Hepatitis is inflammation of the liver that is characterized by the presence of inflammatory cells in liver tissue. There are multiple causes of hepatitis including viral, chemical, autoimmune and metabolic. The main viruses that cause hepatitis are hepatitis A, B, C, D, and E viruses. Hepatitis A virus is transmitted through the fecal-oral route and causes an acute infection. Hepatitis B and C viruses are transmitted through blood and bodily fluids and can cause both acute and chronic infections. Hepatitis D virus only occurs in those already infected with hepatitis B. Prevention strategies include vaccination, harm reduction education, and screening of blood and organ donors.

1. HepatitisHepatitis
andand
HIVHIV
Duncan Whittaker BSc FIBMSDuncan Whittaker BSc FIBMS
Virology Department ManagerVirology Department Manager
Sheffield Teaching HospitalsSheffield Teaching Hospitals

2. HepatitisHepatitis
 What is HepatitisWhat is Hepatitis
 inflammation of the liverinflammation of the liver
 characterized by the presence ofcharacterized by the presence of
inflammatory cells in the tissue of the organinflammatory cells in the tissue of the organ..

3. HepatitisHepatitis
Normal liver FunctionNormal liver Function
 MetabolismMetabolism
 (protein, carbs, lipids)(protein, carbs, lipids)
 SynthesisSynthesis
 (Proteins, Coagulation factors)(Proteins, Coagulation factors)
 StorageStorage
 (Glycogen, Vitamins)(Glycogen, Vitamins)
 ProtectionProtection
 (Detoxification, phagocytosis)(Detoxification, phagocytosis)

4. What Causes HepatitisWhat Causes Hepatitis
ChemicalChemical
 AlcoholAlcohol
 DrugsDrugs
 Paracetamol, amoxycillin, antituberculosis medicines, minocyclineParacetamol, amoxycillin, antituberculosis medicines, minocycline
 Toxin effectToxin effect
 mushrooms, carbon tetrachloridemushrooms, carbon tetrachloride
InfectiousInfectious
 ViralViral
 FungalFungal
 ParasiticParasitic
 Toxoplasma, LeptospiraToxoplasma, Leptospira
 Bacterial infectionBacterial infection
 Q FeverQ Fever
Auto Immune diseaseAuto Immune disease
 A1H.A1H.
 Systemic Lupus Erythematosus (SLE)Systemic Lupus Erythematosus (SLE)
Metabolic DiseaseMetabolic Disease
Wilsons DiseaseWilsons Disease

5. HepatitisHepatitis
SymptomsSymptoms
 Jaundice,Jaundice,
 Dark urine, pale stools, “Yellow Eye”.Dark urine, pale stools, “Yellow Eye”.
 Nausea,Nausea,
 Arthralgia,Arthralgia,
 Rashes.Rashes.
 FeverFever
 Pain/Tenderness.Pain/Tenderness.

6. Liver DysfunctionLiver Dysfunction
JaundiceJaundice
 Accumulation of Bile productsAccumulation of Bile products
 Failure of Bilirubin metabolismFailure of Bilirubin metabolism
Abnormal Serum ProteinsAbnormal Serum Proteins
 Albumin, Gamma globulins, ALP.Albumin, Gamma globulins, ALP.
HepatitisHepatitis
 Immune response damages the Liver.Immune response damages the Liver.
 Cytotoxic effect on attached virions.Cytotoxic effect on attached virions.

7. Viral HepatitisViral Hepatitis
 The viruses causing Hepatitis are variedThe viruses causing Hepatitis are varied
and belong to different families.and belong to different families.
 The pathogenic effect varies significantly.The pathogenic effect varies significantly.
 Acute = Resolve after weeks or months.Acute = Resolve after weeks or months.
 Chronic = Months, years or for life.Chronic = Months, years or for life.

8. Viral HepatitisViral Hepatitis
 Hepatitis A Virus (HAV)Hepatitis A Virus (HAV)
 Hepatitis B Virus (HBV)Hepatitis B Virus (HBV)
 Hepatitis C Virus (HCV)Hepatitis C Virus (HCV)
 Hepatitis D Virus (delta HDV)Hepatitis D Virus (delta HDV)
 Hepatitis E Virus (HEV)Hepatitis E Virus (HEV)
 Hepatitis FHepatitis F
 Hepatitis G Virus (HGV)Hepatitis G Virus (HGV)
 Hepatitis H (SENV)Hepatitis H (SENV)
 Herpes VirusesHerpes Viruses
 Cytomegalovirus (CMV)Cytomegalovirus (CMV)
 Epstein Barr Virus (EBV)Epstein Barr Virus (EBV)
 FOFO
 BBBB
 BBBB
 BBBB
 FOFO
 FOFO
 BBBB
 BBBB
 BBBB

9. Hepatitis AHepatitis A
 HAV : PicornavirusHAV : Picornavirus
 Small round RNA virus of HeparnavirusSmall round RNA virus of Heparnavirus
family.family.
 Naked and sphericalNaked and spherical
 Faecal-oral, highly contagious.Faecal-oral, highly contagious.
 Acute infectionAcute infection
 Incubation period: Average 30 days (Range 15-50 days)
 Replication in GI tract & Shed in faeces. Can beReplication in GI tract & Shed in faeces. Can be
asymptomaticasymptomatic
 person-person, unhygenic living conditions.person-person, unhygenic living conditions.
 Virus shed before symptoms appear.Virus shed before symptoms appear.
 Short viraemic phase, ? Parenteral transmission.Short viraemic phase, ? Parenteral transmission.
 Global PrevalenceGlobal Prevalence

11. Hepatitis AHepatitis A
PathologyPathology
• Incubation time - 2- 6 weeksIncubation time - 2- 6 weeks
• Symptoms vary in severitySymptoms vary in severity
• Asymptomatic > Full hepatitisAsymptomatic > Full hepatitis
• Increased severity with AgeIncreased severity with Age
• More common in ChildrenMore common in Children
• Children = GI symptomsChildren = GI symptoms
• Adults = Fatigue, joint pain.Adults = Fatigue, joint pain.
• 3-4 week duration.3-4 week duration.
DiagnosisDiagnosis
 ImmunoassaysImmunoassays
 IgG and IgM.IgG and IgM.

12. HAVHAV

13. Hepatitis AHepatitis A
Prevention and ControlPrevention and Control
 VaccinationVaccination
 Passive immunisation – NormalPassive immunisation – Normal
Human Gamma globulin . Short termHuman Gamma globulin . Short term
immunity.immunity.
 Avoid exposure.Avoid exposure.
 Improved Hygene in endemic areasImproved Hygene in endemic areas
 No treatment availiable.No treatment availiable.

14. Hepatitis BHepatitis B
 HBV : HepadnavirusHBV : Hepadnavirus
 DS DNADS DNA
 Spherical with envelope.Spherical with envelope.
 Genotypes A-HGenotypes A-H
DiseaseDisease
 Acute and Chronic infection.Acute and Chronic infection.
 Rash/Joint pain prevalent in Acute.Rash/Joint pain prevalent in Acute.
 Usually Self Limiting - Carrier state rare in UK.Usually Self Limiting - Carrier state rare in UK.
EpidemiologyEpidemiology
 Global PrevelanceGlobal Prevelance
 Developed countries -IVDA and STDDeveloped countries -IVDA and STD
 Highest prevalence in Far East - PerenteralHighest prevalence in Far East - Perenteral

15. Hepatitis BHepatitis B
Symptoms and PrognosisSymptoms and Prognosis
 6-12 week incubation, can be asymptomatic in6-12 week incubation, can be asymptomatic in
acute infection.acute infection.
 Fulminent HepatitisFulminent Hepatitis
 Rare Complication in acute infection. Fatal.Rare Complication in acute infection. Fatal.
 Can lead to chronic infection.Can lead to chronic infection.
 Chronic Persistent Hepatitis – asymptomaticChronic Persistent Hepatitis – asymptomatic
 Chronic Active Hepatitis - symptomatic exacerbations ofChronic Active Hepatitis - symptomatic exacerbations of
hepatitishepatitis
 Risk of cirrhosis, Chronic Liver Disease andRisk of cirrhosis, Chronic Liver Disease and
Liver carcinoma.Liver carcinoma.

16. Hepatitis BHepatitis B
 EpidemiologyEpidemiology
 Global PrevalenceGlobal Prevalence
 Developed countries -IVDA and STDDeveloped countries -IVDA and STD
 Highest prevalence in Far East - PerenteralHighest prevalence in Far East - Perenteral
 >350 million chronic carriers world wide.>350 million chronic carriers world wide.
 Eastern Asia and Sub-Saharan Africa.Eastern Asia and Sub-Saharan Africa.
 Approx 1 – 2 million annual deaths.Approx 1 – 2 million annual deaths.
 Vertical transmission common in endemic areas.Vertical transmission common in endemic areas.
Commonly acquired at birth Greater chance of CarrierCommonly acquired at birth Greater chance of Carrier
status.status.
 Non-endemic areas - Acquired during adulthood SelfNon-endemic areas - Acquired during adulthood Self
limitinglimiting..

18. Symptomatic Infection
Chronic Infection
Age at Infection
Chronic Infection (%)
SymptomaticInfection(%)
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
0
20
40
60
80
100100
80
60
40
20
0
Outcome of Hepatitis B Virus Infection
by Age at Infection
ChronicInfection(%)

19. Hepatitis BHepatitis B
TransmissionTransmission
 Most bodily fluids infective during acuteMost bodily fluids infective during acute
illness.eg. Blood, sweat, semen, breastillness.eg. Blood, sweat, semen, breast
milk and tears.milk and tears.
 Percutaneous (Blood contact, Sharps, IVDU,Percutaneous (Blood contact, Sharps, IVDU,
Tattooing, ear piercing, acupuncture)Tattooing, ear piercing, acupuncture)
 Perinatal (vertical transmission)Perinatal (vertical transmission)
 Sexual ActivitySexual Activity

20. Hepatitis BHepatitis B
DiagnosisDiagnosis
 ScreeningScreening
 HBsAg in Blood, serum, oral fluid.HBsAg in Blood, serum, oral fluid.
 DiagnosisDiagnosis
 A battery of serological tests are used for the diagnosis of acute and chronic hepatitis BA battery of serological tests are used for the diagnosis of acute and chronic hepatitis B
infection.infection.
 HBsAgHBsAg
 used as a general marker of infection.used as a general marker of infection.
 Anti-HBSAnti-HBS
 used to document recovery and/or immunity to HBV infection.used to document recovery and/or immunity to HBV infection.
 anti-HBc IgManti-HBc IgM
 marker of acute infection.marker of acute infection.
 anti-HBc IgGanti-HBc IgG
 past or chronic infection.past or chronic infection.
 HBeAgHBeAg
 indicates active replication of virus and therefore infectiveness.indicates active replication of virus and therefore infectiveness.
 Anti-HbeAnti-Hbe
 virus no longer replicating. However, the patient can still be positive for HBsAg which isvirus no longer replicating. However, the patient can still be positive for HBsAg which is
made by integrated HBV.made by integrated HBV.
 HBV-DNAHBV-DNA
 indicates active replication of virus, more accurate than HBeAg especially in cases ofindicates active replication of virus, more accurate than HBeAg especially in cases of
escape mutants. Used mainly for monitoring response to therapyescape mutants. Used mainly for monitoring response to therapy
 Genotyping.Genotyping.

21. Self LimitingSelf Limiting

22. Chronic InfectionChronic Infection
HBV DNA

23. Hepatitis BHepatitis B
Prevention and ControlPrevention and Control
 Hepatitis B specific Immune Globulin (HBIG).Hepatitis B specific Immune Globulin (HBIG).
(passive immunisation)(passive immunisation)
 From Donors, used in NIs and Natal care.From Donors, used in NIs and Natal care.
 HBV vaccine (active immunisation)HBV vaccine (active immunisation)
 Family/babies, at risk patients/workers, prisonersFamily/babies, at risk patients/workers, prisoners
• Condom use.Condom use.
• ScreeningScreening
• (Blood products and pregnancy)(Blood products and pregnancy)
• EducationEducation

24. Hepatitis BHepatitis B
 TreatmentTreatment
 Specialist management.Specialist management.
 InterferonInterferon
 Antiviral therapyAntiviral therapy
 Genotype dependantGenotype dependant
 No treatment for acute infection.No treatment for acute infection.
 Liver transplantLiver transplant

25. Hepatitis CHepatitis C
 HCV : FlavivirusHCV : Flavivirus
 SS RNA VirusSS RNA Virus
 EnvelopedEnveloped
 SphericalSpherical
 6 genotypes (at least)6 genotypes (at least)
DiseaseDisease
Acute after 6-12 weeks incubation.Acute after 6-12 weeks incubation.
More common asymptomatic infection.More common asymptomatic infection.
Many become carriers. Approx 80%Many become carriers. Approx 80%
50% carriers develop chronic liver disease, with half50% carriers develop chronic liver disease, with half
progressing to liver cirrhosis.progressing to liver cirrhosis.
Links with Carcinoma.Links with Carcinoma.

27. Hepatitis CHepatitis C
EpidemiologyEpidemiology
 Blood borneBlood borne
 IVDAs at High RiskIVDAs at High Risk
 Receivers of Blood & Blood ProductsReceivers of Blood & Blood Products
 Occupational risk.Occupational risk.
 Prison.Prison.
DiagnosisDiagnosis
 HCV Ab testing.HCV Ab testing.
 Combined HCV Ab/AgCombined HCV Ab/Ag
 RNA testingRNA testing
 GenotypingGenotyping

28. Hepatitis CHepatitis C
 GenotypingGenotyping
 6 Genotypes6 Genotypes
 Determining the HCV genotype is useful in makingDetermining the HCV genotype is useful in making
recommendations regarding therapy.recommendations regarding therapy.
 Genotype 1b associated with aggressive infection andGenotype 1b associated with aggressive infection and
interferon failure.interferon failure.
 Genotypes 2 and 3 are two to three times more likely toGenotypes 2 and 3 are two to three times more likely to
respond to interferon-based therapy than patients withrespond to interferon-based therapy than patients with
genotype 1.genotype 1.
 when using combination therapy, the recommended dosewhen using combination therapy, the recommended dose
and duration of treatment depend on the genotype. Forand duration of treatment depend on the genotype. For
patients with genotypes 2 and 3, a 24-week course ofpatients with genotypes 2 and 3, a 24-week course of
combination treatment is adequate, whereas for patientscombination treatment is adequate, whereas for patients
with genotype 1, a 48-week course is recommended.with genotype 1, a 48-week course is recommended.
 Tested in conjunction with Viral Load.Tested in conjunction with Viral Load.
 Viral RNA testing can help detect treatment failuresViral RNA testing can help detect treatment failures

30. Hepatitis CHepatitis C
Prevention and ControlPrevention and Control
 Blood donor screeningBlood donor screening
 Cessation of needle sharingCessation of needle sharing
 EducationEducation
 Transmission from sexual contact small.Transmission from sexual contact small.
 No vaccine available.No vaccine available.

31. Hepatitis DHepatitis D
 Deltaviridae family.Deltaviridae family.
 Spherical.Spherical.
 ssRNA genome.ssRNA genome.
 Defective virus (requires HBsAg).Defective virus (requires HBsAg).
 Only ever present as co infection with HBVOnly ever present as co infection with HBV
 There are two types of infection:There are two types of infection:
 Co-infection with HBVCo-infection with HBV
 (self-limiting, only 5% chronic)(self-limiting, only 5% chronic)
 Superinfection with HDV in chronic HBV patientsSuperinfection with HDV in chronic HBV patients
 (80% chronic)(80% chronic)
 Chronic HDV leads to Cirrohsis in 80% of cases.Chronic HDV leads to Cirrohsis in 80% of cases.

32. Hepatitis DHepatitis D
PreventionPrevention
 HBV vaccine protects against HDV.HBV vaccine protects against HDV.
TreatmentTreatment
 Virus hard to clear.Virus hard to clear.
 Liver transplant.Liver transplant.
DiagnosisDiagnosis
 HDV antigen, IgG, IgM.HDV antigen, IgG, IgM.
TransmissionTransmission
 Similar to HBV in high HDV endemic areas.Similar to HBV in high HDV endemic areas.
 Specialist risk groups in non-endemic areas.Specialist risk groups in non-endemic areas.
EpidemiologyEpidemiology
 Mediterranean, South America, Middle East and Far EastMediterranean, South America, Middle East and Far East

33. Hepatitis EHepatitis E
 HEV : Calicivirus.HEV : Calicivirus.
 Small SS RNA virus.Small SS RNA virus.
 Genomically similar to otherGenomically similar to other
Hepatitis.Hepatitis.
 Naked.Naked.
EpidemiologyEpidemiology
 Rarely acquired in UKRarely acquired in UK
 Sporadic UK acquisition occursSporadic UK acquisition occurs
 Travel associated.Travel associated.

34. Hepatitis EHepatitis E
DiseaseDisease
 Symptoms similar to HAVSymptoms similar to HAV
 Often asymptomatic .Often asymptomatic .
 Severe infection in PregnancySevere infection in Pregnancy
 (3(3rdrd
Trimester, high mortality of up to 40%).Trimester, high mortality of up to 40%).
 Incubation period 2-9 weeks.Incubation period 2-9 weeks.
 No chronic infectionNo chronic infection
 Possibly persistent (PCR +ve > 6 Months).Possibly persistent (PCR +ve > 6 Months).
EpidemiologyEpidemiology
 Endemic in areas of poor sanitation.Endemic in areas of poor sanitation.
 Major cause of worldwide acute viral hepatitis.Major cause of worldwide acute viral hepatitis.
 Developed country outbreaks are rare.Developed country outbreaks are rare.

35. Hepatitis EHepatitis E
TransmissionTransmission
 Faecal-oral.Faecal-oral.
 Contaminated water.Contaminated water.
 person-person spread – Rareperson-person spread – Rare
Prevention and TreatmentPrevention and Treatment
 Improved sanitation.Improved sanitation.
 No Vaccine Available.No Vaccine Available.
DiagnosisDiagnosis
 IgG and IgM immunoassays.IgG and IgM immunoassays.
 PCRPCR

36. Hepatitis FHepatitis F
 Hepatitis FHepatitis F is technically a nonexistent virus. However,is technically a nonexistent virus. However,
an infection common in the Far East has shown that aan infection common in the Far East has shown that a
new virus, which is neither hepatitis B or C, hasnew virus, which is neither hepatitis B or C, has
emerged. In some circles, this virus is being recognizedemerged. In some circles, this virus is being recognized
as the hepatitis F virus. (Meers et al)as the hepatitis F virus. (Meers et al)

37. Hepatitis GHepatitis G
Hepatitis G (HGV)Hepatitis G (HGV)
 FlavivirusFlavivirus
 SS RNASS RNA
 Genetically similar to HCV.Genetically similar to HCV.
 So far, it does not seem to be infectious or cause anySo far, it does not seem to be infectious or cause any
illness, but tends to coexist with other kinds of hepatitisillness, but tends to coexist with other kinds of hepatitis
infections.infections.
 HGV is a bloodborne virus transmitted in the sameHGV is a bloodborne virus transmitted in the same
manner as other hepatitis viruses with about one in fivemanner as other hepatitis viruses with about one in five
people that have HCV also carrying HGV.people that have HCV also carrying HGV.

38. Hepatitis HHepatitis H
Hepatitis HHepatitis H
 will undoubtedly be the name given to the nextwill undoubtedly be the name given to the next
hepatitis virus to be isolated. Scientists are at ahepatitis virus to be isolated. Scientists are at a
loss and are trying to understand why 10-15% ofloss and are trying to understand why 10-15% of
chronic hepatitis patients do not fit into any ofchronic hepatitis patients do not fit into any of
the other hepatitis virus categories. So this maythe other hepatitis virus categories. So this may
be a category waiting for a virus to claim it.be a category waiting for a virus to claim it.
There is evidence, however, of another hepatitisThere is evidence, however, of another hepatitis
virus that has been temporarily labeled "non-virus that has been temporarily labeled "non-
A,non-E". A patent is in progress for it to beA,non-E". A patent is in progress for it to be
calledcalled S.E.N.-VS.E.N.-V..

39. Other Causes of Viral HepatitisOther Causes of Viral Hepatitis
 Yellow Fever- Haemorrhagic fever,Yellow Fever- Haemorrhagic fever,
affects the liver, high mortality (20-50%),affects the liver, high mortality (20-50%),
South America and Sub-Saharan Africa.South America and Sub-Saharan Africa.
 EBV,EBV,
 CMVCMV
 Rubella.Rubella.

40. Diagnostic ProfilesDiagnostic Profiles
 Acute HepatitisAcute Hepatitis
 HBsAg, HCV Ag/Ab, HAV IgM, CMV IgM, EBV IgMHBsAg, HCV Ag/Ab, HAV IgM, CMV IgM, EBV IgM
 HEV IgG/IgM with Relevant Travel History / animal ContactHEV IgG/IgM with Relevant Travel History / animal Contact
 Rubella, Toxoplasma, Parvovirus – Congenital jaundiceRubella, Toxoplasma, Parvovirus – Congenital jaundice
 Chronic Hepatitis B – Pre +Post treatmentChronic Hepatitis B – Pre +Post treatment
 HBsAg, HBeAg, Anti-HBe, HB core IgG,IgM HBV Viral LoadHBsAg, HBeAg, Anti-HBe, HB core IgG,IgM HBV Viral Load
 Chronic Hepatitis C – Pre treatmentChronic Hepatitis C – Pre treatment
 HCV Ab, HCV Ag, HCV Viral Load + GenotypeHCV Ab, HCV Ag, HCV Viral Load + Genotype
 Chronic Hepatitis C – Post TreatmentChronic Hepatitis C – Post Treatment
 HCV Viral LoadHCV Viral Load
 Hepatitis StatusHepatitis Status
 HBsAg, HCV Ab, HAV AbHBsAg, HCV Ab, HAV Ab
 Post HBV VaccinationPost HBV Vaccination
 Anti HBsAnti HBs
 Pre HBV VaccinationPre HBV Vaccination
 HBsAg , HBcAbHBsAg , HBcAb

41. HepatitisHepatitis
ANY QUESTIONS?ANY QUESTIONS?

42. HIVHIV
Human Immunodeficieny VirusHuman Immunodeficieny Virus
 lymphadenopathy-associated virus (LAV)lymphadenopathy-associated virus (LAV)
 Human T-Cell Lymphotropic Virus III (HTLVIII)Human T-Cell Lymphotropic Virus III (HTLVIII)

43. HIVHIV
 LentivirusesLentiviruses“Lenti” meaning Slow.“Lenti” meaning Slow.
 Long incubation periods.Long incubation periods.
 No early symptomsNo early symptoms
 Members of Retrovirdae family.Members of Retrovirdae family.
 SS RNA virusSS RNA virus

44. HIVHIV
EpidemiologyEpidemiology
1.1. ? Introduction in 1960s? Introduction in 1960s
2.2. Global pandemicGlobal pandemic
3.3. 90% of HIV in developing world90% of HIV in developing world
4.4. Sub-saharan Africa up to 40% of adultsSub-saharan Africa up to 40% of adults
OriginOrigin
1.1. Close relationship with simian (SIV)Close relationship with simian (SIV)
2.2. Human social behaviourHuman social behaviour

45. Origins of HIVOrigins of HIV
 Thought to be a descendant of a SimianThought to be a descendant of a Simian
Immunodeficiency Virus (SIV) whichImmunodeficiency Virus (SIV) which
crossed the species barrier.crossed the species barrier.
 Source of HIV-1 appears to be theSource of HIV-1 appears to be the
chimpanzee.chimpanzee.
 Source of HIV-2 appears to be the sootySource of HIV-2 appears to be the sooty
mangabee (W Africa)mangabee (W Africa)

46. Structure and Classification ofStructure and Classification of
HIVHIV
 ssRNA genomessRNA genome
 Size 80-100nmSize 80-100nm
 EnvelopedEnveloped
 SphericalSpherical
 Contains ReverseContains Reverse
Transcriptase (RT)Transcriptase (RT)

47. RetrovirusRetrovirus
 ReplicationReplication
 Binding (Via Cell receptorBinding (Via Cell receptor
eg CD4)eg CD4)
 PenetrationPenetration
(binding-change in envelope-(binding-change in envelope-
fusion-entry)fusion-entry)
 TranscriptionTranscription
(Via Cells own polymerase)(Via Cells own polymerase)
 TranslationTranslation
(of Virus proteins)(of Virus proteins)
 Progeny assemblyProgeny assembly
 BuddingBudding

48. HIV ReplicationHIV Replication
 Virus encounters a CD4+ cellVirus encounters a CD4+ cell
 Virus binds to host cell - gp120 binds toVirus binds to host cell - gp120 binds to
the CD4 receptorthe CD4 receptor
 Membranes of the cell and virus fuseMembranes of the cell and virus fuse
releasing the RNA, proteins andreleasing the RNA, proteins and
enzymes into the cytoplasm.enzymes into the cytoplasm.
 Reverse transcriptase converts the viralReverse transcriptase converts the viral
RNA into DNARNA into DNA

49. HIV ReplicationHIV Replication
 Viral DNA moves to the nucleus and isViral DNA moves to the nucleus and is
spliced into the host cell’s DNA with thespliced into the host cell’s DNA with the
help of viral integrasehelp of viral integrase
 A triggering event transcribes this proviralA triggering event transcribes this proviral
DNA into HIV mRNADNA into HIV mRNA
 HIV mRNA transported to ribosomes andHIV mRNA transported to ribosomes and
translated into long chains of viraltranslated into long chains of viral
proteins.proteins.
 HIV mRNA also acts as genomic RNAHIV mRNA also acts as genomic RNA

50. HIV ReplicationHIV Replication
 Viral protease chops long chains of proteinViral protease chops long chains of protein
into short chainsinto short chains
 Proteins aggregate around the RNA and,Proteins aggregate around the RNA and,
as the virus buds through the cellas the virus buds through the cell
membrane , the envelope is acquired.membrane , the envelope is acquired.
 The mature virus then goes on to infectThe mature virus then goes on to infect
the next cellthe next cell

51. HIV ReplicationHIV Replication

52. The HIV Global PandemicThe HIV Global Pandemic
((Estimated statistics by end Dec 2007)Estimated statistics by end Dec 2007)
 The number of people worldwide infected withThe number of people worldwide infected with
HIV is estimated at 33.2 millionHIV is estimated at 33.2 million
 More than 90% live in the developing worldMore than 90% live in the developing world
 More than 70% live in sub-Saharan AfricaMore than 70% live in sub-Saharan Africa
 The number of deaths globally in 2007 isThe number of deaths globally in 2007 is
estimated at 2.7 millionestimated at 2.7 million
 The number of infections acquired in 2007 isThe number of infections acquired in 2007 is
thought to be 2.0 millionthought to be 2.0 million

53. A global view of HIV infection
33 million people [30–36 million] living with HIV, 2007
2.2

54. HIVHIV
DistributionDistribution
 HIV 2 uncommon outside W.AfricaHIV 2 uncommon outside W.Africa
 Co infection rareCo infection rare
TransmissionTransmission
 MSM (Men Who Have sex with Men)MSM (Men Who Have sex with Men)
 Increasing Female infection in developedIncreasing Female infection in developed
countries.countries.
 UKUK
 MSM>Bisexual>Heterosexual>IVDAMSM>Bisexual>Heterosexual>IVDA

55. Transmission of HIVTransmission of HIV
The virus is found in many body fluids includingThe virus is found in many body fluids including
semen, CSF, cervical fluid, blood and breast milksemen, CSF, cervical fluid, blood and breast milk
 Unprotected sexual Intercourse – bothUnprotected sexual Intercourse – both
homosexual and heterosexualhomosexual and heterosexual
 Vertical transmission from mother to childVertical transmission from mother to child
usually during delivery or by breast feedingusually during delivery or by breast feeding
 Parenteral Transmission - Intravenous DrugParenteral Transmission - Intravenous Drug
Abuse (sharing needles), contaminated bloodAbuse (sharing needles), contaminated blood
and blood products, needle stick injuries,and blood products, needle stick injuries,
unsterilised surgical equipmentunsterilised surgical equipment

56. Factors Affecting theFactors Affecting the
Transmission of HIVTransmission of HIV
 Virus typeVirus type
 HIV-1 appears to transmit more readily than HIV-2HIV-1 appears to transmit more readily than HIV-2
 Presence of genital lesions or ulcers oftenPresence of genital lesions or ulcers often
caused by other sexually transmittedcaused by other sexually transmitted
diseasesdiseases
 Type of sex – transmitted more frequentlyType of sex – transmitted more frequently
during anal sexduring anal sex
 During heterosexual sex the virus isDuring heterosexual sex the virus is
transmitted more readily from male to femaletransmitted more readily from male to female
than vice versa.than vice versa.
 CircumcisionCircumcision
 Viral loadViral load

57. HIV TransmissionHIV Transmission
Sexual IntercourseSexual Intercourse
 Virions in semen and cervical fluidVirions in semen and cervical fluid
 Male>female = Higher transmissionMale>female = Higher transmission
 Transmission depends on :Transmission depends on :
 Viral load, Skin breakage, skin lesionsViral load, Skin breakage, skin lesions
 Increase in sexual promiscuity.Increase in sexual promiscuity.

58. HIV TransmissionHIV Transmission
Blood (Parenteral)Blood (Parenteral)
 IVDA, Blood products, Non disposablesIVDA, Blood products, Non disposables
 Cases of post transfusion infection.Cases of post transfusion infection.
 Needle stick injury (0.3%)Needle stick injury (0.3%)
 Mucous membrane exposure (Rare)Mucous membrane exposure (Rare)
Mother to Child (Perinatal)Mother to Child (Perinatal)
 Transmission between 19% and 40%Transmission between 19% and 40%
 Normally notNormally not in uteroin utero
 Breast milkBreast milk

59. Prevention of HIVPrevention of HIV
 EducationEducation
 Use of condomsUse of condoms
 Use of sterile needles/ surgical instrumentsUse of sterile needles/ surgical instruments
 Treatment for other sexually transmittedTreatment for other sexually transmitted
diseasesdiseases
 Screening of blood supply and blood productsScreening of blood supply and blood products
 Treatment of Positive patientsTreatment of Positive patients
 to reduce the HIV viral loadto reduce the HIV viral load
 Screening of pregnant womenScreening of pregnant women
 Screening of sex workersScreening of sex workers
 Actions to prevent vertical transmissionActions to prevent vertical transmission
 treatment, caesarean section, bottle feeding.treatment, caesarean section, bottle feeding.
 Currently there is no effective vaccineCurrently there is no effective vaccine

60. Laboratory Diagnosis of HIVLaboratory Diagnosis of HIV
ScreeningScreening
 Combined Testing for antibody to HIV 1 andCombined Testing for antibody to HIV 1 and
HIV2 and Antigen HIV-1HIV2 and Antigen HIV-1
 44thth
Generation testsGeneration tests
 Reduced non detection window to 3 weeksReduced non detection window to 3 weeks
Sample TypesSample Types
 EDTA BloodEDTA Blood
 SerumSerum
 PlasmaPlasma
 Oral FluidOral Fluid
 Dried Blood Spot.Dried Blood Spot.

61. Laboratory Diagnosis of HIVLaboratory Diagnosis of HIV
Point of CarePoint of Care
 44thth
generation now available.generation now available.
 Results from VB in as little as 20 minutes.Results from VB in as little as 20 minutes.
 Can be used in clinics and for “out of hours”Can be used in clinics and for “out of hours”
testing.testing.
 Helps in PEP administration where laboratoryHelps in PEP administration where laboratory
testing not available.testing not available.
 CautionCaution
 Not as sensitive in acute infectionNot as sensitive in acute infection

62. Laboratory Diagnosis of HIVLaboratory Diagnosis of HIV
Baseline Testing New diagnosisBaseline Testing New diagnosis
 HIV viral load (Quantitative RT PCR)HIV viral load (Quantitative RT PCR)
measures the amount of HIV RNA in themeasures the amount of HIV RNA in the
patients bloodpatients blood
 Routinely only available for HIV1Routinely only available for HIV1
 CD4 cell countCD4 cell count
 Tests for Viral ResistanceTests for Viral Resistance
 Detection of antibodies to persistentDetection of antibodies to persistent
infections e.g. CMV, EBV, Toxoplasmainfections e.g. CMV, EBV, Toxoplasma

63. HIVHIV
Cellular EffectCellular Effect
 Infects CD4+ cellsInfects CD4+ cells
(Lymphs,mono,dendritic and brain)(Lymphs,mono,dendritic and brain)
 Does not destroy the cellDoes not destroy the cell
 CD4 not only receptorCD4 not only receptor

64. HIV and AIDSHIV and AIDS
Case DefinitionsCase Definitions
Depend upon CD4 count and clinical featuresDepend upon CD4 count and clinical features
Cat ACat A
 Seroconversion,asymptomatic,lymphadenopathySeroconversion,asymptomatic,lymphadenopathy
 Non-specific symptoms, rash, flu-likeNon-specific symptoms, rash, flu-like
Cat BCat B
 T-cell immunity defect, Candida, HSV.T-cell immunity defect, Candida, HSV.
Cat CCat C
 AIDS Indicator ConditionsAIDS Indicator Conditions
 Fever >month, Weight loss, diarrhoeaFever >month, Weight loss, diarrhoea
 Secondary infectious disease, i.e. bacteria, fungi.Secondary infectious disease, i.e. bacteria, fungi.

65. Course of DiseaseCourse of Disease
1)1) Acute PhaseAcute Phase
 Following infection by the virus there is a 3-Following infection by the virus there is a 3-
4 week incubation period followed by a4 week incubation period followed by a
short acute viral or flu-like illness sometimesshort acute viral or flu-like illness sometimes
with a rashwith a rash..
 Viral Antigen detectable within 1-2 weeks ofViral Antigen detectable within 1-2 weeks of
infection.infection.
 The viral load is high at around six weeks and theThe viral load is high at around six weeks and the
CD4+ T cell count drops. Within a few weeks theCD4+ T cell count drops. Within a few weeks the
CD4+count is back to near normal levels and theCD4+count is back to near normal levels and the
viral load drops.viral load drops.

66. 2) The Asymptomatic Phase2) The Asymptomatic Phase
 Period of latency – usually 7-10years – butPeriod of latency – usually 7-10years – but
during this time virus production within infectedduring this time virus production within infected
cells is very active and CD4+ T-cell numberscells is very active and CD4+ T-cell numbers
decrease at a steady rate.decrease at a steady rate.
 Antibody can be demonstrated fromAntibody can be demonstrated from
approximately 6-12 weeks post infection.approximately 6-12 weeks post infection.
 Patients may have no symptoms or sufferPatients may have no symptoms or suffer
sporadically from fatigue, weight loss, thrush orsporadically from fatigue, weight loss, thrush or
generalised lymphadenopathy and shingles.generalised lymphadenopathy and shingles.

67. 3) AIDS3) AIDS
 When sufficient CD4 lymph cells haveWhen sufficient CD4 lymph cells have
been destroyed (<200) then thebeen destroyed (<200) then the
symptomatic phase presents (AIDS) Thesymptomatic phase presents (AIDS) The
patient develops opportunistic infectionspatient develops opportunistic infections
and often malignancy.and often malignancy.
 Without treatment, survival of AIDSWithout treatment, survival of AIDS
patients can be as little as 1 yearpatients can be as little as 1 year

68. HIV COURSE OF DISEASEHIV COURSE OF DISEASE

69. HIV and AIDSHIV and AIDS
Opportunistic Infections (OI)Opportunistic Infections (OI)
ViralViral
JCV, Parvo, Papilloma, Hep B, HSV, EBV, CMV, VZVJCV, Parvo, Papilloma, Hep B, HSV, EBV, CMV, VZV
MycobacterialMycobacterial
TB + Other - Co infection seriousTB + Other - Co infection serious
BacterialBacterial
S.pneumo, Salmonella, S.aureusS.pneumo, Salmonella, S.aureus
FungalFungal
C.albicans, Cryptococcus, Aspergillus, HistoplasmaC.albicans, Cryptococcus, Aspergillus, Histoplasma
MalignanciesMalignancies
Kaposi’s Sarcoma, Lesions or plaques onKaposi’s Sarcoma, Lesions or plaques on
cutaneous/mucous membranes.cutaneous/mucous membranes.
ProtozoaProtozoa
Pneumocystis (pneumonia), Toxoplasma (Brain)Pneumocystis (pneumonia), Toxoplasma (Brain)

70. Treatment for HIVTreatment for HIV
 Nucleoside analogues – inhibit ReverseNucleoside analogues – inhibit Reverse
TranscriptaseTranscriptase
 Non – nucleoside analogues – inhibitNon – nucleoside analogues – inhibit
Reverse TranscriptaseReverse Transcriptase
 Protease Inhibitors – inhibit the formation ofProtease Inhibitors – inhibit the formation of
viral proteinsviral proteins
 Integrase inhibitorsIntegrase inhibitors
 Entry inhibitorsEntry inhibitors
 Highly Active Anti Retroviral TherapyHighly Active Anti Retroviral Therapy
(HAART) – a combination of the above(HAART) – a combination of the above

71. Number of people receiving antiretroviral drugs
in low- and middle-income countries, 2002−2007
Source: Data provided by UNAIDS & WHO, 2008.
end-
2002
end-
2004
end-
2003
end-
2005
0.4
0.8
1.2
1.6
2.2
2.8
Millions
Year
2.4
2.6
3.0
0.0
0.2
0.6
1.0
1.4
1.8
2.0
end-
2007
end-
2006
North Africa and
the Middle East
Eastern Europe and
Central Asia
East, South and
South-East Asia
Latin America and
the Caribbean
Sub-Saharan
Africa
5.2

72. Common drugs in useCommon drugs in use
 5 drug classes5 drug classes
1) NNRTIs (non-nucleoside reverse transcriptase1) NNRTIs (non-nucleoside reverse transcriptase
inhibitors)inhibitors)
EFAVIRENZEFAVIRENZ (neurocognitive SE like dizziness/vivid(neurocognitive SE like dizziness/vivid
dreams/depression)dreams/depression)
NEVIRAPINENEVIRAPINE (liver abnormalities)(liver abnormalities)
ETRAVIRINEETRAVIRINE (fewer SEs but more expensive)(fewer SEs but more expensive)
2) NRTIs (nucleoside reverse transcriptase inhibitors)2) NRTIs (nucleoside reverse transcriptase inhibitors)
TENOFOVIRTENOFOVIR
EMTRICITIBINEEMTRICITIBINE (combined as TRUVADA; risk of renal tubule(combined as TRUVADA; risk of renal tubule
toxicity)toxicity)
ABACAVIRABACAVIR
LAMIVUDINELAMIVUDINE (combined as KIVEXA; risk of hypersensitivity(combined as KIVEXA; risk of hypersensitivity
reactions)reactions)
Truvada plus efavirenz is marketed as Atripla. This is the only one tabletTruvada plus efavirenz is marketed as Atripla. This is the only one tablet
once a day drug and is the most common 1once a day drug and is the most common 1stst
line regimen.line regimen.

73. Common drugs (continued)Common drugs (continued)
 3) PIs (Protease inhibitors)3) PIs (Protease inhibitors)
Lopinavir/ritonavir boosterLopinavir/ritonavir booster (combined as Kaletra)(combined as Kaletra)
Darunavir/ritonavir boosterDarunavir/ritonavir booster (given separately)(given separately)
Atazanavir/rtonavir boosterAtazanavir/rtonavir booster (given separately)(given separately)
Advantage of atazanavir is that it is only given once daily.Advantage of atazanavir is that it is only given once daily.
Quite a low barrier to resistance.Quite a low barrier to resistance.
Caution if taking antacids as can affect absorption and drug levels ofCaution if taking antacids as can affect absorption and drug levels of
the PI’s. PIs cause diarrhoea! Darunavir is the best tolerated of all.the PI’s. PIs cause diarrhoea! Darunavir is the best tolerated of all.
 4) Integrase inhibitors4) Integrase inhibitors
Raltegravir/ElvitegravirRaltegravir/Elvitegravir
Very few drug interactions so good for people on lots of other medicines.Very few drug interactions so good for people on lots of other medicines.
Very expensive!Very expensive!

74. Common drugs in use continuedCommon drugs in use continued
 5) Entry inhibitors5) Entry inhibitors
T20 (enfuvirtide, blocks Gp41)T20 (enfuvirtide, blocks Gp41)
Maraviroc (Selsentry, a CCR5 receptor blocker)Maraviroc (Selsentry, a CCR5 receptor blocker)
Expensive, only used in very specific situations.Expensive, only used in very specific situations.
Maraviroc needs a tropism test to predict its suitability for useMaraviroc needs a tropism test to predict its suitability for use
Both drugs brittle in terms of resistance.Both drugs brittle in terms of resistance.
T20 is given by sub-cut injection; good if worried about absorption ofT20 is given by sub-cut injection; good if worried about absorption of
some other drugs.some other drugs.

75. How does resistance occur?How does resistance occur?
 HIV genome contains 10HIV genome contains 1044
nucleotidesnucleotides
 Replication is anReplication is an error proneerror prone procedure, poor proof readingprocedure, poor proof reading
 101099
new virions are generated per daynew virions are generated per day
 Approx 1 mutation per virion per replication cycleApprox 1 mutation per virion per replication cycle
 Produces a ‘pool’ of viral quasi-speciesProduces a ‘pool’ of viral quasi-species
 Single-point mutations, multiple-point mutations, insertions,Single-point mutations, multiple-point mutations, insertions,
or deletionsor deletions
 Structural alteration of protein product (affects folding intoStructural alteration of protein product (affects folding into
tertiary structure)tertiary structure)
 Prevents or reduces ability for inhibitor (drug) to bindPrevents or reduces ability for inhibitor (drug) to bind
 Affects removal of chain terminatorsAffects removal of chain terminators
Under drug selection pressure, completeUnder drug selection pressure, complete
replacement of wild-type (WT) virus by drug-replacement of wild-type (WT) virus by drug-
resistant virus can occur in 14 to 28 daysresistant virus can occur in 14 to 28 days

76. Selection of resistant viral species underSelection of resistant viral species under
drug pressure- a dynamic processdrug pressure- a dynamic process
CausesCauses
Poor adherencePoor adherence
Inadequate drug levelsInadequate drug levels
Inadequate drug potencyInadequate drug potency
Pre-existing/transmittedPre-existing/transmitted
resistanceresistance
Wild type virus Resistant virus
Rx begins
Incomplete
suppression
allows viral
division
Acquired mutation
confers survival
advantage
Fit virus
becomes
dominant
Time

77. Patient re-populated withPatient re-populated with wildwild
typetype virus on removal of failingvirus on removal of failing
regimenregimen
Drug Pressure
Removed
Resistance
mutations are
archived

78. THE ENDTHE END
Thank YouThank You
Contact detailsContact details
duncan.whittaker@sth.nhs.ukduncan.whittaker@sth.nhs.uk
Tel: 0114 226 9494Tel: 0114 226 9494