Review Article MANAGEMENT OF ORAL MANIFESTATIONS IN HIV/AIDS : A REVIEW. University Journal of Dental Sciences

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1 University Journal of Dental Sciences MANAGEMENT OF ORAL MANIFESTATIONS IN HIV/AIDS : A REVIEW Review Article Kriti Garg, Vishal Mehrotra, Rohan Sachdev, Ankit Mehrotra, Garima Singh 1,2,3,4,5 Rama Dental College Hospital & Research Center, Kanpur ABSTRACT : HIV (Human Immunodeficiency Virus) is a retrovirus that gradually attacks the immune system, which protects human body against illness. HIV infected person becomes a easy target for opportunistic infections and diseases. The two main types are HIV-1 and HIV-2. HIV-1 is the most common type found worldwide. Management of HIV infection of body as well oral lesions will require a prolonged period of followup and monitoring of these HIV-infected individuals Keywords : HIV, AIDS, Oral Lesions, Medicines Conflict of interest: Nil No conflicts of interest : Nil INTRODUCTION : Acquired Immunodeficiency Syndrome (AIDS) is caused by a retrovirus known as the Human immunodeficiency Virus (HIV). To date there are two types of HIV; HIV-1 and HIV-2. HIV -1 is known to cause AIDS. It is thought that 80% of people infected with HIV-1 will progress to clinical AIDS within 10 years.1 HIV infected person becomes a easy target for opportunistic infections and diseases. This virus multiplies in T-helper cell (CD4) and gradually depletes them.2 Management of HIV infection will require a prolonged period of follow-up and monitoring of these HIVinfected individuals. The chronic nature of the infection and the social stigma associated with AIDS makes management of HIV infection more than just providing medical care to these patients. it is necessary to have a multidisciplinary approach to the care of HIV-infected patients.2 As per WHO, together, the 13 protocols provide a comprehensive evidencebased tool offering clear, specific advice on diagnosing and managing a wide range of HIV/AIDS health-related issues for adults, adolescents and children. Major topics include ART, the management of opportunistic infections, tuberculosis coinfection, hepatitis coinfection, injecting drug use, sexual and reproductive health, prevention of mother-to-child transmission, immunizations, palliative care and postexposure prophylaxis.2,3 Main Objectives of treatment of HIV infected person are as follows:2 To identify early HIV infection To provide continuous care to asymptomatic To provide early intervention To provide adequate medical care with therapy when required To delay progression to full-blown AIDS Oral manifestations are the earliest and most important indicators of HIV infection. Oral lesions can not only indicate infection with HIV, they are also among the early clinical features of the infection and can predict progression of HIV disease to AIDS. Dental expertise is necessary for proper management of oral manifestations in HIV infection.4 WHO collaborating center and EC clearing house revised the classification (Table-1) of oral lesion associated with HIV infection in to5 : University Journal of Dental Sciences, An Official Publication of Aligarh Muslim University, Aligarh. India 17

2 Table-1 : Classification of HIV associated oral manifestation as per WHO THERAPUTIC MODALITIES : With increased knowledge of HIV pathogenesis, new medications are continuously being developed to slow the progression of HIV disease.6 T H E R A P U T I C A N D P R O P H Y L E C T I C MODALITIES: The management of HIV disease can arbitrarily be divided into a preventive and treatment branch, includes anti-retroviral to prevent further infection and slow down the replication of HIV, cytokines to offset cell depletion often associated with antiretroviral therapy, immune modulators to improve the existing immune response and anti-invectives for opportunistic infections.6 Most patients are treated with combinations of different medications with advantage over single drug therapy: it may extend the duration of effectiveness beyond that of a single drug; it has the potential for synergistic activity: it may diminish the development of resistant viral strains and it may reduce the level of side effects from a single agent by decreasing dosages.6 RETROVIRAL THERAPY : Several different approaches have been applied to prevent or slow HIV infectivity and replication. The most common and the only FDA approved anti-retroviral inhibits HIV replication with the help of nucleoside analogs. These compounds have a dual action: they act as competitive inhibitors of the reverse transcriptase and they prematurely terminate proviral DNA synthesis. The four anti-retroviral nucleoside analogs approved for use in the United States are zidovudine, dideoxyinosine( ddi), dideoxycytidine (ddc) and stavudine or d4t.6 NUCLEOSIDE ANALOGS : Zidovudine (AZT, azidothymidine, Retrovir, ZDV) was the first agent approved by the FDA for the treatment of HIV. In 1984 it was discovered that it could inhibit HIV replication. Initial dosage of the drug were very high, resulting in severe drug toxicity but recent clinical trials have established its efficacy and reduced toxicity when used in lower doses in asymptomatic patients with HIV and CD4 counts below 500cells/mm3. The optimum dosage has subsequently been reduced from 800 to 1200 mg daily to 300 to 600 mg orally in equally divided dose. Early administration of zidovudin delays the progression of the disease from the asymptomatic stage to the more advanced stages. Current recommendations in the United States are to administer 500 to 600 mg zidovudine orally in equally divided daily doses for patients with CD4+ cell counts of 500 cell/mm3 and below, regardless of symptom. In cases of deterioration zidovudine is recommended.6 The second anti-retroviral drug approved by the FDA was ddi (dideoxyinosine, Videx, didanosine) 200mg/bid administered as chewable tablets or as a powder dissolved in water twice daily. The chewable tablets are buffered to enhance gastric absorption of the drug. This drug is used as initial retroviral therapy in combination with zidovudine or as monotherapy in patients with CD4+ cell counts below 500 cells/mm3 who are intolerant to zidovudin.6,7 The most potent HIV inhibitor nucleoside analogs is ddc ( dideoxycytidine, HIVID, zalcitabine) 0.75mg/tid is approved to be used in combination with zidovudine in patients with HIV and CD4 cell count below 300 cells/mm3.6,7 The latest nucleoside analog is d4t or stavudine, 40mg/bid is indicated in patients who do not tolerate or who show no benefit to other nucleoside analogs.6,7 NON-NUCLEOSIDE ANALOGS : They inhibit reverse transcriptase but do not terminate DNA synthesis by incorporation during the transcription p r o c e s s. N o n - n u c l e o s i d e a n a l o g s i n c l u d e d e o x y f l u o r o t h y m i d i n e ( F L T ), c a r b o c y c l i c didehydrodideoxyguanosine(carbovir), 3-thiacytidine( 3TC, Lamivadine), foscarnet( foscavir), neviraprine and tetrahydroimidazobenzodiazepine( TIBO).6 University Journal of Dental Sciences, An Official Publication of Aligarh Muslim University, Aligarh. India 18

3 PROTEASE INHIBITORS : In the mid-1990s a new class of antiretroviral medication was introduced-protease inhibitors. These powerful medications prevent the breakdown of viral proteins into appropriate building blocks for viral replication. This group includes medications are amprenavir (APV), indinavir (IDV), nelfinavir (NFV), ritonavir (RTV) and saquinavir : was the first drug of this class to receive Food and Drug Administration approval in Nov 1995.(SQV).8,9 Now a days due to high level of toxicity and the rapid development of drug resistance, antiretroviral medications are given as double or triple therapy usually consist of combination of at least 3antiviral drugs:2nrti's with either a PI or an NNRTI, referred to as highly active anti-retroviral therapy or HAART.8, 10 It is now recognized that after the initiation of HAART the antiviral response can be seen at least 6weeks with a reduction in plasma HIV viral load by one log and after 24 weeks reaching undetectable levels in the plasma.11 With the advent of HAART the prevalence of oral candidiasis, oral hairy leukoplakia and HIV associated periodontal disease have decrease in adults.6 ANTIFUNGAL MEDICATIONS : 1) AMPHOTERICIN B ( Fungizone): An intravenous medication used for the treatment of progressive disseminated fungal infections. This drug is usually used in individuals with very low CD4 cell counts.6 2) CLOTRIMAZOLE (Mycelex): This is used for the treatment of candidiasis in the form of cream, tablet or troche. It the most commonly used oral troche for oral candidiasis.6 3) FLUCONAZOLE(Diflucan): It is approved for the treatment of candidiasis and as prophylaxis for cryptococcosis.6 4) ITRACONAZOLE (Sporanox): This oral medication is approved for the treatment of blastomycosis and histoplasmosis but also appears to be effective against candidiasis.6 5) KETOCONAZOLE (Nizoral): It has been used for the treatment of candidiasis, blastomycosis and histoplasmosis.6 ANTIVIRAL MEDICATIONS : 1) ACYCLOVIR ( Zovirax): Acyclovir is an anti-herpetic medication used mainly to treat infections caused by herpes simplex viruses. It is also used to treat cytomegalovirus infections and oral hairy leukoplakia.6 2) GANCICLOVIR( DHPG, Cytovene): Ganciclovir is used in the treatment of cytomegalovirus retinitis in HIV infected patients. This medication is administered intravenously.6 3) FOSCARNET( trisodium phosphonoformate,pfa, Foscavir) : Foscarnet is administered intravenously and is primarily used it treat cytomegalovirus retinitis.6 ANTINEOPLASTIC AGENTS : 1) ALPHA INTERFERON( recombinant alpha interferon, Roferon, Intron A, Alferon-N injection) : This is the first drug approved for the treatment of Kaposi's sarcoma. This compound may be used in combination with zidovudine. This drug is administered intramuscularly.6 ANTIMYCOBACTERIAL MEDICATIONS: 1) A M I K A C I N S U L P H A T E ( A m i k i n ) : A n aminoglycoside antibiotic used for the treatment of mycobacterium avium-intracellulare and it is administered intramuscularly.6 2) AZITHROMYCIN (Zithromax) : This is an oral macrolide antibiotic used for the treatment of Mycobacterium avium intracellulare,toxoplasmosis and cryptosporidiosis.6 3) CIPROFLOXACIN (Cipro): It is an oral quinolone antibiotic used for combination treatment of Mycobacterium avium intracellulare. 6 4) ETAMBUTOL (Myambutol): It is used in combination with other medication for the treatment and prophylaxis of tuberculosis and Mycobacterium avium intracellulare.6 5) ISONIAZID( INH): It is used for the treatment and prophylaxis of tuberculosis.6 6) PARA-AMINOSALICYLIC ACID: An oral antibiotic used for the treatment of multiple drug resistant tuberculosis.6 7) RIFAMPIN (MYCOBUTIN): Rifampin is used for treatment and prophylaxis of tuberculosis and Mycobacterium avium intracellulare.6 8) STREPTOMYCIN: This drug is used for the treatment of multiple drug-resistant tuberculosis. This drug is administered intramuscularly.6 University Journal of Dental Sciences, An Official Publication of Aligarh Muslim University, Aligarh. India 19

4 ANTI WASTING SYNDROME MEDICATIONS 1) DRONARINOL( Marinol): This drug is used to stimulate appetite in patients with HIV and anorexia.6 2) MEGESTROL ACETATE (Megace): Megestrol acetate is used as an appetite stimulant for malnourished persons.6 CYTOKINES 1) EPO (Epoetin alfa,procrit,epogen) :This is a synthetic compound that stimulates red blood cell production.6 2) G-CSF(Filgrastim,Neupogen, Amgen):This is a recombinant protein of the naturally occurring granulocyte colony stimulating factor which induces proliferation and differentiation of granulocytes.6 3) GM-CSF(Sargramostim,Leukine, Immunex):This is a recombinant protein of the naturally occurring granulocyte-macrophage colony stimulating factor which induces proliferation and differentiation of granulocytes and macrophages.6 ANTI HIV DEMENTIA MEDICATION 1) METHYLPHENIDATE HYDROCHLORIDE (Ritalin):This drug is used to improve symptoms related to HIV dementia by acting as a central nervous system stimulant.6 MISCELLANEOUS 1) LEUCOVORIN (Folic acid) : This medication is used with a folic acid antagonist such as pyrimethamine to diminish the toxicity of this drug.6 2) DIPHENOXYLATE HYDROCHLORIDE with ATROPINE SULPHATE( Lomotil): This medication is related to the narcotic meperidine. It also has an anticholinergic effect and is used for patients with diarrhoea.6 VACCINES : Vaccination or immunotherapy of pregnant HIV-1 infected women is one of the most direct goals in vaccine development. Immunization trials of pregnant women with recombinant envelope glycoproteins have been carried out and although safety and toxicity trials were highly successful. 12 THERAPY USED IN ORAL LESIONS Current therapies of oral lesions associated with HIV/AIDS are as follows: FUNGAL LESIONS Treatment of oral candidiasis includes topical and systemic antifungal medications.6,8 Common topical treatment include nystatin oral suspension 100,000units/ml ; 10ml swished and swallowed four to five times per day and nystatin troche: dissolved in the mouth four to five times per day.8 Ointment and creams such as 1% clotrimazole ointment, 2% ketoconazole cream or nystatin cream are efficacious in treating angular cheilitis.8 Common systemic antifungals include ketoconazole 200mg tab;one tab twice a day with food, fluconazole 100mg tab;200mg on day1 followed by 100mg daily for 14 days and itraconazole 100mg tab ;200mg daily with food. 6,8 For deep seated fungal infections intravenous amphotericin B has been used in a dose of 50 mg in 500cc DW rinse and spit out,3times daily.6,8 VIRAL LESIONS For HSV-1 infections acyclovir 200mg orally five times/daily. although famciclovir can also be used.8 For cytomegalovirus infections a recommended regimen for intra oral lesions is high dose acyclovir therapy 800mg orally five times a day for a minimum of 2 weeks.8 For Epstein Barr virus lesions acyclovir 800mg orally five times a day is effective to achieve the resolution of the lesion with in 2weeks. Prophylactic therapy with 800mg acyclovir per day may be necessary to prevent recurrence.8 For Varicella zoster infection treatment usually is focused on supportive care and is centered on the prevention of post herpetic neuralgia and dissemination. High doses of oral acyclovir 800mg orally five times a day, famciclovir 500mg orally three times a day or valacyclovir 500 mg orally three times a day.8 For Human Papilloma virus lesion treatment include surgical removal, laser ablation, cryotherapy and topical application of keratinolytic agents. For smaller lesions topical application of 25% podophyllum resin may be used to reduce the size. Intralesional injections of antiviral agents have also been used. Interferon-alpha in intralesional injections 1,000,000 IU/cm2 once weekly and subcutaneous injections 3000,000IU/cm2 twice weekly have been shown to be effective in long term University Journal of Dental Sciences, An Official Publication of Aligarh Muslim University, Aligarh. India 20

5 resolution of lesions.8 BACTERIAL LESIONS Treatment for both nectrotising ulcerative gingivitis (NUG) & necrotizing ulcerative periodontisits (NUP) consists of debridement of necrotic soft and hard tissue, antibiotic therapy with metronidazole or tetracycline 500mg four times a day for a week and a follow up with scaling and debridement.8 Antifungal drugs also prescribed with antibiotics.8 Chlorohexidine gluconate (0.12%) mouth rinses are recommended as maintenance therapy.8 KAPOSI'S SARCOMA Treatment of Kaposi sarcoma includes radiation 800 to 200rad,followed by surgical excision.6,8.9 Intralesional injections with chemotherapeutic agents such as vinblastin sulfate 0.1mg/mm2 or sodium tetradecly sulfate 0.1 mg/mm2.intralesional injections are most effective for small nodular lesions and as an adjuvant to radiation.8,13 Guliver potsangbam et al(2007) reported that intralesional vinblastin in the dose of 0.01mg/lesion for palatal lesions every two weeks is effective in treatment and for the pedunculated mass 0.04mg of vinblastin is injected inside tumor mass every two weeks.8,12,13,14 Antiangiogenesis agents such as thalidomide, Kishore shetty reported as a initiating dose of 200mg/day and then increase up to 200mg/day on a biweekly basis tolerated to a maximum dose of 1000mg/day60 and oral 9-cis retinoic acid are also useful in the treatment of KS.8,12,14 NON SPECFIC LESIONS For the treatment of minor aphthous ulcer an analgesic mouthrinse such as 2 to 4% viscous lidocaine solution;10ml swished and expectorated.8 Kishore shetty et al (2006) reported use of thalidomide in the treatment of oral aphthous ulcers in a dose of 200mg po qhs vs,for 4weeks.13 For major aphthous ulcer systemic corticosteroids are used. Topical formulation of clobetasol or fluocinanide gel applied directly to the lesion, dexamethasone elixir mouth rinses 0.5mg/5ml and systemic administration of 60 to 80 mg of prednisone per day for 10days.For steroid resistant patients alternative therapy of 100 to 200 mg thalidomide may be used.8 Levamisole 50mg/three times per day followed by an 11day latent period ;with repeating cycle 3times.6 Antibiotics and antifungal agents may be used concurrently when appropriate to prevent bacterial or fungal superinfections.8 CONCLUSION : Prevention and treatment of oral disease is required to maintain quality of life and to improve prognosis of patients infected with human immunodeficiency virus (HIV). Management requires a team approach and close collaborations with the appropriate responsible physicians and other health care workers. Oral infections are frequent and usually opportunistic and management is based in certain cardinal principles. Infections may disseminate and can be persistent and severe; multiple concurrent or consecutive infections with different microorganisms are frequent; fungal, viral and parasitic infections are rarely curable and long term antimicrobial therapy may be required. Any treatment regimens used to treat HIV infected individuals should not be further immunosuppersive, as it may induce dental caries by aggravating symptoms like Xerostomia, adverse drug reactions etc. Much has been learned about AIDS in past few years, However, no cure available. REFERENCES a Vaidya KA, Kadam AV and Nema V. Anti-Retroviral Drugs for HIV: Old and New. Austin J HIV/AIDS Res 2016;3(2) : data/assets/pdf_file/0004/ 78106/E90840.pdf?ua 4. Maeve M.Coogan,John Greenspan and Stephen J.Challacombe.Oral lesions in infection with human immunodeficiency virus.bulletin of the World Health Organization 2005;83(9): Neleena R. kumar et al. Oral manifestations in HIV infection. JIAOMR 2006, 18:01, Michael Glick.Dental Management of patients with HIV Patients-Michael-Glick/dp/ P.T.Cohen, Merle Sande, Paul A. Volberding.The AIDS knowledge base; A textbook on HIV disease from the University of California,San Francisco and San Francisco General Hospital;3rd edition. University Journal of Dental Sciences, An Official Publication of Aligarh Muslim University, Aligarh. India 21

6 8. Greenberg &Glick.Burket's Oral Medicine,Diagnosis and Treatment.10ed 2003: Lauren L.Patton et al. Changing prevalence of oral manifestations of human immunodeficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89: Anwar R. Tappuni,Garry J.P.Fleming. The effect of antiretroviral therapy on the prevalence of oral manifestations in HIV-infected patients:a UK study.oral Srug Oral Med Oral Pathol Oral Radiol Endod 2001;92: Raghu Radhakrishanan et al. Plasmablastic lymphoma of the oral cavity in an HIV positive child.oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100: B.C.Muzyka et al. Prevalence of HIV-1 and oral lesions in pregnant women in rural Malawi.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92: Guliver Potsangbam et al.intra lesional injection of Vinblastin in a pedunculated oral Kaposi's sarcoma in a patient of AIDS.Journal of Indian Academy of Clinical Medicine 2007;8(1): Kishore Shetty. Thalidomide in the concurrent management of recurrent aphthous ulcerations and Kaposi's sarcoma in HIV patients with severe immunosuppression. Oral Oncology 2006;42: CORRRESPONDING AUTHOR: Dr. Kriti Garg 117/k-68 Sarvodaya Nagar, Kanpur drkritigarg@gmail.com Mobile: University Journal of Dental Sciences, An Official Publication of Aligarh Muslim University, Aligarh. India 22

Section H: Treatments

TIME THIS SECTION BEGINS RECORDED HERE TSST04H Section H: Treatments H1. Have you ever taken AZT, a protease inhibitor, or any other drugs such as those listed on this card to treat your HIV infection