The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells.

HIV protease inhibitor treatment is associated with insulin resistance. We have recently demonstrated that the HIV protease inhibitor indinavir influences initial insulin signaling steps in HepG2 cells. Here we investigated in the same cell model whether indinavir alters insulin-stimulated glycogen synthesis. Since an altered phosphotyrosine phosphatase activity could represent a mechanism by which insulin signaling is influenced, we also assessed potential indinavir effects on protein tyrosine phosphatase activity directed against tyrosine phosphorylated insulin receptor substrate-1. HepG2 cells were incubated for 48 h without or with indinavir (100 micro mol/l). Subsequently, the insulin-stimulated incorporation of 14C-glucose into glycogen was measured. In indinavir-treated cells the insulin effect on glycogen synthesis was reduced by 30 +/- 4.5 %. Dephosphorylation of immobilized tyrosine-phosphorylated insulin-receptor substrate-1 by the cell extracts was determined using a microwell plate-based method, and indinavir treatment did not alter this dephosphorylation. In conclusion, our data suggest that indinavir affects insulin-stimulation of glycogen synthesis in liver cells, and this may be related to the previously observed alterations in insulin signaling. Direct effects of indinavir on the GLUT4 transport system, that have been suggested from data in other cell systems, are unlikely in HepG2 cells that express no or almost no GLUT4 transport system. Finally, our data do not support the hypothesis that indinavir alters insulin signaling by influencing protein tyrosine phosphatase activity directed against insulin receptor substrate-1.     

Virological response to protease inhibitor therapy in an HIV clinic cohort

OBJECTIVE: New antiretroviral strategies aim to reduce plasma HIV RNA (viral load) to below the limits of detectability of assays with the objective of reducing viral replication in order to stop or reverse the pathogenic process and prevent development of drug resistance. First use of a protease inhibitor might offer the most realistic chance of achieving this aim. Our objective was to study the virological response to protease inhibitors in patients taking them for the first time. METHODS: A total of 901 patients from a large outpatient clinic were followed a mean of 15 months from the time of starting a protease inhibitor until 1 May 1998. Viral load and CD4 cell count measurements were made on average every 34 days. RESULTS: Overall there was a 79% [95% confidence interval (CI), 76-82] probability of the patients achieving a viral load < 500 copies/ml by 24 weeks after starting the protease inhibitor. In a multiple Cox regression model, those with lower initial viral load [relative hazard (RH), 0.72; P < 0.0001], higher CD4 cell count (RH, 1.07; P = 0.002), those starting other new drugs at same time as the protease inhibitor (RH, 1.46 for two versus none; P = 0.003), those who were antiretroviral-naive, and those using indinavir or nelfinavir were more likely to achieve such levels. In those 651 patients achieving viral load < 500 copies/ml within 24 weeks, there was an estimated 53% (95% CI, 51-55) probability of rebound of viral load to > 500 copies/ml by 52 weeks from the first undetectable value. Again, those who had started other new drugs at the same time as the protease inhibitor (RH, 0.57; P = 0.003 for starting two versus none) tended to experience a lower probability of viral load rebound, as did those with higher initial CD4 cell count (RH, 0.87 per 100 x 10(6)/l higher; P = 0.0007). Those who took saquinavir achieved less durable virological responses than those who took other protease inhibitors. CONCLUSIONS: Starting protease inhibitor therapy with two other new antiretroviral drugs simultaneously with protease inhibitor therapy offers a better best chance of achieving sustained viral load < 500 copies/ml than starting fewer new drugs.     

Risk factors for indinavir-related renal colic in HIV patients: predictive value of indinavir dose/body mass index

In a prospective study evaluating risk factors for indinavir-related renal colic in 555 HIV-infected patients receiving highly active antiretroviral therapy, followed-up fir 24 months, 23.6% developed one or more renal colic episodes, and 50 patients stopped indinavir. No correlation was observed between renal colic onset and sex, age, CD4 cell count, history, and hepatitis B or C virus co-infection, but baseline anthropometric values were significantly related to the onset of renal colic.     

Risk factors for new-onset diabetes mellitus in patients receiving protease inhibitor therapy.

BACKGROUND: Metabolic complications including diabetes mellitus (DM) have been associated with protease inhibitor (PI) therapy. Risk factors for the development of DM are not well-defined. OBJECTIVES: To determine risk factors for the development of new-onset DM in patients initiated on PI therapy. METHODS: A retrospective cohort study was conducted to identify predictors of developing DM in subjects started on PI therapy between January 1997 and January 2003. Diabetes cases were defined as physician documentation of DM in the outpatient medical chart and/or those subjects receiving an antidiabetic agent. Logistic regression was used to examine the relationship between new-onset DM and demographic characteristics, and between new-onset DM and total treatment days with PI therapy. Body mass index could not be entered into the model due to missing height measurements. RESULTS: A total of 496 subjects on PI therapy were included, of which 18 (3.6%) developed DM. The mean age of the subjects was 43.4+/-9.4 years (range 19 to 77) and the mean duration of therapy was 3.0+/-1.9 years (range 0.17 to 7.9). In the multivariate model, older subjects were more likely to develop DM (OR 1.12, 95% CI 1.05 to 1.19; P=0.001). This corresponds to a 12% increased risk of DM for each one-year increase in age. Subjects that weighed more had an increased risk (OR 1.06, 95% CI 1.03 to 1.10; P=0.001), as did those belonging to a non-Aboriginal minority group when compared with Caucasians (OR 6.67, 95% CI 1.56 to 28.41; P=0.01). A longer duration of PI therapy was also significantly associated with developing DM (OR 1.52, 95% CI 1.07 to 2.17; P=0.02). CONCLUSION: A longer duration of PI therapy is associated with an increased risk of developing DM. As with HIV-negative subjects, demographic characteristics such as age, weight and ethnicity were important predictors of developing DM in the present study.     

Risk factors for methadone outside treatment programs: implications for HIV treatment among injection drug users

BACKGROUND: Diversion of methadone outside treatment programs occurs, yet reasons for use of 'street methadone' are characterized poorly. Self-medication for withdrawal symptoms is one plausible hypothesis. Among HIV-infected drug users, some antiretroviral medications can reduce potency of methadone, yet any association between such effects and the use of supplemental methadone sources remains undetermined. OBJECTIVE: To estimate the frequency and risk factors for use of street methadone. METHODS: Injection drug users (IDUs) recruited through extensive community outreach in 1988-89 and 1994 were followed semi-annually with questionnaires about health history, use of licit and illicit drugs including methadone and HIV-related assays. Analyses were performed using generalized estimating equation logistic regression. RESULTS: Of 2811 IDUs enrolled and eligible for analysis, 493 people reported use of street methadone over 12 316 person-years of follow-up (4.0/100 person-years). In multivariate analyses, street methadone use was more common among women, whites, those 40-59 years old, those who reported withdrawal symptoms, past methadone program attendance (6-12 months before visit), recent heroin injection with or without cocaine (but not cocaine alone), smoking or sniffing heroin and reported trading sex. Street methadone was not associated with HIV infection or treatment. CONCLUSION: The results suggest that older IDUs still using heroin may be using street methadone to treat signs of withdrawal. The absence of a higher rate of street methadone use in HIV seropositive IDUs reveals that antiretroviral/methadone interactions are not a primary determinant of use outside of treatment settings.     

Risk factors for human herpesvirus 8 infection in a cohort of drug users in the Netherlands, 1985-1996

To elucidate the mode of human herpesvirus 8 (HHV-8) transmission in a population of Amsterdam drug users, HHV-8 seroprevalence and seroincidence were determined in 1179 drug users in the Amsterdam Cohort Studies (1985-1996). Risk factors for HHV-8 infection were examined. Serum samples were screened with an enzyme immunoassay by using HHV-8 lytic capsid (open-reading frame [ORF] 65) and latent nuclear (ORF73) antigens; positive results were confirmed by Western blot and immunofluorescence assay. Seroprevalence (men, 3.4%; women, 1.4%) and seroincidence (men, 0.08; women, 0.05/100 person-years) were low in this study. Infections with human immunodeficiency virus (HIV) type 1, hepatitis B virus (HBV), and hepatitis C virus (HCV), but not HHV-8, were associated with injection drug use (IDU). Independent risk factors for HHV-8 seropositivity were homosexual contacts and Mediterranean nationality for men and sexual contact with bisexual men, absence of a steady partner, and unprotected commercial sex for women. Unlike HIV-1, HBV, or HCV infection, HHV-8 infection is uncommon in Amsterdam drug users, as is HHV-8 transmission through IDU.     

Risk factors and HIV seropositivity among injecting drug users in Bangkok.

Bangkok experienced an extremely rapid spread of HIV infection among drug injectors in 1987 and 1988. This study examines risk factors for HIV infection and deliberate risk-reduction efforts by drug injectors. Two subsamples of injecting drug users were recruited in November 1989, a group in drug-use treatment (n = 342) and a group new to the treatment system (n = 259). Subjects were interviewed about AIDS risk behavior, and a blood sample was collected for HIV testing. Seroprevalence was 39 and 27% in the in-treatment sample and the new-to-treatment sample, respectively. The in-treatment sample seroprevalence rate is similar to rates observed 6 and 12 months earlier. Three factors were independently associated with HIV infection: subsample, having been in prison, and sharing injection equipment with two or more individuals in the previous 6 months. Deliberate risk reduction was reported by 92% of individuals, with 59% reporting that they had stopped sharing injection equipment. It appears that large-scale risk reduction has greatly slowed HIV transmission among drug injectors in Bangkok.     

Risk factors for hypertension in a national cohort study

Hypertension continues to be a major public health problem in the United States. We used data from the National Health and Nutrition Examination Survey Epidemiologic Followup Study (1971-1984) to examine predictors of hypertension for the 7,073 participants free from hypertension at the baseline examination. The follow-up period averaged 10 years. Body mass index was positively related to the probability of hypertension developing among white men (n = 2,370), white women (n = 3,949), black men (n = 231), and black women (n = 523). Education was inversely associated with the probability of hypertension developing among white women and was of borderline significance among white men and black women. In a subanalysis of white men (n = 1,790) and white women (n = 3,063) who completed the 24-hour recall dietary questionnaire, dietary consumption of sodium, calcium, and potassium did not predict the development of hypertension. The failure of our study to support findings relating intake of dietary cations to the development of hypertension may be attributable to imprecision in the measurement of dietary data and misclassification of hypertension status. These data reinforce the importance of weight control in the primary prevention of hypertension.     

Risk factors related to hypertension among patients in a cohort living with HIV/AIDS

IntroductionStudies disagree as to whether there is a greater prevalence of hypertension among HIV/AIDS patients and the role of antiretroviral therapy.ObjectiveEvaluate the prevalence of hypertension and risk factors in a cohort of HIV-infected patients, with emphasis on antiretroviral therapy.MethodCase-control study conducted at baseline of a cohort, between June/2007 and December/2008 in Pernambuco/Brazil. Blood pressure was classified as normal, prehypertension, and hypertension.ResultsOf 958 patients, 245 (25.6%) had hypertension (cases), 325 (33.9%) had prehypertension, and 388 (40.5%) were normotensive (controls). Comparison between hypertensive and normotensive patients showed that traditional factors, such as age > 40 (OR = 3.06, CI = 1.91- 4.97), male gender (OR = 1.85, CI = 1.15-3.01), BMI > 25 (OR = 5.51, CI = 3.36-9.17), and triglycerides > 150 mg/dL (OR = 1.69, CI = 1.05-2.71), were independently associated with hypertension. Duration of antiretroviral therapy and CD4 > 200 cells/mm³ were associated with hypertension in univariate analysis, but did not remain in final model. Type of antiretroviral schema and lipodystrophy showed no association with hypertension.ConclusionHypertension in HIV/AIDS patients is partially linked to invariable factors, such as age and sex. Efforts should be directed toward controlling reversible factors, particularly excessive weight gain and unsuitable diet.     

Associations between amino acids in the evolution of HIV type 1 protease sequences under indinavir therapy

Significant diversity exists in amino acid sequences encoding HIV-1 protease in individuals naive for protease inhibitors, which could influence the rate of evolution of resistance. High-level resistance to indinavir requires multiple substitutions among at least 11 amino acid sites, and no single substitution was observed in all of 29 resistant isolates obtained from patients on long-term indinavir monotherapy. We have analyzed the evolution of PR in these sequences. The divergence from the baseline amino acid sequence by week 24 was 4%, increasing more than 7% by week 60. The mean difference between sequences from different patients at baseline was 6% (3-9%), rising to 10% after 40 weeks (3-16%), although at all time points nonsynonymous substitutions were less frequent than synonymous nucleotide changes. Analysis of associations between variants at different amino acid sites using a mutual information statistic revealed four pairs of sites to be significantly associated. In three cases these associations included residue 82. Clusters of baseline and week 24 amino acid sequences identified by maximum parsimony did not correlate significantly with the IC95 to indinavir, although a weak correlation of baseline clusters with phenotype at the week 24 time point was suggested.     

Risk factors for incident condyloma in a multinational cohort of men: the HIM study

Identifying factors associated with condyloma are necessary for prevention efforts. Risk factors for incident condyloma were examined in a cohort of 2487 men from the United States, Brazil, and Mexico and were followed up every 6 months (median, 17.9 months). Factors strongly associated with condyloma were incident infection with human papillomavirus (HPV) types 6 and 11 (hazard ratio [HR], 12.42 [95% confidence interval {CI}, 3.78-40.77]), age (HR, 0.43 [95% CI, .26-.77]; 45-70 vs 18-30 years), high lifetime number of female partners (HR, 5.69 [95% CI, 1.80-17.97]; ≥21 vs 0 partners), and number of male partners (HR, 4.53 [95% CI, 1.68-12.20]; ≥3 vs 0 partners). The results suggest that HPV types 6 and 11 and recent sexual behavior are strongly associated with incident condyloma.     

Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment

Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associated with abnormal serum lipoprotein concentrations. The purpose of this review is to describe serum lipid abnormalities related to protease inhibitor use. A MEDLINE search up to June 1, 1999, and abstracts from recent scientific meetings were primary data sources. Lipid disturbances in HIV-infected patients receiving protease inhibitors generally consist of elevated triglycerides and total cholesterol levels; HDL cholesterol is often reduced. The pathophysiological mechanism by which the protease inhibitors induce these lipid abnormalities has been hypothesized, but is unknown. Cases of pancreatitis and coronary heart disease have been described in hyperlipidemic patients receiving protease inhibitors. Treatment of protease inhibitor-related hyperlipidemia is unknown. Exchanging the offending protease inhibitor for nevirapine may be helpful in certain patients. Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of individuals.     

Carotid artery intima-media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure

CONTEXT: The impact of HIV infection and exposure to antiretroviral therapy on the development of subclinical atherosclerosis is incompletely understood. OBJECTIVE: To compare intima-media thickness (IMT) of the carotid artery between HIV-infected subjects receiving protease inhibitor-containing regimens and subjects not receiving these regimens and to compare differences in the IMT of the carotid artery between HIV-infected subjects and HIV-uninfected subjects. METHODS: A prospective matched cohort study in university-based outpatient clinics. Groups of three individuals (triads) matched on the following characteristics were enrolled: age, sex, race/ethnicity, smoking status, blood pressure and menopausal status. Group 1, HIV-infected subjects with continuous use of protease inhibitor (PI) therapy for > or = 2 years; group 2, HIV-infected subjects without prior PI use; and group 3: HIV-uninfected. Ultrasonographers at six sites sent standardized ultrasound images to a central reading site for carotid IMT measurements. Carotid IMT was compared within the HIV-infected groups (1 and 2) and between the HIV-infected and uninfected groups in a matched analysis. RESULTS: One hundred and thirty-four individuals were enrolled in 45 triads. The median IMT in groups 1, 2 and 3 was 0.690, 0.712 and 0.698 mm, respectively. There were no statistically significant differences in IMT between groups 1 and 2, or in the combined HIV groups compared with the HIV uninfected group. Significant predictors of carotid IMT in a multivariate model included high-density lipoprotein (HDL) cholesterol, the interaction of HDL cholesterol and triglycerides, age and body mass index. CONCLUSIONS: We found no association between PI inhibitor exposure or HIV infection and carotid IMT.     

Lifestyle factors for drug users in relation to risks for HIV

Lifestyle factors in drug users may render them particularly vulnerable to HIV infection. This study examined a group of 74 registered drug users at a Drug Dependency Clinic and compared lifestyle factors in those who were HIV-positive and those HIV-negative. Despite HIV status, sharing was extensive (over 90%). Sharing with partners only is not fail-safe as partners in turn shared. Sexual behaviour within this group may exacerbate risk. A number of subjects reported previous Sexually Transmitted Diseases which may in themselves indicate high levels of sexual activity and act as co-factors for virus spread. Soliciting for sex was reported present among the positives and negatives. Condom use for primary or prophylactic protection was rarely undertaken. There were no differences between HIV-positive and HIV-negative respondents indicating the high level of risk faced by the group as a whole. This presents a challenge for the provision of adequate and appropriate health advice and care.     

A 6-base pair insertion in the protease gene of HIV type 1 detected in a protease inhibitor-naive patient is not associated with indinavir treatment failure

Insertions in the protease gene of HIV-1 were rarely found and are not associated with reduced effectiveness of protease inhibitors although they are thought to be selected by protease inhibitor therapy. This is the first report of a 6-basepair insertion in the protease gene prior to protease inhibitor therapy.     

Risk factors for nursing home placement in a population-based dementia cohort

OBJECTIVE: To examine risk factors for nursing home placement in a population-based dementia cohort. METHODS: The Mayo Clinic Medical Records linkage system was used to identify all patients with onset of dementia between 1980 and 1984. The patient group included 314 cases who met DSM-III-R criteria for dementia, including 220 cases who were community dwelling at onset. All dementia patients were followed until death. A control group included 323 patients who did not, at any point, meet DSM-III-R criterion for dementia. The groups were initially matched on age, gender, and year of initial registration. Demographic, medical, social, and functional predictors were examined as static and time-dependent risk factors for nursing home placement in the initial community-dwelling subgroups, using stepwise Cox regression modeling. RESULTS: Of the 314 dementia patients, 282 took residence in licensed skilled nursing homes for at least 6 weeks, suggestive of custodial care, at some point during the course of their illness. In the control group, 162 of the 323 people required nursing home placement. Within controls, the predictor variables of time to nursing home placement included initial age, being divorced, living in a townhome, apartment or assisted living apartment, change in Charlson comorbidity score, and change in amount of daily assistance required. Within the dementia sample, seven predictors were eventually determined to be associated with time to nursing home placement. These included total number of years of education, age at onset of dementia, being single, living in a retirement or supervised apartment at onset, change in Charlson comorbidity score, and a change in the amount of daily assistance required. CONCLUSIONS: Cumulative incidence of placement was 90% in the dementia cohort and 50% in the controls. Certain variables seem to impact time to nursing home placement in all older persons, whether they have dementia or not. Among these are age, living in assisted living settings, increasing comorbidity scores, and increasing need for functional assistance. Certain additional factors may have a specific impact in dementia. Among these is education, which seems to provide a protective effect. These predictors may be important covariates in clinical dementia studies that include time to nursing home placement as an outcome variable.