Endocrine disorders in HIV infection

Katherine Samaras : Department of Endocrinology, St Vincent’s Hospital and UNSW; Adipose Biology Group, Diabetes Program, Garvan Institute of Medical Research, Sydney NSW

Endocrine abnormalities are common in human immunodeficiency virus (HIV) infection, due to specific effects of the virus, HIV-related disease, complications of drug therapy, drug-drug interactions and the effects of restoration of the immune system after the commencement of combination antiretroviral therapy (cART) (Table 1).

Table 1. Endocrine disorders due to effects of the HIV virus, HIV-related disease, immune reconstitution and drug therapy (ADD unde Table: NRTI: nucleoside reverse transcriptase inhibitor; PI: protease inhibitor)
  Direct HIV-1 virus effects HIV-related disease Immune reconstitution Drug effects
Adrenal disease Adrenalitis (rare)

Infections

Cytomegalovirus

Toxoplasmosis
Mycobacterial

(M. tuberculosis,

M. avium-intracellulare complex)

Malignancy
Kaposi sarcoma

Addison disease (rare)

Reduced corticosteroid synthesis: antifungals (ketoconazole)

Pituitary suppression: cytochrome P450 3A4 drug interactions with inhaled or oral steroids

Thyroid disease    

•Graves disease

•Hashimoto hypothyroidism

Interferon-induced thyroid disease
Diabetes mellitus      

Pentamidine-induced insulin deficiency (type  1 diabetes)

PI- and NRTI-induced insulin resistance

Type 2 diabetes mellitus

Calcium metabolism Osteoporosis     NRTI-related osteroporosis
Sex hormones   Androgen deficiency   Androgen deficiency

Diabetes mellitus

Disturbances in glucose metabolism (insulin resistance, impaired glucose tolerance and diabetes mellitus) are among the most common endocrine disorders found in treated HIV-infection.[1][2] Diabetes and its prediabetic disorders of impaired fasting glucose and impaired glucose tolerance are defined (Box 1), using either fasting, non-fasting glucose levels, non-fasted HbA1c levels, or glucose responses to an oral glucose tolerance test. Criteria using the diagnostic cut-offs of the Americal Diabetes Society are shown.[3] Diabetes may be preceded by either impaired fasting glucose or impaired glucose tolerance for 5-10 years. Detecting prediabetes is a golden opportunity for diabetes prevention (see below). Insulin resistance is difficult to measure in individual patients and is not recommended. Measures such as fasting insulin levels or insulin levels following an oral glucose load are unreliable and accurately not reproducible.[4]

Box 1. International criteria for diagnosis of diabetes mellitus and other glucose disorders
  Fasting glucose1 2 hour glucose2 Random glucose HbA1c
Normal

< 5.6 mmol/L

     
Diabetes mellitus

> 7.0 mmol/L

> 11.1 mmol/L

> 11.1 mmol/L

with symptoms3

> 6.5%
Impaired fasting glucose

5.6 - 6.9 mmol/L

100-125 mg/dL

     
Impaired glucose tolerance  

7.8 - 11.0 mmol/L

   
  1. fasting is defined as no caloric intake for at least 8 hours
  2. following 75 g of an anhydrous glucose load, dissolved in water
  3. polyuria, polydipsia or unexplained weight loss
  4. HbA1c: glycated haemoglobin, measured on non-fasted blood

Before the availability of cART, most diabetes cases occurred in patients treated with pentamidine for Pneumocystis jirovecii infection and were characterised by insulin deficiency and ketoacidosis (type 1 diabetes mellitus), since pentamidine destroys pancreatic insulin-secreting beta-cells.[5][6][7] The most common form of diabetes mellitus in patients living with HIV in the cART era is type 2 diabetes, due to a combination of insulin resistance and insufficient insulin secretion to meet demand.[8]

The exact prevalence and incidence of diabetes in treated HIV infection is difficult to establish. It is likely to have changed over time, reflecting changes in prescribing of medications such as HIV nucleoside reverse transcriptase inhibitors (NRTIs) and HIV protease inhibitors (PIs), in addition to changes in societal promoters of diabetes, such as obesity, high-energy diets and sedentariness. Further, there are clear ethnic groups with high genetic susceptibility to diabetes. Prevalence rates for type 2 diabetes with the use of older cART regimens (to which many patients were exposed) range from 7%–13%.[9][10][11]

More recent studies show diabetes rates in HIV patients to be twice that of age-matched controls,[12] with rates of impaired fasting glucose and diabetes of 9.1% and 4.5% respectively in an Italian cohort.[13] The Swiss HIV Cohort reported diabetes rates of 7%,[14] higher than the 3% rate found in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study.[15] Incidence studies report [16] 72 cases per 1000 patient-years of follow-up in the D:A:D Study after 3.8 years follow-up[17] and 14.1 cases per 1000 patient-years after 10-years follow-up in a large French study.[18] Recent observational data on diabetes in US youth with HIV-infection show a five-fold rate increase in the periods of time between 2004-7 and 2008-2014.[19] This increased rate may reflect the impact of the US obesity epidemic in promotion of diabetes, differences in ascertainment and diabetes screening over the observation period or differences in cART used over time.

The treatment of type 2 diabetes in people with HIV infection requires lifestyle changes with an emphasis on healthy weight and, more importantly, healthy waist circumference, with appropriate nutritional and physical activity advice. Since the epidemic of overweight and obesity now affects more than 50% of Australians, this epidemic has also affected people with HIV infection. Those at higher risk type 2 diabetes include people with a family history or ethnic susceptibility (e.g. people with Indigenous Australian, South East Asian, South Asian, Pacific Islander or South American Indian heritage) and need particular consideration for screening of diabetes and early intervetion.

In addition to a healthy weight-maintaining diet and physical activity, metformin is the mainstay of glucose lowering therapy. In people with treated HIV infection, metformin is an insulin sensitiser, reduces abdominal obesity and improves glycaemic control.[20] Metformin is contraindicated in the presence of severe renal impairment or cardiac failure, where it may induce lactic acidosis. Care should be taken in patients receiving NRTIs, who have impaired renal function or elevated plasma lactic acid levels. A number of oral (sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose co-transporter 2 (SGLT2) inhibitors) and injectable (glucagon-like peptide-1 (GLP-1) analogues, insulin) agents are used to treat type 2 diabetes, with individualised therapy aiming to bring glucose levels to target, using glycated haemoglobin (HbA1c) as an index of glucose levels over 3 months. HbA1c targets are individually set, based on age and the risk of adverse effects from hypoglycaemia. Usual HbA1c targets are 6.5-7.0% for most aduts with type 2 diabetesand 7.0-7.5% for adults with type 1 diabetes. Higher HbA1c targets are approproiate in elderly people, those with hypoglycaemia unawareness or with severe past hypoglycaemic events.

In addition to glucose level control, standard diabetes care includes aggressive cardiovascular risk reduction (applying secondary prevention targets for blood lipid levels and blood pressure, with annual review for complications, including examination for neuropathy, retinopathy and measurement of urinary microalbumin levels.

Many cases of type 2 diabetes can be prevented by modest weight loss, increased physical activity with a reduction in sedentariness and a healthy diet that is limited in energy-dense foods. If prediabetes is detected, lifestyle management with modest weight reduction can prevent almost half progressing to diabetes mellitus. This prevention is augmented to a lesser degree by the addition of metformin.

Figure 1 is a cardiometabolic screening algoritm designed for the care of people with HIV, which may be useful in the primary and secondary setting in the cardiometabolic care of people with teated HIV infection.

Figure 1. Clinical algorithm for cardiometabolic protection in HIV treatment-experienced people[21]

fig1

fig1 part2

Source: Samaras K.[22] Used with permission of author.

Thyroid disease

Autoimmune thyroid disease is sometimes encountered in HIV infection, either as a consequence of immune reconstitution related to use of cART or as a complication of immunomodulatory therapy. Graves disease and, less commonly, primary hypothyroidism due to Hashimoto thyroiditis may occur as a consequence of aberrant immune tolerance during immune reconstitution, with development of thyroid receptor antibodies and/or thyroid peroxidase antibodies.[23][24][25][26][27] Immunomodulatory therapy with agents such as interferon- used in the treatment of hepatitis C infection[28] can cause the production of stimulatory antibodies that results in Graves disease and thyrotoxicosis.[29] Clinicians should be alert to the possibility of hypothyroidism or thyrotoxicosis following immune reconstitution.[30]

Adrenal disease

Adrenal insufficiency is uncommon, but can occur as a consequence of infection (HIV-1, cytomegalovirus [CMV], toxoplasmosis, mycobacteria), neoplastic disease (Kaposi sarcoma or other malignancies) or, very rarely, autoimmune disease (Addison disease). Adrenal insufficiency is more common in the setting of acquired immune deficiency syndrome (AIDS), with abnormal stimulated cortisol responses in 26% of tested subjects.[31]

The symptoms that should alert a clinician to the possibility of adrenal insufficiency include unexplained fatigue, weight loss, nausea, weakness, postural presyncope, myalgias, arthralgias, sweatiness and confusion. Drug therapy can be associated with reduced synthesis of adrenal hormones (e.g. ketoconazole) or induced metabolism of steroids (e.g. rifampicin, phenytoin).[32] A history of recent withdrawal of oral or inhaled corticosteroid drugs should be sought.[33] Clinical features of adrenal insufficiency include cachexia, pigmentation of the skin or oral mucosa, or a postural drop in blood pressure. Pigmentation will not be found in adrenal insufficiency of pituitary origin, due to deficiency of adrenocorticotrophin hormone (ACTH), which is rare. Biochemistry may show hyponatremia, hyperkalaemia or hypoglycaemia. The diagnostic test for primary adrenal insufficiency is the short synacthen test, where a normal stimulated cortisol response would exceed 550 nmol/L. Secondary adrenal insufficiency (due to pituitary disease) will produce a normal response to cosyntropin testing and is diagnosed by an insulin-induced hypoglycaemia test.

Adrenal insufficiency is treated with glucocorticoid and mineralocorticoid therapy. Corticosteroid requirements vary and should be individualised to ensure symptomatic improvement, normalisation of electolytes and no postural blood pressure drop. Examples of glucocorticoid replacement types and doses are: prednisone 2.5-5 mg on waking, 1-2.5 mg early afternoon; or cortisone acetate 12.5-25 mg on waking, 10-12.5 mg early afternoon; or hydrocortisone 10-20 mg on waking, 4-8 mg early afternoon. Patients will also require mineralocorticoid support with fludrocortisone. 0.05-0.1 mg per day in two divided doses, adjusted to clinical response in blood pressure, aiming for normotension and no postural drop.

Acute adrenal insufficiency may occur in the setting of acute infection, surgery or other physical stress and may manifest with vomiting, hypotension, haemodynamic shock and coma. It is prevented and treated with intravenous glucocorticoids. For example, intravenous hydrocortisone 50-100 mg twice daily with acute illness or at surgery and 1-2 days following surgery, for prevention. Higher doses are required with severe illness, such as hydrocortisone 100 mg every 6-8 hours.

People with adrenal insufficiency or chronic corticosteroid therapy with acute minor illness should be advised to take double the usual doses of corticosteroids for 2-5 days, until the illness has passed.

An excess of adrenal hormones (Cushing syndrome) can occur in patients receiving PIs. Interference with the cytochrome p450 3A4 enzyme system results in the reduced elimination of oral and inhaled steroids. Cushing syndrome can occur rapidly in patients receiving standard doses of oral steroids, in addition to inhaled steroids (for example, fluticasone), with pituitary-adrenal suppression occurring with long term therapy.[34] Cushing syndrome should be suspected on historical and clinical evidence and diagnosed by detection of low or undetectable cortisol levels in a clinically Cushingoid patient. Treatment is by reduction of oral steroid doses or gradual reduction in inhaled steroids, where the underlying respiratory disease permits. For those patients receiving inhaled steroids, simple strategies will reduce steroid exposure and its side effects. These strategies include using dosing devices with lower oral cavity deposition (e.g. aerosolised rather than inhalers) with spacers and always rinsing, gargling and spitting (not swallowing). Other strategies may include changing the inhaled steroid therapy to agents that are not predominantly metabolised by the specific cytochrome p450 isoenzymes.

Disorders of calcium metabolism and osteoporosis

Hypercalcaemia is uncommon in HIV infection. Primary hyperparathyroidism with hypercalcaemia could be expected at the same rate as the population without HIV infection. If hypercalcaemia is found with low parathyroid hormone (PTH) levels, underlying infection, malignancy or lymphoma need exclusion.

Bone loss, low bone density and osteoporosis are found in HIV-wasting syndrome and patients receiving long-term cART.[35] Multiple factors specific to HIV infection and its treatment contribute, including viral effects, medication effects (tenofovir, PIs) and low androgen levels. Other secondary causes for osteoporosis should be excluded, such as hypogonadism, thyrotoxicosis, primary hyperparathyroidism, Cushing syndrome, renal phosphate wasting, coeliac disease and multiple myeloma. In patients with established osteopenia or osteoporosis, clinicians should ensure an adequate intake of dietary calcium (at least 1000 mg daily) and that serum levels of 25-hydroxy vitamin D are about 80 nmol/L or higher. Weight bearing physical activity is essential (20 minutes of walking at least three times weekly and, if possible, a weight training program), in addition to other lifestyle interventions such as reducing excessive alcohol or caffeine consumption and smoking cessation. In male androgen deficiency and hypogonadism, treatment with androgen supplementation with testosterone has shown benefit.[36] Other therapies such as the bisphosphonates alendronate and zoledronic acid have been shown of benefit in people living with HIV with osteoporosis.[37][38] Consensus expert opinion on osteoporosis treatment in treated HIV infection recently recommended medication switches: tenofovir to abacavir or raltegravir; and PI-based regimens to raltegravir-based regimens.[39]

Sex steroids

Male hypogonadism

Low androgen levels in men with HIV infection appear relatively common, often in the setting of low or inappropriately normal gonadotrophin levels. The cause of the low androgen level is not completely understood, however contributors include the usual causes of hypogonadism in men. There appears to be an association with HIV wasting and lipodystrophy.[40]

Androgen deficiency in men leads to lean tissue and bone loss, fatigue and mood disturbance. Other symptoms may include a loss of body hair, testicular atrophy, reduced pubic hair and reduced libido. Clinical confirmation includes the findings of gynaecomastia, reduced secondary sex characteristics and small, soft testicles. Clinical signs that may suggest a secondary cause, including the presence of a goitre and thyrotoxicosis, a testicular mass, signs of chronic liver or pituitary disease. Biochemical confirmation is undertaken by measuring two early morning testosterone levels (at 8-9 am), along with follicle-stimulating hormone (FSH) and lutenising hormone (LH) levels, prolactin and thyroid stimulating hormone (TSH) levels. Diagnosis and examination for causes of testicular failure are detailed elsewhere.[41]

The Pharmaceutical Benefits Scheme (PBS) in 2015 introduced rigorous prescribing requirements for subsidised testosterone replacement, requiring two early morning testosterone levels below 8.0 nmol/L and endocrinological evaluation. This change to the PBS listing occurred in an environment of widespread over-use and abuse of androgenic anabolic steroids in the community for body building, body dysmorphia, anti-ageing and wellness concerns.

Treatment options include injectable testosterone (testosterone esters, 200-250 mg every 2-3 weeks, or long-acting testosterone undecanoate 1000 mg intramuscular injection every 10-12 weeks), transdermal testosterone by patch, gel or lotion applied daily. Men receiving androgen supplementation require annual digital rectal examination and prostate specific antigen measures.

Female hypogonadism

Secondary amenorrhoea is common in women with HIV, affecting about one in four women.[42] The prevalence of amenorrhoea is higher among women who have lost significant amounts of weight in the setting of HIV wasting.[43] Evaluation should exclude pituitary disease (by measuring prolactin, LH and FSH), thyrotoxicosis, premature menopause, polycystic ovary syndrome, in addition to rare causes of hyperandrogenism.

Treatment in women with premature menopause (i.e. earlier than 45 years of age) usually takes the form of the oral contraceptive pill or hormone replacement therapy, to alleviate symptoms of oestrogen deficiency and maintain bone mass. Therapy should be offered until about the usual age of menopause, that is, 50-53 years. The presence of a past history of stroke, deep vein thrombosis or pulmonary embolism, or current cigarette smoking may alter recommendations for hormonal therapy.

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