The SPRINT-1 trial was an open-label, randomized, multicentre phase II study evaluating boceprevir, an NS3 protease inhibitor, in combination with peginterferon alpha-2b and ribavirin for treatment-naive patients with genotype 1 hepatitis C. Its decisive significance lay in demonstrating that a direct-acting antiviral could raise the likelihood of sustained virologic response beyond that achieved with interferon-based treatment alone, helping move hepatitis C therapy toward mechanism-specific antiviral combinations.

Causes and Background

The trial emerged from a therapeutic problem that conventional therapy had not solved. Combination treatment with pegylated interferon and ribavirin produced sustained virologic response in more than half of patients with chronic infection overall, yet more than half of those with genotype 1 infection still failed to achieve that endpoint. A sustained virologic response was described as a complete recovery from infection, including virologic recovery and remodeling of fibrosis when no competing liver comorbidities were present. The persistent treatment gap encouraged investigators to study viral enzymes as drug targets and led to the development of direct-acting antiviral drugs directed against specific stages of the hepatitis C viral cycle.

Boceprevir belonged to the first generation of genotype 1-directed protease inhibitors. The wider therapeutic field also included NS5B polymerase inhibitors, NS5A inhibitors, entry inhibitors, new interferons, and cyclophilin inhibitors, but SPRINT-1 specifically tested the addition of boceprevir to the established peginterferon-and-ribavirin backbone. The study therefore represented both a new pharmacological strategy and a test of whether targeted inhibition could improve the established standard rather than replace it immediately.

What Happens in the Trial

SPRINT-1 was conducted as an open-label, randomized, multicentre phase II trial in treatment-naive patients with genotype 1 hepatitis C. The boceprevir-containing strategy used a four-week lead-in phase with the standard combination before patients received triple therapy. In the reported treatment schedule, patients received 24 to 44 weeks of triple therapy after that lead-in, depending on the treatment plan and virologic response.

The study found that approximately 65% of treatment-naive genotype 1 patients achieved sustained virologic response with boceprevir-based therapy. This result formed part of the evidence that first-generation protease inhibitors increased sustained virologic response rates by roughly 20 to 30 percentage points compared with earlier interferon-based approaches. The response was not simply attributed to longer exposure to conventional treatment: the trial tested the clinical value of adding a drug aimed directly at the viral protease.

The treatment design also introduced response-guided logic into the emerging therapeutic model. In related first-generation protease-inhibitor evidence, treatment duration could be shortened for patients who achieved an extended rapid virologic response, defined by undetectable HCV RNA after four and twelve weeks of triple therapy. This approach illustrated the broader shift toward using early viral kinetics to individualize therapy, even though the SPRINT-1 regimen itself was reported through its boceprevir lead-in and subsequent 24-to-44-week treatment structure.

Results and Clinical Consequences

The trial helped establish boceprevir as one of the drugs responsible for the first major improvement in genotype 1 treatment efficacy. Its findings were incorporated into the broader conclusion that first-generation protease-inhibitor triple therapy could produce sustained virologic response in around 65% of previously untreated genotype 1 patients. This represented a substantial advance over conventional interferon monotherapy, which achieved sustained virologic response in only 33% to 45% of patients with end-stage renal disease in pooled analyses, and less than 20% in patients without end-stage renal disease in the cited comparison.

The significance of the result extended beyond the trial population. Hepatitis C was treated in the book as a systemic infection capable of causing hepatic, autoimmune, dermatological, and renal disease, including cryoglobulinemic membranoproliferative glomerulonephritis. Clearing the virus was therefore relevant not only to liver disease but also to renal injury and to the management of patients with chronic kidney disease, dialysis dependence, or a need for kidney transplantation. At the same time, treatment decisions in chronic kidney disease had to balance the severity of kidney and liver disease, treatment risks, and comorbidities such as cardiovascular disease.

The trial’s success also strengthened the case for treating hepatitis C before or around major renal replacement decisions when clinically appropriate. HCV infection was associated with increased mortality among dialysis patients, while transplantation remained the preferred renal replacement strategy for infected patients without advanced liver injury. The SPRINT-1 result did not itself answer those transplant questions, but it contributed to a therapeutic environment in which viral eradication became a more realistic clinical objective.

Limitations and Aftermath

The advance came with substantial costs. The first-generation triple-therapy strategy was limited by safety concerns, including cutaneous rash and anemia, as well as by cost, adherence requirements, viral resistance, and drug interactions. These problems were especially consequential in patients with chronic kidney disease, because the kidneys play a major role in the clearance and filtration of interferon and ribavirin. Ribavirin was contraindicated when creatinine clearance was below 50 ml/min because renal elimination and overdosing could produce dramatic anemia.

The contrast with renal transplant recipients was even sharper. Earlier post-transplant alpha-interferon treatment had produced low sustained virologic response, frequent adverse effects, and a serious risk of acute rejection and graft loss; a meta-analysis cited in the book found an estimated sustained virologic response of 18% and a treatment dropout rate of 35% for alpha-interferon-based therapy in renal transplant patients. SPRINT-1 did not remove those transplant-specific hazards, but its demonstration of direct antiviral efficacy helped point toward therapies that might eventually reduce dependence on interferon and improve treatment feasibility in medically fragile populations.

Boceprevir and telaprevir were approved in 2011 after temporary compassionate-use approval in some countries for patients with cirrhotic genotype 1 infection who had previously relapsed or responded only partially to combination therapy. SPRINT-1 thus belongs to the transition between the older interferon-centered era and the subsequent expansion of direct-acting antiviral therapy. Its contribution was not a final solution: it showed that targeted viral inhibition could materially improve cure rates, while also making clear that the next generation of treatment would need to preserve that efficacy with fewer toxicities, simpler administration, fewer interactions, and greater reliability across kidney disease and transplant settings.