Clarithromycin resistance is considered “all or none”, such that clarithromycin resistance reduces clarithromycin triple therapy effectively to just amoxicillin and the antisecretory drug. This results in resistant infections receiving a PPI or P-CAB plus amoxicillin dual therapy and susceptible infections receiving PPI or P-CAB plus amoxicillin and clarithromycin. The results are visualized using an H. pylori nomogram (Figure 1) [22].

High H. pylori cure rates with amoxicillin require the antisecretory drug to achieve and sustain a high pH [23]. Effectiveness is thus positively related to the potency of the antisecretory drug and inversely correlated with the ability of the stomach to make acid. PPIs’ relative potency is assessed as the proportion of a 24-h day during which the pH is maintained at pH 4 or above (pH4 time) [24]. Pantoprazole, omeprazole, and lansoprazole are rapidly metabolized by CYP2C19, which reduces their effectiveness in populations where rapid metabolizers are common (e.g., most of the Western world). Rabeprazole and esomeprazole are the most potent PPIs and are minimally affected by CYP2C19. They are preferred PPIs for H. pylori therapy [25].

Amoxicillin dual therapy using traditional PPIs is unable to reliably cure a high proportion of cases in Western populations. In contrast, rabeprazole or esomeprazole dual therapies have often proved effective in Japan and in some Chinese populations [26,27,28,29,30,31,32,33,34,35].

The effectiveness of vonoprazan plus antibiotics for the treatment of H. pylori infections was first demonstrated in Japan [36]. The Japanese pivotal clinical study compared b.i.d dosing of a low potency PPI (lansoprazole 30 mg; equivalent to 27 mg omeprazole) [24] with 20 mg of vonoprazan (approximately equivalent to >40 mg of esomeprazole b.i.d.), each given b.i.d. for the cure of H. pylori infections [36]. With clarithromycin-susceptible infections, both the vonoprazan- and PPI-containing triple therapies produced high (~97%) and near-identical cure rates [36]. However, in the presence of clarithromycin resistance, the regimens were reduced to the antisecretory drug plus amoxicillin. The cure rates of the dual therapies were therefore dependent on the relative antisecretory potency of the antisecretory drug (i.e., the cure rate was 40% with lansoprazole vs. 82% with the more potent vonoprazan) [21]. The overall high cure rate obtained (82%) with clarithromycin resistance was consistent with the notion that clarithromycin was responsible for only a small proportion of those cured (i.e., 82% would have been cured without clarithromycin) [21]. It was also noted that the optimization of the vonoprazan–amoxicillin dual therapy should produce a highly effective dual therapy without the need for clarithromycin. However, vonoprazan triple therapy was introduced despite more than 80% receiving unneeded clarithromycin. Vonoprazan–clarithromycin triple therapy is currently the most widely used treatment of H. pylori in Japan with more than 1.5 million patients treated yearly [37]. However, over time, the overall cure rates have fallen closer to 80% as clarithromycin resistance has continued to increase [38]. In the U.S./European trial, the cure rates for both clarithromycin-susceptible and resistant strains were unacceptably low and the proportion receiving unneeded clarithromycin was higher (>90%) (see below) [39]. Despite the poor outcomes, both vonoprazan triple and dual therapies were approved in the United States and Europe, although neither has yet been released due to manufacturing issues.

The results of the Japanese pivotal study (high success with the amoxicillin dual therapy and a high rate of unnecessary clarithromycin) have been confirmed by 11 vonoprazan triple therapy studies that provide cure rates in relation to clarithromycin resistance (i.e., the success is attributable to the amoxicillin) [36,40,41,42,43,44,45,46,47,48,49,50] (Figure 1).

The mean cure rate attributable to amoxicillin dual therapy with a 7-day vonoprazan triple therapy was 81.7 ± 6% [36,40,41,42,43,44,45,46,47,48,49,51]. A second approach to quantitate the proportion receiving unnecessary clarithromycin was to examine the cure rates of dual therapy (which functionally contains no clarithromycin) vs. triple therapy with clarithromycin in the same populations (Figure 2A) [50]. These different comparisons all confirmed that the majority of the clarithromycin given in vonoprazan triple therapy was unneeded.

The U.S./European vonoprazan–amoxicillin–clarithromycin clinical trial differed from the Japanese trials in dosing, duration, and effectiveness. Despite higher doses of antibiotics and doubling the duration from 7 to 14 days, both the U.S./European study and a study in Thailand yielded relatively poor cure rates compared to Japan, even with susceptible strains (e.g., 85.7% with the P-CAB) [39,54]. This was both unexpected and unprecedented [20,55] (Figure 3).

The cure rate with susceptible strains using amoxicillin b.i.d. was 6.2% greater than dual therapy with amoxicillin t.i.d. The proportion receiving unnecessary clarithromycin was also evaluated both in relation to the differences in cure rates with susceptible vs. resistant infections and with dual vs. triple therapies (Figure 3 and Figure 4) [20].

In Japan, the quantity of clarithromycin used per million cases treated using either the 200 or 400 mg b.i.d. approved dosages of clarithromycin (i.e., dose times duration times the number participants) would be, respectively, 2800 kg and 5600 kg. In the United States and Europe, where the clarithromycin dosage is 1 g/day for 14 days, the results per million treated is equivalent to 14,000 kg/year or 6.35 tons/year/million treated. In both instances, 80% to 90% of the clarithromycin would be unnecessary (i.e., misused). As noted above and evident in Figure 4, optimizing the vonoprazan–amoxicillin dual therapy should achieve equivalent or superior results without the need for clarithromycin.