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Reply to: "Is resistance to direct-acting antivirals in sub-Saharan Africa a threat to HCV elimination? Recommendations for action"
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"African countries should avoid the temptation to be the beneficiaries of generic first-line NS5A inhibitors, despite their low price, in regions of high intrinsically-resistant subtype prevalence."
To the Editor: We thank Gupta et al. for their letter responding to our article 'Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of Hepatitis C?'.
We agree that our results in conjunction with other studies and the available epidemiological data are cause for potential concern. Our study may be something of a canary in the coalmine; the data are derived from a relatively small number of individuals, in a migrant African population, yet have potentially important implications beyond our centre's experience. Our findings in an African diaspora are not a substitute for evaluating the prevalence of these polymorphisms in different countries and regions of sub-Saharan Africa (SSA). Despite the fact that 14% of the global HCV burden is located in SSA there has been an almost total absence of registration trials of DAAs conducted in the region.
Trials of treatments for globally prevalent infections, including HCV and HBV need to encompass regional diversity. The concentration of trials hitherto conducted in Europe and North America points to a failure of the pharmaceutical industry to recognise the significant burden of disease beyond high-income countries.
Further studies of the local prevalence of different subtypes and their associated resistance-associated substitution (RAS) profile are urgently needed. However, our published analysis assists in drawing attention to the need to avoid the risk of resistance that could be engendered by first generation NS5A inhibitors as first-line therapies in the region.
Gupta et al. make the point that in the sub-Saharan African setting, these genotypes are far from unusual. We wholeheartedly endorse this view. We chose this nomenclature for clarity, "unusual" connotating these genotypes as remarkable and different variants, rather than uncommonly occurring. These genotypes are seldom seen in Europe, but as we discuss in our paper, are not unusual in Africa. A more useful terminology may be 'distinct African subtypes' denoting that the genotypic HCV distribution and relative prevalence of certain subtypes in Africa is distinct and different from that described elsewhere. There is a lack of large scale prevalence studies on the genotypic distribution of HCV in African countries, but compiling the available evidence suggests that non 1a/1b and non 4a/4d subtypes are common.
Secondly, evidence is accumulating from ours and other studies that extensive viral diversity is present in these subtypes; they show a high prevalence of baseline RAS; response rates of these 1 and 4 'African subtypes' to first line NS5A inhibitors are suboptimal in the DAA era. These data include the study conducted in Rwanda where patients with genotype 4r, who accounted for 15% of patients, only experienced a 56% sustained virological response (SVR) rate; similarly in a French cohort subtype 4r accounted for 5% of all treatment failures, with similar results in a recently published analysis from South Africa.
These subtypes are difficult to characterise and treat even in well-resourced Western settings. We relied on next generation sequencing to fully characterize the sub-genotype, a methodology which is not routinely available in SSA. It is indeed important to document SVR rates in African programs. It is imperative, as we and Gupta et al. suggest, that effective treatments are used in the first-line setting: African countries should avoid the temptation to be the beneficiaries of generic first-line NS5A inhibitors, despite their low price, in regions of high intrinsically-resistant subtype prevalence. Recall of patients for retreatment after unsuccessful DAA treatment will be difficult. This evidence should induce policymakers and the pharmaceutical industry to facilitate access to the most potent pan-genotypic regimens in Africa. Finally, the efficacy of second generation NS5A inhibitors and even triple regimens against the prevalent subtypes requires validation.

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