3. The early years
• AIDS first recognised in 1981
• HIV
– originated from non-human primates
– transferred to humans during late 19th or 20th century
– most recent common ancestor probably between 1902-21
• HIV-1
– more virulent, global spread
– closely related to virus found in chimpanzees
• HIV-2
– less transmissible, W Africa mainly
– closely related to Old world monkey virus
4.
5. Definitions and Staging
• HIV infection
• AIDS: CD4 count < 200 at least once before OR WHO
Stage 3 or 4 condition
• WHO-
• CDC-
7. Global figures
• 36.7 million people living with HIV at the end of 2015
– 15 countries account for 75% of all people living with HIV
– 25.6 million in sub-Saharan Africa
• 1 in 20 adults
– 16 million are women >15 years
• 80% in sub-Saharan Africa
– 3.2 million children
• 3 in 5 people with HIV are not accessing treatment
• New infections peaked in 1997
– fallen by 21% since then
– offset by reductions in AIDS-related deaths
9. African epidemic patterns
Predominantly heterosexual epidemic
• Unprotected sex with multiple partners
• Large pool of serodiscordant couples (36-
85%)
• Subsequent transmission in long term
relationships
Paid sex
• a third of all transmissions in Ghana
Injection drug use
• minor factor: only 3.8% of newly
infected in Kenya 2006
• emerging risk group
• but main driver for epidemic in
Mauritius
MSM
• 20% of new HIV infections in
Senegal
• majority bisexual (82% of
surveyed men in Senegal)
10. Nigeria HIV figures
• First case reported in 1986
• 3.5 million people estimated to be living with HIV in 2015
– second largest number of people living with HIV in the world
• Adult prevalence rate peaked at 5.8% in 2001
– highest prevalence rate of 21% recorded from Benue sentinel sites
– currently 3.2% prevalence in 15-49 year olds
• Bulk of infections (42%) occur in those practicing low-risk sex
13. Transmission
• Sexual transmission-predominant mode of transmission
worldwide is heterosexual transmission
• Injection drug use
• Blood and blood product transfusion
• Occupational transmission (healthcare and laboratory workers)
now rare
• MTCT- during pregnancy (20-30%), delivery (50-60%) and via
breastmilk (12-20%)
• Human bite transmission is possible but rare. HIV has been found
in saliva but at very low levels. Saliva contains enzymes that
render HIV ineffective
16. Pathophysiology
• HIV is an enveloped, single-
stranded RNA virus belonging to
the family Retroviridae
• Two human immunodeficiency
viruses exist: HIV-1 and HIV-2
– HIV-1 has worldwide
distribution, accounts for
most infections outside
western Africa
- HIV-2 infection
• virus differs by 60% in genetic make-up
• causes a similar clinical syndrome
• but less efficiently transmitted
• lower levels of viraemia
• slower progression to AIDS
• naturally resistant to non-nucleoside
reverse transcriptase inhibitors
17. Pathophysiology
• Subtypes based on genetic heterogeneity
• Association with
– specific geographical areas
– less with transmission
– less with resistance patterns
• HIV-1 Groups M, O and N
• Group M (or Main strain)
– nine subtypes (A-K)
– numerous subtypes (e.g.A1-A4)
– circulating recombinant forms CRF
• Subtype B – Americas and
Europe
• Subtype C – half of all
strains globally
18. Replication Cycle
• Why is HIV a problem? Because it gets into the body,
infects T-lymphocytes (specifically CD4+ T-lymphocytes)
which protect against certain infections
• To cause damage it needs to attach to and enter these cells
and others that carry the CD4 molecule, multiply, release
new viral particles which go on to further infect other CD4
positive cells thereby propagating the virus
• HIV is an RNA virus that integrates itself into the genome of
target cells of the host
19. Replication
• HIV has gp-120 which binds to the CD4 protein on the
surface of target cells such as T lymphocytes
• After binding, the gp-120 undergoes conformational
change
• This change facilitates binding of the virus to co-
receptors on host target cells (CCR5 and CXCR4)
• All of this leads to membrane fusion between the virus
and the target cell via the viruses’ newly exposed gp41
20. Replication cycle
• The viral RNA protein is extruded into the host cell
cytoplasm and uncoated
• Viral reverse transcriptase transcribes the viral RNA to
DNA which then forms double stranded DNA in the
host target cell cytoplasm
• This then penetrates the nucleus where it is integrated
into host cell chromosome with the help of the
integrase enzyme
21. Replication cycle
• The integrated proviral DNA gets transcribed into
mRNA, genomic RNA
• mRNA gets translated into proteins which are arranged
into a new viral particle that then buds off from the
host cell and is cleaved by the protease enzyme to
release a mature viral particle
• This viral particle then repeats the cycle
23. Pathogenesis
• Profound immunodeficiency
• Qualitative and quantitative deficiency of helper T Cells
• Helper T cells are defined by presence of CD4 molecule on the
surface
• Depletion of CD4 T cells occurs by:
Direct infection and destruction by the virus
Immune clearance of infected cells
Cell death associated with aberrant immune activation
Immune exhaustion from aberrant cellular activation
• CD4+ T cells below a threshold predispose to OIs
• Reversal of CD4/CD8 ratio
24. Natural Course of Infection
Acute infection:
• 1-3 months
• Uncontrolled viral replication High viremia
• CD4 count drops acutely
• Immune response yet to begin
Clinical Latency:
• 8-10 years
• CD4 rises but not to pre-infection levels
• Viral load drops to viral set point
AIDS:
• 2-3 years
• Again CD4 drops rapidly and viral load rises abruptly
25. Immune Activation
• Normal response to any foreign antigen or pathogen
• Associated with inflammation
• Aberrant because it is exaggerated and life-long; at
varying degrees throughout the course
• Aids viral replication
• Induction of immune dysfunction
• Increases incidence of chronic metabolic and other
non-infectious conditions
28. Diagnosis of HIV Infection
INDIRECT
• Antibody testing: 3 to 12 weeks
Standard screening test
ELISA or EIA platform (highly sensitive)
Commercially available as rapid kits for HIV1/2
4th generation EIA combined with p24 detection
DIRECT
• p24 antigen testing: 16 days
• Nucleic acid testing:12 days
30. Acute HIV Syndrome
• 3-6 weeks after infection
• Symptomatic for one to several weeks
• Resolve with immune response and decline in viremia
• Drop in CD4 count followed by recovery of counts prior
to stage of clinical latency
32. Clinical Latency
• Duration varies
• Median time is 8-10 years
• Average decline of CD4 count by about 50 cells per year
• High viral load correlates with rapid progression and
shortened clinical latency
• LTNP have low VL and very little CD4 decline over time
• Disease is active even though there are no symptoms
33. Symptomatic Disease
• Usually CD4 < 200
• AIDS defining illnesses if CD4 is allowed to decline
• If on treatment, more non AIDS related illnesses
• Infections associated with impaired cellular immunity
• Also remain prone to non AIDS related pathogens
commonly found in healthy or non-HIV patients
35. Goals of Therapy
• Suppression of viral replication
• Immune reconstitution
• Control of immune activation and chronic inflammation
• Primary and secondary prevention of opportunistic
infections
• Prolongation of life
• Never stop ART unless you have no choice
36. 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2011 2013 2014 2015 2016
AZT ddI ddC d4T 3TC IDV DLV EFV AMP LOP/ TDF ATV FOS TPV DRV RAL RIL DOL EVG TAF BIC
SQV RIT ABC RIT FTC MVC ETR (COB)
NVP T-20
Nucleoside RT inhibitors
Non nucleoside RT inhibitors
Protease inhibitors
Entry inhibitors
Integrase inhibitors
Introduction of antiretroviral drugs
Slide courtesy of Prof Andrew Lever
HIV Treatment
37. Principles of treatment
• TEST AND TREAT!
• Combination Therapy
2NRTIs + NNRTI (1st line therapy)
2NRTIs + PI (2nd line therapy)
2NRTIs + Integrase inhibitor
2NRTIs + Fusion Inhibitor
2NRTIs + CCR5 Antagonist
• Uninterrupted, lifelong treatment
• Primary and secondary prophylaxis
42. Special Considerations
• HIV/Hep B co-infection: use dually active agents
• HIV/TB co-infection: ensure right timing of HAART
• Anemia: avoid AZT
• Psychiatric illness: avoid EFV if feasible
• Elevated LFTs: avoid NNRTIs
• High CD4 count at start: avoid NVP
• Renal impartment: avoid TDF (TAF is preferred and
eventually will be available locally)
43. Switch vs Substitution
• Substitution: changing a drug in a regimen because of
drug toxicity. Within same regimen line. Both drugs
may have similar resistance profiles
• Switch: changing some or all drugs within a regimen to
a different line because of regimen failure
• Always ensure adherence before switching
44. Treatment Failure Definitions
• Clinical Failure: New or recurrent WHO stage 4
condition after 6 months of effective therapy
• Immunologic failure: CD4 count falls to baseline or
below OR remains persistently below 100 after 6
months of effective therapy
• Virologic failure: >1000 copies/mL of HIV RNA after 6
months of treatment with adherence support
47. The Acutely Ill AIDS Patient
• Time is of the essence
• Many deaths occur within the first 48 hours
• Consider drug toxicity
• Substitute drugs rather than stop regimen
• Switch regimen if failing
• Consider non-AIDS related infections
• Always screen for TB (leading cause of M and M)
• Be aggressive with investigating and treating
• Adhere to general medical principles for the critically ill
48. HIV/TB co-infection
• Very common OI in Nigeria
• Can occur at any CD4 count
• Atypical presentation
• Non-cavitary
• Bilateral disease
• Miliary TB
• Extrapulmonary involvement
• Disseminated disease
DIAGNOSIS
• AFB Smear and culture
• Gene Xpert
• CXR
WHO Criteria
• Any fever
• Any cough
• Any significant weight loss
• Any chronic cough contact
49. HIV/TB co-infection
TREATMENT
• 4 Drug regimen (RHZE) for induction
• 2 Drug regimen (RH) for maintainance
• Duration varies but 6,9 or 12 months usually
Already on HAART
Start TB treatment immediately, continue HAART
ART Naïve
Start TB treatment immediately
CD4<50: start ART within 2 weeks
CD4>50: start ART after 8 weeks of TB treatment
50. Respiratory Disease
• One of the most frequent complications of HIV
infection
• Bacterial pneumonia: Tuberculosis, Pneumocystic
jirovecii (PCP), Streptococcus pneumoniae,
Haemophilus influenzae
• Prone to infections with encapsulated organisms due to
altered B cell function and defects in neutrophil
function
52. Immune Reconnstitution Inflammatory
Syndrome (IRIS)
• Paradoxical: worsening of an existing clinical condition
• Unmasking: Abrupt appearance of a new clinical finding
• Occurs weeks to months following initiation of HAART but
up to 2 years documented
• Seen when starting HAART at very low CD4 count
• Occurs commonly with TB
• Can be fatal
• Manage with NSAIDS and/or steroids or thalidomide
55. Oral Acyclovir
Percent of Persons Infected after a Decade of Use
Typical use
Perfect use
Male circumcision
Microbicides
Diaphragm
Male condom
Oral ARV
0 40 60 80
20
Female condom
Abstinence
Trussell (2004); NCHS (2005)
Slide courtesy of Prof Muktar Aliyu
Effectiveness of Various Forms of Prevention
56. Treatment is Prevention!
Test
Adoption of safer
behaviors by HIV(+) persons
Treat with ART
+
Adherence
Maintain viral suppression
Decrease in HIV Transmission
Vermund SH, Hayes RJ. Combination Prevention: New Hope
for Stopping the Epidemic. Curr HIV/AIDS Rep 2013 Slide courtesy of Prof Sten Vermund
57. Relief on the Egyptian tomb of Ankh-Mahor (2300 BC) Slide courtesy of Prof Sten Vermund
HIV prevention programmes
