Effects of Long Term Use of Antiretroviral Therapy (ART) on the Oral Mucosa

Objective:  The long term use of potent medications in the treatment of AIDS/HIV often has unwanted effects on host tissues.  The adverse effects of ART in AIDS patients on the oral mucosa have not been studied.  The purpose of this Initiative is to stimulate research on the long term effects of ART on, for example, the qualitative and quantitative composition of the saliva, innate and adaptive immune networks of the oral mucosa, and oral epithelial structures and functions.  Such research will provide valuable insight into the cellular and molecular mechanisms responsible for occurrence or re-occurrence of oral disorders in HIV infected/AIDS patients, despite having been treated with ART.  In order to obtain results that are especially relevant to humans, these studies will be restricted to the use of ex-vivo human organotypic models of the oral mucosa, simian models for AIDS, and tissues from individuals receiving ART.  A goal of the initiative is to identify novel strategies for prevention and management of oral manifestations of HIV infection and AIDS by reducing the negative effects of ART.

Background:  The life expectancy of patients with HIV/AIDS infection has dramatically improved over the past 10 years.  In part, this is due to the advent of multiple classes of anti-retroviral therapeutic regimens and a better understanding of the management of AIDS-associated medical complications.  The survival of the patients, however, is dependent on the continuous treatment with ART.  HIV infected patients are generally treated with drug combinations that include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), lamivudine (3TC), Videx (ddI), emtricitabine (FTC), Tenofovir (TDF), abacavir (ABC) and/or protease inhibitors (PIs) such as nelfanavir (NFV), retonavir (RTV), liponavir (LPV), atazanavir (ATZ) and indinavir (IDV).  Another class of compounds that is frequently used in combination with NRTIs and PIs is the non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as delavirdine (DLV), efavirenz (EFV) and nevirapine (NVP).  Combination of some of these drugs has been shown to reduce HIV viral load in the peripheral circulation and lymphoid tissues and to partially restore the patent’s immune response. Some of them also have been proven to be valuable in preventing mother to child transmission.

Despite having many beneficial effects on HIV infected/AIDS patients, ART has been shown to have some negative effects.  Long term use of ART has been associated with mitochondrial dysfunction in lymphocytes, liver, muscle, and fat cells.  Chronic ART exposure increases oxidative stress in endothelial cells and induces mononuclear cell recruitment, effects which may eventually precipitate the cardiovascular complications observed in HIV-1⁺ individuals on antiretroviral therapy.  Patients on long term ART demonstrate abnormal function as shown by increased insulin resistance, increased amounts of intra-abdominal fat, hypertriglyceridemia and hypertension.   In addition, these patients suffer from lipoatrophy of subcutaneous fat and bone demineralization.  The latter has been associated with low bone density and high osteoclast activity. 

Studies that address the long term effects of ART on oral mucosal epithelial structure, substructures and function are lacking.  Oral epithelial cells are rich sources of microbicidal agents and innate host immune factors that target oral opportunistic infections.  Yet the effect of ART on the homeostasis of these factors in the oral cavity has not been sufficiently studied.  Oral warts, salivary gland disorders and possibly HPV associated premalignant oral lesions have been described as increased in patients receiving ART. These findings suggest that, despite having many beneficial effects on the host, ART may increase the risk of certain oral complications of AIDS. 

This initiative will encourage the use of molecular, cellular and high-throughput technology approaches to study the long term effects of exposure to ART on oral health.   Investigators will likely use tissues from healthy individuals and AIDS patients on ART, in vitro models of human oral mucosa and mucosal tissues from nonhuman primate models exposed to ART.

Current NIDCR/NIH Portfolio:  Currently there are no grants in the NIDCR or other Institute portfolios in this area of investigation.

Recommendations from Workshops:  Research on the effects of long term use of ART on the oral mucosa were recommended at the NIDCR sponsored Workshop “HIV/AIDS Associated Oral Viral Infections: Pathogenesis and Transmission” held in April 2004 in Bethesda, MD.

Funding Mechanisms:  This initiative will utilize the R01 and R21 mechanisms