The newly approved HCV protease inhibitors boceprevir and telaprevir promise to revolutionize HCV treatment.
Hepatitis C virus (HCV) treatment will change dramatically with the FDA's recent approval of two new oral HCV protease inhibitors, boceprevir and telaprevir. When used in combination with current standard therapy (peginterferon and ribavirin [PR]), these new drugs substantially improve cure rates and often reduce the overall duration of therapy. Although data are still emerging, these new drugs are likely to benefit HIV-coinfected patients as well.
Boceprevir
Boceprevir (Victrelis) was approved by the FDA on May 13, 2011, for the treatment of chronic HCV genotype 1 infection both in patients who are treatment-naive and in those with prior treatment failure.1 The approval was based on two large, manufacturer-sponsored, phase III, randomized, controlled trials.
CLINICAL TRIALS
Treatment-Naive Patients
In the SPRINT-2 trial,2 1097 treatment-naive patients with HCV genotype 1 infection (159 blacks; 938 nonblacks) underwent a 4-week lead-in period of PR and then received one of the following:
Among nonblacks, sustained virologic response (SVR) rates were significantly higher in the boceprevir groups (67%–68%) than in the control group (40%). Blacks had lower SVR rates in all three groups, but B+PR still outperformed PR in this population; SVR rates were 42% in the RGT group, 53% in the fixed-duration group, and 23% among controls. Overall, 44% of patients in the RGT group had undetectable HCV RNA from week 8 to week 24 and therefore received shorter-duration therapy (28 weeks total).
Previously Treated Patients
The RESPOND-2 trial3 involved 403 patients with HCV genotype 1 infection who had a partial response to — or a relapse following — prior PR therapy. Of note, so-called prior null-responders (patients who had not previously achieved a
2 log IU/mL drop in HCV RNA by week 12) were not included in this trial. Patients received 4 weeks of lead-in therapy with PR (which, in this trial, consisted of peginterferon α-2b and ribavirin). Treatment arms were the same as in SPRINT-2, except that here, the RGT arm involved B+PR for 32 weeks beyond lead-in, with an additional 12 weeks of PR alone if HCV RNA was detectable at week 8. SVR rates were significantly higher in the boceprevir groups (59% in the RGT group; 66% in the fixed-duration group) than in the control group (21%).
DOSING
Boceprevir should be prescribed only in combination with PR and should be taken at a dose of 800 mg (four 200-mg capsules) three times daily with food. PR should be administered alone for a 4-week lead-in period. Response-guided therapy is recommended for patients without cirrhosis who are treatment-naive or who have had partial response to, or relapse following, prior interferon/ribavirin therapy. Guidelines for treatment duration in such patients, as recommended in the package insert,1 are shown in Table 1.
Because patients with compensated cirrhosis have relatively poor results with therapy, the recommended boceprevir-based treatment for this population is 4 weeks of PR followed by 44 weeks of B+PR. In addition, 44 weeks of B+PR should be considered for previously untreated patients who have a poor response to lead-in PR, defined as a <1 log IU/mL reduction in HCV RNA at week 4. Although the efficacy of boceprevir in prior null-responders has not been studied, if treatment is considered for such an individual, 4 weeks of PR followed by 44 weeks of B+PR should be given.
B+PR treatment should be stopped based on futility in any patient with an HCV RNA level100 IU/mL at treatment week 12 or confirmed detectable HCV RNA at treatment week 24.
DRUG INTERACTIONS
Boceprevir is a strong inhibitor of CYP3A4/5 and should not be administered with drugs that are highly affected by this pathway, such as alfuzosin, rifampin, simvastatin, carbamazepine, phenytoin, and oral midazolam.
ADVERSE EVENTS
In phase II and III clinical trials,1 49% of patients in the boceprevir groups had hemoglobin values <10 g/dL, compared with 28% of those in the control groups. Use of erythropoiesis-stimulating agents to treat anemia was more frequent in the boceprevir groups (43%) than in the control groups (24%). However, the rate of study-drug discontinuation because of anemia was low (1%). Decreased neutrophil and platelet counts were more common in the boceprevir groups, as was dysgeusia (35%–44% in boceprevir groups vs. 11%–16% in control groups).
Telaprevir
Telaprevir (Incivek) was approved by the FDA on May 23, 2011, based on data from manufacturer-sponsored trials in treatment-naive and treatment-experienced patients chronically infected with HCV genotype 1.4 In these trials, PR consisted of peginterferon α-2a and ribavirin.
CLINICAL TRIALS
Treatment-Naive Patients
In the phase III ADVANCE trial,5 1088 treatment-naive patients were randomized to one of three treatments (none of which involved a lead-in period):
In the phase III ILLUMINATE study,7 researchers examined two treatment durations among patients who had achieved eRVR with a 12-week course of T+PR, followed by PR alone. In all, 322 patients were randomized at week 20 to receive a total of 24 or 48 weeks of therapy. SVR rates were 92% and 88%, respectively, demonstrating noninferiority of the 24-week regimen in this patient group.
Previously Treated Patients
In the phase III REALIZE trial,8 662 patients with prior PR treatment failure (i.e., relapse, partial response, or null response) were randomized to 48 weeks of therapy with one of the following approaches:
DOSING
Telaprevir should be prescribed only in combination with PR and should be taken at a dose of 750 mg (two 375-mg tablets) three times daily with food. It should be administered for 12 weeks in all patients, followed by PR alone for an additional 12 or 36 weeks, depending on viral response and prior response status. Guidelines for treatment duration, as recommended in the package insert,4 are shown in Table 2.
Prior partial-responders should receive T+PR for the first 12 weeks, followed by an additional 36 weeks of PR alone. Treatment-naive patients with cirrhosis who have undetectable HCV RNA at weeks 4 and 12 may also benefit from an additional 36 weeks of PR. If therapy is considered for prior null-responders, T+PR for 12 weeks followed by an additional 36 weeks of PR should be given.
Therapy should be stopped in any patient with an HCV RNA level1000 IU/mL at treatment week 4 or week 12 or confirmed detectable HCV RNA at treatment week 24.
DRUG INTERACTIONS
Telaprevir inhibits CYP3A and should not be administered with drugs that are highly affected by this pathway, including alfuzosin, rifampin, HMG CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin), and oral midazolam.
ADVERSE EVENTS
The main adverse effects of telaprevir are rash, anemia, nausea and other gastrointestinal symptoms, dysgeusia, and anorectal discomfort. In clinical trials, rash developed in 56% of patients who received T+PR, compared with 34% who received PR alone. Severe rash was reported in 4% of those receiving T+PR, versus <1% of those who received PR alone.4 Patients with mild to moderate rashes may continue therapy with careful monitoring. Telaprevir should be stopped if a rash progresses and becomes severe, or if systemic symptoms develop.
PR treatment is associated with decreased hemoglobin concentrations, and the addition of telaprevir is associated with an additional decrease. In clinical trials, 36% of patients who received T+PR had hemoglobin values <10 g/dL, compared with 17% of those who received PR alone.4 (Use of growth factors — allowed in the boceprevir studies — was not permitted in the telaprevir trials.9) However, the rate of telaprevir discontinuation because of anemia was low: Among patients receiving T+PR, 4% stopped telaprevir, and 1% discontinued T+PR.
Boceprevir vs. Telaprevir: What We Know and Don't Know
Not surprisingly, emergence of drug-resistance mutations has been observed in patients who have received these agents. Drug resistance may become undetectable after HCV protease inhibitors are stopped, but we do not yet know whether these resistant variants would reemerge if therapy were restarted.
Improving HCV Therapy for HIV-Coinfected Patients
HCV treatment in HIV-coinfected individuals has traditionally been challenging, given their low rates of SVR. However, emerging data from a recent phase II, randomized trial demonstrate that telaprevir may improve virologic responses in HIV-infected patients with genotype 1 HCV infection.11 In that study, 60 patients were treated with PR plus telaprevir or placebo for 12 weeks, followed by PR alone to complete 48 weeks of therapy. In an interim analysis involving 59 patients, 70% of those in the telaprevir group had undetectable HCV RNA at week 4, compared with 0% in the control group. At week 12, the numbers were 68% versus 14%. Table 3 shows results stratified by receipt of antiretroviral therapy (ART); notably, only those receiving tenofovir/FTC/efavirenz or tenofovir/FTC + ritonavir-boosted atazanavir were eligible for the portion of the study examining responses in ART-treated patients. Currently, neither telaprevir nor boceprevir is approved for treating chronic HCV infection in HIV-positive patients. Although these findings suggest that telaprevir may be beneficial, longer-term results are still pending.
Little is known about drug interactions between HCV protease inhibitors and ART. Use of efavirenz reduces telaprevir levels; as a result, in the ongoing phase II study summarized above, the dose of telaprevir was increased to 1125 mg every 8 hours in the efavirenz group. In healthy-volunteer studies, ritonavir-boosted atazanavir had less effect on telaprevir exposure than did other HIV protease inhibitors.12 Coadministration of efavirenz reduces trough concentrations of boceprevir, but the clinical implications are not clear.13 Interactions between boceprevir and commonly used HIV protease inhibitors have not yet been reported.
Conclusions and Future Challenges
Use of boceprevir or telaprevir together with PR will revolutionize HCV treatment, leading to improved outcomes and a shorter duration of treatment for many patients. As we take stock of this breathtaking advance, we should also pause to consider some unanswered questions:
Finally, boceprevir and telaprevir are administered with peginterferon/ribavirin, and patients who cannot tolerate these medications will not benefit from the newly approved drugs yet. Fortunately, many new anti-HCV drugs — including polymerase and NS5A inhibitors — are being investigated in clinical trials. Hopefully, they will eliminate interferon from our HCV toolbox in the future.
— Isaac I. Bogoch, MD, and Rajesh T. Gandhi, MD
Dr. Bogoch is a Fellow in the Division of Infectious Diseases at Massachusetts General Hospital in Boston. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care May 27, 2011
Boceprevir
Boceprevir (Victrelis) was approved by the FDA on May 13, 2011, for the treatment of chronic HCV genotype 1 infection both in patients who are treatment-naive and in those with prior treatment failure.1 The approval was based on two large, manufacturer-sponsored, phase III, randomized, controlled trials.
CLINICAL TRIALS
Treatment-Naive Patients
In the SPRINT-2 trial,2 1097 treatment-naive patients with HCV genotype 1 infection (159 blacks; 938 nonblacks) underwent a 4-week lead-in period of PR and then received one of the following:
- Boceprevir plus PR (B+PR) for 24 weeks, with an additional 20-week course of PR alone if HCV RNA was detected between weeks 8 and 24 (the response-guided therapy [RGT] group)
- B+PR for 44 weeks (the fixed-duration group)
- PR plus placebo for 44 weeks (the control group)
Among nonblacks, sustained virologic response (SVR) rates were significantly higher in the boceprevir groups (67%–68%) than in the control group (40%). Blacks had lower SVR rates in all three groups, but B+PR still outperformed PR in this population; SVR rates were 42% in the RGT group, 53% in the fixed-duration group, and 23% among controls. Overall, 44% of patients in the RGT group had undetectable HCV RNA from week 8 to week 24 and therefore received shorter-duration therapy (28 weeks total).
Previously Treated Patients
The RESPOND-2 trial3 involved 403 patients with HCV genotype 1 infection who had a partial response to — or a relapse following — prior PR therapy. Of note, so-called prior null-responders (patients who had not previously achieved a
2 log IU/mL drop in HCV RNA by week 12) were not included in this trial. Patients received 4 weeks of lead-in therapy with PR (which, in this trial, consisted of peginterferon α-2b and ribavirin). Treatment arms were the same as in SPRINT-2, except that here, the RGT arm involved B+PR for 32 weeks beyond lead-in, with an additional 12 weeks of PR alone if HCV RNA was detectable at week 8. SVR rates were significantly higher in the boceprevir groups (59% in the RGT group; 66% in the fixed-duration group) than in the control group (21%).DOSING
Boceprevir should be prescribed only in combination with PR and should be taken at a dose of 800 mg (four 200-mg capsules) three times daily with food. PR should be administered alone for a 4-week lead-in period. Response-guided therapy is recommended for patients without cirrhosis who are treatment-naive or who have had partial response to, or relapse following, prior interferon/ribavirin therapy. Guidelines for treatment duration in such patients, as recommended in the package insert,1 are shown in Table 1.
Because patients with compensated cirrhosis have relatively poor results with therapy, the recommended boceprevir-based treatment for this population is 4 weeks of PR followed by 44 weeks of B+PR. In addition, 44 weeks of B+PR should be considered for previously untreated patients who have a poor response to lead-in PR, defined as a <1 log IU/mL reduction in HCV RNA at week 4. Although the efficacy of boceprevir in prior null-responders has not been studied, if treatment is considered for such an individual, 4 weeks of PR followed by 44 weeks of B+PR should be given.
B+PR treatment should be stopped based on futility in any patient with an HCV RNA level
100 IU/mL at treatment week 12 or confirmed detectable HCV RNA at treatment week 24.DRUG INTERACTIONS
Boceprevir is a strong inhibitor of CYP3A4/5 and should not be administered with drugs that are highly affected by this pathway, such as alfuzosin, rifampin, simvastatin, carbamazepine, phenytoin, and oral midazolam.
ADVERSE EVENTS
In phase II and III clinical trials,1 49% of patients in the boceprevir groups had hemoglobin values <10 g/dL, compared with 28% of those in the control groups. Use of erythropoiesis-stimulating agents to treat anemia was more frequent in the boceprevir groups (43%) than in the control groups (24%). However, the rate of study-drug discontinuation because of anemia was low (1%). Decreased neutrophil and platelet counts were more common in the boceprevir groups, as was dysgeusia (35%–44% in boceprevir groups vs. 11%–16% in control groups).
Telaprevir
Telaprevir (Incivek) was approved by the FDA on May 23, 2011, based on data from manufacturer-sponsored trials in treatment-naive and treatment-experienced patients chronically infected with HCV genotype 1.4 In these trials, PR consisted of peginterferon α-2a and ribavirin.
CLINICAL TRIALS
Treatment-Naive Patients
In the phase III ADVANCE trial,5 1088 treatment-naive patients were randomized to one of three treatments (none of which involved a lead-in period):
- Telaprevir plus PR (T+PR) for 8 weeks, followed by PR alone. Patients who had extended rapid virologic response (eRVR; defined as undetectable HCV RNA at weeks 4 and 12) stopped PR at week 24, whereas those without eRVR continued therapy until week 48.
- T+PR for 12 weeks, followed by PR alone. Patients with eRVR stopped PR at week 24, whereas those without eRVR continued therapy until week 48.
- PR for 48 weeks (control group)
In the phase III ILLUMINATE study,7 researchers examined two treatment durations among patients who had achieved eRVR with a 12-week course of T+PR, followed by PR alone. In all, 322 patients were randomized at week 20 to receive a total of 24 or 48 weeks of therapy. SVR rates were 92% and 88%, respectively, demonstrating noninferiority of the 24-week regimen in this patient group.
Previously Treated Patients
In the phase III REALIZE trial,8 662 patients with prior PR treatment failure (i.e., relapse, partial response, or null response) were randomized to 48 weeks of therapy with one of the following approaches:
- T+PR for 12 weeks, followed by PR alone for 36 weeks
- Lead-in PR for 4 weeks, followed by T+PR for 12 weeks, and then PR alone for 32 weeks
- PR for 48 weeks (control group)
DOSING
Telaprevir should be prescribed only in combination with PR and should be taken at a dose of 750 mg (two 375-mg tablets) three times daily with food. It should be administered for 12 weeks in all patients, followed by PR alone for an additional 12 or 36 weeks, depending on viral response and prior response status. Guidelines for treatment duration, as recommended in the package insert,4 are shown in Table 2.
Prior partial-responders should receive T+PR for the first 12 weeks, followed by an additional 36 weeks of PR alone. Treatment-naive patients with cirrhosis who have undetectable HCV RNA at weeks 4 and 12 may also benefit from an additional 36 weeks of PR. If therapy is considered for prior null-responders, T+PR for 12 weeks followed by an additional 36 weeks of PR should be given.
Therapy should be stopped in any patient with an HCV RNA level
1000 IU/mL at treatment week 4 or week 12 or confirmed detectable HCV RNA at treatment week 24.DRUG INTERACTIONS
Telaprevir inhibits CYP3A and should not be administered with drugs that are highly affected by this pathway, including alfuzosin, rifampin, HMG CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin), and oral midazolam.
ADVERSE EVENTS
The main adverse effects of telaprevir are rash, anemia, nausea and other gastrointestinal symptoms, dysgeusia, and anorectal discomfort. In clinical trials, rash developed in 56% of patients who received T+PR, compared with 34% who received PR alone. Severe rash was reported in 4% of those receiving T+PR, versus <1% of those who received PR alone.4 Patients with mild to moderate rashes may continue therapy with careful monitoring. Telaprevir should be stopped if a rash progresses and becomes severe, or if systemic symptoms develop.
PR treatment is associated with decreased hemoglobin concentrations, and the addition of telaprevir is associated with an additional decrease. In clinical trials, 36% of patients who received T+PR had hemoglobin values <10 g/dL, compared with 17% of those who received PR alone.4 (Use of growth factors — allowed in the boceprevir studies — was not permitted in the telaprevir trials.9) However, the rate of telaprevir discontinuation because of anemia was low: Among patients receiving T+PR, 4% stopped telaprevir, and 1% discontinued T+PR.
Boceprevir vs. Telaprevir: What We Know and Don't Know
- A 4-week lead-in period of PR is given with boceprevir but not with telaprevir.
- In treatment-naive patients with genotype 1 HCV infection, both boceprevir and telaprevir improve SVR rates and, for many patients, reduce the duration of treatment. Neither drug is indicated for treatment of non–genotype 1 HCV infection.
- In previously treated patients, telaprevir improves SVR rates in both prior responders and prior null-responders. Boceprevir has been studied only in patients who had at least a partial response to PR therapy in the past — and has been shown to improve SVR rates in this population.
- Both boceprevir and telaprevir are approved for three-times-daily dosing, and the pill burden is considerable. Telaprevir may be effective when dosed at 1125 mg twice daily,10 but larger studies are needed.
- In a retrospective subgroup analysis of the boceprevir phase III trials, patients with the favorable IL28B genotype (C/C) had higher response rates than those with unfavorable genotypes. This was particularly true among previously untreated patients.1 In a retrospective subgroup analysis of the telaprevir trials, patients with any IL28B genotype appeared to have higher SVR rates with T+PR than with PR alone.4
- A head-to-head trial comparing the drugs has not been performed, so we do not yet know which one is better.
Not surprisingly, emergence of drug-resistance mutations has been observed in patients who have received these agents. Drug resistance may become undetectable after HCV protease inhibitors are stopped, but we do not yet know whether these resistant variants would reemerge if therapy were restarted.
Improving HCV Therapy for HIV-Coinfected Patients
HCV treatment in HIV-coinfected individuals has traditionally been challenging, given their low rates of SVR. However, emerging data from a recent phase II, randomized trial demonstrate that telaprevir may improve virologic responses in HIV-infected patients with genotype 1 HCV infection.11 In that study, 60 patients were treated with PR plus telaprevir or placebo for 12 weeks, followed by PR alone to complete 48 weeks of therapy. In an interim analysis involving 59 patients, 70% of those in the telaprevir group had undetectable HCV RNA at week 4, compared with 0% in the control group. At week 12, the numbers were 68% versus 14%. Table 3 shows results stratified by receipt of antiretroviral therapy (ART); notably, only those receiving tenofovir/FTC/efavirenz or tenofovir/FTC + ritonavir-boosted atazanavir were eligible for the portion of the study examining responses in ART-treated patients. Currently, neither telaprevir nor boceprevir is approved for treating chronic HCV infection in HIV-positive patients. Although these findings suggest that telaprevir may be beneficial, longer-term results are still pending.
Little is known about drug interactions between HCV protease inhibitors and ART. Use of efavirenz reduces telaprevir levels; as a result, in the ongoing phase II study summarized above, the dose of telaprevir was increased to 1125 mg every 8 hours in the efavirenz group. In healthy-volunteer studies, ritonavir-boosted atazanavir had less effect on telaprevir exposure than did other HIV protease inhibitors.12 Coadministration of efavirenz reduces trough concentrations of boceprevir, but the clinical implications are not clear.13 Interactions between boceprevir and commonly used HIV protease inhibitors have not yet been reported.
Conclusions and Future Challenges
Use of boceprevir or telaprevir together with PR will revolutionize HCV treatment, leading to improved outcomes and a shorter duration of treatment for many patients. As we take stock of this breathtaking advance, we should also pause to consider some unanswered questions:
- How will clinicians choose between these new agents?
- Do all patients need the new drugs, or can some patients, such as those with favorable host and viral factors, be treated with PR alone?
- Does boceprevir require the 4-week PR lead-in period for maximum effectiveness?
- Should prior null-responders be treated with telaprevir-based therapy — which is expected to have a response rate of approximately 30% — or should they wait for development of better therapies in the future?
- How should liver-transplant patients with graft HCV reinfection be treated?
- How should patients with decompensated cirrhosis, in whom PR therapy is contraindicated, be treated?
Finally, boceprevir and telaprevir are administered with peginterferon/ribavirin, and patients who cannot tolerate these medications will not benefit from the newly approved drugs yet. Fortunately, many new anti-HCV drugs — including polymerase and NS5A inhibitors — are being investigated in clinical trials. Hopefully, they will eliminate interferon from our HCV toolbox in the future.
— Isaac I. Bogoch, MD, and Rajesh T. Gandhi, MD
Dr. Bogoch is a Fellow in the Division of Infectious Diseases at Massachusetts General Hospital in Boston. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care May 27, 2011
Citation(s):
1. Victrelis (boceprevir) capsules [prescribing information]. Whitehouse Station, NJ: Merck; 2011. (http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf)
2. Poordad F et al. for the SPRINT-2 investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011 Mar 31; 364:1195.
- Medline abstract (Free)
3. Bacon BR et al. for the HCV RESPOND-2 investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011 Mar 31; 364:1207.
- Medline abstract (Free)
4. Telaprevir (Incivek) capsules [prescribing information]. Cambridge, MA: Vertex; 2011. (http://pi.vrtx.com/files/uspi_telaprevir.pdf)
5. Jacobson IM et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology 2010 Oct; 52(S1):427A.
6. Hofmann WP and Zeuzem S. A new standard of care for the treatment of chronic HCV infection. Nat Rev Gastroenterol Hepatol 2011 May; 8:257.
- Medline abstract (Free)
7. Sherman KE et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study. Hepatology 2010 Oct; 52(S1):401A.
8. 65% of people whose prior treatment for hepatitis C was unsuccessful achieved SVR (viral cure) with telaprevir-based therapy in phase 3 REALIZE study [press release]. Cambridge, MA. Vertex; Sep 7 , 2010. (http://investors.vrtx.com/releasedetail.cfm?ReleaseID=505239)
9. Pawlotsky J-M. The results of phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: A new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterol 2011 Mar; 140:746.
- Medline abstract (Free)
10. Marcellin P et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology 2011 Feb; 140:459.
- Medline abstract (Free)
11. Sulkowski M et al. Interim analysis of a phase 2a double-blind study of TVR in combination with pegIFN-alfa2a and RBV in HIV/HCV co-infected patients. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 146LB. (http://www.retroconference.org/2011/Abstracts/42467.htm)
12. van Heeswijk R et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 119. (http://www.retroconference.org/2011/Abstracts/41437.htm)
13. Kasserra C et al. Clinical pharmacology of BOC: Metabolism, excretion, and drug-drug interactions. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 118. (http://www.retroconference.org/2011/Abstracts/41140.htm)
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