The increasing prevalence of HIV/Helicobacter pylori co-infection over time, along with the evolution of antiretroviral therapy (ART)

Introduction

Thirty years after discovery, the global HIV/AIDS pandemic is still ongoing. Approximately 78 million people have been affected to date, with more than 36 million currently living with HIV infection or AIDS (UNAIDS, 2016).

During the course of the disease, people living with HIV (PLHIV) often have a variety of gastrointestinal symptoms including dyspepsia. Gastrointestinal symptoms can be caused by HIV per se, opportunistic and non-opportunistic infections including Helicobacter pylori (H. pylori), and adverse effects of highly active antiretroviral therapy (HAART) (Serlin & Dieterich, 2008; Edwards et al., 1991; Nkuize et al., 2010).

H. pylori has the main role in the pathogenesis of chronic gastritis, peptic ulcer disease, gastric cancer, MALT lymphoma and several extra-gastric manifestations (Kusters, Van Vliet & Kuipers, 2006; Wotherspoon et al., 1991). It is one of the most common bacterial pathogens affecting the general population (Logan & Walker, 2001) and its prevalence is estimated to be up to 50% worldwide (Höcker & Hohenberger, 2003). The risk factors and routes of transmission still remain unclear. The most important risk factor seems to be a lower socioeconomic status in early childhood, allowing easy person-to-person transmission (Brown, 2000; Stone, 1999).

The prevalence of H. pylori infection among PLHIV varies from 10 to 76%, depending on the time period, geographical location and population (Nkuize et al., 2010; Marano, Smith & Bonanno, 1993; Fialho et al., 2011; Chiu et al., 2004; Mohamed et al., 2002). Earlier studies reported lower prevalence of this co-infection among PLHIV compared to matched HIV negative controls, contrary to data from the recent HAART era, where the H. pylori prevalence rate in PLHIV approaches the rate observed in general population.

Material and Methods

The aim of this study was to analyze the prevalence H. pylori co-infections, within the HIV community as well as to describe endoscopic findings, gastritis topography and histology, along with patient demographic characteristics across three different periods of time, during which antiretroviral therapy (ART) has evolved, from pre-HAART (1993–1997), to the early HAART (1999–2003) and modern HAART era (2011–2015).

This retrospective case-control study was carried out at the Hospital for Infectious and Tropical Disease of the Clinical Center of Serbia at the Faculty of Medicine, University of Belgrade, which is our the major reference center for the management of HIV infections. The study included HIV positive patients who underwent esophagogastroduodenoscopy (EGD) due to dyspeptic symptoms.

Results

A total of 212 PLHIV and 1617 HIV negative patients, all with dyspeptic symptoms who underwent endoscopic examination during the three defined HAART periods were included in this retrospective case-control study. The three control groups, for the pre-HAART, early HAART and modern HAART periods consisted of 598, 603 and 416 patients, respectively.

The pre-HAART HIV positive group (G1) consisted of 66 patients, of which 44 (66.7%) were males while the remaining 22 (33.3%) were females, with a mean age of 38.0 ± 10.5 years. The youngest patient was aged 21, while the oldest patient was 68 years old. The prevalence of H. pylori infection in this group was 18.2% (Table 1, Fig. 1).

The early-HAART HIV positive group (G2) consisted of 53 patients, of which 32 (60.4%) were males while 21 (39.6%) were females. The mean age was 40.8 + 10.6 years. The youngest patient was 18, while the oldest patient was 63 years old. The prevalence of H. pylori infection in this group was 30.2% (Table 1, Fig. 1).

The modern-HAART HIV positive group (G3) consisted of 93 patients, of whom 74 (79.6%) were males and 19 (20.4%) were females, with the mean age of 42.2 + 11.8 years. The youngest patient was 24, while the oldest patient was 83 years old. The prevalence of H. pylori infection in this group was 34.4 % (Table 1, Fig. 1).

The age and gender of patients, across all three groups did not differ significantly, although there were more males in G3 than in G2 (p = 0.012). In all three groups the majority of patients had secondary education; the level of education did not differ between G1 and G2 (p = 0.719), while G3 patients had somewhat higher level of education than G1 (p = 0.007) and G2 (p = 0.044). The median CD4 cell count/µL was significantly different across groups (97 count/µL (4–545), 250 count/µL (6–792) and 435 count/µL (2–1622), in groups G1–3, respectively, p < 0.001). G3 patients had the highest CD4 + counts, while the lowest count was observed in G1 patients. A significantly lower prevalence of AIDS was observed in G3 than in G2 patients. The level of HIV viremia did not differ significantly between G2 and G3. The level of HIV viremia had not been measured in the pre-HAART era (Table 1).

The median duration of HIV infection from initial diagnosis to the EGD was significantly longer in G3 (5 years (0–29)) compared to G2 (2.5 years (0–15)) and G1 (1 year (0–11)) (p < 0.001).

There were 30 (52.6%) intravenous drug users (IVDUs) in G1, while the sexual route of HIV transmission was more prevalent among patients in groups G2 and G3 (p < 0.001). There was no significant difference in the route of HIV transmission between G2 and G3 (p = 0.101) (Table 1).

The sexual HIV transmission routes included homosexual (MSM), bisexual and heterosexual PLHIV. MSM was the most prevalent in G3. In G1 and G2 however, heterosexuals prevailed (p < 0.001) (Table 2). Males prevailed across all groups (p < 0.001).

The number of PLHIV with pathological EGD findings (erythema, edema, visible vascular pattern, mucosal friability, erosive or hemorrhagic lesion, exudate) were significantly different across groups, with 49 (74.2%) patients in G1, 28 (52.8%) patients in G2 and 38 (40.9%) patients in G3 (G1 vs. G2 p = 0.015; G1 vs. G3 p < 0.001; G2 vs. G3 p = 0.162; G1 vs. G2 vs. G3 p < 0.001). More precisely, pathological EGD findings were more common in G1 than in either G2 or G3 patients. In the latter two groups the number of patients with pathological EGD findings was similar (Table 3).

In PLHIV, the gastritis topography significantly differed between H. pylori positive subgroups (p < 0.001). EGD revealed antral gastritis as the most common in G1 H. pylori positive subgroups patients. The majority of G2 H. pylori positive subgroups patients had either antral or pan-gastritis, while G3 H. pylori positive subgroups patients mostly suffered from pan-gastritis. The histopathological grading of gastritis activity was similar between subgroups, while H. pylori density differed significantly (p < 0.001). The most severe density was recorded in G3 H. pylori positive subgroups patients. Although gastritis activity was similar across subgroups, the mildest cases prevailed in G1, and in G3 there were more patients with moderate activity (p = 0.026). The intensity of lymphoid follicles, mononuclear cell infiltration, and the intestinal metaplasia were similar across subgroups. All cases of gastritis in the presented H. pylori positive cohort were classified as chronic non-atrophic gastritis. Intestinal metaplasia was only sporadically present, mostly replacing one to few foveolae (Table 3).

Patients in the G1 group with H. pylori co-infection were younger than in G2 and G3 subgroups (p = 0.018). Gender distribution was similar across H. pylori positive subgroups. The median CD4 cell counts were lower in G1 than in G3 H. pylori positive subgroup patients (p = 0.013) (Table 4).

The age of the controls differed significantly between three the HAART periods. Control patients from the modern HAART were significantly older than control patients from the pre-HAART and early HAART periods (p < 0.001) (Table 5).

The prevalence of H. pylori infection significantly varied between control groups, decreasing over time from 60.7% in pre-HAART to 38.5% in modern HAART era controls. In modern HAART controls, the prevalence of H. pylori infection was similar to the prevalence of H. pylori infection co-infected modern HAART individuals (Fig. 2).

Discussion

From the very beginning of the HIV/AIDS epidemic in Serbia, it became evident that these patients suffered from various gastrointestinal symptoms, including dyspepsia. The cause of gastrointestinal symptoms could be HIV per se, opportunistic and non-opportunistic infections including Helicobacter pylori (H. pylori), along with adverse effects of highly active antiretroviral therapy (HAART). Therefore, EGD has become an important differential diagnostic tool in the evaluation of gastrointestinal disease in PLHIV (Corley, Cello & Koch, 1999; Korać et al., 2008). ART naïve PLHIV live with the impairment of cell-mediated immunity and are therefore at high risk for opportunistic infections and opportunistic tumors. Introduction of ART in 1986, which evolved from rather a weak mono and/or dual therapy to more potent HAART in 1996, has dramatically changed the course of HIV infection, converting it to a chronic, not necessarily a fatal disease. Good patient adherence to treatment and infection monitoring are of crucial importance (Dieffenbach & Fauci, 2011; Jevtović et al., 2007).

Occasionally, however, especially among late presenters in which HAART is initiated only at a point of profound immunodeficiency, the immune system recovery may be accompanied with the emergency of complications called the immune reconstitution inflammatory syndrome (IRIS). IRIS is a consequence of the restored immune response to specific infectious or non-infectious antigens (DeSimone, Pomerantz & Babinchak, 2000; French et al., 2000; Mayer et al., 2004; Shelburne, Montes & Hamill, 2006). According to our data, the prevalence of HIV/ H. pylori co-infection in Serbia ranges from 18.2% to 34.4%, depending on the study period, namely the type of applied ART. Indeed, the prevalence of HIV/H. pylori co-infection has increased over time, contrary to reduction in H. pylori infection incidence in HIV negative controls. A similar prevalence of H. pylori infection was observed among PLHIV and HIV negative controls in the modern HAART era (Fig. 2). We have not explored the causes of decreasing H. pylori infection prevalence in the HIV negative population, but a possible explanation is the H. pylori infection has had a decreasing trend, most probably by effective application of H. pylori eradication therapy (Malfertheiner et al., 2012).

It seems that HAART may be one of the predisposing factors in PLHIV. HAART enables the immune system recovery, which is associated with an increase in the CD4 cell counts to almost normal values. Altogether, this could play an important role in the pathogenesis of gastritis associated with HIV/H. pylori infection.

In accordance with published data (Nkuize et al., 2010; Marano, Smith & Bonanno, 1993; Fialho et al., 2011; Chiu et al., 2004; Mohamed et al., 2002; Olmos et al., 2004; Nkuize et al., 2012), we also demonstrated the highest CD4 cell counts in HIV/H. pylori co-infected patients. Moreover, CD4 cell counts show a positive increasing trend simultaneous with ART evolution from pre-HAART to modern HAART. This is in concordance with the rising prevalence of H. pylori induced gastritis among co-infected patients.

To the best of our knowledge, this is the first EGD-based morphological comparison of HIV/H. pylori co-infected patients in three different periods of ART evolution. We have demonstrated a significantly reduced incidence of pathological EGD findings in PLHIV with dyspeptic symptoms in the modern HAART era in comparison with PLHIV co-infected during the pre-HAART era. Then, in three time points H. pylori gastritis topography has also changed significantly between the three HAART periods. During the pre-HAART era, gastritis was characterized by mild H. pylori density and moderate activity. This is contrary to gastritis observed in the modern HAART group, where the density became mostly severe, while the activity remained mild. The changes in gastric histological findings may be associated with an increased CD4 cell count in H. pylori positive subgroup, and could suggest that the type and duration of immune and inflammatory responses are responsible for differences in histological presentations of H. pylori associated gastritis. The direct impact of ART on H. pylori infection and gastritis should also be taken into consideration, especially since there is evidence for ART-induced GI symptoms (Wilcox & Saag, 2008).

Finally, it is not only that HAART changed the course of HIV/H. pylori co- infection. Over time, the profile of patients suffering from HIV infection has changed. In Serbia, the first PLHIV were IVDU (Vucic-Jankovic, Ristic & Bakovic, 1996) and this was the most prevalent mode of HIV transmission during the entire pre-HAART period. The epidemiological situation in Serbia is now completely different. Today, in the modern HAART era, the patient population is mostly male, while the dominant route of HIV transmission is sexual intercourse, more precisely MSM. This is reflected in the gender distribution in the modern HAART PLHIV group. In contrast, no differences in gender prevalence were found in the three PLHIV H. pylori positive subgroups which corresponds to the findings of the HIV negative patients infected with H. pylori (Kusters, Van Vliet & Kuipers, 2006; Brown, 2000). Despite the differences in HIV risk behavior, the duration of HIV infection and educational level, PLHIV in the three HIV positive groups from different HAART eras are of similar age as opposed to the three PLHIV H. pylori positive subgroups. In the modern HAART era, PLHIV with H. pylori co-infection were significantly older. This finding is in accordance with the age trend among HIV negative controls.

In the modern HAART era, PLHIV are living longer, are normally integrated in society, with similar risks and diseases as HIV-negative individuals.

Conclusion

Our data may also suggest that H. pylori needs a functional immune system to induce human gastric mucosa inflammation. It is necessary for future studies to investigate the difference between epidemiological characteristics of H. pylori infection in the PLHIV and HIV negative population, expanding conclusions and implications from our study. Altogether, our findings suggest that HAART has an important impact on the EGD features of HIV/H. pylori co-infection.

Supplemental Information