Highly Active Antiretroviral Therapy and Oral Health in HIV Patients

Introduction

Oral manifestations are the first signs of an underlying systemic illness like HIV/AIDS (Patel and Glick, 2005, p. 236). Oral health is an essential constituent of overall health and well being in a patient (Patel and Glick, 2005, p. 223). A patient with HIV is immunocompromised with many common oral lesions. Intra-oral pain seen frequently interferes with the patient’s ability to have adequate oral intake. Incidence of caries increases due to the changes made by medications in the level of salivary flow and the high sugar content of the nutritional supplements (Patel and Glick, 2005, p. 223). The oral manifestations could occur as initial signs, as side effects of medications, underlying systemic disease or as opportunistic infections. Oral lesions are the markers used for the initiation of intervention therapy in immunosuppression and disease progression. Different staging protocols also use the oral lesions. Oral lesions are severely painful and could hamper the intake of nutritious food. Oral health care providers should work in close relationships with physicians and nutritionists to manage the HIV patients (Patel and Glick, 2005, p. 223).

Main text

HAART or highly active anti-retroviral treatment has made a significant change in the treatment and prognosis of HIV/AIDS (Flint, 2006, p. 146). It has suppressed the replication of HIV and enhanced the immune reconstitution. The therapy combines the 20 different drugs available in HAART in diverse manners for the therapy. Oral manifestations have been seen to subside with the HAART. These oral lesions may be forerunners of the failure of the therapy and could be indicative of it when viral load examinations or CD4+ cell counts are not available (Flint, 2006, p. 146). However the oral manifestations could present in other situations too. The immune reconstitution syndrome could present with oral manifestations. Adverse reactions to HAART could also present similarly. It could also be due to a direct inhibitory effect of the protease inhibitors of HAART on oral candidosis.

HAART has four aims. It produces a long-lasting and maximum suppression of the viral load in the blood. Viral load becomes undetectable to less than 50 copies/ mL. after 4-6 months. Immune reconstitution or restoration and preservation of immunological function are other objectives. Quality of life is improved and allows the patient many years of a fairly good life. HIV-related morbidity and mortality has also been reduced (Flint, 2006, p. 146). HAART entails many potentially fatal side-effects or drug interactions. The patient has difficulty to comply with the ingestion of many tablets and the frequent dosing. Viral resistance also has been reported.

Co-morbid oral lesions of HIV infection are easily diagnosed. These oral manifestations are better monitoring features of immune restoration than the biochemical or blood counts (Flint, 2006, p. 146).

The HAART involves four classes of drugs: the fusion inhibitor (FI), the nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitors (PI). The HAART therapy has 3 antiviral agents put together to cause sustained blocks in the viral replication and restore immune function. Resistance is controlled by using three combinations.

The incidence of oral lesions has decreased by 50% in a Mexican study (Ramirez-Amador et al, 2003 ), 10% in an American study (Patton et al, 2000 ), 30% in a Spanish study (Ceballos-Salobrena et al, 2000) and 24% in a UK study (Tappuni and Fleming, 2001). The oral manifestations in these studies included candidosis, hairy leukoplakia, HIV-related periodontal diseases, Kaposi’s Sarcoma, papilloma and salivary gland disease (HIV related). Oral candidosis, the commonest of the oral manifestations, showed a 7% incidence in PI-treated cases compared to 36% incidence in non-treated cases (Cauda et al, 1999 in Flint, 2006, p.147). Oral hairy leukoplakia also was found to decrease with treatment (Patton et al, 2000). A Spanish study on Kaposi’s sarcoma found that this manifestation was not found in patients who were taking HAART. However the study in the US (Patton et al, 2000) and Mexico (Ramirez Amador, 2003) showed no change between those who had treatment and those who had not done so. Patton’s study showed a surprising increase in the prevalence of oral warts and HIV-related salivary gland disease after HAART. Ramirez’s study showed no difference of therapy on the incidence of warts. In HIV children on HAART, no significant difference is seen in the incidence without therapy and after it (Flint, 2008, p. 147).

Studies have reported an increase in the incidence of oral manifestations only if there is non-adherence or non-compliance (Manfredi, 2004). Zalcitabine (NRTI) has been known to be associated with oral ulcers (McNeely et al, 1989). Zidovudine causes mucocutaneous hyperpigmentation (Poizot-Martin et al, 1991). Xerostomia is seen with 30% of patients taking didanosine (Allan et al, 1993) and 7% of patients taking PIs (Danner et al, 1995). Ritonavir has been found to cause taste abnormalities in 20% of patients (Schiffman et al, 1999), circumoral paraesthesia in 25% (Scully and Diz Dios, 2001) and parotid lipomatosis or facial lipoatrophy (Olive et al, 1998). Indinavir has caused cheilosis in 57% of patients (Calista and Boschini, 2000). NNRTIs have very few complications in HIV. However erythema multiforme has been reported with nevirapine (Fagot et al, 2001).

Long term therapy with HAART has increased osteoporosis according to some studies while others deny the connection. Findings are inconsistent. If the association is proved, the implications for periodontal disease would be significant (Yoshihara et al, 2004). Periodontal disease could also be possible in HAART- induced diabetes mellitus and dyslipidaemia (Renvert, 2003). HPV (Human Papilloma Virus)-associated benign lesions of papillomas, condylomas and focal epithelial hyperplasia (Patton et al, 2000) are more consistent and the possibility of related oral malignancies is thereby also increased.

Oral lesions also occur in a “HAART failure” which could be an immunologic failure or virologic failure or a clinical failure (Flint, 2006, p. 148). The regimen failure due to inadequate adherence and compliance, toxicity or suboptimal virologic potency is to be differentiated from HAART failure. HAART is usually started when the CD4+ count is less than 200 cells /mm³ and virological load is more than 55000 copies in full blown AIDS. Virological failure is the incomplete response to HAART. RNA levels would be less than 400 copies/mm³ by 24 weeks or less than 50 copies/ mm³ by 48 weeks. “Immunological failure represents a failure to increase the CD4+ count by 25-50 cells/mm3 per month above baseline in the first year, or a decrease in CD4+ count below baseline levels” (Flint, 2006, p. 148). Successful therapy is indicated by an increase of 150 cells /mm³ in the first year. Clinical failure is when manifestations occur within 3 months of therapy with increased cell counts. Oral manifestations could actually be indicative of a failed HAART therapy. Clinical failure is also indicated by the immune reconstitution syndrome or “HAART attack”. Opportunistic infections increase. Oral manifestations include the increase of HPV lesions (Greenspan et al, 2001) and a salivary disease, diffuse infiltrative lymphocytic disease (Patel and Mandel, 2001). Oropharyngeal candidosis is one oral lesion which could be identified as a marker of immunity in future. It fulfils three criteria required for a marker: “it is not gender- or race-specific, it occurs early in immune dysfunction in the erythematous form, and the prevalence correlates to HIV viral load” (Flint, 2006, p.149).

Protease inhibitors have the ability to inhibit the growth of candida. This could be attributed to the similarity between the aspartic proteinases secreted by the Candida to the HIV proteinase (Munro and Hube, 2002). Oral candidosis was observed to decrease in a study where patients were given PIs but not where they were treated with NNRTIs in a follow-up of 180 days.

No significant increase was observed in the CD4+ cell counts or a decrease in the viraemia. The PI effect is therefore independent of the immune reconstitution (Flint, 2006, p. 150).

In a study in Tanzania, the significance of HAART in oral lesions in 481 adults and 51 children were found to have results similar in other studies. The methods of acquiring information was through interviews, physical examinations, HIV testing and enumeration of CD4+ T cells (Hamza et al, 2006). The patients had been receiving stavudine, lamivudine and nevirapine for less than a year. The adults had lesser incidence of oral lesions while the children did not show any significant difference. Oral candidosis and oral hairy leukoplakia showed a lower prevalence while oral warts and mucosal hyperpigmentation showed an insignificant increase. Other oral lesions did not show a difference in incidence. One limitation in the study was the absence of PI in all the patients’ drug combinations except for one. The incidence of oral lesions did not differ among children whether they were on HAART or not (Hamza et al, 2006).

This point has to be further investigated as some studies have shown a difference. One study showed no difference in the incidence in perinatally infected children (Okunser et al, 2003).

Higher prevalence of enlargement of parotid glands is seen in children and oral candidosis in adults (Greenspan, 1992). Oral warts has been associated with immune reconstitution (Shetty, 2000). The less common associations of HIV like enlarged parotid glands, necrotizing ulcerative gingivitis, recurrent ulcers, Bell’s palsy and herpes zoster show lesser differences between HAART therapy and the lack of it (EC Clearing House, 1993).

Markers of HIV 1 Dental practice has seen the HIV-1 virus infections commonly. Though the transmission of this infection to dental health care workers is low, the likelihood of treating these patients is high (Patton et al, 1999, p.1313). Protease inhibitors have changed the possibility of a death sentence to a chronic manageable disease. The HAART has slowed or reversed the loss of CD4+ cells or T helper lymphocytes which are a hallmark of HIV-1. HAART has to be instituted before the extensive immune system destruction (Patton et al, 1999, p. 1314). Patton also speaks of the extent of oral manifestations being associated with the CD4+ cell counts. Oral manifestations are seen when the CD4+ becomes less than 200 cells/mm³ , nine times more than in patients with more than 500 cells / mm³ (Patton et al, 1999, p. 1319). Oral candidosis and oral hairy leukoplakia were 11 times more likely to manifest in patients with severe immune suppression when CD4+ cells are less than 200/ mm³ than in patients with more than 500 cells. Glick’s study showed that the presence of oral lesions was indicative of the lower immune status (1994). 100% of patients with major aphthous ulceration, 93.5 % of Kaposi’s sarcoma, 86.9% with herpes simplex, 70.1% with oral hairy leukoplakia and 69.9 % with oral candidosis had a CD4+ count of less than 200 cells/ mm³ (Patton et al, 1999, p. 1320). Kaposi’s sarcoma is a marker of severe immune suppression and AIDS (CDC, 1993). The low cell counts are associated with high viral loads of more than 20000copies/mL. Similar conclusions could be made on a study on women (Greenspan, 2004, p. 145). The incidence of erythematous candidiasis fell from 5.48% to 2.99% and pseudomembranous candidiasis fell from 6.70% to 2.85%. No changes were seen in hairy leukoplakia or warts. Recurrence and incidence were reduced with HAART and recurrence is reduced without the influence of CD4 and HIV RNA (Greenspan, 2004, p. 145). Pseudomembranous candidiasis is associated with high viral load and low CD4 count. CD4 count had no influence on hairy leukoplakia. The sentinel role of oral lesions is once again proved.

Common organism in the oral pathology

The mucosatropic Human Papilloma Virus is commonly found in the oral area and genital tract of HIV positive patients (Shetty and Leigh, 2005). Infection can occur with or without mucosal pathology. Oral lesions include condyloma acuminata, focal epithelial hyperplasia, squamous cell carcinomas and verruca vulgaris or oral warts. HPV DNA , types 16 and 18, have been discovered in 20-30% of oral squamous cell carcinomas. HPV associated lesions occur when there is immune suppression. New additional types of oral lesions have been seen in 2.5-4% of HIV patients (Shetty and Leigh, 2005). Cauliflower and spiky warts containing type 7 have been described by Greenspan et al. Flat warts look like focal epithelial hyperplasia and contain types 13, 18 and 32. HPV DNA sequences were found in 67% of the specimens. Squamous cell carcinomas in HIV individuals have an earlier onset with aggressive course and a high rate of HPV DNA (Shetty and Leigh, 2005). HPV DNA was seen in the oral cavities of 2.6% of HIV negative people while 14.4% of HIV positive individuals showed HPV DNA (Coutlee et al, 1996). Usually HAART reduces the oral lesions. However paradoxical findings are now indicated. Increases in oral pathology has been seen in patients with HAART. The host defence against HPV may actually be adversely affected by the HAART (Shetty and Leigh, 2005). The HAART therapy provides for total viral suppression in 30-40% of the HIV population on treatment (AIDS Alert, 2008).

Conclusion

We have seen the relationship between the oral lesions seen in HIV/AIDS and the HAART therapy. Studies have been conducted the world over and many suggestions have come forth. Integrating dental management with nutrition care contributes to the improved systemic oral health and response to the HAART.

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