Approach to the human immunodeficiency virus-infected patient with lipodystrophy

Subcutaneous atrophy and central fat accumulation are common among HIV-infected patients receiving highly active antiretroviral therapy, and may be accompanied by dyslipidemia and insulin resistance. These fat changes, although commonly referred to together as lipodystrophy, are best considered as separate disorders, with distinct pathogeneses and treatment approaches. These morphological and metabolic abnormalities first appeared after introduction of protease inhibitors more than 10 yr ago, but research has demonstrated that their pathogenesis is multifactorial, with contributions from other antiretroviral medications, patient-related factors, and HIV itself. Switching to a less toxic highly active antiretroviral therapy regimen has shown partial effectiveness for the management of fat atrophy and lipid abnormalities. Lifestyle modification or surgical approaches are the treatment of choice for lipohypertrophy, although novel therapies targeting the GH axis show promise. HIV-related dyslipidemia may be difficult to treat, and can be complicated by drug-drug interactions between some lipid-lowering medications and antiretroviral medications. Treatment of diabetes in HIV-infected patients should generally follow established guidelines, but thiazolidinediones, rather than metformin, may be considered first-line treatment in a patient with lipoatrophy, given their potential to increase sc fat. The contribution of body fat changes and metabolic abnormalities to cardiovascular risk and the changing risk profiles of newer antiretroviral regimens are under intense investigation.     

Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome

Although prior studies suggest reduced androgen levels in women with acquired immune deficiency syndrome wasting, little is known regarding the regulation of adrenal and ovarian androgen secretion in such patients. We investigated ovarian and adrenal function in 13 human immunodeficiency virus-infected women with acquired immune deficiency syndrome wasting and 21 age- and body mass index-matched healthy control subjects studied in the early follicular phase. Subjects received hCG (5000 U, im) on d 1 and Cosyntropin (0.25 mg, i.v.) on d 3 after dexamethasone (1 mg, orally, at 2400 h) pretreatment on d 2. At baseline, human immunodeficiency virus-infected subjects demonstrated significantly reduced T [18 +/- 2 vs. 25 +/- 2 ng/dl (0.6 +/- 0.1 vs. 0.9 +/- 0.1 nmol/liter); P = 0.02], free T [1.5 +/- 0.1 vs. 2.4 +/- 0.2 pg/ml (5.3 +/- 0.5 vs. 8.3 +/- 0.6 pmol/liter); P = 0.001], androstenedione [119 +/- 6 vs. 162 +/- 14 ng/dl (4.16 +/- 0.20 vs. 5.66 +/- 0.48 nmol/liter); P = 0.02], and dehydroepiandrosterone sulfate [0.96 +/- 0.17 vs. 1.55 +/- 0.19 microg/ml (2.6 +/- 0.5 vs. 4.2 +/- 0.5 micromol/liter); P = 0.047] levels compared with the control subjects. T [8 +/- 2 vs. 6 +/- 2 ng/dl (0.3 +/- 0.1 vs. 0.2 +/- 0.1 nmol/liter); P = 0.48], free T [0.5 +/- 0.2 vs. 0.4 +/- 0.1 pg/ml (1.7 +/- 0.7 vs. 1.5 +/- 0.5 pmol/liter); P = 0.85], 17 hydroxyprogesterone [0.5 +/- 0.2 vs. 0.7 +/- 0.2 microg/liter (1.6 +/- 0.6 vs. 2.0 +/- 0.6 nmol/liter); P = 0.63], and androstenedione [-1 +/- 12 vs. 8 +/- 11 ng/dl (-0.03 +/- 0.42 vs. 0.28 +/- 0.39 nmol/liter), P = 0.61] responses to hCG were not different between the groups. Cortisol responses were increased and dehydroepiandrosterone sulfate responses were decreased in the human immunodeficiency virus-infected vs. control subjects after ACTH stimulation. The ratio of DHEA to cortisol was significantly decreased at 60 (71 +/- 11 vs. 107 +/- 10; P = 0.02) and 90 (63 +/- 8 vs. 102 +/- 9; P = 0.004) min post-ACTH in the human immunodeficiency virus-infected patients compared with control subjects. Baseline urinary free cortisol levels were not different between the groups [36 +/- 9 vs. 36 +/- 5 microg/24 h (99 +/- 26 vs. 100 +/- 13 nmol/d)]. The DHEA to cortisol ratio correlated with the CD4 count (r = 0.67; P = 0.01). These data demonstrate significant shunting of adrenal steroid metabolism away from androgenic pathways and toward cortisol production in human immunodeficiency virus-infected women with the wasting syndrome. In contrast, our data suggest intact ovarian androgen responsivity to hCG stimulation. Further studies of the mechanism of adrenal steroid shunting and the efficacy of androgen replacement in human immunodeficiency virus-infected women are necessary.     

Factors influencing the development of lipodystrophy in human immunodeficiency virus-infected patients

238 human immunodeficiency virus-infected patients on highly active antiretroviral therapy (HAART) were studied, 67 of whom (28.2%) developed lipodystrophy. The presence of hyperlipidaemia (p = 0.002) and of hepatitis C virus coinfection (p = 0.014) were associated with lipodystrophy, but only the duration of HAART was significantly predictive of lipodystrophy (p < 0.0001) in the multivariate analysis.     

Gynecologic infections in human immunodeficiency virus-infected women.

The maturation of the acquired immunodeficiency syndrome epidemic has now claimed more than 12 million women worldwide, the majority in undeveloped countries where human immunodeficiency virus (HIV) and sexually transmitted infections coexist and interact synergistically. Among HIV-infected women, there is excessive morbidity due to sexually transmitted diseases (STDs) and gynecologic disorders. This review summarizes the expanding understanding of vaginal flora, vaginitis, cervicitis, pelvic inflammatory disease, and genital ulcer disease in HIV-infected women. In addition to the altered clinical course, complications, and management difficulties of STDs, some gynecologic infections may influence HIV transmission as well as the vertical transmission of HIV to the newborn. Finally, severe immunodeficiency allows unusual opportunistic pathogens to invade the upper and lower genital tract. Control and prevention of gynecologic infections in HIV-positive and HIV-negative women are key components to preventing further HIV transmission.     

Anemia in human immunodeficiency virus-infected and uninfected women in Rwanda

To determine the prevalence and risk factors of anemia among human immunodeficiency virus (HIV)-infected women in Rwanda and the influence of highly active antiretroviral therapy (HAART) on anemia, we analyzed 200 HIV-positive women and 50 HIV-negative women in a cross-sectional study. Clinical examinations and iron and vitamin B(12) assays were performed, and complete blood counts, serum folic acid levels, and CD4 cell count determined. The prevalence of anemia was significantly higher among HIV-positive women (29%) than among HIV-negative women (8%) (P < 0.001). Risk factors for anemia were lower body mass index (odds ratio [OR] = 3.4, 95% confidence interval [CI] = 2.4-4.1), zidovudine use (OR = 1.14, 95% CI = 1.01-1.29), lack of HAART (OR = 1.44, 95% CI = 1.21-1.67), oral candidiasis (OR = 1.4, 95% CI = 1.2-1.6), pulmonary tuberculosis (OR = 1.8, 95% CI = 1.7-2.2), cryptococcal meningitis (OR = 1.6, 95% CI = 1.21-1.8), Pneumocystis jiroveci pneumonia (OR = 1.41, 95% CI = 1.20-1.65) and CD4 lymphocyte count < 200 cells/μL (OR = 2.41, 95% CI = 2.01-3.07). The mean ± SD hemoglobin level of 10.9 ± 1.6 g/dL at HAART initiation significantly increased to 12.3 ± 1.5 g/dL in 8 months (P < 0.001). Anemia increases with HIV stage, and HAART is associated with a significant improvement in hemoglobin levels.     

Effects of testosterone replacement in human immunodeficiency virus-infected women with weight loss

The objective of this study was to determine whether physiological testosterone replacement increases fat-free mass (FFM) and muscle strength and contributes to weight maintenance in HIV-infected women with relative androgen deficiency and weight loss. Fifty-two HIV-infected, medically stable women, 18-50 yr of age, with more than 5% weight loss over 6 months and testosterone levels below 33 ng/dl were randomized into this double-blind, placebo-controlled trial of 24-wk duration. Subjects in the testosterone group applied testosterone patches twice weekly to achieve a nominal delivery of 300 mug testosterone over 24 h. Data were evaluable for 44 women. Serum average total and peak testosterone levels increased significantly in the testosterone group, but did not change in the placebo group. However, there were no significant changes in FFM (testosterone, 0.7 +/- 0.4 kg; placebo, 0.3 +/- 0.4 kg), fat mass (testosterone, 0.3 +/- 0.7 kg; placebo, 0.6 +/- 0.7 kg), or body weight (testosterone, 1.0 +/- 0.9 kg; placebo, 0.9 +/- 0.8 kg) between the two treatment groups. There were no significant changes in leg press strength, leg power, or muscle fatigability in either group. Changes in quality of life, sexual function, cognitive function, and Karnofsky performance scores did not differ significantly between the two groups. High-density lipoprotein cholesterol levels decreased significantly in the testosterone group. The patches were well tolerated. We conclude that physiological testosterone replacement was safe and effective in raising testosterone levels into the mid to high normal range, but did not significantly increase FFM, body weight, or muscle performance in HIV-infected women with low testosterone levels and mild weight loss. Additional studies are needed to fully explore the role of androgens in the regulation of body composition in women.     

Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy.

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.     

Absence of polycystic ovary syndrome features in human immunodeficiency virus-infected women despite significant hyperinsulinemia and truncal adiposity

CONTEXT: HIV-infected women increasingly demonstrate insulin resistance and fat redistribution characterized by relative truncal adiposity. It is unknown whether insulin resistance and truncal adiposity are associated with features of the polycystic ovary syndrome in this population. OBJECTIVE: The objective of the study was to characterize ovarian morphology and reproductive indices in a large cohort of HIV-infected women in comparison with healthy age- and body mass index-matched control subjects. SETTING: The study was conducted at an academic medical center. SUBJECTS: Eighty-eight HIV-infected women were compared with 94 age- and body mass index-matched healthy control subjects. MAIN OUTCOME MEASURES: Androgen, SHBG, and gonadotropin levels and ovarian morphology were measured. RESULTS: HIV-infected subjects demonstrated increased visceral adipose tissue (VAT) (101 +/- 6 vs. 71 +/- 5 cm2; P < 0.0001), increased VAT to s.c. adipose tissue ratio, and a trend toward decreased abdominal s.c. adipose tissue. Fasting insulin (12 +/- 1 vs. 6 +/- 1 microIU/ml; P < 0.001) and 2-h glucose (124 +/- 4 vs. 106 +/- 4 mg/dl; P = 0.001) were also significantly increased in the HIV-infected women, compared with control subjects, respectively. Despite significant hyperinsulinemia and visceral adiposity, HIV-infected women did not demonstrate irregular menses or an increased number of small ovarian follicles (8.0 +/- 0.9 vs. 8.5 +/- 0.7 follicles; P = 0.65, HIV-infected vs. controls). Rather, SHBG (124 +/- 10 vs. 84 +/- 4 nmol/liter; P < 0.001) was increased significantly in HIV-infected women, and free testosterone by equilibrium dialysis was significantly reduced (2.2 +/- 0.2 vs. 2.7 +/- 0.2 pg/ml; P = 0.04), as was LH to FSH ratio (0.62 +/- 0.05 vs. 0.83 +/- 0.07; P = 0.03). Menstrual function, androgen levels, and ovarian morphology by ultrasonography were not different between HIV-infected women and healthy controls. CONCLUSIONS: These data demonstrate that among HIV-infected subjects with severe abdominal fat accumulation and hyperinsulinemia, common features of polycystic ovary syndrome are not seen.     

Bronchoscopy in the human immunodeficiency virus-infected patient

The spectrum of pulmonary manifestations in patients infected with human immunodeficiency virus (HIV) is broad, including many infectious and noninfectious complications. In the evaluation of an HIV-infected patient with diffuse pulmonary disease a definitive diagnosis is preferred over empiric therapy in most patients. Patients with focal consolidation usually receive empiric treatment for community-acquired pneumonia, with nonresponders undergoing additional diagnostic testing. Bronchoscopy remains a cornerstone in the diagnostic evaluation. A multilobar bronchoalveolar lavage (BAL) is usually sufficient for the diagnosis of Pneumocystis carinii pneumonia (PCP) and avoids the additional complications of hemorrhage and pneumothorax associated with transbronchial biopsy (TBBX). However, TBBX improves the sensitivity for diagnosis of tuberculosis and fungal pneumonias and is necessary to confirm invasive aspergillosis. Definitive criteria for diagnosis of cytomegalovirus pneumonitis have yet to be established, although bronchoscopic specimens usually are used. Tissue confirmation with TBBX is required for the diagnosis of noninfectious disorders such as non-Hodgkin's lymphoma and lymphocytic and nonspecific pneumonitis. Bronchoscopic visualization of typical lesions often is sufficient for the presumptive diagnosis of Kaposi's sarcoma (KS) although the diagnostic yield is enhanced by the detection of human herpes virus 8 in BAL samples.     

Association of vitamin A deficiency with cervical squamous intraepithelial lesions in human immunodeficiency virus-infected women

To explore the relationship between vitamin A (retinol) deficiency and cervical squamous intraepithelial lesions (SILs) in human immunodeficiency virus (HIV)-infected women, we measured serum retinol concentrations in 1314 women enrolled in the Women's Interagency HIV Study and correlated the results with concurrent cervical cytology. At the baseline visit, 204 (15.5%) of the 1314 patients had retinol concentrations consistent with deficiency (<1.05 micromol/L). Analysis of Papanicolaou smears showed SILs in 216 (16.4%) of 1314 women. Cervical SILs were found to be associated with retinol concentrations <1.05 micromol/L (multivariate odds ratio [OR], 1.63; P=.04) in a multivariate model, which included human papillomavirus (HPV) status and markers of nutritional status and HIV disease stage. In the subset of women with genital HPV (n=774), a multivariate analysis again revealed a significant independent association between retinol <1.05 micromol/L and cervical SILs (multivariate OR, 1.75; P=.02). Our findings suggest that retinol deficiency may contribute to the development of cervical SILs in HIV-infected women.     

Vaginal colonization with Candida spp. in human immunodeficiency virus-infected women: a cohort study

We have conducted a longitudinal study on factors associated with candidal vaginal colonization, a precursor of vaginitis, in a cohort of HIV-infected women in Italy.All consecutive women attending a single, tertiary care clinical site were offered free screening for sexually transmitted infections and genital disorders every 6-12 months. Candidal vaginal colonization was defined as a positive culture for Candida spp. in an asymptomatic woman.From January 1998 to July 2002 we analysed 214 women. The baseline prevalence of candidal vaginal colonization was 16.8%. In the logistic regression analysis, the time since HIV infection > or =36 months (odds ratio [OR] = 0.18, 95% confidence interval [CI] 0.016-0.53, P = 0.002) and a plasma viral load > or =10,000 copies/mL (OR = 3.9, 95% CI 1.03-14.9, P = 0.045) were independently associated with candidal colonization. Among 130 women who were followed for a mean period of 24 months, the incidence of vaginal colonization was 10.7/100 women-years. In the Cox regression analysis, a CD4(+) T-lymphocytes count <100 cells/microL during the follow-up was associated with an increased risk of candidal vaginal colonization (OR = 4.45, C.I. = 1.20-16.81, P = 0.03).Risk of candidal vaginal colonization episodes in HIV-infected women significantly increase when CD4(+) T-lymphocytes are less than 100.     

Ureaplasma urealyticum colonization in the vaginal introitus and cervix of human immunodeficiency virus-infected women

Ureaplasma urealyticum colonization was examined in paired cervical and introital specimens from 56 untreated HIV-seropositive women. Specimens were tested for U. urealyticum by polymerase chain reaction (PCR). Peripheral blood was examined for CD4 lymphocyte counts and HIV RNA concentration. U. urealyticum was detected in the cervix of 38 (69.1%) women. Introital U. urealyticum was present in 16 (28.6%) women, all of whom were cervical-positive. Cervical motion pain was present in 40.0% of women with U. urealyticum in the introitus and cervix, 23.8% of those with only cervical U. urealyticum and 5.9% of women negative for this organism (P=0.03). There was no relation between U. urealyticum colonization and CD4 lymphocyte count. However, 64.3% of women with introital U. urealyticum had circulating HIV RNA levels > 10,000 copies per ml as compared with 28.6% of women with only cervical U. urealyticum and 7.1% of women negative for this organism (P < 0.01).     

Adrenal function in the human immunodeficiency virus-infected patient

Although clinical manifestations of adrenal dysfunction are uncommon in patients infected with human immunodeficiency virus (HIV), subclinical functional abnormalities of the hypothalamic-pituitary-adrenal axis are frequent. Patients infected with HIV usually have higher basal serum cortisol and lower serum dehydroepiandrosterone concentrations than HIV-seronegative individuals. This imbalance has been related to progression of the infection by inducing a shift from T(H)1 to T(H)2 immunologic responses. Although, adrenal reserve may be marginal in HIV-infected patients, clinically evident adrenal insufficiency is uncommon and, when present, it is observed in advanced stages of the infection. Hypocortisolemia should be treated regardless of the existence of associated symptoms. On the contrary, hypercortisolemia in the absence of features of Cushing syndrome is common and should not promote treatment nor specific studies. The possible influence that alterations of the adrenal function could have on the patients' immune status and the eventual effect of antiretrovirals on these alterations merit further investigation.     

Total energy expenditure and carbohydrate oxidation are increased in the human immunodeficiency virus lipodystrophy syndrome

To determine whether total energy expenditure (TEE) is increased in the human immunodeficiency virus (HIV) lipodystrophy syndrome, we compared energy expenditure (EE) and substrate oxidation rates in 12 HIV-infected men with lipodystrophy, 7 HIV-infected men without lipodystrophy, and 14 healthy controls. TEE and nutrient oxidation rates were assessed by whole-room indirect calorimetry. Resting energy expenditure (REE) was measured by indirect calorimetry using the open-circuit technique. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA). Insulin sensitivity was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. TEE adjusted for lean body mass (LBM) was significantly higher in the HIV-infected group with lipodystrophy compared to HIV-infected patients without lipodystrophy (2,873.3 +/- 69 v 2,573.9 +/- 92 kcal/d, P =.02) and compared to healthy controls (2,873.3 +/- 69 v 2,404.0 +/- 64 kcal/d, P <.001). REE and sleeping metabolic rate (SMR) adjusted for LBM were also significantly higher in the HIV-infected group with lipodystrophy compared to both HIV-infected and healthy controls. Carbohydrate oxidation rates adjusted for LBM were higher in men with HIV lipodystrophy as compared to healthy controls (362.5 +/- 23 v 250.0 +/- 22 g/d, P = <.01) and tended to be higher as compared to HIV-infected controls (362.5 +/- 23.6 v 297.3 +/- 31 g/d, P =.1). In conclusion, TEE and carbohydrate oxidation are increased in the HIV lipodystrophy syndrome. The increase in TEE appears to be due to increases in REE. The pathogenesis of elevated EE in HIV lipodystrophy and other forms of lipodystrophy remains to be determined.     

Individual and system level factors associated with treatment nonadherence in human immunodeficiency virus-infected men and women

Antiretroviral treatment nonadherence is complex, implicating more than a patient's ability and motivation to be compliant. The bulk of the research to date focuses on individual level barriers with less emphasis on the many system level factors that potentially impact patients' adherence behaviors. This study examined the effects of system enabling factors in addition to the frequently studied individual predisposing and enabling factors upon nonadherence to treatment. One hundred eighty-two patients from five community-based clinics were interviewed and their medical charts examined. Patients' self-reported nonadherence was correlated with clinicians' assessments of medication and appointment nonadherence. Seven individual predisposing factors (gender, ethnicity, birthplace, years of education, HIV Overview of Problems-Evaluation System [HOPES] psychosocial, Hospital Anxiety and Depression Scale [HADS] anxiety, and HADS depression scores) were found to be significantly associated with treatment adherence/nonadherence. Individual enabling factors (hopefulness and access to health care), as well as treatment by clinic staff, a system enabling factor, were significantly associated with adherence/nonadherence. In a multivariate analysis, six factors - age (younger), gender (female), birth outside the United States, level of hopefulness (lower), access to health care (lower), and treatment by clinic staff (poorer) - accounted for 19.3% of the variance in nonadherence. Results of this study indicated that several individual predisposing and enabling factors were potential predictors of treatment nonadherence; however, system enabling factors, e.g., treatment by clinic staff were also associated with treatment nonadherence. Further studies are needed to examine the complex relationships of individual and system related factors in predicting treatment nonadherence.