Kidney Drug Sevelamer May Reduce Gut Leakage During Acute HIV Infection

The phosphate-binding agent sevelamer can bind to bacterial toxins and reduce excessive immune activation in macaque monkeys with a simian virus similar to HIV, according to a report in the June 2 Journal of Clinical Investigation. A related study, however, failed to see a reduction in inflammation biomarkers in people with untreated HIV disease.

Infection with HIV or its simian relative SIV can rapidly damage the lining of the gut, allowing bacteria and their toxins to spill out of the intestines, a process known as bacterial translocation. Bacterial endotoxin, also known as lipopolysaccharide(LPS), can trigger a systemic inflammatory response, which is thought to contribute to HIV or SIV disease progression and non-AIDS conditions including cardiovascular disease.

Sevelamer, which is used to manage elevated phosphate levels in people with chronic kidney disease, also binds to LPS. Jan Kristoff and Ivona Pandrea from the University of Pittsburg administered sevelamer to pigtailed macaques with acute SIV infection. They found that the drug reduced immune activation and inflammation and was even associated with slightly lower viral replication.

Sevelamer also reduced coagulation (blood clotting) biomarkers, "confirming the contribution of microbial translocation in the development of cardiovascular comorbidities" in non-human primates, the researchers wrote. "Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit non-infectious comorbidities associated with AIDS," they concluded.

A related study by Netanya Sandler from the NIAID Vaccine Research Center and colleagues evaluated whether sevelamer would reduce microbial translocation and inflammation in people with HIV. As described in the May 26 advance edition of the Journal of Infectious Diseases, 36 HIV positive participants who were not taking antiretroviral therapy received sevelamer for 8 weeks.

The researchers found that sevelamer "did not significantly change markers of microbial translocation, inflammation, or T-cell activation." Levels of soluble tissue factor, low-density lipoprotein (LDL or "bad") cholesterol, and oxidized LDL decreased significantly, while D-dimer levels increased, leading the authors to conclude that while "sevelamer does not reduce microbial translocation," it still "may have cardiovascular benefits."

Pandrea noted that the macaques in her study were treated with sevelamer during acute SIV infection, and it may not be as effective for monkeys or people with chronic infection after damage to the gut has already occurred.

Below is an edited excerpt from a University of Pittsburgh press release describing the macaque study in more detail.

Breakthrough in HIV/AIDS Research Gives Hope for Improved Drug Therapy

Pittsburgh -- May 16, 2014 --The first direct proof of a long-suspected cause of multiple HIV-related health complications was recently obtained by a team led by the University of Pittsburgh Center for Vaccine Research (CVR). The finding supports complementary therapies to antiretroviral drugs to significantly slow HIV progression.

The study, which will be published in the June issue of the Journal of Clinical Investigation and is available online, found that a drug commonly given to patients receiving kidney dialysis significantly diminishes the levels of bacteria that escape from the gut and reduces health complications in non-human primates infected with the simian form of HIV. The study was funded by the National Institutes of Health (NIH).

"We now have direct evidence of a major culprit in poor outcomes for some HIV-infected people, which is an important breakthrough in the fight against AIDS,” said Ivona Pandrea, MD, PhD, professor of pathology at Pitt’s CVR. "Researchers and doctors can now better test potential therapies to slow or stop a key cause of death and heart disease in people with HIV."

Chronic activation of the immune system and inflammation are major determinants of progression of HIV infection to AIDS, and also play an important role in inducing excessive blood clotting and heart disease in HIV patients. Doctors believed this was due to microbial translocation, which occurs when bacteria in the gut gets out into the body through intestinal lining damaged by HIV.  However, no direct proof of this mechanism existed.

Dr. Pandrea and her colleagues showed blocking the bacteria from leaving the intestine reduces the chronic immune activation and inflammation. They did this by giving the drug sevelamer, also known by the brand names Renvela and Renagel, to monkeys newly infected with simian immunodeficiency virus, or SIV, the primate form of HIV.

Sevelamer is an oral drug approved by the U.S. Food and Drug Administration to treat elevated levels of phosphate in the blood of patients with chronic kidney disease.

The gut bacteria bind to sevelamer, making it much more difficult for the bacteria to escape into the body and cause serious problems, such as heart disease, while further weakening the immune system and allowing HIV to progress to full-blown AIDS.

In SIV-infected monkeys treated with sevelamer, levels of a protein that indicates microbial translocation remained low. However, in the untreated monkeys the levels increased nearly four-fold a week after SIV infection.

The treated monkeys with the lower rates of microbial translocation also had lower levels of a biomarker associated with excessive blood clotting, showing that heart attacks and stroke in HIV patients are more likely associated with chronic immune system activation and inflammation, rather than HIV drugs.

"These findings clearly demonstrate that stopping bacteria from leaving the gut reduces the rates of many HIV comorbidities," said Dr. Pandrea.

Because most interventions in people infected with HIV begin after the person has reached chronic stages of infection when the gut is already severely damaged, Dr. Pandrea notes, "These treatments may not be as effective later in the infection. Clinical trials in HIV-infected patients were not yet successful in reducing microbial translocation in chronically infected patients. Our study points to the importance of early and sustained drug treatment in people infected with HIV."

Other approaches, such as coupling sevelamer with antibiotics, anti-inflammatory drugs, probiotics or supplementation of existing HIV/AIDS drugs could further reduce the likelihood of microbial translocation. Clinical trials are underway to assess these strategies."

6/4/14

References

J Kristoff, G Haret-Richter, D Ma, I Pandrea, et al. Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication. Journal of Clinical Investigation 124(6):2802-2806. June 2, 2014.

L Shan and RF Siliciano. Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection (Commentary). Journal of Clinical Investigation124(6):2368-2371. June 2, 2014.

NG Sandler, X Zhang, RJ Bosch, et al. Sevelamer does not decrease lipopolysaccharide or soluble CD14 but does decrease soluble tissue factor, LDL, and oxidized LDL levels in untreated HIV infection. Journal of Infectious Diseases. May 26, 2014 (Epub ahead of print).

Other Source

University of Pittsburgh. Breakthrough in HIV/AIDS Research Gives Hope for Improved Drug Therapy. Press release. May 16, 2014.