Our results indicated that there may be more than just sporadic cases of DNI among HIV-infected patients, since the risk of DNI after an HIV attack was significantly elevated even with free access to HAART. In our study, the overall incidence of DNI in HIV-infected patients in Taiwan was 57.01 (per 10000 person-years), the first time this has been estimated in the world. The incidence risk ratio as compared to the control group was 1.60. After adjusting for the confounders, the HR was 1.59 (P < 0.0001). After adjusting for the other risks, we found that the risk of having a deep neck infection increased by 59% post-HIV infection. The log rank test indicated that patients with HIV had a significantly higher incidence rate of DNI than the patients in the comparison cohort (P < 0.0001).
In this study, the mean observation duration was 3.94 years (range: 2–8 years). This duration of time was sufficient to observe the trend and change in the risk of DNI among the HIV-infected patients under HAART. If we compare the incidence rate by follow-up years in the study group with the control group, the incidence rate among patients without HIV infection was relatively stable at about 35.55 ± 1.53 (per 10000 person-years).
After having HIV, the incidence rate for DNI was 74.58 (per 10000 person-years) and the incidence risk ratio was 2.05 (P < 0.0001) in the first follow-up year. Both the incidence rate and incidence risk ratio were highest in the follow-up years. In theory, the incidence of DNI should increase gradually, following the viral replication and CD4+ cell decline of the HIV-infected patients. It is interesting that the incidence rate and relative risk of DNI gradually decreased in the HIV-infected patients throughout the follow-up period. As time passed, the incidence risk ratio became lower and lower. Beyond the 3-year follow-up, the incidence of DNI and risk ratio were still higher than the control group, but they were lower than the previous 3 years, even down to 45.08 (per 10000 person-years) and 1.26 (P = 0.1255), which was not significantly elevated as compared to the control group.
HAART could play a role in this unanticipated result. Although we can hypothesize that this result is largely due to the well-known immune restoration consequences of HAART , we also need to consider the other cofactors implicated in this reduced incidence of DNI. HIV-infected patients are apt to develop aggressive periodontal disease and the associated ulcerative gingivitis, which can result in marked gingival recession and other oral lesions . The increased risk of DNI could be the result of HIV damaging the immune system and decreasing resistance to oral infections, which was then further compounded by poor oral hygiene.
Even immune suppression for HIV-related cancer and related treatments may be a predisposing factor for DNI among HIV-infected patients. HAART has had a major impact on the reduction of plasma HIV RNA and the increase in peripheral CD4+ cells. It can also reduce the incidence of several opportunistic infections, including odontogenic infections and malignancies, especially AIDS-defining cancers [17, 18]. HAART may have the capacity of effectively reducing the incidence rate of DNI.
Because of the side effects and the need for taking HAART continuously at the outset, not all HIV-infected patients accept HAART immediately after their HIV diagnosis. The timing of the initiation of HAART and the regimens are based on the guidelines recommended in the United States . Following the gradual decrease in CD4 and increase in the virus, HIV-infected patients generally conform to the criteria and accept HAART. With more and more HIV-infected patients accepting HAART, the incidence of DNI and its relative risk should gradually decline to a steady level. This trend and the unexpected result suggested that HAART may decrease the risk of DNI among HIV-Infected patients.
Another possible consideration for the decrease in the incidence of DNI in the follow-up years may be the fact that the HIV patients whose immune systems were the most compromised did not survive, thereby decreasing the number of patients with the more severe immunity issues. We tried to evaluate the difference in the survival rates between the HIV patients with a history of DNI and the HIV patients without a history of DNI in order to rule out this hypothesis. In our study, there was no significant decrease in the survival rate of the patients with HIV who had suffered from DNI. On the other hand, there was a significant difference on the losses of follow-up between the study cohorts and control cohorts, so the time-decline in DNI rates on the HIV cohort may be explained by differences on the losses of follow-up in this study. Because of such a limitation, additional research is needed to examine the role of HAART in reducing the risk of DNI among HIV-infected patients.
The use of administrative data to assess the contribution of HIV infection to DNI is subject to several biases such as information bias and selection bias. For example, it is well known that patients with drug abuse have increased rates of periodontitis. It may cause the selection bias which might affect the result of the study. In order to avoid such a bias, we took the diseases which could be predisposing factors of DNI in previous studies including drug abuse as comorbidities for both the study and comparison cohorts. After adjusting for the patient’s comorbidities, the effect of the bias which had affected the HR could be minimized. Likewise co-infection by HPV in patients having sex with men may increase the rate of cancer of oral cavity. If it is the case, the risk of oral cancer might increase significantly in the patients with HIV in comparison to the controls. However, the incidence rate ratio between HIV-infected patients and the controls for oral cancer was 1.23 (95%CI = 0.63-2.41) in the present study. Hence, the effect of confounding variable of HPV infection in present study remains to be proved.
There were several limitations in the present study. First, the diagnosis of DNI was based on the diagnostic code registered by the physicians responsible for the treatment of the patients and was not corroborated by the investigators. Second, the risk of DNI after an HIV attack was severely underestimated, because all of the HIV-infected patients in this study were offered free access to HAART. The real risk of DNI among HIV-infected patients would need to be estimated with untreated patients, but political and ethical reasons prevent such a study in Taiwan. Nonetheless, we still successfully proved the elevated risk of DNI among HIV-infected patients even when they had free access to HAART. The influence of HAART on HIV-infected patients should be compared using untreated patients, but, of course, political and ethical reasons again prevent this study. Fortunately, the long-term trend could be clearly observed in this study. Additional investigations on this issue are needed. Third, although the Taiwanese government will provide all HIV-infected citizens with free access to HAART, the HIV-infected patients make their own decisions as to when to start HAART. The degree of compliance of the patients using HAART was also not covered in this study.