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We recently asked whether you would recommend new hepatitis C virus (HCV) treatment options to an HIV/HCV-coinfected patient who had only a partial response, as well as treatment-limiting adverse effects, on prior peginterferon/ribavirin therapy. Now, two experts describe what they would do.
A 62-year-old man with HIV/HCV genotype 1b coinfection and a remote history of injection-drug use is seen for follow-up to discuss the new treatment options for HCV. He has been on HIV treatment since 1998 and is currently stable on tenofovir/FTC + lopinavir/ritonavir, with a CD4 count of 550 cells/mm3 and an undetectable HIV viral load. He has severe lipoatrophy, presumably as a result of prior treatment with d4T + 3TC, which was given initially as dual therapy and then in combination with indinavir.
He underwent a liver biopsy in 2004 that demonstrated mild portal fibrosis, with few septa and no bridging (Metavir score F2). In 2008, he received peginterferon/ribavirin with appropriate weight-based dosing; at baseline, the HCV RNA level was 7.5 million copies/mL. Within 4 weeks of starting treatment, he had a 2-log decline in HCV RNA, but by 6 months, the HCV RNA was still detectable, at 2600 copies/mL. In addition, he reported several side effects — all of which worsened over time — including severe fatigue, taste disturbance, irritability, and difficulty completing his daily work responsibilities. Most concerning to him, however, was a 10-lb weight loss that made his lipoatrophy much more prominent. The HCV treatment was discontinued, and his symptoms soon resolved.
The patient now comes to the clinic saying he has heard of the new HCV treatment options and wonders whether you would recommend them. He is extremely concerned about side effects and worries that his job might be in jeopardy if he could not work at full capacity.
Would you offer this patient repeat treatment, with interferon/ribavirin + telaprevir or boceprevir? Would you do additional assessments to make this decision, such as repeat liver biopsy, interleukin (IL)-28B genotype, or other noninvasive tests of liver injury? If you decide not to treat him, what would be your major reason or reasons?
If you do treat him:
Which of the new drugs would you prescribe?
What would you cite as the likelihood of cure?
How would you alter the patient's HIV treatment?
How would you plan to manage the side effects of HCV treatment?
There are many reasons to hold off on triple therapy here, including the absence of data from treatment-experienced HIV/HCV-coinfected patients and the risk for side effects that could compromise the patient's job performance. However, I would consider such therapy sooner rather than later if I knew that the patient's underlying liver disease had progressed beyond the mild portal fibrosis seen in 2004. To evaluate this possibility,
I would look for evidence of stable disease, using a noninvasive fibrosis marker. If the fibrosis marker is concordant with the earlier biopsy results, I would counsel the patient to wait on retreatment until more information becomes available on the optimal approach. In the event of discordant findings, I would consider a repeat liver biopsy, because the clinical path ahead is so uncertain.
If the liver biopsy confirms progression to bridging fibrosis or cirrhosis, I would recommend peginterferon/ribavirin + telaprevir for 12 weeks, followed by peginterferon/ribavirin alone for an additional 36 weeks. This approach should give the patient a 40% to 50% percent chance of achieving a sustained virologic response (SVR), based on extrapolation of data from HCV-monoinfected patients (N Engl J Med 2011; 364:2417). Lack of response would put the patient at risk for development of drug resistance, although the long-term clinical implications of such resistance are unclear.
The IL-28B assay is a powerful pretreatment predictor of treatment outcome, but I would not order it for this patient because we already know how he responded to interferon in the past.
Of the two available HCV protease inhibitors, I would consider only telaprevir, because we have pharmacokinetic data on drug–drug interactions to help guide our therapeutic decisions. For example, we know that telaprevir interacts negatively with lopinavir/ritonavir, so I would recommend switching the lopinavir/r in this patient's regimen to either efavirenz or boosted atazanavir (Abstract 119, CROI 2011). If efavirenz is selected, telaprevir dosing would need to be increased (Abstract 146LB, CROI 2011).
Mild-to-moderate rash is seen in approximately half of all patients taking telaprevir, so I would start the patient's new antiretroviral regimen about 4 to 6 weeks before the HCV therapy, to sort out any untoward reactions. I would counsel the patient about the importance of strict medication adherence and the need to take telaprevir according to schedule with a fatty snack (e.g., peanut butter, whole-milk yogurt).
Although this patient had only a partial response to prior peginterferon/ribavirin therapy, he does have a chance at an SVR with novel regimens. Having genotype 1b (rather than 1a) infection works slightly in his favor, because this virus does not readily develop a key resistance mutation to protease inhibitors. Barriers to successful treatment, however, include his high HCV RNA level, the HIV coinfection, and, most importantly, the severe and lifestyle-altering side effects he experienced during previous therapy, which are now reducing his motivation to be treated. Given the high likelihood that these side effects will happen again with retreatment, I would advise him to wait for interferon-sparing regimens — unless he has advancing liver fibrosis.
Although this patient has probably had HCV for decades, his fibrosis still could have advanced considerably since his 2004 biopsy; in several studies, serial biopsies performed over short periods have shown significant progression of fibrosis despite stable HIV disease (AIDS 2007; 21:2209 and Hepatology 2009; 50:1056). To look for signs of advancing liver disease in this patient, I would first perform a careful physical examination and laboratory review. Next, I would restage him, preferably using liver biopsy rather than noninvasive testing, to allow direct comparison with the data we have available from 2004. Predictive IL-28B genetic testing seems unnecessary given that we already know the patient's biological responsiveness to peginterferon/ribavirin (i.e., the previous viral kinetics on treatment).
If I were to treat this patient with combination therapy, I would use telaprevir rather than boceprevir because data are available on its safety and efficacy in HIV/HCV-coinfected patients (Abstract 146LB, CROI 2011). Unfortunately, these data do not extend to coinfected patients with prior HCV treatment experience, so predicting the likelihood of an SVR in this patient is difficult. In monoinfected patients with prior partial response to peginterferon/ribavirin, the SVR rate associated with novel treatments exceeds 50%. I would inform the patient that the rate of response to HCV treatment is generally lower in HIV-coinfected than HCV-monoinfected patients, without quoting an exact number. In terms of managing his HIV treatment alongside the new HCV therapy, I would change his lopinavir/r to either boosted atazanavir or efavirenz (barring evidence of resistance or prior adverse effects), to mimic the regimens used in the telaprevir trial presented at CROI this year.