Julian Falutz

Aerosol Pentamidine for Secondary Prophylaxis of AIDS-related Pneumocystis carinii Pneumonia: A Randomized, Placebo-Controlled Study

OBJECTIVE To assess the safety and efficacy of aerosol pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). PARTICIPANTS Patients recovering from a first confirmed episode of AIDS-related P. carinii pneumonia who had no evidence of either another active AIDS-defining opportunistic infection or another pulmonary abnormality were considered eligible for the study but were included only if they had received no immunomodulators or antiretroviral agents other than zidovudine within 30 days of entry. One hundred sixty-two patients were randomized and started on the study drug. INTERVENTION Patients were randomly assigned to receive aerosol pentamidine, 60 mg per dose, or placebo, delivered using a hand-held, patient-triggered, ultrasonic nebulizer. The induction phase of treatment consisted of 5 doses over 14 days, followed by a maintenance phase beginning on day 21 and consisting of one dose every 2 weeks. RESULTS Thirty-two cases of P. carinii pneumonia were diagnosed before the termination of the trial; 27 cases occurred among 78 patients receiving placebo and 5 occurred among 84 patients receiving aerosol pentamidine. Estimates of the cumulative relapse rate of P. carinii pneumonia by 24 weeks were 50% and 9% for the placebo and pentamidine groups, respectively (P less than 0.001). Adverse reactions attributed to the study drug occurred in 15 of 78 patients receiving placebo and in 28 of 84 patients receiving pentamidine (P = 0.04). These were all mild or moderate in severity and did not preclude continued administration of the study drug. CONCLUSION Intermittent therapy with aerosol pentamidine is highly effective and well tolerated as secondary prophylaxis for AIDS-related P. carinii pneumonia.

A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation.

Objective:To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation. Design and methods:Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters. Results:TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, −4.6 and −9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (−5.4, −3.6 and −15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose. Conclusions:TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.

Effects of Tesamorelin (TH9507), a Growth Hormone-Releasing Factor Analog, in Human Immunodeficiency Virus-Infected Patients with Excess Abdominal Fat: A Pooled Analysis of Two Multicenter, Double-Blind Placebo-Controlled Phase 3 Trials with Safety Extension Data

CONTEXT HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT). OBJECTIVE Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat. DESIGN AND SETTING Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension. PATIENTS A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197). INTERVENTIONS Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily. MAIN OUTCOME MEASURE We evaluated percent change in VAT by computed tomography scan at wk 26. RESULTS At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P < 0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P < 0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P < 0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P < 0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P < 0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P < 0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52. CONCLUSIONS Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.

Frailty in People Aging With Human Immunodeficiency Virus (HIV) Infection

The increasing life spans of people infected with human immunodeficiency virus (HIV) reflect enormous treatment successes and present new challenges related to aging. Even with suppression of viral loads and immune reconstitution, HIV-positive individuals exhibit excess vulnerability to multiple health problems that are not AIDS-defining. With the accumulation of multiple health problems, it is likely that many people aging with treated HIV infection may be identified as frail. Studies of frailty in people with HIV are currently limited but suggest that frailty might be feasible and useful as an integrative marker of multisystem vulnerability, for organizing care and for comprehensively measuring the impact of illness and treatment on overall health status. This review explains how frailty has been conceptualized and measured in the general population, critically reviews emerging data on frailty in people with HIV infection, and explores how the concept of frailty might inform HIV research and care.

Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension.

Background:HIV-infected patients receiving antiretroviral therapy often demonstrate excess visceral fat. A growth hormone-releasing factor, tesamorelin, may selectively reduce visceral fat in this population. We investigated the effects of tesamorelin (GHRH1-44) in HIV-infected patients with central fat accumulation. Methods:A 12-month study of 404 HIV-infected patients with excess abdominal fat in the context of antiretroviral therapy was conducted between January 2007 and October 2008. The study consisted of 2 sequential phases. In the primary efficacy phase (months 0-6), patients were randomly assigned to receive tesamorelin [2 mg subcutaneous (SC) every day] or placebo in a 2:1 ratio. In the extension phase (months 6-12), patients receiving tesamorelin were rerandomized to continue on tesamorelin (2 mg SC every day) or switch to placebo. Patients initially randomized to placebo switched to tesamorelin. Patients and investigators were blinded to treatment assignment throughout the study. The primary endpoint was visceral adipose tissue (VAT). Secondary endpoints included body image, IGF-I, safety measures, including glucose, and other body composition measures. Results:VAT decreased by −10.9% (−21 cm2) in the tesamorelin group vs. −0.6% (−1 cm2) in the placebo group in the 6-month efficacy phase, P < 0.0001. Trunk fat (P < 0.001), waist circumference (P = 0.02), and waist-hip-ratio (P = 0.001) improved, with no change in limb or abdominal SC fat. Insulin-like growth factor-1 increased (P < 0.001), but no change in glucose parameters was observed. Patient rating of belly appearance distress (P = 0.02) and physician rating of belly profile (P = 0.02) were significantly improved in the tesamorelin vs. placebo-treated groups. The drug was well tolerated. VAT was reduced by approximately 18% (P < 0.001) in patients continuing tesamorelin for 12 months. The initial improvements over 6 months in VAT were rapidly lost in those switching from tesamorelin to placebo. Conclusions:Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose.

Clindamycin with Primaquine vs. Trimethoprim-Sulfamethoxazole Therapy for Mild and Moderately Severe Pneumocystis carinii Pneumonia in Patients with AIDS: A Multicenter, Double-Blind, Randomized Trial (CTN 004)

This double-blind, randomized, multicenter trial compared clindamycin/primaquine (Cm/Prq) with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight of > or = 60 kg or 240 mg/1,200 mg q.i.d. if weight of < 60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P = .04), less steroid use (P = .18), and more rashes (P = .07). These differences were even greater for patients with PaO2 of > 70 mm Hg (P = .02, P = .04, and P = .02, respectively). For patients with PaO2 of < or = 70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P = .57), steroid use (P = .74), and rashes (P = .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.

Contribution of Metabolic and Anthropometric Abnormalities to Cardiovascular Disease Risk Factors

Patients with human immunodeficiency virus (HIV) infection have sustained alterations in metabolism (lipids and insulin/glucose homeostasis) and body composition (fat distribution) that are proatherogenic (the Figure). HIV infection itself and/or its therapies may contribute to these alterations (the Table); although most effects are reversible, there are some possibly irreversible consequences of treatment. With the relative restoration to health seen in the era of highly active antiretroviral therapy (HAART), many traditional risk factors and promoters of dyslipidemia and diabetes also are present; they interact with HIV-specific inducers to worsen dyslipidemia and to increase the prevalence of insulin resistance and diabetes. Figure. Overview of the effects of HIV and its therapies on CVD risk. The contribution of traditional risk factors must be kept in mind, and they may occur with increased prevalence in people with HIV infection (eg, smoking). HIV, likely through the inflammatory response, and antiretroviral therapies independently affect many of the mediators of CVD risk. The effects on lipids are a prominent but complex example; HIV infection lowers LDL levels, but antiretroviral therapy raises LDL back up to normal levels. The bidirectional arrows indicate associations, but there is not yet adequate proof of causality. The dotted arrow between body composition and CVD indicates that body fat is known to affect the mediators such as dyslipidemia and insulin resistance but may also have a direct effect. FFA indicates free fatty acids; ARV, antiretroviral. View this table: Table. Effects of HIV Treatment These disturbances in lipid and glucose metabolism and renal disease may contribute, at least in part, to the excess cardiovascular disease (CVD) morbidity and mortality observed in HIV-infected individuals (the Figure). However, the relative contribution to excess CVD risk of traditional CVD risk factors, especially smoking, compared with these infection- and treatment-specific complications requires clarification. More prospective data with multivariable modeling are needed. …

Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation.

Objective:Treatment of HIV patients with daily tesamorelin, a growth hormone-releasing factor analogue, for 26 weeks resulted in a significant decrease in visceral adipose tissue (VAT) and improvement in lipids. The objective of the 26-week extension phase was to evaluate long-term safety and effects of tesamorelin. Design:HIV patients with central fat accumulation in the context of antiretroviral therapy were randomized to tesamorelin 2 mg (n = 273) or placebo (n = 137) s.c. daily for 26 weeks. At week 26, patients originally on tesamorelin were rerandomized to 2 mg tesamorelin (T–T group, n = 154) or placebo (T–P group, n = 50), whereas patients originally on placebo were switched to tesamorelin (P–T group, n = 111). Methods:Safety included adverse events and glucose parameters. Results:Tesamorelin was generally well tolerated. The prevalence of adverse events and serious adverse events during the extension phase was comparable with the initial phase. Changes in glucose parameters over 52 weeks were not clinically significant and similar to those after 26 weeks. The change in VAT was sustained at −18% over 52 weeks of treatment (P < 0.001 versus baseline) as was the change in triglycerides (−51 mg/dl, P < 0.001 versus baseline). Similar sustained beneficial effects were seen for total cholesterol, but high-density lipoprotein decreased minimally over 52 weeks. Upon discontinuation of tesamorelin, VAT reaccumulated. Conclusion:Treatment with tesamorelin was generally well tolerated and resulted in sustained decreases in VAT and triglycerides over 52 weeks without aggravating glucose. Though effects on VAT are sustained during treatment for 52 weeks, these effects do not last beyond the duration of treatment.

HIV-associated Lipodystrophy Syndrome: A Review of Clinical Aspects

Approximately two years after the introduction of highly active antiretroviral therapy for the treatment of HIV infection, body shape changes and metabolic abnormalities were increasingly observed. Initially, these were ascribed to protease inhibitors, but it is now clear that nucleoside reverse transcriptase inhibitors also contribute to lipodystrophy syndrome. The syndrome groups together clinical conditions describing changes in body fat distribution that include lipoatrophy, lipoaccumulation or both. However, there does not appear to be a direct link between lipoatrophy and lipoaccumulation that would support a single mechanism for the redistribution of body fat. Currently, there is no clear definition of lipodystrophy, which explains the difficulty in determining its prevalence and etiology. There are no current guidelines for the treatment of fat distribution abnormalities that occur in the absence of other metabolic complications. The present article reviews the current state of knowledge of the definition, symptoms, risk factors, pathogenesis, diagnosis and treatment of the morphological changes associated with lipodystrophy syndrome.

A frailty index predicts survival and incident multimorbidity independent of markers of HIV disease severity

Objectives:Aging with HIV is associated with multisystem vulnerability that might be well characterized by frailty. We sought to construct a frailty index based on health deficit accumulation in a large HIV clinical cohort and evaluate its validity including the ability to predict mortality and incident multimorbidity. Design and methods:This is an analysis of data from the prospective Modena HIV Metabolic Clinic cohort, 2004–2014. Routine health variables were screened for potential inclusion in a frailty index. Content, construct, and criterion validity of the frailty index were assessed. Multivariable regression models were built to investigate the ability of the frailty index to predict survival and incident multimorbidity (at least two chronic disease diagnoses) after adjusting for known HIV-related and behavioral factors. Results:Two thousand, seven hundred and twenty participants (mean age 46 ± 8; 32% women) provided 9784 study visits; 37 non-HIV-related variables were included in a frailty index. The frailty index exhibited expected characteristics and met validation criteria. Predictors of survival were frailty index (0.1 increment, adjusted hazard ratio 1.63, 95% confidence interval 1.05–2.52), current CD4+ cell count (0.48, 0.32–0.72), and injection drug use (2.51, 1.16–5.44). Predictors of incident multimorbidity were frailty index (adjusted incident rate ratio 1.98, 1.65–2.36), age (1.07, 1.05–1.09), female sex (0.61, 0.40–0.91), and current CD4+ cell count (0.71, 0.59–0.85). Conclusion:Among people aging with HIV in northern Italy, a frailty index based on deficit accumulation predicted survival and incident multimorbidity independently of HIV-related and behavioral risk factors. The frailty index holds potential value in quantifying vulnerability among people aging with HIV.