The Prevalence of Osteoporosis in Hiv Infected Patient and its Correlation with Cd4 Count/Clinical Staging in Indian Population

Human immunodeficiency virus (HIV) is a retroviral disease in which the viruses copy their genetic material into the genetic material of the human beings. Infected cells remain infected for the whole of their life. First discovered in the year 1981, Human immunodeficiency virus infections is considered to be a pandemic by the World Health organization.

HIV/AIDS has long term and short-term complications. Infective complications include: Cytomegalovirus, Candidiasis, Herpes simplex viruses, Mycobacterium avium complex, Pneumocystis pneumonia, Toxoplasmosis and Tuberculosis. Malignancy in HIV includes: - Kaposi's sarcoma, Osteoporosis. Osteoporosis which is characterized by abnormality both in amount and in architectural arrangement of the bone tissue which can lead to increased susceptibility to the fracture causing decrease skeletal strength and leading to increased rate of morbidity and mortality¹,².

Bone mineral density (BMD) can be measured through imaging modalities, such as Dual X-ray absorptiometry (DEXA), with the goal of preventing fractures with early intervention. The World Health Organization has grouped reduced BMD into two categories. Osteoporosis is defined as a bone density less than 2.5 standard deviations of the mean BMD of a sex-matched, young healthy population, i.e. a T-score less than −2.5. Osteopenia is an intermediate category of bone loss defined as a T-score between −1 and −2.5.3 Although these categories were created to classify postmenopausal women, they are often applied to other adult populations. Osteoporosis in its most common form affects the elderly (both sexes) and all racial groups of human beings. Osteoporosis is basically classified on two basic parameters it is a primary or secondary. Primary osteoporosis occurs in all ages in both sex but in females it follows after Menopause in and occurs letter in the life in men. In contrary to primary osteoporosis secondary osteoporosis results from medications or other conditions or diseases³,⁴. Diseases which causes osteoporosis includes endocrine disorders, bone marrow disorders, malabsorption disorder, inflammatory disease which were reported to be associated with osteoporosis and with increased tendency. HIV infection is also important reported to play an important role in osteoporosis there was high incidence of osteoporosis reported in HIV infected individuals⁵.

AIDS is one of the important risk factors for osteoporosis and osteopenia⁶. Since HIV AIDS is associated with numerous metabolic and endocrine complication which can lead to decreased appetite and Hypogonadism. Medication during the therapy also causes decreased bone strength and contribute to the bone loss. Bone remodelling process is basically altered in HIV-infected individuals which can contribute to the bone loss⁷. Osteoporosis is more frequent in patients taking antiretroviral therapy for a longer duration. In HIV the main risk factor for the development of osteoporosis are protease inhibitors, longer duration of HIV therapy, high viral load, decrease CD 4 count, lower body weight before and after therapy, reduced lean body mass, weight loss and impaired functional capacity of the various factor which can further lead to osteoporosis in HIV-infected individuals.

Among HIV-infected patients receiving antiretroviral therapy (ART), reduced BMD has been reported with increasing frequency. Because of the relatively small size of these studies, investigators have generally grouped osteopenia and osteoporosis together, and have not been able to assess accurately the prevalence of osteoporosis per se and its relative risk in HIV-infected patients compared with HIV-uninfected controls⁸,⁹,¹⁰.

The following questions need to be answered:

What is the prevalence of reduced BMD, and more specifically osteoporosis in HIV-infected patients, and what is the risk of these disorders compared with HIV-uninfected control subjects?

What is the risk of reduced BMD and osteoporosis in HIV-infected patients receiving ART compared with ART-naive patients?

The objective of this endeavour was to study the prevalence of osteoporosis in HIV infected patients in Indian population. The prevalence of osteoporosis had been studied in western countries but data from Indian population are lacking.

We included 188 subjects out of which 124 (66%) were HIV positive (diagnosed as per NACO criteria) and 64 (34%) were HIV negative controls. Out of 124 HIV positive patients 104 (83.87%) were males and 20 (16.13%) were females. In control group, 34 (53.12%) were males and 30 (46.88%) were females (Table 1). Majority of patients in both the groups were of age group 31-40 years (Table 1). Mean body mass index (BMI) was 20.03±2.03g/cm2 in HIV positive cases while 22.65±2.46g/cm2 in HIV negative controls. Out of 124 HIV positive patients 35 (56.4%) were taking HAART and 54 (43.6%) were HIV naïve patients. Majority of HIV positive patients were on Zadivudine+ Lamivudine+ Nevirapine regimen (77.14%). In HIV positive patients only 2 patient was >50 years while in HIV negative control 4 patients had age >50 years. Out of 124 (100%) HIV positive patients, 33.87% (n=42) patients had CD4 count in between 100-199/µl, 29.03% (n=36) patients had CD4 count 0-99/µl and 24.19% (n=30) patients had CD4 count greater than 300/µl (Table 1). In 2 HIV positive patients left leg was amputated because of the trauma.

Out of 34 (100%) HIV positive patients between 21-30 years age group 14 (41.2%) patient had osteopenia and 2 (5.9%) patient was osteoporotic. While in control population between 21-30 years none had osteopenia or osteoporosis. Similarly, out of 64 HIV positive patients between 31-40 years of age, 36 (56.2%) had osteopenia and 2 (3.1%) had osteoporosis. While in HIV negative out of 28 in the same age group of 10 (35.72%) patients had osteopenia and none of them were osteoporotic. In the age group 41-50 years only 20% control population had osteopenia while 66.7% of HIV positive patients had osteopenia and 8.3% had osteoporosis (Table 1). Thus, osteoporosis occurred at younger age group in HIV positive patients as compared to HIV negative controls. The prevalence of osteoporosis was higher in HIV positive cases as compared to control group. These findings were similar to that of Arnsten JH et al, (2006)²⁴ who found that in HIV infected the prevalence of osteoporosis was higher in HIV positive cases as compared to control group compared (p value =0.001). They reported increased fracture risk in HIV infected compared with HIV negative controls.

NACO first line regimen were used and it includes NRTI, NNRTI and NVP. Protease inhibitors were used as the second line drugs. The most of the patients (n=54) on ART were on Zadivudine (Z)+ Lamivudine (L)+Neviparine (N) (Table 1). None of the patient was on Protease inhibitor. NACO guidelines for treatment of HIV was used which recommend protease inhibitor as the second line drug. In HIV positive patient with <2 years ART duration 45.45% (n=20) patients were normal, 45.45% (n=20) had osteopenia and 9.1% (n=4) had osteoporosis while in HIV positive patients with >2 years ART duration 53.84% (n=14) were normal, 38.46% (n=10) had osteopenia and 7.69% (n=2) had osteoporosis.

The relation was statistically non-significant (p value= 0.234).Similar results were obtain by Jones S et al, (2008)²³who found that low BMD is prevalent in HIV infected subjects initiation of ART is associated with 2%-6% decreased in BMD over the first two years. Tebas et al, (2007)²⁴ also reported 2-6% decrease in BMD over the first two years. Thus ART itself seems not to be a risk factor for osteoporosis.

Out of the total 188 enrolled population, 124 (66%) were HIV positive of which 104 (84%) were males and 20 (16%) were females and 64(34%) were HIV negative controls out of which 34 (53%) were males and 30 (47%) were females. All patients were non-smoker, had no history of previous fracture and there was no past history of steroid intake. In 2 patients left leg was amputated. (Table 1)

Out of 124 HIV positive patients 70 (56.4%) patients were taking highly active antiretroviral therapy (HAART) and the rest 54 (43.6%) were ART naive patients. (TABLE 1Table 1)

Majority of the patients in both HIV positive and HIV negative groups were of age 31-40 years with 51.61% and 43.45% respectively. In HIV positive patients only one patient was >50 years old while in HIV negative controls 2 cases had age of >50 years. (Table 1)

In HIV positive group 70 (56.45%) were on ART while 54 (43.55%) were ART naïve patients. Among HIV positive patients’ majority were on Zidovudine +Lamivudine +Nevirapine (n=54; 84.37%). No patient was on Protease inhibitor regimen. (Table 1)

In HIV positive patients’ majority 42 (33.87%) had CD4 count between 100-199/μl, 30(24%) patients had CD4 count of >300/μl and 36 (29.03%) had CD4 count < 100/μl. (Table 1) Table 2.

In HIV positive patients the mean T-score was minimum at lumbar spine (-1.708±1.068) and maximum at left forearm radius (-0.869±0.912). In HIV negative patients mean T-score was minimum at Left neck femur (-0.490±0.608) and maximum at lumbar spine (0.003±1.10). The mean T-score at all anatomical sites was lower in HIV positive patients as compared to HIV negative controls. (Table 2). At all anatomical sites the difference in T-score in both groups was statistically significant (p<0.05). Thus on the basis of T-score in HIV positive patients 53.22% (n=66) were osteopenic, 6.4% (n=8) were osteoporotic while in HIV negative controls 25% (n=16) were osteopenic and none of the patient was osteoporotic (Table 2). Both HIV patients (n=2) with amputed legs had normal BMD. The mean BMI of osteopenic HIV positive patients was 20.04±1.03 g/cm² while that of osteoporotic patients was 20.01±1.22 g/cm². The mean BMI of HIV positive patients with normal BMD was 20.00±1.03 g/cm².

There was no significant difference in BMI of osteopenic and osteoporotic HIV positive patients. The BMI in both osteopenic and osteoporotic patients was in lower normal range. Z score was taken into consideration but as majority of the enrolled population was males and age < 50 years Z score was not used. Mean Z score of osteoporotic HIV positive patients was -1.3±0.4 and -0.2 ± 0.02 in HIV negative controls. Mean Z score of osteopenic HIV positive patients was -2.4±.2. At all anatomical sites the difference in Z-score in both groups was statistically significant (p <0.05). Thus HIV positive patients had lower Z-score as compared to HIV negative controls. Z-score compares individuals results to those of an age matched population that is also matched for race and gender. The low Z-score increases the suspicion of a secondary disease/ factor in etiology of osteoporosis.

These results were similar to Brown TT et al, (2004)¹⁶ who found that HIV-infected subjects had a higher prevalence of either osteopenia or osteoporosis at the spine, hip, or forearm, compared with HIV-negative controls (63% vs. 32%, P =0.02). Amorosa V et al, (2006)¹⁷also reported high prevalence of bone demineralization among human I mmunodeficiency virus (HIV)-infected patients. Similar results were obtained in the study by Dolan SE et al, (2006)¹⁸ who also reported that HIV infected subjects had lower BMD at lumbar spine (1.01±0.01 vs 1.07±0.01 g/cm2, p=0.001), hip (0.94±0.01 vs 0.98±0.01g/cm2 p=0.02), femoral neck (0.83±0.01 vs 0.87±0.1g/cm2, p=0.02). They also reported that HIV positive patients had higher prevalence of reduced BMD as compared to HIV negative controls. These results were also similar to that of Triant VA et al, (2008)¹⁹ who reported that HIV positive patients had higher prevalence of reduced BMD as compared to HIV negative controls. Similar finding were obtained by Teiciman J et al, (2003)²⁰who also noted reduced BMD of lumbar spine T-score <2.5 was found in 7 (14%) and osteopenia T- score (-1 to -2.5 SD) in 31 (62%) patients. This relationship was also observed by Libois A et al, (2009)²¹ they found that HIV-infected patients suffer more often from osteopenia and osteoporosis than age matched HIV negative subjects. Guerri-Fernandez R et al, (2013)²² found strong association between HIV infection and osteoporosis (osteoporosis evaluated in term of hip fracture incidence). They also found that duration of the HIV infection and HAART or nadir CD4 cells count were not related to BMD loss in this population of women with no AIDS defining event. The only factor associated with BMD loss was a low BMI.

There were multiple etiologies of osteoporosis among them are primary and secondary causes. The secondary causes of osteoporosis includes neoplastic disease, rheumatoid arthritis, endocrine disorders, chronic renal disease, liver disease, chronic intake of drugs that was known to cause osteoporosis: oral corticosteroid, cyclosporine, cytotoxic drugs, excessive thyroxine in previous 6 months before inclusion. These secondary causes were excluded in the beginning of the study. Thus HIV disease itself remains one of the secondary causes of osteoporosis. In HIV patients the important factors that causes osteoporosis includes low BMI, low CD4 count, increase viral load, increased clinical staging, increased age (older age), duration of the ART and ART regimens. Mean BMD at various anatomical is Table 2. In HIV positive patients the mean BMD was minimum at left neck femur (0.869±0.170g/cm2) and maximum at left forearm radius (0.998±0.156 g/cm2) while in HIV negative patient the BMD was minimum at left neck femur (0.987±0.082g/cm2) and maximum at lumbar spine (1.198±0.142g/cm2). (Table 2 MEAN BMD AND T SCORE) .

The mean BMD at all sites was lower in HIV positive patients as compared to HIV negative controls. The difference was statistically significant with p value <0.05. (Table 2 MEAN BMD AND T SCORE)

The T-score in HIV positive patients was minimum at lumbar spine (-1.708±1.068) and maximum at left forearm radius (-0.869±0.912). In HIV negative controls the T-score was minimum at left neck femur (0.490±0.608) and maximum at AP spine (0.003±1.198). (Table 2 MEAN BMD AND T SCORE)

The average T-score at all anatomical sites was lower in HIV positive patients as compared to HIV negative controls (Table 2). The difference was statistically significant at all anatomical sites (p<0.05). (Table 2 MEAN BMD AND T SCORE)

In HIV positive patients 50 (40.32%) were normal, 66 (53.22%) were Osteopenic, 8(6.46%) were osteoporotic while in HIV negative controls 48(75%) were normal,16 (25%) were Osteopenic and 0% were osteoporotic. In HIV negative control population, no patient had osteoporosis. (Table 3)

The prevalence of Osteopenia and osteoporosis in various age group in HIV positive and HIV negative control is given in Table 3.

Out of 34(100%) HIV positive patients between 20-30 years age group 14 (41.2%) patient had osteopenia and 2(5.9%) patient had osteoporosis. While in HIV negative controls of 20-30 years age group none of them had osteopenia or osteoporosis similarly out of 64(100%) HIV positive patients between 31-40 years age groups 36 (56.2%) had osteopenia and 2 (3.1%) patient had osteoporosis. While in HIV negative out of 18 in the age group of 31-40 years 10 (35.72%) patients had osteopenia and none of them were osteoporotic in age group 41-50 years only 20% control population had osteopenia while 66.7% of HIV positive patients had osteopenia and 8.3% had osteoporosis. (Table 3)

Thus, the prevalence of osteoporosis in HIV positive patients was higher in all age groups as compared to HIV negative controls. The difference was statistically significant (p=0.001). In HIV positive Osteopenic patients had mean age of 37.27±7.238 years while in HIV negative controls the mean age of patient with osteopenia was 52.62±11.338. There were no osteoporotic patients in HIV negative control group while there were 4 patients in HIV positive group with mean age of 41.25±12.203 years. Thus, osteopenia and osteoporosis in HIV positive patients occurred more commonly in younger age group as compared to HIV negative controls.

Patients with lower CD4 count had higher percentage of osteopenia and osteoporosis. Thus, patients with higher CD4 count had lower prevalence of osteoporosis relation was Statistically Non-Significant (p=0.217) Figure 1.

Figure 1.Prevalence of osteopenia and osteoporosis with mean CD4 count

124 patients 50 had normal BMD (mean of 215.60/µl), 8 patients had osteoporosis (mean of 179.75/µl), 66 patients had osteopenia (mean of 182.55/µl). Lesser the CD4 count greater was the prevalence of low BMD (osteopenia/osteoporosis). The CD4 counts in between groups and within in groups does not show any significant relation (p-value 0.736).

Out of 124 HIV positive patients, 70 (56.4%) were on ART while rest 54 (43.6%) were ART naïve. Among HIV positive patients on ART 32 (45.7%) were normal (Table 1) while 18 (44.3%) had reduced BMD. These results were similar to that of Brown TT et al, (2009) who found that after 96 weeks the mean percentage change for baseline in total BMD was -2.5% on Lopinavir/Retonavir therapy and 2.3 for Efaverinz no alteration in the rate of BMD change was observed. They also found that the impact of ART initiation on bone mineral density and have generally shown a 2%–6% loss of BMD after 48–96 weeks of therapy, regardless of the type of ART initiated. This degree of bone loss is larger than what would be expected by aging alone and is comparable to the bone loss seen in women aged 50–59 years over 2 years

On basis of T-score, normal HIV positive cases (n=50) had mean CD4 count 215.60±165.455/µl, osteopenic (n=66) had mean CD4 count 182.55 ± 167.906/µl and osteoporotic (n=8) had mean CD4 count 179.75±105.396/µl. Lesser the CD4 count greater was the prevalence of osteopenia and osteoporosis. The CD4 counts in between groups and within in groups does not so any significant relation with p-value 0.736 (Table 4). Similar result were obtained by Mondy K et al, (2003)²⁵ who found that amount of BMD gained depends on immune status and virological control of HIV infected as indication by correlation in between CD4 count, increased duration of HIV.

We found that prevalence of osteopenia and osteoporosis is more in HIV positive patients and it starts occurring at younger age as evidenced by low T-score and low Z-score in this population. In HIV positive patients mean BMD was minimum at left neck femur and maximum at left forearm radius . In HIV negative controls mean BMD was minimum at left neck femur and maximum at lumber spine. The mean BMD at all sites was lower in HIV positive patients as compared to HIV negative controls and the difference was statistically significant (p value <0.05).

In HIV positive patients mean BMD was minimum at left neck femur and maximum at left forearm radius. In HIV negative controls mean BMD was minimum at left neck femur and maximum at lumber spine. The mean BMD at all sites was lower in HIV positive patients as compared to HIV negative controls and the difference was statistically significant (p value <0.05).

On basis of T-score, normal HIV positive cases (n=50) had mean CD4 count 215.60±165.455/µl, Osteopenic (n=66) had mean CD4 count 182.55 ± 167.906/µl and osteoporotic (n=8) had mean CD4 count 179.75±105.396/µl.

Lesser the CD4 count greater was the prevalence of osteopenia and osteoporosis. The CD4 counts in between groups and within in groups does not so any significant relation with p-value 0.736. Similar result was obtained by Mondy K et al, (2003)100 who found that amount of BMD gained depends on immune status and virological control of HIV infected as indication by correlation in between CD4 count, increased duration of HIV.

HIV positive patients should be screened by DEXA for BMD estimation and those with osteopenia or osteoporosis should be treated to prevent morbidity

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