticipated
– New interferon-based regimens
– All-oral regimens retaining ribavirin
– All-oral regimens of just DAAs
Uncertain timeline
Initial DAA studies excluded coinfected patients
18. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Assessing HIV+ Patients for Immediate or
Deferred HCV Therapy
Antiretroviral therapy for HIV treatment-naive HIV/HCV-
coinfected patients
– CD4+ cell count < 500 cells/mm3
: initiate antiretroviral
therapy for HCV treatment optimization[24,25]
– CD4+ cell count > 500 cells/mm3
: may defer antiretroviral
therapy until HCV therapy completed[25]
24. EACS Guidelines, Version 7.0. October 2013. 25. DHHS Antiretroviral Guidelines for Adults and
Adolescents. February 2013. 26. Macías J, et al. Clin Infect Dis. 2013;2013;57:1401-1408.
HCV Therapy in HIV/HCV-Coinfected, HCV Treatment-Naive Patients
Liver Fibrosis
Consider
HCV Therapy
Eligible to
Defer HCV Therapy
No/minimal fibrosis (F0-F2)[24,25]
●
Advanced fibrosis (F3-F4); cirrhosis[26]
●
20. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
SVR With PegIFN/RBV by Genotype:
Coinfection vs Monoinfection
27. Carrat F, et al. JAMA. 2004;292:2839-2848. 28. Laguno M, et al. Hepatology. 2009;49:22-31. 29.
Chung RT, et al. N Engl J Med. 2004;351:451-459. 30. Torriani FJ, et al. N Engl J Med. 2004;351:438-
450.
31. Núñez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982. 32. Peginterferon alfa 2a [package
insert].
SVR Range, %
HIV/HCV Coinfection HCV Monoinfection
GT1 or
GT4[27-31]
GT2 or
GT3[27-31]
GT1 or
GT4[32]
GT2 or
GT3[32]
PegIFN/RBV
(600-1200 mg)
14-35 44-73 0-82* 76-82
*SVR rates for GT1 or GT4 unaffected by baseline viral titer. PegIFN/RBV for 48 weeks
using 1000 mg or 1200 mg dose of pegIFN resulted in higher rates of SVR compared
with 24 weeks of therapy and/or 800 mg dose of pegIFN.
21. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Proposed Optimal Duration of PegIFN/RBV
Therapy in Coinfected Patients
33. EACS Guidelines, Version 7.0. October 2013.
*In patients with baseline low viral load and
minimal liver fibrosis.
**Where no access to DAA available or high
chances of cure even with dual therapy
(favorable IL28B genotype, low HCV viral
load, and no advanced fibrosis).
HCV RNA
negative
Wk 4 Wk 12 Wk 24 Wk 48 Wk 72
GT2/3
GT1/4**
Stop
Stop
GT2/3
GT1/4
24-wk
therapy*
48-wk
therapy
72-wk
therapy
HCV RNA
positive
HCV RNA
negative
HCV RNA
positive
> 2 log drop
in HCV RNA
< 2 log drop
in HCV RNA
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Best Practices in the Management of HCV/HIV Coinfection
Study 110: Telaprevir + PegIFN/RBV in
GT1 HCV/HIV Coinfection
Phase II randomized controlled
trial[34]
– Telaprevir TID + pegIFN/RBV vs
pegIFN/RBV alone for 48 weeks
HCV treatment-naive HIV+ patients
(N = 60)
No HIV breakthrough
Safety and tolerability
– Increased pruritus, headache,
nausea, rash, and dizziness with
telaprevir-based therapy
– Anemia: 18% in both groups
SVR comparable to GT1 HCV-
monoinfected patients (75%)[35]
No ART
EFV/TDF/FTC
ATV/ritonavir
+ TDF/FTC
Total
SVR(%)
n/N = 5/
7
11/
16
12/
15
28/
38
Telaprevir +
PegIFN/RBV
PegIFN/RBV
2/
6
4/
8
4/
8
10/
22
34. Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96.
35. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
100
80
60
40
20
0
71 69
80
74
33
50 50
45
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Best Practices in the Management of HCV/HIV Coinfection
Study P05411: Boceprevir + PegIFN/RBV
in GT1 HCV/HIV Coinfection
Phase II randomized controlled
trial[36]
– PegIFN/RBV lead-in 4 weeks then
boceprevir + pegIFN/RBV for 44
weeks vs pegIFN/RBV alone for 48
weeks
HCV treatment-naive HIV+ patients
(N = 98)
– All with HIV-1 RNA < 50 cells/mL
on antiretroviral therapy
No difference in HIV breakthrough
Safety and tolerability
– Increased anemia, pyrexia, and
decreased appetite with boceprevir-
based therapy
SVR comparable to GT1 HCV-
monoinfected patients (68%)[37]
0
20
40
60
80
100
SVR(%)
PegIFN/RBV
n/N = 10/34
29
40/64
63
Boceprevir +
PegIFN/RBV36. Sulkowski M, et al. Lancet Infect Dis. 2013;13:597-605.
37. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
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Best Practices in the Management of HCV/HIV Coinfection
Recommendations for Coadministration of
TVR and BOC With Select Antiretroviral Agents
Antiretroviral Agent
Telaprevir Boceprevir
Europe[38-40]
US[41]
Europe[38-40]
US[41]
Atazanavir/ritonavir
Monitor for
hyperbilirubinemia
Standard dose
Case-by-case
consideration
Do not use
Darunavir/ritonavir;
fosamprenavir/ritonavir
; lopinavir/ritonavir
Not
recommended
Not
recommended
Not
recommended
Not
recommended
Raltegravir
No dose
adjustment
No dose
adjustment
No dose
adjustment
No dose
adjustment
Efavirenz
Increase dose
(1125 mg q8h)
Increase dose
(1125 mg q8h)
Not
recommended
Do not use
Rilpivirine
No dose
adjustment
No guidance
No dose
adjustment
No dose
adjustment[44]
38. Telaprevir [EU package insert]. 39. Boceprevir [EU package insert]. 40. Kakuda TN, et al. IWCPHT 2012. Abstract O-18. 41.
DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 42. Simeprevir [package insert]. 43. Sofosbuvir
[package insert]. 44. Boceprevir [package insert].
Note: Telaprevir and boceprevir interact with CYP3A4/5 and p-glycoprotein. Simeprevir should not be
coadministered with any boosted or unboosted PI or any NNRTI except rilpivirine.[42]
Sofosbuvir has no
reported DDIs with HIV drugs except tipranavir/ritonavir.[43]
26. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Advantages of Future HCV Therapies
Once-daily dosing
Shorter duration
Simpler regimens—no response-guided therapy
Fewer adverse events
Interferon-free
High efficacy
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Best Practices in the Management of HCV/HIV Coinfection
Caveats to Future HCV Therapies
Clinical trial data in HIV/HCV coinfection still emerging
– DDI data incomplete
– Performance outside select trial populations yet to be seen
Timeline
– Late 2013: FDA approval of simeprevir (GT1) and sofosbuvir
(GT1-4)
– 2014: anticipated FDA approval of faldaprevir (GT1);
first all-oral regimens for GT1 expected to be approved
Costs uncertain, but likely an issue in many regions
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Best Practices in the Management of HCV/HIV Coinfection
C212 Study: Simeprevir + PegIFN/RBV in
GT1 HCV/HIV Coinfection
Phase III randomized controlled
trial[45]
– 24- or 48-week regimens: SPV +
pegIFN/RBV for 12 weeks, then
pegIFN/RBV alone
HCV treatment-naive or
-experienced HIV+ patients
(N = 106)
– 88% on ART (VL < 50 cells/mL)
– Excluded: boosted PIs,
NNRTIs other than RPV
Safety profile similar to
monoinfected pts
– Pruritus and photosensitivity in
20% and 2%, respectively
SVR comparable to GT1 HCV-
monoinfected pts (80%)[46]
7/
10
16/
28
100
80
60
40
20
0
SVR12(%)
78/
106
74
Overall
70
42/
53
79
Naive
57
13/
15
87
Relapsers
n/N =
Partial Null
45. Dieterich D, et al. EACS 2013. Abstract LBPS9/5. 46. Jacobson I, et al. EASL 2013. Abstract 1425.
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Best Practices in the Management of HCV/HIV Coinfection
PHOTON-1: Sofosbuvir + RBV in GT1/2/3
HIV/HCV Coinfection
Phase III open-label study
– 12- (GT2/3 treatment-naive) or 24-
week regimens (GT1 treatment-
naive, GT2/3 treatment
experienced): sofosbuvir + RBV
HCV treatment-naive or
-experienced HIV+ patients
(N = 223)
– Approx 76% on ART (VL < 50
cells/mL), various standard
regimens
Safety profile similar to
monoinfected patients; consistent
with RBV
– Most frequent AEs: fatigue,
insomnia, headache, nausea,
diarrhea
2 patients had transient HIV
rebound due to nonadherence
47. Sulkowski MS, et al. AASLD 2013. Abstract 212.
n/N
87/
114
Virologic Outcomes for
Treatment-Naive Patients
by GT
76
88
67
0
20
40
60
80
100
GT1 GT2 GT3
SVR12(%)
23/
26
28/
42
30. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
STARTVerso4: Faldaprevir + PegIFN/RBV
in GT1 HCV/HIV Coinfection
Phase III open-label study
– 24- or 48-week regimens:
faldaprevir + pegIFN/RBV for 12 or
24 weeks, then pegIFN/RBV alone
HCV treatment-naive or previous
relapser HIV+ patients (N = 308)
– 96% on ART (VL < 50 cells/mL)
Safety profile similar to
monoinfected pts
– Most frequent AEs: nausea, fatigue,
diarrhea, headache
– Decrease in hemoglobin consistent with
pegIFN/RBV historical data
1 patient had HIV rebound requiring
new ART regimen
*24 wks of therapy; †
12 wks of therapy
49. Rockstroh JK, et al. AASLD 2013. Abstract 1099.
72
79
84
0
20
40
60
80
100
Faldaprevir
120 mg*
Faldaprevir
240 mg†
Faldaprevir
240 mg*
n/N =
89/
123
66
84
72/
86
SVR4(%)
32. clinicaloptions.com/hepatitis
Best Practices in the Management of HCV/HIV Coinfection
Summary
Liver disease leading cause of morbidity and mortality in
HIV/HCV coinfection
– Antiretroviral therapy may slow progression
HCV screening at HIV diagnosis and at least annually
HCV treatment considerations
– Treat now or wait for future options?
– First-generation DAAs complex, long duration, AEs, DDIs
– New agents may improve outcomes with shorter therapy,
fewer AEs
– Consider HCV disease stage and risk of progression
Editor's Notes
HCV, hepatitis C virus.
Hepatitis C virus (HCV)/HIV-coinfected patients with untreated HIV are at increased risk for fibrosis progression as CD4+ cell counts decline.[1,2] As a consequence, liver disease has become one of the most prominent causes of death in coinfected individuals and is one of the most important clinical challenges to date.[3] In North America and Europe, one quarter of patients who have HIV infection are coinfected with HCV[4]; however, in areas where injection drug use is the main driver of HIV transmission, such as Eastern Europe (especially Russia and Ukraine), a much higher rate of coinfection—up to 70%—has been reported.[5] As a consequence, screening for hepatitis C is mandatory in all HIV patients.
HCV, hepatitis C virus; MSM, men who have sex with men.
Since 2002, an increasing incidence of acute hepatitis C among HIV-positive men who have sex with men (MSM) has been reported in many North American, European, and Australian HIV cohorts.[6-10] Phylogenetic analysis shows that the transmitted viruses appear in clusters, suggesting more recent introduction of hepatitis C into sexual networks.[9-10]
HCV, hepatitis C virus; MSM, men who have sex with men.
Studies addressing risk factors for hepatitis C transmission among HIV-positive MSM have identified, in particular, traumatic sex practices involving a high likelihood of blood-blood contact, including unprotected anal sex and fisting.[11,12] Additional drivers of infection in this group include multiple partners and the presence of other sexually transmittable diseases. Risk of HCV acquisition is further enhanced in the setting of drugs and alcohol abuse.
Ab, antibody; HCV, hepatitis C virus; IDU, intravenous drug use; MSM, men who have sex with men.
In light of the increased prevalence of hepatitis C and recent outbreaks, repeated screening for hepatitis C (after initial screening at baseline) remains warranted in HIV-infected patients.[13-16] Currently, annual hepatitis C screening in patients at risk appears indicated; however, antibodies to HCV may require up to 1 year to manifest in patients with acute hepatitis C. Therefore, in the setting of suspected acute hepatitis C, it may not be sufficient to perform only HCV antibody tests; direct HCV RNA testing will also be required.
HCV, hepatitis C virus.
The uptake of treatment for hepatitis C has been low, with only 25% of patients in Europe receiving or having received dual hepatitis C therapy. In the United States, less than 10% of patients have been treated with dual therapy. This low rate of treatment has been influenced by the lower rates of efficacy with dual therapy in coinfected patients, the high incidence of adverse effects, and limited access to therapy. Furthermore, because of the anticipated approval of better-tolerated drugs with greater efficacy, many patients and clinicians have delayed initiating therapy until the anticipated agents become available.
AE, adverse event; HCV, hepatitis C virus; RGT, response-guided therapy.
With the approval of telaprevir and boceprevir in 2011, hepatitis C treatment remained a complex endeavor requiring management by expert clinicians.[17,18] Many HIV and hepatitis C drugs are metabolized by the cytochrome P450 system leading to multiple drug-drug interactions. The complexity of hepatitis C care was further exacerbated by the many toxicities and high pill burdens imposed by these regimens.
HCV, hepatitis C virus.
Despite these challenges, delaying therapy may lead to disease progression, including hepatic decompensation and eventually development of hepatocellular carcinoma, especially in patients with low CD4+ cell counts.[19-22] In addition, many transplantation sites still refuse to accept HIV-infected individuals, although HIV in general is not a contraindication for liver transplantation. One reason for this reluctance may be data indicating that after transplantation, HIV/HCV-infected patients experience reduced survival compared with HCV-monoinfected patients.
HCV, hepatitis C virus.
A study in US veterans evaluated the cumulative incidence of hepatic decompensation over time in HIV/HCV-coinfected patients on stable antiretroviral therapy compared with HCV-monoinfected patients.[23] Data from this study suggest that even in the era of HAART, there remains a substantially higher risk of disease progression in coinfected patients. This finding may be tempered somewhat by recognizing that patients who are coinfected may have been diagnosed late and already had advanced fibrosis because of low CD4+ cell count prior to HIV treatment initiation; this may explain some of the difference in liver disease outcomes seen here.
DAA, direct-acting antiviral; HCV, hepatitis C virus.
Deciding to delay therapy in anticipation of upcoming treatment options requires an assessment of the individual patient’s risk of disease progression balanced against the benefits, complexity, and challenges of current hepatitis C therapy. Although easy-to-take, all-oral regimens of direct-acting antivirals for patients infected with all HCV genotypes are likely to be available in the foreseeable future, the precise timeline for their availability is uncertain; this is particularly true of cost reimbursement issues that have delayed the availability of boceprevir and telaprevir in many European countries. Moreover, data on the use of these regimens in HV/HCV-coinfected patients often take longer to emerge than data in HCV-monoinfected patients. Therefore, it is important to discuss the advantages and disadvantages of both current and anticipated regimens for each individual with HIV/HCV coinfection and reach an informed decision regarding whether to treat now or defer therapy.
HCV, hepatitis C virus.
Most importantly, the decision to start hepatitis C therapy or to wait is driven by the baseline fibrosis stage of the coinfected individual.[24,25] Patients who have been identified as having advanced fibrosis, suggesting that they are at increased risk of hepatic decompensation and hepatocellular carcinoma development, are clearly the candidates in whom immediate treatment should be considered.[26] Patients with no or minimal fibrosis have a lower probability of further progression of liver disease and can easily wait in the setting of successful HIV therapy.
Stable control of HIV disease is an important factor in the decision-making process because preventing immunodeficiency slows fibrosis progression. Therefore, current US and European guidelines agree that starting HIV treatment is recommended in any coinfected individual with a CD4+ cell count &lt; 500 cells/mm3.[24,25] For patients who have a CD4+ cell count &gt; 500 cells/mm3, physicians may decide to defer HIV therapy to undertake hepatitis C therapy without the complications of drug-drug interactions and additive toxicities of 2 antiviral regimens.[25]
HCV, hepatitis C virus.
GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.
Turning now to the available treatment options, it is important to recall that the uptake of dual therapy with peginterferon/ribavirin was limited by the perception of lower efficacy in initial peginterferon/ribavirin treatment trials for coinfected patients. Response rates for genotype 1 or 4 were 14% to 35%, demonstrably lower than those seen in HCV-monoinfected individuals.[27-31] However, in the early days of dual therapy, different dosages of ribavirin were used and HIV drugs that have now been shown to lower sustained virologic response (SVR) rates were often coadministered, including zidovudine and didanosine. For genotype 2/3 HCV/HIV-coinfected patients, response rates with appropriate ribavirin dosing and appropriate treatment durations resulted in rates of SVR that approach those seen in HCV-monoinfected genotype 2/3 patients.[32]
DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; IL, interleukin; pegIFN, peginterferon; RBV, ribavirin.
The algorithm in the October 2013 European treatment guidelines[33] recommends that a patient with replicating hepatitis C and a given indication such as elevated liver enzymes and the presence of fibrosis should receive dual therapy with pegylated interferon and weight-based ribavirin; this applies to HCV genotype 2, 3, and 4 as well as genotype 1 in settings where no direct-acting antiviral (DAA)-based regimens are available. Patients with HCV genotype 2/3 showing a rapid virologic response, defined as undetectable HCV RNA at Week 4, qualify for a shorter treatment duration of 24 weeks unless they have cirrhosis at baseline. Patients with genotype 1/4 who achieve rapid virologic response are treated for 48 weeks. Patients with detectable HCV RNA at Week 4 who achieve at least a 2 log decrease in HCV RNA at Week 12 are revaluated at Week 24; if they have undetectable HCV RNA at that time point, patients with genotype 2/3 continue on treatment for a total of 48 weeks and patients with genotype 1/4 for 72 weeks. Overall, treatment duration with dual therapy is somewhat longer in coinfected patients than in monoinfected patients.
ART, antiretroviral therapy; EFV, efavirenz; FTC, emtricitabine; GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TDF, tenofovir; TID, 3 times daily.
The first pilot trial to investigate efficacy and safety of telaprevir-based therapy in treatment-naive genotype 1 HCV/HIV-coinfected patients included patients with CD4+ cell counts &gt; 500 cells/mm3 who were HCV treatment naive and were receiving either efavirenz-based or boosted atazanavir-based antiretroviral therapy.[34] The overall SVR rate of 74% was comparable to those seen in treatment-naive HCV-monoinfected patients[35] and superior to the SVR rates of the peginterferon/ribavirin control arm. Consequently, triple therapy became the new standard of treatment in genotype 1 HCV/HIV-coinfected individuals.
GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.
Similarly, in a study evaluating the efficacy and safety of boceprevir-based triple therapy in treatment-naive genotype 1 HCV/HIV‑coinfected patients, a substantial improvement in overall rates of SVR was seen compared with the peginterferon/ribavirin control arm (63% vs 29%) after 48 weeks of treatment.[36,37]
BOC, boceprevir; DDI, drug-drug interaction; NA, not available; q8h, every 8 hours; TVR, telaprevir.
When patients are considered for hepatitis C treatment with telaprevir- or boceprevir-based therapy, the most important obstacle to overcome is potential drug interactions with HIV drugs. Boosted protease inhibitors (PIs) have been particularly difficult to combine with telaprevir and boceprevir, although atazanavir/ritonavir may be combined with telaprevir and, according to the European guidelines only, with boceprevir in selected patients.[38-44]
Of note, the recently approved HCV PI simeprevir should not be coadministered with any boosted or unboosted PI or any nonnucleoside reverse transcriptase inhibitor except rilpivirine; it can also be administered with raltegravir.[42] By contrast, the recently approved polymerase inhibitor sofosbuvir has no known interactions with commonly used HIV drugs, such as darunavir/ritonavir, efavirenz, raltegravir, and rilpivirine.[43]
HCV, hepatitis C virus.
Future hepatitis C therapies promise significant advances, including once-daily administration, shorter treatment durations for the majority of patients, improved tolerability, and, most likely within the next 2 years, interferon-free—and subsequently interferon-free and ribavirin-free—regimens for patients with all HCV genotypes.
DDI, drug–drug interaction; FDA, US Food and Drug Administration; GT, genotype; HCV, hepatitis C virus.
Although emerging clinical trial data from coinfected individuals are promising, the need for drug-drug interaction data has delayed some of these trials; likewise, as with all new agents, the performance of new agents in real-world settings rather than in selected clinical trial populations remains to be seen. There is also some uncertainty regarding the timeline for availability of new agents and regimens. However, as of November 2013 the PI simeprevir has been approved for use in the United States, Canada, and Europe and in December 2013 the nucleotide polymerase inhibitor sofosbuvir was approved in the United States. Regulatory decisions for both of these agents are also pending in Europe. In 2014, approval of the PI faldaprevir is anticipated, and the first all-oral regimens for HCV genotype 1 may also be approved.
ART, antiretroviral therapy; GT, genotype; NNRTI, nonnucleoside reverse transcriptase inhibitor; peglFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; RPV, rilpivirine; SPV, simeprevir; SVR, sustained virologic response; VL, viral load.
Simeprevir has now been approved for treatment of chronic HCV infection in combination with other antiviral agents in genotype 1 and 4 HCV-infected patients with compensated liver disease, including cirrhosis. The regimen recommended by the US Food and Drug Administration (FDA) is 12 weeks of triple therapy followed by an additional 12 weeks of peginterferon/ribavirin alone for treatment-naive patients and previous relapsers (including patients with cirrhosis), or an additional 36 weeks of peginterferon/ribavirin alone for previous partial or null responders (including patients with cirrhosis).
The US prescribing information for simeprevir does not specifically address its use in HIV-coinfected patients, but it has been evaluated in this setting in the C212 study, a phase III randomized controlled trial evaluating the efficacy and safety of simeprevir in combination with pegylated interferon and ribavirin in genotype 1 HIV/HCV-coinfected individuals.[45] The study included both HCV treatment-naive and treatment-experienced patients, including null responders. Overall, the SVR rates (74%) were comparable to those reported for HCV-monoinfected individuals,[46] although they were lower in patients with previous null response. In addition, the safety profile was similar to that previously seen in monoinfected patients; pruritus and photosensitivity representing notable adverse events.
AE, adverse event; ART, antiretroviral therapy; GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response; VL, viral load.
Sofosbuvir has been approved for treatment of chronic hepatitis C in combination with other antiviral agents in genotype 1, 2, 3, and 4 patients, including those with hepatocellular carcinoma and those with HIV/HCV coinfection. According to the FDA indication,[43] sofosbuvir plus peginterferon/ribavirin for 12 weeks is recommended for genotype 1/4 HCV; sofosbuvir plus ribavirin for 12 weeks is recommended for genotype 2 HCV; and sofosbuvir plus ribavirin for 24 weeks is recommended for genotype 3 HCV and for genotype 1 HCV patients who are ineligible to receive interferon.
The PHOTON-1 phase III trial in HIV/HCV-coinfected patients evaluated sofosbuvir and ribavirin for 24 weeks in genotype 1 HCV patients or 12 weeks in genotype 2/3 HCV patients.[47] To date, only data for treatment-naive genotype 2/3 and genotype 1 patients have been presented. Overall, SVR rates were 76% in genotype 1 patients, 88% in genotype 2 patients, and 67% in genotype 3 patients; data from HCV-monoinfected patients have subsequently demonstrated that 24 weeks of therapy are needed for optimal outcomes in genotype 3 HCV patients.[48] The safety profile was consistent with the adverse events previously associated with ribavirin.
AE, adverse event; ART, antiretroviral therapy; GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; VL, viral load.
STARTVerso4 is the largest HCV/HIV coinfection trial to date investigating the efficacy and safety of the second-wave PI faldaprevir in combination with peginterferon and ribavirin in genotype 1 HIV/HCV-coinfected individuals.[49] This phase III, open-label study used response-guided therapy, and most patients (&gt; 80%) qualified for shorter treatment durations. Although 2 doses of faldaprevir were compared, patients receiving certain antiretroviral agents were assigned to specific doses of faldaprevir because of drug-drug interactions. Of note, boosted darunavir-treated patients were included in this study; darunavir is not recommended to be combined with telaprevir, boceprevir, or simeprevir.
Overall SVR rates were high at 74%, comparable to those seen in monoinfected patients. There were no significant differences between the dosages investigated. Importantly, there was no difference in response rates between patients with cirrhosis or no cirrhosis at baseline.
GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; r, ritonavir; RBV, ribavirin; RVR, rapid virologic response.
Many more studies of DAAs in coinfected patients are currently underway, including studies evaluating response-guided therapy with boceprevir and telaprevir. Additional studies are evaluating telaprevir in cirrhotic patients and other difficult-to-treat patient populations. New DAAs are also being evaluated, including the NS5A inhibitor daclatasvir in combination with peginterferon and ribavirin and also in combination with peginterferon lambda and ribavirin.
Multiple interferon-free regimens are also being studied, including the promising regimen of the PI ABT-450/ritonavir, the NS5A inhibitor ABT-267, and the nonnucleoside polymerase inhibitor ABT-333 plus ribavirin in coinfected individuals.
However, in the modern HIV treatment era with improved antiretroviral treatment regimens, most trials suggest that the outcome and safety of DAA-based HCV therapy do not differ between HCV-coinfected and -monoinfected patients. This suggests that, in the near future, no distinction may be made between HIV-infected and -uninfected patients with hepatitis C.
AE, adverse event; DAA, direct-acting antiviral; DDI, drug-drug interaction; HCV, hepatitis C virus.
In summary, HIV-infected patients with low CD4+ cell counts due to late diagnosis or long-standing HIV infection experience a faster progression of hepatitis C–associated liver diseases and increased morbidity and mortality. Early initiation of HIV treatment prevents immunodeficiency and may significantly slow fibrosis progression and improve overall outcomes. Annual hepatitis C screening is highly recommended for HIV-infected individuals.
HCV therapy is evolving rapidly: 2 new agents were recently approved, and once-daily, well-tolerated, interferon- and/or ribavirin-free options for all HCV genotypes are expected within the next 2-3 years. These developments require physicians to carefully consider whether to initiate or delay hepatitis C treatment in each individual and to reevaluate that decision as new agents become available. The key consideration is each patient’s fibrosis stage: Patients with more advanced fibrosis should consider initiating hepatitis C treatment immediately, whereas patients with little or no fibrosis may be candidates for delaying therapy in anticipation of future regimens.