Miguel A. Escobar, MD:
Patients with hemophilia will experience many challenges throughout their life, whether they be emotional, physical, or logistical. Therefore, HCPs must realize that these challenges are going differ from one patient to another. In addressing these challenges, HCPs must keep in mind that how we address them will differ geographically, from one country to another or one hemophilia treatment center (HTC) to another.

Miguel A. Escobar, MD:
Some of the greatest challenges in managing hemophilia include diagnosis, access to care, and prophylaxis therapy. Although diagnosis is not a major barrier to care in the United States, it certainly can be a challenge in other parts of the world, particularly in developing countries.

Multidisciplinary care is key to the successful management of hemophilia, but patients in many parts of the world experience difficulties accessing care by a multidisciplinary team. For example, approximately 20% of patients with hemophilia in the United States do not have access to multidisciplinary care.¹

There are many reasons patients may not have access to adequate care, so it is important that HCPs are able to consider the nuances in these challenges. For example, continuous IV hematologic prophylaxis to prevent bleeding is one of the most important management strategies for treating hemophilia. However, the high cost and intensive nature of this treatment present major challenges to patients in both developed and developing countries.

Lastly, although there are many patient-centric challenges, there is also a worldwide shortage of specialists, especially hematologists. In other words, there just are not enough specialists to take care of patients with bleeding disorders.^2,3

Miguel A. Escobar, MD:
Addressing the many challenges seen in hemophilia care today requires HCPs to look at them from both the patient perspective and their own perspective. An adult patient likely is going to think about their healthcare needs very differently from their HCP. They may be more concerned about how their condition and treatment might affect their day-to-day responsibilities, such as their job. Another major concern for many adult patients is whether they will be able to cover the financial costs of their treatment. Patients also may be concerned about self-disclosure, impact on their interpersonal relationships, and possible loss of independence. These are all perspectives that HCPs need to consider when developing treatment plans for patients, and they are critical for a multidisciplinary care team to address.

From the HCP perspective, we are most concerned with improving outcomes for patients with bleeding disorders, especially hemophilia. Our goals are to ensure that patients have 0 or minimal bleeds, no arthropathy, and reduced treatment burden; to ensure that they can tolerate therapy; and to prevent declines in quality of life. In addressing the concern of improving patient outcomes, a major factor here is adherence.^4,5

Miguel A. Escobar, MD:

In addition to recognizing the differences between the patient and HCP perspectives, HCPs also must understand that there is no one-size-fits-all method to address unmet needs in hemophilia care. Challenges will differ from one patient to another and one country to another. A key contributing factor to these differences is inequality in national healthcare systems. The reality is that many patients living in developing countries have minimal access to healthcare compared with those living in developed countries. However, even in developed countries, there is inequality in healthcare based on socioeconomic status.

The goal of the healthcare system should be to ensure healthy lives and promote well-being for all, but there are certainly budgetary constraints in any national system. In addition, some countries lack healthcare infrastructure or have difficulty managing their patient registries, thereby impeding access to care. Differences between countries in the structure of healthcare reimbursement systems and cultural factors also may play a role in preventing patients from seeking care. Lastly, a lack of awareness of hemophilia among both patients and HCPs can delay diagnosis and initiation of care globally.

To address these unmet needs, HCPs must take into account the healthcare limitations of each geographic location, as well as each patient’s cultural and socioeconomic factors. One way to bridge these gaps in care is to increase at-home treatment options and care.⁵

Miguel A. Escobar, MD:
Unfortunately, unmet needs can result in a widespread lack of adherence to long-term therapy, which is already a challenge for many patients with chronic conditions.

For example, nonadherence to therapy among patients with hypertension is 27% to 40% globally. Nonadherence to antihypertensive therapy is an even greater challenge in developing countries vs developed countries.⁶ This rate of nonadherence is quite high, especially considering that this treatment is usually a medication that is taken by mouth. The rate of nonadherence to antidepressants is anywhere from 15% to 70%.⁷ Adherence to asthma medication is even lower, with 30% to 70% of patients being nonadherent.⁸ Lastly, the adherence to antiretroviral medications for HIV varies anywhere from 19% to 42%.⁹

These statistics illustrate that nonadherence to therapy is typical of patients with chronic conditions who require long-term therapy. This is exactly what happens with our patients who have hemophilia.

Miguel A. Escobar, MD:
According to the WHO, 5 interacting dimensions can affect patient adherence. One dimension is related specifically to the patient, and another is related to the therapy they are receiving. Other dimensions encompass socioeconomic, healthcare system, and disease- or disorder-related factors.⁵

Miguel A. Escobar, MD:
I think it is important to mention this because the challenges that our patients with hemophilia face all fall into one of these dimensions. Although the sheer number of factors that affect adherence can seem overwhelming, organizing them into specific categories can make them easier to address.

In fact, this applies not only to hemophilia, but also to the management of many of chronic diseases.¹⁰

Miguel A. Escobar, MD:
Why is treatment adherence specifically important in patients with hemophilia? First, data show that consistent treatment adherence decreases arthropathy and prevents bleeds. Thus, adherence decreases the frequency of hospital and emergency department admissions.

Good treatment adherence also increases tolerance to high activity levels and is associated with improved academic or work performance and accomplishments. Perhaps counterintuitively, treatment adherence ensures that therapy is more cost effective for everybody—patients, as well as society. This idea is proven when one understands that healthier patients who are treatment adherent are less likely to seek out costly emergency department care. Ultimately, increased treatment adherence improves patients’ quality of life.^11,12

Miguel A. Escobar, MD:

Now, what is the definition of adherence? What kind of measures can HCPs use to quantify adherence? The most accepted definition in hemophilia management is: Patients infusing 75% to 80% or more of their prescribed doses can be classified as adherent.

Measuring adherence could be as simple as requesting information from patients or their caregivers/families. HCPs also can count patients’ vials or directly supervise them to measure adherence. Nowadays, many HCPs prefer electronic monitoring to do this efficiently. Drug assays are also a quantitative way to measure adherence. Lastly, HCPs can evaluate clinical outcomes to determine if a patient is treatment adherent.^13,14

Miguel A. Escobar, MD:
Now knowing how adherence is defined and measured, I want to discuss the rate of adherence to treatment among patients with hemophilia in the United States. The data come from many sources, namely surveys, the VERITAS-Pro questionnaire, pharmacy or infusion logs, and a randomized clinical trial.

The data show that the patients who were the most adherent were those enrolled on the clinical trial. This is expected, as clinical standards usually entail more intensive patient follow-up. Although adherence was 96% among clinical trial participants, what the data really show is that adherence is much lower in real-world situations. For example, according to data from infusion logs, adherence was very low. In children, adherence was 26%; in adults, adherence was 39%. Using pharmacy logs, adherence was approximately 50% among adolescents and young adults.

According to the VERITAS-Pro questionnaire, adherence among adolescents was 30%. Finally, according to survey data, adherence in both children and adults ranged from 58% to 73%. Although there is a lot of variability among these reports, the take-home message remains the same: Major work must be done to improve adherence to hemophilia therapy among patients in the United States.¹¹

Miguel A. Escobar, MD:
Next, investigators administered the same survey with some modifications to 413 patients with hemophilia who were 25-87 years of age. Among these participants, 4% experienced an interruption in their prophylactic treatment for <1 month; 6% stopped prophylaxis after an average of 16 years. In contrast to the previous survey, only 43% of participants thought they had the same opportunities as healthy individuals.

Participants reported that the most difficult aspects of having hemophilia were:

• Anxiety related to undergoing surgeries
• Not being able to receive treatment for a bleed or being treated incorrectly
• Not being able to perform physical activity
• Difficulty with planning for the future
• Potential consequences of contracting HIV and hepatitis

Many of these challenges are related to the age of this patient population.¹⁹

These results highlight the different perspectives between pediatric and adult patients when it comes to adherence.

Miguel A. Escobar, MD:
This study is a cross-sectional, questionnaire-based study that was conducted in the Netherlands. This questionnaire was administered to children, adolescents, and adults to determine how age affects patients’ treatment adherence.

Adherence starts out very high—at 90% among children. I think it is clear that these children are highly adherent because their parents are the ones administering the treatment. Once the treatment responsibility is given to adolescents, adherence dropped from 90% to approximately 70%. Furthermore, 28% of these individuals were suboptimally adherent to treatment, meaning they were receiving some treatment but not completely following directions as it was prescribed; 3% of adolescents were not adherent at all.

Looking at the adult population, adherence drops even further. Only approximately 50% of adult patients were adhering to treatment as it was prescribed, and 35% were somewhat adherent. The number of nonadherent adult patients increased to 14%. Thus, the data clearly demonstrate a marked decrease in adherence to prophylaxis with increasing age.²⁰

Miguel A. Escobar, MD:
Overall, multiple studies show common themes among patient-reported barriers to prophylaxis. There are personal factors, such as forgetfulness or lack of commitment; age; transitioning to adulthood; and a lack of social or familial support. Infrequent bleeding events, combined with concerns regarding complications and lifestyle disruptions, also can contribute to treatment nonadherence.

There are also structural barriers to consider, such as direct or indirect treatment-related costs, difficulties with reimbursement, and availability of prescribed therapies. Both patients and payers often lack knowledge regarding the importance of prescribed treatments.^21-23

Miguel A. Escobar, MD:
Looking from the HCP perspective, how can we improve adherence? I think patient education about the disease and especially prophylaxis therapy is critical. HCPs need to emphasize that consistent prophylaxis will prevent further complications. HCPs also should promote prophylaxis as a way to enhance activities and decrease the risk of developing inhibitors.

To address patient concerns regarding the risk of complications, HCPs should increase awareness about important studies that have been done and better explain that treatment is based on concrete data. HCPs also can help improve ease of venous access with psychological interventions to decrease anxiety, as well as training for independence with transition programs.

Nowadays, there are therapies for hemophilia that are administered subcutaneously. Therefore, individualized treatment plans for patients can improve adherence by specifically addressing specific patient factors such as therapy burden and risk of infection.²⁴

Miguel A. Escobar, MD:
From the patient perspective, education is key to improving treatment adherence. At all levels, the importance of prophylaxis must be well understood. Improved communication can facilitate this education and improve adherence.

Improving patient‒HCP communication can be done in many ways. More frequent visits to the HTC, Internet dialogue pages, and reminder telephone calls or text messages are all examples of communication channels that can pass on this valuable information.

HCPs should help patients track their adherence to prophylaxis therapy via diaries, while using phone databases to assist in the follow-up process. Patients also can use registries and apps to track their prophylaxis treatment. All this information can then be sent to the HTC to keep HCPs informed.

Finally, improvements in factor concentrates are available to patients, who may need further education. Patients should be informed of long-acting factors, nonreplacement therapies such as rebalancing therapies, and their potential options for gene therapy.

Miguel A. Escobar, MD:
Of importance, HCPs now have additional treatment options for patients with hemophilia who struggle with adherence, such as extended half-life (EHL) factors for prophylaxis. EHL factors reduce the number of infusions that are required of patients. FVIII and FIX products have the potential to improve adherence by mitigating the burden of frequent IV interventions. Better adherence would subsequently reduce bleeding complications and improve quality of life. In addition to maintaining trough levels with fewer treatments, EHL factors also could enable higher trough levels without increasing the frequency of infusions.

Good candidates for EHL products include patients with difficult venous access and poor adherence, and those who are very active and require higher trough levels. Other candidates include those who experience breakthrough bleeds with standard therapies and who desire more improved convenience.^25,26

Miguel A. Escobar, MD:
I have discussed the HCP perspective on what makes a patient a good candidate for EHL products, but what about the patient perspective when switching therapies? A study in Europe surveyed adult patients with hemophilia, as well as the parents of children with hemophilia, to learn of their perceptions of their or their child’s current therapy vs switching to a new EHL product.

Of note, adult patients and parents equally prioritized increased dosing intervals, security during travel, and safety as reasons for switching, whereas only parents significantly prioritized their children’s ability to do sports (P = .0001). Of the potential reasons to switch to a new EHL product, reasons of significance (with P = .0001) included fear of inhibitor development. This is something that is important for HCPs to discuss with patients and their caregivers/families. There are plenty of data showing that there is minimal risk of developing inhibitors to therapy after switching products.²⁷

Miguel A. Escobar, MD:
Although the treatment landscape has no doubt improved for hemophilia, not all treatments are created equal when considering the benefits and limitations of prophylaxis for hemophilia A vs hemophilia B. The most important and obvious benefit of prophylaxis for both disease types is the decrease of complications, fewer bleeds, and improved joint health. For the treatment of patients with hemophilia A, particularly those with inhibitors, patients have the option of using nonfactor replacement therapy, such as SC emicizumab.

A potential drawback of nonfactor SC therapy is the loss of infusion skills, particularly in younger, less experienced patients. The question also remains of whether treatment with emicizumab is going to prolong inhibitor risk, especially in previously untreated patients. These are all potential limitations that researchers and HCPs are currently trying to address.

Unfortunately, emicizumab is not approved to treat hemophilia B. Although some agents are in clinical trials for this disease type, there are no FDA-approved agents for hemophilia B with SC administration and treatment options are limited for those with hemophilia B with inhibitors. However, patients with hemophilia B can achieve true half-life extension with EHL products. In other words, patients with hemophilia B will require less frequent dosing than those with hemophilia A, who may need twice-weekly administration at minimum.^28-30

Miguel A. Escobar, MD:
An ongoing discussion in hemophilia management is whether emicizumab is an effective prophylaxis for infants. Factors that favor this premise include the ability to start prophylaxis very early, administer subcutaneously, and remove the need for central catheter ports. Emicizumab could make prophylaxis therapy for the parents of infants easier and more convenient. However, it does have potential drawbacks. First and foremost, emicizumab has limited available data for this patient population. In addition, delayed exposure to FVIII may alter when these patients will develop inhibitors.

HAVEN-7 is a multicenter, open-label, single-arm phase IIIb trial assessing the efficacy, safety, and pharmacokinetics of emicizumab in previously untreated and minimally treated pediatric patients up to 1 year of age. At interim analysis, the data showed that emicizumab was quite effective: 77% of patients had 0 treated bleeds, and there were no new safety signals. Although the final analysis is still pending, the interim data are promising.^33,34

Miguel A. Escobar, MD:
That brings me to the discussion of how HCPs can tailor therapy to the individual. I think the most important thing to do is sit down with patients and their caregivers/families to thoroughly discuss their options.

This should be a two-way conversation where patients and HCPs have a clear discussion of patients’ activities and goals, and HCPs explain which therapies might be better suited for them depending on their age, joint disease, and activities. HCPs can do this by planning and using different case scenarios and by using pharmacokinetic tools to adjust treatments to patients’ activities. Lastly, HCPs must talk to patients about the importance of adherence to therapy and discuss how they can work with their healthcare team to improve and monitor adherence over time.

Miguel A. Escobar, MD:
In having patient‒HCP discussions about individualizing treatment, HCPs must use consent conversations, which can be enhanced when using the shared decision-making consent model.³⁶ Again, HCPs must involve the patients and their caregivers/families to have two-way conversations and provide adequate information about treatment. Based on this model, HCPs and patients will be able to come to a shared decision, ensuring that patients receive individualized therapy upon which they and the HCP agree.

Miguel A. Escobar, MD:
The treatment landscape for hemophilia is rapidly evolving. Later discussion in this module will explore some of the other agents that are in development. It is critical that HCPs understand what advantages and disadvantages exist with these newer factors and nonfactor replacement therapies and can effectively pass this information on to patients and their caregivers/families.