Endocrine Alterations in Patients With HIV

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  • pancreas insulin resistance_SS_BH0851

    Photo Credit: Jim Dowdalls/Science Source.

  • Insulin Resistance and Type 2 Diabetes

    Insulin Resistance and Type 2 Diabetes

    Insulin resistance and type 2 diabetes are growing concerns in the HIV population because of patients’ improved longevity. At least 20% of people with HIV have insulin resistance,7 and 2% to 14% have type 2 diabetes.3 The etiology of diabetes in HIV is multifactorial. Personal risk factors include age; obesity; genetic profile; hepatitis C virus coinfection; use of atypical antipsychotic medications, corticosteroids, or opioids; and low testosterone levels.3,7 The relationship between HIV and diabetes risk is unclear but it likely involves persistent immune activation and inflammation and the effect of the disease on adipokine dysregulation.6,7

    The prevalence of diabetes is greater in patients taking HAART than in those not receiving HAART.6 Nucleoside analogs (eg, tenofovir and abacavir), newer protease inhibitors (PIs; eg, darunavir and atazanavir), and integrase strand transfer inhibitors are far less likely to promote insulin resistance than older PIs or nucleotide reverse-transcriptase inhibitors (NRTIs).3

    Photo Credit: Jim Dowdalls/Science Source.

  • People with HIV have an increased risk for glucose and lipid disorders, including insulin resistance, glucose intolerance, type 2 diabetes, dyslipidemia, and lipodystrophy (ie, lipoatrophy or lipohypertrophy).3,6 Metabolic disorders in the HIV population likely arise from a combination of traditional risk factors, HIV-related factors, and adverse ART-related effects.3,6 Drugs used to treat various comorbidities may also contribute to metabolic dysregulation.3 Older combination ART regimens are associated with a greater risk for glucose or lipid abnormalities than newer regimens.3 Metabolic disease increases the risk for cardiovascular disease in people with HIV, who already have a greater risk for cardiovascular-related morbidity and mortality than the general population.3,6 There are no guidelines for managing metabolic disorders in people with HIV.3 Generally, the approach is the same as that used for the general population but with consideration of potential drug-drug interactions in patients using ART. Photo Credit: Carolina Biological.

    Metabolic Disease and HIV

    People with HIV have an increased risk for glucose and lipid disorders, including insulin resistance, glucose intolerance, type 2 diabetes, dyslipidemia, and lipodystrophy (ie, lipoatrophy or lipohypertrophy).3,6 Metabolic disorders in the HIV population likely arise from a combination of traditional risk factors, HIV-related factors, and adverse ART-related effects.3,6 Drugs used to treat various comorbidities may also contribute to metabolic dysregulation.3 Older combination ART regimens are associated with a greater risk for glucose or lipid abnormalities than newer regimens.3

    Metabolic disease increases the risk for cardiovascular disease in people with HIV, who already have a greater risk for cardiovascular-related morbidity and mortality than the general population.3,6 There are no guidelines for managing metabolic disorders in people with HIV.3 Generally, the approach is the same as that used for the general population but with consideration of potential drug-drug interactions in patients using ART.

    Photo Credit: Carolina Biological.

  • Approximately 50% of people with HIV have dyslipidemia.3 Common lipid disorders in treated or untreated patients are elevated triglyceride levels and decreased levels of total, high-density lipoprotein, and low-density lipoprotein cholesterol.3,8 Studies consistently associate ART with lipid changes, which may be a direct effect of ART or may result from viral suppression.3,6,8,9 Typical onset of dyslipidemia is within 3 months of starting ART.8 The PIs most likely to induce dyslipidemia are lopinavir, ritonavir, fosamprenavir, and tipranavir; whereas, atazanavir and darunavir are less likely to cause dyslipidemia.3 The non-NRTI efavirenz poses a greater risk for dyslipidemia than the non-NRTIs rilpivirine, etravirine, and nevirapine.3 Older NRTIs affected lipid levels adversely but are rarely used, and the newer NRTIs tenofovir and abacavir may even improve lipid levels.3 Raltegravir and dolutegravir are integrase strand transfer inhibitors, which tend to be lipid neutral and are preferred first-line agents.3

    Dyslipidemia in HIV

    Approximately 50% of people with HIV have dyslipidemia.3 Common lipid disorders in treated or untreated patients are elevated triglyceride levels and decreased levels of total, high-density lipoprotein, and low-density lipoprotein cholesterol.3,8 Studies consistently associate ART with lipid changes, which may be a direct effect of ART or may result from viral suppression.3,6,8,9 Typical onset of dyslipidemia is within 3 months of starting ART.8

    The PIs most likely to induce dyslipidemia are lopinavir, ritonavir, fosamprenavir, and tipranavir; whereas, atazanavir and darunavir are less likely to cause dyslipidemia.3 The non-NRTI efavirenz poses a greater risk for dyslipidemia than the non-NRTIs rilpivirine, etravirine, and nevirapine.3 Older NRTIs affected lipid levels adversely but are rarely used, and the newer NRTIs tenofovir and abacavir may even improve lipid levels.3 Raltegravir and dolutegravir are integrase strand transfer inhibitors, which tend to be lipid neutral and are preferred first-line agents.3

  • Lipodystrophy develops in many patients with HIV. Lipodystrophy is a disorder in fat metabolism that manifests as lipoatrophy, lipohypertrophy, or has a mixed presentation.3 The pathogenesis of HIV-related lipodystrophy includes the disease process, genetic and patient factors, and ART use.3,6 Some studies have found adipose tissue changes in all patients with HIV in whom lipodystrophy developed during treatment.6 Lipoatrophy, which affects one-third of patients, is characterized by loss of subcutaneous adipose tissue from the face, buttocks, and limbs and is more prevalent in older patients and men.3 Low CD4 counts, advanced disease, and genetic polymorphisms play a role, but the greatest contributor is exposure to thymidine analog NRTIs. Lipohypertrophy involves the development of lipomas, which are fatty subcutaneous lumps, in the abdominal compartment, breasts, or anterior back.3 Key contributors include inflammation of adipose tissue, immune activation, and exposure to ART (new or old regimens).3 Photo Credit: Science Source.

    HIV-Associated Lipodystrophy

    Lipodystrophy develops in many patients with HIV. Lipodystrophy is a disorder in fat metabolism that manifests as lipoatrophy, lipohypertrophy, or has a mixed presentation.3 The pathogenesis of HIV-related lipodystrophy includes the disease process, genetic and patient factors, and ART use.3,6 Some studies have found adipose tissue changes in all patients with HIV in whom lipodystrophy developed during treatment.6

    Lipoatrophy, which affects one-third of patients, is characterized by loss of subcutaneous adipose tissue from the face, buttocks, and limbs and is more prevalent in older patients and men.3 Low CD4 counts, advanced disease, and genetic polymorphisms play a role, but the greatest contributor is exposure to thymidine analog NRTIs. Lipohypertrophy involves the development of lipomas, which are fatty subcutaneous lumps, in the abdominal compartment, breasts, or anterior back.3 Key contributors include inflammation of adipose tissue, immune activation, and exposure to ART (new or old regimens).3

    Photo Credit: Science Source.

  • Dyslipidemia is associated with an increased risk for cardiovascular disease in patients with HIV and should be managed with lifestyle changes, lipid-lowering therapy, and possibly changes in ART.3,8 Drug-drug interactions between statins and ARTs are common, especially between simvastatin or lovastatin and PIs.3,8 Switching to a newer ART associated with a decreased risk for lipid alterations may be a better option.8 Few treatments are available for lipodystrophy, and management consists primarily of switching treatment to newer ART regimens associated with less risk for adipose tissue dysfunction.3 Lipoatrophy is rarely reversible, however, and some patients benefit from facial fillers or fat transplantation.3 Switching ART regimens may be less effective for patients with lipohypertrophy because some newer ARTs also cause visceral adipose tissue accumulation. The growth hormone-releasing analog tesamorelin is approved by the US Food and Drug Administration for treatment of visceral adipose tissue in people with HIV. Lipectomy is another option.

    Managing Lipid Disorders in HIV

    Dyslipidemia is associated with an increased risk for cardiovascular disease in patients with HIV and should be managed with lifestyle changes, lipid-lowering therapy, and possibly changes in ART.3,8 Drug-drug interactions between statins and ARTs are common, especially between simvastatin or lovastatin and PIs.3,8 Switching to a newer ART associated with a decreased risk for lipid alterations may be a better option.8

    Few treatments are available for lipodystrophy, and management consists primarily of switching treatment to newer ART regimens associated with less risk for adipose tissue dysfunction.3 Lipoatrophy is rarely reversible, however, and some patients benefit from facial fillers or fat transplantation.3 Switching ART regimens may be less effective for patients with lipohypertrophy because some newer ARTs also cause visceral adipose tissue accumulation. The growth hormone-releasing analog tesamorelin is approved by the US Food and Drug Administration for treatment of visceral adipose tissue in people with HIV. Lipectomy is another option.

  • Hypogonadism develops in approximately 25% of young to middle-aged men who are HIV positive. In uninfected men, hypogonadism typically occurs much later in life.9 Hypogonadism may be primary or secondary.3 The adoption of ART has led to a decline in the incidence of hypogonadism, but rates may rise as patients live longer.3 HIV-associated risk factors for low testosterone include duration of infection or ART use; comorbidities such as lipodystrophy, metabolic syndrome, testicular infection, coinfection with hepatitis B virus or hepatitis C virus; certain inflammatory cytokines; and use of opiates, glucocorticoids, megestrol acetate, or ketoconazole.3 Hypogonadism is associated with nonspecific signs or symptoms such as weight loss, muscle wasting, reduced libido, and low bone density.3 The workup for hypogonadism in men with HIV, like that for the general population, includes measuring serum total testosterone, particularly in symptomatic patients.3 Some men may benefit from short-term testosterone replacement therapy.3 Photo Credit: Anatomical Travelogue/Science Source.

    Hypogonadism in People Who Are HIV Positive

    Hypogonadism develops in approximately 25% of young to middle-aged men who are HIV positive. In uninfected men, hypogonadism typically occurs much later in life.9 Hypogonadism may be primary or secondary.3 The adoption of ART has led to a decline in the incidence of hypogonadism, but rates may rise as patients live longer.3 HIV-associated risk factors for low testosterone include duration of infection or ART use; comorbidities such as lipodystrophy, metabolic syndrome, testicular infection, coinfection with hepatitis B virus or hepatitis C virus; certain inflammatory cytokines; and use of opiates, glucocorticoids, megestrol acetate, or ketoconazole.3

    Hypogonadism is associated with nonspecific signs or symptoms such as weight loss, muscle wasting, reduced libido, and low bone density.3 The workup for hypogonadism in men with HIV, like that for the general population, includes measuring serum total testosterone, particularly in symptomatic patients.3 Some men may benefit from short-term testosterone replacement therapy.3

    Photo Credit: Anatomical Travelogue/Science Source.

  • Although hypogonadism is less common in HIV-positive women than in HIV-positive men, some data have associated HIV with an earlier age at menopause compared with women who are HIV negative.3 Premature menopause is attributable to loss of ovarian function. Other manifestations of HIV-related hypogonadism are prolonged amenorrhea and more menopausal symptoms.3,10 Ovulatory dysfunction resulting in earlier menopause or prolonged amenorrhea can have important health implications. In women of reproductive age, HIV-related ovulatory dysfunction may increase the risk for infertility, and in general, it may contribute to bone loss and an increased risk for osteoporosis.3,10 The use of ART is not associated with earlier onset of menopause,3 but women who do not use ART may have a lower rate of fertility.10

    Hypogonadism in HIV-Positive Women

    Although hypogonadism is less common in HIV-positive women than in HIV-positive men, some data have associated HIV with an earlier age at menopause compared with women who are HIV negative.3 Premature menopause is attributable to loss of ovarian function. Other manifestations of HIV-related hypogonadism are prolonged amenorrhea and more menopausal symptoms.3,10 Ovulatory dysfunction resulting in earlier menopause or prolonged amenorrhea can have important health implications. In women of reproductive age, HIV-related ovulatory dysfunction may increase the risk for infertility, and in general, it may contribute to bone loss and an increased risk for osteoporosis.3,10 The use of ART is not associated with earlier onset of menopause,3 but women who do not use ART may have a lower rate of fertility.10

  • In patients with HIV, the disease process and ART may contribute to bone loss, resulting in osteopenia or osteoporosis and increased fracture risk.3,10 Proinflammatory cytokines and viral load contribute directly to reduced bone mineral density through their effects on osteoclast and osteoblast activity, inhibiting new bone formation and accelerating bone loss.3 Other risk factors for bone loss or fracture in the HIV population include low body mass index, smoking, substance abuse, glucocorticoid therapy, hypogonadism, coinfection with hepatitis B virus or hepatitis C virus, and vitamin D deficiency (affects ~90% of patients).3,11 Bone loss caused by ART emerges within 1 to 2 years after starting therapy.3,11 Tenofovir-based regimens are associated with higher rates of bone loss.3,11 Guidelines suggest avoiding tenofovir disoproxil fumarate or PI-boosting regimens in patients at high risk.3 Bisphosphonates (eg, alendronate or zoledronate) are recommended for those with HIV who have osteoporosis.3

    Bone Health

    In patients with HIV, the disease process and ART may contribute to bone loss, resulting in osteopenia or osteoporosis and increased fracture risk.3,10 Proinflammatory cytokines and viral load contribute directly to reduced bone mineral density through their effects on osteoclast and osteoblast activity, inhibiting new bone formation and accelerating bone loss.3 Other risk factors for bone loss or fracture in the HIV population include low body mass index, smoking, substance abuse, glucocorticoid therapy, hypogonadism, coinfection with hepatitis B virus or hepatitis C virus, and vitamin D deficiency (affects ~90% of patients).3,11

    Bone loss caused by ART emerges within 1 to 2 years after starting therapy.3,11 Tenofovir-based regimens are associated with higher rates of bone loss.3,11 Guidelines suggest avoiding tenofovir disoproxil fumarate or PI-boosting regimens in patients at high risk.3 Bisphosphonates (eg, alendronate or zoledronate) are recommended for those with HIV who have osteoporosis.3

  • Thyroid disease is uncommon in patients with recent HIV, but the risk for thyroid dysfunction increases with disease progression or opportunistic infections.3,12 Although one-third of patients with HIV may test positive for thyroid dysfunction, an overt thyroid disorder develops in only 1% to 3% of infected patients.12 Cases are generally mild or even asymptomatic.8 The most common thyroid disorders in people with HIV are infective thyroiditis, thyroid neoplasm (eg, Kaposi sarcoma lymphoma), nonthyroidal illness, isolated low free T4 (especially in children), subclinical hypothyroidism with positive antithyroid antibodies and low free tetra-iodothyronine levels, and reconstitution disease.3,12 Studies have associated commencement of HAART with an increased risk for subclinical hypothyroidism and a 2% incidence of Graves’ disease, which usually occurs during the later phase of immune reconstitution. Management of thyroid disease in people with HIV follows guidelines for the general population.3 Photo Credit: BSIP / IMAGE POINT FR.

    Thyroid Disease

    Thyroid disease is uncommon in patients with recent HIV, but the risk for thyroid dysfunction increases with disease progression or opportunistic infections.3,12 Although one-third of patients with HIV may test positive for thyroid dysfunction, an overt thyroid disorder develops in only 1% to 3% of infected patients.12 Cases are generally mild or even asymptomatic.8 The most common thyroid disorders in people with HIV are infective thyroiditis, thyroid neoplasm (eg, Kaposi sarcoma lymphoma), nonthyroidal illness, isolated low free T4 (especially in children), subclinical hypothyroidism with positive antithyroid antibodies and low free tetra-iodothyronine levels, and reconstitution disease.3,12 Studies have associated commencement of HAART with an increased risk for subclinical hypothyroidism and a 2% incidence of Graves’ disease, which usually occurs during the later phase of immune reconstitution. Management of thyroid disease in people with HIV follows guidelines for the general population.3

    Photo Credit: BSIP / IMAGE POINT FR.

  • Adrenal insufficiency is a relatively common endocrine complication in patients with HIV/AIDS and can be primary or secondary.4 Patients with adrenal insufficiency may exhibit fatigue, weight loss, refractory hypotension, anorexia, or fever.3 Laboratory tests in patients with adrenal insufficiency may reveal hyponatremia, hyperkalemia, or hypoglycemia. Multiple opportunistic pathogens can contribute to adrenal dysfunction in patients with HIV, but the most common is cytomegalovirus.4 With the widespread use of ART, however, infiltration of the adrenal gland caused by infection or HIV-associated malignancy has become less common.3 A more frequent cause of adrenal insufficiency today is iatrogenic adrenal suppression resulting from drug-drug interactions between HAART and steroids, which can manifest as Cushing syndrome.3,4 Adrenal insufficiency is life threatening but correctable, and clinicians need to maintain a high index of suspicion for this complication. Diagnosis is challenging, and a cosyntropin stimulation test is indicated.3

    Adrenal Insufficiency

    Adrenal insufficiency is a relatively common endocrine complication in patients with HIV/AIDS and can be primary or secondary.4 Patients with adrenal insufficiency may exhibit fatigue, weight loss, refractory hypotension, anorexia, or fever.3 Laboratory tests in patients with adrenal insufficiency may reveal hyponatremia, hyperkalemia, or hypoglycemia.

    Multiple opportunistic pathogens can contribute to adrenal dysfunction in patients with HIV, but the most common is cytomegalovirus.4 With the widespread use of ART, however, infiltration of the adrenal gland caused by infection or HIV-associated malignancy has become less common.3 A more frequent cause of adrenal insufficiency today is iatrogenic adrenal suppression resulting from drug-drug interactions between HAART and steroids, which can manifest as Cushing syndrome.3,4 Adrenal insufficiency is life threatening but correctable, and clinicians need to maintain a high index of suspicion for this complication. Diagnosis is challenging, and a cosyntropin stimulation test is indicated.3

It is estimated that 37 million people in the world have HIV or AIDS,1 including more than 1 million people in the United States.2 Individuals with HIV experience a range of endocrinopathies and metabolic disorders that result directly from the effects of HIV on endocrine function or arise secondary to interactions between endocrine organs and opportunistic infections, neoplasms, or antiretroviral therapy (ART).3 Adrenal, gonadal, thyroid, bone, or metabolic dysfunction are common and can occur at any stage of HIV/AIDS.4

As the use of highly active ART (HAART) has expanded, the life expectancy for people with HIV has improved greatly, and the lifespan of a 20-year-old starting ART today approaches that of the general population.5 This has led to a shift in the spectrum of endocrine and metabolic disorders, with a sharp decrease in glandular infiltration and a growing prevalence of treatment-related or age-related conditions.3,4

Compiled by Christin L. Melton

This slideshow originally appeared here.

References

  1. World Health Organization. Global Health Observatory (GHO) data. 2018. Accessed April 14, 2018.
  2. Centers for Disease Control and Prevention. HIV Basics: Basic Statistics. Updated December 18, 2017. Accessed April 15, 2018.
  3. Mirza FS, Luthra P, Chirch L. Endocrinological aspects of HIV infection [published online January 8, 2018]. J Endocrinol Invest. doi: 10.1007/s40618-017-0812-x
  4. Brown TT. The effects of HIV-1 infection on endocrine organs. Best Pract Res Clin Endocrinol Metab. 2011;25:403-413.
  5. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017;4(8):e349-e356.
  6. Lake JE, Currier JS. Metabolic disease in HIV infection. Lancet Infect Dis. 2013;13:964-975.
  7. Araujo S, Bañón S, Machuca I, Moreno A, Pérez-Elias MJ, Casado JL. Prevalence of insulin resistance and risk of diabetes mellitus in HIV-infected patients receiving current antiretroviral drugs. Eur J Endocrinol. 2014;171(5):545-554.
  8. Kelesidis T, Currier JS. Dyslipidemia and cardiovascular risk in human immunodeficiency virus infection. Endocrinol Metab Clin North Am. 2014;43(3):665-684.
  9. Rochira V, Guaraldi G. Hypogonadism in the HIV-infected man. Endocrinol Metab Clin North Am. 2014;43(3):709-730.
  10. Yalamanchi S, Dobs A, Greenblatt RM. Gonadal function and reproductive health in women with human immunodeficiency virus infection. Endocrinol Metab Clin North Am. 2014;43(3):731-741.
  11. Compston J. Osteoporosis and fracture risk associated with HIV infection and treatment. Endocrinol Metab Clin North Am. 2014;43(3):769-780.
  12. Weetman AP. Thyroid abnormalities. Endocrinol Metab Clin North Am. 2014;43(3):781-790.

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