Tamsin A. Knox

Weight Loss and Wasting Remain Common Complications in Individuals Infected with Human Immunodeficiency Virus in the Era of Highly Active Antiretroviral Therapy

It has been postulated that the use of highly active antiretroviral therapy (HAART) would reduce the occurrence of human immunodeficiency virus (HIV)-associated weight loss and wasting. To test this assumption, we evaluated, by means of longitudinal analysis, a prospective cohort of 469 HIV-infected individuals enrolled in a study of the impact of HIV on nutrition. Overall, 156 individuals in the cohort (33.5%) met at least 1 of these definitions of wasting. Furthermore, 58% of the cohort (289 patients) lost >1.5 kg of weight in a 6-month period between any 2 study visits. More than 50% of the cohort was receiving HAART at the time that they met 1 of the definitions of wasting; with regard to the occurrence of wasting; no differences were related to therapy.

Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy.

Weight loss and wasting have long been established as strong predictors of mortality in HIV-infected patients. Today, despite the effectiveness of highly active antiretroviral therapy (HAART), there is evidence that HIV-related wasting is still an important comorbidity in many patients. We conducted a study to determine if wasting is still associated with decreased survival in patients receiving HAART and which parameter (weight, fat-free mass [FFM], body cell mass [BCM], or fat mass [FM]) is most strongly associated with mortality. The study population consisted of 678 HIV-positive participants enrolled in the Nutrition for Healthy Living study. Weight, FFM, BCM, and FM were assessed for all participants at 6-month intervals. At each follow-up visit, percent losses of each parameter were calculated from values at baseline and the previous visit. Cox proportional hazards models were used to estimate and compare the relative risks of death for each parameter, adjusting for potential confounders such as HAART use, body mass index, and CD4 cell counts. In analyses examining the parameters separately and together in the same model, weight loss emerged as the strongest independent predictor of mortality. Weight loss of >or=10% from baseline or the previous visit was significantly associated with a four- to sixfold increase in mortality compared with maintenance or gaining of weight. Even one episode of weight loss of >or=3% from baseline or >or=5% from the previous visit was predictive of mortality. In summary, despite the apparent benefits of HAART use on HIV-related survival, weight loss remains an independent predictor of mortality. In addition, FFM or BCM estimated using bioelectrical impedance analysis does not add further prognostic value over weight loss.

The effect of protease inhibitors on weight and body composition in HIV-infected patients

Objectives:To determine the nutritional changes that occur in HIV-infected patients receiving protease inhibitor (PI) therapy and to determine the effects of PI treatment on physical functioning and health perceptions in patients with HIV infection. Design:Longitudinal data analysis of 38 patients from a large Nutrition and HIV cohort. Methods:Patients were included if they had started PI therapy after enrollment in the cohort, if they had taken the drug for at least 4 months without interruption and if data on weight, body composition and viral loads were available. Results:Mean person-months of follow-up was 8.1 months before and 12.2 months after PI treatment. Weight (1.54 kg, P < 0.0001), body mass index (0.50 kg/m2, P < 0.0001), physical functioning (8.52 points, P = 0.0006) and current health perception (6.7 points, P = 0.01) increased significantly, and the daily caloric intake increase was close to significance (915.5 kJ/day, P = 0.06), after treatment with PI. Lean body mass did not change. Patients who responded to PI therapy with decreased viral load (n = 28) had significantly greater weight gain per month than non-responders. Conclusions:PI therapy of HIV infection is associated with weight gain and improvement in quality of life indices. The weight gain is mainly in fat mass, with no change in lean body mass (skeletal muscle). Optimal therapy of HIV-infected patients with weight loss may require highly active antiretroviral therapy combined with an anabolic stimulus such as exercise, anabolic steroids or human growth hormone.

A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis

BACKGROUND/AIMS Primary sclerosing cholangitis (PSC) is a progressive disease with no accepted effective treatment. Because methotrexate was associated with clinical and histological improvement in two men with PSC, we conducted a prospective trial of methotrexate in PSC. METHODS A prospective placebo-controlled, double-blind trial of methotrexate in PSC was performed. Twenty-four patients with PSC were randomized to receive methotrexate or placebo for a 2-year period. Seven of 12 taking methotrexate and five taking placebo had cirrhosis. Serial liver biopsies, endoscopic retrograde cholangiopancreatography (ERCP), and biochemical tests of liver function were followed. RESULTS There were no significant changes in liver histological results, ERCP findings, tests of liver function (other than alkaline phosphatase), or outcome between the two groups. Mean alkaline phosphatase levels decreased by 152 IU in the methotrexate group and increased by 30 IU in the placebo group (P = 0.032). Patients taking methotrexate were more likely to reduce or discontinue cholestyramine than patients taking placebo. CONCLUSIONS This study does not support efficacy for methotrexate in the treatment of PSC. On the basis of this study, the empiric use of methotrexate in patients with PSC is not recommended. However, methotrexate is being further evaluated in patients with precirrhotic PSC.

Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial.

OBJECTIVES:Dietary folate intake is inversely associated with the risk of colorectal cancer. This study investigated the effect of folate supplementation on genomic DNA methylation and DNA strand breaks in exons 5–8 of the p53 gene of the colonic mucosa, two provisional biomarkers of colon cancer.METHODS:Twenty subjects with adenomas were randomized to receive either folate (5 mg/day) or placebo for 1 yr after polypectomy. At baseline, 6 months and 1 yr, systemic and colonic measures of folate status were determined, as were the biomarkers mentioned earlier.RESULTS:Folate supplementation increased serum, red blood cell and colonic mucosal folate concentrations (p < 0.02). Folate supplementation also increased the extent of genomic DNA methylation at 6 months and 1 yr (p = 0.001), whereas placebo administration was associated with an increase in the extent of genomic DNA methylation only at 1 yr. Similarly, folate supplementation decreased the extent of p53 strand breaks in exons 5–8 at 6 months and 1 yr (p < 0.02), whereas placebo administration was associated with a decrease in the extent of p53 strand breaks only at 1 yr.CONCLUSIONS:Both of these provisional biomarkers of colon cancer underwent accelerated improvement at 6 months with folate supplementation. However, these markers also improved with placebo at 1 yr. Therefore, potential confounding factors that seem to modulate these biomarkers need to be identified and corrected in order for these markers to serve as suitable surrogate endpoints in folate chemoprevention trials.

Prevalence of, Evolution of, and Risk Factors for Fat Atrophy and Fat Deposition in a Cohort of HIV-Infected Men and Women

BACKGROUND At present, no uniform definition of human immunodeficiency virus (HIV)-associated lipoatrophy exists. The risk factors for fat atrophy (FA) and central fat deposition (FD) are multifactorial. We assessed the evolution and predictors of FA and FD in HIV-infected men and women. METHODS Participants (n = 452) were evaluated at baseline (starting in November 1998) and 1 year later. FA was defined as triceps skin-fold measurement less than the 10th percentile on the National Health and Nutrition Examination Survey for sex and age. FD was defined as a waist-to-hip ratio of > 0.95 for men and of > 0.85 for women. Predictors of the baseline prevalence of FA and FD and new cases of each syndrome after 1 year were determined. RESULTS The baseline prevalences of FA, FD, and combined FA and FD were 35%, 44%, and 14%, respectively. Twenty-two percent of subjects had newly developed FA at 1 year, and 16% of subjects with FA at baseline did not have it at 1 year. Also, 23% of subjects had newly developed FD at 1 year, and 15% of those with FD at baseline did not have it at 1 year. The risk of developing new FA was increased among participants with low triceps skin-fold values (P < .001), smaller hips (P < .001), higher nadir HIV load (P = .006), abacavir use (P < .001), stavudine use (P < .001), and use of highly active antiretroviral therapy (P = .002). The risk of developing new FD was higher among women (P < .001) and among participants with greater body fat levels (P = .005) and higher triglyceride levels (P < .001), and it was lower among those with a high school education (P = .003) and higher triceps skin-fold values (P = .026). CONCLUSIONS FA and FD are common in HIV-infected patients, but may change over time in the individual. FA and FD appear to be different syndromes, because risk factors for the development differ, and the prevalence of the combined syndrome differs from the prevalences of the 2 independent syndromes.

Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection

OBJECTIVE:The aim of this study was to determine the prevalence of gastrointestinal dysfunction in the era of improved treatment of HIV infection.METHODS:Gastrointestinal function was studied cross-sectionally in 671 persons with HIV. Absorptive function was measured by a 25-g D-xylose test, a Sudan-III stain for fecal fat on a 100-g fat diet, and serum levels of micronutrients.RESULTS:Eighty-eight percent had at least one abnormality of gastrointestinal function: 47.7% had low D-xylose absorption; 40.3% had a history of liver disease; 38.9% had diarrhea; 28.3% had chronic diarrhea; 22.5% had borderline or low serum vitamin B12 levels; 12.2% had stool pathogens; and 7.2% were hypoalbuminemic. Men were more likely to have low D-xylose absorption, diarrhea, and stool pathogens than women. Intravenous drug users (IVDUs) were more likely to have a history of liver disease and hypoalbuminemia. However, borderline or low vitamin B12 levels were less frequent in IVDUs; they tended to have less diarrhea and a lower prevalence of stool pathogens. Despite less history of liver disease, 14.1% of women were hypoalbuminemic. Differences in patterns of gastrointestinal dysfunction are unlikely to be due to severity of immunosuppression as abnormalities were seen in all risk groups with CD4 >200 cells/mm3. D-xylose absorption below 30 mg/dl, current diarrhea, and borderline levels of vitamin B12 were associated with advanced immunosuppression.CONCLUSIONS:Abnormalities of gastrointestinal function are common in the current era of HIV treatment, appear early in the course of HIV infection, and in the absence of diarrhea. Gender and IVDU are important determinants of the type and frequency of gastrointestinal abnormalities.

Treatment of primary biliary cirrhosis with low-dose weekly methotrexate

Nine women with symptomatic precirrhotic primary biliary cirrhosis have been treated with oral pulse methotrexate, 15 mg/wk, for 12-34 months. Three women had pruritus, two fatigue, and four pruritus and fatigue. Itching disappeared and fatigue lessened or disappeared in all within 4-11 months after starting methotrexate. All who itched were able to discontinue cholestyramine (five) or antihistamines (two). Biochemical tests of liver function improved in all patients and then worsened in three when methotrexate was discontinued or the dose lowered. Mean serum alkaline phosphatase decreased from 471 to 171 U/L (P less than 0.01), serum bilirubin from 0.99 to 0.59 mg/dL (P less than 0.05), and serum alanine aminotransferase from 132 to 61 U/L (P = 0.02), and serum cholesterol fell from 265 to 213 mg/dL (NS). The decrease in serum cholesterol was significant, P = 0.05, if data were used just from the six women whose baseline serum cholesterol levels were elevated. Serum albumin remained normal in all. The serum bilirubin levels became normal in three of four patients with elevated levels. The serum alkaline phosphatase levels became normal in four patients and the alanine aminotransferase levels in three. Liver histology improved in five patients and was stable in the remaining four based on a quantitative evaluation of coded liver biopsy specimens. The improvement in histology was primarily due to decreased portal inflammation and bile duct injury. The titer of antimitochondrial antibody decreased in seven patients. The data suggest that methotrexate may be effective treatment for precirrhotic primary biliary cirrhosis. Controlled trials are needed to evaluate long-term efficacy and toxicity.

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.

The Impact of Cirrhosis on CD4+ T Cell Counts in HIV-Seronegative Patients

BACKGROUND Studies of the progression liver fibrosis in human immunodeficiency virus (HIV) and hepatitis C virus-coinfected patients suggest that cirrhosis is associated with immunosuppression, as measured by low absolute CD4(+) T cell counts. However, we hypothesized that, in patients with advanced liver disease, low CD4(+) T cell counts may occur secondary to portal hypertension and splenic sequestration, regardless of the presence or absence of HIV infection. METHODS Sixty HIV-seronegative outpatients with cirrhosis were enrolled during the period 2001-2003 in a prospective, cross-sectional study of the association between liver disease and CD4(+) T cell counts and percentages. Demographic characteristics, liver disease-related characteristics, and laboratory results--including CD4(+) T cell parameters--were collected. RESULTS A total of 39 patients (65%) had a low CD4(+) T cell count; 26 patients (43%) and 4 patients (7%) had CD4(+) T cell counts <350 and <200 cells/mm(3), respectively. Abnormal CD4(+) T cell counts were associated with splenomegaly (P=.03), thrombocytopenia (P=.002), and leukopenia (P<.001). The percentage of CD4(+) T cells was normal in 95% of patients who had a low absolute CD4(+) T cell count. CD4(+) T cell counts were significantly lower among cirrhotic patients than among 7638 HIV-seronegative historic control subjects without liver disease. CONCLUSIONS Cirrhosis is associated with low CD4(+) T cell counts in the absence of HIV infection. Discordance between low absolute CD4(+) T cell counts and normal CD4(+) T cell percentages may be attributable to portal hypertension and splenic sequestration. Our findings have significant implications for the use and interpretation of absolute CD4(+) T cell counts in HIV-infected patients with advanced liver disease.