2. HIV Infection
• HIV causes acquired immunodeficiency syndrome(AIDS).
• Clinical manifestations of AIDS result from consequences
of a critically impaired immune system.
• Almost 90% of deaths are caused by opportunistic infectio
ns.
Pathogenesis
• HIV is retrovirus (family - retroviridae; subfamily -lentivirus
).
• RNA virus which has enzyme reverse transcriptase and c
onsists of a lipid bilayer membrane surrounding the capsid.
• surface glycoprotein molecule(gp120) has strong affinity f
or CD4 receptor protein on T –helper/inducer lymphocytes.
• Monocytes and macrophages also express CD4 receptor.
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4. • HIV entry is a complex multistage process involving CD4 at
tachment, binding to chemokine co – receptors such as CC
R - 5 and CXCR - 4, and membrane fusion.
• After penetrating the host cell, the virus sheds its outer coat
and releases its genetic material (RNA).
• Viral RNA is converted to viral DNA using nucleosides, by r
everse transcriptase.
• Viral DNA is integrated(inserted) into the host genome(DN
A) by the enzyme integrase.
• Viral DNA undergoes transcription and translation, producin
g new viral proteins.
• New virus particles are assembled and bud out of the host
cell.
• Maturation of new virus particles into infectious virions requ
ire the action of protease enzyme.
• Protease cleaves the precursor proteins into functional poly
peptides.
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7. Clinical Manifestations
• Sequelae of untreated HIV infection divided into five group
s:
1. Opportunistic infections (infections that do not normally c
ause disease in immunocompetent hosts) e.g. P. jiroveci p
neumonia, CMV retinitis
2. Infections that can occur in immunocompetent patients b
ut are more frequent, more severe and more atypical in HIV
patients e.g. Salmonella, herpes simplex and Mycobacteriu
m tuberculosis
3. Malignancies that occur rarely in immunocompetent patie
nts e.g. Kaposi’s sarcoma, non – Hodgkin’s lymphoma.
4. Direct manifestations of HIV infection e.g. HIV encephal
opathy, HIV myelopathy, HIV enteropathy
5.Consequences of chronic immune reactivation e.g. prema
ture CVD death, neurocognitive dysfunction, loss of bone m
ineral density
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8. WHO clinical staging of HIV/AIDS
Primary HIV Infection
•Asymptomatic
•Acute retroviral syndrome (fever, arthralgia, pharyngitis,rash a
nd lymphadenopathy)
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Stage Clinical presentation
1 • Asymptomatic
• Persistent generalised lymphadenopathy
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Clinical Stage Clinical presentation
2 a. Moderate unexplained weight loss (<10%)
b. Recurrent respiratory infections(sinusitis, tonsillitis,
otitis media and pharyngitis)
c. Herpes zoster
d. Angular cheilitis
e. Recurrent oral ulceration
f. Papular pruritic eruptions
g. Seborrhoeic dermatitis
h. Fungal nail infections
3 a. Unexplained severe weight loss( > 10%)
b. Unexplained chronic diarrhoea (> 1 month)
c. Unexplained persistent fever ( > 1month)
d. Persistent oral candidiasis
e. Oral hairly leukoplakia
f. Pulmonary tuberculosis
g. Severe bacterial infections (pneumonia, empyema,
pyomyositis, bone/joint infection, meningitis)
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Clinical Stage Clinical presentation
3 h. Acute necrotising ulcerative stomatitis, gingivitis
i. unexplained anaemia (Hb < 8g/dL)
j. Neutropenia ( < 500cells/µL)
k.Chronic thrombocytopenia ( < 50,000cells/µL)
4 a. HIV wasting syndrome
b. Pneumocystis jiroveci pneumonia
c. Recurrent severe bacterial pneumonia
d. Chronic herpes simplex infection
e. Oesophageal/oropharyngeal candidiasis
f. Extra pulmonary tuberculosis
g. MAC/MAI
h. Progressive multifocal encephalopathy
i. Chronic cryptospridiosis
j. Chronic isosporiasis
k. Disseminated mycosis e.g. histoplasmosis
13. Investigations/ Monitoring
Current and previous infections
• Initial diagnosis of HIV infection made by detecting antibo
dies (sero - conversion) against HIV within 3 – 4 weeks of i
nfection.
• Up to 3 months of ‘window period’ after exposure require
d to exclude infection.(what does this mean???)
• If HIV infection confirmed, patient should be tested for pot
ential pathogens e.g. syphilis, hepatitis, CMV, varicella zost
er, T. gondii.
CD4 count
• Measures the number of CD4 – positive T – lymphocytes i
n a sample of peripheral blood.
• Normal range is 500 – 1500 cells/mm3
• level of Immunosuppression can be estimated by monitori
ng a patient’s CD4 count.
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14. • CD4 count is used as a major indicator of when to conside
r starting antiretroviral therapy.
Viral load
• Measures the number of HIV RNA in a sample of peripher
al blood.
• Estimates the amount of circulating virus in the blood.
• Correlates with prognosis e.g. high viral load predicts fast
er disease progression.
• Reduction in viral load due to antiretroviral therapy is asso
ciated with clinical benefit.
• Clinical decisions such as when to start or change antiretr
oviral therapies can be made based on viral load.
Resistance testing
• Genotypic HIV resistance test is recommended soon afte
r diagnosis due to potential of transmitted (primary) resistan
ce.
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15. • Resistance testing allows selection of appropriate initial th
erapy.
• Further resistance tests should be performed at any subs
equent virological failure to direct therapy choice.
Tropism testing
• Viruses may enter the cell using CCR5 co-receptor, CXC
R4 co-receptor or both.
• Viruses which only use one co-receptor are CCR5 – tropic
or CXCR4 – tropic viruses.
• Viruses which can use both co-receptor types are called d
ual – tropic.
• Mixed – tropic refers to a mixture of virus populations.
• Tests should be performed in real time as viral tropism ch
anges as the disease progresses.
•If CCR5 inhibitors are to be used, it is essential to determin
e that the virus is CCR5 - tropic (no significant use of CXC
R4 receptor)
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16. • If CCR5 inhibitors are to be used, it is essential to determi
ne that the virus is CCR5 - tropic (no significant use of CXC
R4 receptor)
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17. Pharmacological management of HIV Infection
Goals of drug therapy
1.Improve the quality and duration of life
2.Prevent deterioration of immune function and/or restore i
mmune status
3.Treat and/or prevent opportunistic infections
4.Relieve symptoms
Antiretroviral therapy
•Currently one of the fastest evolving areas of medicine.
•Specific details of treatment will continue to change as ne
w drugs emerge.
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18. General principles of antiretroviral therapy
1.A combination of three antiretroviral agents, selected on b
asis of treatment history and resistance tests, should be pr
escribed to increase efficacy and reduce development of dr
ug-resistant virus.
2.A regimen should contain at least one drug that penetrate
s the central nervous system and confers protection agains
t HIV – related encephalopathy/ dementia.
3.Treatment strategies should be adopted that sequence dr
ug combinations, taking potential cross-resistance and futur
e therapy options into consideration.
4.Regimen adopted for a patient should be tailored to suit d
aily lifestyle (high level of adherence is required)
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21. Nucleoside and nucleotide analogue reverse tran
scriptase inhibitors( NRTIs)
Mechanism of action
•NRTIs are phosphorylated intracellularly and then inhibit re
verse transcriptase enzyme acting as a false substrate.
•Nucleotide analogues only require two intracellular phosph
orylations e.g. tenofovir
•Activation of nucleoside analogues is a three – stage proc
ess.
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23. Formulation combining two NRTIs with an NNRTI:
•Tenofovir + emtricitabine + efavirenz ( Atripla®)
Combinations that should be avoided:
•Zidovudine + stavudine ( intracellular competition resulting
in antagonism)
•Stavudine + didanosine (unacceptable toxicity i.e. lactic aci
dosis, lipodystrophy)
•Tenofovir + didanosine (unacceptable rates of virological fa
ilure and potential CD4 count decline)
Adverse effects of NRTIs
•ABC – Usually well tolerated
•Rash, headache, nausea and vomiting,diarrhoea, reduced
appetite (common side effects)
•Lactic acidosis, may increase risk of cardiovascular diseas
e.
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24. • ddI – nausea, bloating, diarrhoea
• Pancreatitis, liver failure, peripheral neuropathy, hyperuricaemi
a, lactic acidosis
• FTC – Headache(most common), nausea, diarrhoea, dizzines
s, lactic acidosis
• 3TC – Generally well tolerated
• GI disturbances, headache, anaemia, neutropenia
• Lactic acidosis
• d4T – peripheral neuropathy, pancreatitis, lactic acidosis, incre
ased risk of lipoatrophy/lipodystrophy syndrome.
• TDF – diarrhoea, nausea and vomiting, flatulence and headac
he (most common)
• Renal impairment and hypophosphataemia.
• AZT – nausea, vomiting, headache, fatigue, muscle pain
(common)
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25. • AZT – haematological toxicities (neutropenia, anaemia), myop
athy, lactic acidosis, increased risk of lipoatrophy/lipodystrophy
syndrome.
Non - nucleoside analogue reverse transcriptase inhibitor
s( NNRTIs)
Mechanism of action
• NNRTIs inhibit the reverse transcriptase enzyme by binding to
its active site.
• They do not require prior phosphorylation and can act on cell –
free virions as well as infected cells.
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26. Examples of NNRTIs
•Efavirenz (EFV, Sustiva®)
•Nevirapine (NVP, Viramune®)
•Etravirine (ETR, Intelence®)
•Rilpivirine (RPV, Edurant®)
•Resistance to NNRTIs occurs rapidly in incompletely suppressiv
e regimens and it is therefore essential that they are prescribed
with at least two NRTIs or a combination of NRTIs and PIs.
•Cross resistance between NVP and EFV is high.
•Etravirine has a different resistance profile( used as an alternati
ve first – line NNRTI)
•NNRTIs have much longer plasma half – lives than PIs and NR
TIs
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27. • When stopping NNRTI- based regimens, continue other agents
for a period after cessation of NNRTI or switching to a boosted
PI prior to regimen discontinuation. ..this is what we call coverin
g the tail or tail cover of NNRTIs.7 days cover
Adverse effects of NNRTIs
• EFV – CNS disturbances (sedation, feeling stoned, dizzy, impai
red concentration, vivid dreams, mood swings, hallucinations)
• Rash
• Raised LFTs
• Hyperlipidaemia
• lactic acidosis, may increase risk of cardiovascular disease
• NVP – Rash, raised LFTs/hepatitis,
• Nausea, headache, sedation, fatigue
• Should not be started in women with CD4 count > 250cells/mm
3 or men with CD4 count > 400cells/mm3 : greater risk of rash –
associated hepatic events.
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28. • ETV – Rash,
• nausea,
• Diarrhoea, abdominal pain
• Headache, pyrexia, fatigue
• RPV – Headache, depression, insomnia, rash, raised LFT
s, lipodystrophy
• Less CNS disturbances than efavirenz and non – teratoge
nic.
Protease inhibitors (PIs)
Mechanism of action
• PIs bind to the active site of the HIV – 1 protease enz
yme, preventing the maturation of newly produced virions
so that they remain non – infectious
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29. Examples of PIs
•Atazanavir (ATV, Reyataz®)
•Darunavir (DRV, Prezista®)
•Fosamprenavir (FPV, Telzir®)
•Indinavir (IDV, Crixavan®)
•Lopinavir co – formulated with ritonavir (LPV/r, Kaletra®)
(ritonavir does not add to antiviral activity - it is a pharmacokineti
c enhancer)
•Nelfinavir (NFV, Viracept®)
•Ritonavir (RTV, Norvir®)
•Saquinavir (SQV, Invirase®)
•Tipranavir (TPV, Aptivus®)
•RAINS LTDF
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30. • Use of ritonavir – boosted PIs has superseded use of single
PIs due to:
1.Better pharmacokinetic profiles( ↑ Cmax, ↑ t1/2 due to inhibitio
n of cytochrome P450 enzymes)
2.Superior efficacy data
3.Reduced likelihood of resistance development
• Newer PIs such as TPV and DRV are effective against ma
ny viruses resistant to earlier PIs.
• DRV is used in first – line PI therapy as once daily boosted a
gent (800mg with 100mg of ritonavir).
• Cobicistat is an alternative booster to ritonavir e.g.
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31. Adverse effects of PIs
•ATV –Nausea, diarrhoea, headache, rash, jaundice (most co
mmon)
•Hperbilirubinaemia
•Raised LFTs
•Does not appear to elevate lipids
•ECG changes
•lipodystrophy
•DRV –Nausea, vomiting, diarrhoea, constipation, abdominal
pain, rash Hyperlipidaemia(most common)
• raised LFTs
•Lipodystrophy
•FPV - Nausea, vomiting, diarrhoea, rash, fatigue (most com
mon)
•Hyperlipidaemia, raised LFTs, Lipodystrophy
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32. • NFV – diarrhoea and flatulence, nausea,(most common)
• Hyperglycaemia
• Lipodystrophy
• SQV - Nausea, vomiting, diarrhoea, abdominal pain, anorexia,
asthenia
• Prolonged QT interval, raised LFTs, Lipodystrophy
• TPV - Nausea, vomiting, diarrhoea, fatigue, raised LFTs, Lipo
dystrophy
Entry inhibitors
• currently two types of entry inhibitors (fusion inhibitors and C
CR5 inhibitors) are available.
.
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33. Fusion inhibitors
Mechanism of action
•Block the structural rearrangement of HIV – 1 gp41 thus stop t
he fusion of the viral cell membrane with the target cell membr
ane, preventing viral RNA from entering the cell.
•Enfuvirtide (T – 20, Fuzeon®) is administered subcutaneously
and largely used in heavily treatment experienced patients.
•Main side effect is injection site reaction.
Adverse effects
•Insomnia,
•headache,
•lymphadenopathy,
•eosinophilia
•hypersensitivity reactions
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34. CCR5 inhibitors
Mechanism of action
•Selectively bind to the human chemokine receptor CCR5, pre
venting CCR5 – tropic HIV – 1 from entering cells.
•Maraviroc (MVC, Celsentri®) is indicated for use in patients wit
h only CCR5 – tropic virus, which is determined by tropism just
prior to commencing treatment.
•Usually used in patients with resistance to one or more other
antiretroviral classes.
Adverse effects
•Nausea (most common)
•Vomiting, abdominal pain, constipation, bloating
•Dizziness, paraesthesia, somnolence, rash, insomnia, raised
LFTs
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35. Integrase inhibitors
Mechanism of action
•Bind to integrase enzyme, thus blocking the integration of viral
DNA into host DNA.
•Was initially used in patients with resistant virus
•Increasingly used in first – line regimens or where tolerability
with initial regimens is an issue.
Examples include:
•Raltegravir (RAL, Isentress®)
•Elvitegravir (requires boosting with cobicistat)
•Dolutegravir
Adverse effects
•Nausea and headache, dizziness, vertigo, abdominal pain, flat
ulence, constipation, pruritus, arthralgia, fatigue, raised creatin
e kinase, myopathy and rhabdomyolysis.
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36. Toxicity of antiretroviral therapies
Mitochondrial toxicity
•Increasingly recognised in patients with prolonged exposur
e to nucleoside analogue antiretrovirals e.g. d4T, ddI and to
a lesser extent, AZT.
•Explains such side effects as peripheral neuropathy, myop
athy, pancreatitis, and lactic acidosis.
•Side effects are managed by switching the likely offending
agent, if possible.
•NRTIs also function as substrates for other enzymes like D
NA polymerase gamma (involved in the replication of mitoc
hondrial DNA)
•Disruption of DNA polymerase gamma is thought to result i
n a wide variety of adverse effects ranging from lactic
acidosis to hepatic steatosis
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37. Rash and hepatitis
•recognised as common side effects of NNRTIs.
•Incidence and severity appear greatest with NVP in patients w
ith higher CD4 count (>250cells/mm3 for women and > 400cell
s/mm3 for men)
•Management is either close observation (mild-to-moderate ca
ses) or withdrawal of offending drug(severe cases).
•ABC Hypersensitivity presents in the first 6 weeks of therapy a
s a progressive illness with fevers, rash and flu-like symptoms.
•Manage ABC – induced hypersensitivity by withdrawing ABC.
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38. Lipodystrophy
•Characterised by lipoatrophy ( fat loss from the face , upper li
mbs and buttocks) and/ or lipohypertrophy (abnormal fat depos
ition, affecting the abdomen and neck).
•d4T and AZT are associated with lipoatrophy while PIs induce
lipohypertrophy.
•Management involves avoiding or switching away from offendi
ng drugs and/or cosmetic approaches (fillers or liposuction).
Metabolic disturbances
•Hypercholesterolaemia and hypertriglyceridaemia are associa
ted with PIs.
•Incidence appears lower with ATV.
•Managed by reducing modifiable risk factors, switch away fro
m offending agent to a metabolically favourable agent or adjun
ctive lipid - lowering therapy
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39. • Renal impairment
Renal impairment has been reported with TDF.
• Creatinine clearance should be calculated and proteinuria qu
antified prior to commencing therapy with TDF and should be
monitored regularly.
Cardiovascular disease
• Increased risk of cardiovascular disease is associated with us
e of some PIs ( LPV/r, IDV) and with NRTI, ABC.
• Risk is independent of the effects on lipids and mechanism is
yet to be determined.
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40. Preferred 1st line cART and alternative regimens by specific
populations
•XTC is 3TC or FTC
•EFV is the preferred NNRTI for first line cART initiation.
•Consider using EFV at all times unless there are contraindications to it
s use.
•EFV is associated with central nervous system(CNS) side effects (e.g. d
izziness, drowsiness, insomnia, abnormal dreams, and impaired concen
tration) that generally occur with the first few doses and usually diminis
h or disappear after 2-4 weeks.
Special popul
ations
Description Preferred 1st line cA
RT
Alternative regimen
Adults A once-daily fixe
d-dose combinat
ion
is recommended
TDF (TAF) + XTC +DT
G
TDF (TAF) + XTC + EFV
ABC +3TC + DTG
40
42. Children (0 -2weeks)
•First-line regimen: AZT + 3TC + NVP
•Alternative regimen: AZT + 3TC + RAL
Children (2 weeks -5 years old)
•Less than 20kg
•First-line regimen: ABC + 3TC +LPVr
•Alternative regimen: AZT +3TC + LPVr or AZT +3TC + RAL
42
43. Children (2 weeks -5 years old)
•BETWEEN 20 -24.9KG
•First-line regimen: ABC + 3TC + DTG
•Alternative regimen: AZT +3TC + LPVr or ABC +3TC + LPVr
•Equal or greater than 25KG
•First-line regimen: TAF+ XTC + DTG
43
44. Elimination of Mother to child Transmissio
n (EMTCT)
• CHILD BORN TO HIV POSTIVE MOTHER.
1.AT BIRTH
Do HIV testing, if negative start :
AZT + 3TC +NVP for 12 weeks
2. AFTER 6 WEEKS
Test still negative , continue with AZT + 3TC +NVP
3. AFTER 10 WEEKS
Test still negative , continue with AZT + 3TC +NVP
44
45. Elimination of Mother to child Transmissio
n (EMTCT)
4. AFTER 14 WEEKS
Test still negative , continue with AZT + 3TC +NVP
If mother virally suppressed stop AZT + 3TC +NVP
5. AFTER 6 MONTHS
Test still negative , continue with AZT + 3TC +NVP
If mother virally suppressed stop AZT + 3TC +NVP
NOTE : DO THE SAME AT 9, 12, 18 AND 24 MONTH
If the child is found positive during this route visits start ART
.
45
46. FIRST LINE FOR HIV 2/ HIV 1 CO INFE
CTION
• 1. ADULTS
TDF (TAF) +3TC + DTG
• 2. CHILDREN
ABC + 3TC + LPVr
46
47. SECOND LINE TREATMENT
1 . CHILDREN > 5 YEARS
FIRST LINE: ABC + 3TC + LPVr
SECOND LINE : AZT + 3TC + RAL or AZT + 3TC + DTG
2 CHILDREN 5 - 10 YEARS
FIRST LINE: ABC + 3TC + EFV
SECOND LINE : AZT + 3TC + LPV r or AZT + 3TC + DTG
3.ADULTS
FIRST LINE: TDF + 3TC + DTG
SECOND LINE : AZT + 3TC + LPVr
FIRST LINE: TDF + XTC + EFV
SECOND LINE : AZT + 3TC + DTG
47
48. PRE EXPOSURE PROPHYLAXIS (PrEP
)
• The recommended treatment :
TDF or TAF + XTC
PrEP only becomes effective after 7days (21 day in women
) after starting the medications
PrEP should be discontinued after 4 weeks of elimination
of risky exposure
48
49. Post Exposure Prophylaxis
• Recommended treatment
1. medium risk: invasive injury, no blood visible on the need
le
Preferred treatment: TDF or TAF + XTC +DTG
Alternative treatment : TDF or TAF + XTC + DRVr
• 2. high risk: large volume of blood/fluids, known HIV patie
nt, large bore needle, deep extensive injury
Preferred treatment: TDF or TAF + XTC + LPVr
Alternative treatment : TDF or TAF + XTC + ATVr
49
50. Post Exposure Prophylaxis
3. penetrative sexual abuse
•AZT + 3TC + LPVr (children < 20kg)
•AZT + 3TC + DTG (children equal or greater than 20kg)
•TAF + FTC + DTG (children equal or greater than 25kg)
50
Editor's Notes
Stage one :asymptomatic stage.
stage two:dematological effects:
stage three:systemic and soft tissue infections and
stage four :all forms of infections are found.
Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex ("MAC"), which is made of three mycobacteria species, M. avium, M. intracellulare, and M. chimaera.[1] This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.
M. avium, M. intracellulare, and M. chimaera are each saprotrophic organisms present in soil and water; entry into hosts is usually via the gastrointestinal tract, but also can be via the lungs.
MAC infections can cause fevers, diarrhea, malabsorption, as well as loss of appetite and weight loss, and can disseminate to the bone marrow. Therapy for MAI is typically resistant to standard mycobacterial therapies.
HIV-associated nephropathy (HIVAN) refers to kidney disease developing in association with HIV infection. The most common, or "classical", type of HIV-associated nephropathy is a collapsing focal segmental glomerulosclerosis (FSGS), though other forms of kidney disease may also occur with HIV.Regardless of the underlying histology, renal disease in HIV-positive patients is associated with an increased risk of death.
HIVAN may be caused by direct infection of the renal cells with the HIV-1 virus, with resulting renal damage through the viral gene products. It could also be caused by changes in the release of cytokines during HIV infection. Usually occurs only in advanced disease and approximately 80% of patients with HIVAN have a CD4 count of less than 200. HIVAN presents with nephrotic syndrome and progressive kidney failure. Despite being a cause of chronic kidney failure, kidney sizes are usually normal or large.
Lactic acidosis is when lactic acid builds up in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.
Take Note: Should not be started in women with CD4 count > 250cells/mm3 or men with CD4 count > 400cells/mm3 : greater risk of rash – associated hepatic events.
Cobicistat is an alternative booster to ritonavir e.g. TDF, FTC+ Cobicistat + Elvitegravir
Lactic acidosis is when lactic acid builds up in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.
Myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease (myo- Greek μυο "muscle" + pathos -pathy Greek "suffering").
