Longitudinal anthropometric changes in HIV-infected and HIV-uninfected men

BACKGROUND: Although morphologic abnormalities are common among HIV-infected persons receiving highly active antiretroviral therapy (HAART), longitudinal comparative body shape changes among HAART-treated HIV-infected men versus HIV-seronegative men of similar age remain unclear. METHODS: Since September 1999, men enrolled in the Multicenter AIDS Cohort Study underwent body mass index (BMI) and circumference measurements of the waist, hip, thigh, and arm at each semiannual visit. Changes in these measurements that occurred between 1999 and 2003 among HIV-infected men were compared with measurements of HIV-seronegative men using linear mixed effects regression models. The HIV-infected men were further stratified by treatment group (no antiretroviral therapy [ART], monotherapy or combination [mono/combo] ART, or HAART). Analyses were adjusted for age, nadir CD4 cell count, and BMI (for circumference measurements). RESULTS: Over the 4-year observation period, mean BMI increased significantly among the 392 HIV-seronegative men (0.12 kg/m/y; P < 0.001) but did not change in the 3 HIV-infected groups (combined n = 661). Mean waist and hip circumferences increased significantly in all groups. Hip circumferences increased more slowly in the HIV-positive HAART-treated group (n = 488) than in the HIV-seronegative group (0.18 vs. 0.49 cm/y; P < 0.001), however, yielding a more rapid increase in the waist/hip ratio in the HIV-positive, HAART-treated group over time (0.005 per year; P < 0.001). CONCLUSIONS: The increased rate of change in waist/hip ratio in HIV-infected men receiving HAART compared with HIV-seronegative men is attributable to slower increases in hip circumference rather than an increased rate of change in waist circumference. These findings underscore the importance of body fat composition changes in the peripheral compartment relative to the central compartment among HIV-infected men receiving HAART.     

Hypofibrinolytic state in HIV-1-infected patients treated with protease inhibitor-containing highly active antiretroviral therapy

Decreased insulin sensitivity, hyperlipidemia, and body fat changes are considered as risk factors for coronary heart disease (CHD). A clustering of such factors (metabolic syndrome [MSDR]) exponentially increases the risk. Impaired fibrinolysis and increased coagulation are additional independent risk factors for CHD. We studied the effects of protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) on metabolic and hemostatic parameters in 363 HIV-infected individuals, of whom 266 were receiving PI-containing HAART and 97 were treatment naive. The fasting plasma levels of insulin, glucose, triglycerides, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, plasminogen activator inhibitor type 1 (PAI-1), and fibrinogen were evaluated together with the areas of visceral adipose tissue and the visceral adipose tissue/subcutaneous adipose tissue area ratio. The levels of insulin, triglycerides, cholesterol, and low-density lipoprotein cholesterol; visceral adipose tissue area; low-density lipoprotein/high-density lipoprotein ratio; and visceral adipose tissue/subcutaneous adipose tissue area ratio were significantly increased in patients receiving PI-containing HAART compared with treatment-naive patients. The levels of PAI-1 and fibrinogen were significantly higher in patients receiving PI-containing HAART. PAI-1 levels were higher in individuals with MSDR but also in patients without MSDR who were receiving PI-containing HAART. PAI-1 was independently correlated to use of PI-containing HAART, triglyceride level, insulin level, and body mass index (p <.001). These findings suggest that patients receiving PI-containing HAART have decreased fibrinolysis and increased coagulability, which may thus represent additional risk factors for cardiovascular disease in this patient group.     

13C-methionine breath test detects distinct hepatic mitochondrial dysfunction in HIV-infected patients with normal serum lactate

OBJECTIVE: To assess mitochondrial respiratory chain dysfunction in different treatment groups of HIV-infected patients with normal serum lactate by measuring hepatic mitochondrial decarboxylation capacity by the C-methionine breath test (MeBT) and to correlate MeBT results with mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMCs). METHODS: Four groups were studied: HIV-negative controls (n = 10), treatment-naive patients (n = 15), antiretroviral therapy (ART)-treated patients with asymptomatic disease (n = 15), and patients with long-term treatment and clinical evidence of lipoatrophy (n = 15). After oral administration of C-methionine, CO2 exhalation was determined by infrared spectroscopy. MtDNA content in PBMCs was assessed by real-time polymerase chain reaction quantification. RESULTS: CO2 exhalation in lipoatrophic patients and therapy-naive patients was distinctly decreased when compared with that in healthy controls and asymptomatic patients (P < 0.001). The functional mitochondrial impairment in lipoatrophic patients was associated with a 47% decline in mtDNA content. MeBT results and mtDNA were significantly correlated in ART-treated patients (r = 0.77, P < 0.0001). CONCLUSIONS: MeBT is a simple noninvasive method to detect mitochondrial dysfunction in HIV-infected patients that correlates with mtDNA depletion in PBMCs of ART-treated individuals. Decreased hepatic methionine metabolism in therapy-naive patients may reflect the functional relevance of viral-mediated mitochondrial toxicity.     

Association between hepatitis C virus coinfection and regional adipose tissue volume in HIV-infected men and women

OBJECTIVE: Coinfection with hepatitis C virus (HCV) is reported to be associated with a higher prevalence of lipodystrophy than HIV infection alone. We examine the association between HCV and adipose tissue volume in HIV-infected men and women. METHODS: Cross-sectional analysis of HIV-infected subjects from the study of Fat Redistribution and Metabolic Change in HIV Infection. MRI measured regional adipose tissue volume. Detectable HCV RNA defined HCV infection. RESULTS: Twenty percent of 792 men and 26% of 329 women were HIV/HCV-coinfected. HIV/HCV-coinfected and HIV-monoinfected women had similar amounts of subcutaneous adipose tissue (SAT) in the leg, lower trunk, upper trunk, and arm and similar amounts of visceral adipose tissue (VAT). Similar findings were seen in men, except in the leg and VAT. After adjustment, HCV infection remained associated with more leg fat in men (12.2%, 95% confidence interval [CI]: 0.3 to 25.3; P = 0.043). Among those on stavudine, HIV-monoinfected men had less leg fat (-7% effect per year of stavudine use, 95% CI: -9 to -5; P < 0.001); a weaker association was seen in HIV/HCV-coinfected men (-2% effect, 95% CI: -7 to 3; P = 0.45). Indinavir was associated with less leg fat (-4% in HIV-monoinfected men, 95% CI: -6 to -1; P = 0.002; -5% in HIV/HCV-coinfected men, 95% CI: -11 to 2; P = 0.14). CONCLUSIONS: Our findings suggest that HIV/HCV coinfection is not associated with less SAT in men and women. HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.     

Fat distribution in HIV-infected women in the United States: DEXA substudy in the Women's Interagency HIV Study

Surveys in HIV-infected men on antiretroviral therapy (ART) consistently demonstrate decreased levels of peripheral fat, with variable effects on central fat. This substudy of the Women's Interagency HIV Study was undertaken to examine fat distribution in a well-characterized cohort of HIV-positive and HIV-negative women in the United States. Whole-body dual-energy x-ray absorptiometry scanning with standardized regional analysis was performed in 271 nonpregnant women. Results were compared in the following groups: HIV negative (n = 88); and HIV positive on no ART (n = 70), highly active ART with a protease inhibitor (HAART/PI) (n = 48), or non-PI-containing HAART (n = 53). The groups were well matched with respect to race, with the majority of women coming from racial/ethnic minorities. The majority of both HIV-positive and HIV-negative women were overweight (body mass index [BMI] >/=25 kg/m), and many were obese (BMI >30 kg/m). Leg fat in both groups on HAART was significantly lower than in HIV-negative women (P = 0.01 and <0.0001 vs. HIV-negative for HAART/PI and HAART/no PI, respectively), whereas trunk fat was lower only in HAART/no PI (P = 0.0004 vs. HIV-negative). Thus, consistent with reports in men, lower levels of peripheral (leg) fat are seen in HIV-infected women on HAART, despite the high prevalence of obesity in this population.     

Antiviral activity of enteric-coated didanosine,stavudine, and nelfinavir versus zidovudine plus lamivudine and nelfinavir

OBJECTIVE: To assess and compare the activity and safety of capsules containing enteric-coated beadlets of didanosine given once daily with stavudine and nelfinavir with that of a standard reference triple drug regimen of zidovudine plus lamivudine and nelfinavir. DESIGN: Multinational, 49-site, prospective, open-label, randomized, two-arm comparison study. PARTICIPANTS: HIV-infected subjects with limited or no previous antiretroviral therapy who had plasma HIV RNA levels of >or=2000 copies/mL and CD4 cell counts of >or=200/mm3 (511 were randomized to treatment groups, and 352 completed the study). INTERVENTIONS: Triple antiretroviral therapy for 48 weeks: didanosine EC (400 mg once daily), stavudine (40 mg twice daily), and nelfinavir (750 mg three times daily) or a twice-daily coformulation of zidovudine (300 mg) plus lamivudine (150 mg) and nelfinavir (750 mg three times daily). MAIN OUTCOME MEASURE: Proportion of subjects with HIV RNA levels of <400 copies/mL at week 48 based on an "intent-to-treat, missing = treatment failure" analysis. RESULTS: The two treatment groups were similar in the proportion of treatment responders (i.e., HIV RNA level of <400 copies/mL), with 54% of subjects in the didanosine EC and zidovudine plus lamivudine treatment groups responding at week 48. Results of other analyses supported those of the primary analysis. The two study regimens were associated with similar numbers of adverse events. CONCLUSIONS: The antiviral efficacy of a triple combination regimen containing once-daily didanosine EC is similar to that of a reference triple combination regimen.     

Lopinavir/ritonavir plus nevirapine as a nucleoside-sparing approach in antiretroviral-experienced patients (NEKA study)

OBJECTIVES: To compare the efficacy and safety of a nucleoside-sparing approach with a conventional highly active antiretroviral therapy (HAART) regimen in antiretroviral-experienced patients with prolonged viral suppression. METHODS: Pilot study including 31 antiretroviral-experienced patients with HIV RNA <80 copies/mL. Subjects were randomly assigned to lopinavir/ritonavir (LPV/rtv) 400/100 mg BID plus nevirapine (NVP) 200 mg BID (NVP group, n = 16) or LPV/rtv plus the 2 previous NRTIs (NRTI group, n = 15). The primary endpoint was the percentage of subjects who maintained viral suppression at week 48. Changes in lipid metabolism, mitochondrial parameters, and LPV trough levels were also assessed. RESULTS: All patients maintained viral suppression after 48 weeks. No subject discontinued therapy because of adverse events. HDL cholesterol increased by 28% at week 24 (P < 0.0001) and 10% after 48 weeks of follow-up (P = 0.319) in the NVP group. In the NRTI group, LDL cholesterol increased by 14% at week 48 (P = 0.076). Mitochondrial DNA/nuclear DNA ratio and mitochondrial respiratory chain complex IV activity showed a trend toward increasing in the NVP group. Mean (SD) LPV trough levels were 6340 (2129) ng/mL in the NRTI group and 5161 (2703) ng/mL in the NVP group (P = 0.140). CONCLUSIONS: In antiretroviral-experienced subjects with sustained viral suppression, dual therapy with NVP plus LPV/rtv at standard dosage was as potent and safe as standard-of-care HAART at 48 weeks of follow-up. This approach may reduce mitochondrial toxicity and improve LPV/rtv-associated lipid abnormalities. The results of this pilot study support the study of this approach in a larger, randomized trial.     

Soluble urokinase plasminogen activator receptor is a marker of dysmetabolism in HIV-infected patients receiving highly active antiretroviral therapy

Circulating soluble urokinase plasminogen activator receptor (suPAR) reflects the immune and pro-inflammatory status of the HIV-infected patient. Highly active antiretroviral therapy (HAART) suppresses suPAR. Independent of the immune response to HAART, suPAR remains elevated in some HIV-infected patients, reflecting possibly a low-grade pro-inflammatory state. Low-grade inflammation has been implicated in insulin resistance and other features of dysmetabolism. Accordingly it is hypothesized that circulating suPAR is associated with the metabolic status of HIV-infected patients on HAART. Fasting plasma suPAR was determined in 36 normoglycaemic HIV-infected patients on HAART (n = 18 lipodystrophic, and n = 18 non-lipodystrophic) who had estimated insulin sensitivity (Rd) and non-oxidative glucose disposal (NOGM) by euglycaemic hyperinsulinaemic clamps, indirect calorimetry, and glucose tracer infusion. Five patients had circadian suPAR concentrations measured (24 hr, 20 min-intervals). suPAR and non-HDL-cholesterol were higher and Rd, NOGM, and limb fat were lower in lipodystrophic patients than in non-lipodystrophic patients (P < 0.05). suPAR correlated positively with non-HDL-cholesterol and inversely with Rd, NOGM and limb fat (P < 0.005, n = 36). suPAR also correlated positively with leukocyte count and TNF-alpha (P < 0.01, n = 36) but not with IL-6. In multiple regression analyses suPAR was a stronger predictor of dysmetabolism than TNF-alpha and IL-6. Circadian suPAR did not systematically fluctuate. In conclusion, suPAR may reflect the metabolic status of the HIV-infected patient on HAART, thus linking low-grade inflammation, immune constitution, lipid and glucose metabolism, and fat redistribution. Circadian suPAR concentration appeared stable, suggesting that sampling schedule does not affect measurement. Further studies addressing whether suPAR predicts lipodystrophy and dysmetabolism in HIV-infected patients are warranted.     

Initial response to highly active antiretroviral therapy in HIV-1C-infected adults in a public sector treatment program in Botswana

OBJECTIVE: To describe the response to highly active antiretroviral treatment (HAART) in a public sector pilot antiretroviral (ARV) treatment program in Botswana. METHODS: The response to HAART is described in adult HIV-infected ARV-naive patients initiating treatment from April 2001 to January 2002 at Princess Marina Hospital in Gaborone, Botswana. Patients had medical and laboratory evaluations before initiating ARV treatment and were followed longitudinally. For analysis, data were collected from charts and patient management records. RESULTS: One hundred fifty-three ARV-naive patients initiated HAART. Most received didanosine plus stavudine (ddI + d4T) with efavirenz or nevirapine. The mean CD4 cell count increase was 149 cells/mm at 24 weeks and 204 cells/mm at 48 weeks. The percentage of patients with an HIV-1 RNA level < or =400 copies/mL was 87.0% at 24 weeks and 78.8% at 48 weeks. The Kaplan-Meier 1-year survival estimate was 84.7% (79.0%, 90.8%), with a 3.2-fold increased risk (P = 0.004) of mortality among patients with a CD4 cell count <50 cells/mm. The 1-year Kaplan-Meier estimate of toxicity-related drug switches was 32.2% (20.3%, 40.4%). The most common toxicity was peripheral neuropathy, occurring more frequently in patients with a preexisting diagnosis of peripheral neuropathy and among those placed on ddI + d4T-containing regimens. CONCLUSIONS: An excellent response to HAART was observed among HIV-1C-infected patients, paralleling those seen elsewhere. Despite excellent responses, high rates of toxicity were observed for ddI + d4T-containing regimens.     

Effects of weight, body composition, and testosterone on bone mineral density in HIV-infected women

Recent studies suggest that bone loss occurs among HIV-infected women. This study examined the effects of reduced androgen levels, changes in weight, body composition, and menstrual dysfunction on bone mineral density (BMD) among 152 HIV-infected women characterized by normal weight (>90% ideal body weight [IBW], n = 124) and low weight (相似文献   

Quantitation of blood lymphocyte mitochondrial DNA for the monitoring of antiretroviral drug-induced mitochondrial DNA depletion

OBJECTIVE: To investigate the impact of antiretroviral treatment on the mitochondrial DNA (mtDNA) content of peripheral blood mononuclear cells (PBMCs) from HIV-1-infected patients. DESIGN: As absolute mtDNA copy numbers widely differ between individuals, we performed a longitudinal analysis where the patient's first historical specimen was obtained as a baseline reference for relative comparison with subsequent samples from that patient. METHODS: mtDNA and nuclear DNA quantitation per cell (beta-globin gene copies) were both measured by real-time polymerase chain reaction analysis of whole DNA extracts of 361 serial live-cryopreserved PBMCs collected in former trials and clinical follow-ups from 60 individuals with established or recently acquired HIV-1 infections before and during administration of various antiviral combination therapies. RESULTS: mtDNA amounts were stable or increasing over years of natural HIV-1 infection in untreated patients (n = 7), consistent with our finding of a lack of differences in mtDNA copy numbers in patients with either a long established or recent lentivirus infection. Our quantitation system revealed significant changes in mtDNA copy number depending on the designated triple, quadruple, or quintuple anti-HIV drug combinations. Zidovudine + zalcitabine + ritonavir and zidovudine + lamivudine + didanosine regularly lead to mtDNA depletion in each of the treated patients, whereas none of 7 patients (and 35 cell specimens) receiving a stavudine + lamivudine + indinavir combination had any significant mtDNA content variations. In 7 patients, mtDNA copy numbers returned to pretreatment levels and/or higher levels without any interruption of the previously mtDNA-depleting antiretroviral drug combination. CONCLUSION: Our assay system allowed the detection of significant changes in the mtDNA content of PBMCs from HIV-1-infected patients taking antiretroviral drugs, as has been reported in the literature with other detection systems. Yet, mtDNA copy numbers regularly diminished during administration of some but not all nucleoside analog-containing combinations. This, plus the occasional finding that depleted mtDNA contents spontaneously increased to baseline levels and/or higher levels during uninterrupted treatment, should raise a note of caution about resorting to the PBMC mtDNA marker for monitoring of antiretroviral drug-related mitochondrial toxicities.