RC HIV control in Africa

Epidemiology of HIV in Africa

37,7 million people are living with HIV globally, of which 25,4 million live in Africa. Especially in southern African countries, the prevalence of HIV is very high:

• Zambia
• Botswana
• Namibia
• South Africa
• Eswatini/Swaziland
• Mozambique
• Zimbabwe

Although the number of new infections is declining worldwide, the majority of new infections occur in Africa. These infections mainly (>60%) occur among women, while in Western Countries mainly men are affected. In general, the transmission rate from men to women is higher, women in Sub-Saharan Africa aren’t in the position to negotiate about safe sex and are often involved with older men.

Subtypes

There are different HIV subtypes circulating. In Africa, HIV-1 subtype C is most common, while in Western Countries most infections are HIV-1 subtype B. This means that research mainly is done for HIV-1 subtype B, while in Africa medication for subtype C is necessary. Subtype C and D also appear more pathologic than subtype B.

Antiretroviral treatment and HIV control in Africa

In 1996, a life-saving combination triple therapy was found. This therapy was very effective in suppressing the virus. However, ART (antiretroviral treatment) was hardly covered in the African region. This was the cause of many protests → ART for Africa. This led to an international response to AIDS:

1. 2000 Durban conference “Breaking the Silence” → the first conference held in an African country
   • It finally became clear how big the problem was
2. 2001 UN Declaration of Commitment on HIV/AIDS
   • Made sure that people who needed it, would get their medication
3. 2002 Global Fund to Fight AIDS, TB and Malaria (GFATM)
   • A lot of money was necessary to get the drugs where they were needed
4. 2003 PEPFAR
   • Emergency plan for AIDS relief

Meanwhile, UNAIDS was in discussion with several pharmaceutical companies to reduce the price of ART’s → the price reduced from $10.000/year to $900/year.

However, around 2004, there were challenges for ART access in Africa:

• Shortfalls in health services
• Lack of knowledge about treatment
• Making decisions about newer treatments
• Risk of resistance to ART

Nevertheless, after 2004 the number of people on ART started rising and is now similar to the numbers in Western Countries. This led to a huge increase in life expectancy → a 25-year-gap. The availability of ART also resulted in less people getting infected with HIV.

WHO guidelines

In 2002, the WHO made guidelines for when to start ART in LMIC. These guidelines evolved over time:

1. 2002: ART for everybody with a CD4-cell count of <200
   • Normal: CD4-cell count is >500
2. 2006: ART for everybody with a CD4-cell count of <200 or with a CD4-cell count <350 and TB
3. The treatment started being given earlier and earlier

In 2015, the START and TEMPRANO trials looked into when ART should be started. It appeared that when ART was initiated immediately, the CD4-cell count started rising more. Also when looking at other factors, it appeared that immediate treatment was better:

• Initiating ART at a CD4 count >500 cells leads to less severe HIV morbidity

• Significantly lower risk of HIV disease progression
• Immediate ART reduced both AIDS-related and non-AIDS-related events

TasP

Because these results were so grand, the studies were stopped and immediate treatment was implemented right away. The new guideline was that ART should be applied for all adults that tested positive for HIV → TasP (test and treat). Advantages of TasP are:

• Nearly normal life span if ART is initiated early enough
• May limit HIV reservoir formation → “functional cure”
• Reduction of TB incidence
  • TB remains the biggest killer among HIV-infected people
• Task-shifting is more feasible
• Better coverage among pregnant women
• Potential of HIV eradication → less new infections

Challenges of TasP are:

• Increasing testing rates
• Expanding number of people eligible for ART → more resources are necessary
• Adherence and retention in care

As of 2020, the implementation of ART recommendation is very good.

Firstline drugs

WHO recommended firstline drugs:

1. 2003: AZT/3TC/EFZ or NVP
2. 2010: AZT or TDF + 3TC or FTC + EFV or NVP
3. 2013: TDF + 3TC or FTC + EFV
4. 2018: TDF/3TC or FTC/DTG

The recommended drugs changed due to availability and side effects/toxicity. Sometimes recommended drugs are not available:

• Costs
• Policies
• Presence in countries

Stavudine

Stavudine was an ART which mainly was given in the 1990’s. In 2010 the WHO recommended to phase out stavudine. This because, although stavudine was cheap and effective, it was highly toxic. Due to unavailability of other drugs, sometimes stavudine is still given in African countries.

Public health approach

Now, DTG is recommended by the WHO as firstline treatment. This has to do with the public health approach in African countries, which contrasts with the individualized treatment which is given in Western countries. Problems of a Public health approach are:

• Standardized, simplified treatment regimens
• Population-based → “one fits all”
• Few lab tests
• Decision making is guided by clinical monitoring, sometimes immunological monitoring and very rarely virological monitoring

90-90-90

90-90-90 was a target for 2020:

• 90% of all living with HIV will know their HIV status
  • Was 81% in 2019
• 90% of all living with HIV will receive ART
  • Was 67% in 2019
• 90% of all receiving ART will have viral suppression
  • Was 59% in 2019

In 2020, the numbers in Eastern and Southern Africa were respectively 89%, 77% and 70%. Thus, the 90-90-90 target was not met. For Western and Central Africa, the numbers were 77%, 73% and 59%. The target for 2030 is 95-95-95.

Achieving virological suppression

Reasons for not achieving virological suppression are:

• Adherence to treatment
  • Reasons for non-adherence are side effects and social factors
• Drug resistance

Other methods of HIV control

• PrEP
• PEP
• Voluntary male circumcision for HIV prevention
  • Makes it harder for the virus to infect
• Gels
  • Have antiretrovirals in them
• Rings
  • The same concept as the Nuvaring
  • Have antiretrovirals on them
  • A nice option if women are not in the position to negotiate about safe sex
• Prevention of mother-to-child transmission
  • HIV positive mothers are given ART during their pregnancy
  • Very effective in prevention transmission to the child

Conclusions

• Access to ART in Africa has increased exponentially since the beginning of this millennium
• The public health approach has made it possible to provide ART to millions of people in developing countries with limited resources
• Most recent HIV guidelines recommend ART for all people living with HIV, as studies show improved health outcomes for HIV at all stages

HIV drug resistance in Africa

There is a nearing crisis in the fight against HIV in Africa → more and more patients are becoming resistant to ART. These patients have to take much more expensive medication, which isn’t always available and is unaffordable. In Uganda, HIV drug resistance is very high (>10%). This is mainly due to the reason that Uganda started ART treatment much earlier than in nearby regions.

Developing HIV drug resistance:

1. When somebody isn’t adherent to ART, the viral load starts to increase again
2. HIV starts copying itself more frequently → mutated forms resistant to ART are formed
3. Resistant forms survive despite treatment

There are 2 types of resistance:

• Acquired resistance: resistance that developed in patients taking ART
  • Patients at first have a good response to ART, but later respond poorly
  • It can be hard for children to consistently take HIV medication due to stigma, the pills being large and tasting strange
• Pretreatment drug resistance: patients who got the resistant virus from somebody else
  • Patients have a poor response to ART from the start
  • 1 in 5 of the babies born in Africa is born with a resistant HIV virus
  • Inconsistent treatment can further increase this resistance

New challenges for people living with HIV in Africa

Studies have shown that despite effective ART, people living with HIV have a higher rate of non-AIDS related morbidity and mortality compared to the general population. This may be do to HIV-induced residual immune activation, despite ART. In this case, the viral load of people treated with ART still is (slightly) high → persistent inflammation and immune activation. This can be due to:

• Residual HIV replication
• Antiretroviral drugs
• Chronic coinfections
• Bacterial translocation
  1. There are less immune cells that can clear pathogenic bacteria
  2. Loss of intestinal integrity and enterocyte apoptosis
  3. The pathogenic bacteria spread → bacterial translocation
• Established vascular damage
  • Plaques causing inflammation and vice versa
• Homeostatic drive

Especially in Africa, residual immune activation or dysfunction is greatly exacerbated, because of:

• Advanced pre-cART immunodeficiency
• Highly prevalent chronic co-infections
  • Hepatitis B, TB, etc.
• Faster disease progression in HIV-1 subtype C and D infections
• Late start with ART medication

The impact of COVID-19 on people living with HIV in Africa

COVID-19 has the following impact on HIV control:

• Interruption of treatment
• Interruption of HIV testing
• People living with HIV are more likely to die of COVID-19

These changes are partly due to lockdowns and fear of being infected by COVID-19. The effects of these changes on HIV control in the African region are yet unknown. Moreover, the percentage of the total population that has received at least 1 COVID-19 vaccine dose in Africa is very low, compared to other countries.

The Constant Gardener

Preparation

Pharmaceutical industry and academic medical researchers → bring up issues which are most relevant for them in relation to:

• Safety
  • Dangerous materials
  • Lab safety hazards
  • Safety of new medication
• Costs
  • Ideal economic market seldomly exists in health care
  • Prices of treatments for rare diseases
  • Price secrecy and discrimination
  • Revenues for patent holders
  • Prices relative to research costs
  • Prices of older drugs
• Reputation
  • Past scandals
  • Heavy fines for big companies guilty of unethical practices
  • Bad reputation leads to difficulty in obtaining clinical trial subjects, high-profile drug withdrawals and an inability to produce and sell due to manufacturing halts
• Time
  • Too little time
  • High time pressure due to high demand
  • Research/medical practices/diagnostic methods taking too much time
• Marketing issues, regulations, position of competitors
  • Reduced demand for prescription medicine
  • Growing competition from generic pharmaceuticals
  • Pharmaceutical fraud
  • Rising consumer expectations and difficulties managing brand health
  • Data breaches and other cybersecurity threats
  • Supply chain disruptions
  • Increasing complexity of regulations

Road Traffic Injuries

Key facts

• Approximately 1,3 million people die each year as a result of road traffic crashes
• The United Nations General Assembly has set an ambitious target of halving the global number of deaths and injuries from road traffic crashes by 2030 (A/RES/74/299)
• Road traffic crashes cost most countries 3% of their gross domestic product
• More than half of all road traffic deaths are among vulnerable road users: pedestrians, cyclists, and motorcyclists
• 93% of the world's fatalities on the roads occur in LMIC, even though these countries have approximately 60% of the world's vehicles
• Road traffic injuries are the leading cause of death for children and young adults aged 5-29 years

Road traffic injuries have a specifically high impact on the burden of diseases in LMIC because of the increase of motorization and urbanization in a setting without much public health infrastructures and safety measures (no seatbelts, no alcohol limitations, etc.).

Risk

People at risk for traffic injuries:

• Low socioeconomic status
• Children and young adults
• Men

Risk factors for traffic injuries:

• Speeding
• Driving under influence
• Nonuse of motorcycle helmets, seatbelts and child restraints
• Distracted driving
• Unsafe road and infrastructure
• Unsafe vehicles
• Inadequate post-crash care
• Inadequate law enforcement of traffic laws

Prevention

Possible ways to prevent road traffic injuries are:

• Designing safer infrastructure
• Incorporating road-safety features into land-use and transport planning
• Improving the safety of vehicles
• Improving post-crash care for victims of road crashes
• Setting and enforcing laws
• Raising public awareness
  
   

RC Paediatrics in LMIC

Premature death

Health determinants contributing to premature death (<70 years) from high to low are:

1. Behavioral patterns
2. Genetic predisposition
3. Social circumstances
4. Health care
5. Environmental exposure

The proportional contribution of healthcare to premature death is 10%. In developed countries, there are many actors in health and health care such as the GGD, RIVM, Medicine Evaluation Board, etc.

Causes

Most of under five deaths are caused by infectious diseases. 35% of all under-five deaths are associated with undernutrition → negatively affects all the other causes of death. In the last 10 years, there have been some changes in the causes of deaths among children:

• Neonatal deaths: the proportion has increased
  • Premature deaths/undernutrition
    • Is hard to distinguish
  • Intrapartum complications
  • Tetanus, congenital anomalies, etc.
• Under 5 deaths: the proportion has decreased
  • Acute respiratory infections
  • Malaria
  • Diarrhea
  • Measles

Neonatal deaths can be decreased by arranging screening during pregnancies, creating safe delivery environments, making people available who can care for the baby when it’s born and specialized care when necessary. Kangaroo care (skin-to-skin contact with the baby) is a simple intervention that can save lives. Thus, there have been improvements, but there is still a long way to go.

IMCI

In the Netherlands, there are 140/10.000 skilled health workers, while in Malawi, this is only 3,5/10.000. The principle of IMCI (integrated management of childhood illness) is to deliver high-quality treatment with limited resources for sick children in LMIC. IMCI doesn’t only look at curative care to be taken by health care workers, but also at prevention on the part of families and communities. The objectives of the strategy are to reduce death and the frequency and severity of illness and disability, and to contribute to improved growth and development.

IMCI recently has been redubbed to IMNCI → integrated management of neonatal and childhood illness.

Objectives

IMCI wants to reach the following objectives with task shifting:

• Reduce death
• Reduce frequency and severity of illness and disability
• Improve growth and development

IMCI promotes growth, prevents disease and responds to sickness.

Diagnostic difficulties

For many sick small children, a single diagnosis may not be apparent or appropriate:

• Cough and/or fast breathing → pneumonia, severe anemia, p. falciparum malaria
• Lethargy or unconsciousness → cerebral malaria, meningitis, severe dehydration, very severe pneumonia
• Measles rash → pneumonia, diarrhea, ear infection
• Very sick young infant → pneumonia, meningitis, sepsis

Emergency Triage Assessment and Treatment

Emergency Triage Assessment and Treatment (ETAT) is an examination for general danger signs:

• Convulsions
• Lethargy/unconsciousness
• Inability to drink/breastfeed
• Vomiting

Looking at these danger signs is a way to triage → to determine which child needs treatment first.

Assessment

The IMCI sick child age 2 months-5 years assessment goes as follows:

1. General danger signs: in case any general danger sign is present, the child needs urgent attention
   • Convulsions
   • Lethargy/unconsciousness
   • Inability to drink/breastfeed
   • Vomiting
2. Asses main symptoms
   • Cough/difficulty breathing
   • Diarrhea
   • Fever
   • Ear problems
3. Asses nutrition and growth

Dependent on the severity, arrangements are made:

• Urgent referral
• Treatment at an outpatient health facility
• Home management

Diarrhea

Case

A 4-year-old girl is vomiting and has diarrhea. According to IMCI, the following should be done:

• Ask about
  • Start complaints
  • Frequency vomiting
  • Frequency diarrhea
  • Bloody stools
  • Urine production
  • Presence of tears
• Physical examination
  • Lethargy
  • Sunken eyes
  • Ability to drink
  • Skin pinch of the abdomen → if it takes more than 1-2 seconds to recoil, there is dehydration

Next, dehydration should be classified:

• Severe dehydration: 2 of the following signs
  • Lethargic or unconscious
  • Sunken eyes
  • Not able to drink or drinking poorly
  • Skin pinch goes back very slowly
• Some dehydration: 2 of the following signs
  • Restless and irritable
  • Sunken eyes
  • Drinks eagerly/is thirsty
  • Skin pinch goes back slowly
• No dehydration: not enough signs to classify as some or severe dehydration

Treatment

Severe dehydration should be treated quickly. The therapy depends on what resources are available:

1. Can you give IV fluids immediately?
2. Is IV treatment available nearby?
   • Refer urgently, try ORS during the trip
3. Are you trained to use a nasogastric tube?
   • ORS (oral rehydration solution) by tube/mouth
     • Water with a bit of salt and glucose
   • 20 ml/kg/h for 6 hours
4. Can the child drink?
   • ORS by tube/mouth
   • 20 ml/kg/h for 6 hours
5. After 4 hours, reassess and select a plan to continue

In case of some dehydration:

1. Show the mother how to give ORS
   • Frequent small sips
   • If the child vomits, wait 10 minutes
   • Continue breastfeeding
2. After 4 hours
   • Reassess
   • Select a plan to continue
   • Begin feeding

In case of no dehydration, diarrhea should be treated at home. 3 rules should be followed:

• Give extra fluid
• Continue feeding
• When to return
  • Drinking poorly
  • Becoming more ill
  • Blood in stool

Clinical division

The most common causes of diarrhea are:

• Acute gastroenteritis
  • Clinic
    • Most common
    • Watery diarrhea
    • Dehydration
    • Good prognosis in case or ORS early nutrition
  • Common pathogens
    • Rotavirus
    • E. Coli
    • Shigella
    • Campylobacter
    • Salmonella
    • Cholera
    • Amoebiasis
    • Giardiasis
  • Underlying causes
    • Poor water supply
    • Poor sanitation
    • Poor hygiene
    • Poor education
    • Overcrowding
    • Poverty
• Dysentery
  • Clinic
    • Mucus and blood in stool
    • Ulcerative invasion in colon
    • Risk of systemic spread
• Persistent diarrhea
  • Clinic
    • >14 days
    • Severe intestinal damage
    • Difficult to treat → significant mortality
    • Associated with measles, TB and HIV

Management

Principles of management of diarrhea are:

• Prevention of dehydration
• Treatment of dehydration
• Prevention of undernutrition

ORS

ORS is:

• Effect based on glucose-Na coupled transport in the small intestine
• Rice and cereal based on the volume of diarrhea and duration of illness
• Cereal based ORS has a better effect on the nutritional status

Malnourished patients need less Na and more K → ReSoMal. In case there is a zinc deficiency, zinc is a great solution.

Antibiotics

Generally, antibiotics should not be used to treat diarrhea. Exceptions are cholera, shigella, giardia and entamoeba histolytica.

Prevention

Diarrhea can be prevented with:

• Improved nutrition
  • Uninterrupted breastfeeding
• Use of safe water
• Good personal and domestic hygiene
• Rotavirus vaccine

Respiratory problems

Case

A 6 month old baby has difficulty breathing. The IMCI guidelines are:

• Respiratory rate
  • Cut off for fast breathing
    • Age 2-12 months: >50 breaths/min
    • Age 12 months-5 years: >40 breaths/min
• Lower chest wall indrawing
• Stridor

Next, the cough/difficulty breathing is classified:

• Severe pneumonia/very severe disease
  • Any general danger sign
  • Chest indrawing
  • Stridor in calm child
• Pneumonia
  • Fast breathing
• No pneumonia → cough or cold
  • No signs of pneumonia or very severe disease

Treatment

Treatment options for respiratory problems are:

• Severe pneumonia or very severe disease
  • Bezulpenicillin IM/IV
  • Referral
• Pneumonia
  • Co-trimoxazol
  • Amoxicillin
• No pneumonia
  • Relieve high fever
  • Clear secretions
  • Advise the mother

Clinical division

Common causes for pneumonia are:

• Neonates
  • Group B streptococcus
  • E. Coli
• Under fives
  • RSV
  • Parainfluenza
  • Influenza
  • Adenovirus
  • CMV
  • Streptococcus pneumonia
  • Haemophilius influenza
• School age
  • Mycoplasma
  • Streptococcus pneumonia

Prevention and control

• Education of families and health workers
• Birth spacing
  • Reduces overcrowding and malnutrition
• Breastfeeding
  • Reduces malnutrition and protects against respiratory disease
• Immunisation
  • Particularly measles and pertussis
• Improvement of housing conditions
  • Reduction of indoor air pollution

RC E-health

KNCV

KNCV is the largest international NGO exclusively dedicated to fighting TB. They have 115 years of experience in all aspects of TB care and prevention. KNCV is a multi-disciplinary organization that works worldwide, has regional and country offices and more than 60 dedicated staff members.

Dedication

Patients need to be very dedicated to adhere to their TB treatment:

• Treatment takes a minimum of 6 months
• Side-effects can be severe
• Improvement occurs after a month → patients think they can stop their treatment

Missing doses of medication during TB has serious negative effects:

• Patients are more likely to stop their treatment
• Patients can develop resistance to anti-TB drugs
• Patients are 5 times more likely to get TB again

DOT

The WHO developed the DOT (directly observed treatment) approach. This is a way to monitoring whether patients are taking their TB treatment. However, DOT is problematic and there are many challenges.

Challenges for patients are:

• Daily/weekly transport to the clinic leads to high costs and logistic issues
• Loss of income due to missing work for daily/weekly clinic visits
• Visiting a TB facility can increase stigma against a patient

Challenges for healthcare workers are:

• Heavy workload for directly observing a high number of patients
• Heavy workload in case of house visits to observe patients at home
• Not all patients require the same level of monitoring and support

COVID-19 also brought additional challenges. As COVID-19 spread around the world in 2020, health workers, testing machines, laboratories and health centers were diverted from existing diseases like TB to fight the new pandemic.

Digital health

Digital health in the patient pathway can support TB patients:

1. Mobile phones help healthcare workers to find patients
2. Social media channels promote and raise awareness on TB
3. Connected diagnostics instantly share lab results
4. Digital tools support clinical decision making and educate patients
5. Digital tools assist stock management and procurement of medicines
6. Digital innovations support medication adherence

Digital innovations to support medication adherence (DATs)

Benefits of DATs for people affected by TB are:

• A patient can decide where to take their medication
• A patient can be prompted by text message to take a certain action
• A patient receives individualized information about their treatment via text messages or voice recordings on their mobile phones

Benefits of DATs for health staff are:

• With the app, healthcare workers have access to real-time adherence information per patient
• The adherence platform can send healthcare workers automated alerts and reports about their patients, prompting actions
• Machine algorithms on the adherence platform help to automatically identify which patients need more attention/support

Technologies

There are 3 technologies that have been implemented in countries:

• 99DOTS
  1. Every time a pill is pushed out, a hidden number appears which the patient has to text to a free number
  2. The code becomes visible on a platform
  3. If the patient forgets to take the pill, he receives a message
  4. The information is presented to the patient when he comes to the clinic
• Smart pill box/evriMED
  1. A cardboard box with a module sends information about whether the patient has opened the box to a platform
• Video supported treatment (VOT)
  1. Video calls are made while patients take their medication
  2. The healthcare workers see the patients taking their pills

The idea is that these technologies create real-time monitoring and support.

Implementation challenges

DATs implementation challenges are:

• Technology gap between generations
• Data privacy
• Illiteracy
• Motivation

Ascent

The Adherence Support Coalition to End TB (ASCENT) generates evidence for digital adherence technology (DAT) use, establishes a global market for DAT products, and engages TB stakeholders at all levels.

Participating health facilities in the ASCENT project are in Ethiopia, Philippines, South Africa, Tanzania and Ukraine. ASCENT students do the following:

• Provide countries with information about whether and how to scale-up DAT technologies, including for whom do the DATs work and why?
• Several sub-studies will assess the how and why the intervention may work in patients receiving treatment for both DS- and DR-TB participants in order to translate the successes into routine TB country programs
• An effectiveness evaluation aims to answer the question, what is the impact on TB epidemiology from DAT?

RC Women, population and health

Cervical cancer

Cancer is the global threat to human development, especially in LMIC. Every 2 minutes, a woman dies from cervical cancer, of which 85% live in LMIC. Cervical cancer affects the society in many ways:

• Macro-economic
  • Increased health expenditure
  • Increased labor and productivity losses
• Micro-economic
  • Impact on women and their families
  • Much of women’s work is not associated with monetary transactions → not reflected in in macro-economic indicators

Human papilloma virus

Human papilloma virus is necessary in the development of cervical carcinoma → detectable in 99,7% of all cervical cancers. It is a common infection → 80% of women are infected, but only a small part of the infections turn into cancer. It is sexually transmitted. The squamocolumnar junction is susceptible to the HPV virus. It becomes a chronic infection when it isn’t eradicated by the body. Eventually it turns into pre-malignant lesions. In 10-15 years, it develops into an invasive carcinoma.

Causes

Causes of cervical cancer are:

• HPV types and variants
• Host factors
  • Genetics
  • Immunological factors
• Hormonal factors
  • Long-term OC use
  • High parity
• Tobacco smoking
• HSV-2 and c. trachomatis

Prevention

Cervical cancer is preventable:

• Primary prevention: HPV vaccination
• Secondary prevention: screening
  • Detects early stages of cervical cancer
  • Early detection leads to effective treatment and better prognosis
  • Cost-effective
• Tertiary prevention: surgery of early carcinomas

Screening

Due to the 10-15 year lead time, cervical cancer is a “perfect” disease for screening.

Screening in the Western World is done with a cervical smear. A pathologist will investigate this smear using cytology. In case the smear is abnormal, colposcopy will be done. Treatment options are surgery, chemotherapy and radiotherapy.

Treatment of cervical cancer in LMIC is difficult and scarce. Most patients with cervical cancer die within a few months. Thus, prevention of development of cervical carcinoma by screening is the key. However, cervical cytology isn’t ideal in LMIC:

• Complex laboratory test
• Requires trained cyto-technicians for reading
• Pathologists are necessary
• Expensive
• Continuous monitoring is needed
• Follow-up of women is difficult
• Usually only available in larger cities

Screening alternatives are Visual Inspection with Aceto-Acid (VIA):

• Cheap
• Available everywhere
• Fits in approach

Maternal morbidity and mortality

Most teenage and unintended pregnancies occur in Sub-Saharan Africa. Skilled birth attendance is very important in LMIC → linked with the maternal mortality ratio, but also with education.

Maternal death

WHO: maternal death is the death of a woman while pregnant or within 42 weeks of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.

There are 2 ways to measure maternal mortality:

• Maternal mortality ratio: number of maternal deaths in a population in a certain period/number of live births occurring in the same period per 100.000
• Maternal mortality rate: average annual number of maternal deaths in a population/average number of women of reproductive age (15-49)

Causes

There are direct and indirect causes of maternal death:

• Direct causes: dying as a result of the pregnancy
  • Haemorrhage
    • Post-partum haemorrhage is the biggest cause of maternal death
  • Hypertension
  • Sepsis
  • Abortion
• Indirect causes: when pregnancy worsens a disease
• Accidental causes: a woman that happens to be pregnant dying of an unrelated cause → not a maternal death

Mahmoud Fathalia: “Women are not dying because of diseases we cannot treat, they are dying because societies have yet to make the decision that their lives are worth saving.”

Three delay model

According to the three delay model, there are 3 phases which can lead to delay:

1. Decision to seek care
2. Identifying and reaching medical facility
3. Receipt of adequate and appropriate treatment

Whether these phases are reached, is dependent on socio-economic factors:

• Socioeconomic/cultural factors
• Accessibility of facilities
• Quality of care

Iceberg

Maternal mortality is the tip of the iceberg. Underneath lies severe maternal morbidity and mild maternal morbidity, which can also occur in developed countries.

Obstetric interventions

It is important to realize that obstetric interventions such as caesarean sections can also be the cause of maternal mortality. This is very dependent on the health facility where the intervention takes place.

RC Causes of severe anemia in African children

Definition

Anemia is defined as a haemoglobin concentration below a specified cut-off point. That cut-off point depends on the age, gender, physiological status, smoking habits and the altitude at which the population being assessed lives.

Symptoms

Clinical features of anemia can be moderate to severe:

• Fatigue
• Loss of stamina
• Breathlessness
• Tachycardia

Prevalence

Anemia is a global problem:

• 24% of all children <5 years have anemia
• 40% of all pregnant women have anemia

It mostly is present in Sub-Saharan Africa → 60-80% of the population has anemia.

Causes

Anemia can have different mechanistic causes:

• Blood loss
  • Acute (e.g. accidents)
  • Chronic (e.g. hookworms or schistosomiasis)
• Haemolysis
  • Infections (malaria, sepsis)
  • Hemoglobinopathies (SCD, Thalassemia, G6PD)
• Red Cell production failure (RCPF)
  • Chronic or repeated infections
    • Malaria, TB, salmonella, HIV, EBV, EMV, etc.
    • Host immune response to infection
    • Micronutrient deficiencies (iron)

Thus, infections keep on popping up in each of the categories.

Anemia has an increased risk in LMIC due to:

• Social-economic status
• Malnutrition
• Infections
• Genetics

Iron supplementation

Strangely, iron deficiency reduces the risk of anemia. This has led to controversies around preventive iron supplementation in children as a public health strategy. On the other side, ID leads to impaired physical and mental development. Therefore the WHO says: “Daily iron supplementation is recommended as a public health intervention in school-age children living in settings where anaemia is highly prevalent, for preventing ID and anaemia.”

Relationship between malaria and ID

In malaria-endemic areas, the provision of iron supplementation in infants and children should be done in conjunction with public health measures to prevent, diagnose and treat malaria.

Malaria and ID are important co-existing public health problems across sub-Saharan Africa, and their relationship is complex and incompletely understood. There appears to be an increased ID during malaria season. Also, interrupted malaria transmission is associated with reduced iron levels. People with sickle-cell traits are 30% less likely to have ID anemia, and also are less likely to get malaria.

Iron supplementation, via tablets or syrups and micronutrient powders, are the primary interventions to manage ID and anemia in children. However, there are long-standing concerns regarding the safety and efficacy of iron supplements in malaria-endemic countries, where they may predispose individuals to malaria and other infections and be poorly absorbed. New strategies are needed for the management of ID.

Pathways responsible for ID in malaria

Hemolysis and induction of inflammation causes malaria to lead to ID:

1. Hepcidin is upregulated by inflammation
2. Hepcidin inhibits duodenal iron absorption and macrophage iron recycling through degrading ferroportin

In short, a malaria infection upregulates hepcidin, resulting in hepcidin-mediated blocks in iron absorption.

Old age in a global village

Every person in every country in the world should have the opportunity to live a long and healthy life. Yet, the environments in which we live can favor health or be harmful to it. Environments are highly influential on our behavior and our exposure to health risks (for example air pollution, violence), our access to services (for example, health and social care) and the opportunities that ageing brings.  

The number and proportion of people aged 60 years and older in the population is increasing. In 2019, the number of people aged 60 years and older was 1 billion. This number will increase to 1.4 billion by 2030 and 2.1 billion by 2050. This increase is occurring at an unprecedented pace and will accelerate in coming decades, particularly in developing countries. 

This historically significant change in the global population requires adaptations to the way societies are structured across all sectors, for example in health and social care, transportation, housing and urban planning. Working to make the world more age friendly is an essential and urgent part of our changing demographics.

RC Global Mental Health

Common MNS

The most common MNS (mental, neurological and substance use) disorders are:

• Depression
• Bipolar disorder
• Schizophrenia
• Dementia
• Developmental disorders

According to the WHO, the percentage of people with mental disorders not receiving any treatment is 76-85%.

Global burden of disease

The contribution of MNS disorders to the global burden of disease in LMIC is 15% → 80% of the global burden of disease due to mental health is found in LMIC.  Mental illnesses are amongst the leading causes of disability worldwide and are the leading cause of death in young people → the DALY is high, particularly for people between 15-44 years. Depression is the mental disorder with the highest burden of disease and is 1,5-2x more prevalent in LMIC.

The state of mental health in LMIC is bad, there is a vicious cycle → poverty and poor education causes ill mental health and vice versa. Also, stigma and insufficient knowledge about mental illnesses form a major problem → people with mental illnesses often are treated badly.

Risk factors

Risk factors for mental health problems are:

• Access to drugs and alcohol
• Displacement
• Isolation and alienation
• Lack of education, transport and housing
• Neighborhood disorganization
• Peer rejection
• Poor nutrition
• Poverty
• Social disadvantage
• Etc.

Challenges

Challenges when combating MNS disorders in LMIC are:

• Stigma and discrimination
• No available treatment
  • Poor resources for medication
• Shortage of psychiatrists and mental professionals
• Poor quality of care for many of those who do receive treatment

Solutions

Mental disorders often are neglected → there is a tremendous shortage of money and medical professionals that can treat the diseases. Global mental health should have an integration in the whole public health approach.

mhGAP

A solution to raise capacity for mental health treatment is task shifting. The WHO Mental Health Gap Action Program (mhGAP) is a WHO program to scale up care for mental, neurological and substance use disorders. The initial focus was on improving care for mental disorders and epilepsy in non-specialist care settings.

SUNDAR

Prof. Vikram Patel suggests that a potential solution would be to train members of communities to give mental health interventions, empowering ordinary people to care for others:

• Interpersonal psychotherapy for depression using villagers
• Cognitive behavior therapy by maternal health workers for mothers who are depressed
• Psychosocial interventions by counsellors

This can be done using SUNDAR:

• Simplify the message
• UNpack the treatment
• Deliver it where people are
• Affordable and available human resources
• Reallocation of specialists to train and supervise

The Movement for Global Mental health aims to improve services for people with mental disorders worldwide.

RC Pharmacy and fake drugs

WHO Essential Medicines List

The WHO Essential Medicines List shows the minimum needs for a basic health care system. The core list is selected by a WHO expert committee. This list contains the most efficacious, safe and cost-effective medicines for priority conditions. There also is a complementary list which contains less cost effective or special monitoring required medicines.

There is a separate list for adults and children. The current versions are the 21^stWHO Essential Medicines List (EML) and the 7^thWHO Essential Medicines List for Children (EMLc), updated in June 2019.

Progress

Thirty years ago, the concept of a national medicine policy was unknown in most countries. Over 100 countries have medicine policies in place or under development. These policies act as frameworks to advance pharmaceutical sector reforming.

Building blocks

The WHO essential Medicines List has 5 building blocks:

1. Selection and responsible use
2. Affordable prices and sustainable financing
3. Assured quality
4. Reliable and efficient supply chain
5. Policy and governance of systems

Access

More than 1/3 of the world’s population lack a regular access to essential medicines. In Africa less than 50% of the population have regular access.
 

Advantages

Advantages of the WHO Essential Medicines list:

• Rationalize the purchasing and distribution of medicines
• Cornerstone of national medicine policies
• Collect and make pricing information public
• Generic medicine has brought down the price

Goals

Medicine princes are not static → high medicine prices are a growing challenge for health systems. Therefore, the goal of the WHO Essential Medicine list is promoting affordable and fair pricing and effective financing

2019 update

In 2019, several treatments were added to the list:

• 12 cancer medicines
• New oral anti-coagulants
• Biologicals for chronic inflammatory diseases
• Heat stable carbetocin
  • Similar to oxytocin, but does not need refrigeration

WHO Essential Diagnostics List

In 2018, the first essential diagnostics list was published. The WHO Essential Diagnostics List is a catalogue of the tests needed to diagnose the most common conditions as well as a number of global priority diseases. It contains 113 products.  The list gives diagnostic advice for primary care and for more advanced laboratories.

Good pharmacy practice

2 things are essential for good pharmacy practice:

• Good storage practice
  • Temperature, refrigerator, etc.
• Good distribution practice
  • Stock keeping

Drug supply in LMIC

Issues related to drug supply in LMIC:

• Affordability
• Availability
• Safety
• Effective drugs
• Storage and transport
• Paediatric formulations

Substandard and falsified medical products

Medicine quality is an urgent issue, consequences can be fatal. Problems with medicine may appear local, but are shaped by complex global dynamics, such as international supply chains. In 2020:

• 2 billion people have no access to basic health care, including essential medicine
• 2,5 billion people risk being tipped into abject poverty by healthcare costs
• Limited access to good quality, safe and effective medical products creates a vacuum filled by substandard and falsified medical products

The market for medicine around the world is growing. This growth mostly occurs in LMIC. The increase isn’t only in safe medicine, but also in substandard and falsified medicine.

Falsified medical products

Falsified medical products are medical products that deliberately misrepresent their identity, composition or source. They may:

• Contain no active ingredient
• Contain the wrong active ingredient
• Contain the wrong amount of the active ingredient
• Have passed the expiry date and be repackaged
• Be a very different medicine
• Have packaging designed to deceive

Substandard medical products

Substandard medical products are also called “out of specification”. These are authorized medical products that fail to meet either their quality standards or their specifications, or both:

• Produced by unregistered manufacturers
• Do not meet approved quality standards
• May be poorly packaged
• May be poorly transported and storage

FS medical products are often produced in very poor and unhygienic conditions by unqualified personnel, contain unknown impurities and are sometimes contaminated with bacteria.

Consequences

Consequences of FS medicine are:

• Threat to health
• Promote drug resistant infections
  • Resistance against Artemisinin started in areas where between 38-90% of antimalarials were FS
• Waste of money from families and health systems
• Undermine confidence in health workers and systems
• Create distrust about effects of vaccines and medicine
• Income for criminals

GSMS

The Global Surveillance and Monitoring System (GSMS) aims to:

• Improve the quality of reporting of FS medicine
• Ensure that data are carefully collected and analyzed
• Ensure that data are used to influence policies and procedures and protect health

The GSMS was launched in 2013. It is a voluntary process with 4 steps:

1. Reports of suspected SF medical products to the regional medicines regulatory authority (NMRA)
2. Assessment and response by the NMRA
   • The NMRA detects cases and reports them
3. NMRA focal point searches and reports to WHO’s surveillance and monitoring system database
4. Immediate technical assistance and alerts are issued by the WHO when requested and appropriate

Detection and prevalence

Anti-malarials and antibiotics are amongst the most commonly reported FS medical products. An estimated 1 in 10 medical products in LMIC is substandard or falsified. However, the more one looks, the more one finds. FS medical products are present all over the world, however they are most likely to reach patients in situations where there is constrained access to quality and safe medical products, poor governance and weak technical capacity.

FS medical products are by their very nature difficult to detect:

• Are often designed to appear identical to the genuine product
• Producers and healthcare workers may be reluctant to report an FS medical product
• There also are jurisdictional complexities → it is difficult to determine where in the production chain the product becomes FS
  • Often, the ones who sell the product aren’t aware it’s falsified

Field surveys are a way to find FS products, but are few and expensive:

• Ideally, they are random samples for representative cross-section of outlets
• Test samples for active ingredients → bioavailability

Some studies are available:

• Several studies in Asian and African countries into anti-malarials
  • In high-income countries, random sampling is not efficient
• Some risk-based surveillance from medicine bought over the internet
• Some attempts by INTERPOL and national authorities

To deal with FS medicine, one needs to take into account political and economic drivers at multiple levels.

Causes

The root cause of FS medicine is making money:

• Producers using poor quality ingredients
• Distributers using cheap storage facilities
• Pharmacists changing expiration dates
• Criminals selling fake medicine

Root causes leading to FS medicine are:

• Constrained access to affordable, safe and quality medical products
  • If medicines are too expensive, people buy from unlicensed suppliers
  • Disease outbreak leading to a rapid increase in demand for medicine, test kits and PPE
  • Disruption of distribution, poor infrastructure, war, disasters
  • Unethical practices influence demand
• Lack of good governance
  • Overstretched regulatory networks
  • Lack of transparency and accountability
  • No establishing reporting culture
  • Weak responses to falsification
• Weak technical capacity
  • Substandard medicine is a combination of technical deficit and poor oversight
  • Rapid expansion of globalized supply chains and demand further stretch technical capacity

Counterfeit medicines

There are different organizations that deal with SF medicines and give drug alerts:

• FDA in the USA
• Falsified medicine directive (FMD) in Europe
  • Every package has a unique number
  • Every package is checked in a national drug database

RC LMIC and patents for drugs and vaccines

Technology development process

In the development process of technology, several things need to be done to protect your knowledge and results:

• Patent rights
• Copyrights
• Design rights
• Trademarks
• Trade secrets

Only after this, an impact can be made.

Patent

A patent is a quid pro quo between the government and the inventor:

• Complete disclosure of the invention → by the inventor
• Exclusive right for 20 year to exclude others to make, use, offer, sell or import the invention → by the government

This promotes the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries.

License

A license is a permission to use an invention.

Vaccines

Most doses of vaccines are bought by developed countries, leaving less or poorer options for LMIC.