Kathleen Mulligan

Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

BACKGROUND Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. METHODS We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. RESULTS The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). CONCLUSIONS Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

Self-management interventions for chronic illness

An increasing number of interventions have been developed for patients to better manage their chronic illnesses. They are characterised by substantial responsibility taken by patients, and are commonly referred to as self-management interventions. We examine the background, content, and efficacy of such interventions for type 2 diabetes, arthritis, and asthma. Although the content and intensity of the programmes were affected by the objectives of management of the illness, the interventions differed substantially even within the three illnesses. When comparing across conditions, it is important to recognise the different objectives of the interventions and the complexity of the issues that they are attempting to tackle. For both diabetes and asthma, the objectives are concerned with the underlying control of the condition with clear strategies to achieve the desired outcome. By contrast, strategies to deal with symptoms of pain and the consequences of disability in arthritis can be more complex. The interventions that were efficacious provide some guidance as to the components needed in future programmes to achieve the best results. But to ensure that these results endure over time remains an important issue for self-management interventions.

Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection.

Summary: Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV‐infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT; N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9 ± 3 mg/dl; p = .0136), insulin (+12.2 ± 4.9 U/ml; p = .023), triglycerides (+53 ± 17 mg/dl; p = .0069), and total and LDL cholesterol (+32 ± 11 and +18 ± 5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow‐up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.

Objective: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV‐1 infection and potent antiretroviral therapy, but limited data ate available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. Participants: A 12‐member panel representing international expertise in HIV‐1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society‐USA, a not‐for‐profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society‐USA; the panel members are not compensated for their participation. Evidence: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. Process: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. Conclusions: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV‐1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long‐term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long‐term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the riskbenefit ratio of antiretroviral therapies.

Metabolic effects of indinavir in healthy HIV-seronegative men

BackgroundTherapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition. MethodsIndinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy. ResultsFasting glucose (4.9 ± 0.1 versus 5.2 ± 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 ± 12.2 versus 83.9 ± 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 ± 1.7 versus 15.9 ± 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 ± 0.3 versus 2.8 ± 0.5; P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 ± 0.4 versus 6.5 ± 0.6 mmol/l; P < 0.05) and insulin levels (223.1 ± 48.8 versus 390.3 ± 108.8 pmol/l; P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 ± 1.4 versus 8.6 ± 1.2 mg/kg ⋅ min per μU/ml insulin; 95% confidence interval 0.6–3.0; P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 ± 1.4 versus 15.2 ± 1.4 kg; P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography. ConclusionsIn the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.

Nutritional recommendations for the management of sarcopenia.

The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.

Recombinant Human Growth Hormone in Patients with HIV-Associated Wasting: A Randomized, Placebo-Controlled Trial

Body wasting is an increasingly frequent acquired immunodeficiency syndrome (AIDS)-defining condition [1, 2]. Wasting is associated with impaired functional performance and quality of life [3]. Prospective [4-6] and retrospective [7-9] studies have shown that loss of weight [4, 7-9] and body cell mass [5-7] are statistically related to death in patients with human immunodeficiency virus (HIV) infection. The effect of weight and body composition on survival was notably independent of other factors that were thought to influence mortality. Nutritional supplementation [10, 11] and appetite stimulation [12, 13] can increase body weight and body fat in patients with HIV-associated wasting, but these treatments do not consistently restore lean tissue. The apparent failure of nutritional therapy to restore lean tissue suggests that, in some HIV-infected patients, metabolic alterations either promote nitrogen wasting or at least prevent repletion of lean tissue during periods when the patients presumably have adequate energy intake. Although increases in body fat in this setting may not be intrinsically harmful, body fat content is not correlated with survival [5, 7]. Thus, optimal therapy for patients with HIV-associated wasting should specifically reverse or forestall loss of lean tissue. Pharmacologic doses of growth hormone have induced nitrogen retention and increased protein synthesis and lean body mass in other catabolic states [14-17]. This treatment has also produced weight gain and nitrogen retention in a short-term study [18] of patients with HIV-associated wasting. The results of an open-label study [19] of a small group of patients with HIV-associated wasting suggested that growth hormone may have a sustained effect on lean body mass. We report the results of a randomized, multicenter, double-blind, placebo-controlled study that assessed the effects of growth hormone therapy on weight, body composition, functional performance, and quality of life in patients with HIV-associated wasting. Methods Patients Eligible patients were 18 years of age or older and had antibodies to HIV type 1, documented unintentional weight loss of at least 10% or weight less than 90% of the lower limit of ideal body weight [20], a Karnofsky score of 50 or greater, and life expectancy of 4 months or longer. Patients had to be able to consume at least 75% of maintenance energy requirement based on concurrent body weight. Patients had to have been receiving a stable regimen of antiretroviral therapy for at least 30 days before study entry and had to continue to receive antiretroviral therapy during the study. Exclusion criteria included pregnancy; severe diarrhea ( 6 stools per day); use of anabolic agents, glucocorticoids, appetite stimulants, or parenteral or tube feeding; initiation of therapy for a systemic infection within 30 days of enrollment; an active malignant condition other than localized Kaposi sarcoma (<10 cutaneous lesions, <2 cm in diameter); recent radiotherapy or systemic chemotherapy; untreated hypertension; history of diabetes mellitus, significant cardiovascular disease, chronic edema, or the carpal tunnel syndrome; fasting glucose level greater than 6.7 mmol/L; triglyceride level greater than 5.6 mmol/L; amylase level more than 3 times the upper limit of normal; or hemoglobin level less than 85 g/L. The study was approved by the institutional review board at each participating center, and signed informed consent was obtained before patients were enrolled. Baseline measures included results of history and physical examination; weight; body composition; assessment of treadmill work output and quality of life; routine hematologic and biochemical assessments; and measurement of insulin-like growth factor 1 levels, CD4+ and CD8+ lymphocyte counts, and p24 antigen levels. Plasma HIV RNA levels were measured in a subset of patients from whom appropriate samples were available. Patients were randomly assigned to receive recombinant human growth hormone derived from mammalian cells (Serostim, Serono Laboratories, Norwell, Massachusetts), 0.1 mg/kg of body weight subcutaneously every evening (average dosage, 6 mg/d), or an equivalent amount of placebo. This dose of growth hormone caused weight gain and nitrogen retention in a short-term study of patients with HIV-associated wasting [18]. Patients were randomly assigned according to a computer-generated randomization list that was balanced across all patients and within sites. Kits that contained either the active study drug or placebo in identical vials were given to the study sites. Patients and investigators were blinded to the content of the vials until the study was complete. Patients were reevaluated at weeks 1, 2, 6, and 12; adverse events were recorded and laboratory assessments were done at these evaluations. Doses were reduced for patients with fasting triglyceride levels greater than 7.9 mmol/L, fasting glucose levels greater than 8.9 mmol/L, moderate hypertension, arthralgia that did not respond to anti-inflammatory therapy, the carpal tunnel syndrome, edema that did not respond to diuretics, moderate systemic allergic reaction, or severe paresthesia. The dose was reduced by 50% and again by 50% if symptoms did not resolve within 10 days. Patients in whom symptoms persisted at the lowest dose were withdrawn from the study. Severe events that required suspension of treatment included fasting triglyceride levels of 16.9 mmol/L or greater, glucose levels of 22.2 mmol/L or greater, pseudotumor cerebri, congestive heart failure, pancreatitis, marked hypertension (blood pressure > 200/110 mm Hg), intolerable paresthesia, or severe systemic allergic reaction. If symptoms resolved within 5 days, patients could resume therapy at 50% of the dose used at the time of the event. Treatment was discontinued immediately and not resumed in patients who developed a new occurrence of cancer (including Kaposi sarcoma) and in patients who had progression of existing Kaposi sarcoma (new lesions or >50% growth of existing lesions). Patients who had acute infections could remain in the study at the discretion of the investigator. Outcome Assessments All measurements were done by investigators and their associates at each study site; investigators and associates were unaware of assignment to growth hormone or placebo. At baseline and 6 and 12 weeks, weight and body composition were measured after overnight fasting and voiding. Patients wore only a hospital gown. Weights were measured on the same calibrated scales (certified to have an accuracy to 0.2 kg and a coefficient of variation of 0.3%) throughout the study; the average of three determinations was used. Weight was also recorded at weeks 1 and 2 but not necessarily in the fasting state. Body fat, lean body mass, and bone mineral content were measured by dual-energy x-ray absorptiometry [21-23] with either a Lunar model DPX (Madison, Wisconsin) or Hologics model QDR-1000W or QDR-2000W (Waltham, Massachusetts). Scanning was done with the same equipment and software throughout the study. Total body water was measured by deuterium oxide dilution [24], and extracellular water was measured by sodium bromide dilution [25]. Plasma samples were collected at baseline and 3 hours after patients ingested 10 g of deuterium oxide and 5 g of 4 M sodium bromide. Patients fasted throughout the test period. For assessment of work output, patients walked on a treadmill at increasing workloads according to an adaptation of a protocol for patients with limited exercise capacity [26]. Speed or grade was increased at 3-minute intervals, and exercise was terminated when patients reached volitional exhaustion or estimated maximal heart rate [26]. Work output was calculated from body weight and treadmill speed and grade [27]. Changes in overall health status, functioning, disability, and symptoms were assessed by having patients complete a visual analogue self-appraisal (on a scale of 1 to 10) of overall quality of life and a self-administered questionnaire, the HIV-Patient Assessed Report of Status and Experience (HIV-PARSE) [28]. The HIV-PARSE questionnaire contains modified items and scales from the Medical Outcomes Study that can be analyzed separately or as an overall index [29] and that have been shown to reflect differences in quality-of-life outcomes with HIV therapies [30]. Laboratory Assessments Routine hematologic and biochemical variables were measured in the clinical laboratories at each site. Enrichment of deuterium oxide in plasma was determined by isotope ratio mass spectrometry [24]. Concentration of bromide in plasma was determined by ion chromatography [25]. Levels of plasma insulin-like growth factor 1 were measured by radioimmunoassay [31]. Levels of immune-complex dissociated p24 antigen were measured in acid-treated sera [32]; a change in p24 antigen levels was defined as an increase or decrease from baseline of 50% or greater, as long as one sample was 30 pg/mL or greater. Levels of HIV RNA in plasma were measured by branched-DNA assay [33, 34]. Statistical Analysis Sample size was calculated to detect a 2% difference between groups in weight change at week 12 with at least 80% power for a two-sided test with 5% type I error, assuming an SD of 4%. The groups were compared at baseline using analysis of variance. Analysis of variance was also used to compare changes in weight and body composition in patients who had measurement at baseline and week 12 and at least 80% compliance with the dosing regimen. An intention-to-treat analysis using the Wilcoxon rank-sum test was done on changes from baseline to the last postbaseline value measured in each patient, regardless of whether they completed the study or complied with the dosing regimen. The Wilcoxon rank-sum test was also used to evaluate the change in work output during treadmill exercise. We investigated a treatment-by-center interaction for data that did not have a normal distri

Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study.

Background Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers. Methods Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies. Results There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60−−180 min) insulin reached comparable levels (394 ± 13 versus 390 ± 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 ± 2.2 μM and the 2-h area under the curve was 13.5 ± 3.1 μM⋅h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg⋅min per μ UI/ml (95% confidence interval for change, 3.7–6.1;P < 0.001) on indinavir (average decrease, 34.1 ± 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg⋅min (P < 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies. Conclusions A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.

Psychosocial interventions for caregivers of people with dementia: A systematic review

The content of interventions for caregivers of dementia patients is highly varied. None of the reviews conducted to date have focused on evaluating the effects of the content of interventions exclusively for dementia caregivers, and this issue is not well understood. The purpose of this review was to first identify the type of components (e.g. education, counselling) that have been utilized in psychosocial/psycho-educational interventions for dementia caregivers, and to evaluate the success of the different components or combination of components in producing positive outcomes for dementia caregivers. Forty studies were included in the review. Approximately two-thirds of the interventions did not show improvements in any outcome measures. Among those studies, which did demonstrate improvements, the inclusion of social components (e.g. social support) or a combination of social and cognitive (e.g. problem solving) components seemed to be relatively effective. It is important to note, however, that these analyses were based on small numbers and the review was limited by a number of methodological issues (e.g. poor description of interventions). To advance our understanding of the efficacy of psychosocial interventions for caregivers of people with dementia, a more systematic approach is required. Intervention components need to be carefully contrasted in appropriately designed studies of sufficient size.

Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides

Objective:To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. Methods:Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. Results:Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (−16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (−13.1%) compared with efavirenz (+1.8%; P = 0.003). Conclusions:Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.