Currently, clinical guidelines do not recommend screening for H. pylori
in asymptomatic individuals.49-53
Our results suggest that H. pylori
screening and treatment has the potential to significantly reduce gastric cancer incidence among both men and women, and there appear to be strategies that would be considered cost-effective in China. Reductions were greatest when screening occurred at age 20, suggesting that H. pylori
prevention efforts should target younger age groups. This policy-relevant result presents an interesting contrast to the older age groups who are the focus of on-going H. pylori
clinical trials and from which results are awaited.7
We also found that opportunities for rescreening did not provide substantial additional benefit provided the false-negative rate of serological screening was less than 15%. The reduction in gastric cancer risk was greater among women than men, reflecting the higher proportion with gastritis or atrophy who benefited from treatment.
Using a cost-effectiveness threshold of the GDP per capita ($1,700 in China), we found screening for H. pylori at age 20 would be considered very cost-effective for both men and women. For cohorts of all ages, screening or treatment at the youngest age was more cost-effective than all other strategies. For example, for a cohort of 20-year olds, delaying screening for 10 or 20 years versus beginning screening at age 20 was not only less effective, but more costly, as at older ages, a greater proportion of the cohort had progressed to more advanced precancerous lesions and did not benefit from H. pylori treatment as a result.
Given a specific cost-effectiveness threshold, we found that the optimal strategy was influenced by the underlying seroprevalence of H. pylori
infection. This could be particularly important for establishing regional priorities within China because there is geographical variation of H. pylori
At the GDP per capita threshold, H. pylori
screening once would be optimal in regions where H. pylori
seroprevalence was between 40 and 80%; in regions where more than 80% were infected, universal treatment would be the preferred strategy. Because we did not include the consequences of antibiotic resistance and treatment side-effects, the threshold for universal treatment may be higher, although studies have consistently found rates of amoxicillin-resistant H. pylori
equal to less than 1%56
and our results did not significantly change when we assumed treatment for side-effects increased antibiotic costs by 50%. As the emergence of resistant strains would adversely impact the efficacy of H. pylori
treatment regimens, as well as antibiotic efficacy against other infections, efforts to minimize noncompliance should accompany all screening strategies.
From a public health perspective, screening for H. pylori
is particularly attractive. Because reinfection in adulthood is rare, once treated, individuals do not need to be rescreened or retreated. This differs with prevention programs for other cancers such as breast, colon and cervical, which rely on routine screening to detect precancerous or cancerous growths or lifestyle changes that require continual modification of diet, exercise or smoking habits to achieve significant reductions in cancer risk. For example, H. pylori
screening once would result in an average life expectancy gain of 17.0 days which is 2 to 4 times greater than the estimated 4.3–9.4 days achieved with biennial mammography screening to prevent breast cancer among Hong Kong Chinese women.57
In addition, H. pylori
screening is appealing because of the low false-negative risk associated with the high sensitivity of serology tests available to detect the infection. Although test specificity may be lower, the consequences of false-positives are small given the low cost of antibiotic treatment and occurrence of adverse side-effects. For example, even at a 30% false positive rate, the ICER of H. pylori
screening increased only to $1,440/YLS.
Adherence to the 14-day antibiotic regimen is critical to the effectiveness of an H. pylori screening program. More convenient and tolerable, shorter duration regimens with comparable eradication rates may improve patient adherence and minimize the emergence of antibiotic resistance from incomplete treatment. Although we reflected compliance rates of the clinical trial, real world rates are likely to be lower. By lowering treatment effectiveness by 25% to estimate the impact of lower compliance and adherence rates, we found that the cost-effectiveness of a single H. pylori screening would still be considered good value for resources given the GDP per capita threshold. However, if real world screening participation rates are lower than 70% or the per-person cost of H. pylori screening is $2 to $3 higher, universal treatment would be a strategy to seriously consider, even in medium-prevalence regions, although these thresholds are likely conservative as costs associated with consequences of treatment (i.e., antibiotic resistance and side-effects) were not included in our analyses.
Our findings are consistent with previous cost-effectiveness analyses that suggest H. pylori
screening is cost-effective in both relatively low-risk populations in the US and UK ($10,000–$40,000/YLS)58-62
and high-risk populations in China or Taiwan ($200–$17,000/YLS).33,63
In contrast to previous models, we based treatment effectiveness on empirical data from an ongoing randomized clinical trial which showed H. pylori
treatment reduced the prevalence precancerous gastric lesions.36
In addition, because we modeled gastric cancer development through a series of precancerous lesions, we were able to evaluate alternative assumptions on treatment impact. Although the ability of H. pylori
treatment to heal gastritis and halt progression to precancerous lesions is well-supported by clinical evidence, the impact on regression is still debated.25
If treatment only reduced disease progression among individuals with gastritis, we found that screening once for H. pylori
could still reduce the risk of gastric cancer among young adults by more than 10%. Specific to a low-efficacy dual therapy regimen no longer considered a choice of treatment,64
our estimate likely provides a lower bound estimate upon which higher-efficacy triple therapies can improve upon.
We also reflected in our model the impact of disease natural history uncertainty on outcomes by using an array of natural history parameters that provide a good fit to observed epidemiologic data. Although we estimated that screening once for H. pylori could significantly reduce cancer risk, we found that estimates of the absolute magnitude of benefit varied considerably when we explicitly considered the underlying uncertainty around disease progression and regression, highlighting the need for more data. As ongoing clinical trials are focused on older age groups, future clinical trials on younger adults are needed, with specific attention to the presence of precancerous lesions at time of treatment and high-efficacy, well-tolerated regimens that can achieve high compliance rates and minimize the emergence of antibiotic resistance. Given the need to follow large numbers of individuals for several years or decades, these trials will take many years to complete. In the short term, clinical trials with intermediate outcomes as their primary endpoints, such as the progression to atrophy or intestinal metaplasia, can provide valuable information on the effectiveness of H. pylori treatment. Our model suggests that if treatment reduces the risk of progression to atrophy by more than 40%, H. pylori screening once could be an effective and cost-effective gastric cancer prevention policy. Empirical data, especially on gastritis, from large, well-designed, randomized controlled trials should be high-priority. In addition, studies providing better estimates of disease progression rates for all precancerous lesions can reduce the uncertainty around disease natural history and provide insight into the management of advanced precancerous lesions, such as intestinal metaplasia, for which H. pylori treatment is unlikely to benefit and surveillance guidelines are currently unavailable.
Our analysis has several limitations. Data were combined from multiple sources with varied study designs, and many variables are uncertain. On the basis of the data from prospective cohort studies, we assumed that all lesions are reversible, though at some point in the precancerous process, this may no longer be biologically possible.20,65
Although a proportion of the regression observed in the prospective cohort studies may stem from low biopsy sensitivity for advanced lesions and histological misclassification, data on the precise proportion attributable are unavailable. Similarly, although some clinical studies suggest that H. pylori
treatment may reduce disease progression among individuals with intestinal metaplasia, we conservatively assumed that lesions beyond atrophy do not benefit from treatment. As China-specific data on the proportion of intestinal type gastric cancers were unavailable, we also relied on data from Sweden. Because the incidence of intestinal type gastric cancers has declined more rapidly in developed countries, we may have therefore underestimated the proportion.66
All of these assumptions bias our results against treatment effect.
In addition, we included only the benefit of treatment on intestinal type gastric cancer reduction. H. pylori
treatment may also reduce the risk of MALT lymphomas,67
and dyspepsia-related illness,69
and thus, our analysis does not reflect these health gains or treatment cost reductions that may result from the reduction of these diseases. Although H. pylori
infection may protect against cardia or esophageal adenocarcinomas, the causal link is still uncertain and was not incorporated into our model.70
Finally, our results are based on data from one specific region in China and may not be generalized to other regions where disease progression may differ given the prevalence of other risk factors. Nonetheless, H. pylori
is the leading risk factor for gastric cancer and the relative risk associated with the infection (5.9)2
is three- to four-fold higher than other important risk factors, including smoking (1.5-2.2).71
As such, our results likely provide reasonable estimates of the comparative benefits and economic consequences of H. pylori
screening in other regions of China, as well as other countries, that share similar risk factor profiles to Linqu.
Screening young adults for H. pylori, followed by treatment in those who test positive, has the potential to prevent 1 in every 4 to 6 cases of gastric cancer in China, and would be considered cost-effective using the GDP per capita threshold. Although additional criteria such as affordability, capacity to deliver and equity are equally influential and important to consider, these results clearly illustrate the potential promise of gastric cancer prevention. Given the ease of detecting and treating H. pylori infection and the poor prognosis and limited treatment options for gastric cancer, better data on the effectiveness of treatment to reduce disease progression are needed while results from ongoing clinical trials are eagerly awaited.