Patients & Caregivers

Inhibitors

The emergence of inhibitors manifests as an immune reaction in people with Hemophilia undergoing clotting factor concentrate therapy.
The immune system protects the body by forming antibodies to fight harmful foreign substances. In some PwH, the immune system views infused clotting factors as foreign proteins and develops antibodies to fight them. As a result, inhibitors end up negating the infused factor.

Antibodies to clotting factor develop in about:

• 10-20% of people with severe Hemophilia A
• 2-3% percent of people with Hemophilia B

Developing inhibitors is one of the worst things that can happen to a PwH. These patients experience more severe bleeds, greater complications and excessive expenses.

Clinically, the presence of inhibitors is suspected if there is:

• Inadequate response to factor replacement
• Increased frequency of bleeding
• Allergic responses to factor administration

Treating inhibitors is one of the biggest challenges for PwH today. It is important to diagnose inhibitors as swiftly as possible in order to implement its management in the comprehensive Hemophilia care plan.

HIV in PwH

The treatment of Hemophilia relies solely on blood or blood products. Modern safe products are available today, compared to the less secure options like whole blood, Fresh Frozen Plasma (FFP), or lyophilized cryoprecipitate used 30 to 35 years ago, when HIV/AIDS and hepatitis were not yet understood and blood screening was insufficient. However, many Hemophilia patients in India continue to resort to unsafe blood products due to the high cost of Anti Hemophilic Factor (AHF) treatment. This exposes them to HIV/AIDS and hepatitis infections alongside their inherited condition, leading to severe physical, emotional, and financial complications.

Living with HIV is comparable to managing Hemophilia. Both are lifelong conditions demanding constant care. Both impact daily life in various ways including personal relationships, education, employment, and coping with health setbacks. Adapting to a healthier lifestyle involving diet, exercise, proper hygiene, and stress management can improve overall well-being, prevent interference in infection control, and help manage bleeding episodes in HIV positive PwH.

HIV evolves rapidly, generating mutations in its structure, some affecting targeted regions for anti-HIV drugs, resulting in drug-resistant strains. Adherence to treatment plans is crucial, involving timely drug intake and specific dietary instructions. Inconsistent medication can lead to treatment failure and the emergence of drug-resistant HIV.

How is HIV transmitted?

HIV transmission primarily occurs through blood, semen, and vaginal fluids exchange. HIV-positive individuals can control its spread by modifying personal habits, practicing safe sex with condoms, using lubricants, and avoiding reusing needles or sharing equipment. Pregnant HIV-discordant couples (where only one partner is HIV-positive) should consider methods like timed ovulatory intercourse, artificial insemination with ‘washed’ sperm, or in-vitro fertilization to minimize transmission risks during conception.

For individuals affected by HIV and Hemophilia, Hemophilia Foundation India’s Special Needs Cell offers support. The cell has set guidelines to support PwH who are infected with HIV, in consultation with HFI Medical Advisory Board (MAB). The advice of the MAB is especially significant for those infected by HCV and for those who develop inhibitors.This includes providing free CFC treatment when available, reimbursing medical bills for opportunistic infection treatment, and covering upto 50% of the costs of Anti-Retroviral Therapy (ART) drugs for impoverished PwH with CD4 cell counts near or below 200. By following these guidelines, individuals can better manage the challenges of living with both HIV and Hemophilia.

Hepatitis in PwH

The management of hepatitis B and C virus infections among people with Hemophilia is crucial due to the higher prevalence of these infections in this population. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have a prevalence of 4% and 0 – 1.7% respectively in the general Indian population. However, the prevalence is notably higher among PwH, reaching 5-10% for HBV and 30-35% for HCV among those who receive multiple transfusions. These infections lead to substantial health challenges and mortality in this group.

Diagnosis of hepatitis involves using a range of tests, including HBV antigen and HCV antibody tests. Additional markers like IgM core antibody, HBeAg, HBV DNA PCR, and HCV RNA PCR are used when antiviral treatment is considered.

Diseases caused by HBV or HCV vary, with acute and chronic infection categories:

• Acute infection: characterized by distinct phases and can lead to hepatic failure.
• Chronic infection: extends beyond 6 months and may result in chronic hepatitis or cirrhosis.

The spectrum of disease caused by HBV or HCV infection include acute infection, acute hepatitis, fulminant hepatic failure, subacute hepatic failure, chronic hepatitis, cirrhosis, and hepatocellular carcinoma.

Antiviral treatment is indicated for patients with HBV/HCV-related chronic hepatitis, cirrhosis, and replicative HBV or HCV infections. It aims to convert them to non-replicative status and reduce liver cancer risk.

Acute HBV generally doesn’t require antiviral therapy due to low chronicity risk (10%), while acute HCV requires treatment (if viremic) due to high chronicity risk (85%).

Lamivudine benefits patients with HBV-related fulminant and sub-acute hepatic failure and replicative HBV infection.

Treatment options:

• HBV: PEG Interferon alpha, Interferon alpha, Lamivudine.
• HCV: PEG Interferon alpha, Interferon alpha, Ribavirin
• Genotyping and viral load quantification guide treatment duration for chronic HCV.
• Portal hypertension: Managed with drugs like Propranolol, endoscopic therapy, or porto-systemic shunt surgery.
• Fluid overload: Addressed with salt and fluid restriction and Spironolactone diuretics.
• Hepatic encephalopathy: Treated with anti-hepatic coma measures and addressing precipitating factors.

The cost-effective management of complications of liver disease involves various interventions such as drugs to reduce portal pressure, dietary restrictions, anti-hepatic coma measures, and, in severe cases, liver transplantation.

Vaccination against hepatitis B is recommended for all Hemophiliacs. While there is no vaccine available for hepatitis C, accurate diagnosis, appropriate interventions, and monitoring play a pivotal role in ensuring the well-being of PwH with concurrent HBV/HCV infections.

Mental Health and Social Support

Though not curable, Hemophilia has treatments and management techniques which, when implemented correctly, can allow for a high quality of life and near-complete social integration.

However, it is imperative to provide adequate education to children with Hemophilia to make them completely aware of their condition and equip them with the resources to function successfully in their everyday lives.

Recognizing risks

There are some elements that have a negative impact on the wellbeing of children with Hemophilia either by increasing chances of accidents, or by causing significant mental anguish.

The three main sources of risks are:

• Personality and behavior patterns of the PwH
• Levels of education and awareness of family and caregivers
• The impact of larger community and social scenarios

These risks can proliferate in certain harmful ways:

Social and familial support

A focus on personal growth, family support, and a nurturing educational environment can go a long way to enhance the well-being of children with Hemophilia. Encouraging self-esteem, autonomy, and open communication builds resilience. Providing emotional support, a stable climate, and psychological acceptance fosters a sense of belonging. Social and scholastic activities ensure inclusion, promoting a fulfilling and balanced life for patients.

Some other ways to ensure support and positive impact are:

Children with Hemophilia & Promoting Well-being in Hemophilia Patients

There are strategies and coping mechanisms that PwH, children with Hemophilia and their caregivers can implement in order to ensure a higher quality of life. It is important for communities at large to come together and create safer, more Hemophilia-friendly physical and psychosocial spaces.

Some actionable steps for various stakeholders are:

• Personal resistance development for PwH:
  • Improving self-esteem through focusing on positive aspects of personality.
  • Encouraging diverse interests and flexible goal-setting.
  • Helping children understand and accept disease-imposed limits.
• Reorienting self-perception of the disease as a challenge to be overcome:
  • Fostering responsibility for self-care and shared therapy responsibility.
  • Recognizing and acknowledging the futility of complaining while expecting validation for discomfort.
  • Redirecting conversations to focus on positive aspects of solutions.
• Promoting autonomy and self-care in children with Hemophilia:
  • Fostering independent decision-making and self-injections.
  • Acknowledging and crediting autonomy-driven behavior.
  • Assigning tasks based on capacity and gradually reducing supervision.
• Promoting confidence and assertiveness:
  • Addressing discomfort arising from feeling different.
  • Reinforcing the value of making independent decisions.
  • Fostering the ability to differentiate between peer influence and personal choices.
• Family protection encouragement:
  • Modeling exemplary behaviors regarding the disease.
  • Helping parents distinguish appropriate responses.
  • Cultivating a tolerant atmosphere for mistakes and learning.
  • Discussing over-protective and hyper-permissive parenting.
  • Balancing attention to health with normal activities.
• Promoting emotional support:
  • Emphasizing the importance of listening and shared feelings.
  • Creating time for talking, playing, and sharing.
  • Promoting respect for diversity among family members.
• Stable and predictable environment:
  • Including children in rule-making decisions.
  • Regulating bedtime, playtime, and meal times.
  • Ensuring coherence between both parents’ rules.
• Supporting parents:
  • Showing empathy for parents’ emotional reactions.
  • Helping parents understand and manage their emotions.
  • Offering access to specialized help if needed.
• Improving social and scholastic care:
  • Maintaining a strong relationship with the school and teachers.
  • Sharing education strategies with teachers about Hemophilia.
  • Encouraging low-risk activities and acknowledging achievements.
  • Fostering participation in social networks and altruistic groups.

Product Safety

Patients with Hemophilia are particularly prone to blood-borne infectious agents. This is because of lack of blood safety measures. Given the unattainable expenses of Coagulation Factor Concentrates in India, PwH tend to depend largely on unsafe wet blood products like Fresh Frozen plasma or cryoprecipitate. These expose them to blood-borne infections such as hepatitis (HBV and HCV), cytomegalovirus (CMV) and HIV.

Almost 75% of Hemophilia patients may die as a result of an HIV infection. This is because even a single HIV positive blood donor who may have slipped through the cracks in a pool of 20000 donors will contaminate the entire batch of factors. Only a 100% screening of tainted blood can provide a safe supply to PwH.

HIV-infected Hemophilia patients have to grapple with failing health along with skyrocketing medical expenses. Those who have the misfortune of being infected with both HIV and HCV tend to face liver failure or progressive liver disease as a result of the drugs used for treatments.

Research agencies working in the field of HIV AIDs support a broad program of research on Hemophilia and other bleeding disorders with a primary focus on ensuring the safety and adequacy of blood supply.

Future Prospects

Significant strides have been achieved in enhancing the safety of the blood supply to reduce the risk of transfusion-transmitted diseases among Hemophilia patients. Nevertheless, concerns persist for those reliant on blood products, as potential contaminants pose ongoing threats.

International studies indicate that routine transfusions can prevent debilitating joint issues. However, the drawbacks of treatment, including its expense, catheter-related dangers, and inconveniences in the treatment regimen, could become obsolete with the prospect of a cure. Currently, there are promising indications that gene therapy holds the potential to be that curative solution. Although gene therapy’s intricacies are more complex than initially envisioned, Hemophilia stands as one of the first genetic disorders poised for successful treatment.

Historical Context

Historical accounts reflect early attempts at treatment with unconventional substances, such as egg white extracts and peanut flour. Notable advancements were later made in blood transfusion techniques. In 1840, surgeon Samuel Lane reported utilizing fresh blood to control postoperative bleeding in a severe Hemophilia case. Discoveries like factor VIII identification and the development of assays paved the way for therapeutic advancements.

Plasma concentrates derived from animals were introduced in the 1950s, though allergic reactions were prevalent. Dr. Edwin Cohn’s work on plasma fractionation led to the creation of human factor VIII concentrates. Notably, cryoprecipitate, rich in factor VIII, emerged as a milestone development. Lyophilized coagulation factor concentrates provided practical benefits, enabling home treatment and reducing physical and psychological constraints.

The advent of HIV had dire consequences for patients globally, prompting research into heat treatments and solvent-detergent processes to mitigate virus transmission risks. Additionally, Desmopressin (DDAVP) emerged as an option to elevate factor levels.
 

Gene Therapy on the Horizon

The sequencing of the factor VIII gene in 1984 led to the availability of recombinant factor VIII. This marked a leap forward in safety and stimulated the adoption of prophylactic treatment. As the journey towards a cure continues, gene therapy presents a tangible prospect.

Theoretically, if patients could produce just 1% of normal factor levels, their condition could transform into a milder form. The transfer of a corrected gene into a patient, enabling self-production of the necessary factor, holds the potential for a cure. Hemophilia’s characteristics make it an ideal candidate for gene therapy’s initial success.

The ability to alleviate severe symptoms and reduce reliance on replacement products via gene therapy is compelling. The controlled production of factor VIII and IX following gene therapy is less critical than in other disorders. However, cautious consideration is necessary to avoid overproduction, which could increase clotting risks.

Progress and Future Directions

The International Workshop on Gene Therapy for Hemophilia highlighted the feasibility of gene therapy as a cure. The development of vectors to transfer functional genes into patients, while preventing immune responses, remains a challenge. Research efforts have led to significant insights into Hemophilia gene expression regulations.

Current and future research spans various viral and non-viral gene delivery systems, aiming to repair or introduce functional genes into cells, thus fostering the production of functional protein. Hemophilia models have proven the feasibility of gene therapy, facilitating preclinical studies.

NIH initiatives, workshops, and collaborations underscore the dedication to advancing gene therapy for Hemophilia. Interest extends beyond Hemophilia, with hopes of applying successful gene therapy technology to complex diseases. Research prioritizes safe and effective gene therapy, bridging preclinical to clinical phases.

As gene therapy evolves, it holds the promise of transforming the lives of Hemophilia patients, potentially eliminating the lifelong reliance on replacement products and minimizing the impact of the disease. With ongoing research and advancements, gene therapy for Hemophilia remains a beacon of hope for patients worldwide.

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