Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110.

BACKGROUND: Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches. METHODS: Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48. RESULTS: Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm. CONCLUSIONS: Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy.

OBJECTIVE: We conducted a randomized placebo-controlled trial to examine the effects of metformin on visceral adipose tissue (VAT), appendicular fat, lipid profile and insulin sensitivity in HIV-infected persons with central adiposity and mild insulin resistance. METHODS: Forty-eight HIV-infected men and women with a self-reported increase in abdominal girth and an abnormal waist-to-hip ratio were randomly assigned in double-blind fashion to receive metformin 1500 mg or placebo daily for 24 weeks. Persons with diabetes were excluded. The following measures were obtained at baseline and 24 weeks: single-slice computed tomography (CT) scan, dual-energy X-ray absorptiometry (DEXA), lipid profile and oral glucose tolerance test. RESULTS: The median fasting insulin concentration of all participants was 12.3 microU/mL. The percentage change in VAT was not significantly different between the metformin and placebo groups in univariate analysis and linear regression analysis adjusting for age, height, baseline VAT and insulin area under the curve (10.1% vs 3.2%; P=0.58). Metformin was associated with a significant decrease in appendicular fat mass compared with placebo (-686.0 vs 161.0 g; P=0.03). There was no significant change in lipid profile or insulin sensitivity between the two groups at 24 weeks. CONCLUSION: Metformin should be used with caution in the treatment of HIV lipodystrophy, and, if used, should be reserved for persons with adequate peripheral fat and marked insulin resistance.

Cost-effectiveness of clinical interventions for AIDS wasting.

Economic studies of HIV/AIDS interventions are important for providing cost-effective care. This paper presents a costeffectiveness study of a three-arm clinical trial conducted at Tufts University School of Medicine/New England Medical Center in Boston, Massachusetts that treated 50 patients with AIDS wasting from March 1998 through January 2001. This study compared the costs and impacts of a nutritional counseling intervention alone (NC arm), the nutrition intervention with oxandrolone (OX arm), and the nutrition intervention with progressive resistance training (PRTarm) for the treatment of AIDS wasting. The cost of each intervention was derived for both the three-month clinical trial and a six-month estimated community model (ECM), its projected adaptation to community-based medical care. The cost determination involved obtaining and multiplying unit economic costs and quantities expended of each resource within each study arm. The ECM average cost per client in the cost-effectiveness analysis incorporated both institutional and societal perspectives. The costeffectiveness analysis compared the cost of each intervention to its quality-adjusted life-year (QALY) gain (Zeckhauser and Shepard, 1976). From a societal perspective, for the NC arm, the cost per client totaled US dollars 983 for the actual and US dollars 596 under the ECM. For the OX arm, the cost per client totaled US dollars 3,772 for the actual study and US dollars 3,385 under the ECM. For the PRT arm, the cost per client totaled US dollars 3,189 for the actual study and US dollars 2,987 under the ECM. Under the societal perspective the cost per QALY was US dollars 55,000 (range: US dollars 51,000 to US dollars 83,000) for the NC arm, US dollars 151,000 (range: US dollars 149,000 to US dollars 171,000) for the OX arm, and US dollars 65,000 (range: US dollars 44,000 to US dollars 104,000) for the PRTarm. When using only an institutional perspective, the cost per QALY was US dollars 45,000 (range: US dollars 42,000-US dollars 64,000) for the NC arm, US dollars 147,000 (range: US dollars 147,000 to US dollars 163,000) for the OX arm, and US dollars 31,000 (US dollars 21,000 to US dollars 44,000) for the PRTarm. This paper shows that cost and cost-effectiveness analyses can be adapted to a community setting by combining information from community practice and costs with data from a randomized trial. Compared to other AIDS treatments, such as highly active antiretroviral therapies, all three interventions were affordable, but their cost-effectiveness was intermediate. Oxandrolone was the least cost effective of the interventions, even compared to nutrition alone, as it included similar or somewhat greater costs for less of an increase in quality of life. PRT was the most cost-effective treatment for AIDS wasting, particularly from an institutional perspective. Third party payers should consider coverage of PRT.

Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women.

BACKGROUND: Alterations in body composition have been reported in HIV-positive adults receiving highly active antiretroviral therapy (HAART), but the magnitude and potential determinants of these changes are unclear. OBJECTIVE: We compared total and regional body composition, as measured by dual-energy X-ray absorptiometry, in 203 HIV-positive men and 62 HIV-positive women according to HAART. DESIGN: This was a cross-sectional analysis of a cohort study of nutrition and HIV infection. RESULTS: After adjustment for age, weight, race, and exercise habits, total weight and fat mass did not differ significantly in men or women by HAART. Trunk fat was greater in men (1.0 kg; P < 0.001) and women (1.4 kg; P = 0.005) and leg fat was lower in men (-1.0 kg; P < 0.001) and women (-1.5 kg, P = 0.005) receiving HAART than in those not. This corresponded to a greater percentage of total fat mass located in the trunk (men: 7.5%, P < 0.001; women: 5.1%, P = 0.02). Lean mass was also greater with longer duration of HAART in men (P < 0.002). In men receiving HAART, total and regional bone mineral content were less than in the men not receiving HAART (P < 0.001). These effects increased with longer duration of HAART. Protease inhibitors were associated with the largest differences in regional fat. CONCLUSIONS: HAART is associated with redistribution of fat mass from the legs to the trunk, despite no significant differences in total fat mass or weight. In men, HAART is also associated with a reduction in bone mineral content, suggesting that HAART increases the risk of central obesity and osteoporosis.

Nutrition in the era of highly active antiretroviral therapy.

Despite tremendous advances in treatment, persons with human immunodeficiency virus (HIV) infection commonly experience a variety of nutritional problems, such as weight loss, fat redistribution, and obesity. We discuss basic dietary and metabolic problems as they pertain to persons with HIV infection and provide practical suggestions for their management. In all persons, changes in weight are caused by disruptions of energy balance, which can be disturbed by alterations in energy intake (effective ingestion of calories), energy expenditure (use of calories), or both. Factors that contribute to the disturbance of energy balance are discussed in the context of HIV infection. Management of weight loss and weight gain may then be directed at the affected components of energy balance. This information is intended to raise health care providers' attention to nutrition in their patients, including monitoring of weight, dietary issues, and relevant symptoms, and to encourage liaisons with experienced dietitians and exercise trainers.

Management trends. Resting energy expenditure in the HAART era.

HIV infection in the HAART era is often accompanied by nutritional complications, including rapid weight loss and weight gain. Changes in weight are directly related to shifts in energy balance. Understanding the interplay between dietary intake and energy utilization is important for investigating the factors contributing to a person's weight shifts. Total energy use includes resting metabolic rate, or resting energy expenditure (REE), and voluntary activity, both of which are commonly abnormal in persons with HIV infection. There is now evidence that both the level of viral load and the use of HAART affect REE. The role of energy expenditure in lipodystrophy is unknown but is an area of research interest. The current understanding of energy balance in persons with HIV infection is explained here for the health care provider.

Elevated resting energy expenditure among HIV-seropositive persons receiving highly active antiretroviral therapy.

OBJECTIVES: To ascertain the relationships between resting energy expenditure (REE), HIV RNA in plasma, and highly active antiretroviral therapy (HAART). DESIGN: Cross-sectional analysis using data of a large cohort study of nutrition in relation to HIV disease. METHODS: HIV RNA in plasma, REE, fat-free mass (FFM), and medication regimens were assessed at 530 visits among 372 participants in a cohort study of HIV-seropositive men and women. RESULTS: HIV RNA in plasma was directly correlated with REE. After adjustment for FFM, age, CD4 cell count and HAART use, there was an increase in REE of 90 kJ/day per log10 copies/ml increase in HIV RNA [95% confidence interval (CI) 16-164; P = 0.02). HAART use had an independent effect on REE. In patients reporting HAART use, adjusted REE was 339 kJ/day higher than in those not reporting HAART use (95% CI 177-501; P = 0.0001). CONCLUSIONS: Viral load and HAART appear to exert independent effects on REE. Although HAART may decrease metabolic rate by lowering viral burden, it appears to increase metabolic demands through some mechanism(s) independent of its effect on viral burden. This may result in elevated REE despite control of viral replication.

Effect of a single bout of acute exercise on plasma human immunodeficiency virus RNA levels.

Acute exercise is known to activate the immune system and thus could lead to increased human immunodeficiency virus (HIV) replication. We sought to determine whether a single acute bout of exercise, similar to what people experience when starting an intensive exercise program, has a detrimental effect on plasma HIV RNA levels. Twenty-five patients with HIV infection performed one 15-min bout of acute exercise. Absolute neutrophil counts, serum creatine phosphokinase, and 72-h urinary 3-methylhistidine (a marker of muscle protein breakdown) were measured before and after the exercise, along with plasma HIV RNA levels. There were increases in neutrophil counts (P < 0.06), serum creatine phosphokinase (P < 0. 01), and urinary 3-methylhistidine (P < 0.01) in response to exercise, indicating a mild acute-phase response with muscle proteolysis. However, mean HIV RNA, which was elevated at baseline in 22 of the 25 subjects (mean of 4 x 10(5) +/- 0.7 x 10(5) copies/ml), did not increase during the week after exercise (P = 0. 12). Small changes in RNA were seen in the three subjects with initially undetectable HIV RNA, but the significance of these changes is unclear. Acute exercise does not have a deleterious effect on HIV replication in adults with high viral loads. Because regular exercise training has not been shown to activate the acute-phase response, the lack of increased viral loads in response to an acute exercise intervention suggests that exercise training is safe in people with HIV infection.

Exercise and the treatment of wasting: aging and human immunodeficiency virus infection.

A common feature of human immunodeficiency virus (HIV) infection and aging is the loss of skeletal muscle mass. Although the causes of this loss of muscle are multifactorial, there may be some shared characteristics to this loss, and therefore common strategies for its prevention or reversal. For example, loss of muscle mass early in life and early in the progression of HIV infection may result from decreased levels of physical activity. The rapid loss of skeletal muscle mass at the end of life (sometimes referred to as failure to thrive syndrome) and in acquired immunodeficiency syndrome (AIDS) patients may also have common cause: cachexia. However, it also must be pointed out that loss of skeletal muscle mass with advancing age also may result from losses of motor units, decreased rate of skeletal muscle protein synthesis, and impaired regulation of appetite. These factors have not been demonstrated to be consequences of HIV infection. The use of exercise to treat the losses of muscle size, strength, and functional capacity holds great promise. Although the losses of muscle with HIV infection may be more rapid and dramatic than those seen with aging, resistance exercise training can attenuate or arrest this loss. In elderly people, resistance exercise has been demonstrated to result in increased nitrogen balance, muscle mass and strength, functional capacity, energy requirements, and when combined with a protein calorie supplement, increased energy intake. The use of resistance exercise in HIV-infected patients may also provide similar results. This review discusses many of the changes in body composition, physiological function, and metabolism associated with aging and HIV infection. The specific effects of exercise in the elderly and in patients infected with HIV on the treatment of muscle wasting, and its consequences are also discussed.

Age- and time-related changes in extracellular viral load in children vertically infected by human immunodeficiency virus.

BACKGROUND: It is known that plasma or serum viral load is high in vertically HIV-infected children during the first year of life, but the changes in these titers after the first birthday have not been described. Information on the natural history of circulating extracellular virus will be useful in elucidating the pathogenesis of pediatric HIV infection and in using viral load measurement to guide prognosis and therapy. METHODS: We measured serum RNA by reverse transcriptase-polymerase chain reaction and immune complex-dissociated p24 antigen enzyme-linked immunosorbent assay over time in 48 unselected children followed in our clinics and analyzed the findings in relation to age and clinical outcome. RESULTS: In first-available samples from the 48 children there was a gradual reduction in HIV RNA values with increasing age, with a slope of -0.21 log copy/ml/year (P < 0.001, R2 = 0.6022). This downward trend was seen in subsets of children with all degrees of immunodeficiency. The mean slope of repeated HIV RNA measurements in individual children was similarly in a downward direction (slope -0.11 (P = 0.007 for difference from zero)). The slope was more negative in children who were younger at baseline. Immune complex-dissociated p24 antigen values were much less predictable and predictive. CONCLUSIONS: Viral load in vertically infected children, measured by reverse transcriptase-polymerase chain reaction, falls very gradually over time, descending from very high titers at the end of the first year, and reaching values seen in horizontally infected adults at approximately 5 years of age.

The association between youth, women, and acquired immunodeficiency syndrome.

This article compares the characteristics of women and heterosexual men with AIDS in New York City. The analysis was performed using the New York City AIDS Surveillance Database, namely, those 37,002 persons diagnosed from 1984 to 1993 between ages 15 and 64, excluding men who report sex with other men as their sole risk behavior. The median age at diagnosis was 34 years for women with heterosexually acquired disease, 36 years for women with a history of injection drug use, and 39 years for men, most of whom used injection drugs (p < 0.001). The proportion of women and the rate of increase of this proportion were greater among younger AIDS cases. By 1993 women comprised the majority of cases under age 30, and most of these young women had heterosexually acquired disease. For each decrease in 5-year age group under age 45, the odds of a case being a woman increased by 30% (95% confidence interval = 27, 33%) after adjustment for year. CD4 cell count reporting, and race/ethnicity. There was a somewhat greater youth-gender effect among black persons with AIDS (6% additional increase for each decrease in age group; 95% confidence interval = 3, 10%). Therefore, women are overrepresented among younger persons with AIDS, particularly persons of color. They are largely infected through heterosexual contact with men who have used intravenous drugs.

Lack of effect of cimetidine on lymphocyte subsets in patients infected with human immunodeficiency virus type 1.

Cimetidine, widely used for peptic ulcer disease, blocks type 2 histamine receptors present on immune cells, including T cells, B cells, and monocytes. As an earlier published study showed evidence of increases in CD4 cell counts due to this drug, we conducted a randomized, placebo-controlled, 8-week trial of oral cimetidine (400 mg p.o. t.i.d.) in a study involving 182 patients infected with human immunodeficiency virus (HIV). Overall, cimetidine-treated patients had a decline in CD4+ cell counts that was no different from the decline for placebo-treated persons, neither during the first 8 weeks of the trial (mean drop, 7.1% [standard error, 12.1-1.8] vs. 6.7% [standard error, 11.6-1.5]) nor during the subsequent 8 weeks of open-label administration of cimetidine. No differences were evident between the treatment groups in terms of the percentage reactive to p24 antigen at baseline, and p24 antigen concentrations did not change from baseline to the end of week 8. In summary, cimetidine is well tolerated by HIV-infected individuals but alters neither CD4+ cell counts nor at least one quantitative measure of viral load, HIV p24 antigen levels.

Compliance with zidovudine therapy in patients infected with human immunodeficiency virus, type 1: a cross-sectional study in a municipal hospital clinic.

PURPOSE: To determine the extent of and clinical variables associated with zidovudine compliance. PATIENTS AND METHODS: A survey of 83 patients infected with human immunodeficiency virus (HIV) followed in a municipal hospital clinic was performed. Compliance histories were validated by serum and urine zidovudine levels. Patient characteristics included 46% white, 63% with a history of intravenous drug use, and 59% reporting a diagnosis of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The main outcome measure was greater than 80% compliance with prescribed doses of zidovudine over the previous week. RESULTS: Sixty-seven percent of the study patients reported greater than 80% compliance with prescribed doses of zidovudine over the previous week. The most common explanations given for missing a dose were "forgot to take zidovudine" and "did not have the medication with me." Five variables were independently associated with greater than 80% compliance as determined by stepwise multiple logistic regression: patient belief that zidovudine prolongs life (odds ratio [OR] 9.3, [95% confidence interval (CI) 2.4, 36.7]), a diagnosis of AIDS or ARC (OR 5.5, [CI 1.5, 20.4]), use of a medication timer (OR 4.4, [CI 1.0, 19.1]), no history of intravenous drug use (OR 3.7, [CI 1.0, 14.2]), and taking one to three other medications with zidovudine. CONCLUSIONS: High compliance with zidovudine was achieved by HIV-infected patients in a municipal hospital clinic, many of whom had a history of intravenous drug use. Compliance with zidovudine may be enhanced by a patient's belief that it prolongs life and the use of a medication timer for proper dosing.

Expanding access to investigational new therapies.

One important role for the primary care provider is to be familiar with all available treatment options for HIV disease. Because only a few treatments are approved, unapproved therapy becomes important for many patients. As a result, clinicians have had systems developed that create access to promising investigational drugs. In addition, because of the urgent need to increase the number of proven treatments, some clinicians have chosen to become more directly involved in the evaluation of new treatments for HIV disease by becoming community based "clinician-researchers."

Hospitalization decision in febrile intravenous drug users.

PURPOSE: To determine the frequency and to identify predictive factors of occult major illness in febrile intravenous drug users (IVDUs) presenting to an emergency room. PATIENTS AND METHODS: A prospective follow-up study was performed involving a consecutive series of 296 presentations of febrile IVDUs to a public hospital emergency room. Follow-up information was obtained for 283 presentations (95.6%). Physician's initial assessment was obtained for 204 presentations (70%). Illness was classified as major or minor using explicit criteria. Frequency of occult major illness was determined among patients without obvious major illness on presentation. Risk factors for occult major illness were determined. RESULTS: Occult major illness occurred in 11 patients (4%). This represented 11% of the 103 presentations without obvious major illness on presentation. Pneumonia and cellulitis occurred in 128 of 180 patients (71%) with obvious major illness on presentation. Bacteremia was present in seven of 11 patients with occult major illness. Physician predictions were not sufficiently sensitive to provide the basis of the hospitalization decision in febrile IVDUs. The best combination of features suggesting major illness were last use of intravenous drugs less than 5 days and fever greater than 38.8 degrees C (102.0 degrees F) (sensitivity 64%, specificity 77%). CONCLUSION: Clinical tests and physician assessments are unable to distinguish occult major illness from minor illness among febrile IVDUs at presentation. Occult major illness is best identified by blood culture. If patient follow-up is unreliable, then hospitalization of febrile IVDUs, while awaiting blood culture results, remains a wise policy.