Tuesday, August 31, 2010

Health-Related Quality of Life is Prognostic of Survival in Patients With Cancer

From Medscape Medical News
Lara C. Pullen, PhD

August 30, 2010 (Shenzhen, China) — Health-related quality of life (HRQL) was found to be prognostic of survival in patients with hepatocellular and cholangiocarcinoma in a study presented here at the International Union Against Cancer (UICC)'s biennial World Cancer Congress 2010. This was true even when demographic, disease-specific, and treatment-related factors were controlled for.

More research needs to be performed to determine whether HRQL is actually a proxy for factors such as treatment adherence or sickness behavior, researchers said.

The results of this study were presented by Jennifer Steel, PhD, clinical psychologist at the University of Pittsburgh Medical Center in Pennsylvania. Dr. Steel told Medscape Medical News that "health-related quality of life may also be utilized in the design and interpretation of clinical trials testing novel treatments for cancer, not only as an end point. HRQL may be used to facilitate stratification of patients in randomized controlled trials or as a covariate when analyzing between-group differences in assessing treatment efficacy. Further research is warranted to determine if interventions improving HRQL also result in survival benefits; however, this remains a controversial area of investigation."

The study involved 321 patients who had been diagnosed with hepatocellular or bile duct carcinoma. They were administered the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary instrument. Cox regression and Kaplan–Meier survival analyses were used to test the association between the 5 domains of HRQL and survival.

Overall, HRQL was found to be significantly (P = .03) associated with survival after adjustment for demographic (i.e., age, sex) and disease-specific (i.e., MELD score, tumor size, number of lesions, vascularity of lesion, vascular invasion) variables and treatment.

The physical well-being subscale of HRQL and the HepCS subscale of the HRQL were found to be significantly associated with survival (P = .02 and P = .05, respectively). The HepCS subscale measures symptoms and adverse effects.

Carolyn Gotay, PhD, professor at the School of Population and Public Health at the University of British Columbia in Vancouver, explained during an interview with Medscape Medical News that "these findings are consistent with a large body of research that indicates that the way patients evaluate their own well-being is linked to their prognosis." Dr. Gotay was not affiliated with this study.

David Cella, PhD, is the professor and chair of the Department of Medical Social Sciences at the Northwestern University Feinberg School of Medicine in Chicago, Illinois. He was also not involved in the study, but discussed its clinical implications with Medscape Medical News. "The only downside to [quality of life] assessment is burden to the provider, which can be minimized with automated administration and scoring/reporting. Patients appreciate the concern demonstrated by asking the questions."

UICC World Cancer Congress 2010: Abstract POS-A065. Presented August 19, 2010.

Alcohol Use Linked to Risk for Hormone-Sensitive Breast Cancers

From Medscape Medical News
Laurie Barclay, MD

August 25, 2010 — Alcohol use is linked to a risk for hormone-sensitive breast cancers, according to results from the Women's Health Initiative (WHI) Observational Study reported Online First August 23 and to appear in the September 22 print issue of the Journal of the National Cancer Institute.

"Alcohol consumption is a well-established risk factor for breast cancer," write Christopher I. Li, MD, PhD, from Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues. "This association is thought to be largely hormonally driven, so alcohol use may be more strongly associated with hormonally sensitive breast cancers. Few studies have evaluated how alcohol-related risk varies by breast cancer subtype."

As part of the prospective WHI, the goal of this analysis was to determine the association between self-reported alcohol intake and the risk for postmenopausal breast cancer. Of 87,724 participants enrolled from 1993 through 1998, a total of 2944 were diagnosed with invasive breast cancer during follow-up through September 15, 2005.

Based on multivariable adjusted Cox regression models used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), along with 2-sided statistical tests, alcohol intake was directly associated with an overall risk for invasive breast cancer, invasive lobular carcinoma, and hormone receptor-positive tumors (for all, P trend ≤ .022).

The association between alcohol intake and breast cancer was stronger for certain types of invasive breast cancer than for others.
The risk for hormone receptor-positive invasive lobular carcinoma in women who drank at least 7 alcoholic beverages per week was nearly double that in never-drinkers (HR, 1.82; 95% CI, 1.18 - 2.81), but the risk for hormone receptor-positive invasive ductal carcinoma was not statistically significantly increased (HR, 1.14; 95% CI, 0.87 - 1.50). The difference in HRs per drink per day among current drinkers was 1.15 (95% CI, 1.01 - 1.32; P = .042).

Absolute rates of hormone receptor-positive lobular cancer were 5.2 per 10,000 person-years among never-drinkers and 8.5 per 10,000 person-years among current drinkers. For hormone receptor-positive ductal cancer, absolute rates were 15.2 and 17.9 per 10,000 person-years, respectively.

"Alcohol use may be more strongly associated with risk of hormone-sensitive breast cancers than hormone-insensitive subtypes, suggesting distinct etiologic pathways for these two breast cancer subtypes," the study authors write.

Limitations of this study include observational design with possible residual confounding, and assessment of alcohol use only at baseline, so that extensive measurement errors or changes in alcohol use could affect the study conclusions. In addition, data on tumor characteristics were based on information abstracted from local pathology reports, which may have led to an unknown degree of misclassification because of variations in histology and hormone-receptor assessment across the United States.

"[T]his study provides prospective evidence that the relationship between alcohol use and breast cancer risk varies by breast cancer subtype, with risks most pronounced for invasive lobular and hormone receptor–positive tumors," the study authors conclude.
"Hence, alcohol is another established breast cancer risk factor that appears to be differentially associated among breast cancer subtypes, and this pattern of associated risks indicates that tumors defined by both histology and hormone receptor status have somewhat different etiologic determinants. These findings highlight the importance of incorporating breast cancer subtype information in etiologic studies of the disease."

This work was supported by the WHI program, which is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services. The study authors have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online August 23, 2010.

Cranberry Juice Fights Urinary Tract Infections Quickly

From WebMD Health News
Katrina Woznicki

August 26, 2010 — Scientists report that within eight hours of drinking cranberry juice, the juice could help prevent bacteria from developing into an infection in the urinary tract.

Previous studies have suggested that the active compounds in cranberry juice are not destroyed by the digestive system after people drink them, but instead work to fight against bacteria, including E. coli. This latest study, presented at the national meeting of the American Chemical Society in Boston, affirms that and provides evidence of the medicinal value of cranberries.

The new research suggests that the beneficial substances in cranberry juice could reach the urinary tract and prevent bacterial adhesion within eight hours.

Researchers from the Worcester Polytechnic Institute in Massachusetts grew strains of E. coli in urine collected from healthy people before and after they drank cranberry juice cocktail.

How Cranberry Juice Treats Urinary Tract Infections

A mixture of cranberry juice, water, and sweeteners found in cranberry juice cocktail was used for the study because it is the most popular cranberry beverage.
The researchers discovered that in petri dishes, cranberry metabolites in the juice prevented E. coli from sticking to other bacteria, limiting its ability to grow and multiply.
If E. coli is able to connect with other bacteria, such as the bacteria found in the urinary tract, it forms a layer or "biofilm." This allows the bacteria to multiply and produce an infection.

"A number of controlled clinical trials -- these are carefully designed and conducted scientific studies done in humans -- have concluded that cranberry juice really is effective for preventing urinary tract infections," says study researcher Terri Anne Camesano, PhD, in a news release. "That has important implications, considering the size of the problem and the health care costs involved."

Urinary tract infections are more common among women than men. According to the researchers, one in three women has had a urinary tract infection.

Urinary tract infections can occur anywhere along the urinary tract, which includes the bladder, urethra, and ureter. These infections account for 8 million trips to the doctor's office every year and cost more than $1.6 billion to treat.

Camesano said people should not self-treat urinary tract infections, and anyone who suspects they have an infection should see a doctor, but drinking cranberry juice may be an easy, inexpensive way to help keep E. coli at bay.

In the event of a urinary tract infection, antibiotics are the most common treatment. If left untreated, particularly in children, the elderly, or people with other chronic medical conditions, urinary tract infections can become more severe.

SOURCES:
News release, American Chemical Society.
National Institute of Diabetes and Digestive and Kidney Diseases.

BPA Linked to Higher Testosterone Levels

From WebMD Health News
Denise Mann

August 27, 2010 — Men who are exposed to high levels of the controversial plastic chemical bisphenol A (BPA) may show a small, but significant increase in blood levels of the male sex hormone testosterone, a study shows. These testosterone levels still remained within the normal range.

The study is published in Environmental Health Perspectives.

Some preliminary research has linked elevated testosterone to an increased risk for heart disease and certain cancers, but whether BPA significantly affects testosterone and whether this has any effect on health remains unproven.

BPA is an ingredient found in the liners of some food cans, feeding cups, and baby bottles. Growing numbers of companies now offer BPA-free bottles. Citing "potential health concerns," the FDA has called for more study on BPA.

In the CHIANTI Adult population study, researchers measured BPA levels in the urine of 715 Italian men and women aged 20 to 74 over a 24-hour period. There were detectable levels of BPA in more than 95% of the men.

The average daily exposure was more than 5 micrograms of BPA per day, which is slightly higher than levels seen in U.S studies. Men who had the highest levels of BPA in their urine showed an increase in the amount of testosterone in their blood, the study showed.

"BPA is what's known as an anti-androgen. That means that it blocks the normal action of testosterone in the body and what we might be seeing is the body making more testosterone to overcome this," says study researcher Tamara Galloway, PhD.

Galloway is a professor of ecotoxicology at the University of Exeter, U.K. "The levels we saw in our study group were still within the normal range for healthy men, so we can't say for sure what the effects might be," she says in an email.

Second Opinion

"Small fluctuations in endocrine function could have a lot of consequences, some which may not have been characterized yet," says John Meeker, ScD, an assistant professor of environmental health sciences at the University of Michigan School of Public Health in Ann Arbor, who has conducted studies on BPA and testosterone.

The new study "is adding to a small, but growing body of literature that background exposures to BPA could have potential health implications for people in the general population," he tells WebMD. "Human studies are limited, but there are a number underway so we should know a bit more about the human health risks of BPA exposure in the near future."

Meantime, Meeker, along with the FDA and other groups, suggest limiting exposure to BPA.

Some urge caution in drawing any conclusions based on the new findings.

"The bio-monitoring data represents exposure only over the last 24 hours. The study cannot establish a cause-effect relationship for any biological event that occurs at an earlier time," says Steven G. Hentges, PhD, of the Polycarbonate/BPA Global Group of the American Chemistry Council, a trade group in Arlington, Va.

"The small changes in testosterone levels appear to be within normal ranges and there is no indication that these changes are associated with any health effect," he tells WebMD in a written statement. What's more, testosterone levels are known to vary significantly throughout the day and seasonally.

Elizabeth Whelan, ScD, MPH, the president of American Council on Science and Health, a public health group in New York City, agrees. "It is no surprise that BPA was measurable in urine, but as to BPA being causally related to an increase in testosterone, the authors note that their evidence does not prove causation," she says. "There is no reason to believe that trace environmental exposures to BPA would affect testosterone levels any more than eating a meal consisting of natural soy, which is a potential natural endocrine modulator."

Concerns About BPA

Others aren't willing to take any chances regarding BPA.

Calling this an "important study," Robin M. Whyatt, DrPH, a professor of clinical environmental health sciences and the deputy director of the Columbia Center for Children's Environmental Health in New York City, says that "these findings are a clear indications that BPA is an endocrine disruptor and the effects on testosterone levels are of concern."

Whyatt's group is now looking at early-life exposures to BPA and subsequent obesity and metabolic syndrome in later childhood.

“This compelling new study is another piece of evidence that everyday exposures to BPA are affecting human health," says Sonya Lunder, MPH, a senior analyst at the Environmental Working Group, a nonprofit organization that advocates for public health issues. "The finding bears more follow-up, especially to determine the overall effects of this short-term alteration in hormone levels. However, it points to the immediate need to reduce BPA exposures, not just for infants and children, but for all age groups," she says in an email.

SOURCES:

Acetaminophen Use in Adolescents May Double Risk for Asthma

From MedscapeCME Clinical Briefs

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD
CME/CE Released: 08/17/2010;

August 17, 2010 — Acetaminophen use in adolescents is linked to development and/or maintenance of asthma, rhinoconjunctivitis, and eczema, according to the results of a global study reported online August 13 in the American Journal of Respiratory and Critical Care Medicine.

"This study has identified that the reported use of acetaminophen in 13- and 14-year-old adolescent children was associated with an exposure-dependent increased risk of asthma symptoms," said first author Richard W. Beasley, MD, professor of medicine at the Medical Research Institute of New Zealand in Wellington, in a news release, on behalf of the International Study of Asthma and Allergies in Childhood (ISAAC).

At 113 centers throughout 50 countries, 322,959 adolescent children (aged 13 - 14 years) enrolled in ISAAC Phase Three completed written and video questionnaires regarding current symptoms of asthma, rhinoconjunctivitis, and eczema. They also completed a written environmental questionnaire regarding potential risk factors such as acetaminophen exposure in the preceding 12 months. Logistic regression allowed calculation of the odds ratio (OR) of current asthma symptoms associated with acetaminophen use, which was the main study endpoint.

Recent use of acetaminophen was associated with an exposure-dependent greater risk for current asthma symptoms, based on multivariate analyses. For medium use (at least once in the last year) vs no use, the OR was 1.43 (95% confidence interval [CI], 1.33 - 1.53). For high use (at least once in the last month) vs no use, the OR was 2.51 (95% CI, 2.33 - 2.70).

"The overall population attributable risks for current symptoms of severe asthma were around 40 percent, suggesting that if the associations were causal, they would be of major public health significance," Dr. Beasley said. "Randomized controlled trials are now urgently required to investigate this relationship further and to guide the use of antipyretics, not only in children but in pregnancy and adult life."

In multivariate analysis, there was also an acetaminophen exposure–dependent increased risk for current symptoms of rhinoconjunctivitis (OR, 1.38 [95% CI, 1.29 - 1.47] and OR, 2.39 [95% CI, 2.24 - 2.55] for medium and high use, respectively) and eczema (OR, 1.31 [95% CI, 1.21 - 1.42] and OR, 1.99 [95% CI, 1.82 - 2.16] for medium and high use, respectively).

"Acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis and eczema in adolescent children," the study authors write.

An accompanying "at a glance commentary" notes that potential mechanisms for these effects of acetaminophen include oxidant-induced airways inflammation and enhanced Th2 responses.

Limitations of this study include cross-sectional design, precluding determination of causality; and potential confounding factors.

Birth-Cohort Study Also Conducted

Clinical Context

A recent study, published in the current issue of the American Journal of Respiratory and Critical Care Medicine, conducted by Amberbir and colleagues reported that acetaminophen use was associated with increased risk of wheeze, but not eczema, in a small cohort of patients in Ethiopia.

Previously, in 2008, Beasley and colleagues, the current study authors, conducted Phase Three of ISAAC, and in the September 20, 2008, issue of The Lancet, they reported that acetaminophen use (paracetamol) in the first year of life was associated with a greater risk for asthma symptoms in children aged 6 to 7 years.

The current study by Beasley and colleagues uses data from ISAAC Phase Three to evaluate whether acetaminophen use is linked with a greater risk for asthma, allergy, or eczema symptoms in children aged 13 to 14 years.

Clinical Implications

•Recent acetaminophen use is linked with an exposure-dependent increased risk for asthma symptoms in adolescents.
•Recent acetaminophen use is linked with an exposure-dependent increased risk for rhinoconjunctivitis and eczema symptoms in adolescents.

Sunday, August 29, 2010

New TB Test Must Reach More People: Expert

From Reuters Health Information

HONG KONG (Reuters) Jul 29 - A new diagnostic tool that detects drug-resistant tuberculosis in a matter of hours must be made available to populations vulnerable to the disease, a World Health Organization expert said.

"New diagnostic tools offer the opportunity to increase the sensitivity of TB diagnosis in general and to shorten the diagnosis of MDR-TB (multidrug-resistant TB)" from weeks to hours, regional adviser on TB for the WHO in the Western Pacific region, said on Thursday.

"These tools are very expensive, but the scale up should be carefully planned. That requires money, training, infrastructure," she said in a telephone interview after a meeting organized by the WHO in the Philippines on the disease.

The meeting was attended by representatives from countries in the Western Pacific region with a high TB burden, such as China, Cambodia, Vietnam, Laos, Philippines and Papua New Guinea.

According to the WHO, there are 120,000 new cases of MDR-TB in the Western Pacific each year, which makes up 28% of the global caseload.

Combined with cases in southeast Asia, all MDR-TB cases in Asia make up 58% of the global caseload.

"We are not detecting enough TB cases and we are not detecting them early enough. We have to target high risk TB groups, such as migrants, the homeless and patients with certain risk factors, like HIV," Van Weezenbeek said.

"We are doing a poor job when it comes to diagnosing TB in children. We expect to increase the detection of childhood TB by the introduction of routine contact investigation, ensuring that the household contacts of infectious patients are screened."

China ranked second in the world with 112,000 drug-resistant TB cases in 2007, after India with 131,000. Russia has 43,000 cases, while South Africa has 16,000 and Bangladesh 15,000.

TB killed 1.8 million people across the world in 2008, or a person every 20 seconds. It is not only a scourge in poor countries but also in the West, where it has flared anew in the last 20 years because of AIDS.

Sugar-sweetened Carbonated Beverage Consumption Correlates with BMI, Waist Circumference, and Poor Dietary Choices in School Children

From BMC Public Health
Kate S Collison; Marya Z Zaidi; Shazia N Subhani; Khalid Al-Rubeaan; Mohammed Shoukri; Futwan A Al-Mohanna

Abstract
Background: The prevalence of obesity and overweight is increasing globally. Frequently coexisting with under-nutrition in developing countries, obesity is a major contributor to chronic disease, and will become a serious healthcare burden especially in countries with a larger percentage of youthful population. 35% of the population of Saudi Arabia are under the age of 16, and adult dietary preferences are often established during early childhood years.

Our objective was to examine the dietary habits in relation to body-mass-index (BMI) and waist circumference (W_C), together with exercise and sleep patterns in a cohort of male and female Saudi school children, in order to ascertain whether dietary patterns are associated with obesity phenotypes in this population.

Methods: 5033 boys and 4400 girls aged 10 to 19 years old participated in a designed Food Frequency Questionnaire. BMI and W_C measurements were obtained and correlated with dietary intake.

Results: The overall prevalence of overweight and obesity was 12.2% and 27.0% respectively, with boys having higher obesity rates than girls (P ≤ 0.001). W_C and BMI was positively correlated with sugar-sweetened carbonated beverage (SSCB) intake in boys only. The association between male BMI and SSCB consumption was significant in a multivariate regression model (P < 0.0001).

SSCB intake was positively associated with poor dietary choices in both males and females. Fast food meal intake, savory snacks, iced desserts and total sugar consumption correlated with SSCB intake in both boys (r = 0.39, 0.13, 0.10 and 0.52 respectively, P < 0.001) and girls (r = 0.45, 0.23, 0.16 and 0.55 respectively, P < 0.001).

Older children reported eating significantly less fruit and vegetables than younger children; and less eggs, fish and cereals. Conversely, consumption of SSCB and sugar-sweetened hot beverages were higher in older versus younger children (P < 0.001). BMI and W_C were negatively correlated with hours of night-time sleep and exercise in boys, but only with night time sleep in girls, who also showed the lowest frequency of exercise.

Conclusions: A higher intake of SSCB is associated with poor dietary choices. Male SSCB intake correlates with a higher W_C and BMI. Limiting exposure to SSCB could therefore have a large public health impact.

Tai Chi May Be Useful to Treat Fibromyalgia

From Medscape Medical News

Laurie Barclay, MD

August 18, 2010 — Tai chi may be a helpful intervention for patients with fibromyalgia, according to the results of a single-blind, randomized trial reported in the August 19 issue of the New England Journal of Medicine.

"Previous research has suggested that tai chi offers a therapeutic benefit in patients with fibromyalgia," write Chenchen Wang, MD, MPH, from Tufts Medical Center, Tufts University School of Medicine in Boston, Massachusetts, and colleagues. "...[Tai chi] combines meditation with slow, gentle, graceful movements, as well as deep breathing and relaxation, to move vital energy (or qi) throughout the body. It is considered a complex, multicomponent intervention that integrates physical, psychosocial, emotional, spiritual, and behavioral elements."

Fibromyalgia was defined by American College of Rheumatology 1990 criteria. Participants (n = 66) were randomly assigned 1:1 to receive classic Yang-style tai chi or a control intervention consisting of wellness education and stretching. In both groups, participants received 60-minute sessions twice weekly for 12 weeks.

Fibromyalgia Impact Questionnaire (FIQ) score (ranging from 0 - 100) at the end of 12 weeks was the main study outcome, with higher scores indicating more severe symptoms. Secondary outcomes were summary scores on the physical and mental components of the Medical Outcomes Study 36-Item Short-Form Health Survey. To assess durability of the response, these tests were performed again at 24 weeks.

Improvements in the FIQ total score and quality of life in the tai chi group were clinically important. For this group, mean baseline and 12-week FIQ scores were 62.9 ± 15.5 and 35.1 ± 18.8, respectively, vs 68.0 ± 11 and 58.6 ± 17.6, respectively, in the control group. The mean between-group difference from baseline in the tai chi group vs the control group was −18.4 points (P < .001).

The tai chi group also fared better than the wellness intervention group in physical component scores of the Short-Form Health Survey (28.5 ± 8.4 and 37.0 ± 10.5 for the tai chi group vs 28.0 ± 7.8 and 29.4 ± 7.4 for the control group; between-group difference, 7.1 points; P = .001) and mental component scores (42.6 ± 12.2 and 50.3 ± 10.2 vs 37.8 ± 10.5 and 39.4 ± 11.9, respectively; between-group difference, 6.1 points; P = .03).

These improvements were still present at 24 weeks (FIQ score between-group difference, −18.3 points; P < .001), with no reported adverse events.

Limitations of this study include lack of double blinding, lack of generalizability because treatment was delivered by a single tai chi master at a single center, and follow-up limited to 24 weeks.

"In conclusion, our preliminary findings indicate that tai chi may be a useful treatment in the multidisciplinary management of fibromyalgia," the study authors write. "Longer-term studies involving larger clinical samples are warranted to assess the generalizability of our findings and to deepen our understanding of this promising therapeutic approach."

N Engl J Med. 2010;363:743-754.

What is this new "Superbug

Preventing Infections: Spreading the Word?
Luke Chen, MD, Infectious Diseases, 10:33PM Aug 14, 2010

Recent US press and media have honed in on a new type transferable antibiotic resistance in gram-negative organisms.

NDM-1 (New Delhi Metallo-beta-lactamase 1) is named after the city that was visited by the patient in whom the first organism carrying this enzyme was isolated.
NDM-1 is a new type of plasmid-mediated resistance that can hydrolyze all beta-lactams, carbapenems but generally not monobactams (e.g. aztreonam). The plasmid can concurrently carry other resistance-conferring genes and can be transferred between types of gram-negative bacteria.

The NDM-1 resistance is detectable using current CLSI recommendations and the modified-Hodge test. Patients suspected or shown to have this type of drug resistance should be isolated with contact precaution and have strict hand hygiene with approved products.
So far, this resistance is not widespread.



References: Yong D et al. Antimicrob Agents Chemother 2009. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786356/

Saturday, August 28, 2010

Risk of Cardiovascular Events and All-Cause Mortality in Patients Treated With Thiazolidinediones in a Managed-Care Population

A new analysis of diabetes medications Avandia (rosiglitazone) and Actos (pioglitazone) revealed that the risk of heart attack and/or heart failure, or death were the same, approximately 4%. The study has been published in the latest issue of Circulation: Cardiovascular Quality and Outcomes, an American Heart Association journal.

Takeda Pharmacuetical Co. makes Actos, while GlaxoSmithKline (GSK) makes Avandia. Avandia sales had dropped after a previous study had found it was linked to higher heart disease risk.
American regulators are reviewing whether Avandia should be taken off the market after an FDA Advisory Committee said warnings about heart disease risks should be added to prescription information.

Debra Wertz, Pharm.D., lead author and outcomes research manager, HealthCore, Inc., research subsidiary of health insurance company WellPoint, Inc., said:

This study provides patients and their doctors with another source of information about rosiglitazone and pioglitazone as they determine the best therapy for diabetes patients.

This latest 33-month study, involving over 36,000 patients aged 54 years (average) and 14 months treatment on Actos or Avandia found that:
602 who took Avandia (rosiglitazone) had a heart attack and/or heart failure, or died.
96 had a heart attack.
265 had heart failure.
24 had both heart attack and heart failure.
217 died

599 who took Actos (pioglitazone) had a heart attack and/or heart failure, or died.
121 had a heart attack.
243 had heart failure.
18 had both heart attack and heart failure
217 died

This translates into approximately 4% of all patients taking either Actos or Avandia.
58% of the patients in this study were male. Wertz and colleagues obtained death records from the National Death Index, a central database administered by the National Center for Health Statistics.

The patients were divided into two equal groups, one receiving Avandia and the other Actos. After adjusting for factors such as age, gender, previous heart and blood vessel disease, complications related to diabetes, and severity indicators, they compared the incidence of heart failure, heart attack and death for 14 months (average) treatment and 19 months follow up after treatment.

Diabetes, a chronic disease in which the patient's body cannot produce enough insulin, or does not use it properly, has a significant risk of blood-sugar buildup, resulting in a higher risk of cardiovascular problems - the main cause of diabetes-related deaths.

Avandia both belong to a class of medications called thiazolidinediones (TZDs), which help the body use insulin more effectively - they improve the body's sensitivity to insulin, resulting in better blood-sugar control.

Wertz said:

Besides its findings that rosiglitazone and pioglitazone have comparable risks, what distinguishes this latest study from other claims-based analyses is its analysis of death records, which include out-of-hospital deaths.

Wertz added that this latest study monitored patients for longer than some earlier ones.

Mark J. Cziraky, Pharm.D., study co-author, and vice president of research development and operations at HealthCore, said:

One of the reasons we embarked on this analysis was to see if there were any differences in effect that we could identify between these two agents. We did not find that with the approach and methods we took within this population.

authors
Debra A. Wertz, PharmD; Chun-Lan Chang, PhD; Chaitanya A. Sarawate, MS; Vincent J. Willey, PharmD; Mark J. Cziraky, PharmD and Rhonda L. Bohn, MPH, ScD
Circulation: Cardiovascular Quality and Outcomes. 2010
Published online before print August 24, 2010, doi: 10.1161/CIRCOUTCOMES.109.911461

Written by Christian Nordqvist


View drug information on ACTOS; Avandia.

Friday, August 27, 2010

Vitamin D Deficiency Linked to Autoimmune Diseases

From WebMD Health News

Salynn Boyles

August 26, 2010 — There is now biologic evidence to back up the belief that vitamin D may protect against autoimmune diseases and certain cancers.

A new genetic analysis lends support to the idea that the vitamin interacts with genes specific for colorectal cancer, multiple sclerosis, type 1 diabetes, and other diseases, says Oxford University genetic researcher Sreeram Ramagopalan.

The study is published in Genome Research.

When Ramagopalan and colleagues analyzed the binding of vitamin D receptors to gene regions previously identified with different diseases, they found evidence of increased binding for multiple sclerosis, Crohn's disease, lupus, rheumatoid arthritis, colorectal cancer, and chronic lymphocytic leukemia (CLL).

"Genes involved in autoimmune disease and cancer were regulated by vitamin D," Ramagopalan tells WebMD. "The next step is understanding how this interaction could lead to disease."

Role of Vitamin D Supplementation

The role of vitamin D supplementation in preventing these diseases is also not well understood.

Exposure to sunlight is an efficient way to raise blood levels of vitamin D hormone, and food sources of the nutrient include oily fish like salmon, fortified milk, and other fortified foods.

But most people would have a hard time getting the vitamin D they need from food, and the increased use of sunscreen has reduced sun exposures.

By one recent estimate, as many as half of adults and children in the U.S. were deficient in the vitamin.

Current recommended daily vitamin D intake is 200 IU (international units) for those up to age 50; 400 IU for people 51 to70; and 600 IU for those over 70. Most experts say that these doses are too low.

Many experts, including Ramagopalan, say 2,000 IU of the vitamin may be optimal for preventing disease.

Blood levels of the vitamin are measured as 25-hydroxyvitamin D. Levels below 20 nanograms per milliliter are generally considered deficient.

Harvard School of Public Health nutrition researcher Edward Giovannucci, MD, says blood 25-hydroxyvitamin D levels of between 30 and 40 nanograms per milliliter may be about right for reducing the risk of autoimmune diseases and certain cancers.

While he says some people can reach these levels without supplementation, many others would need to take 1,000 to 2,000 IU of the vitamin a day.

"Based on what we know, I think it is reasonable to recommend that people maintain blood levels of around 30 nanograms per milliliter," he says.

Unanswered Questions

But vitamin D researcher JoAnn E. Manson, MD, says it is way too soon to recommend taking much larger doses of vitamin D than are recommended.

Manson chairs the preventive medicine department at Brigham and Women's Hospital in Boston and is principle investigator of a large U.S. study on vitamin D.

Still in the recruitment stage, the five-year, 20,000-person study will explore the impact of 2,000 IU of vitamin D on the risks for a wide range of health conditions, including cancer, heart disease, diabetes, hypertension, and depression. The study will also examine the effects of the fatty acid omega-3.

"I think it is important that we not leap ahead of the evidence in recommending high doses of vitamin D," she says. "We will soon have a better understanding of the optimal doses of vitamin D and the optimal blood levels associated with the best balance of benefits and risks. But right now there are many unanswered questions."

SOURCES:

Friday, August 20, 2010

Can Will Power Triumph Over the "Fatso" Gene?

From Medscape Genomic Medicine > Genomics in Practice
Jacquelyn K. Beals, PhD

Summer weather is here again, and with it comes the predictable upsurge in ads for how to look your best in a bikini, tank suit, or Speedo®, depending on your age, figure, or (lack of) self-confidence. Muscles are in, cellulite is frowned on, and fat -- as usual -- is a dirty word. For everyone who dismisses excess weight, saying, "It's in my genes," the bad news is that they're partly right. The good news is that in this realm, as in many others, genes are not destiny.

If ever a gene came by its nickname naturally, it's FTO. Officially designated in humans as the "fat mass and obesity associated" gene, it first gained attention in 1994 as 1 of 6 genes whose deletion caused fused toes in mutant mice. In normal mice, FTO expression was especially high in regions of the hypothalamus involved in energy balance. Its expression levels in these regions were regulated by variations in food intake.[1]

The function of human FTO was demonstrated in 2007.[2] A genome-wide association study involving nearly 39,000 people found that people with 2 copies of an FTO variant weighed an average of 3 kg more than did people with no copies of that variant. Among the study populations, 16% of participants were homozygous for the variant, and the association existed in children as young as age 7 years.

FTO's association with obesity was difficult to ignore: The odds ratio for obesity in homozygotes was 1.67 -- that is, individuals with 2 copies of the variant were 67% more likely to be obese than people without the variant.[2] Although the original genetic designation in mice referenced "fused toes," human FTO clearly deserved its nickname "fatso."

"Fatso" Association With Diabetes Differs Between Ethnic Groups
Considering the association of FTO with obesity, it came as no surprise that FTO variants were also associated with diabetes. Higher body weight, greater likelihood of diabetes mellitus -- it seemed obvious. FTO variants appeared to influence 2 of the 4 major diagnostic criteria for metabolic syndrome. At least that seemed to be the case, until investigators looked beyond their studies on "individuals of European inheritance."

A recent study reported in the May issue of PLoS One [3] assessed 4 single nucleotide polymorphisms (SNPs) of FTO in men and women of European and African American descent enrolled in the Atherosclerosis Risk in Communities (ARIC) study.

In white individuals (1004 with diabetes and 10,038 without), the study showed that the FTO genotypes of each of the 4 single-nucleotide polymorphisms (SNPs) studied (rs9939609, rs17817449, rs8050136, and rs1421085) were significantly associated with body mass index (BMI), waist-hip ratio, and waist circumference (P < .001 in each analysis), but not with height. Among African Americans (670 with diabetes and 2780 without), the rs1421085 genotype was significantly associated with BMI (P = .02); however, waist-hip ratio, waist circumference, and height were not associated with any of the 4 FTO SNP genotypes.

Assessment of FTO risk alleles by race showed that risk alleles of all 4 SNPs were associated with diabetes in white participants (odds ratios, 1.18-1.19; P < .001 for each SNP). But in African American participants, only rs1421085 risk variants were significantly associated with diabetes (odds ratio, 0.79; P = .03). Thus, the same allele that "conferred an elevated risk of being obese for both white and African-American participants" decreased diabetes risk 21% in African Americans. When analyses were adjusted for BMI, all significant associations between genotype and diabetes were retained.

BMI May Mediate FTO Influence on Diabetes
The authors acknowledge that FTO variants have repeatedly been associated with BMI and diabetes in Europeans, but replications in other ethnic groups (including African Americans, Hispanics, Asians, and Oceanics) have been less consistent across numerous studies. Several possibilities may account for the differences between ethnic groups.

The SNPs may be tightly linked in white persons but less strongly linked in people of African heritage. Alternatively, all 4 SNPs may be correlated with the "true causative mutation" in white persons, but only the rs1421085 SNP is correlated with the "true causative mutation" in African Americans. A third possibility -- which the authors present hesitantly -- is that the "genetic architecture of diabetes" differs between ethnic groups. The latter possibility is supported by rs1421085 protecting African Americans against diabetes while contributing significantly to obesity in both whites and African-Americans.

One of the more likely possibilities is that interaction between FTO variants and diabetes is mediated by BMI. The association between FTO genotype and BMI in African Americans was demonstrated only for rs1421085, and at a much lower level of significance (P = .02) than was seen in whites (P < .001). Thus, an association with diabetes might be more difficult to demonstrate in African Americans.

Eat More, Gain More -- For This I Need Genetics?
Although the "correct" possibility is still unknown, there is increasing evidence that FTO affects weight by influencing eating behavior and, specifically, by increasing energy intake and decreasing the satiety response. In several studies,[4,5] SNP rs9939609, which we met above, exerted some of its influence on weight via appetite by reducing the satiety response -- individuals with the rs9939609 variants demonstrated "low postprandial decrease in hunger."

So should individuals with these FTO variants resign themselves to obesity?
In April, a research study published in Archives of Pediatrics and Adolescent Medicine answered this question with a resounding "no."[6] Focusing on FTO SNP rs9939609, the study in European adolescents determined that increased physical activity could "offset the genetic predisposition to obesity associated with the FTO polymorphism."

In this case, at least, genes are not destiny. Even when satiety signals are reduced, willpower and lifestyle changes can prevail. Whether this comes as good news or bad is something that individuals -- and their physicians -- will have to decide for themselves. Meanwhile, summer is upon us and, for the moment, a tall glass of iced tea (no sugar, thanks) sounds pretty good.

Wednesday, August 18, 2010

Antagonistic People Have Thicker Carotid Walls, Increased CVD Risk

From Heartwire
Lisa Nainggolan

August 16, 2010 (Baltimore, Maryland) — Antagonistic people, particularly those who are competitive and aggressive, could be increasing their risk of MI or stroke, new research indicates [1].

Studying more than 5000 people in Sardinia, Italy, US scientists found that those who scored high for antagonistic traits on a standard personality test had greater thickening of the carotid arteries on ultrasound compared with people who were more agreeable. Intima-media thickness (IMT) of the carotid artery is an independent risk factor for cardiovascular events, say Dr Angelina R Sutin (National Institute on Aging, Baltimore, MD) and colleagues in their paper published online August 16, 2010 in Hypertension.

"We found that although men tended to have thicker arterial walls than women, antagonistic women had [thickness of] arterial walls similar to that of antagonistic men," Sutin told heartwire . "So the association between antagonism and arterial thickness was much stronger for women." And although arterial thickening is a sign of aging, young people with antagonistic traits already had such thickening, even after controlling for confounding factors such as smoking, she said.

She cautions, however, that this was a population-based sample and more research needs to be done in clinical settings. Nevertheless, doctors might want to consider antagonism and other facets of personality traits when assessing an individual's risk, she says. The study results could help determine who might benefit from targeted interventions such as anger management, for example.

Antagonism Results in a Similar Risk to Metabolic Syndrome

Sutin et al explain that a substantial body of literature illustrates how individual differences in antagonism-related traits predict a variety of cardiovascular outcomes, but much of this work has focused on the clinical manifestations of coronary heart disease. Advances in noninvasive technology have now made it possible to assess potential markers of atherosclerosis, a preclinical state of CHD, they note.

They examined the concurrent and prospective associations between six facets of trait antagonism and IMT in 5614 Italians in four villages in Sardinia as part of the Sardinia Study of Aging. Participants' ages ranged from 14 to 94 years (average age 42), and 58% were female. They answered a standard personality questionnaire, which included six components of agreeableness: trust, straightforwardness, altruism, compliance, modesty, and tender-mindedness.

The researchers also took two measures of IMT, three years apart, to see whether these traits predicted increases in arterial thickening. Participants were also screened for high blood pressure, cholesterol levels, triglycerides, fasting glucose, and diabetes, and the results were adjusted for these parameters.

Those who scored in the bottom 10% of agreeableness and were therefore the most antagonistic had about a 40% increased risk for elevated IMT; the effect on artery walls was thus similar to having metabolic syndrome, say the researchers.

"Determining which personality traits contribute to arterial thickening will help to identify who is most at risk and who would benefit most for targeted interventions," Sutin and colleagues conclude.

Beer Drinking Increases Risk for Psoriasis in Women

From Medscape Medical News
Fran Lowry

August 17, 2010 — Consumption of regular, but not light, beer is associated with an increased risk for the development of psoriasis among women, but other alcoholic beverages do not increase this risk, according to new research published Online First August 16 in the Archives of Dermatology.

"Psoriasis is a common immune-mediated skin disease. The association between alcohol consumption and increased risk of psoriasis onset and psoriasis worsening has long been suspected," write Abrar A. Qureshi, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and colleagues.
"Risk for psoriasis may vary by type of alcoholic beverage, given previous evidence that different types of alcoholic beverages have conferred deleterious effects in other inflammatory diseases."

If this were so, then it would have practical implications for psoriasis prevention and management, the study authors write. The aim of this study, therefore, was to evaluate the independent association between alcohol consumption and the risk for the development of psoriasis. The study authors also sought to determine if there was an association between the type of alcoholic beverage and the risk for psoriasis.

Dr. Qureshi and colleagues assessed data from 82,869 women who were aged 27 to 44 years in 1991. The women were participants in the Nurses' Health Study II, an ongoing longitudinal study of 116,430 registered nurses from 15 states in the United States. Responding to biennial questionnaires, the women reported the amount and type of alcohol they consumed. They also reported whether they had received a diagnosis of psoriasis. The period of follow-up was from 1991 to 2005.

During this time, there were 1150 cases of incident psoriasis, 1069 of which were used for analysis. Compared with women who did not drink alcohol, the risk for psoriasis was 72% greater among women who had an average of 2.3 drinks per week or more (multivariate relative risk [RR], 1.72; 95% confidence interval [CI], 1.15 - 2.57). When this risk was examined by type of alcoholic beverage, the researchers found that women who drank 5 or more regular beers per week had a 1.8-fold greater risk for the development of psoriasis (multivariate RR for ≥ 5 drinks per week, 1.76; 95% CI, 1.15 - 2.69), but that consumption of light beer, red or white wine, and liquor was not associated with this risk.

The association between psoriasis and regular beer intake became stronger in a subset of women with a confirmed diagnosis, who had provided more details about their condition on a 7-item self-assessment questionnaire. In this subset, the risk for psoriasis was 2.3 times higher for women who drank 5 or more beers per week than women who did not drink beer (multivariate RR for ≥ 5 drinks per week, 2.29; 95% CI, 1.36 - 3.85).

"Nonlight beer was the only alcoholic beverage that increased the risk for psoriasis, suggesting that certain non-alcoholic components of beer, which are not found in wine or liquor, may play an important role in new-onset psoriasis," the study authors write. "One of these components may be the starch source used in making beer. Beer is one of the few nondistilled alcoholic beverages that use a starch source for fermentation, which is commonly barley...Starch sources such as barley contain gluten, which has been shown to be associated with psoriasis."

Noting the limitations of their study, the authors state that the retrospective recall of psoriasis onset may have led to misclassifications of psoriasis onset. They were also unable to examine whether the risk for psoriasis differed regarding early-onset vs later-onset psoriasis given the age of the study cohort. Finally, the study was observational, and the cohort consisted of well-educated women and does not represent a random sample of US women, they write.

"Women with a high risk of psoriasis may consider avoiding higher intake of nonlight beer," the study authors conclude. "We suggest conducting further investigations into the potential mechanisms of nonlight beer inducing new-onset psoriasis."

This study was supported by grants from the National Institutes of Health and the National Cancer Institute. Dr. Qureshi has disclosed various financial relationships with Amgen and Genentech.

Arch Dermatol. Published online August 16, 2010.

Monday, August 16, 2010

FDA to Look Into Possible Cancer Risk With ARBs

From Heartwire > Alerts, Approvals and Safety Changes > Alerts

Lisa Nainggolan

July 16, 2010 (Bethesda, Maryland) — The US FDA has become the latest regulatory agency to say it will investigate a possible link between angiotensin-receptor blockers (ARBs) and cancer, in a safety alert for human medical products issued yesterday [1]. The move follows a meta-analysis reported in Lancet Oncology last month, which found a modest, but significant, increased risk of primarily lung cancer associated with the use of these antihypertensive agents.

The week after this paper was published, the European Medicines Agency (EMA) announced it would review the possible risk of cancer in patients taking ARBs, based on this. But many hypertension doctors are unhappy about the meta-analysis, citing many flaws, as reported by heartwire ; they also fear it will stop patients from taking their much-needed medication.

In its safety alert, the FDA says it has "not concluded that ARBs increase the risk of cancer. The agency is reviewing information related to this safety concern and will update the public when additional information is available. FDA believes the benefits of ARBs continue to outweigh their potential risks."

References

Friday, August 13, 2010

Caveats and Concerns With New Study on Hormone Therapy and Breast Cancer

From Medscape Medical News

Janis C. Kelly

August 12, 2010 — The use of postmenopausal hormone therapy (HT) dropped from about 40% of eligible women to about 20% after the 2002 report from the Women's Health Initiative (WHI) clinical trial that found an elevated risk for breast cancer associated with HT, but about 30 million women per year still use HT in the United States.

New data from the California Teachers Study might renew concern about this link.

In a report published online August 10 in Cancer Epidemiology, Biomarkers & Prevention, Tanmai Saxena, an MD/PhD student at the Keck School of Medicine at the University of Southern California, in Los Angeles, and colleagues found that women who used estrogen therapy (ET) for more than 15 years had a 19% greater risk of developing breast cancer than women who had never used ET.

The authors also found that breast cancer risk was higher for women who took postmenopausal hormones for longer periods, and highest for those using combined estrogen plus progestin (EPT).

Current use of either ET or EPT was associated with higher risk than past use of the same regimen, and risk increased with the number of days per month of progestin in a current EPT regimen.

Notably, the results suggest that there is also an increased risk for tumors that are HER2-positive. The study is one of the first to include data on HER2 status.

Caveats

The researchers analyzed HT use and the subsequent development of breast cancer in 56,867 perimenopausal and postmenopausal women, 2,857 of whom (5%) were subsequently diagnosed with pathologically confirmed invasive breast cancer. Mean follow-up was 9.8 years. The analysis included type, pattern, and recency of HT use.

Breast cancer expert Rowan T. Chlebowski, MD, PhD, from the University of California, Los Angeles, told Medscape Medical News that clinicians should consider several points when interpreting data from this observational study.

First, Dr. Chlebowski, who was lead author of the WHI study of EPT (JAMA. 2003:289:3243-3253), noted that the significant increase in breast cancer risk in the California Teachers Study was associated with the use of estrogen alone for 15 years or more, but that in real-world settings, few women take any type of ET or EPT for more than a few years. "The patient who is continuing to take ET or EPT after 15 years might also be different from a typical patient in other ways," he said. Also, in the WHI randomized trial, there was a strong trend toward lower breast cancer risk with ET.

Dr. Chlebowski pointed out that the California Teachers Study investigators controlled for differences in mammography use only in the last 2 years of the 9.8-year follow-up. He said that because women taking HT are known to have more mammograms, the data might partly reflect differences between screened and unscreened populations. "We know that with screening we find more, smaller, lower-grade, and [estrogen-receptor]-positive tumors," he said.

Data on HER2 and BMI

The California Teachers Study produced some surprises, senior author Giske Ursin, MD, PhD, told Medscape Medical News.

There may be some increased risk for tumors that are HER2-positive.
Dr. Ursin, who is from Institute of Basic Medical Sciences at the University of Oslo, Norway, said that they "expected that hormone therapy would only increase the risk of the most benign breast cancer subtype (i.e. the type with estrogen and progesterone receptors, but which do not have HER2 receptors). Although overall our findings are consistent with this —the hormone users tend to get relatively small and less lethal tumors — our findings on HER2 are not conclusive and suggest that there may be some increased risk for tumors that are HER2-positive as well."

Dr. Ursin said that an increased risk for HER2-positive cancers would be "worrisome," but that further study is needed on the matter.

"We know that there are large differences in survival, depending on which molecular subtype of breast cancer women develop. We need to understand which subtype hormone users develop," she said.

Women who used EPT for 15 or more years had an 83% greater risk than those who did not use HT. Breast cancer risk was highest among women who used the combination regimen.

The data also showed that HT-associated breast cancer risk was highest for women with a body mass index (BMI) below 25 kg/m2. In contrast, obese women (i.e., a BMI of 30 kg/m2 or more) had no further increase in risk associated with EPT.

The authors suggest that this might just mean that in obese women, the additional risk associated with HT fades to insignificance against the background of circulating estrogens produced by peripheral aromatase activity in fat tissue.

Finally, the risk for breast cancer was confined to tumors that were positive for both estrogen and progestin receptors. The risk was somewhat weaker for HER2-negative tumors.

Limit Postmenopausal HT to Brief Duration

HT is "prescribed for the treatment of menopausal symptoms around the time of menopause, and we currently recommend a relatively short duration of treatment," Dr. Ursin said.

It is the estrogen component of EPT "that is useful to treat menopausal symptoms. The [progesterone] component is added because, in women with a uterus, [estrogen] treatment alone increases the risk of endometrial cancer greatly. However, while [estrogen] alone does little to the breast, EPT increases the risk of breast cancer. In general, women with a uterus should be prescribed EPT, and women without a uterus can manage with [estrogen] treatment alone," she advised.

Clinicians vary in their approaches to HT, said Dr. Ursin. "Certain gynecologists are very careful with finding the right dose for each woman, and some even prescribe [estrogen] alone for women who have a uterus, but then monitor the uterus carefully. Please keep in mind that the risk of breast cancer associated with EPT is relatively moderate. The risk of endometrial cancer with [estrogen] alone is much higher — a more than 4-fold increase in risk in this same population of California teachers," she said.

Dr. Ursin and Dr. Chlebowski have disclosed no relevant financial relationships.

Cancer Epidemiol Biomarkers Prev. Published online August 10, 2010. Abstract

Wednesday, August 11, 2010

NIH Launches Phase 1 Dengue Vaccine Trial

From Medscape Medical News

Martha Kerr

August 10, 2010 — The National Institutes of Health announced today that phase 1 testing of a vaccine against the mosquito-borne dengue virus has begun.

The vaccine was developed at the National Institute of Allergy and Infectious Diseases (NIAID), and phase 1 testing is taking place at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

The new vaccine is tetravalent, incorporating all 4 dengue viruses — DENV-1, DENV-2, DENV-3, and DENV-4 — transmitted by Aedes mosquitoes. Someone with antibodies against only 1 or a few of the virus serotypes is actually at higher risk of developing a severe form of the disease, researchers say.

Development of the tetravalent live-attenuated vaccine at NIAID was led by Stephen S. Whitehead, PhD, and Brian Murphy, MD, who started by testing 7 monovalent vaccines. "Our overall strategy was to identify the best individual candidate for each serotype, based on safety and ability to induce an immune response, and to then combine those into a tetravalent vaccine," Dr. Whitehead said in an NIAID release announcing the launch of clinical testing of the vaccine.

Evaluation of a second candidate combination vaccine is taking place at the University of Vermont in Burlington. Trials of a third are scheduled to begin soon at Johns Hopkins. These early clinical trials are designed to test the safety and immunogenicity in healthy adults 18 to 50 years of age.

Volunteers will receive 1 dose of the assigned vaccine or placebo and will be monitored for 6 months. After determining which tetravalent vaccine is most promising, the researchers will test that candidate in a trial in a new group of volunteers in Brazil, where dengue is highly prevalent.

Phase 2 testing will include both unexposed subjects and those previously infected with dengue, and will evaluate the need for a booster shot within a few months of the initial vaccination.

"If everything goes well after that stage, we hope to start the final phase of human testing in 3 to 4 years," said Johns Hopkins lead investigator Anna Durbin, MD. "Controlling the mosquito vector can work, but it is very expensive and difficult to sustain," she pointed out. "In the long run, vaccination would be a more efficient and cost-effective approach."

Dengue virus is prevalent in tropical and subtropical regions of the world, and each year infects about 50 million to 100 million people. There are approximately 25,000 deaths annually, most of them in children. About 2.5 billion people in more than 100 countries worldwide live in endemic areas, and the prevalence is increasing.

"This is an important milestone for NIAID's intramural scientists in the development of a model dengue vaccine, which could potentially have a major impact in preventing dengue," says NIAID director Anthony S. Fauci, MD. "With increasing infection rates and disease severity around the world and the discovery of dengue in parts of Florida, finding a way to prevent dengue infection is an important priority."

For more information, see NIAID's Dengue Fever portal.

HBV Doubles Lymphoma Risk

From Medscape Medical News

Janis C. Kelly

August 11, 2010 — Patients with hepatitis B (HBV) infection are twice as likely to develop diffuse large B-cell lymphoma or some other subtype of non-Hodgkin's lymphoma (NHL), and over 3 times more likely to develop malignant immunoproliferation than those who are negative for hepatitis B surface antigen (HBsAg).

These are the conclusions of a study published online August 4 in the Lancet Oncology by Eric Engels, MD, from the National Cancer Institute, in Rockville, Maryland, Sun Ha Jee, PhD, from the Graduate School of Public Health, Yonsei University, in Seoul, South Korea, and colleagues.

Dr. Jee told Medscape Medical News that "the most important finding was the increased risk of non-Hodgkin's lymphoma, particularly diffuse large B-cell lymphoma, which is among the most common subtypes of lymphoma. This increased risk was almost double the risk seen in uninfected people and was present over a period ranging up to 14 years."

The researchers used data from the Korean Cancer Prevention Study to determine whether chronic HBV infection was associated with the subsequent development of NHL in 603,585 people.

HBV infection was endemic in South Korea until 1995, when the universal HBV vaccination of neonates was implemented. Before that, about 7% of South Korean adults had detectable plasma concentrations of HBsAg, which is an indication of chronic HBV infection. HBV infection remains common in South Korean adults because of infections acquired in childhood, before the vaccine was available.

The analysis showed that 53,045 study subjects (9%) were positive for HBsAg at baseline. NHL developed subsequently in 133 people who were hepatitis B positive and in 905 who were hepatitis B negative. The NHL incidence was 19.4 per 100 000 person-years in the positive group, and 12.3 per 100 000 person-years in the negative group (hazard ratio [HR], 1·74; 95% confidence interval [CI]. 1.45 - 2.09, adjusted for sex, age at baseline, and enrolment year). NHL risk was consistently higher in the positive group during the 14 years of follow-up.

The researchers also examined the risk for various NHL subtypes. They found an increased risk for diffuse large B-cell lymphoma (HR, 2.01) and for other or unknown subtypes (HR, 1.65).

They also found a nearly 4-fold increased risk for malignant immunoproliferation, a constellation of immune disorders related to NHL (HR, 3.79).

Hepatitis B positivity was not associated with follicular or T-cell NHL, Hodgkin's lymphoma, multiple myeloma, or various leukemias.

Several studies have already established a causal link between hepatitis C (HCV) infection and increased risk for NHL, but studies on hepatitis B and NHL have so far been small. The link to NHL for both HBV and HCV is thought to involve chronic immune stimulation in the setting of sustained liver infection. Sustained immune activation can lead lymphocytes to develop DNA mutations that promote their proliferation and progression to NHL.

Association Does Not Prove HBV Causes NHL

Dr. Jee emphasized that association is not causality.

"Additional case–control and cohort studies are needed to replicate our findings in other populations and to evaluate further whether other lymphoma subtypes are associated with hepatitis B infection. It is also important to determine whether hepatitis B treatment reduces the risk of developing non-Hodgkin's lymphoma, and to determine whether treatment for hepatitis B can lead to remission of lymphoma in the people who have already developed the cancer," he said.

The authors note that "for HCV-infected patients with low-grade NHL (especially marginal zone lymphomas), HCV treatment seems effective for hematological remission. Thus, we speculate that treatment directed at HBV in similar low-grade NHL might lead to a clinical response and remove the need for chemotherapy."

Implications for Treating NHL Patients

This study has immediate clinical implications, however.

"In countries such as South Korea, where hepatitis B virus infection is common, physicians should routinely screen patients with non-Hodgkin's lymphoma and other hematologic malignancies for this infection, because chemotherapy can lead to severe liver damage in the absence of specific prophylaxis," Dr. Jee said.

In an accompanying editorial, Sook-Hyang Jeong, MD, from Seoul National University in South Korea, warned against assuming that HBV vaccination will prevent NHL.

"Although the study had some limitations, such as absence of HCV and HIV data and lack of information about replication status of HBV or severity of liver disease, it presented reliable evidence for an important role of HBV infection in lymphomagenesis. If the association is causal, might the globally increasing implementation of universal HBV vaccination and increasing use of antiviral drugs for treatment of chronic HBV-related liver disease reduce development of NHL? Engels and colleagues commented that the causal association is small in magnitude, and that HBV infection would account for only a few NHL cases. Thus, those efforts would be expected to have a limited effect on NHL incidence," Dr. Jeong writes.

Dr. Jeong also points out that although there is some evidence suggesting that antiviral therapy for HCV in low-grade NHL might have produced hematological remission, "similar results from antiviral therapy for HBV have not been reported." Dr. Jeong said that "[lymphomagenesis] mechanisms involving HBV seem to differ from those involving HCV."

Dr. Jee and Dr. Jeong have disclosed no relevant financial relationships.

Coronary Calcium Controversy Continues

From Heartwire

Reed Miller

August 9, 2010 (Rio de Janeiro, Brazil) — Experts continue to debate the significance of a Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography Using 64 Detectors (CORE64) substudy, in which the absence of coronary calcification did not exclude the possibility of obstructive coronary disease in symptomatic patients [1].

On the basis of the results of the 291-patient study, authors Dr Ilan Gottlieb (Federal University of Rio de Janeiro, Brazil) and colleagues concluded that a zero coronary artery calcium score (CACS) with computed tomography (CT) should not be "used as a gatekeeper" to prevent symptomatic patients from undergoing angiography. As reported by heartwire , the results of the study sparked a debate about the utility of CT calcium scoring after they were published in the February 16, 2010 issue of the Journal of the American College of Cardiology.

That debate continues in five letters to the editor published in the August 10, 2010 issue of that journal. The letters are both critical of and favorable toward the CORE64 substudy and the accompanying editorial by Dr Rita Redberg (University of California, San Francisco), which argued that the incremental value of calcium scoring over traditional coronary disease predictors alone has not been demonstrated [2].

In their letter, Drs Luis Correia and Fabio Esteves (Medical School of Bahia, Salvador, Brazil) argue that the low negative predictive value of 68% found in the CORE64 study is "strikingly different from that reported in most trials" [3]. Likewise, Dr Matthew Budoff (Los Angeles Biomedical Research Center, CA) points out that Gottlieb et al's conclusions appear to contradict current professional guidelines for coronary calcium scoring and more than 1000 studies, including several that were five to 10 times larger than this CORE64 substudy [4].

Correia and Esteves contend that Gottlieb et al's calculations of sensitivity, specificity, negative predictive value, and positive predictive are in error. They argue that Gottlieb et al defined a negative test result as a CACS >0, when negative results should suggest only no disease. "If a negative test result was appropriately defined as a zero CAC score, the actual negative predictive value (number of patients without stenosis >50% divided by the number of patients with zero calcium score) would be 81% (58 of 72).

In their response [5], Gottlieb et al explain that the predictive values in their paper "have slightly different meanings than commonly utilized in other trials, [because] we chose to take a different perspective." Gottlieb et al state that their goal was to determine whether a CACS of zero could predict the absence of obstructive coronary artery disease, whereas the other trials referred to by the letter writers examined whether the presence of calcium increases the likelihood of chest pain being related to significant stenosis.

"Using our approach of calling a zero CACS a positive scan, the positive predictive value refers to the ability of zero calcium to rule out obstructive CAD. This is in fact the same message of a negative predictive value using the 'conventional' approach." So the predictive value was low in their study (68%) and the sensitivity of zero calcium to detect the absence of disease and rule out obstructive CAD was also low, at 45%, the authors explain. "When our results are interpreted from this perspective, they are clearly consistent with previously published studies."

In their letter to the editor, Dr Michael Blaha, Dr Roger Blumenthal, and Dr Khurram Nasir (Johns Hopkins University, Baltimore, MD) defend the approach used by Gottlieb et al and disagree with the statement in Redberg's editorial that the results are "starkly" different from those of previous studies [6]. They point out that when the differences in patient population are taken into account and the predictive values are calculated in the same way, the negative and positive predictive values in the CORE64 data are not much different than those found in previous studies.

Gottlieb et al argue that their approach is a more accurate test of the utility of calcium scoring when used specifically to rule out obstructive disease in symptomatic patients in order to discharge them from the emergency department or to guide outpatient investigation of their chest pain.

What Is the Value of Calcium Scoring?

The CORE64 authors stress that it would "be a grave mistake" to generalize their findings for all subgroups, because their study focused only on symptomatic patients. Therefore, Budoff's contention that their study contradicts more than 1000 studies with more than 100 000 patients "regrettably misses the fact that the vast majority of the published CACS literature refers to asymptomatic patients."

Redberg's editorial "took a broader view than our data warrant," Gottlieb et al argue in their response. "We acknowledge the role CACS has for risk stratification in selected symptomatic populations as well as in epidemiologic studies of atherosclerotic disease."

Gottlieb told heartwire that "it's very inappropriate to use the calcium score to rule out obstructive coronary disease, especially among acute chest-pain patients . . . because it depends very heavily on the prevalence of disease that you're looking at."

"We're not talking about asymptomatic patients. [Those patients] benefit a lot from calcium scores. It's a really great thing to do among certain groups of asymptomatic people," Gottlieb said, observing that some of the letters to the editor appear to conflate the asymptomatic and symptomatic populations. "This is a major mistake. It is a major division. If the patient is asymptomatic, the investigation algorithm should be very different than if the patient is symptomatic."

In her reply to the letters to the editor [7], Redberg points out that none of the letters "address the key clinical point of whether an imaging test such as coronary artery calcium will give us new information that leads to better patient care and improved outcomes. . . . Despite the use of CACS for the past 20 years, there are still no data for either the asymptomatic or symptomatic group to show that this information benefits our patients."

She points out that the most recent US Preventive Services Task Force recommendation statement on congestive heart disease risk assessment concludes that there is still not enough evidence to weigh the benefits and harms of using "nontraditional risk factors" to screen asymptomatic men and women with no history of coronary disease, and that the task force stated that there remains a critical gap in the evidence for screening with coronary artery calcium scoring because of the lack of information on how this type of screening will ultimately reduce the risk for coronary adverse events.

"Before subjecting healthy men and women to a test with significant radiation--2 to 7 mSv or 100 chest roentgenograms--one must be able to tell patients that there is a benefit from having this test," Redberg argues. "With no known benefit, CACS fails this essential criterion, and the harm, including cancer risk from radiation, and incidental findings prevail."

References

Longer HRT Use May Raise Breast Cancer Risk

Study Also Shows Higher Risk for Thinner Women Who Take Hormone Replacement Therapy
By Kathleen Doheny
WebMD Health News
Reviewed by Laura J. Martin, MD

Aug. 10, 2010 -- Hormone replacement therapy (HRT) and breast cancer risk have been long studied, and now a new analysis finds higher risks for normal-weight women and those on combination estrogen/progestin therapy.

While many studies have looked at the link, the new research sheds some new light on the topic, says researcher Tanmai Saxena, an MD/PHD student at the University of Southern California Keck School of Medicine in Los Angeles.

"The study further develops which women are at particular risk with HRT," he tells WebMD. Among his findings: "There is a risk associated with long-term HRT, both estrogen and combination [therapy]. As it turns out, the women who are thinner at menopause when they go on HRT have a higher risk of breast cancer."

The new analysis included 2,857 women participants in the California Teachers Study, all diagnosed with invasive breast cancer and followed on average for about 10 years.

The study is published in Cancer Epidemiology, Biomarkers & Prevention.

HRT and Breast Cancer Risk: Study Details
Saxena and his colleagues looked at the type of hormone therapy used -- estrogen alone or combined with progestin -- and for how long; the researchers took into account the women's body mass index (BMI) and other factors.

When the researchers compared women who had never used hormone therapy to those who reported 15 or more years of estrogen therapy, the estrogen users had a 19% greater breast cancer risk.

Those who used combination therapy for 15 or more years fared worse, with an 83% increased breast cancer risk.

Why so high for the combination therapy? Progestin signals breast tissue to divide, Saxena says, and rapid cell replication boosts the risk of getting cancer.

Body mass index played in to the degree of risk, Saxena found. Women with a BMI of 30 or above, considered obese, did not have an elevated breast cancer risk with increased duration of hormone use, but those with BMI below 29.9 did. However, Saxena points out, obesity alone is a risk factor for breast cancer.

The increased risks found with hormone therapy were confined to specific types of breast cancer tumors -- those positive for both estrogen and progesterone and HER2-positive.

That's bad news tempered with some not so bad, according to Saxena. "If you do get breast cancer from HRT, it tends to be the type more responsive to therapy."

Bottom line of the new analysis? "There are benefits in the relief of menopausal symptoms with hormone therapy, but the risks from hormone therapy are different for different women," Saxena says. "At the end of the day you want to be on hormone therapy for the least amount of time possible and at the lowest dose possible."

While Saxena can't pinpoint a number of years that are "safe," he says that he found elevated risks on combination therapy even for short-term use -- less than five years.

One co-author of the study, Christina A. Clarke, served as an expert witness for plaintiff lawyers pursuing litigation over Prempro hormone therapy.

Method of Suicide Attempt Influences Risk for Later Successful Suicide

From Medscape Medical News

Megan Brooks

August 3, 2010 — The method used in an initial suicide attempt influences the risk for a later successful suicide, with those who attempt suicide by hanging, drowning, shooting by firearm, jumping, or gassing most likely to succeed on subsequent attempts, new research suggests.

"Intensified aftercare is warranted for suicide attempts" involving these methods, the researchers conclude in a report published online July 13 in the British Medical Journal.

The study also shows that people who attempt suicide by these highly lethal methods are likely to choose the same method on subsequent attempts.

Using Swedish national registry data, Bo Runeson, MD, PhD, and colleagues from the Karolinska Institute in Stockholm, Sweden, studied 48,649 individuals admitted to the hospital between 1973 and 1982 after attempted suicide. They compared risks for subsequent suicide attempt by index suicide method during a 21- to 31-year follow-up period, ending in 2003.

During follow-up, a total of 5740 subjects (11.8%) successfully committed suicide and the risk for suicide varied considerably by the method used on the index suicide attempt.

Attempted suicide by poisoning was the most common method, used by 83.8% of attempters, and was linked to most later successful suicides (n = 4270).

However, the highest relative risk for eventual successful suicide was found for those in whom the index attempt was by hanging, strangulation, or suffocation. In this group, 258 men (53.9%) and 125 women (56.6%) later successfully committed suicide (hazard ratio, 6.2; 95% confidence interval, 5.5 – 6.9; after adjustment for age, sex, education, immigrant status, and co-occurring psychiatric morbidity), and 333 of these individuals (87%) did so within 1 year of the index attempt.

First Year Most Risky

"As in previous studies, successful suicide was particularly common during the first year after the index attempt," the study authors note, perhaps stemming from a distressing life situation or "intense symptom rich phases of coexisting psychiatric disorder." For example, when stratified by psychiatric comorbidity, 69% of subjects who attempted suicide by hanging and had a psychotic disorder died from suicide within 1 year.

"The important short term excess in suicide rate after a suicide attempt by such means has not been acknowledged in previous studies," they note, "and suggests possible benefits of more focused aftercare during the first few years after admission to hospital."

For other methods — gassing, firearm/explosive, jumping, and drowning — relative risks were significantly lower than for hanging but still increased at 1.8, 3.2, 3.2, and 4.0, respectively. Cutting, and “other” methods conferred risks at levels similar to that of poisoning (the reference category).

Most of those who successfully committed suicide used the same method as they did at the index attempt, the study authors report. For example, 93% of men and 92% of women who used hanging in the index attempt later died from suicide by hanging; 82% of men and 86% of women who used drowning in the index attempt died by drowning later.

The researchers note that aftercare for suicide attempters is often based on estimates of suicidal intent. Other reports suggest that psychiatric disorders should be considered. The new data, the study authors say, “strongly indicate that such assessments should also be guided by the method used.”

Keith Hawton, MD, of the Centre for Suicide Research, University Department of Psychiatry, Warneford Hospital, in Oxford, England, agrees. However, he warns in an accompanying editorial that "although use of more lethal methods of self harm is an important index of suicide risk, it should not obscure the fact that self harm in general is a key indicator of an increased risk of suicide."

Dr. Runeson and colleagues and Dr. Hawton have disclosed no relevant financial relationships.

BMJ. 2010;340:c3222. Published online July 13, 2010.

Prenatal Cigarette Exposure Increases Risk for Psychiatric Illness Into Adulthood

Have posted this on my other blog-postnatalconfinement.blogspot.com
But posting here to remind ladies about the very serious and long term impact of smoking during pregnancy.

Please stop!!!

Megan Brooks

August 3, 2010 — The risk for psychiatric illness is significantly higher in young adults exposed to cigarette smoke in the womb relative to those without prenatal cigarette smoke exposure, even after adjusting for maternal psychiatric illness and other confounding factors, according to a Finnish study reported in the August issue of the Archives of General Psychiatry.

"This association seemed to be robust because it could be found in a large group of diagnoses and the dose relationship was also strong," first study author Mikael Ekblad, BM, of University of Turku, Finland, and colleagues note in the article.

Prenatal smoking exposure impairs fetal growth and modulates brain development, which may alter mental development of the offspring, they point out.

The researchers used population-based, longitudinal registry data to evaluate the effects of prenatal smoking exposure on psychiatric morbidity among 175,869 Finnish young adults born from January 1, 1987, through December 31, 1989, with follow-up lasting 18 to 20 years. They had information on mothers' smoking habits (self-reported) during pregnancy and other relevant background factors, as well as psychiatric history of mothers and offspring.

Smoking during pregnancy was reported by 26,075 mothers (15.3%). Of these, 8866 (34.0%) smoked more than 10 cigarettes a day. In 5487 children (3.2%), maternal smoking history was unknown.

The prevalence of any psychiatric diagnosis was 15.0% after excluding the children with unknown maternal smoking history. The prevalence was 13.7% in unexposed children (the reference group), 21.0% in those exposed to fewer than 10 cigarettes a day (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.47 – 1.60), and 24.7% in those exposed to more than 10 cigarettes a day (aOR, 1.85; 95% CI, 1.74 – 1.96).

Prenatal smoke exposure significantly increased the risk for most of the psychiatric diagnoses, with the exception of schizophrenia and anorexia diagnoses, the study authors report. The strongest effects were seen for psychiatric disorders due to psychoactive substance use and behavioral and emotional disorders. The lack of a statistically significant finding for schizophrenia may be due to a fairly low number of cases in the study.

There were 870 total deaths in the study population (5.7 per 1000), of which 64 (7.4%) were suicides (excluding children with unknown maternal smoking data). After adjusting for confounding factors, young adults exposed to >10 cigarettes a day during gestation had a significantly increased risk for early death (OR, 1.69; 95% CI, 1.31 – 2.19) compared with unexposed young adults. The mortality rate per 1000 children was 4.7 for unexposed children vs 6.3 and 9.1 for exposure to <10 and >10 cigarettes per day, respectively.

Results Generally Mirror Prior Studies

Commenting on the study for Medscape Medical News, David M. Fergusson, PhD, of the Department of Psychological Medicine, Christchurch School of Medicine & Health Sciences in New Zealand, who was not involved in the study, said, "The results are generally consistent with previous research that has suggested that maternal smoking may be associated with increased risks of at least some mental disorders."

In their report, Dr. Ekblad's team points to several study strengths, including a large national study population; the ability to control the child's outcome for maternal mental illness, which has not been done previously in similar large epidemiologic studies; and adjustment for a wide range of background factors, such as 5-minute Apgar scores, the child's birth weight, maternal age, and the mother's psychiatric morbidity before the child's birth.

Limitations of the study include lack of information on alcohol and illicit drug use during pregnancy; self-reported maternal smoking history; potential concern about accuracy of diagnoses; and lack of socioeconomic data, such as parents' educational level and exposure to passive smoke in the home, which can affect risk for psychiatric problems.

"The study," Dr. Fergusson noted, "adds to previous research by being based on a large population (but) is limited by the use of official record data."

The control of confounding factors is "limited," he added, "raising the possibility that the findings may reflect the presence of other factors, which are associated with pregnancy smoking. A further limitation is that the mechanisms by which pregnancy smoking may lead to increased risks of a wide range of mental disorders are by no means clear."

Nonetheless, Dr. Fergusson said this new study further reinforces public health messages regarding the adverse effects of smoking during pregnancy. "It is well known that pregnancy smoking increases the risk of miscarriage, stillbirth, and low-birth-weight infants. The present findings raise the possibility that exposure to pregnancy smoking may have adverse effects on longer-term mental health of offspring," he noted.

The study was supported by the Turku University Hospital Research Foundation, the Finnish Foundation for Alcohol Studies, and the South-West Finnish Fund of Neonatal Research. The study authors and Dr. Fergusson have disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2010;67:841-849.

Tuesday, August 10, 2010

Some Evidence Vitamin D Might Fight Respiratory Infections

From Reuters Health Information

By Amy Norton

NEW YORK (Reuters Health) Aug 05 - A daily vitamin D supplement may help young men enjoy more sick-free days during cold and flu season, a small study suggests.

Vitamin D has been the subject of much research of late, with studies linking low vitamin D levels in the blood to higher risks of type 1 diabetes and severe asthma attacks in children and, in adults, heart disease, certain cancers and depression.

But whether vitamin D is the reason for the excess risks -- and whether taking supplements can curb those risks -- has yet to be shown.

Because rates of vitamin D insufficiency rise during the winter in many parts of the world, researchers have been interested in whether the vitamin might play a role in people's susceptibility to colds, flu and other respiratory infections.

Some past research has indeed found that people with relatively lower vitamin D levels tend to have higher rates of respiratory infections, said Dr. Ilkka Laaksi of the University of Tampere in Finland, the lead researcher on the new study.

Along with that evidence, recent lab research has shown that vitamin D may play an important role in the body's immune defenses against respiratory pathogens, Dr. Laaksi told Reuters Health by e-mail.

For the current study, reported online July 15th in the Journal of Infectious Diseases, Dr. Laaksi's team randomly assigned 164 male military recruits to take either 400 IU of vitamin D or placebo every day from October to March.

At the end of the study, the researchers found no clear difference between the two groups in the average number of days missed from duty due to a respiratory infection -- which included bronchitis, sinus infections, pneumonia, ear infections and sore throat.

On average, men who took vitamin D missed about two days from duty because of a respiratory infection, compared with three days in the placebo group. That difference was not significant in statistical terms.

However, after adjustment for smoking status, flu vaccination, and other factors, the hazard ratio for absence from duty due to respiratory illness was lower in men who took vitamin D.

The findings, Dr. Laaksi said, offer some evidence of a benefit from vitamin D against respiratory infections.

Still, the extent of the benefit was not clear. While recruits in the vitamin group were more likely to have no days missed from duty, they were no less likely to report having cold-like symptoms at some point during the study period.

Moreover, recent studies on the usefulness of vitamin D for warding off respiratory ills have come to conflicting conclusions.

A study of Japanese schoolchildren published earlier this year found that those given 1,200 IU of vitamin D each day during cold and flu season were less likely to contract influenza A compared to children taking placebo.

On the other hand, a recent study of 162 adults found that those who took 2,000 IU of vitamin D everyday for 12 weeks were no less likely to develop respiratory infections than those given placebo pills.

Dr. Laaksi said larger clinical trials looking at different doses of vitamin D are still needed before the vitamin can be recommended for curbing the risk of respiratory infections.

SOURCE: http://link.reuters.com/dan53n

J Infect Dis 2010.

Monday, August 9, 2010

Early Antiretroviral Therapy Cuts HIV-Related Mortality by 75%

From MedscapeCME Clinical Briefs

News Author: Martha Kerr
CME Author: Désirée Lie, MD, MSEd

July 27, 2010 — Researchers in Haiti are reporting that early initiation of antiretroviral therapy in HIV-infected adults, beginning when CD4+ T-cell counts drop below 350 cells/mm3, is associated with a 4-fold lower rate of death and a 2-fold lower rate of incident tuberculosis, compared with the old standard of waiting to initiate treatment until CD4+ counts fall below 200 cells/mm3.

These findings are in line with the newly updated World Health Organization (WHO) guidelines, issued November 30, 2009, which recommend early initiation of antiretroviral therapy.

The findings were presented at AIDS 2010, the XVIII International AIDS Conference, and have been published in the July 15 issue of the New England Journal of Medicine.

The study involved 816 HIV-infected adults in Haiti with a confirmed CD4+ T-cell count that was between 200 and 350 cells/mm3 at baseline and no history of an AIDS illness.

Patients were randomized to early treatment (within 2 weeks of enrollment) with zidovudine, lamivudine, and efavirenz, or to standard treatment with the same regimen initiated when CD4+ T-cell counts fell below 200 cells/mm3 or when clinical AIDS developed. Median time to treatment in the standard-care group was 2 years. All subjects also received isoniazid and trimethoprim–sulfamethoxazole prophylaxis with nutritional support.

Patrice Severe, MD, from Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), in Port au Prince, and colleagues assessed patients monthly for a median of 21 months from 2005 to 2008. The primary study endpoint was survival.

There were 23 deaths in the standard-care group and 6 in the early-treatment group (hazard ratio [HR] for standard care, 4.0; 95% confidence interval [CI], 1.6 - 9.8; P = .001). There were 36 incident cases of tuberculosis in the standard-care group, and 18 in the early-treatment group (HR, 2.0; 95% CI, 1.2 - 3.6; P = .01).

Dr. Severe and colleagues write that "antiretroviral therapy that is initiated when the CD4+ T-cell count is greater than 200 and less than 350 per cubic millimeter, as compared with antiretroviral therapy that is deferred until the CD4+ T-cell count falls to 200 per cubic millimeter or less or an AIDS-defining illness develops, results in a 75% reduction in the rate of death and a 50% decrease in the incidence of tuberculosis."

Patients receiving standard care had higher rates of infectious diseases in general and more treatment-limiting drug reactions than those in the early-treatment group. They also required more frequent monitoring of CD4+ T-cell counts. With standard care, the survival rate is approximately 80% at 5 years.

Delaying treatment until CD4+ cell counts fall below 200 cells/mm3 "consumed resources and the time of highly trained healthcare workers, factors that may in part offset the cost of starting antiretroviral therapy earlier," Dr. Severe and colleagues observe.

"At current pricing, 2 years of antiretroviral drugs will cost approximately $400 per person. Thus, for a cost of approximately $400 per person, the rate of death can be decreased by 75%, and the incidence of active tuberculosis by 50%," the researchers write.

Meanwhile, Médecins Sans Frontières (MSF) held a press conference on July 15 to announce cuts in AIDS funding from donor countries to resource-poor countries, and to release a new report on the consequences of delayed, deferred, or denied AIDS treatment.

The report was presented by Nathan Ford, medical coordinator of the MSF Campaign for Access to Essential Medicines. Among the consequences itemized in the report are the following:

* Limiting treatment means "choosing who lives and who dies"
* Delaying or deferring treatment leads to increases in transmission, illness, and death
* Losing a stable drug supply means sharp increases in viral load and a resulting increase in HIV transmission
* Switching from first-line drugs to those with a lower base price means using less effective and more toxic drugs, and an increase in comorbidities
* Cutting back on funding for treatment means sacrificing long-term survival

Implementing the new WHO recommendations "means lowering the treatment threshold and increasing the number of patients eligible for treatment by about 30% to 40%," Mr. Ford told Medscape Medical News.

Mr. Ford charged donor countries with being "short-sighted" by backing the old WHO recommendations of initiating antiretroviral treatment when CD4+ counts fall below 200 cells/mm3.

"Early treatment should be seen as less expensive, with increased survival, less toxicity, and fewer comorbidities," he told Medscape Medical News. "This point has been missed in some of their policies. . . . HIV is a life-long illness. No treatment doesn't mean [patients] go away. It just means they come back later and sicker," and put a costly strain on limited resources that outstrip the small savings seen with a policy of delaying treatment."

Sharonann Lynch, MSF HIV/AIDS policy advisor, who moderated the conference, asserted that donor countries should not be allowed to back "Big Pharma," and pharmaceutical companies should be made to see that the policy of delayed treatment is not to their advantage, either.

The GHESKIO study was supported in part by grants from the National Institute of Allergy and Infectious Diseases and from the Fogarty International Center. Support for antiretroviral medications was provided by the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and by GlaxoSmithKline and Abbott. The researchers have disclosed no relevant financial relationships. Mr. Ford and Ms. Lynch are employees of Médecins Sans Frontières and have disclosed no relevant financial relationships.

N Engl J Med. 2010;363:257-265.
Clinical Context

Early antiretroviral treatment in HIV-infected patients without AIDS but with CD4+ counts between 200 and 350 cells/mm3 has been found in observational studies to be associated with better survival duration and lower rates of tuberculosis infection.

This is an open-label randomized trial to compare mortality associated with early vs standard initiation of antiretroviral therapy in adults infected with HIV-1 with CD4+ counts between 200 and 350 cells/mm3.