Benicar Superior to Cozaar in New Study

Benicar Superior to Cozaar in New Study
Drug Discovery & Development - October 06, 2010

Patients treated with Benicar in BeniVICTOR study experienced significantly greater blood pressure reductions and higher goal attainment rates than patients treated with Cozaar after 8 weeks.
New study results show that patients treated with Benicar (olmesartan medoxomil) 40 mg once daily had significantly greater reductions in blood pressure and higher rates of goal attainment than patients receiving Cozaar (losartan potassium) 100 mg once daily at week 8, according to findings of a new head-to-head study presented today at the late breaker session at the 23rd Scientific Meeting of the International Society of Hypertension (ISH) in Vancouver, Canada. Benicar and Cozaar* are two of the leading angiotensin II receptor blockers (ARBs). The study did not evaluate the Cozaar 50 mg BID (twice a day) dose.
The BeniVICTOR study, Benicar Efficacy: New InVestigation In the Comparison of BP reductions beTween Olmesartan and losaRtan in patients with hypertension, met its primary endpoint of mean change from baseline in Seated Diastolic Blood Pressure (SeDBP) at 8 weeks. At week 8, patients treated with Benicar 40 mg achieved reductions of 13.6 mm Hg Seated Systolic Blood Pressure (SeSBP) and 9.7 mm Hg SeDBP from a mean baseline blood pressure of 158.2/101.1 mm Hg. Patients treated with Cozaar 100 mg experienced a smaller mean blood pressure reduction of 9.7/7.1 mm Hg from a baseline of 158.3/101.3 mm Hg. The treatment difference between Benicar 40 mg versus Cozaar 100 mg was 3.9/2.5 mm Hg (P less than or equal to 0.0001).
Further, patients treated with Benicar reported significantly greater goal attainment when compared to patients treated with Cozaar. At week 8, a significantly greater proportion of patients treated with Benicar 40 mg achieved a blood pressure goal of <140/90 mm Hg than patients treated with Cozaar 100 mg (31.6 percent versus 19.5 percent, respectively; P<0.0001).
"Achieving blood pressure control is difficult for many patients so being able to identify which angiotensin II receptor blocker provides superior blood pressure reduction can be very important for physicians," said Dr. Henry Punzi of the Trinity Hypertension and Metabolic Research Institute in Carrollton, Texas. "Many patients come close to achieving goal, but are unable to cross the threshold of controlled blood pressure. For many patients, a reduction of two or three points in their blood pressure is the difference between being able to achieve control or remaining uncontrolled. The results of BeniVICTOR show that Benicar was more effective at reducing blood pressure than Cozaar, which could help bridge the gap for many patients."
High blood pressure can cause permanent changes to blood vessels and the heart that may create serious problems elsewhere in the body. Hypertension is one of the most prevalent conditions in the United States, affecting approximately one in three American adults (about 74.5 million people aged 20 and older) and approximately one billion people worldwide. High blood pressure is often difficult to control, and of those with high blood pressure, approximately 56 percent, do not reach recommended blood pressure levels. The number of people with high blood pressure is expected to reach about 1.6 billion worldwide by 2025.
Date: October 5, 2010
Source: Daiichi Sankyo, Inc. 

Positive Results in Phase 2 Locteron Trial

Positive Results in Phase 2 Locteron Trial
Drug Discovery & Development - October 29, 2010

Biolex Therapeutics, Inc. announced positive efficacy, safety and tolerability results from its 72-week SELECT-2 Phase 2b dose-finding Phase 2b trial of Locteron, the company’s lead product candidate for the treatment of hepatitis C. For each of the three Locteron doses tested in SELECT-2, the percentage of patients who maintained undetectable levels of virus at week 60 of the trial, 12 weeks after completion of 48 weeks of treatment (SVR12), were comparable with or exceeded the response rate for the PEG-Intron control. As a result of its controlled-release mechanism, Locteron was dosed half as frequently as PEG-Intron. PEG-Intron is one of two currently marketed pegylated interferon products for the treatment of hepatitis C, a market that currently exceeds $2.5 billion in worldwide sales.
Additional results from SELECT-2 demonstrated the substantial tolerability advantages of Locteron. Patients treated with each of the three Locteron doses in SELECT-2 reported a statistically significant reduction in flu-like adverse events (p<0.001) compared to the PEG-Intron group. Accordingly, Locteron patients in all three dose groups used less concomitant medications (analgesics and antipyretics) than the PEG-Intron patients during the study period. Lastly, patients receiving the two lower doses of Locteron experienced lower rates of depression and discontinuations due to adverse events than patients receiving PEG-Intron.
“The strong viral response of Locteron achieved with once-every-two-week dosing is an improvement over current interferons, and I am impressed by the consistency of the flu-like effect across trials and different reporting methodologies,” said Nezam Afdhal, M.D., Chief of Hepatology at Beth Deaconess Medical Center, Harvard Medical School. “The reduction in symptoms of depression is quite promising and needs to be followed up in additional clinical evaluation. The Locteron safety and tolerability results are clearly important as recent clinical results demonstrate that interferon is likely to remain a core component of future treatment regimens that incorporate the new direct-acting anti-virals, highlighting the need for a more tolerable interferon to reduce the side-effect burden on patients from these multi-drug combinations and maximize their adherence to treatment.”
Date: October 28, 2010
Source: Biolex Therapeutics, Inc. 

FDA Refuses Approval for Qnexa

FDA Refuses Approval for Qnexa
Matthew Perrone
Drug Discovery & Development - October 29, 2010

WASHINGTON (AP) - Federal health regulators have decided not to approve an experimental diet pill called Qnexa, which had been touted by many experts as the most promising weight-loss drug in more than a decade.
The drug's maker, Vivus Inc., said in a statement Thursday that the Food and Drug Administration declined to approve the drug in its present form. The agency asked for more study results and additional information on its possible health risks, including major cardiovascular events and risks for women of childbearing potential.
The FDA did not ask for any new clinical studies, but more may be required if the agency's concerns aren't addressed, Vivus said.
The company plans to respond to the FDA in about six weeks.
"We remain confident in the efficacy and safety profile of Qnexa demonstrated in the clinical development program and look forward to continue working with the FDA towards the approval for the treatment of obesity," Vivus CEO Leland Wilson said in a statement.
Its shares added 5 cents to $6.18 in aftermarket trading Thursday. The stock added 5 cents to $6.13 during the regular session.
Vivus, based in Mountain View, Calif., is one of three small drugmakers racing to win approval for their weight-loss drugs. Many analysts picked Qnexa as the most promising contender because of the high level of weight loss reported in company studies: On average, patients lost more than 10 percent total body mass. That compared to weight loss of under 5 percent with drugs currently on the market, like Roche's Xenical.
But Qnexa's outlook took a significant hit in July, when a panel of experts assembled by the FDA voted 10-6 to not recommend the drug's approval. Panelists said the drug was associated with a number of dangerous side effects, including suicidal thoughts, heart palpitations, memory lapses and birth defects.
With rates of obesity and diabetes rising globally, doctors say new weight-loss drugs are needed, though the drug class has a history of safety problems.
Vivus is the second weight-loss drug rejected by the FDA in the past week. On Saturday, Arena Pharmaceuticals announced that the agency declined to approve its drug lorcaserin, citing tumors seen in rats during early stage testing. The San Diego-based company said it still hopes to win approval for the drug and would submit more detailed information, at the agency's request.
FDA's rejection of drugs from Vivus and Arena will focus new attention on the third competitor in the weight-loss drug race: Orexigen Therapeutics. The company's drug Contrave has shown weight loss between 5 and 10 percent with modest side effects, though FDA's decisions this week suggest a strict standard for safety.
One of the key researchers in the development of Qnexa warned that the FDA's negative decision on the drug could have a cooling effect on industry efforts.
"If there isn't any kind of path forward for this drug I think it is going to shut down all obesity drug development for a decade," said Dr. Tim Garvey of the University of Alabama. Garvey conducted two clinical trials of Qnexa and has consulted for Vivus.
"Why would a company put all that investment into developing a drug if the FDA signals they aren't willing to approve it," he said.
With U.S. obesity rates nearing 35 percent among adults, doctors and public health officials say new weight-loss therapies are desperately needed. And even a modestly effective drug could have blockbuster potential.
But the search for a drug that helps patients safely shed pounds has been largely unsuccessful. Two weeks ago Abbott Laboratories withdrew its pill Meridia from U.S. and Canadian markets after regulators said it increased the risk of heart attack and stroke.
Date: October 28, 2010
Source: Associated Press

GlobeImmune Expands GI-5005 Trial

GlobeImmune Expands GI-5005 Trial
Drug Discovery & Development - October 28, 2010

GlobeImmune Inc. announced the expansion of its Phase 2b clinical trial of GI-5005, an investigational Tarmogen product for the treatment of hepatitis C virus (HCV) infection. The Company previously reported data demonstrating a 60% improvement in sustained virologic response (SVR) in chronically infected HCV patients with the hardest-to-treat IL28B T/T genotype when GI-5005 was added to standard of care (SOC) versus SOC alone (60% vs. 0% SVR).  The Company plans to enroll 40 additional subjects with the IL28B T/T genotype.  Approximately 20% of chronically infected HCV patients have the IL28B T/T genotype and those patients are least likely to respond to treatment with SOC.  Data from the additional 40 subjects will allow for more precise powering of pivotal clinical trials.
“HCV patients with the IL28B T/T genotype have a very poor prognosis with current treatment options,” said Timothy C. Rodell, M.D., President and CEO of GlobeImmune.  “We believe that GI-5005 addresses a fundamental deficit in patients carrying the T allele of the IL28B gene by augmenting their deficient T cell immune response against HCV.  Our phase 2 immunology data indicate that a limited T cell immune response is likely why the current standard of care, which acts primarily by inhibiting viral replication, has limited efficacy in this patient group.”
“Patients with the IL28B T/T genotype have the lowest rates of sustained virologic response to today’s standard of care and will very likely continue to have lower response rates and a high rate of anti-viral resistance with the addition of a protease inhibitor,” said Mitchell L. Shiffman, M.D., Director of The Liver Institute of Virginia. “Preliminary data strongly suggest that GI-5005 enhances the ability of a patient with the IL28B T/T genotype to respond to HCV treatment.  This represents the first significant advance in our ability to treat chronic HCV in patients who are genetically less sensitive to interferon.  The expansion of the GlobeImmune program to specifically study patients with the IL28B T/T genotype is an important step for successful treatment of these patients in the future.”
Additional data from the original 140 subjects enrolled in the trial will be presented this week at 61st Annual Meeting of the American Association for the Study of the Liver (AASLD) in Boston.
Tarmogens are whole, heat-killed recombinant S. cerevisiae yeast that are engineered to express one or more disease-related proteins.  GlobeImmune’s GI-5005 Tarmogen is a therapeutic vaccine product candidate that contains conserved HCV proteins and is designed to generate an HCV-specific T-cell response.
Date: October 28, 2010
Source: GlobeImmune Inc. 

Ligocyte VLP Candidate Performs Well in Phase 1/2

Ligocyte VLP Candidate Performs Well in Phase 1/2
Drug Discovery & Development - October 28, 2010

LigoCyte Pharmaceuticals, Inc., a private, clinical-stage biopharmaceuticals company developing innovative vaccine products, announced positive results from a Phase 1/2 challenge study of its norovirus virus-like particle (VLP) vaccine candidate. Baylor College of Medicine’s Robert Atmar, M.D., the study’s principal investigator, shared data from the trial via an oral presentation at the Infectious Diseases Society of America (IDSA) 2010 Annual Meeting on October 23 in Vancouver, British Columbia.
“We are extremely pleased with the opportunity to share the important results from this carefully designed proof-of-concept, multi-center challenge study. Challenge studies are rigorous tests and we have established for the first time that immunized subjects can reduce their risk of norovirus illness by receiving a vaccine,” said Donald P. Beeman, Chief Executive Officer. “The study data are very encouraging, indicating statistically significant reductions in clinical norovirus illness, infection, and severity of illness in subjects who received vaccine compared to those who received placebo.”
In his presentation, entitled “Efficacy of An Intranasal (IN) Norovirus (NoV) Vaccine to Prevent Acute Gastroenteritis (AGE) Following Experimental Live GI.1 NoV Challenge,” Dr. Atmar described the challenge study in which 84 adults completed the challenge after receiving two doses of the vaccine or placebo. The vaccine was generally well tolerated, and demonstrated 47 percent efficacy against any norovirus illness, including mild illness, (p=0.006) and 26 percent efficacy against norovirus infection (p=0.046). In the 77 adults who completed the trial as per its original protocol, vaccination decreased the incidence of AGE due to norovirus from 69.2 percent to 36.8 percent and the incidence of norovirus infection from 82.1 percent to 60.5 percent. The severity of illness was also significantly reduced in those vaccinated within the trial (p=0.011).
“At LigoCyte, we are focused on developing a vaccine that has the potential to help address the critical unmet medical need resulting from the burden of norovirus illness in both developed and developing countries,” added Mr. Beeman.
Date: October 25, 2010
Source: LigoCyte Pharmaceuticals, Inc. 

Otsuka's tolvaptan approved in Japan

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Otsuka's tolvaptan approved in Japan
October 28, 2010

Ian Haydock

ian.haydock@informa.com

Japan's ministry of health, labour and welfare has issued a formal final approval for the use of Otsuka Pharmaceutical's vasopressin V2-receptor antagonist diuretic, Samsca (tolvaptan), in patients with congestive heart failure (CHF).

Biogen Idec ready to fight off oral MS competition

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Biogen Idec ready to fight off oral MS competition
27 October 2010
Sukaina Virji

Biogen Idec has come out fighting in the face of oral competition to its multiple sclerosis treatments Tysabri and Avonex.
Profits were down for the third quarter but the company posted better than expected earnings on the back of strong Avonex (interferon beta-1a) sales.

Original Article

Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects

W. Philip T. James, M.D., D.Sc., Ian D. Caterson, M.D., Ph.D., Walmir Coutinho, M.D., D.Sc., Nick Finer, M.B., B.S., Luc F. Van Gaal, M.D., Ph.D., Aldo P. Maggioni, M.D., Christian Torp-Pedersen, M.D., Ph.D., Arya M. Sharma, M.D., Ph.D., Gillian M. Shepherd, B.Sc., Richard A. Rode, Ph.D., and Cheryl L. Renz, M.D. for the SCOUT Investigators

N Engl J Med 2010; 363:905-917September 2, 2010

Abstract

Article

References

Citing Articles (2)

Background

The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established.

Full Text of Background...

Methods

We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death).

Full Text of Methods...

Results

The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased.

Full Text of Results...

Conclusions

Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Full Text of Discussion...

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US FDA advisors unimpressed by Arena's Lorqess

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US FDA advisors unimpressed by Arena's Lorqess
17 September 2010
Daniel B. Moskowitz

The US FDA's endocrinologic and metabolic drug advisory committee has recommended against approving Arena Pharmaceuticals'weight-loss drug Lorqess (locaserin), its lead drug candidate. On the question of whether the available data demonstrate that the potential benefits of locaserin outweigh

Eisai gives up on sibutramine in Japan

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Eisai gives up on sibutramine in Japan
October 28, 2010 
Ian Haydock

Eisai has withdrawn a Japanese approval application for the obesity drug sibutramine, following originator Abbott's decision to pull the product from several major markets.
Eisai held exclusive development and marketing rights in Japan and had filed for sibutramine's approval in November 2007,

Abbott voluntarily pulls obesity drug Meridia from US & Canada

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Abbott voluntarily pulls obesity drug Meridia from US & Canada
11 October 2010
Nancy Faigen

Abbott Laboratories has withdrawn its obesity drug Meridia (sibutramine) from the US market at the FDA's request.
Following a review of detailed SCOUT data, agency officials concluded that the drug's modest benefit on weight loss does not outweigh the risk of heart attack or stroke. Health Canada..

Cetuximab May Work for Some Colorectal Cancer Patients

Cetuximab May Work for Some Colorectal Cancer Patients
Drug Discovery & Development - October 27, 2010

Even though the cancer-treatment agent cetuximab is not considered effective treatment for KRAS (a gene)-mutated metastatic colorectal tumors, new research indicates that patients with colorectal cancer not responding to chemotherapy and a certain variation of this gene who were treated with cetuximab had longer overall and progression-free survival than patients with other KRAS-mutations, according to a study in the October 27 issue of JAMA.
"Recent retrospective correlative analyses of metastatic colorectal cancer trials indicate that patients with KRAS-mutated tumors do not benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab," the authors write. However, they add there are indications that not all KRAS mutations are equal in their biological characteristics, including anecdotal reports indicating that a minority of patients with KRAS-mutated tumors can respond to anti-EGFR therapy.
Wendy De Roock, M.D., of the University of Leuven, Leuven, Belgium, and colleagues conducted a study to examine whether a certain KRAS mutation (p.G13D) may be associated with a better outcome after cetuximab treatment than observed with other KRAS mutations. The study included a pooled data set of 579 patients with chemotherapy-refractory (not responsive to treatment) colorectal cancer treated with cetuximab between 2001 and 2008 and who were included in other clinical trials or received off-study treatment. Various analyses of the data were performed. The main efficacy outcome measure was overall survival; secondary efficacy measures were response rate and progression-free survival.
The researchers found that among patients who received any cetuximab-based treatment (cetuximab monotherapy or cetuximab plus chemotherapy) (n = 571), overall and progression-free survival were significantly longer in patients with p.G13D-mutated tumors (overall survival: n=32; median [midpoint], 7.6 months; progression-free survival, n = 32; median, 4.0 months) than in patients with other KRAS-mutated tumors (overall survival: median, 5.7 months; progression-free survival: median, 1.9 months).
"In a large, retrospective pooled exploratory analysis of patients with chemotherapy-refractory colorectal cancer, we show for the first time that there is a positive association between KRAS p.G13D mutations and cetuximab treatment in regard to better overall and progression-free survival," the authors write. They add this effect may not be due to a real reduction in tumor burden but to a delay in progression.
"Prospective randomized trials are needed before conclusions about potential beneficial effects of cetuximab in p.G13D-mutated chemotherapy-refractory metastatic colorectal cancer should be inferred."
Date: October 26, 2010
Source: University of Leuven 

Pharmaxis Announces Phase 3 Data

Pharmaxis Announces Phase 3 Data
Drug Discovery & Development - October 27, 2010

Pharmaceutical company Pharmaxis announced significant results of pooled data from its two large scale six month Phase 3 trials of Bronchitol (inhaled mannitol) in people with cystic fibrosis.
The combined results have been presented for the first time at the North American Cystic Fibrosis Conference (NACFC) currently underway in Baltimore.  In addition, more results from the second trial (CF302) have been released to supplement the top line results reported on 22nd June 2010.
The two studies were of similar design and encompass 643 patients from 11 countries.  Over the 26 weeks of the two studies, patients treated with Bronchitol had an average 7.3% improvement in lung function (FEV1) compared to baseline (p<0.001) and a highly significant improvement compared to patients in the control group (p<0.001). In the sub group of patients who were also on rhDNase, patients taking Bronchitol showed a 5.3% improvement from baseline (p<0.001), that was again superior to the control group (p=0.020). In the sub group of patients who were not on rhDNase, patients taking Bronchitol showed a 9.44% improvement from baseline (p<0.001), that was also superior to the control group (p=0.009). The overall rate per annum reduction in exacerbations for patients on Bronchitol versus those on control was 25% (NS) and the number of patients experiencing an exacerbation was 29% lower for those taking Bronchitol (NS). This result was achieved in a well treated patient population who overall had a very low rate of exacerbations in the study.
“This comprehensive analysis of the pooled results provides an important insight into the overall benefits Bronchitol can provide to patients who are receiving current best standard of care” said Pharmaxis Chief Executive Officer Dr. Alan Robertson. “The number of exacerbations in the two studies was fairly low, reflecting the aggressive treatment with antibiotics that is now common practice in the clinic.  Despite this, Bronchitol produced a clinically relevant reduction in exacerbations in patients completing the study, and together with recent data showed sustained benefit in lung function out beyond 18 months.”
Other results from CF302 presented at the NACF conference underlined both the good safety profile of Bronchitol and patient adherence. Overall adverse events on Bronchitol were similar to those experienced on control with 7% of patients taking Bronchitol withdrawing due to adverse events compared to 4% of patients on control.  There was no increase in the numbers of bacteria present in the lungs.  The most commonly reported adverse event related to treatment was cough occurring in 6% of the Bronchitol group and 3.3% of the control group.
Moira Aitken, M.D., F.R.C.P. (Edin), Professor of Medicine, Division of Pulmonary and CCM, University of Washington, and lead principal investigator of CF302, stated “We are excited by the results of the Bronchitol Phase 3 clinical program.  Across both trials, inhaled mannitol was well tolerated and demonstrated an early and sustained improvement in lung function.  This improvement in FEV1 was achieved on top of aggressive use of concomitant medications such as inhaled antibiotics and rhDNase.  These results, coupled with Bronchitol’s novel formulation and portable dry powder inhaler administration, suggest that it will have a significant impact on CF patient well-being.”
Date: October 22, 2010
Source: Pharmaxis 

Nymox BPH Drug in Phase 3 Trials

Nymox BPH Drug in Phase 3 Trials
Drug Discovery & Development - October 27, 2010

Nymox Pharmaceutical Corporation provided an update on the company's Phase 3 pivotal trials for NX-1207, Nymox's investigational drug for benign prostatic hyperplasia (BPH). The Safety Monitoring Committee meeting of October 25, 2010 was favorable and indicated no significant safety concerns for the two pivotal U.S. trials to date. Patient recruitment and trial activities for pivotal U.S. studies NX02-0017 and NX02-0018 are proceeding at over 70 well-known urology investigative sites throughout the U.S.
NX-1207 has been shown to improve the signs and symptoms of BPH, producing improvements which reached statistical significance compared to double-blinded placebo and study controls. A single administration of NX-1207 2.5 mg has produced on average improvements in the standardized BPH symptom score (8-10 points at 90 days) that were approximately double that reported for currently approved BPH drugs (3-5 points). The drug is administered by a urologist in an office setting and involves little or no pain or discomfort. NX-1207 has not been found to have the sexual, blood pressure, or other side effects of the approved drugs. Follow-up studies have shown clinical efficacy effects in men lasting up to 5 years after a single treatment.
Date: October 27, 2010
Source:Nymox Pharmaceutical Corporation 

Gene Variants Lead to Worse Outcome with Clopidogrel

Gene Variants Lead to Worse Outcome with Clopidogrel
Drug Discovery & Development - October 27, 2010

An analysis of data from previously published studies indicates that use of the antiplatelet drug clopidogrel for patients who have common genetic variants of a certain gene and are undergoing a procedure such as coronary stent placement have an associated increased risk for major adverse cardiovascular events, particularly development of blood clots in stents, according to a study in the October 27 issue of JAMA.
Clopidogrel, one of the most commonly prescribed medications, has been shown to reduce cardiovascular events in patients undergoing percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries). "However, there is a large degree of interindividual variability in the pharmaco-dynamic response to clopidogrel," the authors write. Data suggest its pharmacologic effect varies based on variations of the gene CYP2C19, but there is uncertainty regarding the clinical risk given by certain variations.
Jessica L. Mega, M.D., M.P.H., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues conducted a meta-analysis to determine the risk of major adverse cardiovascular outcomes among carriers of 1 or 2 reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. The analysis included data from 9 studies and 9,685 patients (of whom 91.3 percent underwent PCI and 54.5 percent had an acute coronary syndrome), 863 experienced the composite outcome of cardiovascular death, heart attack, or stroke; and 84 patients had stent thrombosis (blood clot) among the 5,894 evaluated for such.
There were 6,923 patients (71.5 percent) with no CYP2C19 reduced-function alleles (an alternative form of a gene), 2,544 (26.3 percent) with 1 reduced-function CYP2C19 allele, and 218 (2.2 percent) with 2 reduced-function CYP2C19 alleles. "Compared with CYP2C19 noncarriers, there was a significantly increased risk of cardiovascular death, myocardial infarction, or stroke in the 26.3 percent of the overall study population who carried only 1 reduced-function CYP2C19 allele. Similarly, there was a significantly increased risk of cardiovascular death, myocardial infarction, or stroke in the 2.2 percent of the overall study population who carried 2 reduced-function CYP2C19 alleles," the researchers write.
The authors also found that both carriers of only 1 reduced-function CYP2C19 allele and carriers of 2 alleles were at significantly increased risk of stent thrombosis when compared with CYP2C19 noncarriers.
"In conclusion, the findings of this collaborative meta-analysis demonstrate that common genetic variants in the CYP2C19 gene are associated with almost 1 in 3 patients not receiving ideal protection from ischemic events when treated with standard doses of clopidogrel for PCI. Given how widely clopidogrel is used to treat patients with cardiovascular disease, determination of the optimal antiplatelet treatment doses or regimens for individual patients is needed to tailor therapy appropriately," the authors write.
Date: October 26, 2010
Source: Brigham and Women's Hospital 

Antimicrobial and non-antimicrobial tetracyclines in human cancer trials

Antimicrobial and non-antimicrobial tetracyclines in human cancer trials

Pharmacological Research
Article in Press, Uncorrected Proof

Christopher Richards^a, Liron Pantanowitz^b and Bruce J. Dezube^{a, ,}

^a Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
^b Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Available online 15 October 2010.

Abstract

Tetracyclines are capable of inhibiting mammalian collagenases by non-antimicrobial mechanisms. Because collagenases and other matrix metalloproteinases have been linked to cancer pathogenesis, this property of tetracycline's has led to speculation that these drugs could be used to slow tumor growth, invasion and metastasis in neoplasms that overly express these enzymes. The FDA has already approved two tetracycline derivates for treatment of chronic inflammatory periodontal disease and chronic inflammatory skin disease. Here we review the efforts to determine the efficacy of tetracyclines as chemotherapeutics in human cancer trials. While the majority of clinical trials have yielded disappointing results, tetracyclines have been shown to be generally well tolerated and have significant anti-proliferative effects in certain cancer types. In particular the chemically modified tetracycline derivative COL-3 (also known as CMT-3) has been shown to cause dramatic improvement in the tumor burden of patients with Kaposi Sarcoma. The experience using tetracyclines as chemotherapeutics is relatively limited, but further success is possible if future trials are focused on specific cancer subtypes that are known to rely heavily on collagenases and other matrix metalloproteinases for their pathogenesis.

Keywords: Tetracyclines; Matrix metalloproteinases; Kaposi Sarcoma; Metastat; COL-3; CMT-3

Abbreviations: MMP, Matrix metalloproteinase; ECM, Extracellular matrix; VEGF, Vascular endothelial growth factor; BFGF, Basic-fibroblast growth factor; LFTs, Liver function tests; AMC, AIDS Malignancy Consortium; NCI, National cancer institute; HIV, Human immunodeficiency virus; AIDS, Acquired immunodeficiency syndrome; HAAR, Highly active antiretroviral therapy; TKS, Kaposi Sarcoma; RCC, Renal cell cancer; OAL, Ocular adnexal lymphoma; IL-2, Interleukin-2; TNF-α, Tumor necrosis factor-α

Effects of esomeprazole on healing of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers

Effects of esomeprazole on healing of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in the presence of a continued NSAID treatment: characterization of molecular mechanisms

Pharmacological Research
Article in Press, Accepted Manuscript

Matteo Fornai^a, Rocchina Colucci^a, Luca Antonioli^a, Oriana Awwad^a, Clara Ugolini^b, Marco Tuccori^a, Federica Fulceri^b, Gianfranco Natale^b, Fulvio Basolo^c and Corrado Blandizzi^{a, ,}

^a Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55–56126 Pisa, Italy
^b Department of Human Morphology and Applied Biology, Via Roma 55–56126 Pisa, Italy
^c Department of Surgery, University of Pisa, Via Roma 57–56126, Pisa, Italy

Received 30 June 2010; 

revised 13 October 2010; 

accepted 13 October 2010. 

Available online 20 October 2010.

Abstract

Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6 μmol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5 μmol/kg/day), lansoprazole (15 μmol/kg/day) or famotidine (20 μmol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E₂ (PGE₂) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE₂ levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE₂ levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF, PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: 1) acid-dependent reduction of pro-apoptotic signalling; 2) acid-independent restoration of proliferating/repairing pathways.

Keywords: Esomeprazole; NSAIDs; gastric ulcer healing; oxidative damage; apoptosis

Differential effects of statins on endogenous H2S formation in perivascular adipose tissue

Differential effects of statins on endogenous H₂S formation in perivascular adipose tissue

 

 

Pharmacological Research
Article in Press, Uncorrected Proof

Grażyna Wójcicka^a, Anna Jamroz-Wiśniewska^a, Pepa Atanasova^b, George N. Chaldakov^c, Beata Chylińska-Kula^a and Jerzy Bełtowski^{a, ,}

^a Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland
^b Department of Anatomy, Histology and Embryology, Medical University of Plovdiv, Plovdiv, Bulgaria
^c Division of Cell Biology, Medical University, Varna, Bulgaria

Received 28 September 2010; 

revised 13 October 2010; 

accepted 13 October 2010. 

Available online 20 October 2010.

Abstract

Hydrogen sulfide (H₂S) is a new gasotransmitter synthesized enzymatically froml-cysteine in cytosol and is oxidized in mitochondria. In the cardiovascular system, H₂S regulates vascular tone, inhibits atherogenesis, and protects against myocardial ischemia–reperfusion injury. We examined the effect of statins on vascular H₂S production. Male Wistar rats received pravastatin (40 mg/kg/day) or atorvastatin (20 mg/kg/day) for 3 weeks and then H₂S formation was measured in aortic media, periaortic adipose tissue (PAAT) and the liver. Only atorvastatin increased H₂S production in PAAT whereas both statins stimulated its formation in the liver. Neither statin affected H₂S production in aortic media. H₂S formation in post-mitochondrial supernatant was higher than in mitochondria-containing supernatant and was not influenced by statins in any tissue. In addition, oxidation of exogenous H₂S in isolated liver mitochondria was slower in statin-treated than in control rats. These data indicate that statins increase net H₂S production by inhibiting its mitochondrial oxidation. Statins had no effect on the activity of H₂S-metabolizing enzyme, sulfide:quinone oxidoreductase, measured at saturating coenzyme Q concentration. Both statins reduced CoQ₉ concentration in plasma and liver, but only atorvastatin decreased CoQ₉ in PAAT. Atorvastatin attenuated phenylephrine-induced contraction of PAAT+ but not of PAAT− aortic rings. Effects of atorvastatin on net H₂S production, mitochondrial H₂S oxidation and aortic contractility were abolished by supplementation of exogenous CoQ₉. In conclusion, lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H₂S production in perivascular adipose tissue by inhibiting its mitochondrial oxidation. This effect is mediated by statin-induced CoQ₉ deficiency and results in the augmentation of anticontractile effect of perivascular adipose tissue.

Graphical abstract

Keywords: Statins; Hydrogen sulfide; Perivascular adipose tissue; Coenzyme Q; Potassium channels

Placebo in clinical trials: are they justified and credible?

Placebo in clinical trials: are they justified and credible?

• Alain Braillon,

Ann Intern Med published online October 25, 2010
Disued and sacked by the French Dept. of Health (see HealthWatch Newsletter, issue 79, October 2010. Available Golomb et al rightly questioned the composition of the placebo in clinical trials.(1) I crave that they use their database for 2 major questions yet unanswered. More... Golomb et al rightly questioned the composition of the placebo in clinical trials.(1) I crave that they use their database for 2 major questions yet unanswered.
In what percentage of cases the Helsinki declaration (point 32) which clearly requires "that patients are not randomized to a clearly inferior treatment." is implemented? Indeed serious breaches exit, even for diseases with a high short term mortality where patients can receive a placebo despite that an effective treatment is recommended.(2)
In what percentage of cases the placebo composition can allow for a credible "double-blind" statement?
References
1 Golomb BA, Erickson LC, Koperski S, Sack D, Enkin M, Howick J. What's in placebos: who knows? Analysis of randomized, controlled trials. Ann Intern Med. 2010 19;153:532-5.
2 Braillon A. Sciensationalism. Am J Med. 2010 Sep 29. PMID: 20887967 In press, available on line

In what percentage of cases the Helsinki declaration (point 32) which clearly requires "that patients are not randomized to a clearly inferior treatment." is implemented? Indeed serious breaches exit, even for diseases with a high short term mortality where patients can receive a placebo despite that an effective treatment is

What's in Placebos: Who Knows?

What's in Placebos: Who Knows? Analysis of Randomized, Controlled Trials

1. Beatrice A. Golomb, MD, PhD;
2. Laura C. Erickson, BS;
3. Sabrina Koperski, BS;
4. Deanna Sack, BS;
5. Murray Enkin, MD; and
6. Jeremy Howick, PhD

Ann Intern Med October 19, 2010 153:532-535;

+ Author Affiliations

1. From the University of California, San Diego, School of Medicine, San Diego, California; McMaster University, Hamilton, Ontario, Canada; and Centre for Evidence-Based Medicine, University of Oxford, Oxford, United Kingdom.

Abstract

Background: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting.

Purpose: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials.

Data Sources: 4 English-language general and internal medicine journals with high impact factors.

Study Selection: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009.

Data Extraction: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus.

Data Synthesis: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002).

Limitation: Journals with high impact factors may not be representative.

Conclusion: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

Primary Funding Source: University of California Foundation Fund 3929—Medical Reasoning.

Effectiveness of omalizumab in patients 50 years and older with severe persistent allergic asthma

Background

Omalizumab is approved for the treatment of severe allergic asthma.

Objectives

To compare the efficacy of omalizumab therapy in patients 50 years or older with patients younger than 50 years.

Methods

Between November 2005 and November 2007 a total of 174 asthma patients 50 years or older (40.7% male, 51.1% taking oral corticosteroids, and mean [SD] serum IgE level of 315 [353] U/L) and 297 asthma patients younger than 50 years (40.0% male, 50.5% taking oral corticosteroids, and mean [SD] serum IgE level of 363 [431] U/L) who met the European Union criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab for 4 months as part of 2 postmarketing surveillance trials.

Results

Compared with the pretrial period omalizumab treatment reduced the rate of severe exacerbations in patients 50 years or older by 68.9% (P < .001) and in patients younger than 50 years by 75.4% (P < .001). After 4 months there was a marked reduction of daily asthma symptoms and nocturnal awakenings by 67.8% and 72.6% in the older and by 79.3% and 82.5% in the younger patients, respectively (P < .001, all 4 comparisons). In 60% of patients 50 years or older lung function improved compared with 69% of patients younger than 50 years. Efficacy of omalizumab was rated as excellent or good by most physicians in patients 50 years or older (68.4%) and younger than 50 years (76.8%, P = .05 elderly vs younger). Adverse events were reported in 35.5% of patients 50 years or older and 32.1% of patients younger than 50 years. There was a higher rate of discontinuation of omalizumab therapy in older patients (20.9% vs 11.1%, P = .006).

Conclusions

The present study confirms the clinical efficacy of omalizumab in patients with severe allergic asthma irrespective of age in a real-life setting outside the omalizumab trial program.

Stephanie Korn, MD, Christian Schumann, MD†, Cornelia Kropf, MD†, Kathrin Stoiber, MD†, Antje Thielen‡, Christian Taube, MD, Roland Buhl, MD, PhD

Annals of Allergy, Asthma & Immunology - Volume 105, Issue 4, Pages 313-319 (October 2010)

 Pulmonary Department, Mainz University Hospital, Mainz, Germany

† Pulmonary Department, Ulm University Hospital, Ulm, Germany

‡ Novartis Pharma GmbH, Nürnberg, Germany

Editorial

Preventing Mother-to-Child Transmission of HIV — Protecting This Generation and the Next

Marc Lallemant, M.D., and Gonzague Jourdain, M.D.

N Engl J Med 2010; 363:1570-1572October 14, 2010

Approximately half of the 33.4 million persons living with the human immunodeficiency virus (HIV) worldwide are women of reproductive age, and among the 2.1 million HIV-infected children, virtually all were infected during pregnancy, delivery, or breast-feeding.1 Since 2002, the number of newly infected children has declined, probably owing to increased implementation of interventions for the prevention of mother-to-child transmission of HIV and the global stabilization of HIV prevalence among women.2 With these advances, new challenges have surfaced.

In 2008, almost half of HIV-infected pregnant women received antiretroviral medications for the prevention of mother-to-child transmission.1 In most cases, the simplest intervention, single-dose nevirapine, was given to the mother during labor and to the infant after birth. Nevirapine halves the risk of peripartum transmission3 but persists at clinically significant levels for days, potentially selecting HIV resistance mutations that may negatively affect the efficacy of nevirapine-based therapies when mothers and infected children subsequently require treatment for their own health. This poses an important public health challenge, since nevirapine-based therapies are the most widely available and affordable treatments in resource-limited countries, where more than 95% of infections in infants and children occur.

Because resistance mutations may fade away over time, there has been considerable uncertainty regarding treatment outcomes with regimens based on non-nucleoside reverse-transcriptase inhibitors (NNRTIs) as compared with outcomes with NNRTI-sparing regimens, when therapy is initiated more than 6 months after exposure to single-dose nevirapine. Two articles in this issue of the Journal 4,5 provide some of the most clear, concrete, and consistent evidence to address this question.

Lockman and colleagues report the results of the Optimal Combination Therapy after Nevirapine Exposure (OCTANE) A5208 trial,4 in which 241 HIV-infected mothers who had been exposed to single-dose nevirapine 6 months or more before randomization were assigned to receive ritonavir-boosted lopinavir–based therapy or nevirapine-based therapy. After 2 years, 8% of the women in the ritonavir-boosted lopinavir group had virologic failure (or died), as compared with 26% in the nevirapine group. In the nevirapine group, the proportion of women with resistance mutations detectable at the time of the initiation of treatment was small (13%), but these women had the highest failure rate, 73%, as compared with 19% among women in the nevirapine group without resistance mutations. In a companion trial involving women who had not been exposed to single-dose nevirapine, failure rates were 14% in both the ritonavir-boosted lopinavir group and the nevirapine group.

Palumbo and colleagues5 report similar findings among children. In the P1060 trial, 164 HIV-infected children were randomly assigned to ritonavir-boosted lopinavir–based therapy or nevirapine-based therapy more than 6 months after exposure to single-dose nevirapine. After 24 weeks, 40% of the children in the nevirapine group, as compared with 22% in the ritonavir-boosted lopinavir group, had treatment failure or discontinued the study treatment (the corresponding rates for treatment failure were 27% and 10%). Again, resistance mutations, detectable at initiation in 9.3% of children in the nevirapine group who were tested, predicted treatment failure: 83% with resistance mutations had treatment failure, as compared with 36% without resistance mutations. No unexpected toxic effects were observed, and deaths in both studies were unlikely to have been attributable to the study treatments.

The OCTANE and P1060 studies confirm that women and children in whom therapy is initiated 6 months or more after exposure to single-dose nevirapine have diminished response to nevirapine-based therapy, as compared with ritonavir-boosted lopinavir–based therapy, and the difference in failure rates is largest among those with detectable resistance mutations at initiation. One important point — although it is to be interpreted with caution — is that the differential response between nevirapine-based therapy and ritonavir-boosted lopinavir–based therapy tended to decrease as the interval between exposure to single-dose nevirapine and initiation of therapy increased; however, there is no clear cutoff time for equivalence. Furthermore, the bulk sequencing performed in these studies to determine the presence of HIV-resistant clones at baseline is a relatively insensitive technique (detecting variants that are present more than 20% of the time); however, a more sensitive test may improve the prediction.

These results support the updated World Health Organization (WHO) recommendations that a regimen based on ritonavir-boosted lopinavir should be used for women and for children younger than 24 months of age if they have had previous exposure to single-dose nevirapine.6 The results of these studies also pose additional important questions. First, what are the differences in long-term response (at 5 or 10 years) to the two treatments, after allowing for discontinuation of treatment owing to toxic effects and response to second-line therapies? Treatment options are severely limited in developing countries. Longer follow-up of these cohorts and broader end points than those in these studies are essential for informing long-term policy and practice. It is possible that nonsignificant differences between the nevirapine group and the ritonavir-boosted lopinavir group that were seen over the short term in the P1060 study, such as increases in the percentage of CD4+ lymphocytes and in z scores for height and weight, could translate into more important differences over the long term.

Second, are there safe and feasible strategies for the preservation (or recycling) of nevirapine-based therapy? The Pediatric Nevirapine Resistance Study (ClinicalTrials.gov number, NCT00117728) involving children exposed to single-dose nevirapine proposed an innovative approach of switching to nevirapine after 3 months of virologic suppression with the use of ritonavir-boosted lopinavir–based therapy.7 Although preliminary results suggest that virologic replication is not as well controlled with nevirapine as it is with continued ritonavir-boosted lopinavir, this strategy could be considered after a longer induction with ritonavir-boosted lopinavir–based therapy to allow for further decay of resistance mutations or could be used in older children, for whom a longer time has elapsed since exposure to single-dose nevirapine.

Third, since the cost of ritonavir-boosted lopinavir is considerably higher than that of nevirapine, is there a role for resistance screening to identify those who require ritonavir-boosted lopinavir–based therapy? Furthermore, when genotyping is not available, is it feasible (albeit controversial) to initiate a nevirapine-based therapy under close laboratory monitoring, with swift provision of second-line therapy in the event of failure? This would preserve the potent, low-cost, well-tolerated nevirapine-based therapy for those — the majority — who would respond to it. Cost-effectiveness analyses are needed alongside these important trials before large-scale implementation is considered.

The results of the OCTANE and P1060 trials are highly relevant despite the paradigm shift away from interventions incorporating single-dose nevirapine to interventions comprising highly active antiretroviral drugs for the prevention of mother-to-child transmission. In resource-limited settings, where many women still present late for antenatal care and too few are screened for CD4+ cell count, single-dose nevirapine will most likely remain an important component of the toolkit for the prevention of mother-to-child transmission. Nonetheless, these studies highlight the weaknesses in the current implementation of strategies for the prevention of mother-to-child transmission. Early and effective antenatal and postnatal HIV care are needed, including the provision of efficacious antiretroviral regimens, or “tails,” for both mothers and children who are being exposed to single-dose nevirapine, in order to avert resistance mutations in the first place.8,9 With provision of an efficacious tail, the response to nevirapine-based therapy in women and infected children would probably be considerably better than it was in the two studies in this issue of the Journal. However, we do not yet know how to effectively avoid resistance mutations in children with long-term exposure to nevirapine prophylaxis during breast-feeding.

These studies help equip us with strategies to deal with the current imperfections in our scale-up efforts. With the new WHO guidelines calling for increased access to therapy and prophylaxis for both immunocompromised and nonimmunocompromised pregnant women and timely provision of maternal and infant antiretroviral prophylaxis throughout pregnancy, delivery, and breast-feeding, the goal of eradication of pediatric HIV is within sight.2,6 Reaching that goal will require long-term investment in health systems, integration of strategies for the prevention of mother-to-child transmission into maternal and child health programs and national HIV treatment programs, access to laboratory monitoring, and second-line and third-line regimens. It is remarkable that despite the economic downturn, major international agencies and nongovernmental organizations have committed themselves to this ambitious goal.10

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From Institut de Recherche pour le Développement, Marseille, France; Harvard School of Public Health, Boston; and Chiang Mai University, Chiang Mai, Thailand.

Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure

Paul Palumbo, M.D., Jane C. Lindsey, Sc.D., Michael D. Hughes, Ph.D., Mark F. Cotton, M.Med., Ph.D., Raziya Bobat, M.D., Tammy Meyers, M.D., Mutsawashe Bwakura-Dangarembizi, M.D., Benjamin H. Chi, M.D., Philippa Musoke, M.B., Ch.B., Portia Kamthunzi, M.D., Werner Schimana, M.D., Lynette Purdue, Pharm.D., Susan H. Eshleman, M.D., Ph.D., Elaine J. Abrams, M.D., Linda Millar, B.A., Elizabeth Petzold, Ph.D., Lynne M. Mofenson, M.D., Patrick Jean-Philippe, M.D., and Avy Violari, F.C.Paed.

N Engl J Med 2010; 363:1510-1520October 14, 2010

Background

Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown.

Methods

We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board.

Results

A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events.

Conclusions

Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.)

Original Article

Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure

S. Lockman, M.D. Hughes, J. McIntyre, Y. Zheng, T. Chipato, F. Conradie, F. Sawe, A. Asmelash, M.C. Hosseinipour, L. Mohapi, E. Stringer, R. Mngqibisa, A. Siika, D. Atwine, J. Hakim, D. Shaffer, C. Kanyama, K. Wools-Kaloustian, R.A. Salata, E. Hogg, B. Alston-Smith, A. Walawander, E. Purcelle-Smith, S. Eshleman, J. Rooney, S. Rahim, J.W. Mellors, R.T. Schooley, and J.S. Currier for the OCTANE A5208 Study Team

N Engl J Med 2010; 363:1499-1509October 14, 2010

Background

Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus.

Methods

In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death.

Results

A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P=0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died.

Conclusions

In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National Institute of Allergy and Infectious Diseases and the National Research Center; ClinicalTrials.gov number, NCT00089505.)