Whitney Palmer

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Apremilast vs CF101 for Psoriasis

Published on the Nov. 16, 2016, Rheumatology Network website

By Whitney L. Jackson

Despite major steps forward in treating psoriasis over the past two decades, treatments can often take harsh tolls on the body, prompting some people to stop treatment. There’s a need, then, for new, convenient therapies that are both safe and effective, causing as little negative impact as possible.

Recently, a small molecule drug apremilast (Otezla), was approved to treat moderate-to-severe psoriasis. But, investigators are also looking into whether another mediation, CF101 (Piclidenoson), might have a longer-lasting positive effect. It’s an orally-bioavailable adenosine receptor that prompts an anti-inflammatory response, leading to the inhibition of tumor necrosis factor-⍺, interleukin -6 and -12, macrophage inflammatory proteins, and receptor-activator of NF-KB ligand.

According to the result of a Phase 2/3 multi-center, randomized, double-blind, placebo-controlled study with nearly 330 participants, published in the Journal of Drugs in Dermatology, researchers found apremilast and CF101 both offer safe, effective treatments. Apremilast outperforms CF101 through 16 weeks, but its benefits plateau at that point. CF101’s ameliorative impact takes hold at this point and carries on through 32 weeks.

Consequently, investigators determined, CF101 offers promise as an effective, long-term psoriasis treatment. And, the safety results support data from other Phase 2 CF101 studies that the drug is effective across different systemic inflammatory diseases.  Other studies have also demonstrated CF101 is effective in treating rheumatoid arthritis after 12 weeks of therapy.

This is important because existing research shows the median survival for biologics in psoriasis was 47 months. Between 10% and 20% of patients experience a loss of biologics efficacy each year, causing 67% of them to stop treatment altogether.

Study Design

To unearth CF101’s effect, researchers assigned, in a blinded placebo-controlled period, 103 subjects to receive oral doses of CF101 1mg, CF101 2mg, or a matching placebo twice daily. After an analysis at 12 weeks, the CF101 group was deemed futile and was discontinued.

During a second study phase, investigators divided 223 additional patients between a CF101 mg oral daily group and a placebo group for 16 weeks. Subsequently, in an open label expansion period, researchers continued the CF101 participants with that therapy, but switched the placebo group to CF101 2mg for the study remainder, as well.

Safety and efficacy were examined at 4, 8, 12, 16, 20, 24, and 28 weeks. Final assessments were made at 32 weeks.

Of the initial participant group, 260 individuals (88.7%) completed the study, 125 were in the CF101 group (86.2%) and 135 received placebo treatment (91.2). Those who wither did so because of lack of efficacy, unacceptable concomitant medication or therapy, investigator decision for the patient’s best interest, non-compliance, and lost to follow-up.

Safety & Efficacy

To determine whether CF101 is safe and effective, investigators created two endpoints. First, they analyzed the number of subjects that achieved PASI 75 at 12 weeks, and, second, they looked at the number of subjects that reached PASI 75 at week 16. They also analyzed the number that achieved PGA of 0 or 1 at 12 and 16 weeks.

The first endpoints weren’t met, but between weeks 16 and 32, CF101 participants demonstrated PASI 50, 75, 90, and 100 rates of 63.5%, 35.5%, 24.7%, and 10.4%, respectively.

Figuring out the drug’s safety was also paramount. To do so, investigators examined treatment emergent-adverse events and changes in vital signs, physical examinations, clinical laboratory tests (liver, kidney, hematology, chemistry, urinalysis, and pregnancy tests), and ECG findings.

According to results data from the primary endpoint, the treatment groups showed no statistically-significant difference at week 12. Of the CF101 2mg group, only 12 of 141 participants (8.5%) achieved PASI 75 at week 12. In the placebo group, it was 10 out of 144 (6.9%).

The second endpoint also showed no statistical significance at week 12. Nine out of 141 CF101 2mg subjects (6.4%) and 5 of 144 placebo subjects (3.5%) achieved PGA of 0 or 1 during this time.

Study data also revealed more positive results. At weeks 20 to 32, the CF101 group showed linear improvement in PASI 50 (63.5% of patients at week 32), PASI 75 (35.5%), PASI 90, (24.7%), and PASI 100 (10.6%). At week 32, PASI mean percent improvement was 57%.

Researchers also compared CF101 efficacy rates against apremilast global Phase 3 trial. Based on the comparison, CF101 efficacy rates continued to rise past 16 weeks of treatment. Apremilast levels plateaued at this point.

The data supports any benefits coming from CF101 because placebo responses are rare at PASI 90 and Psi 100. The number of participants achieving PGA of 1 or 2 with CF101 2mg was also significantly higher between weeks 24 and 32.

Treatment Emergent-Adverse Events

Some participants experienced at least one treatment emergent-adverse event. In the CF101 2mg group, 37 of 145 subjects (25.5%) experienced an adverse event, as did 29 of 148 placebo participants (19.6%). Overall, these negative events occurred evenly across the studies.

In the blinded placebo-controlled period phase, for the CF101 group, infections and infestations were most common – 10 of 145 participants (6.9%) experienced one. In the placebo group, 13 of 148 (8.8%) did. Gastrointestinal disorders, including abdominal pain, diarrhea, dry mouth, and nausea were also common. Eight CF101 participants (5.5%) experienced them, and 3 placebo participants (2%) did.

Infections and infestations were also the most common negative events for the CF101 open label expansion group, affecting 23 of 275 participants (8.4%).

The remainder – and majority – of treatment emergent-adverse events that occurred were mild and determined to be unrelated to CF101. Severe adverse effects did happen, although they were also unrelated to the drug. Four participants experienced a severe problem, and one participant died.

Apremilast vs CF101

Characteristic Apremilast CF101
Brand Name Otezla Piclidenoson
Conditions Treated Psoriasis; Psoriatic Arthritis Psoriasis; Psoriatic Arthritis; Rheumatoid Arthritis
Administration Oral Oral
Adverse Impacts Diarrhea; Nausea; Upper Respiratory Infection; Tension headache; Headache Diarrhea; Nausea; Kidney disorders; Nervous system disorders; Musculoskeletal disorders
Impact Anti-inflammatory effect Anti-inflammatory effect


Function Small-molecule inhibitor for phosphodiesterase 4 Adenosine receptor inhibiting tumor necrosis factor-⍺, interleukin-6 and -12, macrophage inflammatory proteins, and receptor activator for NF-KB ligand
Avoid Pregnancy; Breastfeeding Pregnancy; Breastfeeding

To read the article at its original location: http://www.rheumatologynetwork.com/psoriatic-arthritis/apremilast-vs-cf101-psoriasis


November 17, 2016 Posted by | Healthcare | , , , , | Leave a comment

Radiology’s Role in Integrated Health Care Systems

Published on the Nov. 16, 2016, DiagnosticImaging.com website

By Whitney L. Jackson

For most of you, diving into radiology practice meant joining an academic department, launching a private venture, or signing on with a teleradiology company. Those three practice models consume the lion’s share of all radiologists reading studies today.

However, another model exists – the integrated health care delivery approach most widely touted by Kaiser Permanente. Through this multi-physician, multi-specialty design, Kaiser Permanente offers health care services, including radiology, through networks of medical centers.

It’s a system that places significant weight on preventive care and positive patient outcomes. To meet that goal, said Bruce Wollman, MD, associate medical director for the Mid-Atlantic Permanente Medical Group, all providers, including radiologists, proactively work together with radiology playing a big role.

“Radiology is the center of the medical universe. In a system, like Kaiser, in which patient care is first and foremost, radiology has a very prominent voice,” he said. “But, Kaiser is a big group. We’re not just a big radiology practice, but thousands of doctors of all specialties all working together on the same team.”

And, just as the system design is a little different, so are the reimbursement and referral models.

In private, academic, and teleradiology practice, the overarching reimbursement model is still fee-for-service in which you are paid for the number of studies you read. Kaiser’s integrated health delivery model is different, Wollman said. Instead of being paid per scan, Kaiser physicians are salaried. Just like surgeons aren’t paid for the number of operations they perform, and radiologists’ salaries are not based purely on the number of studies they interpret.

The outcome, he said, is optimized patient care.

“There’s no financial incentive for us to recommend additional imaging or surgeries or other things,” he said. “The financial incentive of the organization is to keep our patients healthy, so there’s no need for us to do things just for the sake of additional billing.”

To read the remainder of the article at its original location: http://www.diagnosticimaging.com/practice-management/radiologys-role-integrated-health-care-systems

November 17, 2016 Posted by | Healthcare | , , | Leave a comment

Infections and Biologics in Rheumatoid Arthritis

Published on the Nov. 11, 2016, Rheumatology Network website

By Whitney L. Jackson

Biologics might have revolutionized treatment for rheumatoid arthritis, but existing research also points out that using these medications can increase the risk of serious infections or hospitalizations in some patients.

According to registry and observational studies, risk levels for infection are highest during the first six months of tumor necrosis factor inhibitor biologics treatment with a plateau hitting between 24-to-36 months.

A new study published in Current Rheumatology Reports reviewed key studies into these rheumatoid arthritis-related negative incidents, finding risk is greater with tumor necrosis factor inhibitor biologics than with traditional disease-modifying anti-rheumatic drugs.

To highlight this difference in risk, researchers discussed several existing studies that address individual questions of how biologic treatments affect rheumatoid arthritis in an attempt to help clinicians and patients make the most informed decisions about therapies.

Biologics Use

The biologics, which inhibit key cytokines and cytokine pathways, most often used to treat rheumatoid arthritis are etanercept, infliximab, golimumab, certolizumab pegal, adalimumab, anakinra, tocilizumab, abatacept, and rituximab. Despite their benefits, patients and providers worry both about injection site reactions, as well as infections.

Role of Disease in Risk

According to one study, it’s the altered immune system response present with rheumatoid arthritis that increases the infection risk. These patients have a greater chance of failing traditional disease-modifying anti-rheumatic drugs, making them candidates for biologics. However, if a patient has active rheumatoid arthritis, as well as a serious infection, it’s difficult to identify whether biologics are truly responsible for the infection.

Comparing biologics patients with those receiving other treatments, such as methotrexate, can help providers and patients better understand the risk. This data comes from observational studies, but it’s limited by confounding bias, channeling bias, differential follow-up, detection bias, and follow-up loss.

Rheumatoid Arthritis Role in Infections

Overall, rheumatoid arthritis patients have a higher ratio for developing infections than patients that don’t have rheumatoid arthritis.

A study of 609 rheumatoid arthritis patients and 609 non-rheumatoid arthritis patients, all over age 18, revealed rheumatoid arthritis patients have higher rates in 11 infection categories (95% CI, 1.41 to 1.65). Only two categories – urosepsis/pyelonephritis and gastroenteritis – didn’t pose a higher risk level.

Hospitalized Infection Risk

Rheumatoid arthritis patients have a two-fold increased adjusted risk of hospitalized infections when compared to those without rheumatoid arthritis. A retrospective cohort study performed with 1999-2006 claims data revealed the risk of hospitalized infections with a rate ratio of 1.88 (95% CI 1.71 to 2.07).

Rheumatoid Arthritis and Hospitalized Infections

Higher disease activity in rheumatoid arthritis patients does correlate to an increased rate of hospitalized infections.

Based on data from the Consortium of Rheumatology Researchers of North America, culling data from 16,242 patients, researchers identified 2,282 infections during 7,290 patient-years of follow-up. Of those incidents, 59 became hospitalized infections.

Every 0.6 increase in the disease activity score 28 used to assess clinical disease activity was associated with a 25% increased rate of infections that led to hospitalizations. These results, researchers said, indicate that controlling rheumatoid arthritis disease activity as best as possible could not only improve function and quality of life, but it could also lower infection risk rates.

Biologics and DMARD Differences

Patients using tumor necrosis factor inhibitor biologics do experience a greater infection risk during their first six months of treatment (95% CI 1.3 to 2.6). According to researchers, the risk is higher compared to traditional disease-modifying anti-rheumatic drugs by 1.2 to 1.8 times for up to 24 months following the beginning of biologics therapy (95% CI 0.6 to 1.3).

Using data from the British Society for Rheumatology Biologics Register, investigators compared serious infections between 11,798 biologics-treated patients and 3,598 disease-modifying anti-rheumatic drugs. Of those patients 1,808 developed at least one serious infection with incidence rates of 42/1,000 patient years of follow-up with biologics (95% CI 40 to 44) and 32/1,000 patient years of follow-up with disease-modifying anti-rheumatic drugs (95% CI 1.1 to 1.5).

Serious infection risk rates didn’t differ much for the three biologics examined – adalimumab, etanercept, and infliximab.

Do Biologics Differ?

For those using biologics therapy, serious infections are defined as ones needing hospitalization, intravenous antibiotic therapy, life-threatening, or ones that lead to significant disability. However, biologic therapies aren’t all the same when facing these negative events, such as pneumonia and cellulitis.

In a study using data from the Dutch Rheumatoid Arthritis Monitoring registry, researchers discovered the adjusted risk of serious infections was significantly lower with etanercept than with infliximab (HR=0.49, 95% CI 0.29 to 0.83) or with adalimumab (HR=0.55, 95% CI 0.44 to 0.67). Among this group, lower respiratory infections were the most common.

A study examining serious infections in the first 12 months of biologic and disease-modifying anti-rheumatic drug therapy supported those findings. Among rheumatoid arthritis patients, infliximab was linked to a significant increase in serious infections compared to etanercept (HR=1.26, CI 95% 1.07 to 1.45) and adalimumab (HR=1.23, 95% CI 1.02 to 1.48). Based on these results, glucocorticoid use was associated with dose-dependent infection increases.

In addition, a study of 11,466 patients with psoriasis or psoriatic arthritis examined serious infection risks with four biologics: infliximab, adalimumab, ustekinumab, and etanercept. The cumulative incidence rate was 1.45 per 100 patient years (323 serious infections), and the respective rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient years for ustekinumab, etanercept, adalimumab, and infliximab, respectively. By comparison, rates for non-methotrexate/non-biologics were 1.05 and 1.28 per 100 patient years for methotrexate/non-biologics.

Biologics and Hospitalized Infection Risk

Overall, research shows using biologics increases the risk of hospitalized infections compared to traditional disease-modifying anti-rheumatic drugs. However, there are no studies directly comparing biologics and corticosteroids.

Biologics Risk Increase as a Group

In a group of rheumatoid arthritis patients, pneumonia and urinary tract infections were the most common infections. Study data showed current biologic use was linked with significantly higher hospitalized infection risks (relative risk 1.21; 95% CI 1.02 to 1.43). Methotrexate and hydroxychloroquine use were associated with lower risk – 0.81 (95% CI 0.70 to 0.93) and 0.74 (95% CI 0.62 to 0.89), respectively.

Biologics Differences and Hospitalized Infection Risks

When compared, adjusted hospitalized infection rates for etanercept, adalimumab, abatacept, and rituximab were similar. However, the rate was increased for infliximab (HR 2.3, 95% CI 1.3 to 4.0).

According to study data, hospitalization risks were greater with older patients and those with chronic obstructive pulmonary disease. Prednisone doses of >7.5 mg/day and chronic inflammation were also linked to an increased hospitalized infection risk.

Biologics, Hospitalized Infections, and Concomitant Use

Based on existing research, the verdict is still out on whether concomitant use of biologics is effective. In a study comparing denosumab and zoledronic acid, investigators found the rate of hospitalized infections was comparable (HR=0.89, 95% CI 0.69 to 1.15).

Although the study demonstrates concomitant use of denosumab might be safe, these results cannot be generalized to other concomitant biologic use for rheumatoid arthritis treatment. In fact, other studies show concomitant biologics use in rheumatoid arthritis patients increases infection rates without improving efficacy.

Infection Risk and Switching Biologics

When assessing the risk of hospitalized infections for rheumatoid arthritis patients, the overall crude incidence rate was 15.3 per 100 patient years (95% CI 14.7 to 15.9), ranging from 13.1 per 100 patient years for abatacept to 18.7 per 100 patient years for rituximab. The results also showed that infection risks were greater for infliximab and etanercept than they were for abatacept.

Another study looking at switched biologic therapy for rheumatoid arthritis patients determined the hazard rate for all infections was significantly higher for adalimumab, etanercept, and infliximab. Rates were not higher for abatacept. When compared to rituximab, severe infection risk was significantly higher for infliximab, but not for abatacept, adalimumab, or etanercept.

To read the article at its original location: http://www.rheumatologynetwork.com/rheumatoid-arthritis/infections-and-biologics-rheumatoid-arthritis


November 16, 2016 Posted by | Healthcare | , | Leave a comment

Review: Treatment for Lupus Nephritis

Published on Nov. 10, 2016, Rheumatology Network website

By Whitney L. Jackson

Among lupus patients, lupus nephritis can be one of the most common and most severe disease manifestations — affecting 40% of lupus patients. For nearly 50 years, though, treatments have advanced, and lupus nephritis outcomes have improved.

Now, a new literature review study reveals those therapeutic steps forward have stalled. The plateau began in 2000. In fact, the risk of developing lupus nephritis-related end stage renal disease (ESRD) at 5, 10, and 15 years has stagnated at 11%, 17%, and 22% for the past decade.

According to study authors from Brigham and Women’s Hospital in Boston, this freeze isn’t related to ongoing work.

“The lack of progress in lupus nephritis outcomes is not due to lack of effort,” they wrote. “In fact, alongside government funding, private agencies have emerged as important drivers of lupus nephritis research through their own investigations and funding mechanisms.”

Still, the reasons for the stymied progress remain unclear. Researchers hypothesize poor healthcare access for some groups, limited efficacy of current treatments, and adverse effects of those treatments might be to blame.

To shed more light on this problem, the study authors reviewed existing literature. They analyzed existing incidence and outcomes data, reviewed diagnosis and treatment guidelines, and evaluated the role rheumatologists play in the therapeutic process.


While lupus nephritis impacts 40% of lupus patients, it is far more common in nonwhite populations and affects women more than men. According to data from a 2000-2004 Medicaid study, lupus nephritis is 3.8 times more likely in blacks, 3.7 times more in Asians, 2.3 times more in Native Americans, and 1.9 times more in Hispanics.

The incidence of lupus nephritis is also greater among patients who experience lupus onset in childhood versus as an adult – 37% versus 20%, respectively.

Barriers to Care

Regardless of ethnicity, however, existing research points to socioeconomic status as a significant contributing factor to increase lupus nephritis incidence. Based on findings from a 2010 Journal of Rheumatology study, patients in poor urban areas are less likely to have insurance, and they use emergency department services more.

In addition, these patients usually live more than 200 miles away from a rheumatologist, or immunosuppressive medications might be unavailable or cost-prohibitive. In some cases, available care could simply be substandard.

Treatment Recommendations

Overall, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) and the European Dialysis & Transplant Association (ERA-EDTA) recommend lupus patients be closely monitored from lupus nephritis outset through routine screenings and kidney biopsies.

Authors Paul Hoover, M.D., and Karen Costenbrader, M.D., highlighted six additional, official recommendations designed to maximize lupus nephritis treatment outcomes:

1.      All lupus nephritis patients should receive adjunctive medication, including hydroxycholorquine (HCQ) that reduces systemic lupus relapses and may be associated with slowing renal damage, thrombosis, hyperglycemia, and hyperlipidemia, as well as a reno-protective agent and a lipid-lowering statin. Any woman considering pregnancy should be counseled about the effects of therapy on a fetus.

2.      EULAR/ERA-EDTA endorses low-to-moderate oral glucocorticoid doses, plus azathioprine for individuals with proteinuria >1g/day or urinary acanthocytes.

3.      Patients with Class III or IV proliferation glomerulonephritis induction therapy should receive induction therapy with moderate oral glucocorticoid doses, plus intravenous cyclophosphamide or mycophenolate mofetil (MMF) or without initial pulses of intravenous methylprednisolone.

4.      For maintenance therapy, it’s recommended that MMF or azathioprine be used with or without low-dose glucocorticoids.

5.      EULAR/ERA-EDTA recommends treatment of “active lesions” only.

6.      EULAR/ERA-EDTA recommends the continuing maintenance therapy for two years after complete remission (proteinuria <0.5mg/day – near normal glomerular filtration rates).

Poor Outcomes Due to Treatment

Historically, adherence to lupus and lupus nephritis treatment has been low with less than 25% of lupus patients having adherence rates of more than 80% over two years. This often leads to lupus relapse, kidney problems, and hospitalizations.

Existing literature shows, though, that some providers are turning to serial serum HCQ level measurements to determine whether patients are adhering to treatment regimens. HCQ levels between 500-to-2,000 ng/ml are associated with modestly-improved lupus disease activity. This type of measurement could point to treatment adherence. Behavioral therapy and patient education could also be effective, though they haven’t been tested with lupus nephritis patients yet.

Adherence isn’t the only factor that determines outcomes, however.

Recent research suggests that genetics might play a role, as well. Over the past decade, investigations have identified more than 50 lupus risk loci. Many of these focus on lupus nephritis: BLK, STAT4, TNFS4, IKZFI, IRF5, TLR9, TNFAIP3, TNIP3, ACE, KLK, FCGR2A, FCGR3A, and ITGAM. For example, APOLI1 risk alleles associated with ESRD are 60-times more likely in blacks than whites, more than doubling their risk of developing ESRD and shortening their time to developing the disease by two years.

Most participants were European and Asian, however, so it’s unclear if this data is accurate across ethnicities.

However, there are treatment-related factors that contribute to poor outcomes, investigators said. In fact, Hoover said, the research review revealed a surprising finding. Glucocorticoids and long-term immunosuppression – despite effectively controlling lupus activity – have significant side effects, such as infections.

Traditionally, glucocorticoid use induces successful remission within six months. However, in one Medicaid study of 33,000 lupus patients – 7,100 of which had lupus nephritis – the incidence rate of serious infection is more than 2-fold higher for lupus nephritis patients than those with lupus alone. However, the highest risk rate was among those treated with glucocorticoids followed by those treated with immunosuppressive drugs.

It is possible to minimize bad outcomes by following vaccination guidelines before beginning immunosuppressive treatment for lupus and lupus nephritis patients. Only killed infections, such as influenza, pneumococcus, hepatitis B, and HPV, are used – live vaccines are avoided.

But, in the long term, glucocorticoid use presents significant challenges to lupus nephritis treatment. Over time, continued use can cause osteoporotic fractures, avascular necrosis, diabetes mellitus, cataracts, glaucoma, and premature death.

Because of these negative effects, ACR has issued recommendations for all patients treated with glucocorticoids. Before patients begin a regimen, providers should: evaluate all patients for fall risk, counsel them on smoking cessation, encourage reduced alcohol consumption, promote modest weight loss and exercise, and encourage patients to get enough calcium and Vitamin D.

The ACR also recommends anti-osteoporotic medication for patients with prior fragility fractures. However, selecting the best anti-osteoporotic medication can be difficult. Among patients with renal insufficiency or ESRD, bisphosphonates are contraindicated for use. And, there’s no general consensus on whether these drugs can be used with women of child-bearing years.

Treatment Possibilities

Given the negative impacts of prolonged glucocorticoid usage among lupus nephritis patients, the authors wrote, the use of low-dose or glucocorticoid-free treatments are under investigation.

Although previous research with rituximab, the monoclonal antibody that targets the B-cell surface protein CD20, showed no statistical improvement in outcomes for patients who received MMF and glucocorticoids, a recent study is showing more promise. Of 50 lupus nephritis patients treated without oral glucocorticoids, 52% achieved complete renal remission at 1 year. Participants received two pulses of methylprednisolone and two 1-gram doses of rituximab, separated by two weeks, as well as MMF.

This study, the authors wrote, is setting the foundation for similar ones to determine whether lupus nephritis patients can be successfully treatment without glucocorticoids or with lower doses.

The Future

As treatment for lupus nephritis moves forward, the authors wrote, changes must be made to encourage and ensure that lower-income and nonwhite patients receive better therapies and experience improved outcomes.

Alongside creating modified therapies that change dosing levels for glucocorticoids, implementing behavioral interventions that address treatment adherence rates could be effective. Additionally, exploring personalized medicine as a method to target individuals who are genetically pre-disposed to poor outcomes can move the needle for most positive outcomes.

Ultimately, the authors said, additional steps must be taken to improve access to care overall because any delay in diagnosis and treatment inevitably leads to negative impacts on a patient’s kidneys.

To read the article at its original location: http://www.rheumatologynetwork.com/lupus/review-treatment-lupus-nephritis


November 16, 2016 Posted by | Healthcare | , | Leave a comment

The Assessment: Bedaquiline for TB Treatment

Published on the Nov. 11, 2016, Rheumatology Network website

By Whitney L. Jackson

The face of tuberculosis treatment is changing for the first time in 40 years, particularly when it comes to the drug-resistant forms of the disease.

Approved in 2012 by the U.S. Food and Drug Administration (FDA), bedaquiline is an antimycobacterial drug that inhibits mycobacterial ATP synthetase and drains cellular energy stores. Based on how it works, bedaquiline maintains its effectiveness against certain forms of tuberculosis that are already resisting other, existing drugs.

But, despite its benefits, initial studies revealed more patients receiving bedaquiline died than those taking a placebo therapy regimen. The question has been whether adding bedaquiline into the tuberculosis treatment regimen is worth the risk.

The Infection Problem

According to the World Health Organization (WHO), there were 8.6 million new tuberculosis cases in 2012. Incidence rates of drug-resistant tuberculosis have also been rising in the 27 most affected countries, leading the WHO to estimate there were 450,000 new drug-resistant cases globally in 2012, as well.

Overall, based on data cited in a New England Journal of Medicine editorial, tuberculosis infection carries substantial morbidity and mortality risks – among sputum-smear positive, HIV-negative patients, the 10-year fatality rate is 70%. New treatments are needed to combat this continued problem, but their use must be weighed against the likelihood they will lead to avoidable deaths.

Bedaquiline Approval

Despite bedaquiline presenting more deaths, the FDA made a rare move. It approved the drug for use despite the risks based on the results of a two-stage, Phase 2 trialthat included sputum-positive participants who were sensitive to at least three of the five drugs used in the antimycobacterial drug regimen for multi-drug resistant pulmonary tuberculosis. The preferred background regimen included: kanamycin, ofloxacin, ethambutol, pyrazinamide, and cycloserine or terizidone.

During the first stage, 47 patients were blindly assigned to receive 8 weeks of placebo or bedaquiline, in addition to the background regimen. After 8 weeks, sputum-culture conversion was much better for bedaquiline patients (48%) than placebo (9%). In the second phase, 79 patients received bedaquiline, and 81 received placebo care. Sputum conversion, again, was much shorter for the bedaquiline group – 83 days versus 125 days.

However, the study also revealed more deaths occurred with bedaquiline. Only two placebo patients died, but 5 of 10 deaths in the bedaquiline group were attributed to disease progression. The drug’s benefit was significant enough, however, to win FDA approval.

Introducing Bedaquiline Treatment

Based on the FDA’s decision, a new study, published in PLOS, investigated different strategies for introducing bedaquiline to patients who could benefit from it. Each method was based on a patient’s resistance pattern and was designed to maximize efficacy and minimizing negative impacts. Effectively implementing antibiotic introduction strategies is important because it can affect the development of acquired resistance to new drugs, existing drugs, or both.

The new study used previously-published aggregate data to create a Markov decision model, based on a group of hypothetical patients who were beginning multi-drug resistant tuberculosis treatment. To test the various treatment methods, investigators assumed the population was mostly 30-year-old men who were susceptible to bedaquiline. They had either multi-drug resistant tuberculosis without additional resistance (67.1%), multi-drug resistant tuberculosis with resistance to at least one fluoroquinolone or at least one second-line injectable (26.2%), or multi-drug resistant tuberculosis with resistance to at least one fluoroquinolone and at least one second-line injectable (6.7%).

Investigators sampled 5,000 random parameter sets to create their decision model. They included estimating life expectancy, resistance acquisition patterns, and the number of – and outcomes – of secondary tuberculosis cases.

Given the questions around bedaquiline’s impact, researchers concentrated on mortality, resistance, and transmission outcomes.

To test effectiveness, researchers designed four treatment strategies:

  • Withholding bedaquiline from all patients
  • Providing bedaquiline to patients with extensively drug-resistant tuberculosis
  • Providing bedaquiline to patients with pre-extensively drug-resistant tuberculosis or extensively drug-resistant tuberculosis
  • Providing bedaquiline to all patients with multi-drug resistant tuberculosis

Researchers assured all multi-drug resistant tuberculosis patients received bedaquiline from baseline. For all other strategies, they assumed a 13-week lag time after treatment launch.


The decision model results supported the FDA’s decision to approve bedaquiline for patients who don’t have other treatment options.

Among multi-drug resistant tuberculosis patients, using bedaquiline maximized life expectancy in 76.8% of the 5,000 parameter simulations. For all other patients, the optimal strategy seemed to be withholding bedaquiline, indicating – for this group – the bedaquiline benefit of reducing culture conversion time doesn’t outweigh the mortality risk.

When most parameters remained at fixed midpoints, the “all multi-drug resistant tuberculosis” strategy is preferred when it can reduce the median culture conversion time by at least 35 percent over what the background drug regimen only is able to produce. It’s also best when the added bedaquiline mortality risk is less than 0.00025 per week – roughly 1.3 deaths per 100 patient years.

Overall, researchers said, making bedaquiline available to all patient with multi-drug resistant tuberculosis minimizes the actual number of and expected number of lives lost to secondary tuberculosis infections. After using the best strategies for each patient, life expectancy for the hypothetical 30-year-old participants reached 36.12 years compared to 34.67 years when suboptimal therapies were used.

Data analysis also showed, based on drug-susceptibility testing, the “all multi-drug resistant tuberculosis” method provides optimal life expectancy in 69.3% of cases. Pre-extensively drug resistant tuberculosis and extensively-drug resistant tuberculosis do so in 16.9% of situations, and no bedaquiline optimizes life expectancy in only 13.7% of instances.


The study did have limitations, however, other than presenting all participants as 30-year-old men. Investigators didn’t explore all potential bedaquiline use strategies, such as early drug substitution methods. They also held parameters unrelated to bedaquiline constant throughout the study even though reproducing those circumstances with actual study participants isn’t possible. They also assumed the background drug regimen effect would be the same for all patients even though those conditions are not reproducible in the real world.

Additionally, researchers did not consider the impact of introducing bedaquiline to HIV-positive participants.

Future Concerns

As with all drugs, acquired resistance is a concern with bedaquiline, especially because the medication is a new treatment for tuberculosis. On average, in the simulation, 5.88% of patients developed bedaquiline resistance when the drug was made available to all multi-drug resistant tuberculosis patients. When bedaquiline was only given to extensively-drug resistant tuberculosis patients, drug resistance developed in only 3.5% of cases.

There’s a hope, though, researchers said, that expanding bedaquiline use could help protect the efficacy of the existing drug regimen. By offering an additional drug to fight infection, bedaquiline could potentially limit resistance to medications already in use. So far, based on the study’s findings, that benefit does materialize. Only 2.56% of patients developed extensively-resistant tuberculosis when all patients received bedaquiline compared to the 9.82% that do so when the drug is only given to extensively-drug resistant patients.

Ultimately, researchers said, their study highlights the need to investigate bedaquiline’s impact and benefit in real-world circumstances. Continued analysis of the drug’s safety and efficacy is paramount. If the results can be duplicated, a strong case could be made – even if it leads to future bedaquiline resistance – to extend the drug’s use beyond compassionate use situations, particularly where rapid second-line drug susceptibility testing isn’t an option.

To read the article published at its original location: http://www.rheumatologynetwork.com/rheumatoid-arthritis/assessment-bedaquiline-tb-treatment

November 16, 2016 Posted by | Healthcare | , | Leave a comment


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