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The epidemic of acute HCV infection among HIV-infected men who have sex with men (MSM) is ongoing. Transmission of drug-resistant variants (DRVs) after HCV treatment failure could pose a major threat to the effectiveness of future therapies. We determined the baseline prevalence of pre-existing DRVs in the HCV NS3 protease gene and their effects on the addition of telaprevir (TVR) to standard pegylated interferon and ribavirin (PEG-IFN/RBV) for acute HCV infection in individuals enrolled in a multicentre randomized controlled trial (2013 and 2014). The HCV NS3 viral protease was analyzed using Sanger and next-generation sequencing (NGS) for DRVs at baseline (n = 31), and at viral breakthrough following TVR-based treatment (n = 3) or PEG-IFN/RBV alone (n = 2). Sequence analysis indicated that all individuals were infected with HCV genotype 1a. Complete (100%) concordance was seen between Sanger and NGS for high levels of mutant viral populations. The simeprevir-associated Q80K variant was present at high frequency in the German samples (7/11–64%) and infrequently in the UK samples (1/20–5%). In the three TVR-based treatment failures, V36M/l and R155K/T emerged, but not R155G which was detectable at low levels in two individuals at baseline. Failure rate at week 24 was 26.7% (with baseline DRVs) vs. 6.3% (without baseline DRVs), p = 0.17). Comparison of sequences pre- and post-therapy in 5 who failed therapy revealed the emergence of not previously described variants V193G, E176K, P189S (on TVR), and V181S in one instance each. The presence of baseline DRVs for the NS3 protease gene of HCV genotype 1a did not appear to predict treatment failure in our patient cohort. Where detected, Q80K was present at high levels (>98%), but had no effect on outcomes and remained high after failure.