Proton pump inhibitors may blunt CD4 cell gains, cause immune activation, in people with HIV

Proton pump inhibitors should be used with caution in people with HIV, US researchers say, after finding that people who received long-term treatment for gastric reflux with the drugs failed to gain CD4 cells and experienced more immune activation. The findings are published in advance online in Clinical Infectious Diseases.

Proton pump inhibitors (PPIs) such as lansoprazole, pantoprazole and omeprazole are frequently prescribed to manage gastric reflux by suppressing stomach acid production. Gastric reflux is a common condition that is caused by hiatus hernia or by stress, smoking, coffee, alcohol, fatty or acidic foods, eating too close to bedtime, and by obesity or pregnancy. Gastric reflux is also a side-effect of some HIV medications, as well as drugs used to treat hypertension.

Although PPIs are considered safe for long-term use, there is some evidence that the drugs promote bacterial overgrowth in the large intestine. PPI treatment is associated with an increased risk of gastrointestinal infections such as salmonella and campylobacter, two of the most frequent causes of food poisoning.



When blood pressure (the force of blood pushing against the arteries) is consistently too high. Raises the risk of heart disease, stroke, kidney failure, cognitive impairment, sight problems and erectile dysfunction.

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.


Single-celled micro-organisms.

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.


In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

Gut bacterial overgrowth may be a particular problem in people living with HIV because bacteria from the gut can cross an intestinal wall that is damaged as a result of HIV infection, and cause immune activation.

The strength of immune activation predicts the progression of HIV disease in untreated people. In people on antiretroviral treatment, immune activation is still detectable and is associated with lower CD4 cell counts. There is some evidence that immune activation also contributes to the development of cardiovascular disease in people living with HIV.

To study the impact of PPIs on immune activation and CD4 cell counts, researchers from the University of Texas recruited 77 people living with HIV who had been receiving antiretroviral treatment for at least 18 months and who had an undetectable viral load for at least 12 months before joining the study.

The study population consisted of 37 people who had taken PPIs for at least six months out of the previous 12 and 40 people who did not use PPIs. The study excluded people who had received antibiotic treatment in the previous month.

All participants were male, recruited through the Veterans Affairs Medical Center. PPI users were older (59 years vs 54 years) and more likely to be taking statins or hypertension medication but were otherwise well matched. The study population was 48% African-American, 35% men who have sex with men, 32% heterosexual and 19% had hepatitis C. The median CD4 cell count at study enrolment was 626 cells/mm3 (609 cells/mm3 in the PPI group and 641 cells/mm3 in the non-PPI group). Just under half were taking protease inhibitor-based treatment (44%), while 55% were taking a non-nucleoside reverse transcriptase inhibitor. Participants had been on treatment for a median of 12 years.

PPI users had been taking the drugs for a median of 3.7 years prior to enrolment.

The researchers measured two markers of immune activation – soluble CD14 and activated CD8+-CD38+HLA-DR T-cells – and found that sCD14 was significantly higher in people taking PPIs (P < 0.01). One marker of microbial translocation, LBP, was elevated in this group, while another marker of intestinal repair was reduced in the PPI group.

After controlling for age, hypertension and statin use, a multivariate analysis showed that PPI use was significantly associated with higher levels of sCD14 as a marker of immune activation.

People taking PPIs also experienced a median CD4 cell decline of 18 cells in the year preceding enrolment in the study, whereas people not taking PPIs gained a median of 54 cells/mm3, and this difference was statistically significant (p = 0.03). The study authors say that immune activation is the most likely cause, and that “cautious use of PPIs is advised in this population” until more studies can be done to look at long-term effects in larger populations.

In particular, studies are needed in women as well as men, and must examine whether long-term PPI use results in poorer CD4 cell recovery after starting treatment and if higher immune activation in PPI users has any harmful clinical consequences.


Serpa JA et al. Long-term use of proton pump inhibitors is associated with increased microbial product translocation, innate immune activation, and reduced immunologic recovery in patients with chronic HIV-1 infection. Clin Infect Dis, advance online publication, 7 July 2017.