An overview of the HIV pandemic, as presented to foreign trained medical graduates in a lecture in LUTH

1. HIV
Dr Mallum
Senior Registrar,
Dept of Internal Medicine
LUTH

2. INTRODUCTION
• Human immunodeficiency virus (HIV) is a
blood-borne virus typically transmitted via
sexual intercourse, shared intravenous drug
paraphernalia, and mother-to-child
transmission (MTCT), which can occur during
the birth process or during breastfeeding.
• There are two types: HIV1 and HIV2.

3. SUBTYPES OF HIV 1
• Ten genetically distinct subtypes: Major group
(Group M) contains subgroups A to K. Group O
(Outliers) contains distinct group of
heterogeneous viruses. Found only in West
Africa. Group N (interaction between group M
and group O viruses

4. HIV-2
• HIV2 was isolated in West Africa and is
confined primarily to West Africa. Compared
to HIV1, HIV2 is less transmissible and affected
patients are less infectious. Develops more
slowly. Associated with less viral burden. Has
slower rate of cell decline and clinical
progress. Does not respond to non nucleoside
analogues.

5. HISTORY OF HIV IN NIGERIA
• The first two cases of HIV and AIDS in Nigeria
were identified in 1985
• HIV prevalence rose from 3.8 percent in 1993
to 5.4 percent in 1999. Following a peak of 5.8
percent in 2001, HIV prevalence then declined
steadily throughout the decade.

6. HIV2
• Less transmissible , has 5 – 9 fold lower
probability of transmission per sexual act.
• Associated with Less viral burden
• Shower rate of cell decline and clinical
progression rates of progression to HIV – related
disease, AIDS and Mortality
• . Vertical transmission .lesser
• . NRTls Less active
• . NNRls not active
• .Pls active

7. EPIDEMIOLOGY
• Worldwide, Nigeria has the second highest
number of new infections reported each year
• Approximately 80 percent of HIV infections in
Nigeria are a result of heterosexual sex.
• Women are particularly affected by HIV; in
2009 women accounted for 56 percent of all
adults aged 15 and above living with the virus

8. MODES OF TRANSMISSION
• Sexual: heterosexual male to female or female
to male; homosexual male to male or female
to female.
• Parenteral: Blood transfusions, use of
intravenous injections by intravenous drug
users, needle stick accidents.
• Mother to child transmission in utero and
during labour, post partum in breast milk.

9. EPIDEMIOLOGY
• Risk of Occupational Transmission
• 1. percutaneous exposure to infected blood - 0.3%
• 2. mucus membrane exposure - 0.09%
• 3. skin exposure <0.09%
• Most-at-risk groups in Nigeria include brothel and non-
brothel based female sex workers (FSW), men-who-
have-sex-with-men (MSM), injecting drug users (IDUs),
transport workers, members of the Armed Forces and
Police.

10. Structure of HIV
• HIV is a Retrovirus and belongs to the family
of Lentivirus.
• Surrounded by a lipoprotein membrane
• Gp120 is an external glycoprotein
• Gp41 is a transmembrane protein
• P24 is the core antigen
• P17 is anchored inside the viral lipoprotein
membrane

11. VIRAL GENOME
• Gag, pol and env genes
• Gag = Group AntiGen
• Pol= POLymerase
• Env= ENVelope
Gag codes for p7,p17,p24
Pol codes for p11 protease,p66 reverse
transcriptase,p32 integrase
Env codes for Gp41 and Gp120

12. HIV REPLICATION CYCLE
• Fusion – Gp 120
• Uncoating
• Reverse transcription – reverse transcriptase
• Integration of proviral DNA- integrase
• Transcription
• Cleavage of precursor molecules- protease
• Assembly
• Budding + maturation

13. IMMUNOPATHOPHYSIOLOGY
• The Gp120 receptor on the HIV membrane
binds to the CD4 receptor and CCR5 or CXCR4
receptors co receptors.
• The Gp41 receptor initiates cell membrane
fusion.
• Upon entry, the enzyme reverse transcriptase
produces

14. IMMUNOPATHOPHYSIOLOGY OF HIV
• The Virus migrates to lymphoid tissue early in
infection and actively replicates rapidly in
lymphoid tissue,CD4 cells and follicular
dendritic cells.

15. IMMUNOPATHOPHYSIOLOGY OF HIV
• There is loss of CD4 T lymphocytes due to :
-Syncytial cell formation
-Cytotoxic and antibody dependent killing of
both infected and unifected cells
-Damage to CD4 membranes from budding of
newly formed
-Domination of host cell protein synthesis by
viral RNA and protein synthesis

16. IMMUNOPATHOPHYSIOLOGY OF HIV
• In addition to loss of CD4 lymphocytes, there
is dysfunction of:
Monocytes,cytotoxic T-cells,T suppressor cells,T
Natural killer cells,B lymphocytes.

17. IMMUNOPATHOPHYSIOLOGY OF HIV
• CYTOTOXIC T CELLS
• Dysfunction is implicated in causation of:
-Herpes zoster,herpes simplex types 1,2 and 8
-CMV,EBV,Hepatitis
T-suppressor cells
-Heightened hypersensitivity reactions
-HIV nephropathies and arthropathies from
immune complex disorder

18. IMMUNOPATHOPHYSIOLOGY OF HIV
• Natural killer cells:
-Predisposition to cancers such as Kaposi’s
Sarcoma,Lymphoma,CA cervix.
B cells:
Dysfunction causes bacterial infections like Skin
Sepsis,Pharyngitis,Pneumonia,UTI,Septicaemia,P
ID,Malaria

19. HIV mutation
• HIV has potential for mutation because
reverse transcriptase is an error prone
enzyme.
• Mutation may be responsible for change in
viral infectivity,fitness and ARV resistance, and
escape from CD8 cells and neutralizing
antibodies.

20. PATHOGENESIS OF ACUTE HIV-1
INFECTION.
• The progression is usually:
-Infection of CD4 cells and macrophages at site
of infection,Dissemination to lymph
nodes,Viraemia resulting from viral replication,
development of HIV specific antibodies(Humoral
immunity), and then HIV specific CD4 and CD8
cells(Cellular immunity).

21. PATHOGENESIS OF CHRONIC HIV-1
INFECTION.
• High turnover of CD4 cells
• Viral load reaches set point
• Immune activation results in immune
dysfunction
• Viral reservoirs result from sanctuary sites like
the brain and genitourinary tract,persistence
in lymphoid tissue.

22. IMMUNE RESPONSE IN CHILDREN
• Absolute CD4 is age-dependent, therefore
CD4% is used
• Viral set point is higher.
• 15-20% of children develop AIDS or die within
1 year
• 10% survive for 5-6 years.

23. CLINICAL FEATURES
• Acute seroconversion illness : flu like illness -
fever,malaise,generalised rash
• Generalised lymphadenopathy
• AIDS presents as recurrent,severe infections
or opportunistic malignancies
• The risk of non-AIDS morbidity and mortality
like cardiovascular disease,liver disease,
cancer is higher.

24. Non-AIDS related complications that may be
more common in patients with HIV
• Hypertension
• Diabetes mellitus and insulin resistance
• Cardiovascular disease
• Pulmonary hypertension
• Cancer- lung cancer, skin cancer, colorectal
cancer, prostate cancer
• Osteopenia and osteoporosis

25. Non-AIDS related complications that may be
more common in patients with HIV
• Liver failure- chronic viral hepatitis and alcohol
misuse
• Kidney failure
• Peripheralneuropathy
• Frailty
• Cognitive decline and dementia

26. HIV and TB co-infection
• M. tuberculosis
↑HIV replication and ↑HIV
progression
• HIV
↑ Risk of active TB

27. HISTORY
• Risk factors for possible exposure to HIV
-Unprotected sexual intercourse especially
receptive anal intercourse
-Large number of sexual partners
-Previous or current STDS
-Sharing of IV drug paraphernalia
-Receipt of blood products
-Mucosal contact with infected blood or needle-
stick injuries
-Maternal HIV infection

28. PHYSICAL EXAMINATION
• Generalised lymphadenopathy,weight loss
• Anaemia,
• Evidence of opportunistic infections such as
herpetic lesions,oral candidiasis

29. DIAGNOSIS OF HIV/AIDS
• Historically,
• presumptive diagnosis 1981 to 1987
• definitive diagnosis 1987-1993
• Definitive diagnosis with
- Severity at presentation
- Response to ARVS
from 1993- date

30. DEFINITIVE DIAGNOSIS
• This combines clinical manifestation with
laboratory evidence.
• The CDC published the diagnostic criteria in
1987 which included 20 clinical conditions
which were expanded to 23 in 1993.

31. Fungal Infections
• Candidiasis of oesophagus
• Coccidiomycosis- disseminated or
extrapulmonary
• Cryptococcosis-extrapulmonary
• Histoplasmosis-Disseminated or
extrapulmonary
• Pneumocystis carinii pneumonia

32. VIRAL INFECTIONS
• CMV of organs other than liver or spleen
• CMV retinitis
• HIV encephalopathy
• Herpes simplex: chronic ulcers> 1 month
• Progressive Multifocal Encephalopathy(JC
virus)

33. Protozoal & Bacterial Infections
Protozoal infections:
• Isosporiasis Chronic intestinal >1 month
• Cryptosporidiasis Chronic intestinal > 1month
• Toxoplasmosis of the brain > 1 month

34. Bacterial Infections:
• Mycobacterium Avium complex or M . Kansaii
• Recurrent salmonella infection
• Mycobacterium TB(Pulmonary) (added in
1993)
• Recurrent bacterial pneumonia (added in
1993)

35. Opportunistic cancers:
-Kaposi Sarcoma
-Burkitt’s Lymphoma
-Immunoblastic lymphoma
-Primary lymphoma of the brain
-Invasive Cervical Ca (added in 1993)

36. HIV wasting syndrome:
• Persistent fever
• Temp >38.5 for 1 month
• Loss of weight in excess of 10% of pre illness
weight
• Chronic diarrhoea for >1 month
• Chronic fatigue

37. CDC CLASSIFICATION
• Category A: Asymptomatic HIV infection without symptoms
or AIDS-defining illness
• Category B: HIV infection with symptoms attributable to ,or
complicated by , HIV infecton
-Bacillary angiomatosis
-Oropharyngeal candidiasis
-Vulvovaginal candidiasis
-Pelvic inflammatory disease
-Cervical dysplasia(moderate or severe)/cervical CA in situ
-Oral hairy leukoplakia
-Idiopathic Thrombocytopenic purpura
-

38. CDC CLASSIFICATION
• Category B:
- Constitutional symptoms : fever >38.5 degrees
C, or diarhoea > 1 month
- Peripheral neuropathy
- Herpes zosters (shingles) , involving 2 or more
dermatomes or 1 or more dermatome.
• Category C:HIV infection with AIDS defining
illnesses.

39. CDC CLASSIFICATION
• CD4 counts are further used to subdivide the
categories:
-CD4 counts >500/uL : categories A1,B1,C1
-CD4 counts 200-400/uL: categories A2,B2,C2
-CD4 counts <200/uL: categories A3,B3,C3
Once an HIV infection is staged into a higher
category it stays in that category permanently.

40. WHO CLINICAL STAGING
• Stage 1:
-Asymptomatic
-Generalised lymphadenopathy
Performance scale 1: normal activity.

41. WHO CLINICAL STAGE 2
• Weight loss < 10% body weight
• Mucocutaneous manifestations:
-seborrheic dermatitis
-prurigo
-fungal nail infections
-recurrent oral ulcerations
-angular stomatitis
• Herpes zoster in last 5 years
• Recurrent upper respiratory tract infections
Performance scale 2: symptomatic,normal activity.

42. WHO CLINICAL STAGE 3
• Weight loss> 10% body weight
• Chronic diarrhoea > 1 month
• Prolonged fever(intermittent or constant)> 1 mth
• Oral candidiasis
• Oral hairy leukoplakia
• Pulmonary TB in past 1 year
• Severe bacterial infections
(pneumonia,pyomyositis)
• Performance scale 3: Bedridden <50% of day
during last month

43. WHO CLINICAL STAGE 4
• AIDS defining illnesses
• And/or performance scale 4: Bedridden > 50%
of the day in the last 1 month
• WHO clinical staging is important in resource-
poor countries who may not be able to afford
CD4 counts. Treatment should be initiated in
stages 3 and 4.

44. LABORATORY DIAGNOSIS
Involves detection of :
• Antibody to the virus:
-serologic screening
-serologic confirmatory test
• Detection of Virus itself
• Secondary testing to assist with diagnosis or
staging
-Viral culture,Lymph node biopsy,Pro viral DNA
PCR,Genotyping of viral DNA/RNA

45. HIV TESTING
• HIV pre-test counselling.
• Serological test (typically, ELISA and/or rapid
• tests) for HIV antibodies, followed by Western
• Blot confirmatory test.
• Post-test counselling, including information on
• reducing risky behaviour, irrespectively whether
• the HIV test turned to be positive or negative.

46. SEROLOGIC TESTING
• All testing and counselling services must
include the five C's recommended by WHO:
informed Consent, Confidentiality,
Counselling, Correct test results and linkage to
Care, treatment and other services.
• Antibodies appear 6-8 weeks after exposure.
• This is called the window period or serologic
latency period.

47. Screening test:Enzyme linked
Immunoadsorbent Assay(ELISA)
• ELISA is cheap, easy to perform, highly
reproducible and is the most common diagnostic
test available
• 3 types of ELISA:
-Direct
-Indirect
-Sandwich
Drawbacks include high false positive and negative
rates,failure to diagnose neonatal infection and
those in window period

48. ELISA
• ELISA’s can detect HIV1 types M,N,O and HIV2.
• Results typically reported as positive,negative,
indeterminate.
• HIV2 should be tested for in patients from an
HIV2 endemic region or those with
indeterminate testing in HIV1.
• Early detection is facilitated by combination
screens, and additional detection of p24
antigen or viral RNA.

49. HIV SCREENING RECOMMENDATIONS
• -All adolescents and adults at increased risk
for HIV, and pregnant women(USPSTF)
• -Persons at high risk to be screened at least
annually (CDC)
• -

50. Confirmatory test
• Antibodies to viral antigens are detected:
• Viral antigens are produced from 3 main genes
gag,env,pol
• Gag gene products :p56,p27,p17
• Env: p160,gp120,gp41
• Pol: p66-RT heavy chain,p51-RT Light chain,P-
32 integrase enzyme, p10 protease enzyme

51. WESTERN BLOT TEST
• Commonest confirmatory test
• The red cross criteria is unequivocal evidence
of antibody to at least one product of each of
3 viral genes
• CDC recommends that presence of any two of
the following is a positive result:
-p160,gp120,gp41,p24

52. CD4 T cell count
• Reference range for CD4 counts is 500-2000 cells/uL.
• After seroconversion,CD4 tends to decrease(700/uL) and
continues to decline over time
• A CD4 count < 200/uL is considered AIDS-defining.
• There may be discordance between absolute CD4 T cell
counts and CD4 T cell percentages esp in those with active
Hepatic C infection and advanced Liver disease.
• In children, CD4 % <25 % consider starting therapy

53. VIRAL LOAD
• Viral load is a surrogate marker of viral
replication.
• The test is conducted using Nucleic acid sequence
based analysis(NASBA) or Reverse transcriptase
PCR for amplification of viral RNA.
• Patients with viral loads >30,000/uL are more
likely to die of AIDS.
• Optimal viral suppression is to an undetectable
level (<20-75cells/mls)
• Virologic failure= viral load >200 cells/mls

54. SECONDARY HIV TESTING
• Viral culture: less sensitive in patients with low
viral loads, may be performed as part of
phenotypic drug resistance testing.
• Lymph node architecture: HIV DNA,RNA,and
proteins may be detected with molecular
techniques.
• Pro viral DNA PCR: Performed in newborns
because maternal antibodies persist for 9
months.Two negative results seperated by a
month considered negative.

55. SECONDARY HIV TESTING
• Genotyping of viral DNA/RNA.
-sequencing of viral genome to detect mutations
that result in resistance to drugs/drug classes.

56. BASE LINE TESTING
• Testing for other infections :
-Purified protein derivative(PPD) skin testing for
Tuberculosis + Chest X-ray
-CMV testing: anti-CMV IgG indicates previous infxn
-Syphilis testing:Rapid plasma reagin
-Rapid amplification testing for
chlamydia,gonorrhea
-Hepatitis A,B,C testing:may need vaccination or RX
-Antitoxoplasma antibody: Prophylaxis if CD4<100
-Ophthalmologic examination for CMV retinitis

57. BASE LINE TESTING
• Base line tests prior to commencing ARVs
-Liver function tests
-serum chemistries
-Blood Urea nitrogen/serum creatinine
-Fasting Lipid Panel
-Vitamin B12 and folate levels
-Thyroid function
-Urinalysis: to evaluate HIV-associated nephropathy
-Drug screen

58. MANAGEMENT
• The current Department of Human and Health
services (DHHS) recommendations on
initiation of anti retroviral therapy(ART) are:
-ART should be initiated in all patients with
history of AIDS-defining illness or CD4 count >
350 cells/uL
-ART should be commenced regardless of CD4 in
: pregnant women,patients with HIV-associated
nephropathy, those with HBV co-infection.

59. MANAGEMENT
• CD4 counts 350-500/uL : 55% strong
recommendation, 45% moderate
recommendation.
• CD4 counts > 500/ul

60. ANTI RETROVIRAL THERAPY
• Classes of antiretroviral agents:
-Nucleoside reverse transcriptase inhibitors(NRTIs)
-Non-nucleoside reverse transcriptase
inhibitors(NNRTIs)-1997
-protease inhibitors(PIs)-1995
-Fusion inhibitors -2003
-CCR5 Co receptor antagonists (entry inhibitors)
-HIV integrase strand transfer inhibitors -2007
There are now more than 20 approved
antiretroviral drugs.

61. ANTI RETROVIRAL THERAPY
• Both NRTIs and NNRTIs interfere with viral
replication by inhibiting reverse transcriptase
• PIs inhibit Protease, an enzyme involved in
replication
• Fusion or entry inhibitors prevent HIV from
binding to or entering cells.
• Integrase inhibitors interfere with integrase
the enzyme HIV needs to insert genetic
material into cells.

62. Nucleoside reverse transcriptase
inhibitors(NRTIs)
• Lamivudine 3TC
• Abacavir ABC
• Zidovudine AZT or ZDV
• Stavudine d4T
• Didanosine ddI
• Emtricitabine FTC
• Tenofovir TDF

63. Non-nucleoside reverse transcriptase
inhibitors(NNRTIs)
• Delavirdine DLV
• Efavirenz EFV
• Etravine ETR
• Nevirapine NVP
• Rilpivirine

64. PROTEASE INHIBITORS
• Amprenavir AMP
• FOS- APV Fosamprenavir Telzir
• Atazanavir ATV
• Darunavir DRV
• Indinavir IDV
• Lopinavir + ritonavir LPV/RTV
• Nelfinavir NFV
• Ritonavir RTV
• Saquinavir SQV
• Tipranavir TPV

65. FUSION OR ENTRY
INHIBITORS/INTEGRASE INHIBITORS
• Enfuvirtide T-20- binds to GP41
• Maraviron MVC- binds to CCR5 receptor
• Integrase inhibitors:
Raltegravir RAL

66. Highly active anti retroviral
therapy(HAART)
• Taking a combination of three or more anti
retroviral agents is called HAART.
• This vastly reduces the rate at which
resistance occurs.
• The most common combination is 2 NRTIs
with either a NNRTI or “boosted” protease
inhibitor.
• Fixed dose combinations reduce the number
of pills to be taken daily.

67. Highly active anti retroviral
therapy(HAART)
• Regimen selection is based on the following:
-Virologic efficacy
-Toxicity
-pill burden
-dosing frequency
-Drug-drug interaction profile
-Drug resistance testing results
-co morbid conditions

68. ARV REGIMENS
• First Line ARV regimens
-{ AZT/3TC + NVP or EFV ] Recommended
- TDF/FTC + NVP or EFV
• Women of Childbearing age who may get pregnant
• AZT/3TC + NVP or
• TDF/FTC + NVP
•
• Any patients with TB co infection
• AZT/3TC + EFV or
• TDF/FTC + EFV

69. ADDITIONAL TREATMENTS
• Prophylaxis is indicated for :
-pneumocystis jiroveci
-Toxoplasma
-Mycobacterium Avium complex
- Fungal infections : fluconazole to prevent
candidal or cryptococcal infections at CD4< 50/uL
- Viral infections: oral ganciclovir for CMV in
advanced AIDS

70. ADDITIONAL TREATMENTS
• Treatment of HIV lipodystrophy
• Suppressive therapy for HSV-2 : acyclovir
• Treatment of HIV associated diarrhoea.

71. TREATMENT OF HIV AND TB CO
INFECTION
Criteria Anti-TB treatment ART
Extrapulmonary TB
(Irrespective of CD4
count)
Start immediately Start ART as soon as TB
treatment is tolerated
(between 2 weeks and 2
months)
Pulmonary TB CD4 <
200/mm3
Start immediately Start ART as soon as TB
treatment is tolerated
(between 2 weeks and 2
months)
Pulmonary TBCD4
between 200-350/mm3
Start immediately Start ART after completion
of initial TB treatment
phase (if severely
compromised start earlier)
Pulmonary TBCD4
>350/mm3
Start immediately Monitor CD4
countConsider ART if CD4
cell count drops below
350/mmm3

72. Side effects of ARVS: NNRTIs
-Nevirapine can cause a severe skin rash. It has
also been found to be hepatotoxic
-Efavirenz can cause CNS manifestations like
mood alterations.

73. IMMUNE RECONSTITUTION INFLAMMATORY
SYNDROME
AMONG PATIENTS WITH HIV-RELATED TB
• Fever
• New or worsening adenitis - peripheral or central
nodes
• New or worsening pulmonary infiltrates, including
respiratory failure
• New or worsening pleuritis, pericarditis, or ascites
• Intracranial tuberculomas, worsening meningitis
• Disseminated skin lesions
• Epididymitis, hepatosplenomegaly, soft tissue
abscesses

74. NRTIs
• Abacavir causes a hypersensitivity reaction
• Stavudine- neuropathy
• Lamivudine- anaemia
• Didanosine- pancreatitis
• Lactic acidosis

75. PROTEASE INHIBITORS
• Lipid abnormalities -Hyperlipidemia
• fat accumulation
• Indinavir – nephrolithiasis
• Insulin resistance

76. DRUG INTERACTIONS
• Rifampicin and Nevirapine both induce
CYP3A4
• Avoid combination of Rifampicin and
Nevirapine,replace with Efavirenz
• Rifabutin can be combined with Nevirapine
• Avoid combination of zidovudine and
stavudine due to antagonism
• Also avoid tenofovir and didanosine due to
antagonism

77. PREVENTION
• Education of risk groups
• Practising safer sex and abstinence
• Rigorous testing of donor blood
• Institution of measures to prevent
MTCT(mother to child transmission) during
pregnancy,labour,delivery & post partum
period.
• Post exposure prophylaxis for health workers