INFECTIOUS DISEASES AND GLOBAL HEALTH
HIV AND AIDS INTRODUCTION
Short summary viral replication of HIV: HIV fuses with the surface of
the host cell. The viral capsid enters the cell, disintegrates and the HIV
protein called reverse transcriptase transcribes the viral RNA into DNA.
The viral DNA is transported across the nucleus, where the HIV protein
integrase integrates the HIV DNA into the host’s DNA. The host’s
normal transcription machinery transcribes HIV DNA into multiple
copies of new HIV RNA. Some of this RNA becomes the genome of a
new virus, while the cell uses other copies of the RNA to make new
HIV proteins. The new viral RNA and HIV proteins move to the surface
of the cell, where a new, immature HIV forms. Finally, the virus is
released from the cell, and the HIV protein called protease cleaves
newly synthesized polyproteins to create a mature infectious virus.
HIV and DC4 cells
- HIV infects and destroys CD4 cells
- Only 1% of these cells are present in the blood, majority in lymph nodes (mostly gut)
- Loss of CD4+ memory T-cells decreases ‘cellular immunity’ and predisposes to certain infection and
malignancies
- CD4 also on other cells: megakaryocytes HIV can cause low blood platelets, glial cells in the brain
HIV can lead to dementia
- ‘viral setpoint’ and CD4-cell loss: when viral load is low or going down, CD4 counts will be higher or
going up
CLINICAL PRESENTATION
Primary HIV
- Usually 2-4 weeks after infection
- Flu-like syndrome: fever, lymphadenopathy, pharyngitis, rash etc; sometimes severe:
meningoencephalitis
- Laboratory results
o Mononucleosis (atypical lymphocytes)
o High plasma HIV-RNA (106 copies/ml)
o Incomplete antibody response
o Temporary drop in CD4
If not treated, HIV (human immunodeficiency virus) can lead to AIDS (acquired immunodeficiency disease) =
an HIV infection with either a CD4+ T cell count below 200 cells per µL or the occurrence of specific diseases
associated with HIV infection (opportunistic infections):
- Fungi; pneumocystis, cryptococcus, candida, histoplasmosis
- Parasites: toxoplasmosis (cerebral), cryptosporidium, leishmania, microspore.
- Bacteria: mycobacterium, tuberculosis, atypical mycobacteria, salmonella
- Viruses: HSV, CMV retinitis (blindness), VZV, JC
- Malignancies: Kaposi sarcoma (HHV-8), lymphoma (EBV), others
Besides infections and AIDS:
1
, - Cardiovascular disease
- ‘normal’ malignancies
- Allergy and autoimmune disease more rapid ‘aging’ of many organ systems (liver, kidney, lungs, brain,
bone, …)
- Patients who live longer: chronic disease
Summary clinical course, natural course of disease after infection is variable:
- Acute HIV (viral syndrome)
- Many patients with asymptomatic infection
- (opportunistic) infection & malignancies (AIDS)
- ‘chronic HIV’ – organ dysfunction
HIV TREATMENT
Anti-retroviral treatment (ART)
- Entry blockers
- Reverse transcriptase inhibitors
- Integrase inhibitors
- Protease inhibitors
ART given for multiple reasons (symptom reduction, transmission prevention, slowing down of chronic HIV,…)
and is extremely effective. However, there can be some side effects such as Steven-Johnson syndrome (SJS) and
mitochondrial toxicity:
- Nucleoside RT inhibitors (NRTIs)
- Phosphorylation intracellularly
- Also inhibition of gamma-polymerase (replication mtDNA)
- Affects respiratory chain: less ATP, effect on fatty acid metabolism (accumulation triglycerides), less
DNA synthesis
- Time and concentration dependent (esp. older drugs)
- Lethal if unrecognised
- Not seen with newer drugs!
Monitoring HIV treatment: plasma HIV RNA (viral load) to assess level of HIV viremia and CD4+ T lymphocyte
cell count (or CD4 count) to assess immune function.
HIV indicator condition with undiagnosed HIV = STDs, malignant lymphoma, anal cancer, Herpes Zoster,
Hepatitis B or C, …
HIV IN THE NETHERLANDS
- Becoming a chronic disease
- Higher CD4 at time of diagnosis
- Very effective treatment, few deaths
- More non-communicable co-morbidity
- PreP: fewer new infections
Many other parts of the world: too little progress in control, large gaps in ‘cascade of care’, AIDS/opportunistic
infections/high mortality, stigma/social issues/dwindling investments etc
DISEASE HETEROGENEITY: IDENTIFYING CAUSES ALONG THE PATIENT JOURNEY
2
,While disease may have established typical presentation, in daily practice presentation may be (very)
heterogenous ; at different phases along patient trajectory, for different aspects of disease presentation: onset,
symptoms, natural course, treatment response.
- Heterogeneity caused by: disease characteristics itself, patient characteristics, care characteristics,
wider context
Relevance of diagnosis: a diagnosis informs about prognosis (natural course), e.g. life expectancy, future health,
future functioning and well-being, … a diagnosis informs how treatment will change the natural course. (also
important for epidemic conditions)
Diseases show heterogeneity in…
- Onset; why one person gets a disease/diagnosis and why another doesn’t
- Symptoms
- Natural progression
- Treatment response and outcomes
Depends: personal characteristics, care characteristics
- E.g. Dementia
o Significant cognitive decline from previous level of performance in one or more domains
o Interference with everyday activities
o Stages: mild cognitive impairment (MCI), dementia
- E.g. HIV associated neurocognitive disorders (HAND)
o The presence of neurocognitive deficits in HIV-infected individuals without alternative
explanation other than HIV infection
o Stages: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND),
HIV-associated dementia (HAD)
How to study heterogeneity? Identify where the heterogeneity occurs;
Conclusion
- While disease may have established typical presentation, in daily practice disease presentation may be
(very) heterogenous
o At different phases along patient trajectory
o For different aspects of disease presentation: onset, symptoms, natural course, treatment
response
- Heterogeneity can be cause by
o Disease characteristics itself
o Patients characteristics
o Care characteristics
3
, o Wider contexts
VARIATION IN QUALITY OF PROFESSIONAL CARE: HIV AS AN EXAMPLE
Central question in quality of care research: how can we achieve that, in daily practice, patients receive the
best available prevention, diagnosis and treatment of their health problems?
- What is appropriate care
- Is appropriate care provided
- What are the determinants
- How to improve care for patients, what are the conditions for sustainable improvement?
Improvement interventions are morelikely to be successful if determinants that influence (help/hinder)
appropriate care inform the choice of intervention.
In conclusion
- Large variation in quality of care between organizations and professionals
- This variation can be explained by many determinants
- To successfully influence variation, we need tailored interventions
HIV – VIROLOGY AND ANTIRETROVIRAL THERAPY
RETROVIRUSES – A HISTORICAL PERSPECTIVE
Transformation of cells by a virus was associated with integration of viral DNA in the host genome > to great
surprise, these tumour viruses were found to have RNA genomes, how could viruses transform cells?
Reverse transcriptase discovery:
- Enzyme that counters the central dogma (DNA > RNA > protein) reverses the flow of genetic
information
- Temin: RNA viruses must convert their genetic material from RNA to DNA that is subsequently
integrated in the host DNA
- Baltimore: enzyme that converts RNA to DNA must be carried along in the viral particle, as no such
enzymes exist in eukaryotic host cells
HIV – STRUCTURE AND CLASSIFICATION
Baltimore classification
- Class VI: ssRNA (+/) retrovirus: make ssRNA (+) genome by transcription of (-) strand of dsDNA
- Single stranded, positive sense (+) RNA genomes
- Cytoplasmic (+) strand RNA viruses directly translate the incoming viral RNA
- Retroviruses use the incoming (+) strand RNA to create a DNA intermediate
4
HIV AND AIDS INTRODUCTION
Short summary viral replication of HIV: HIV fuses with the surface of
the host cell. The viral capsid enters the cell, disintegrates and the HIV
protein called reverse transcriptase transcribes the viral RNA into DNA.
The viral DNA is transported across the nucleus, where the HIV protein
integrase integrates the HIV DNA into the host’s DNA. The host’s
normal transcription machinery transcribes HIV DNA into multiple
copies of new HIV RNA. Some of this RNA becomes the genome of a
new virus, while the cell uses other copies of the RNA to make new
HIV proteins. The new viral RNA and HIV proteins move to the surface
of the cell, where a new, immature HIV forms. Finally, the virus is
released from the cell, and the HIV protein called protease cleaves
newly synthesized polyproteins to create a mature infectious virus.
HIV and DC4 cells
- HIV infects and destroys CD4 cells
- Only 1% of these cells are present in the blood, majority in lymph nodes (mostly gut)
- Loss of CD4+ memory T-cells decreases ‘cellular immunity’ and predisposes to certain infection and
malignancies
- CD4 also on other cells: megakaryocytes HIV can cause low blood platelets, glial cells in the brain
HIV can lead to dementia
- ‘viral setpoint’ and CD4-cell loss: when viral load is low or going down, CD4 counts will be higher or
going up
CLINICAL PRESENTATION
Primary HIV
- Usually 2-4 weeks after infection
- Flu-like syndrome: fever, lymphadenopathy, pharyngitis, rash etc; sometimes severe:
meningoencephalitis
- Laboratory results
o Mononucleosis (atypical lymphocytes)
o High plasma HIV-RNA (106 copies/ml)
o Incomplete antibody response
o Temporary drop in CD4
If not treated, HIV (human immunodeficiency virus) can lead to AIDS (acquired immunodeficiency disease) =
an HIV infection with either a CD4+ T cell count below 200 cells per µL or the occurrence of specific diseases
associated with HIV infection (opportunistic infections):
- Fungi; pneumocystis, cryptococcus, candida, histoplasmosis
- Parasites: toxoplasmosis (cerebral), cryptosporidium, leishmania, microspore.
- Bacteria: mycobacterium, tuberculosis, atypical mycobacteria, salmonella
- Viruses: HSV, CMV retinitis (blindness), VZV, JC
- Malignancies: Kaposi sarcoma (HHV-8), lymphoma (EBV), others
Besides infections and AIDS:
1
, - Cardiovascular disease
- ‘normal’ malignancies
- Allergy and autoimmune disease more rapid ‘aging’ of many organ systems (liver, kidney, lungs, brain,
bone, …)
- Patients who live longer: chronic disease
Summary clinical course, natural course of disease after infection is variable:
- Acute HIV (viral syndrome)
- Many patients with asymptomatic infection
- (opportunistic) infection & malignancies (AIDS)
- ‘chronic HIV’ – organ dysfunction
HIV TREATMENT
Anti-retroviral treatment (ART)
- Entry blockers
- Reverse transcriptase inhibitors
- Integrase inhibitors
- Protease inhibitors
ART given for multiple reasons (symptom reduction, transmission prevention, slowing down of chronic HIV,…)
and is extremely effective. However, there can be some side effects such as Steven-Johnson syndrome (SJS) and
mitochondrial toxicity:
- Nucleoside RT inhibitors (NRTIs)
- Phosphorylation intracellularly
- Also inhibition of gamma-polymerase (replication mtDNA)
- Affects respiratory chain: less ATP, effect on fatty acid metabolism (accumulation triglycerides), less
DNA synthesis
- Time and concentration dependent (esp. older drugs)
- Lethal if unrecognised
- Not seen with newer drugs!
Monitoring HIV treatment: plasma HIV RNA (viral load) to assess level of HIV viremia and CD4+ T lymphocyte
cell count (or CD4 count) to assess immune function.
HIV indicator condition with undiagnosed HIV = STDs, malignant lymphoma, anal cancer, Herpes Zoster,
Hepatitis B or C, …
HIV IN THE NETHERLANDS
- Becoming a chronic disease
- Higher CD4 at time of diagnosis
- Very effective treatment, few deaths
- More non-communicable co-morbidity
- PreP: fewer new infections
Many other parts of the world: too little progress in control, large gaps in ‘cascade of care’, AIDS/opportunistic
infections/high mortality, stigma/social issues/dwindling investments etc
DISEASE HETEROGENEITY: IDENTIFYING CAUSES ALONG THE PATIENT JOURNEY
2
,While disease may have established typical presentation, in daily practice presentation may be (very)
heterogenous ; at different phases along patient trajectory, for different aspects of disease presentation: onset,
symptoms, natural course, treatment response.
- Heterogeneity caused by: disease characteristics itself, patient characteristics, care characteristics,
wider context
Relevance of diagnosis: a diagnosis informs about prognosis (natural course), e.g. life expectancy, future health,
future functioning and well-being, … a diagnosis informs how treatment will change the natural course. (also
important for epidemic conditions)
Diseases show heterogeneity in…
- Onset; why one person gets a disease/diagnosis and why another doesn’t
- Symptoms
- Natural progression
- Treatment response and outcomes
Depends: personal characteristics, care characteristics
- E.g. Dementia
o Significant cognitive decline from previous level of performance in one or more domains
o Interference with everyday activities
o Stages: mild cognitive impairment (MCI), dementia
- E.g. HIV associated neurocognitive disorders (HAND)
o The presence of neurocognitive deficits in HIV-infected individuals without alternative
explanation other than HIV infection
o Stages: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND),
HIV-associated dementia (HAD)
How to study heterogeneity? Identify where the heterogeneity occurs;
Conclusion
- While disease may have established typical presentation, in daily practice disease presentation may be
(very) heterogenous
o At different phases along patient trajectory
o For different aspects of disease presentation: onset, symptoms, natural course, treatment
response
- Heterogeneity can be cause by
o Disease characteristics itself
o Patients characteristics
o Care characteristics
3
, o Wider contexts
VARIATION IN QUALITY OF PROFESSIONAL CARE: HIV AS AN EXAMPLE
Central question in quality of care research: how can we achieve that, in daily practice, patients receive the
best available prevention, diagnosis and treatment of their health problems?
- What is appropriate care
- Is appropriate care provided
- What are the determinants
- How to improve care for patients, what are the conditions for sustainable improvement?
Improvement interventions are morelikely to be successful if determinants that influence (help/hinder)
appropriate care inform the choice of intervention.
In conclusion
- Large variation in quality of care between organizations and professionals
- This variation can be explained by many determinants
- To successfully influence variation, we need tailored interventions
HIV – VIROLOGY AND ANTIRETROVIRAL THERAPY
RETROVIRUSES – A HISTORICAL PERSPECTIVE
Transformation of cells by a virus was associated with integration of viral DNA in the host genome > to great
surprise, these tumour viruses were found to have RNA genomes, how could viruses transform cells?
Reverse transcriptase discovery:
- Enzyme that counters the central dogma (DNA > RNA > protein) reverses the flow of genetic
information
- Temin: RNA viruses must convert their genetic material from RNA to DNA that is subsequently
integrated in the host DNA
- Baltimore: enzyme that converts RNA to DNA must be carried along in the viral particle, as no such
enzymes exist in eukaryotic host cells
HIV – STRUCTURE AND CLASSIFICATION
Baltimore classification
- Class VI: ssRNA (+/) retrovirus: make ssRNA (+) genome by transcription of (-) strand of dsDNA
- Single stranded, positive sense (+) RNA genomes
- Cytoplasmic (+) strand RNA viruses directly translate the incoming viral RNA
- Retroviruses use the incoming (+) strand RNA to create a DNA intermediate
4
