Chapter 25. AIDS Endocrinopathies

• ACTH Adrenocorticotropic hormone
• AIDS Acquired immunodeficiency syndrome
• BMD Bone mineral density
• CMV Cytomegalovirus
• CRH Corticotropin-releasing hormone
• CVD Cardiovascular disease
• DHEA Dehydroepiandrosterone
• DXA Dual energy x-ray absorptiometry
• FSH Follicle-stimulating hormone
• GH Growth hormone
• GHRH Growth hormone–releasing hormone
• GnRH Gonadotropin-releasing hormone
• HAART Highly active antiretroviral therapy
• HDL High-density lipoprotein
• HIV Human immunodeficiency virus
• IGF Insulin-like growth factor
• IL Interleukin
• IMT Intima media thickness
• LDL Low-density lipoprotein
• LH Luteinizing hormone
• M/I Glucose disposal adjusted for insulin level
• MRI Magnetic resonance imaging
• NRTI Nucleoside reverse transcriptase inhibitor
• NNRTI Nonnucleoside reverse transcriptase inhibitor
• PI Protease inhibitor
• PPARγ Peroxisome proliferator-activated receptor γ
• PTH Parathyroid hormone
• RANK Receptor activator of nuclear factor kappa
• REE Resting energy expenditure
• RXR Retinoid X receptor
• SREBP Sterol regulatory enhancer-binding protein 1
• T3 Triiodothyronine
• T4 Thyroxine
• TBG Thyroxine-binding globulin
• TNF Tumor necrosis factor
• TRH Thyrotropin-releasing hormone
• VLDL Very low density lipoprotein

Symptoms consistent with endocrine disorders and alterations in endocrine laboratory values are not unusual in individuals infected with the human immunodeficiency virus (HIV). Some of these changes are common to any significant systemic illness; others appear to be more specific to HIV infection or its therapies. Alterations can be found in HIV infection even before clinically significant immunocompromise occurs. As the infected individual becomes immunocompromised, opportunistic infections and neoplasms—as well as the agents used in the treatment of these disorders—can give rise to further changes in endocrine function. Herein we discuss alterations in endocrine function that can accompany HIV infection and acquired immunodeficiency syndrome (AIDS), focusing on evaluation and interpretation of clinical and laboratory findings.

In the era of highly active antiretroviral therapy (HAART), clinical thyroid dysfunction is relatively uncommon in stable HIV-infected patients. In several large studies, the prevalence of hypothyroidism was 1% to 2.5% and hyperthyroidism was 0.5% to 1%. The prevalence of subclinical disease was higher, with subclinical hypothyroidism between 3.5% and 20% and subclinical hyperthyroidism <1%, although definitions varied between studies. These data do not support screening for thyroid disease above the standard guidelines. With advanced HIV disease, alterations in thyroid function tests do occur but generally do not result in clinical dysfunction. In patients with AIDS, the effects of opportunistic infections and neoplastic involvement of the thyroid, as well as the effects of some medications used to treat HIV-infected patients, should be considered.

Alterations in Thyroid Function Tests

HIV-infected patients can show alterations in thyroid function tests that are largely asymptomatic. Some of the changes are similar to those seen in the classic euthyroid-sick syndrome, whereas others are unique to the HIV disease state. Advanced HIV is associated with a decrease in thyroid hormone levels, triiodothyronine (T3) and thyroxine (T4), similar to that seen in the euthyroid-sick syndrome. When HIV-infected patients were stratified by weight loss and the presence of secondary infection, a decline in T3 levels corresponded to the severity of disease, consistent with the euthyroid-sick syndrome. Deterioration in nutritional status can also contribute to the decrease in T3 and T4, because there is a strong correlation between albumin levels and both free T4 and total T3 levels. In the euthyroid-sick syndrome, decreased levels of serum thyroid hormones are due to impaired peripheral T4 to T3 conversion by 5′ deiodinase. In HIV-infected patients, decreases in serum free T4 and free T3 may be due to decreased extrathyroidal conversion of T4 to T3, an increase in serum binding proteins, and/or decreased secretion of TSH.

Despite the similarities in serum thyroid hormone levels between HIV and the euthyroid sick syndrome, significantly ill HIV-infected patients often do not demonstrate the elevated reverse T3 levels characteristic of the euthyroid sick syndrome. The significance of this difference is unknown.

Another characteristic finding in HIV-infected patients is an elevation in thyroxine-binding globulin (TBG), which rises progressively with advancing immunosuppression. TBG levels correlate inversely with the CD4 lymphocyte count, and in the past were used as a surrogate marker for disease progression. The increase in TBG does not appear to be due to generalized changes in protein synthesis, increases in sialylation and altered clearance of TBG, or changes in estrogen levels. The cause and clinical significance of the increased TBG found in HIV-infected patients are unknown. However, increases in TBG affect total T4 and T3 measurements, and this should be considered when interpreting these tests in HIV-infected patients.

Subtle alterations in TSH dynamics have been reported in stable HIV-infected patients. Although their TSH and free T4 levels remain within the normal range, these individuals demonstrate significantly higher TSH values and lower free T4 values than uninfected controls. In circadian studies, HIV-infected individuals have higher TSH pulse amplitudes with unchanged pulse frequency as well as a higher peak TSH in response to thyrotropin-releasing hormone (TRH) stimulation. These studies are consistent with a subtle state of compensated hypothyroidism in HIV infection; the mechanisms underlying these alterations have not been elucidated.

The typical pattern of alterations in thyroid function tests in HIV-infected patients is outlined in Table 25–1.

Opportunistic Infections and Neoplasms

Opportunistic pathogens and neoplasms can invade the thyroid in HIV-infected individuals but generally do not cause clinical thyroid dysfunction. Although the prevalence of thyroid involvement is unknown, autopsy of 100 AIDS patients prior to the era of HAART showed the presence of Mycobacterium tuberculosis in 23% of patients' thyroids, followed by cytomegalovirus (CMV) (17%), Cryptococcus neoformans (5%), Mycobacterium avium (5%), Pneumocystis carinii (4%), and other bacteria or fungi (7%).

A few of these pathogens are noteworthy because they have been associated on occasion with both hyper- and hypothyroidism. Pneumocystis carinii has been associated with inflammatory thyroiditis accompanied by hypothyroidism in seven cases, hyperthyroidism in three cases, and normal thyroid function in one case. Antithyroid antibodies were negative in all six cases in which they were measured. Radionuclide scanning in seven cases revealed poor visualization of the entire thyroid gland in patients with bilateral disease and nonvisualization of the affected lobe in patients with unilateral disease. Two patients with hyperthyroidism had normalization of thyroid function after treatment of the P. carinii infection. Kaposi sarcoma has also been reported to infiltrate the thyroid gland and resulted in significant destruction and hypothyroidism in at least one case. In two cases, lymphoma was associated with thyroid infiltration, causing thyroidal enlargement.

Medication Effects

Several medications used to treat HIV-infected patients can alter the clearance of thyroid hormone by inducing hepatic microsomal enzymes. These medications include rifampin, phenytoin, ketoconazole, and ritonavir. Patients with normal thyroid function should not be clinically affected, although decreases in T4 may be observed. However, patients receiving l-thyroxine may require increased doses, and patients with decreased pituitary or thyroid reserve may develop clinically apparent hypothyroidism. Isolated, but well-documented reports of need for increased thyroxine doses after starting ritonavir and decreased doses after indinavir have been published; these medications affect glucuronidation, but given the common use of high doses of these drugs in the past, it is surprising how rarely problems present. Interferon-alpha, a therapy used for Kaposi sarcoma and hepatitis C (an increasing coinfection with HIV), has been associated with autoimmune diseases of the thyroid, including hyperthyroidism and hypothyroidism. Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25–2.

With the advent of HAART, there have been case report series of newly diagnosed autoimmune diseases such as Graves disease, Hashimoto thyroiditis, and alopecia areata. Immune reconstitution with HAART raises the possibility of subsequent induction of autoimmune diseases. The cases appeared late after immune reconstitution (8-32 months). Possible theories include thymic regeneration or peripheral T lymphocyte expansion causing irregularities in tolerance, leading to autoimmune dysfunction. Other studies, however, could not link autoimmune thyroid disease to HAART, and the low prevalence in the large published studies suggests that increased screening above standard guidelines may not be warranted.

Opportunistic infections commonly involve the adrenal glands but rarely occupy enough of the gland to cause adrenal insufficiency. Impaired adrenal reserve without overt symptoms of adrenal insufficiency has been described in patients with HIV. Those patients with a subnormal response to dynamic testing represent a group for which there is controversy over when to give baseline replacement glucocorticoids (or mineralocorticoids) or increased doses in stressful situations, especially when baseline levels are normal or elevated. With restoration to health by treatment of opportunistic infections or HIV itself, many of these patients no longer have adrenal insufficiency.

Opportunistic Infections and Neoplasms

Opportunistic organisms are found commonly in the adrenal glands of patients dying of AIDS although they rarely cause clinical adrenal insufficiency. CMV has been associated with significant necrosis of the adrenal gland, although the amount of tissue affected rarely reaches 90%, thought necessary to cause clinical adrenal insufficiency. In one preliminary study, however, the presence of CMV retinitis was associated with an increased rate of adrenal insufficiency compared with AIDS patients without that disorder. Less common opportunistic infections involving the adrenals include Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Cryptococcus neoformans, Histoplasma capsulatum, P. carinii, and Toxoplasma gondii. In addition, Kaposi sarcoma and lymphoma can involve the adrenals, but rarely to the extent of inducing adrenal insufficiency.

Glucocorticoids

Classic clinical symptoms of adrenal insufficiency are seldom seen, but some clinicians view the weakness and weight loss observed in patients with AIDS as an indicator of adrenal insufficiency. HIV-infected patients usually have normal or, even more commonly, elevated basal cortisol levels. The elevated levels occur most commonly in advanced disease, which may be a stress response, but is confounded by an increase in cortisol-binding globulin. Adrenocorticotropic hormone (ACTH) levels have mostly been found to be normal or elevated in patients with elevated basal cortisol levels, although some reports of low levels exist. Some of these alterations may be mediated by multiple cytokines; both interleukin (IL)-1 and tumor necrosis factor (TNF) can directly stimulate cortisol secretion, while IL-1 and IL-6 can stimulate ACTH and corticotropin-releasing hormone (CRH) release. On the other hand, IL-2 and IL-4 increase sensitivity to cortisol. An increase in cortisol levels may also be a direct response to HIV infection itself. The HIV envelope protein gp120 increases cortisol levels. HIV-1 virus encodes several proteins such as Vpr and Tat that may increase cortisol sensitivity. An increased cortisol to dehydroepiandrosterone (DHEA) ratio correlates with body weight loss and HIV-associated malnutrition.

Subclinical abnormalities in hypothalamic pituitary axis dynamics are often present. Nearly all HIV-infected patients have a normal cortisol response to the standard high-dose (250 μg) ACTH stimulation testing. Other studies have shown that stimulation with low-dose cosyntropin (1 μg) resulted in a diagnosis of glucocorticoid insufficiency in roughly 10% to 20% of outpatients with HIV and up to 50% of critically ill HIV-infected patients. During CRH stimulation testing, a reduced ACTH or cortisol response was seen in up to 50% of stable HIV-infected patients with CD4 counts less than 500/μL. The abnormalities of decreased reserve either at the pituitary or at the adrenal level in HIV infection are similar to those that occur in other infections or serious illnesses.

Although clinically significant abnormalities in glucocorticoid secretion appear to be uncommon, subtle alterations in adrenal biosynthesis may be more common. HIV-infected patients have reduced products of the 17-deoxysteroid pathway (corticosterone, deoxycorticosterone, and 18-hydroxydeoxycorticosterone) with normal or elevated products of the 17-hydroxy pathway (cortisol) before and after ACTH stimulation. It is not known whether this alteration represents an early indication of evolving adrenal insufficiency or is an adaptive response that shifts adrenal synthetic activity to steroids that are crucially needed under conditions such as HIV infection that impose physical stress. Twenty-four-hour urine-free cortisol levels do not predict the subtle adrenal alterations in HIV-infected patients, but may indicate adequate adrenal function.

Glucocorticoid resistance has been described in HIV-infected patients. This syndrome is characterized by symptoms of weakness, fatigue, weight loss, and hyperpigmentation, with elevated cortisol levels and mildly increased ACTH levels. Decreased lymphocyte glucocorticoid receptor affinity for glucocorticoids has been described in these patients. A similar state is seen in glucocorticoid-resistant asthma patients. Increased expression of the beta form of the glucocorticoid receptor, which inhibits the alpha form, has also been reported. Partial glucocorticoid resistance could explain the finding of increased basal cortisol in some HIV-infected patients, but the prevalence and clinical significance of this syndrome are uncertain.

Adrenal Androgens

HIV-infected patients have decreased basal adrenal androgen levels and impaired adrenal androgen responses to ACTH stimulation. Decreased adrenal androgens have been seen at all stages of HIV infection, as well as in HIV-negative intensive care unit patients. Thus, this change may not be specific to HIV infection but may instead be a feature of the physiologic response to illness, which is often accompanied by increased cortisol. In two studies, a fall in DHEA levels predicted progression to AIDS independent of CD4 cell counts. DHEA has been shown in vitro to inhibit HIV replication, which raised the possibility that the decreased DHEA levels observed in HIV-infected patients might influence the effects of the HIV infection. However, the efficacy of DHEA replacement in HIV-infected patients has never been demonstrated. Adrenal androgens may be decreased in women with HIV infection; low-dose testosterone replacement has been shown to induce small improvements in lean mass, depression, and sexual function.

Mineralocorticoids

Although electrolyte disturbances are not uncommon in HIV-infected patients, provocative testing of the mineralocorticoid axis has revealed few abnormalities. In contrast to glucocorticoid levels, basal and ACTH-stimulated aldosterone levels have been found to be normal in almost all HIV-infected patients studied, including both outpatients and inpatients. Nevertheless case reports of hypo- and hyperaldosteronism appear in the literature, although there is no evidence that these disorders are increased in HIV infection. Longitudinal studies suggest that the aldosterone response to ACTH stimulation may diminish with progression to later stages of HIV infection in up to half of HIV-infected patients; however, basal levels of aldosterone and plasma renin activity remain normal, and clinically significant hypoaldosteronism does not develop.

The usual pattern of alterations in adrenal hormones is shown in Table 25–3.

Medication Effects

Several medications used in the treatment of HIV-related disorders can alter glucocorticoid metabolism. Ketoconazole inhibits the cytochrome P450 enzymes P450scc and P450c11, decreasing cortisol synthesis and leading to adrenal insufficiency in patients with decreased adrenal reserve. Rifampin increases hepatic metabolism of steroids and may lead to adrenal insufficiency in patients with marginal adrenal reserve.

Megestrol acetate has intrinsic cortisol-like activity, decreasing serum cortisol and ACTH levels through suppression of the hypothalamic-pituitary-adrenal axis centrally. Patients taking megestrol have decreased cortisol and ACTH levels in response to metyrapone testing. They may become frankly Cushingoid and may show signs of adrenal insufficiency upon its rapid discontinuation. Some HIV protease inhibitors (PIs) block the metabolism of the inhaled steroid fluticasone by CYP3A4 and can lead to Cushing syndrome even in the absence of systemic steroid use. PIs do not seem to have an effect on plasma cortisol levels. However, there is debate in the literature about whether these agents increase or decrease urinary free cortisol or 17-hydroxycorticosteroid excretion.

Medications used to treat HIV-related illnesses can lead to electrolyte disturbances mimicking disorders of mineralocorticoids. Trimethoprim impairs sodium channels in the distal nephron, decreasing potassium secretion, which can result in hyperkalemia. Pentamidine has also been associated with hyperkalemia in rare instances, perhaps through nephrotoxicity. Sulfonamides are associated with interstitial nephritis and hyporeninemic hypoaldosteronism. Finally, amphotericin B causes renal potassium and magnesium wasting.

Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25–2.

Summary of Adrenal Disorders

In summary, there is little evidence for clinically significant impairment of adrenal steroid excretion in HIV infection. The subtle alterations in the glucocorticoid and androgen synthesis pathways may be an adaptive response to physiologic stress and may occur with other illnesses. Patients with HIV infection who exhibit symptoms consistent with adrenal hormone deficiency should undergo provocative testing in the same manner as uninfected individuals. Patients with both low baseline and abnormal glucocorticoid or mineralocorticoid responses to provocative testing should be treated with physiologic replacement doses of oral glucocorticoids or mineralocorticoids. Patients on replacement should be covered with high doses of glucocorticoids (usually 150-300 mg of hydrocortisone per day or equivalent) during episodes of severe illness. Electrolyte abnormalities should prompt evaluation for medication effects and the presence of renal disease.

The HIV-infected patient with a minimally elevated or frankly high basal cortisol who does not increase significantly after ACTH stimulation poses a difficult problem. Most of these individuals have normal responses to prolonged ACTH stimulation, and seronegative patients with significant illness can have similar patterns that revert to normal after treatment of the illness. Chronic glucocorticoid therapy may have significant adverse consequences in these individuals, who are already immunocompromised. Most HIV-infected patients with this pattern and even many with baseline low levels during acute illness do not appear to require long-term glucocorticoid replacement. Consideration could be given to administering short courses of steroid therapy during significant illness for individuals with indeterminate stimulation results based on clinical judgment and individual patient circumstances.

Osteopenia and Osteoporosis

There is evidence of low bone mass and, less commonly, osteoporosis in HIV-infected patients either without therapy or while receiving HAART, but the etiology remains controversial. The incidence of fractures may be increased, but there are too few studies of fracture rate to know with certainty. Therapy with bisphosphonates is effective at increasing bone mineral density (BMD) in HIV-infected patients, but there are no convincing data on fracture prevention.

Prior to the introduction of HIV PIs, low BMD was not commonly observed in HIV-infected patients. The few clinical studies on the effects of HIV on bone mineralization suggested that HIV had relatively little effect on BMD. One study followed 45 HIV-infected men for 15 months and found no change in lumbar spine and hip BMD. However, histomorphometric analysis of bone biopsies from AIDS patients showed some evidence of decreased bone formation and bone turnover; these changes were more marked in more severely affected patients. HIV itself may have an indirect effect on BMD by activating the receptor activator of nuclear factor kappa B ligand (RANK-L), which activates osteoclasts and their precursors. Activated T cells express the receptor for RANK-L—that is, RANK. The cytokines TNF-alpha and IL-1, whose levels may be increased in HIV infection, also have been shown to activate RANK-L.

After the introduction of PI-based HAART, reports of osteoporosis began to emerge. Some cross-sectional studies suggested that patients on PIs had a higher prevalence of osteoporosis and osteopenia compared to HIV-infected patients not taking PIs. However, other studies did not find a specific association of PIs with decreased BMD by dual energy x-ray absorptiometry (DXA). To date, most cross-sectional studies have shown that both HIV-infected men and women, on any form of HAART, have lower BMD or a higher prevalence of osteopenia, compared to gender- and ethnicity-matched control subjects. In one meta-analysis of 20 papers, the prevalence of reduced BMD was 67%, and the prevalence of osteoporosis was 15% in HIV-infected patients, which represents a 6.4-fold greater prevalence of reduced BMD and 3.7-fold greater prevalence of osteoporotic T scores compared to controls. Furthermore, those treated with ARV had a 2.5-fold higher prevalence of reduced BMD than those who were ARV-naive. Lactic acidemia associated with nucleoside reverse transcriptase inhibitor (NRTI) use has been hypothesized to contribute to bone demineralization. However, the role of specific ARV drugs as a cause of bone demineralization remains debated, as many recent studies fail to show an association between osteopenia and individual drugs. Thus, ARV use per se is associated with lower BMD. Divergent effects of PIs on bone cells in vitro have been reported.

Another meta-analysis found that the effect of HIV infection was mostly accounted for by decreased weight. Other studies have found associations of low albumin and past steroid use with low BMD. A randomized longitudinal study showed that continuous ARV therapy, used to suppress HIV, was associated with greater loss of bone mass and perhaps more fractures than intermittent ARV therapy designed to reduce drug exposure. However, the absolute rate of BMD loss by DXA was actually quite small in those on continuous ARV therapy (−0.5%/year at the hip and −0.7%/year at the spine). In a large database analysis, the fracture rate was increased 1.7-fold in HIV-infected Caucasian men and 1.4-fold in HIV-infected Caucasian and African American women compared to their respective controls.

Treatment for HIV-associated osteoporosis with bisphosphonates has been examined. Multiple studies have shown that the bisphosphonates alendronate and zoledronic acid given either with or without calcium and vitamin D supplementation to HIV-infected patients with osteopenia or osteoporosis improved BMD in the lumbar spine and hip after 1 to 2 years of therapy. The effects of treatments for other HIV-related problems on BMD or bone markers have been assessed. Eugonadal men with AIDS wasting syndrome treated with intramuscular testosterone for 3 months had small increases in lumbar spine BMD; however, high doses of testosterone were associated with decreases in HDL cholesterol levels. Recombinant growth hormone (GH) treatment for 24 weeks in HIV wasting syndrome did not affect BMD. Short-term growth hormone–releasing hormone (GHRH), used to treat HIV-infected men with abdominal fat accumulation, was associated with an increase in bone turnover markers; however the effect of GHRH use on BMD remains to be determined.

Osteonecrosis

Osteonecrosis has been reported both in adults and in children infected with HIV, and there is concern about the rising prevalence of osteonecrosis in this population. The most likely reason for the apparent rise in prevalence of the syndrome is increased awareness among clinicians. A study of 339 HIV-infected patients reported a prevalence of asymptomatic osteonecrosis, diagnosed by magnetic resonance imaging (MRI) as 4.4%. The annual incidence has been reported to be between 0.08% and 1.3%, which is much higher than the annual incidence in the general population (0.01%-0.135%).

The clinical presentation and anatomic distribution are similar to HIV-negative patients. The most common location for osteonecrosis is the hip, but other locations include the humeral heads, femoral condyles, and scaphoid and lunate bones. In HIV infection, the majority of large joint involvement is bilateral. Cases of osteonecrosis of the jaw/oral cavity have also been reported.

Plain film x-rays often underdiagnose osteonecrosis as changes on x-ray are confined to advanced stage (III and IV) disease; MRI is more effective at finding early-stage disease. Some data support treatment with bisphosphonates in early disease involving major joints to reduce pain, but there are inadequate randomized, controlled trials to assess whether such therapy prevents progression. Core decompression with and without bone graft has had some success. Total joint replacement may be the only recourse in late disease (eg, following collapse of the femoral head).

An association between osteonecrosis and PIs was initially reported; however, subsequent studies have failed to show a causal relationship with PI use. Other possible etiologies include those that may be more frequent in patients with HIV infection (corticosteroid use, HIV-associated vasculitis, chemotherapy, and irradiation) and other traditional risk factors (ethanol use, sickle cell disease, hemoglobinopathies, and clotting disorders).

Calcium and Phosphate Homeostasis

Calcium, phosphate, and calciotropic hormone disturbances are associated with several HIV-related illnesses and medications. Hypercalcemia with an elevated 1,25-dihyroxyvitamin D level has been associated with both AIDS-related lymphoma and infections with M. tuberculosis, M. avium-intracellulare, P. jiroveci, C. neoformans, and Coccidioides immitis. This hypercalcemia is likely due to increased extrarenal 1-alpha hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by inflammatory macrophages or tumor cells. In CMV infection, activated T cells or proinflammatory cytokines may secrete factors that activate osteoclasts, causing hypercalcemia. The syndrome has also been reported after starting antiretroviral therapy, with improvements in lymphocyte function, as part of the immune reconstitution syndrome. Recombinant human GH treatment has been associated with slight increases in serum calcium levels in some studies.

Mild hypocalcemia has been associated with HIV disease. HIV-infected patients have been shown to have low 1,25–hydroxyvitamin D and 25-hydroxyvitamin D levels, but normal vitamin D–binding protein levels, suggesting an impairment in 1-alpha hydroxylation and a compromised nutritional state. Low 1,25-hydroxyvitamin D levels are associated with advanced disease stage and increased TNF-alpha levels.

Inadequate parathyroid hormone (PTH) responses (ie, functional hypoparathyroidism) may also contribute to the hypocalcemia seen with HIV. PTH levels have been shown to be decreased in HIV-infected patients compared to controls. Parathyroid cells may be targeted by HIV infection: they express CD4 receptors which when activated affect PTH secretion. Invasion of the parathyroid gland by neoplasms and infections can also rarely occur.

Severe hypocalcemia is usually due to medications used to treat opportunistic infections. Variations on Fanconi syndrome are reported increasingly. Hypocalcemia and hypophosphatemia have been reported with tenofovir and adefovir (which are used to treat HIV) and cidofovir (which is used to treat CMV). Hypocalcemia has also been seen during therapy for CMV retinitis with foscarnet. Foscarnet can complex ionized calcium and may have mineral wasting effects at the level of the renal tubule, leading to concurrent hypomagnesemia and hypokalemia. Hypocalcemia and hypomagnesemia have also been reported during pentamidine treatment, and the combination of foscarnet and pentamidine can result in severe, even fatal, hypocalcemia. Trimethoprim-sulfamethoxazole, ketoconazole, and aminoglycosides are also associated with hypocalcemia. Ketoconazole and rifampin can alter vitamin D metabolism but usually do not produce clinically significant effects. Ketoconazole can reduce serum levels of 1,25-dihydroxyvitamin D and lower total—but not ionized—calcium levels. Rifampin and rifabutin can decrease 25-hydroxyvitamin D levels, but usually do not appear to significantly change calcium or PTH levels; one case has been reported of severe osteomalacia attributed to rifabutin.

Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25–2.

Testicular Function

Testicular atrophy is common in AIDS patients. Histopathologic changes include decreased spermatogenesis, thickened basement membrane, and an interstitial infiltrate. Possible causes of testicular atrophy include opportunistic infection by M. avium-intracellulare, Toxoplasma, and CMV, hypogonadism, HIV infection itself, and chemotherapy toxicity. HIV-infected men generally have oligoteratospermia, and as the disease state becomes more severe, the sperm can become grossly abnormal. Hence, male fertility decreases with advancing disease.

Semen washing has been used as a technique for HIV-discordant couples to reduce the risk of viral transmission. The three-step process involves gradient centrifugation, washing, and spontaneous migration to obtain motile sperm. There have been several thousand published cases of semen washing followed by either intrauterine or in vitro fertilization. These observational reports have shown that semen washing is a relatively safe and effective means of establishing pregnancy in HIV-negative women. Still, there is concern that the risk of infection is not completely eliminated after the procedure.

Hypogonadism is a common finding in men, particularly with advanced HIV disease. Prior to the introduction of HAART, hypogonadism was observed in approximately 40% of HIV-infected men. With the widespread use of HAART, the prevalence of hypogonadism has declined to 20%. Early in HIV infection, testosterone levels are normal or even elevated. Elevated basal luteinizing hormone (LH) levels and an increased LH response to gonadotropin-releasing hormone (GnRH) have been observed in these patients, suggesting pituitary dysfunction. In the later stages of HIV infection, low serum testosterone levels are seen, often accompanied by symptoms of decreased libido or erectile dysfunction. Because hypogonadism is associated with loss of lean body tissue and muscle mass, it is thought to contribute to AIDS wasting syndrome. Hypogonadal men infected with HIV tend to have low or normal LH and follicle-stimulating hormone (FSH) levels, similar to that seen in hypogonadotropic hypogonadism. However, GnRH testing in hypogonadal men with HIV has been normal in most cases. Primary hypogonadism with elevated LH and FSH levels has been observed but is far less common.

Several etiologies of the hypogonadism in men infected with HIV have been proposed, and in many cases, the cause of hypogonadism is multifactorial. Chronic illness and weight loss can alter the hypothalamic-pituitary axis. HIV infection increases the levels of the cytokines IL-1 and TNF, which have been shown to suppress hypothalamic pituitary function. Direct pituitary or hypothalamic invasion by toxoplasmosis or CMV is rare. There are divergent data on the extent to which treatment of HIV with ARV drugs increases testosterone levels.

Medications can also alter testicular function. Ketoconazole inhibits gonadal steroidogenesis, resulting in lower testosterone levels, oligospermia, and gynecomastia. Megestrol acetate, a progesterone-like agent, can lead to decreases in testosterone in HIV-infected men, perhaps through central feedback on gonadotropins. Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25–2.

Most of the studies of testosterone replacement have been performed in the context of AIDS wasting syndrome in which muscle and fat mass are decreased. Testosterone therapy in hypogonadal men with HIV increases lean body mass, but only small improvements in strength are seen. Most studies find that testosterone replacement therapy results in improved sexual functioning, mood, and energy. Testosterone therapy does not appear to exacerbate Kaposi sarcoma, although the studies of this relationship have involved limited numbers of patients.

Ovarian Function

Women represent one of the fastest growing populations with HIV infection. Two key issues include the effects of reproductive function on the natural history of HIV disease, and conversely, the effects of HIV on reproductive function. Recent studies found that women infected with HIV possess 30% to 50% lower HIV-1 RNA levels than men. Limited data suggests that the ovulatory cycle affects HIV infection in women. Early studies suggested no association between the menstrual cycle and HIV-1 RNA levels but may have included women with anovulatory cycles. In ovulating women, HIV-1 RNA levels have been shown to decline from the early follicular phase to the luteal phase. Menopause does not seem to affect the progression of HIV disease or the response to therapy.

In addition to affecting HIV-1 RNA levels, the menstrual cycle may also affect the pharmacokinetics of drugs used to treat HIV infection. Zidovudine levels have been shown to be negatively correlated with estradiol levels, suggesting that the menstrual cycle may affect zidovudine glucuronidation. Further studies are warranted.

Pregnancy does not seem to have a deleterious effect on maternal progression of HIV disease. However, an increase in HIV-1 RNA levels may occur in the early postpartum period. Several, but not all, studies suggest that pregnancy increases the rate of detection of HIV-1 in the genital tract. When HIV-1 is identified in the genital tract, the risk of perinatal transmission has been consistently shown to increase. Simple ARV regimens at the time of delivery have been shown to significantly reduce transmission of HIV to the child.

It is unclear whether HIV infection itself causes menstrual irregularities and/or amenorrhea. Early studies reported menstrual irregularities in HIV-infected women. However, these studies relied on self-report of menstrual symptoms and cycles, and many studies had enrolled an inadequate number of HIV-negative women as controls. Recent studies suggest that HIV may alter menstrual function only slightly. One large study of 802 HIV-infected and 273 HIV-negative women matched for demographic characteristics, body mass index, and substance abuse found that HIV infection increased the odds of having a very short or long cycle. There were no differences in amenorrhea, length of menses, or variability between the two groups. Another study of 197 HIV-infected women and 189 HIV-negative women found that HIV was not associated with menstrual dysfunction.

It is also uncertain whether HIV has an effect on the onset and symptoms of menopause. The average age at menopause in HIV-infected women has been reported to be between 46 and 50 years. While some studies contrast that to reported average age at menopause in controls being slightly greater than 50, the range in multiple population studies is actually 48 to 51. The diagnosis of menopause is complicated by the occurrence of amenorrhea lasting more than 1 year (which meets the clinical definition of menopause) in HIV-infected women who do not have ovarian failure as indicated by normal FSH and LH levels. Factors associated with such amenorrhea include opiate use, low body mass index, and low serum albumin levels suggesting hypothalamic dysfunction and malnutrition as causes rather than menopause. There are conflicting data concerning whether HIV is associated with increased or decreased symptoms of menopause.

With HIV infection, fertility rates decline. Quantifying the rate of decrease in fertility in the United States has been difficult due to confounding factors such as sociodemographics, drug use, weight loss, systemic illness, and sexually transmitted diseases. In Africa, where therapy for HIV was rare, there are numerous studies establishing an association between untreated HIV infection and infertility in virtually all age groups. In sub-Saharan Africa, HIV infection has been shown to account for a population–attributable decline in total fertility of 0.37% for each percentage point of HIV prevalence.

Like men, women infected with HIV have a decline in serum testosterone and adrenal androgen levels with progression of HIV disease and development of complications. Approximately 50% of women with AIDS-related wasting have low androgen levels. Androgen-deficient women may have subtle symptoms of decreased energy, libido, mood, strength, and bone mass. Despite the increased prevalence of androgen deficiency in study subjects with advanced disease, clinical laboratory diagnosis remains difficult in the female population. Total testosterone levels may be increased due to elevations in sex hormone–binding globulin in HIV-infected women, whereas free testosterone levels for women are not well-standardized in clinical laboratories.

Hormonal contraception is affected by ARV therapy. The estrogen component is metabolized by CYP3A4 enzyme. Many of the PIs and some nonnucleoside reverse transcriptase inhibitors (NNRTIs) either inhibit or induce CYP3A4, thus altering ethinyl estradiol and norethindrone levels. Other medications used to treat opportunistic infections such as rifabutin and rifampicin can also induce CYP3A4. There are very few studies on the effects of these medications on ovulation in subjects taking oral contraceptives. The Centers for Disease Control and Prevention recommend using barrier methods or condoms in addition to or in place of oral contraception.

Opportunistic Infections and Neoplasms

In autopsy series of AIDS patients, nearly 10% of pituitary glands demonstrate some degree of infarction or necrosis; infectious organisms such as CMV, P. carinii, Cryptococcus, Toxoplasma, and Aspergillus have been observed. Antemortem pituitary function was not reported in these patients.

Anterior Pituitary Function

Hypopituitarism appears to be rare in AIDS patients; stimulation with TRH, GnRH, or CRH results in normal pituitary responses in almost all patients. Likewise, prolactin levels generally have been found to be normal, with a normal response to TRH stimulation. Some patients have shown a higher maximal pituitary response to stimulation testing compared with uninfected subjects, but the clinical significance of this alteration is not known.

The GH axis has received particular attention in children with HIV who can have poor growth velocity, especially when symptomatically ill. Most of these children demonstrate normal GH levels, although low insulin-like growth factor (IGF)-I levels can be seen. Low IGF-I in the setting of relatively normal GH is often seen in states of malnutrition, which may partially explain this finding. In adults, IGF-I levels may be low in malnourished or symptomatic HIV-infected patients but are usually normal in clinically stable individuals. Circadian GH secretion does not appear to be altered in adults with HIV infection, except in the presence of visceral obesity.

Posterior Pituitary Function

Posterior pituitary function may be altered in HIV infection. Hyponatremia is common in both inpatients and outpatients with HIV. Inappropriately high serum antidiuretic hormone levels have been seen in euvolemic AIDS patients with hyponatremia; however, many of these patients had pulmonary or cerebral infections, which themselves can cause the syndrome of inappropriate antidiuretic hormone secretion. As with any patient, destruction of the posterior pituitary by infection or tumor can lead to central diabetes insipidus; like anterior pituitary destruction, this appears to be rare in HIV infection.

Prior to the introduction of HAART, weight loss and tissue wasting were commonly observed complications of AIDS in up to 30% of patients infected with HIV. A characteristic feature of this syndrome includes wasting of muscle, which is directly associated with increased morbidity and mortality. Muscle is disproportionately lost compared to fat in men. In contrast, women start with higher fat mass, and fat depletion dominates muscle loss until fat reserves are decreased. Weight loss can either be gradual or rapid in nature. Gradual weight loss has been associated with gastrointestinal disease, whereas rapid weight loss is usually seen during opportunistic infections.

The pathogenesis of wasting remains poorly understood. Several etiologies have been proposed including starvation, cachexia, hypermetabolic state, and hypogonadism. Starvation implies solely a limitation of calories, which may occur due to decreased appetite or decreased intake due to gastrointestinal infections with marked diarrhea. Cachexia refers to a state in which muscle is disproportionately lost due to direct effects on muscle. A hypermetabolic state has been proposed as a cause of AIDS wasting syndrome, because resting energy expenditure (REE) has been observed to be increased in HIV infection. However, the increase in REE is also seen in HIV-infected subjects with stable weight. HIV patients with either opportunistic infections or gastrointestinal disease have decreased caloric intake, but do not show the protective decrease in REE that occurs in pure starvation. Hence, the combination of decreased caloric intake and hypermetabolism is the driving force for wasting. The persistent metabolic defects make recovery from wasting incomplete, and recurrent events lead to progressive, step wise wasting.

Hypogonadism is a prominent finding in up to 50% of men and women with AIDS wasting. A direct correlation between testosterone levels and decreased muscle and fat mass exists. Resistance to GH has also been demonstrated in patients with more than a 10% loss in body weight.

Because a 10% loss of weight is associated with increased morbidity and mortality in patients infected with HIV, clinical trials have targeted the restoration of appetite, weight, and lean body mass. The cannabinol derivative dronabinol increased subjective appetite in patients with AIDS wasting syndrome, but had little or no effect to promote weight gain. Megestrol acetate increased appetite and weight, but resulted in mostly gain of fat.

Currently, recombinant GH therapy is the only Food and Drug Administration–approved treatment specifically for AIDS wasting syndrome that increases lean body mass. At high doses (0.1 mg/kg/d), 3 months of GH therapy increased lean body mass by 3 kg and weight by 1 kg. However, patients did experience side-effects including swelling and joint pain. In a lower-dose study (1.4 mg/d), patients had no significant increase in lean body mass after 12 weeks, which suggests that high-dose GH therapy is required. Therapy with recombinant GH is quite costly, especially if given at higher doses.

Androgen therapy has been studied extensively, because almost half of patients with AIDS wasting syndrome exhibit decreased levels of testosterone. In a meta-analysis of six clinical trials, testosterone therapy was shown to increase lean body mass and weight, especially when the therapy was given intramuscularly as opposed to transdermally. However, there have been no studies in which subjects have been randomized to different routes of administration of testosterone. Because testosterone may decrease HDL cholesterol levels, there is some concern about the long-term effects of testosterone therapy on lipid profiles and cardiovascular risk. However, no other side-effects were reported in these small, short-term studies.

Anabolic steroids have similar effects on the AIDS wasting syndrome. Nandrolone decanoate is an injectable testosterone derivative that is approved for treating anemia in patients with chronic renal failure. Two studies of nandrolone decanoate in men found that lean body mass and strength significantly increased. Nandrolone therapy improved lean body mass and weight without evidence of acute toxicity. Therapy using oral anabolic steroids oxandrolone and oxymetholone also increases lean body mass and weight in men and women, but it is associated with significant hepatic transaminitis as well as dyslipidemia.

Another approach has been to use anticytokine therapies to treat patients with AIDS wasting syndrome, but the results have been disappointing. Two studies reported small increases in weight after treatment with thalidomide, a TNF inhibitor. However, TNF levels actually increased and the patients experienced significant side effects including rash, fever, and increased viral load.

Shortly after the introduction of HAART with PIs, a constellation of symptoms appeared including abdominal obesity, lipoatrophy in the extremities and face, dorsicocervical fat pads (buffalo hump), gynecomastia, breast enlargement, increased neck circumference, and lipomas along with insulin resistance and dyslipidemia. These changes were clustered into a single syndrome reminiscent of the metabolic syndrome and named HIV lipodystrophy.

In retrospect, some of these changes are not related to HAART with PIs. The appearance of lipoaotrophy, fat accumulation in the dorsocervical fat pad, lipomas, and breast hypertrophy was reported in patients on two NRTIs before the introduction of HAART or PIs. The presence of dorsocervical fat pads and lipomas is striking, but their prevalence is low.

Furthermore, the original description of the HIV lipodystrophy syndrome has been refuted, as it has been shown definitively that the major changes in fat (lipoatrophy and abdominal obesity) are not part of the same syndrome, but have different causes. Unfortunately, there is still no widely accepted definition of HIV lipodystrophy that is used in the literature. Depending on the definition of HIV lipodystrophy, the prevalence of these findings varies widely (11%-83%). Part of the confusion is due to differences in methodology used to report fat loss or gain. Many early studies relied on the patient's self-report and/or the clinician's subjective assessment. Later studies quantified fat by anthropometrics or DXA. Neither technique permits the isolation of subcutaneous from visceral fat in the abdomen and trunk; therefore computed tomography and MRI are needed and have been utilized more recently to separately quantify fat in these compartments. Because changes in fat may take years to develop, many studies in the field are cross-sectional rather than prospective in design. In these cross-sectional studies, it is unclear how to match patients to a control group with normal fat distribution, given that most healthy adults are overweight.

Despite these challenges, it has become apparent that peripheral fat loss in the extremities and face does occur with increased frequency in patients taking HAART. In one study, 50% of HIV-infected subjects fell below the lowest decile (10%) of leg fat in controls. However, loss of subcutaneous fat in the abdomen also occurs. In contrast, it is not clear that visceral adipose tissue mass is increased in HIV infection. Furthermore, recent cross-sectional and prospective data showed that increased visceral fat is not linked to loss of subcutaneous fat.

Several etiologies have been proposed for the development of lipoatrophy associated with HIV, but to date no mechanism has been definitively linked to the disorder. The thymidine-based nucleoside analogs, stavudine and zidovudine, have the strongest association with the development of peripheral lipoatrophy. These NRTIs have been proposed to cause lipoatrophy through mitochondrial injury by inhibiting mitochondrial DNA polymerase-γ or depleting mitochondrial DNA. Fortunately, the use of stavudine and zidovudine has decreased. Abacavir is the NRTI with the least effect on fat. Some PIs (eg, indinavir) and NNRTIs (eg, efavirenz) may contribute secondarily to the lipoatrophy observed with NRTI therapy, but there are not enough trials to understand fully the effects of each ARV drug.

The development of central lipohypertrophy is even less well understood. While central lipohypertrophy has been attributed to PI use, the evidence is controversial. In the first reports of appearance of buffalo hump, half of the patients were not on PI therapy or HAART. Recent data suggest that increased visceral fat may be due to restoration to health and normal aging.

Much research has focused on the treatment of the fat changes associated with HIV. Fat loss, especially in the face, can reveal the HIV status of a patient and lead to social stigmatization. The metabolic sequelae can also predispose the patient to the development of hypertriglyceridemia and atherosclerosis. One proposed strategy is to reverse the peripheral lipoatrophy by switching ARV drugs. Substituting another NRTI for a thymidine NRTI, such as stavudine or zidovudine, causes a minimal, albeit statistically significant increase in subcutaneous fat. Lipoatrophy does not fully resolve. In one study, switching from stavudine or zidovudine to abacavir caused a 0.4-kg increase in total limb fat after 24 weeks and a 1.3-kg increase in total limb fat after 104 weeks. However, that gain is insufficient to reach the levels seen in control populations. Complete cessation of therapy without replacement of NRTI results in virologic failure. Switching from PIs to nevirapine, efavirenz, or abacavir did not improve peripheral lipoatrophy. The newer NRTIs, tenofovir and emtricitabine, have been associated with less peripheral lipoatrophy than stavudine.

Thiazolidinediones are potentially attractive agents for treatment of peripheral lipoatrophy and insulin resistance. As ligands for the transcription factor perioxosome proliferator–activated receptor gamma (PPARγ), thiazolidinediones promote adipocyte differentiation. Unfortunately, two randomized studies found no improvement and a third showed minimal improvement in lipoatrophy after thiazolidine treatment for at least 24 weeks. However, the studies did show the expected improvement in insulin resistance.

Reconstructive therapy is available for peripheral lipoatrophy. Injectable skin fillers for the face include bioabsorbable and permanent fillers. Bioabsorbable fillers such as poly-l-acetic acid stimulate collagen production. In one open-label, single-arm study, 43% of patients had an increase in cutaneous thickness greater than 10 mm in the face after 96 weeks of therapy. The effects on collagen production last for approximately 18 months. Hyaluronic acid has also been used to a lesser extent in the treatment of facial lipoatrophy. Side-effects include easy bruisability, redness, and swelling. Permanent fillers are generally not recommended due to the dynamic nature of fat loss in peripheral lipoatrophy. More invasive procedures include autologous fat transplants.

Central lipohypertrophy has been treated with GH and GHRH analogues. At high doses (6 mg/d), GH decreased visceral fat by 21% to 24%. However, a significant number of patients experienced joint swelling, fluid retention, and deterioration in glucose tolerance. A lower dose of GH (3 mg/d) also reduced visceral fat, although to a lesser extent. With further dose reduction, GH (1 mg/d) decreased total fat, but did not significantly alter visceral fat content. A GHRH analogue, tesamorelin, is a recently approved therapy for reduction of visceral obesity in HIV-lipodystrophy that limits the side-effects of excessive GH secretion by increasing the endogenous pulsatility of GH secretion. Tesamorelin (2 mg/d) given for 26 weeks decreased visceral fat by 15%. Unlike GH therapy, tesamorelin did not induce insulin resistance; there were fewer GH-like symptoms of joint and fluid retention. GH therapy is very expensive, and the effects of GH and GHRH reverse when therapy is stopped.

Shortly after the introduction of HAART, reports of impaired fasting glucose, glucose intolerance, diabetes, and hyperlipidemia appeared in the HIV literature. Given the close temporal relationship to the introduction of PIs, studies focused on the association with PIs. However, other factors such as restoration of health, immune reconstitution, and body composition changes (including lipoatrophy and visceral hypertrophy) may also contribute to the disturbances in metabolism. To clarify these issues, several groups have given HIV antiretroviral drugs to healthy, HIV-seronegative volunteers in order to define direct drug effects. In the sections later, the results in HIV-infected subjects will be compared to those in healthy volunteers to understand the effects of drug versus disease. Metabolic effects are specific to certain drugs and not an effect of the PI class as a whole.

Insulin Resistance, Glucose Intolerance, and Diabetes

With the reports of rapid onset of diabetes after introduction of HAART with a PI, researchers looked for effects of PI on insulin resistance. Subsequent studies looked at hepatic glucose production and insulin secretion.

Several factors contribute to the development of insulin resistance in the setting of HIV. Unlike other infectious states, in which insulin resistance is common, early in the epidemic, AIDS was found to be associated with an increase in insulin sensitivity (Table 25–4). Compared with 10 healthy controls, insulin sensitivity was higher in 10 stable patients with symptomatic HIV. However, with asymptomatic HIV infection, another early study found that there was no change in insulin sensitivity compared with healthy controls. Insulin resistance is common in healthy subjects. Thus, improvement of HIV infection alone may contribute to an observed decrease in insulin sensitivity. More recent studies have found insulin resistance in ARV-naïve, HIV-infected subjects.

Body composition influences insulin sensitivity. Patients studied early in the epidemic, were thin, if not cachectic. In recent studies body weight was higher even in many ARV-naïve patients. Increased visceral fat in the abdomen has been linked to insulin resistance in subjects with or without HIV disease. Upper trunk fat is also independently, strongly associated with insulin resistance. Likewise, severe lipoatrophy has been linked to insulin resistance regardless of HIV status. The lesser levels of lipoatrophy seen in most HIV-infected patients may also contribute. It should be recognized that each of these factors may contribute in an additive way to insulin resistance.

Much attention has focused on the role of individual therapies in the induction of insulin resistance. Some PIs have been reported to decrease insulin-mediated glucose disposal per unit insulin level (M/I) during the hyperinsulinemic, euglycemic clamp, a technique during which insulin is infused at a steady rate and glucose infused to maintain euglycemia, which directly measures insulin action. In a double-blind, placebo-controlled study in healthy normal volunteers, a single dose of indinavir has been shown to decrease insulin-mediated glucose disposal by 34% (Table 25–5). Indinavir for 4 weeks has also been shown to cause a 17% decrease in insulin-mediated glucose disposal as well as deterioration in glucose tolerance. A single dose of ritonavir decreased insulin sensitivity by 15%. Lopinavir/ritonavir has less of an effect on insulin sensitivity, but the magnitude of this effect is not clear (see Table 25–5). In two studies, lopinavir/ritonavir given for 4 weeks caused no change in insulin sensitivity, whereas in shorter studies, lopinavir/ritonavir given for 1 to 5 days was associated with a 13% to 24% decrease in insulin sensitivity. The study reporting a 13% decrease compared rates in the same subjects on placebo and lopinavir/ritonavir; the study reporting the 24% decrease presented pooled data from some subjects who received both placebo and drug on different occasions, some drug only and some placebo only.

Of note, not all PIs decrease insulin-mediated glucose disposal. In double-blind, placebo-controlled studies, atazanavir and amprenavir had no effect on insulin sensitivity in healthy normal volunteers (see Table 25–5). NNRTIs have not been associated with insulin resistance. In studies where PIs are replaced with NNRTIs, insulin resistance improved.

The mechanism of insulin resistance with PIs includes the acute blockade of the peripheral insulin-regulated glucose transporter (GLUT)4. In vitro studies have shown that PIs (indinavir, ritonavir, and amprenavir) selectively inhibit 2-deoxyglucose transport into 3T3-L1 adipocytes without affecting early insulin-signaling events or the translocation of intracellular GLUT4 to the surface. Indinavir has also been shown to block partially GLUT2, the glucose transporter postulated to be involved in glucose sensing in the pancreas and regulation of insulin secretion. Recently, an analog of the peptidomimetic phenylalanine moiety found in all PIs has been shown to inhibit GLUT4-induced glucose transport in vitro. Because serum levels of PIs vary, some PIs, such as amprenavir, may block GLUT4 in vitro but have no effect in patients.

Increased insulin resistance has also been found in HIV-infected subjects on NRTI therapy. However, it is unclear if the effects of NRTIs are a direct effect of the drug, reactivation of the immune system, restoration of health, or changes in body composition. When stavudine was given to healthy volunteers, there was no decrease in M/I.

In addition to peripheral insulin resistance, impairment in insulin secretion was reported in HIV patients on PI therapy. In HIV-infected subjects treated with either nelfinavir, indinavir, lopinavir/ritonavir, or saquinavir, beta cell function assessed by first-phase insulin secretion showed a 25% decrease. However, insulin secretion in the HIV-infected patients was higher than controls before PI therapy and was reduced only to that of controls after PI therapy. The HIV-infected patients had suppression of HIV RNA levels and increases in CD4 counts. More recently, healthy normal volunteers were given lopinavir/ritonavir for 4 weeks, and no effect was seen on first-phase insulin secretion. Thus, it is not clear whether currently used PIs alter insulin secretion.

Hepatic glucose production is also increased in some patients on PIs. Endogenous glucose production, comprised mostly of hepatic gluconeogenesis and glycogenolysis, is the largest determinant of fasting glucose and can be measured by tracer stable isotope technology. In studies of healthy normal volunteers, indinavir increased endogenous glucose production in the fasting state. During the hyperinsulinemic, euglycemic clamp, indinavir blunted the ability of insulin to suppress endogenous glucose production. Endogenous glucose production was not increased in rats treated with intravenous indinavir during a hyperinsulinemic, euglycemic clamp study. However, the method of stable isotope analysis was different in the rat and human studies, which may explain the discrepancy in results. In humans, full-dose ritonavir has a small detrimental effect on endogenous glucose production, while amprenavir had no effect. The effects of other PIs remain to be determined.

Adipocytokine levels have been explored in HIV infection, and they may explain some of the results in glucose metabolism. Adiponectin, a hormone secreted by adipocytes, has been shown to increase peripheral and hepatic insulin sensitivity. Adiponectin levels inversely correlate with the amount of visceral fat in HIV-negative subjects. In patients with HIV-associated peripheral lipoatrophy, adiponectin levels are reduced. Low adiponectin levels have been proposed to mediate some of the insulin resistance observed in peripheral lipoatrophy and visceral lipohypertrophy. The mechanism which reduces adiponectin levels is unknown. Some have attributed the reduction to PI therapy. In vitro studies of cultured fat cells have suggested that PI treatment suppresses adiponectin mRNA and protein expression. However, two studies in healthy normal volunteers found that in fact adiponectin levels were increased during treatment with the PIs indinavir or lopinavir/ritonavir. The discrepancy in the effect of PIs on adiponectin levels in vitro and in humans is not well understood.

Levels of leptin, another hormone secreted by adipocytes, correlate with insulin resistance. However, some diseases with very low leptin levels also have insulin resistance. Leptin levels have been shown to be decreased in HIV patients with peripheral lipoatrophy.

Current guidelines set forth by the International AIDS Society-USA (IAS-USA) suggest measuring fasting glucose levels before and during PI therapy. In patients with risk factors for diabetes or with peripheral lipoatrophy or visceral lipohypertrophy, oral glucose tolerance testing may be warranted. Patients with preexisting abnormalities in glucose metabolism or with first-degree relatives with diabetes mellitus should consider avoiding the PIs most associated with insulin resistance; atazanavir and newer PIs may be better choices.

Treatment of PI-induced diabetes should ideally be tailored to the specific alteration in glucose metabolism. Although there are no studies of treatment of PI-induced diabetes per se, there are studies of therapy of patients who have HIV-associated lipoatrophy and lipohypertrophy who also are taking PIs. Thiazolidinediones can ameliorate peripheral insulin resistance induced by PIs. Thiazolidinediones improve insulin resistance in patients with HIV-associated lipoatrophy and lipohypertrophy. Proliferation of lipomas has been reported in one patient with HIV-associated lipoatrophy. Given the recent findings that thiazolidinediones decrease BMD and may increase fracture risk, caution is warranted in HIV-infected patients as they may be at higher risk for bone loss and fracture. Metformin decreases hepatic glucose production and peripheral insulin resistance. Metformin should be used with caution in combination with NNRTI's stavudine and didanosine, which, like metformin, are associated with increased lactic acidosis. Sulfonylureas may prove to be useful in improving insulin secretion. Due to the risk of hypoglycemia, sulfonylureas should be used with caution in treating mild PI-induced diabetes.

Other medications used to treat opportunistic infections are associated with hyperglycemia and hypoglycemia. Pentamidine causes pancreatic beta cell toxicity, acutely leading to hypoglycemia, and over the long-term, it causes diabetes mellitus. Hypoglycemia during pentamidine treatment is associated with increased length of treatment, higher cumulative doses, and renal insufficiency. Patients who develop hypoglycemia in association with pentamidine therapy are at increased long-term risk of developing diabetes mellitus. HIV-infected patients who develop diabetes mellitus following pentamidine therapy have low C peptide levels, suggesting beta cell destruction. Aerosolized pentamidine therapy has also been reported to cause hypoglycemia and diabetes mellitus. Pentamidine, trimethoprim-sulfamethoxazole, and the nucleoside analogs didanosine and zalcitabine have been associated with acute pancreatitis. Megestrol acetate, which has intrinsic glucocorticoid activity, may be associated with diabetes mellitus in HIV-infected patients, perhaps through its glucocorticoid activity, although the rate of hyperglycemia in controlled clinical trials appears to be low. GH can also cause insulin resistance, leading to hyperglycemia and diabetes. Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25–2.

Lipid Disorders

Alterations in lipid and lipoprotein profiles are common in patients infected with HIV. The observed changes can be due to a number of interrelated issues, including HIV infection itself, antiviral medications, body composition changes, and immune reconstitution. A rational approach to disturbances in lipid metabolism is to assess the status of the HIV infection, medications used to treat HIV, and presence of body composition changes (including peripheral lipoatrophy and central lipohypertrophy). The following section reviews the lipid and lipoprotein profiles individually, with an emphasis on studies prospectively measuring fasting lipid levels.

HIV infection is associated with a mild increase in triglyceride and very low density (VLDL) cholesterol levels (see Table 25–4). Triglyceride and VLDL cholesterol levels rise in association with advancing HIV disease and correlate with HIV RNA levels. The increased triglycerides are thought to be due to interferon-alpha induced decreased clearance of triglycerides and, to a lesser extent, increased VLDL production.

Several antiviral medications can increase triglyceride levels. Full-dose ritonavir can cause a two- to three-fold increase in triglyceride levels, probably by increased VLDL production (see Table 25–5). Ritonavir has been shown in vitro to inhibit the degradation of apolipoprotein B, a protein involved in the formation of VLDL particles. Other studies have suggested that activated sterol regulatory-binding proteins (SREBPs) in the liver are involved in the increase in VLDL production. Because of its ability to inhibit the hepatic enzyme CYP3A4, ritonavir is used to increase the pharmacologic doses of other PIs metabolized through the same cytochrome system. Boosting doses of ritonavir (100 mg twice daily) have also been shown to increase triglycerides, albeit to a lesser extent. The combination lopinavir/ritonavir given to healthy normal volunteers increased triglycerides and VLDL cholesterol levels by 83% and 33%, respectively. Tipranavir/ritonavir produces similar increases to those of lopinavir/ritonavir in HIV-infected individuals. Not all PIs alter triglyceride levels; in healthy normal volunteers, administration of indinavir and atazanavir resulted in no change in triglyceride levels (see Table 25–5). The data are mixed on amprenavir and nelfinavir, with some studies showing an increase in triglycerides and others finding no effect.

The NNRTI efavirenz is associated with increased triglycerides. Again, this is not a class effect as another NNRTI, nevirapine, has not been associated with alterations in triglyceride metabolism.

The effects of NRTIs on lipid metabolism have not been well studied. In some, but not all studies, stavudine use was associated with increased triglyceride levels. The most informative trial compared stavudine with tenofovir and found an increase in triglycerides in the stavudine arm, but not in the tenofovir arm. Given that all subjects got efavirenz, a likely interpretation is that there was a lipid-lowering effect of tenofovir; other data support this interpretation, as adding tenofovir to an effective ARV regimen lowers lipids.

The original clinical syndrome of HIV lipodystrophy has also been reported to be associated with increased triglyceride levels. One study found that 57% of patients with both peripheral lipoatrophy and central lipohypertrophy had triglyceride levels above 300 mg/dL. It has long been recognized that visceral obesity in the general population is associated with high triglycerides. However, recent data suggest that lower body fat is protective, as increased levels of lower body fat are associated with lower triglycerides in both HIV-infected patients and controls. Therefore, the loss of lower body fat in HIV-associated lipoatrophy is another reason why triglycerides are high in HIV infection. Hypertriglyceridemia is well known to be multifactorial; genes, diet, alcohol, and physical activity also play a role. In HIV infection, one can add the synergistic effects of the host response to HIV itself, treatment with ritonavir and efavirenz, and HIV-lipoatrophy to the pathogenesis.

After the introduction of HAART, a reported increase in low-density lipoprotein (LDL) cholesterol levels was largely attributed to PI therapy. Recently, it has become increasingly clear that factors other than PIs contribute to this rise in LDL cholesterol levels. In the early stages of HIV infection, LDL cholesterol levels fall (see Table 25–4). With effective therapy, LDL cholesterol levels rise in response to suppression of the infection, independent of the type of therapy. Most, but not all PIs have been associated with increases in LDL cholesterol levels, but average levels are not high. Studies in healthy normal volunteers have provided insight into the direct effects of PIs on cholesterol metabolism apart from those associated with HIV infection. Indinavir, ritonavir, lopinavir/ritonavir, and atazanavir all have no effects on LDL cholesterol levels in healthy normal volunteers (see Table 25–5). In patients with HIV infection, treatment with the NNRTI nevirapine raises LDL cholesterol levels. Studies that involve switching patients from PIs to the NNRTIs nevirapine and efavirenz found that LDL cholesterol levels do not change. Hence, the increase in LDL cholesterol seen in HIV-infected patients is not solely an effect of PI therapy, but likely represents suppression of HIV and restoration to health. Tenofovir may lower LDL levels.

HIV infection and the NNRTIs have significant effects on high-density lipoprotein (HDL) metabolism. Early in the course of HIV infection, prior to the appearance of clinically evident disease, HDL cholesterol levels decline to levels around 25 to 35 mg/dL (see Table 25–4). With advancing HIV disease, HDL cholesterol levels continue to decline to less than 50% of baseline values. The pathogenesis of these changes is not well understood. Shortly after the introduction of PIs, one cross-sectional study reported decreased HDL cholesterol levels in HIV-infected patients. However, subsequent studies have failed to show a decrease in HDL cholesterol levels in either HIV-infected patients or healthy normal volunteers. Indeed, some studies have found modest increases (13%-21%) in HDL cholesterol levels during treatment with indinavir, nelfinavir, amprenavir, and atazanavir therapy in prospective studies of HIV-infected patients. More impressive is the nearly 50% increase in HDL cholesterol seen during treatment with the NNRTI nevirapine. Efavirenz has also been shown to increase HDL cholesterol levels by 15% to 23%. When patients were switched from PIs to the NNRTIs efavirenz and nevirapine, somewhat smaller increases were seen again supporting the concept that HAART with PI induces small increases in HDL. Hence, the increase in HDL cholesterol levels is likely directly due to NNRTI therapy. In some studies, HDL levels have been reported to be lower in patients with HIV-associated lipodystrophy, but the extent to which that decrease is due to HIV is not clear. Visceral obesity and upper trunk fat are associated with lower HDL levels.

A panel of the IAS-USA has suggested guidelines for the diagnosis and treatment of dyslipidemia in HIV-infected subjects. The National Cholesterol Education Program guidelines are recommended for initiating therapy in patients infected with HIV. To monitor for dyslipidemia, a fasting lipid panel should be obtained before initiating or switching therapy. Lipid panels should be repeated 3 to 6 months after starting ARV therapy. In those patients with preexisting cardiovascular disease (CVD) or uncontrollable hyperlipidemia, switching HIV therapy should be considered if the regimen is one linked to the observed dyslipidemia and it is refractory to conventional treatment.

Hypolipidemic therapy should be tailored to the type of dyslipidemia. For patients with triglyceride levels greater than 500 mg/dL, fibrate therapy is recommended. Studies have shown that gemfibrozil and fenofibrate are effective in reducing triglyceride levels in patients infected with HIV, but those who start at high triglyceride levels do not reach normal levels. Fish oil lowers triglycerides, but raises LDL, leading to no net decrease in CVD risk. Niacin is effective and has the advantage of raising HDL levels as well as lowering triglycerides, but niacin-induced insulin resistance may be problematic in HIV-infected patients. HMG-CoA reductase inhibitors may be better second-line agents for lowering triglycerides. As with HIV-negative patients, combination pharmacologic therapy may be required to correct extremely elevated triglyceride levels.

HMG-CoA reductase inhibitors are effective, first-line agents for the treatment of hypercholesterolemia. However, there are multiple drug-drug interactions that are important in HIV-infected patients. Some statins are metabolized by Cyp3A4 which is induced or inhibited by some ARV drugs. In particular, the combination of PI and simvastatin or lovastatin should not be used. PI, especially ritonavir, which is used to boost levels of many HIV ARV drugs to therapeutic levels, inhibit Cyp3A4 which is the major metabolic pathway for simvastatin and lovastatin. Ritonavir-based regimens increase simvastatin levels by 5- to 32-fold and multiple cases of rhabdomyolysis have been reported on such combinations. Atovastatin activity increases twofold, so 80 mg atorvastatin should be avoided. Lopinavir/ritonavir increases rosuvastatin levels two- to fivefold, and tipranvir/ritonavir increases rosuvastatin levels twofold and atorvastatin levels eightfold by unknown mechanisms. If those PI combinations are used, only low doses of rosuvastatin (5 mg) and atorvastatin (10 mg) should be tried. Thus, pravastatin and fluvastatin XL are recommended as first-line statins for patients on PI- or ritonavir-based HAART.

The effects of HIV protease inhibitors on glucose and lipid metabolism are shown in Table 25–5.

HIV, Antiretroviral Therapy, and Risk of Atherosclerosis

The changes in lipid and glucose metabolism seen in HIV raise the question about whether atherosclerosis increases due to HIV or its therapies. Retrospective studies report an increased prevalence of CVD in HIV-infected patients. Some studies also found an association with ARV therapy, particularly PI therapy, in addition to traditional risk factors such as age, gender, smoking, and LDL and HDL cholesterol levels. Smoking is more prevalent in those with HIV infection versus noninfected controls. Cross-sectional studies of the intima media thickness (IMT) of the carotid and femoral arteries by ultrasound have also shown that traditional CVD risk factors provide the dominant contribution to increased plaque. However, after adjusting for traditional CVD risk factors, HIV infection is an independent risk factor for increased IMT, similar in magnitude to male sex, diabetes, and smoking.

Some of the changes in HIV infection are similar to those seen in other serious illnesses (euhormone-sick syndrome). However, many of the endocrine and metabolic changes that occur with HIV infection are unique to HIV and require careful consideration in diagnosis and treatment. In addition to the HIV disease state itself, several factors contribute to the development of these changes such as opportunistic infections, immune reconstitution, and ARV medications. As patients are living longer due to the introduction of effective ARV therapy, there is increased interest in the long-term implications of metabolic alterations such as insulin resistance, dyslipidemia, and body composition changes. Given the increased atherosclerotic disease in HIV-infected patients, more aggressive treatment of dyslipidemia is warranted.

Thyroid Function

Adrenal Function

Bone and Mineral Metabolism

Gonadal Function

AIDS Wasting Syndrome

Fat Redistribution Associated with HIV

Glucose and Lipid Metabolism

HIV, Antiretroviral Therapy, and the Risk of Atherosclerosis