|Year : 2019 | Volume
| Issue : 1 | Page : 42-50
Craniofacial morphology of HIV infected adolescents on highly active antiretroviral therapy (HAART): An original research
Abhishek Singh Nayyar
Department of Oral Medicine and Radiology, Saraswati-Dhanwantari Dental College and Hospital and Post-Graduate Research Institute, Parbhani, Maharashtra, India
|Date of Web Publication||31-Jul-2019|
Dr. Abhishek Singh Nayyar
Department of Oral Medicine and Radiology, Saraswati-Dhanwantari Dental College and Hospital and Post-Graduate Research Institute, Parbhani, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Numerous studies have illustrated the therapeutic effects of the highly active antiretroviral therapy (HAART) while simultaneously leading to a plethora of associated adverse effects including changes in the craniofacial growth and development. The present study was planned to analyze the craniofacial morphology in adolescents by evaluating the skeletal cephalometric profile of the human immunodeficiency virus (HIV)-infected patients in this age group and comparing them with the HIV-negative controls. Methods: The present study was a planned case–control study that included 25 HIV-positive adolescent patients aged between 10 and 19 years (study group) who were compared with 25 age and sex-matched HIV-negative adolescent controls (control group). All the patients had been HIV-infected via vertical transmission with positive serology confirmed in two different tests and had been on HAART since they were born. Results: In the 10 to 12-year age group, positions of maxilla and mandible in the study group were found to be retruded in relation to the skull base when compared with the control group whereas in the 13 to 15 and 16 to 18-year age groups, maxilla was retruded slightly while the mandible was found to be protruded in the study group in relation to the skull base. Conclusion: Although the differences in majority of the measurements made were not found to be significant enough, the study highlighted the significance of further studies to be conducted in this regard, especially, the longitudinal study designs wherein the said variables can be studied on a follow-up basis to have an idea of the exact changes observed and their pattern in the included groups.
Keywords: Craniofacial morphology, HAART, HIV-positive adolescents
|How to cite this article:|
Nayyar AS. Craniofacial morphology of HIV infected adolescents on highly active antiretroviral therapy (HAART): An original research. J Med Trop 2019;21:42-50
|How to cite this URL:|
Nayyar AS. Craniofacial morphology of HIV infected adolescents on highly active antiretroviral therapy (HAART): An original research. J Med Trop [serial online] 2019 [cited 2019 Dec 13];21:42-50. Available from: http://www.jmedtropics.org/text.asp?2019/21/1/42/263750
| Introduction|| |
With the advent of the highly active antiretroviral therapy (HAART) in the 1990s, there has been a great improvement in the quality of life of the patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS).,, The adverse effects of combination of these antiretroviral drugs started to be identified through compromised physiologic functions in various systems and organs much later. The changes identified in the pediatric group included mitochondrial toxicity, hepatic and renal toxicity, insulin resistance, hypertension, and cardiac dysfunction with an increased risk for cardiovascular diseases and decreased bone mineral density.,,,,,,,,,,,,,,, Dental considerations in patients with HIV/AIDS have, since then, concentrated more on the prevalence, diagnosis, and treatment of the varied oral presentations seen due to immunosuppression.,,, Furthermore, such changes have been recognized not only in the teeth and their associated structures but also in the craniofacial growth pattern seen in the HIV-infected/AIDS patients in the younger age groups who are on HAART., Several studies and various authors have illustrated a plethora of chronic systemic diseases leading to changes in the craniofacial growth and development,,,,,,,, however, there has been a relative dearth of such studies on the HIV-infected/AIDS patients. Also, there is no way to estimate whether disease or its treatment does have an impact on the craniofacial growth and development. Relatively fewer studies have pointed out about the adverse effects of HAART on the HIV-infected/AIDS patients, especially, the adolescents with HIV. In agreement with most of the recent concerns raised in this particular area of research, the present study was carried out to analyze the craniofacial morphology in adolescents by evaluating the skeletal cephalometric profile of the HIV-infected patients in this age group wherein HIV was transmitted via vertical transmission and, hence, submitted to HAART and comparing them with the HIV-negative controls.
| Materials and methods|| |
The present study was a planned case–control study that included adolescent patients seropositive for HIV and the HIV-negative controls who attended the outpatient department for orthodontic treatment over a period of 1 year and selected randomly. The protocol of the study was approved by the University Research Ethics Committee. Twenty-five HIV-positive adolescent patients aged between 10 and 18 years (study group) were selected and then compared with 25 age and sex-matched HIV-negative adolescent controls (control group). All the patients had been HIV infected via vertical transmission with positive serology confirmed in two different tests and had been on HAART since birth. The patients were informed about the study protocol and needed to conduct the study; a written, informed consent of the patients was obtained. The patients were categorized into three age ranges (10–12, 13–15, and 16–18 years). The patients who were undergoing any long-term systemic therapy for severe chronic diseases (except AIDS in study group) and who had received radio/chemotherapy or any previous orthodontic and orthopedic treatment in the past were excluded from the study. The diagnostic aids used for orthodontic documentation included facial photographs, digital orthopantomographs, lateral tele-radiographs, and study models. For the present study, tele-radiographs were used and over them, various cephalometric points of the hard profile were identified and used for evaluating the craniofacial morphology. Cephalometric tracings of 18 (linear and angular) measurements on tele-radiographs were done. The mean values of each measurement was then compared between the two groups based on their specific age range. Overall, 14 points and 18 (linear and angular) measurements were used for the assessment of the craniofacial growth pattern, all based on the previous studies conducted by various authors in the past. To decrease the possibility of errors, cephalometric points and measurements were traced using two different methods. In the initial (semiautomated) method, a dental radiologist used a Compaq Presario microcomputer (specifications: 1.7 GHz, 768 MB RAM, HD 30 GB, Windows XP SP3; Pentium 4; Hewlett Packard, Palo Alto, CA, USA) and Radiocef Studio Software (RadioMemory, Belo Horizonte, Brazil). The cephalometric landmarks were marked manually whereas the software traced the said lines and angles including the relevant measurements. In the second (manual) method, for each radiograph, an orthodontist used a transparent acetate sheet (specifications: Ultraphan; 3M Unitek, Monrovia, CA, USA) measuring 8 × 3 × 10 inches in dimension and 0.003 inches in thickness with a propelling pencil with 0.5-mm thick graphite to mark the required points. All the measurements were listed into a spreadsheet (specifications: Microsoft Office Excel 2007; Microsoft, Redmond, WA, USA) to get the mean values of each angle and linear measurement calculated by the semiautomated and manual methodologies. The data obtained for the study and control groups were compared.
| Statistical analysis|| |
The data was analyzed by using the Epiinfo software (Version 7.2, Atlanta, GA, USA) whereas Bartlett test was performed to verify the homogeneity of the variances (P = 0.05). For variables without a normal distribution, Wilcoxon test was applied to determine the reliability of the agreement between the two measurement methodologies; intraclass correlation coefficient test was used for the conduct of statistical analysis. The significance level was put at 0.05 or 5%. P < 0.05 was considered statistically significant.
| Results|| |
Twenty-five patients were evaluated in the study group of which 10 were girls and 15 were boys, all aged between 10 and 18 years of age with a mean age of 14 years. All the study participants had been diagnosed with HIV since birth and were being treated with HAART from the first year of life. During clinical evaluation, a mean CD4+ cell count of 752 cells/mm3 (minimum, 180 cells/mm3, and maximum, 1727 cells/mm3) was observed in the study group. Two patients detected had no viral load whereas the said patients were also the ones to have CD4+ cell count within the normal range (273 and 180 cells/mm3). Four of the patients used first-line drugs composed of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-NRTI. Twelve patients used second-line combinations including two NRTIs with one protease inhibitor (PI) with ritonavir boosters. Two patients used two NRTIs along with one PI. Three patients used the following combinations: two NRTIs and one PI along with ritonavir boosters along with one PI; two NRTIs with one PI and one integrase inhibitor; and three NRTIs and one PI with ritonavir boosters in the third patient. With reference to the methodologies used for taking the cephalometric values, all the methods used were in strong agreement to each other for almost all the variables studied [Table 1] and had high intraclass correlation coefficient values [Table 2] except Co-A, SN.ANSPNS, and SNB, which, too, had good agreement of 60%. Nevertheless, the agreement was positive also for these variables as the P values obtained were found to be statistically significant. The cephalometric measurements of the study and control groups were compared according to the age ranges included as 10 to 12, 13 to 15, and 16 to 18 years of age [Table 3],[Table 4],[Table 5]. In the 10 to 12-year age group, when considering the mean values, positions of maxilla and mandible in the study group were found to be retruded in relation to the skull base when compared with the control group. Also, the growth pattern in the study group was seen more horizontal with effective size of the bone bases increased than as seen for the control group. Despite the same, though, the difference observed was not found to be statistically significant except for the palatal plane inclination as is seen in [Table 3]. With regard to the mean values in the 13 to 15-year age group, the maxilla was slightly retruded whereas the mandible was found to be protruded in the study group in relation to the base of the skull when compared with the control group. Also, the former had a decreased effective size of the maxillary bone with an increased effective size of the mandible than the latter group. Furthermore, in the 13 to 15-year age group, growth patterns were almost similar in both the study and the control groups. None of the variables related to the maxillary and mandibular positions in an anteroposterior direction, growth pattern, and effective linear measurements in this particular age group showed statistically significant differences between the study and control groups [Table 4]. With regard to the mean values in the 16 to 18-year age group, the position of maxilla in the study group was retruded whereas the mandible protruded in relation to the skull base when compared with the control group. Although, the former had an effective maxillary size smaller than that seen in the latter group, the effective mandibular size was similar between the two groups. Furthermore, the growth pattern was more horizontal in the study group than in the control group, though, the only statistically significant difference found was in the position of the maxilla in the anteroposterior direction (SNA) [Table 5].
|Table 2: Intraclass correlation coefficient (ICC) analysis showing comparison between the two methods of cephalometric measurements|
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|Table 3: Comparison of cephalometric measurements of the study and control groups in the 10 to 12-year age groups|
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|Table 4: Comparison of cephalometric measurements of the study and control groups in the 13 to 15-year age groups|
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|Table 5: Comparison of cephalometric measurements of the study and control groups in the 16 to 18-year age groups|
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| Discussion|| |
The results of the present study revealed that two of the measurements had statistically significant differences, namely, the angle between the palatal plane and base of skull (SN.ANSPNS) and the angle demonstrating position of the maxilla in anteroposterior direction in relation to the base of the skull (SNA). Furthermore, in the 10 to 12 years of age range, the SN.ANSPNS values showed rotation of the maxilla (palatal plane) that was increased in the HIV-positive patients as against the HIV-negative age and sex-matched controls wherein these values were seen to diminish. Also, angle SNA was shown to significantly decrease in the 13 to 15 and 16 to 18-year age groups wherein the reduction in measurements was interpreted as retrusion of the maxillary bone in accordance with the study conducted previously. Furthermore, although, the present study was not longitudinal, three interpretations could be perceived for this type of craniofacial change observed in the study group in the present study with reference to the previously conducted studies, with the first and the most significant interpretation for this type of change seen in the study group was a consequence of the respiratory pattern seen in the HIV-positive adolescents that gets compromised in this group of patients due to recurrent airway infections.,,,,,,,,, Adolescents seropositive for HIV, now, attend the dental hospitals and demand full treatment for their oral health conditions.,, Studies evaluating growth and development of face, have identified that up to 5 years of age, craniometric dimensions get established along with the maxillofacial skeleton and a significant increase in the height and width of the jaws is, also, observed.,,,,,,, However, the greatest gain in growth occurs only after 6 years of age with a continuous increase in jaw length and facial height, width, and depth observed until the craniofacial dimensions reach maturity and become more or less stable during the adolescence between 13 and 15 years of age., Because of the drawbacks inherent in a cross-sectional study, differences that could be found in different age groups in the present study suggested continuous craniofacial growth changes with the whole face growing vertically and horizontally in both the groups. SNA may, also, decrease in patients with compromised respiratory function of upper airway due to habits such as mouth breathing., HIV infection being associated or not associated with varying states of immune activation and inflammatory processes can also affect the process osteoclastogenesis increasing rate of apoptosis of primary osteoblasts, decreasing calcium deposition and alkaline phosphatase activity, diminishing specific bone proteins, and compromising the differentiation of the mesenchymal cells into active bone-forming osteoblasts.,,,, The long-term use of HAART might also be responsible for the systemic changes that affect growth of these seropositive individuals., HAART emerged as a solution to deleterious effects caused by the virus by lowering the circulating viral load. The immunologic reconstitution induced by the use of HAART, expressed by increase in CD4 T lymphocytes, allows these patients to be clinically stable with reductions in the incidence of opportunistic infections that further compromise the nutritional status of these group of individuals and bring malnutrition. Although, gains in height and weight among the HIV patients on HAART are vital and calculable, these gains are relatively less marked than the respective gains seen in the HIV-negative controls. The results of the present study were not supportive of changes in the other linear and angular values included that were found to be statistically insignificant when compared with the control group; however, it was possible to identify a trend toward a decrease in the linear measurements of the maxilla and mandible along with the base of the skull in the study patients, especially, in the age groups of 13 to 15 and 16 to 18 years. In the present study, among the said variables in the mentioned age groups, 14 angular and linear measurements were found to be lower than those seen in the HIV-negative controls. This type of difference could also be observed in five of the measurements in the 10 to 12-year age group as against in seven of the measurements in the 13 to 15-year age group.
| Conclusion|| |
The differences in majority of the measurements made in the HIV-infected and control groups in the present study were not found to be significant enough to generate statistically significant difference in the craniofacial growth pattern studied. Although, 18 comparisons were studied in the included study and control groups in the present study, only two of the measurements had statistically significant differences with marginally significant P values. As no overall differences could be observed between the two groups in the present study, it could be hypothesized that the beneficial effects of HAART overcome the associated adverse effects of the said therapy. The results of the present study, though, highlighted the significance of further studies to be conducted in this regard, especially, the longitudinal study designs wherein the said variables can be studied on a follow-up basis in longitudinal studies to have an idea of the exact changes observed and their pattern in the included groups.
Limitations of the present study
The present study was based on a cross-sectional study design and could not establish a cause and effect relationship that can be considered as the major limitation of the present study. Another limitation and confounding factor in the present study was that only tele-radiographs of adolescents who were referred for orthodontic treatment were included in the present study and, consequently, they had some amount of deviation from normality in both the groups included. Furthermore, it is difficult to correctly predict whether such changes are seen as a result of the active disease process and the reactive immune activation and inflammatory processes seen due to HIV infection or due to HAART as most of the HIV-infected patients who are under medical treatment are already under HAART.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chiappini E, Galli L, Tovo PA. Cancer rates after year 2000 significantly decrease in children with peri-natal HIV infection: a study by the Italian Register for HIV infection in children. J Clin Oncol 2007;25:97-101.
De martino M, Tovo PA, Balducci M. Reduction in mortality with availability of anti-retroviral therapy for children with peri-natal HIV-1 infection: Italian Register for HIV infection in children and the Italian National AIDS Registry. J Am Med Assoc 2000;248:190-7.
Gortmaker S, Hughes M, Cervia J. Effects of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med 2001;345:1522-8.
Jain RG, Furfine ES, Pedneault L, White AJ, Lenhard JM. Metabolic complications associated with anti-retroviral therapy. Antivir Res 2001;51:151-77.
Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM. Metabolic complications and treatment of peri-natally HIV infected adolescents. J Int AIDS Soc 2013;16:18600.
Orellana RV, Fonseca HA, Monteiro AM, Ortega KL, Gallottini MH, Gidlund M et al.
Association of auto-antibodies anti-OxLDL and markers of inflammation with stage of HIV infection. Int J Cardiol 2013;168:1610-2.
Liu K, Sun Y, Liu D, Yin J, Qiao L, Shi Y et al.
Mitochondrial toxicity studied with the PBMC of children from the Chinese national pediatric highly active anti-retroviral therapy cohort. PLoS One 2013;8:e57223.
Miro O, Villarroya J, Garrabou G, Lopez S, Rodriguez de la Concepcion M, Pedrol E et al.
In-vivo effects of highly active anti-retroviral therapies containing the protease inhibitor nelfinavir on mitochondrially driven apoptosis. Antivir Ther 2005;10:945-51.
Abrescia N, D’Abbraccio M, Figoni M, Busto A, Maddaloni A, De Marco M. Hepatotoxicity of anti-retroviral drugs. Curr Pharm Des 2005;11:3697-710.
Aurpibul L, Bunupuradah T, Sophan S, Boettiger D, Wati DK, Nguyen LV et al.
TREAT Asia Pediatric HIV Observational Database: prevalence and incidence of liver dysfunction and assessment of biomarkers of liver disease in HIV-infected Asian children. Pediatr Infect Dis J 2015;34:e153-8.
Fortuny C, Deyà-Martínez Á, Chiappini E, Galli L, de Martino M, Noguera-Julian A. Metabolic and renal adverse effects of anti-retroviral therapy in HIV-infected children and adolescents. Pediatr Infect Dis J 2015;34:S36-43.
Innes S, Abdullah KL, Haubrich R, Cotton MF, Browne SH. High prevalence of dyslipidemia and insulin resistance in HIV-infected pre-pubertal African children on anti-retroviral therapy. Pediatr Infect Dis J 2016;35:e1-7.
Bwakura-Dangarembizi M, Musiime V, Szubert AJ, Prendergast AJ, Gomo ZA, Thomason MJ et al.
ARROW Trial Team: prevalence of lipodystrophy and metabolic abnormalities in HIV-infected African children after 3 years on first-line anti-retroviral therapy. Pediatr Infect Dis J 2015;34:e23-31.
Chatterton-Kirchmeier S, Camacho-Gonzalez AF, McCracken CE, Chakraborty R, Batisky DL. Increased prevalence of elevated blood pressures in HIV-infected children, adolescents and young adults. Pediatr Infect Dis J 2015;34:610-4.
Noguera A, Fortuny C, Munoz-Almagro C. Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to anti-retrovirals. Pediatrics 2004;114:e598-603.
Giaquinto C, Rampon O, Torresan S. Lactic acid levels in infant exposed to anti-retrovirals during fetal life [Abstract 941]. 11th Conference on retroviruses and opportunistic infections, 2004, San Francisco, USA.
Namuyonga J, Lubega S, Musiime V, Lwabi P, Lubega I. Cardiac dysfunction among Ugandan HIV-infected children on anti-retroviral therapy. Pediatr Infect Dis J 2016;35:e85-8.
Sainz T, Alvarez-Fuente M, Navarro ML, Dıaz L, Rojo P, Blazquez D et al.
Subclinical atherosclerosis and markers of immune activation in HIV-infected children and adolescents: the CaroVIH Study, Madrid Cohort of HIV-infected children and adolescents integrated in the pediatric branch of the Spanish National AIDS Network (CoRISPE). J Acquir Immune Defic Syndr 2014;65:42-9.
Guerreiro da Silva Júnior N, Pedreira EN, Tuji FM, Warmling LV, Ortega KL. Prevalence of calcified carotid artery atheromas in panoramic radiographs of HIV-positive patients undergoing anti-retroviral treatment: A retrospective study. Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:67-74.
Ortega KL, Vale DA, Magalhães MH. Impact of PI and NNRTI HAART-based therapy on oral lesions of Brazilian HIV-infected patients. J Oral Pathol Med 2009;38:489-94.
Ortega KL, Rezende NP, Magalhães MH. Diagnosing secondary syphilis in a patient with HIV. Br J Oral Maxillofac Surg 2009;47:169-70.
Ortega KL, Rezende NP, Lotufo MA, Magalhães MH. Mandibular lesion in HIV-positive patient. J Oral Maxillofac Surg 2008;66:2140-4.
Francischini E, Martins FM, Braz-Silva PH, Magalhães MH, Ortega KL. HIV-associated oral plasmablastic lymphoma and role of adherence to highly active anti-retroviral therapy. Int J STD AIDS 2010;21:68-70.
Cruz ML, Cardoso CA. Peri-natally infected adolescents living with human immunodeficiency virus (peri-natally human immunodeficiencyvirus). World J Virol 2015;4:277-84.
Stagi S, Galli L, Cecchi C, Chiappini E, Losi S, Gattinara CG et al.
Final height in patients peri-natally infected with human immunodeficiency virus. Horm Res Paediatr 2010;74:165-71.
El-Bialy T, Aboul-Azm SF, El-Sakhawy M. Study of craniofacial morphology and skeletal maturation in juvenile diabetics (Type I). Am J Orthod Dentofacial Orthop 2000;118:189-95.
Sadeghianrizi A, Forsberg CM, Marcus C, Dahllöf G. Craniofacial development in obese adolescents. Eur J Orthod 2005;27:550-5.
Orup HI Jr, Holmes LB, Keith DA, Coull BA. Craniofacial skeletal deviations following in-utero exposure to the anti-convulsant phenytoin: monotherapy and polytherapy. Orthod Craniofac Res 2003;6:2-19.
Amini F, Jafari A, Eslamian L, Sharifzadeh S. A cephalometric study on craniofacial morphology of Iranian children with beta thalassemia major. Orthod Craniofac Res 2007;10:36-44.
Gjorup H, Kjaer I, Sonnesen L, Haubek D, Beck-Nielsen SS, Hintze H et al.
Craniofacial morphology in patients with hypophosphatemic rickets: cephalometric study focusing on differences between bone of cartilaginous and intra-membranous origin. Am J Med Genet A 2011;155A:2654-60.
Fjeld MG, Arvidsson LZ, Stabrun AE, Birkeland K, Larheim TA, Ogaard B. Average craniofacial development from 6 to 35 years of age in mixed group of patients with juvenile idiopathic arthritis. Acta Odontol Scand 2009;67:153-60.
Al-Thomali Y, El-Bialy TH. Cephalometric craniofacial features of growing patients with chronic renal failure. Arch Oral Biol 2012;57:257-63.
Niles DG, Rynearson RD, Baum M, Neufeld RD, Caruso JM. A study of craniofacial growth in infant heart transplant recipients receiving cyclosporine. J Heart Lung Transplant 2000;19:231-9.
Oliveira MA, Gallottini M, Pallos D, Maluf PS, Jablonka F, Ortega KL. The success of endosseous implants in human immunodeficiency virus-positive patients receiving anti-retroviral therapy: a pilot study. J Am Dent Assoc 2011;142:1010-6.
Trigueiro M, Tedeschi-Oliveira SV, Melani RF, Ortega KL. An assessment of adverse effects of anti-retroviral therapy on development of HIV positive children by observation of dental mineralization chronology. J Oral Pathol Med 2010;39:35-40.
Hsieh YJ, Darvann TA, Hermann NV, Larsen P, Liao YF, Bjoern- Joergensen J et al.
Facial morphology in children and adolescents with juvenile idiopathic arthritis and moderate to severe temporomandibular joint involvement. Am J Orthod Dentofacial Orthop 2016;149:182-91.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]