Introduction
In this study, we aimed to analyze craniofacial morphology by assessing the skeletal cephalometric profiles of HIV-positive patients receiving antiretroviral therapy.
Methods
For this study, 21 HIV-positive patients aged between 6 and 17 years (study group) were selected and compared with 21 normoreactive patients (control group), paired by sex and age. The patients were also divided into 3 age ranges (6-8, 9-12, and 13-17 years) considering the pubertal growth spurt as the central event. Eighteen (linear and angular) measurements were traced on teleradiographs by using 2 methodologies. The mean values of each measurement were compared between the study and control groups by age range.
Results
The majority of the measurements checked in the HIV-positive children and adolescents for the 13-to-17 year age range were diminished, but not enough to generate a statistically significant difference in craniofacial growth. Statistically significant differences ( P <0.05) were found only in the inclination of the palatal plane (6-8 years) and the position of the maxilla in the anteroposterior direction (13-17 years).
Conclusions
These results led us to conclude that some cephalometric measurements of HIV-positive children and adolescents may be similar to those of normoreactive subjects.
Highlights
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The craniofacial morphology of HIV+ patients receiving HAART was studied.
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From 6 to 8 years of age, rotation of the maxilla (palatal plane) was greater in HIV+ patients.
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From 13 to 17 years, HIV+ patients had retrusion of the maxillary bone.
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The HIV+ group seems to have a similar cephalometric profile compared with the control group.
With the implementation of highly active antiretroviral therapy (HAART) in the 1990s, patients with human immunodeficiency virus (HIV+) experienced a significant increase in their quality and expectation of life. But in a short while, the adverse effects of the combination of antiretroviral drugs began to be identified through the compromised physiologic functions in several systems and organs.
Although most reports on the adverse effects of the medication were related to adults, HIV+ children have also been affected. These changes identified in the pediatric population include mitochondrial toxicity, lipodystrophy, dyslipidemias and insulin resistance, hypertension, liver dysfunction, cardiac dysfunction, increased risk for cardiovascular and cerebrovascular diseases, renal toxicity, and low bone mineral density.
Perinatally, HIV infected children also showed a growth deficit resulting in reduced height. Stagi et al stated that “the losses in stature accumulated throughout the total period of childhood and adolescence may contribute to the reduced final height” of perinatally HIV infected patients.
Because these children had reduced bone mineral density, the use of HAART appeared to increase the complications as a result of the low bone mineral density. Since this population is at a stage of growth and development, it is natural that these complications are potentially more severe than they are in adults.
Outpatient dental treatment of patients with HIV/AIDS was initially concentrated on diagnosis, epidemiology, and treatment of oral manifestations caused by immunodepression. With the increased survival and immunologic reconstitution making the opportunist manifestations unfeasible, now the questions relative to the oral health of these patients are focused on their conventional dental management under the deleterious effects caused on various organs and systems by both the medication and the virus itself.
Clinical studies have been conducted to verify the feasibility of dental treatments that act on mineralized tissues, since these may be a new source of concern for dentists treating patients undergoing HAART. Trigueiro et al pointed out a change in the development of mineralized tissues in the oral region of HIV-infected children; they found a delayed dental age compared with chronologic age, including a positive association between antiretroviral therapy and delay in the chronology of tooth mineralization.
Thus, it is possible that changes may be verified not only in teeth, but also in the craniofacial growth pattern of HIV+ children and adolescents undergoing antiretroviral therapy.
Several studies have demonstrated the capacity of medications and chronic systemic diseases to lead to changes in craniofacial growth and development. However, no such studies of HIV/AIDS patients were found; therefore, there is no way to estimate whether the disease or its treatment can influence craniofacial growth.
Recent studies have pointed out that there are few studies about children and adolescents with HIV, and particularly about the adverse effects of HAART on this population. At the 7th World Workshop on Oral health and Disease in AIDS, the researchers identified the need for better knowledge about the orofacial health problems of HIV+ children.
In agreement with the most recent concerns raised in this area of research, the aims of this study were to analyze the craniofacial morphology by evaluating the skeletal cephalometric profile of HIV+ patients, all infected by vertical transmission and submitted to antiretroviral therapy and to compare them with normoreactive patients. We justified the use of a pilot study to verify the need for longitudinal research.
Material and methods
A case-control study was conducted with a convenience sample of consecutive patients seropositive for HIV and normoreactive patients who attended a dental office in São Paulo, Brazil, for orthodontic treatment during 12 months. The protocol of this study was approved by the local research ethics committee.
The study group was composed of 21 patients of both sexes aged between 6 and 17 years. All patients were vertically HIV infected, with positive serology confirmed in at least 2 different tests, and had been undergoing antiretroviral therapy since they were born.
The control group included 21 normoreactive patients matched by sex and age with the study patients, all attending a private dental office in São Paulo, Brazil, for orthodontic treatment. Anamnesis and clinical examinations were the sources of information for verifying the absence of chronic systemic diseases and prolonged use of drugs among the patients.
The patients excluded from the study were those undergoing any long-term systemic therapy for chronic diseases (except AIDS in the study group), who had received radiotherapy, chemotherapy, or any previous orthodontic or orthopedic treatment, and who had any neuropsychomotor impairment.
Orthodontic documentation for diagnosis included facial photographs (2 front views, 1 profile), panoramic radiograph, lateral teleradiograph, and study casts.
For this research, we used teleradiographs only, on which cephalometric points of the hard profile were identified and used for measuring the craniofacial morphology. In total, 14 points and 18 (linear and angular) measurements were used, all based on the studies by El-Bialy et al, Thordarson et al, Niles et al, Fjeld et al, Sadeghianrizi et al, Orup et al, Al-Thomali and El-Bialy, Amini et al, and Gjorup et al ( Fig ).
| S-N (mm) | Linear distance between points S and N. Length of the anterior cranial base. |
|---|---|
| S-Ba (mm) | Linear distance between points S and Ba. Linear size of the posterior base of the skull. |
| Ba-N (mm) | Linear distance between points Ba and N. Linear size of the posterior base of the skull. |
| SNA (°) | Angle between lines SN and NA. Anteroposterior projection of the maxilla. |
| SN.ANSPNS (°) | Angle formed between line from point S to point N in the palatal plane. Inclination of the palatal plane in relation to the base of the skull. |
| N-ANS (mm) | Linear distance between points N and ANS. Anteroposterior linear facial height. |
| Co-A (mm) | Linear distance between points Co and A. Effective length of the maxilla. |
| SNB (°) | Angle determined by the intersection of lines SN and NB: Anteroposterior projection of the mandible. |
| PoOr.NPg (°) | Angle between the Frankfort plane and facial line. Position of menton in the horizontal direction. |
| Co-Gn (mm) | Linear distance between points Co and Gn. Effective length of the mandible. |
| Co-Go (mm) | Linear distance between points Co and Go. Height of the mandibular ramus. |
| Go-Gn (mm) | Linear distance between points Go and Gn. Length of the mandibular body. |
| ANB (°) | Angle determined by the intersection of lines NA and NB: Relative position of the mandible to the maxilla. |
| ANS.Me (mm) | Linear distance between points ANS and Me. Anterior-inferior facial height. |
| ANSPNS.GoMe (°) | Angle between the palatal and mandibular planes. Angular relationship between palatal plane (ANS- PNS) and mandibular body (Go-Me). |
| PoOr.GoMe (°) | Angle between Frankfort plane and line Go-Me. Mandibular plane angle. Indicates growth vector. |
| SN.GoGn (°) | Angle formed between line from points S to N and the line from points Go to Gn. Degree of mandibular rotation in relation to the base of the skull. |
| SN.Gn | Angle formed between the intersection of the line from points S to N and the line passing through points N and Gn. Indicates growth vector. |
To minimize measurement errors, the cephalometric points and measurements were traced with 2 methodologies.
In the first (semiautomated) methodology for tracing the cephalograms, a dental radiology specialist used a Compaq Presario microcomputer (1.7 Ghz, 768 Mb RAM, HD of 30 Gb, Windows XP SP3; Pentium 4; Hewlett Packard, Palo Alto, Ca) and Radiocef Studio 2 software (RadioMemory, Belo Horizonte, Brazil). The cephalometric points were manually marked, and the software traced the lines and angles, including pertinent measurements.
In the second (manual) methodology for each radiograph, a specialist in orthodontics used a transparent acetate sheet (Ultraphan; 3M Unitek, Monrovia, Calif) measuring 8 × 10 in and 0.003 in thick as well as a propelling pencil (Pentel do Brasil, Diadema, Brazil) with 0.5-mm thick graphite to trace the points, with the measurements performed manually.
All measurements were entered into a spreadsheet (Microsoft Office Excel 2007; Microsoft, Redmond, Wash) to obtain the arithmetic mean values of each angle and linear measurement found by the semiautomated and manual methodologies. The data obtained for the study and control groups were compared.
The patients were also subdivided according to the pubertal growth spurt, and the subgroups were compared. We considered that the pubertal growth spurt in girls occurred from 8 years of age, reaching its peak at 12 years, whereas in boys it occurred from 9 years and reached its peak at 14 years. Thus, the time interval between 9 and 12 years was chosen as the main growth spurt period for both sexes. Consequently, 2 other age ranges were defined: before the growth spurt (6-8 years old) and after the growth spurt (13-17 years old).
The data were analyzed by using the Epiinfo software, and the Bartlett test was performed to verify the homogeneity of variances ( P >0.05). For variables without a normal distribution, the Wilcoxon test was applied. The significance level was set at 0.05 or 5%.
To determine the reliability of agreement between the 2 measurement methodologies, the intraclass correlation coefficient was used for statistical analysis.
Results
Twenty-one subjects were evaluated in the study group, of whom 10 were girls and 11 were boys, all aged between 6 and 17 years (mean age, 11.7 years). All had been diagnosed with HIV at birth and treated with antiretroviral therapy since the first year of life. At the time of clinical evaluation, the mean count of CD4+ T lymphocytes in the study group was 752 cells per cubic millimeter (minimum, 180 cells/mm 3 ; maximum, 1727 cells/mm 3 ). Only 2 patients had no undetected viral load (5418 and 41,395 copies). These patients were also the only ones to have CD4+ T lymphocyte counts out of the normal range (273 and 180 cells/mm 3 ). Four used front-line drugs composed of 2 nucleoside reverse transcriptase inhibitors and 1 nonnucleoside reverse transcriptase inhibitor. Twelve patients used second-line combinations (2 nucleoside reverse transcriptase inhibitors plus 1 protease inhibitor with ritonavir booster). Two patients used 2 nucleoside reverse transcriptase inhibitors plus 1 protease inhibitor. Three patients used the following combinations: 2 nucleoside reverse transcriptase inhibitors plus 1 protease inhibitor with ritonavir booster plus 1 protease inhibitor; 2 nucleoside reverse transcriptase inhibitors plus 1 protease inhibitor plus 1 integrase inhibitor; 3 nucleoside reverse transcriptase inhibitors plus 1 protease inhibitor with ritonavir booster.
With regard to the methodologies used for evaluating the cephalometric measurements, we observed that the methods agreed with each other for almost all variables, with high intraclass correlation coefficient values ( Table II ).
| Variable | ICC | P value | 95% CI | |
|---|---|---|---|---|
| N-ANS | 100% | 0.0000 | 1.00 | 1.00 |
| Co-Gn | 92% | 0.0000 | 0.86 | 0.96 |
| Co-Go | 66% | 0.0000 | 0.44 | 0.80 |
| S-N | 98% | 0.0000 | 0.96 | 0.99 |
| S-Ba | 74% | 0.0000 | 0.56 | 0.85 |
| Ba-N | 93% | 0.0000 | 0.87 | 0.96 |
| ANS-Me | 100% | 0.0000 | 1.00 | 1.00 |
| Co-A | 25% | 0.0550 | −0.06 | 0.51 |
| Go-Gn | 94% | 0.0000 | 0.89 | 0.97 |
| SNA | 87% | 0.0000 | 0.78 | 0.93 |
| ANSPNS.GoMe | 100% | 0.0000 | 1.00 | 1.00 |
| SN.ANSPNS | 48% | 0.0006 | 0.21 | 0.68 |
| SNB | 57% | 0.0000 | 0.32 | 0.74 |
| SN.GoGn | 100% | 0.0000 | 1.00 | 1.00 |
| PoOr.NPg | 78% | 0.0000 | 0.63 | 0.88 |
| PoOr.GoMe | 90% | 0.0000 | 0.82 | 0.94 |
| SNGn | 90% | 0.0000 | 0.82 | 0.94 |
| ANB | 83% | 0.0000 | 0.70 | 0.90 |
The exceptions were the variables Co-A, SN.ANSPNS, and SNB, which had agreement of 60%. Nevertheless, we affirmed that the agreement was positive for SN.ANSPNS and SNB, since the P values were statistically significant (less than 0.05). As for the Co-A, the P value was marginally out of the significance range ( Table II ).
The cephalometric measurements of the study and control groups were compared according to the different age groups, as listed in Tables III, IV, and V .
| Measurement | SG (n = 3) | CG (n = 3) | P value | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Median | SD | Q1 | Q3 | 95% CI | Min | Max | Mean | Median | SD | Q1 | Q3 | 95% CI | Min | Max | ||||
| Inf | Sup | Inf | Sup | ||||||||||||||||
| SNA | 79.5 | 79.1 | 2.3 | 82.0 | 77.4 | 73.8 | 85.2 | 77.4 | 82.0 | 83.5 | 82.5 | 3.5 | 87.3 | 80.5 | 74.7 | 92.2 | 80.5 | 87.3 | 0.1266 |
| SN.ANSPNS | 10.1 | 10.3 | 0.4 | 10.4 | 9.7 | 9.3 | 11.0 | 9.7 | 10.4 | 6.6 | 7.0 | 1.1 | 7.4 | 5.4 | 3.9 | 9.3 | 5.4 | 7.4 | 0.0495 |
| N-ANS | 46.7 | 45.0 | 4.3 | 51.5 | 43.5 | 36.1 | 57.2 | 43.5 | 51.5 | 43.5 | 46.5 | 9.4 | 51.0 | 33.0 | 20.2 | 66.8 | 33.0 | 51.0 | 0.8273 |
| Co-A | 83.3 | 84.3 | 3.9 | 86.5 | 79.0 | 73.7 | 92.8 | 79.0 | 86.5 | 81.0 | 81.8 | 5.4 | 86.0 | 75.3 | 67.6 | 94.4 | 75.3 | 86.0 | 0.5127 |
| SNB | 33.3 | 31.5 | 6.4 | 40.5 | 28.0 | 17.3 | 49.4 | 28.0 | 40.5 | 34.3 | 33.0 | 2.8 | 37.5 | 32.5 | 27.5 | 41.2 | 32.5 | 37.5 | 0.8273 |
| PoOr.NPg | 24.4 | 23.3 | 5.6 | 30.5 | 19.4 | 10.4 | 38.4 | 19.4 | 30.5 | 24.8 | 26.1 | 2.3 | 26.1 | 22.2 | 19.2 | 30.4 | 22.2 | 26.1 | 0.8273 |
| Co-Gn | 105.7 | 103.8 | 3.8 | 110.1 | 103.3 | 96.3 | 115.2 | 103.3 | 110.1 | 99.1 | 103.5 | 11.1 | 107.4 | 86.5 | 71.5 | 126.8 | 86.5 | 107.4 | 0.5127 |
| Co-Go | 48.9 | 48.8 | 0.3 | 49.2 | 48.6 | 48.1 | 49.6 | 48.6 | 49.2 | 45.8 | 47.5 | 6.1 | 50.9 | 39.1 | 30.7 | 61.0 | 39.1 | 50.9 | 0.5127 |
| Go-Gn | 68.3 | 66.3 | 5.6 | 74.6 | 63.9 | 54.3 | 82.3 | 63.9 | 74.6 | 65.2 | 63.7 | 8.1 | 73.9 | 58.0 | 45.1 | 85.3 | 58.0 | 73.9 | 0.2752 |
| S-N | 66.1 | 67.6 | 4.6 | 69.8 | 61.0 | 54.8 | 77.5 | 61.0 | 69.8 | 62.6 | 64.0 | 5.4 | 67.1 | 56.6 | 49.2 | 75.9 | 56.6 | 67.1 | 0.2752 |
| Ba-N | 100.0 | 103.5 | 7.1 | 104.7 | 91.8 | 82.3 | 117.7 | 91.8 | 104.7 | 93.4 | 99.2 | 10.6 | 99.9 | 81.2 | 67.0 | 119.9 | 81.2 | 99.9 | 0.2752 |
| S-Ba | 39.8 | 38.8 | 3.3 | 43.5 | 37.2 | 31.6 | 48.0 | 37.2 | 43.5 | 38.2 | 40.8 | 5.2 | 41.6 | 32.2 | 25.3 | 51.1 | 32.2 | 41.6 | 0.8273 |
| ANB | 77.9 | 79.3 | 4.5 | 81.6 | 72.9 | 66.7 | 89.2 | 72.9 | 81.6 | 77.9 | 79.6 | 3.6 | 80.3 | 73.7 | 69.0 | 86.8 | 73.7 | 80.3 | 0.2752 |
| ANS-Me | 62.5 | 58.5 | 7.4 | 71.0 | 58.0 | 44.2 | 80.8 | 58.0 | 71.0 | 60.3 | 63.5 | 6.4 | 64.5 | 53.0 | 44.5 | 76.2 | 53.0 | 64.5 | 0.8273 |
| ANSPNS.GoMe | 27.7 | 26.0 | 6.2 | 34.5 | 22.5 | 12.3 | 43.0 | 22.5 | 34.5 | 29.8 | 30.5 | 2.1 | 31.5 | 27.5 | 24.7 | 35.0 | 27.5 | 31.5 | 0.5127 |
| PoOr.GoMe | 77.3 | 79.8 | 4.9 | 80.5 | 71.7 | 65.1 | 89.6 | 71.7 | 80.5 | 76.8 | 77.3 | 3.7 | 80.2 | 72.9 | 67.7 | 85.9 | 72.9 | 80.2 | 0.8273 |
| SN.GoGn | 89.4 | 91.0 | 3.3 | 91.7 | 85.7 | 81.3 | 97.6 | 85.7 | 91.7 | 89.8 | 89.7 | 4.3 | 94.2 | 85.5 | 79.0 | 100.6 | 85.5 | 94.2 | 0.5127 |
| SN.Gn | 1.6 | 2.7 | 5.3 | 6.2 | −4.3 | −11.7 | 14.8 | −4.3 | 6.2 | 5.6 | 6.8 | 2.9 | 7.8 | 2.3 | −1.7 | 12.9 | 2.3 | 7.8 | 0.8273 |
| Measurement | SG (n = 10) | CG (n = 10) | P value | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Median | SD | Q1 | Q3 | 95% CI | Min | Max | Mean | Median | SD | Q1 | Q3 | 95% CI | Min | Max | ||||
| Inf | Sup | Inf | Sup | ||||||||||||||||
| SNA | 80.6 | 81.2 | 3.8 | 84.6 | 77.1 | 77.9 | 83.3 | 74.0 | 84.8 | 82.0 | 80.9 | 4.2 | 84.2 | 79.6 | 79.0 | 85.0 | 76.9 | 90.9 | 0.8206 |
| SN.ANSPNS | 9.6 | 9.4 | 2.1 | 11.9 | 8.9 | 8.1 | 11.1 | 6.5 | 12.4 | 9.0 | 8.3 | 3.4 | 12.8 | 6.7 | 6.5 | 11.4 | 4.2 | 14.3 | 0.5454 |
| N-ANS | 52.1 | 54.0 | 4.7 | 54.5 | 47.0 | 48.7 | 55.5 | 43.0 | 58.0 | 51.9 | 52.3 | 5.6 | 53.5 | 48.5 | 47.8 | 55.9 | 43.5 | 60.0 | 0.4483 |
| Co-A | 85.7 | 89.3 | 15.8 | 94.0 | 86.0 | 74.4 | 97.0 | 42.7 | 98.4 | 88.5 | 86.5 | 6.7 | 93.2 | 85.2 | 83.7 | 93.3 | 77.6 | 102.0 | 0.5454 |
| SNB | 33.0 | 31.5 | 3.0 | 35.0 | 31.0 | 30.8 | 35.2 | 29.0 | 38.0 | 32.1 | 30.5 | 6.5 | 36.0 | 26.5 | 27.4 | 36.8 | 25.5 | 43.5 | 0.2568 |
| PoOr.NPg | 25.2 | 25.8 | 2.4 | 26.8 | 23.5 | 23.5 | 26.9 | 20.7 | 29.3 | 25.1 | 24.2 | 5.7 | 27.9 | 22.8 | 21.0 | 29.3 | 17.1 | 36.2 | 0.8206 |
| Co-Gn | 114.1 | 112.8 | 5.3 | 118.0 | 111.3 | 110.3 | 118.0 | 104.0 | 121.3 | 112.9 | 113.1 | 6.3 | 114.5 | 110.4 | 108.4 | 117.5 | 98.8 | 122.1 | 0.8206 |
| Co-Go | 55.2 | 53.6 | 6.9 | 57.9 | 50.5 | 50.2 | 60.1 | 48.7 | 71.9 | 50.4 | 51.5 | 4.0 | 53.4 | 46.8 | 47.5 | 53.3 | 42.8 | 55.2 | 0.1509 |
| Go-Gn | 74.6 | 76.1 | 3.6 | 77.0 | 72.3 | 72.0 | 77.1 | 67.1 | 78.6 | 75.0 | 73.8 | 5.4 | 79.8 | 73.2 | 71.2 | 78.9 | 64.3 | 83.9 | 0.8206 |
| S-N | 70.6 | 70.5 | 3.6 | 73.0 | 67.4 | 68.1 | 73.2 | 66.0 | 76.6 | 69.9 | 68.3 | 4.5 | 74.0 | 66.3 | 66.6 | 73.1 | 64.1 | 76.2 | 0.5967 |
| Ba-N | 105.8 | 105.4 | 7.2 | 109.6 | 100.8 | 100.7 | 111.0 | 96.3 | 117.6 | 104.0 | 103.3 | 6.7 | 107.2 | 98.5 | 99.3 | 108.8 | 96.7 | 114.2 | 0.5204 |
| S-Ba | 42.6 | 41.9 | 3.9 | 46.2 | 39.7 | 39.8 | 45.3 | 36.7 | 49.6 | 42.8 | 42.2 | 4.2 | 46.9 | 40.0 | 39.7 | 45.8 | 36.7 | 49.8 | 0.7055 |
| ANB | 77.8 | 78.5 | 4.0 | 82.0 | 74.8 | 74.9 | 80.7 | 71.4 | 82.5 | 79.6 | 79.4 | 3.3 | 82.6 | 76.8 | 77.3 | 82.0 | 75.5 | 84.6 | 0.8501 |
| ANS-Me | 66.5 | 67.3 | 4.9 | 70.0 | 62.0 | 63.0 | 70.0 | 57.5 | 73.0 | 65.4 | 65.8 | 7.8 | 70.0 | 60.0 | 59.8 | 71.0 | 53.0 | 80.0 | 0.5702 |
| ANSPNS.GoMe | 26.9 | 26.8 | 5.1 | 31.5 | 22.5 | 23.3 | 30.5 | 20.0 | 35.0 | 26.7 | 25.5 | 6.2 | 30.5 | 21.5 | 22.2 | 31.1 | 18.5 | 36.5 | 0.8499 |
| PoOr.GoMe | 77.4 | 77.2 | 3.7 | 81.3 | 73.4 | 74.8 | 80.1 | 72.8 | 82.7 | 79.4 | 79.7 | 3.8 | 82.6 | 76.3 | 76.7 | 82.1 | 74.2 | 84.3 | 0.7623 |
| SN.GoGn | 89.1 | 89.4 | 2.9 | 91.6 | 87.1 | 87.0 | 91.2 | 83.0 | 92.3 | 89.0 | 89.2 | 2.1 | 90.2 | 88.3 | 87.5 | 90.5 | 84.7 | 92.7 | 0.5697 |
| SN.Gn | 2.3 | 1.6 | 2.6 | 4.6 | 0.7 | 0.5 | 4.2 | −1.3 | 6.3 | 2.5 | 2.5 | 2.6 | 4.7 | 0.0 | 0.6 | 4.3 | −1.5 | 6.4 | 0.1736 |
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