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The advent of direct-acting antiviral agents (DAAs) that interfere with various steps of the hepatitis C virus (HCV) lifecycle has revolutionized hepatitis C treatment and enabled interferon-free therapy. The outgoing standard of care, pegylated interferon plus ribavirin, lasted 6 to 12 months, caused difficult side effects, and only cured about half of treated patients.

When using interferon-based therapy, hepatitis C viral load, or HCV RNA, was monitored over the course of therapy -- typically from 4 weeks after starting treatment to 24 weeks after its completion -- to allow people without adequate viral suppression to discontinue treatment that was likely to be futile, sparing them months of adverse effects. But the value of viral load monitoring has not been demonstrated for interferon-free therapy, which typically lasts 3 to 6 months, is well-tolerated, and cures upwards of 90% of patients.

Viekira Pak Regimen

David Wyles from the University of California at San Diego presented findings from a study of viral kinetics among people treated with AbbVie's Viekira Pak or "3D" regimen, consisting of the HCV NS3/4A protease inhibitor paritaprevir, NS5A inhibitor ombitasvir, and a ritonavir booster in a once-daily coformulation, taken with the twice-daily non-nucleoside HCV NS5B polymerase inhibitor dasabuvir.

This pooled analysis included 2053 HCV monoinfected individuals treated with the 3D regimen with or without ribavirin in 6 Phase 3 clinical trials, and 63 HIV/HCV coinfected patients treated with the 3D regimen plus ribavirin in the Phase 2 TURQUOISE-I trial. Participants who did not achieve sustained virological response -- or continued undetectable HCV RNA 12 weeks after completion of treatment (SVR12) -- for reasons other the virological failure (for example those lost to follow-up) were excluded from this analysis.

All participants had HCV genotype 1. About 60% of HCV monoinfected and 90% of coinfected patients were men, 6% and 24%, respectively, were black, and the mean age was approximately 51 years. About 80% had unfavorable IL28B gene patterns associated with poor response to interferon, one-third were non-responders to prior interferon-based therapy (a mix of relapsers, partial responders, and null responders), and 19% had liver cirrhosis.

The "vast majority" (>80%) of both monoinfected and coinfected patients achieved HCV RNA below the lower limit of quantification (LLOQ; <25 IU/mL using the Roche assay) by week 2. By week 4, the 5 remaining coinfected patients who were not suppressed at week 2 fell below the LLOQ. By this point most patients in both groups were also below the lower limit of detection (LLOD; <15 IU/mL). Almost all were below the LLOQ and LLOD by week 6.

Cure rates were high regardless of time to initial viral suppression. Between 96% and 100% of patients across all groups who reached LLOQ at 1, 2, or 4 weeks after starting therapy went on to achieve SVR12, as did 92% of monoinfected people who reached LLOQ by week 6. A similar pattern was seen when looking at LLOD, except for higher cure rates among patients who first attained viral suppression by week 6.

Time to viral suppression did not differ significantly according to race, sex, IL28B pattern, prior treatment status, HCV subtype 1a vs 1b, or cirrhosis status, or by CD4 T-cell count among the HIV-positive patients. The only factor associated with shorter time to initial viral suppression was lower baseline HCV viral load. However, baseline HCV RNA did not affect the likelihood of ultimately achieving SVR12.

"High SVR12 rates were achieved in patients with or without cirrhosis regardless of time to initial suppression of HCV RNA," the researchers concluded. "Traditional negative predictors such as cirrhosis, black race, prior [pegylated interferon/ribavirin] null response, and unfavorable IL28B genetic background did not influence time to viral suppression."

In response to a question, Wyles said that whether or not ribavirin was used also did not affect time to viral suppression or SVR12 rates. "Ribavirin doesn’t seem to have much effect on viral kinetics," he said. "It's still a mystery what it does."

Sofosbuvir Combination Regimens

Jérémie Guedj from INSERM in Paris and colleagues performed a related analysis, looking at HCV viral kinetics among patients treated with sofosbuvir-containing interferon-free regimens in the SPARE and SYNERGY trials, while Sreetha Sidharthan from Leidos Biomedical Research and colleagues looked at the utility of HCV viral load monitoring in the SYNERGY and ERADICATE trials.

All 3 trials, conducted by the National Institutes of Health, enrolled primarily low-income people in the Washington, DC area. A majority were men, 85% were African-American and the median age was around 55 years. Most (72%) had harder-to-treat HCV subtype 1a and one-quarter had advanced fibrosis or cirrhosis:

• SPARE: Genotype 1 HCV monoinfected patients treated with sofosbuvir plus ribavirin for 24 weeks (68% SVR12 with standard-dose and 48% with low-dose ribavirin).
• SYNERGY: Genotype 1 HCV monoinfected patients treated with sofosbuvir/ledipasvir (Harvoni) for 12 weeks (100% SVR12), or with sofosbuvir/ledipasvir plus an experimental third direct-acting antiviral, either GS-9669 or GS-9451, for 6 weeks (95% SVR12).
• ERADICATE: Genotype 1 HIV/HCV coinfected patients treated with sofosbuvir/ledipasvir for 12 weeks (98% SVR12).

The researchers used a mathematical model to predict HCV viral load decline over time based on which steps of the viral lifecycle the different direct-acting antivirals target. They predicted that during the first phase of decline, HCV RNA would decrease more rapidly and steeply when using sofosbuvir with other DAAs versus only with ribavirin. They further predicted that combining DAAs would speed up the second phase of viral decline, allowing for shorter treatment.

They found that viral load decline was initially more rapid and steeper among SYNERGY participants treated with sofosbuvir/ledipasvir compared to SPARE patients who received sofosbuvir with ribavirin alone. The researchers concluded that this was due to ledipasvir -- an NS5A replication complex inhibitor -- blocking viral assembly and release, while the delayed response in SPARE suggests that sofosbuvir itself has only a minimal effect at this stage of viral replication.

However, by day 3 of treatment, people treated with sofosbuvir and ribavirin reached low viral load levels similar to those seen in SYNERGY, indicating that sofosbuvir -- a nucleotide analog HCV polymerase inhibitor -- is highly effective at blocking production of HCV RNA (viral genetic material). Surprisingly, the triple DAA combinations appeared to block viral RNA production to a lesser extent than sofosbuvir/ledipasvir alone. But patients who received GS-9451 -- an HCV protease inhibitor -- showed a greater final phase viral decline.

Overall, the model dramatically underestimated cure rates for sofosbuvir-containing regimens, predicting SVR12 rates of 34% for sofosbuvir/ledipasvir for 12 weeks, 6% for sofosbuvir/ledipasvir plus GS-9669 for 6 weeks, and 16% for sofosbuvir/ledipasvir plus GS-9451 for 6 weeks. In fact, 65%, 40%, and 50% of patients, respectively, had undetectable HCV RNA at the end of treatment, and 93%, 95%, and 95% went on to achieve SVR12.

The model predicted that people with any detectable virus at the end of 6 weeks of treatment should experience viral rebound, since at that point there would still be a million new viral particles being produced every day. (This study used a more sensitive assay with a LLOQ of 12 IU/mL and a LLOD of 3 IU/mL.) But this usually did not happen.

"There must be other reasons to explain the high SVR," Guedj said. "We think most of the [newly produced] virus may be uninfectious...treatment may have the effect of replacing a working replication complex with a defective replication complex, which explains how most patients could clear the virus in 6 weeks."

Using the estimated decay rate of functional replication complexes, the researchers predicted that the SVR12 rate would fall to just 42% for sofosbuvir/ledipasvir plus GS-9451 taken for only 4 weeks (and lower for the other regimens). This is, in fact, quite close to the observed 39% SVR4/8 rate seen in the C-SWIFT study of a triple regimen containing sofosbuvir plus Merck's experimental NS5A inhibitor elbasvir and HCV protease inhibitor grazoprevir.

Based on these findings, the researcher concluded that direct-acting antivirals may have a "hidden effect [of treatment] not reflected in measured HCV RNA," and that "viral load kinetics, in particular at [end of treatment], may not be a reliable marker of SVR."

Viral Load Monitoring

Sreetha Sidharthan and colleagues evaluated the ability of HCV RNA levels measured at week 4 and at the end of treatment to predict outcome among 37 HCV monoinfected SYNERGY participants and 50 HIV/HCV coinfected ERADICATE participants treated with sofosbuvir/ledipasvir for 12 weeks (this analysis omitted SYNERGY participants who received one of the triple regimens for only 6 weeks). As noted above, SVR12 rates for this regimen were 100% in SYNERGY and 98% in ERADICATE.

Using the more sensitive Abbott assay with a quantification limit of 12 IU/mL, the majority of patients with HCV RNA >LLOQ, or below the LLOQ but still detectable, at week 4 went on to achieve SVR12. There were 5 patients in SYNERGY and 7 in ERADICATE who still had detectable HCV RNA at the end of treatment, and all achieved SVR12. The negative predictive value of week 4 viral load was less than 13%. Looking at patients with HCV RNA >LLOQ at week 4 and at the end of treatment, a majority achieved SVR12 and the negative predictive value was >11%. Fewer patients had HCV RNA >LLOQ or <LLOQ but detectable using the less sensitive Roche assay.

"Low negative predictive values of HCV RNA at week 4 underscore the importance of continued therapy for patients who fail to achieve undetectable levels of HCV RNA early on during treatment because the likelihood of achieving SVR12 is still high," the researchers concluded.

That is, unlike with interferon-based therapy, patients should not be counseled to discontinue treatment early if viral load remains detectable at week 4, or even at the end of treatment, as there is still a high likelihood of being cured.

As described in the March 2 online edition of Clinical Infectious Diseases, the same research team did another comparison looking at the SYNERGY participants and those treated with sofosbuvir plus ribavirin alone for 24 weeks (the SPARE regimen).

All 55 patients treated with sofosbuvir plus ribavirin had HCV RNA <LLOQ at the end of treatment according to both the Roche and Abbott assays. But only 38 achieved SVR12, yielding a positive predictive value of 69%. Among patients treated with sofosbuvir/ledipasvir, with or without GS-9669 or GS-9451, 100% had HCV RNA <LLOQ according to the Roche assay and 90% did so according to the Abbott test. There was 1 relapse, yielding a positive predictive value of 98%. Further, 6 patients with HCV RNA >LLOQ but detectable (in the at 14-64 IU/mL range) at the end of treatment achieved SVR12, for a negative predictive value of 0%.

"Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at [end of treatment] do not preclude treatment success," the study authors concluded.

4/17/15

References

D Wyles, JJ Eron, R Trinh, et al. High SVR Regardless of Time to Suppression With ABT-450/r/Ombitasvir and Dasabuvir+RBV. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 147.

THT Nguyen, J Guedj, L Canini, et al. The Paradox of Highly Effective Sofosbuvir Combo Therapy Despite Slow Viral Decline. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 148.

S Sidharthan, A Kohli, A Osinusi, S Kottilil, et al. Utility of Hepatitis C Viral-Load Monitoring With Ledipasvir and Sofosbuvir Therapy. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 689.

S Sidharthan, A Kohli, Z sims, S Kottilil, et al. Utility of Hepatitis C Viral Load Monitoring on Direct-Acting Antiviral Therapy. Clinical Infectious Diseases. March 2, 2015 (Epub ahead of print).