2. Outline
Introduction
Epidemiology and impacts
Etiology and Virology
Pathophysiology and pathogenesis
Diagnosis:
Staging of disease
Laboratory diagnosis
Management:
Preventive strategies
HAART
Initiating and monitoring therapy
3. Introduction
Acquired immunodeficiency syndrome (AIDS) is the
most severe manifestation of a clinical spectrum of
illness caused by infection with human
immunodeficiency virus (HIV).
AIDS was first recognized in mid-1981, when unusual
clusters of Pneumocystis jirovecii pneumonia and
Kaposi’s sarcoma were reported in young, previously
healthy homosexual men in US.
In 1983 a cytopathic retrovirus was isolated from
persons with AIDS.
By 1985, Serologic tests to detect HIV had been
developed and licensed.
4. Epidemiology
HIV/AIDS is a global pandemic, with cases reported from
virtually every country.
At the end of 2014, an estimated 36.9 million people were
living with HIV globally.
The annual number of people dying from AIDS related
causes worldwide was 1.2 million in 2014
The 2015 world AIDS Day report showed the new HIV
infections have fallen by 35% since 2000.
In worldwide, 2 million people became newly infected
with HIV in 2014, down from 3.1 million in 2000
The incidence has been decreasing because of:
Natural trends in the pandemic, and
Commencement of HAART and other prevention programs.
5. Epidemiology
Sub-Saharan Africa continues to bear the brunt of the
global HIV epidemic
About 25.8 million (70%) of infected people live in sub-
Saharan Africa.
In 2014, 1.2 million deaths were reported globally, 65.8%
of which occurred in sub –Saharan Africa
Heterosexual exposure is the primary mode of HIV
transmission in sub-Saharan Africa;
Women and girls disproportionately affected, accounting
for 60% of all HIV infections.
6. Ethiopian HIV/AIDS Epidemiology
1984: The first evidence of HIV infection found in
Ethiopia.
1986: The first two AIDS cases reported to the MoH.
Ethiopia is home to approximately 800,000 patients
with HIV/AIDS
The prevalence of HIV/AIDS in the general population
is estimated to be 1.5%
More than 85% of HIV infections occur among adults
between 15-49 years.
The free antiretroviral therapy (ART) program in
Ethiopia, introduced in 2005
By the end of 2011, 249 174 adult patients (86% of
eligible patients) were on ART
6
7. Transmission
Main modes of transmission are:
Sexual:
Heterosexual
Homosexual
Blood transfusion
Needle prick; sharing of sharp materials; injection
drug use
Mother to child [MTCT]
Mucosal exposure to infected blood and some body
fluids.
8. Transmission…
The risk of HIV transmission varies with modes:
Receptive anal intercourse: B/n 1:100 and 1:30,
Insertive anal intercourse 1:1000,
Receptive vaginal intercourse 1:1000,
Insertive vaginal intercourse 1:10,000.
The risk increases with the presence of
ulcerative or inflammatory STDs, trauma, menses, and
lack of male circumcision.
Needle stick with infected blood is approximately 1:300.
The risk increases with depth of penetration, hollow bore
needles, visible blood on the needle, and advanced stage
of disease in the source.
9. Transmission….
Transmission risk from illicit drug use with sharing of
needles from an HIV-infected source is estimated to be
1:150.
Transmission risk from infected blood transfusion is
95%.
The screening of blood before transfusion and prohibiting
donation from high risk groups lowered the chance of HIV
transmission to about 1:1,000,000.
The risk of HIV transmission from a mucosal splash with
infected blood is unknown but is assumed to be lower.
Without PMTCT, MTCT risk rages b/n 13% and 40%.
10. Etiology and Virology
HIV has two major types and several
subtypes/strains:
HIV 1- Pandemic:
HIV M (A,B,C,D,E,F,..K,& others)- >95% Global burden
HIV O
HIV N
HIV 2 – mainly in West Africa .
Subtype C viruses (of the M group) are the most
common, accounting for 50% of infections worldwide.
In sub-Saharan Africa, the majority of infections are
caused by subtype C.
Subtype B viruses are predominant in Americas, western
Europe, and Australia accounting for 12–13% of global
infections.
11. Etiology and Virology
HIV is an RNA virus whose hallmark is the reverse
transcription of its genomic RNA to DNA by the
enzyme reverse transcriptase.
HIV-1 genomes contain
genes for three basic structural proteins [gag , pol, and env]
and at least five other regulatory proteins
The greatest variability in strains of HIV occurs in the viral
envelope.
HIV-2
a related virus, has been isolated in West African patients.
has same genetic organization as HIV-1, but with significant
differences in the envelope glycoproteins
less pathogenic or have a longer period of latency preceding
disease.
13. Etiology and Virology…
The extraordinary diversity of strains has
implications for possible differential rates of:
Disease progression
Responses to therapy, and
The development of resistance to antiretroviral drugs.
also a formidable obstacle to HIV vaccine development
14. Pathophysiology and Pathogenesis
HIV results in the clinical syndromes [AIDS] by one or a
combination of the three known mechanisms:
1. Immunodeficiency [Immune Activation,
Inflammation, and subsequent immune
exhaustion]
2. Autoimmunity, and
3. Allergic and hypersensitivity reactions
15. Pathophysiology and Pathogenesis…
1. Immunodeficiency [Immune Activation, Inflammation
and subsequent immune exhaustion]:
Lymphoid tissues are the major sites for the
establishment and propagation of HIV infection.
The CD4 molecule is the major receptor of HIV:
Predominantly expressed on T- helper lymphocytes.
Also expressed on the surface of monocytes/macrophages and
dendritic/Langerhans cells.
CCR5 and CXCR4 are major co-receptors
Reservoirs can exist in other compartments including:
Monocyte/macrophage liniages
Peripheral blood
The CNS, and
In other unidentified locations.
16. Pathophysiology and Pathogenesis…
Profound progressive immunodeficiency results in both
quantitative and qualitative loss of helper T-lymphocytes
Activation of the immune system and inflammation are
essential components of any appropriate immune
response to a foreign antigen.
However, these responses are aberrant in HIV-infection
which plays a critical role in the pathogenesis.
It ultimately leads to immune exhaustion
17. Pathophysiology and Pathogenesis…
2. Autoimmunity:
Can occur as a result of cellular and humeral immune
dysfunction
Examples are lymphocytic infiltration of organs and
autoantibody production
The phenomena reflects chronic immune system activation
as well as molecular mimicry by viral components.
Auto antibodies to lymphocytes and, to platelets, neutrophils
and many serum proteins have been demonstrated.
The increased occurrence and/or exacerbation of certain
autoimmune diseases have been reported in HIV infection
With the widespread use of effective ART, an immune
reconstitution inflammatory syndrome (IRIS) has become
increasingly common.
18. Pathophysiology and Pathogenesis…
3. Allergic & Hypersensitivity Reactions:
HIV-infected individuals appear to have higher rates of
allergic reactions to unknown allergens as seen with:
Eosinophilic pustular folliculitis , and
Increased rates of hypersensitivity reactions to
medications
19. HIV Replication Cycle
The cycle begins with the high-affinity binding of the gp120
protein to its receptor on the CD4 molecule;
This results in the a conformational change of the gp120 that
facilitates binding to one of the two major co-receptors.
The virus then firmly attaches to the host cell membrane in a
coiled-spring fashion via the newly exposed gp41 molecule.
This facilitates fusion of the virion by penetrating the plasma
membrane of the target cell.
Following fusion the preintegration complex is released into the
cytoplasm of the target cell.
The complex enters the nucleus, the reverse transcription of the
genomic RNA into DNA occurs; and
The protein coat opens to release the resulting double-strand pro-
viral HIV-DNA.
With activation of the cell, Integrase catalyzes the integration of
viral DNA into the host cell chromosomes.
20. Replication Cycle of HIV…
Protease catalyzes cleavage and assembly of long HIV proteins,
enzymes, and genomic DNA to form a mature virion.
Budding of the progeny virion occurs through the host cell
membrane, where the core acquires its external envelope.
Finally a mature virus is released to the circulation to infect
another cell.
The replication cycle is profoundly influenced by a variety of viral
regulatory gene products.
The half-life of a circulating virion is 30–60 min and that of
productively infected cells is 1 day.
About 1010–1011 virions are produced and cleared from the
circulation each day.
About 93–99% of the circulating virus originates from recently
infected, rapidly turning over CD4+ T cells.
21. Summary: Six steps in life cycle of HIV in the body
1. Attachment/Binding: HIV attaches to the CD4 cell.
2. Fusion: The virion penetrates the plasma membrane
of the CD4+ cells.
3. Reverse Transcription: The enzyme reverse
transcriptase makes DNA copy of the viral RNA.
4. Integration: New viral DNA is then integrated into
CD4 cell nucleus using the enzyme integrase.
5. Cleavage and Assembly: The newly formed viral
components are assembled together using the enzyme
protease.
6. Budding and release: The new mature virus gets its
envelop proteins and is released in to the circulation
through budding to continue the cycle.
What is the importance of knowing the life cycle?
[SEE HIV Replication 3D Medical Animation]
23. 23
DIAGNOSIS of HIV/AIDS
A. Clinical Diagnosis of HIV/AIDS:
HIV/AIDS can manifest with a spectrum of illnesses
and diseases as a result of the:
1. Direct effect of HIV infection:
[Inflammation, hypersensitivity/Autoimmunity]
– Nervous (encephalopathy and peripheral
neuropathy)
– Kidney (HIVAN = HIV-associated nephropathy)
– Cardiac (HIV cardiomyopathy)
– Endocrine (hypogonadism in both sexes)
– GI tract (dysmotility and malabsorption)
24. 24
DIAGNOSIS of HIV/AIDS
2. Indirect effects:
Opportunistic infections and tumors as a
consequence of immunosuppression
Drug related
Psychological
These manifestations, with laboratory abnormalities, are
used for disease classification and staging.
25. DIAGNOSIS of HIV/AIDS...
B. Laboratory Findings:
Specific tests for HIV include antibody and antigen
detection.
Conventional HIV antibody testing is done by ELISA.
Positive specimens are then confirmed by a different
method (eg, Western blot).
Nonspecific laboratory findings with HIV infection may
include :
Anemia, leukopenia (particularly lymphopenia), and
thrombocytopenia in any combination,
Elevated ESR,
Polyclonal hypergammaglobulinemia, and others.
26. Natural History of HIV Infection
The typical clinical course of an untreated HIV infection
helps to fully appreciate the complex pathogenic events.
Viral set point: Is the peak viremia during the acute retroviral
syndrome which is followed by a steady-state viremia.
It has important prognostic implications for the
progression of HIV disease in the untreated patient.
Patients with low set point at 6 months to 1 year
following infection progress to AIDS much more slowly.
Most patients are relatively asymptomatic even with
progressive decline of CD4 cells;
However, clinical latency does not mean disease latency or
microbiological latency;
27. Natural History of HIV Infection…
27
27
Year 1
Predictor for:
-Disease progression
-Risk of transmission
Low set point = slower
disease progression
High set point = faster
disease progression
28. Patterns of HIV Disease Progression
28
HIV
Infection
Long-term
Non-progressors
Rapid Progressors
Typical Progressors
<3 years
7-10 years
>10-15 yrs
Normal, Stable CD4
90 %
<5 %
<10 %
30. 31
HIV/AIDS Disease staging...
C. Disease staging:
WHY STAGING?
To assess disease severity, and to monitor disease progression
To decide on criteria to initiate ART
T-staging:
Staging while on ART to asses progress or response.
Up and down staging is possible .
Guides when to change treatment.
31. 32
WHO Staging System for HIV/AIDS [Revised in 2010].
Ethiopia uses the WHO Staging System.
It is a tool used to guide management of HIV patients in
resource limited settings:
Clinically based; CD4 count not required;
Simple, flexible and widely used
It has 4 clinical stages based on the degree of immuno-
suppresion and prognosis.
Puts separate category for Primary HIV infection
Performed at each clinical visit
At Diagnosis
Entry to clinical care (pre-ART)
Follow-up
32. 33
WHO Staging of HIV/AIDS
Primary HIV Infection /Acute retroviral syndrome
Stage I - asymptomatic
Stage II - mild disease
Stage III - moderate disease
Stage IV - advanced immunosuppresion
33. 34
WHO Clinical Stage I
Asymptomatic
or
Persistent generalized lymphadenopathy (PGL):
Bilaterally swollen lymph nodes in accessible areas.
Usually not painful (“Rule of 1,2,3” >1cm,>2 sites, >3
months)
Performance scale 1: able to carry on normal
activity
34. 35
WHO Clinical Stage II
Moderate unexplained weight loss (<10% of
presumed or measured body weight)
Recurrent upper respiratory tract infections
Herpes zoster
Angular cheilitis
Recurrent oral ulcerations
Papular pruritic eruptions[PPE]
Seborrheic dermatitis
Fungal fingernail infections
And/or performance scale 2 (normal activity with
effort,but unable to do active work)
38. 39
WHO Stage III
Conditions where a presumptive diagnosis can be made on the
basis of clinical signs or simple investigations:
Severe weight loss (>10% of presumed or measured body weight)
Unexplained chronic diarrhea for > one month
Unexplained persistent fever (intermittent or constant) for > one month
Oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (TB) diagnosed in last two years
Severe presumed bacterial infections (e.g. pneumonia, empyema,
pyomyositis, bone or joint infection, meningitis, bacteremia)
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
39. 40
WHO Stage III…
Conditions where confirmatory diagnostic testing is
necessary:*
Unexplained anemia (Hg<8 g/dl), and or
Neutropenia (Neutrophill count<500/mm3) and or
Thrombocytopenia (Platelates<50 000/mm3) for more
than one month
Performance Scale 3 (bedridden <50% of the day for the
past month)
42. 43
WHO Stage IV
Conditions where a presumptive diagnosis can be made on the
basis of clinical signs or simple investigations:
HIV wasting syndrome
Pneumocystis pneumonia
Recurrent severe bacterial pneumonia
Chronic herpes simplex infection
Oesophageal candidiasis
Extrapulmonary TB
Kaposi’s sarcoma
Central nervous system (CNS) toxoplasmosis
HIV encephalopathy, or
Performance Scale 4 (bedridden >50% of the day for the past
month)
43. 44
WHO Stage IV…
Conditions where confirmatory diagnostic testing is
necessary:
Disseminated non-tuberculous mycobacteria infection
Progressive multifocal leukoencephalopathy (PML)
Candida of trachea, bronchi or lungs
Cryptosporidiosis
Isosporiasis
Visceral herpes simplex infection
Extrapulmonary cryptococcosis including meningitis
44. 45
WHO Stage IV…
Conditions where confirmatory diagnostic testing is
necessary:
Cytomegalovirus (CMV) infection (retinitis or of an organ
other than liver, spleen or lymph nodes)
Any disseminated mycosis (e.g. histoplasmosis,
coccidiomycosis, penicilliosis)
Recurrent non-typhoidal salmonella septicemia
Lymphoma (cerebral or B cell non-Hodgkin)
Invasive cervical carcinoma
Visceral leishmaniasis
45. 46
HIV Wasting Syndrome
Weight loss >10% body
weight
plus
Unexplained chronic
diarrhea (>1 mo) or
Unexplained fever (>1 mo)
plus chronic weakness
46. 47
Kaposi’s Sarcoma (KS)
Usually, multiple dark
raised lesions
Lesions themselves
are not itchy and
are rarely painful
Courtesy of Tom Thacher, MD
47. Management
Management of HIV/AIDS can be divided into four
categories:
Universal precaution for IP,
Prevention and therapy for opportunistic infections and
malignancies,
Antiretroviral treatment,
Hematopoietic stimulating factors, and
Overall care and support.
1. Prevention:
A. Primary Prevention:
Vaccine development is on trial;
Effective prevention of transmission through universal precautions of IP
is vital.
PMTCT
48. Management…
B. . Secondary Prevention:
HAART and prophylactic regimens can prevent
opportunistic infections and improve survival.
Prophylaxis for common OIs should be given to patients
per the national guideline.
Secondary prophylaxis includes PEP.
49. Management…
2. HAART:
HAART is one component of the comprehensive care and
treatment of PLWHA.
Experimental treatment regimens for HIV infection are
constantly changing.
People are still doing well over 20 years with good
adherence to HAART .
What are goals of HAART?
50. Goals of ART
Clinical goal: Prolong and improve quality of life
Virologic goal: Reduce viral load
HIV RNA < 50 copies/mL or “undetectable” within 4-6
months of ART initiation is good achievement.
Immunologic goal: Immune reconistitution
Therapeutic goals: Maintain future treatment options,
minimizes toxicity and maximizes benefit.
Preventive goals: Reduce HIV transmission:
PMTCT
PEP
51
52. HAART…
Combination of at least 3 drugs:
2 NRTIs; AND
1 NNRTI or 1-2 PIs; OR
Rarely Triple NRTIs
Therapy with only one or two agents allows HIV to
overcome therapy through resistance mutations.
Regular follow up is mandatory with clinical and
laboratory evaluation.
CD4 counts every 3-6 months
Viral load tests every 3-6 months and 1 month following a
change in therapy; and
Other tests should be done regularly based on national
guideline.
53
53
54. What ARV Regimen to start with(WHO-
2013)
Adults (including Pregnant and breastfeeding
women and adults with TB and HBV coinfection)
Preferred first-line regimens
TDF + 3TC (or FTC) + EFV
Alternative first-line regimens
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + NVP
55. What ARV Regimen to start with(WHO-
2013)
Adolescents (10 to 19 years) ≥35 kg
Preferred first-line regimens
TDF + 3TC (or FTC) + EFV
Alternative first-line regimens
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + NVP
ABC + 3TC + EFV (or NVP)
56. What ARV Regimen to start with(WHO-
2013)
Children 3 years to less than 10 years and
adolescents <35 kg
Preferred first-line regimens
ABC + 3TC + EFV
Alternative first-line regimens
ABC + 3TC + NVP
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + EFV
TDF + 3TC (or FTC) + NVP
57. What ARV Regimen to start with(WHO-
2013)
Children <3 years
Preferred first-line regimens
ABC (or AZT) + 3TC + LPV/r
Alternative first-line regimens
ABC + 3TC + NVP
AZT + 3TC + NVP
58. 63
Factors to Consider When Starting Therapy
Ethiopia OI/ARV
guidelines
Potential side effects
Concurrent health
conditions
Including abnormal
laboratory values
Drug interactions
Potential for pregnancy
Prior antiretroviral use
Antiretroviral resistance
Future treatment options
Conditions for storing
medications
Patient ability to follow-up
in clinic and laboratory
monitoring requirements
Potential barriers to
adherence
62. 67
67
Zidovudine (AZT or ZDV)
Dosing: 300mg BID
Reduce ZDV dose for patients with renal compromise
and hepatic failure
Food Interactions
None – with or without food is ok
Food decreases ZDV-related nausea
Drug interactions
Avoid use with:
D4T (competitive antagonism)
Other bone marrow suppressing drugs
TMP/SMX
Pyrimethamine
64. 69
69
Lamivudine (3TC)
Dosing: 150mg BID or 300mg QD
Reduce dose with renal compromise
Food Interactions: no food interactions
Toxicity: very rare
Headache
Occasional nausea
Lactic acidosis, fatty liver
65. 70
70
Stavudine (d4T)
Dosing
30 mg BID
Reduce dose in patients with renal compromise
Food Interactions: None
Toxicity
Peripheral Neuropathy (5-15%, pain, tingling, and
numbness in extremities – Stop drug
Lipoatrophy
Lactic acidosis, fatty liver
Pancreatitis
Hypertriglyceridemia
66. 71
71
Stavudine (2)
Drug interactions
Do NOT use with ZDV (competitive antagonism)
Use with caution: Other ‘D’ drugs, INH, phenytoin,
ethambutol
68. 73
73
Didanosine (ddI)
Dosing
1 x 400mg enteric coated capsule QD (if <60kg: 250mg
QD)
or
2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg:
125 mg BID or 250mg QD)
NOTE: If using buffered tablets, 2 or more tablets must be
used at each dose to provide adequate buffer.
or
250mg reconstituted buffered powder BID (if <60kg:
167mg BID)
69. 74
74
Didanosine (2)
Food Interactions: take on empty stomach
If taken with tenofovir (TDF), can take with or without
food
Reduce dose to 250 mg qd with tenofovir
Stop ddI or reduce dose to 250mg QD for patients that
develop peripheral neuropathy
70. 75
75
Didanosine (3)
Drug interactions
Alcohol: risk of
pancreatitis
Other ‘D’ drugs: risk of
peripheral neuropathy,
pancreatitis
Drugs that require gastric
acidity for absorption:
ketoconazole
INH: risk of peripheral
neuropathy
Toxicity
Peripheral Neuropathy
(5-12%)
GI intolerance
Pancreatitis (7%, fatal
in 2%)
Lactic acidosis, fatty
liver
71. 76
76
Tenofovir Disoproxil Fumarate
(TDF)
Actually, a nucleoTIDE
Dosing: 1 x 300mg tablet QD
Reduce dose with renal compromise
Also has activity against Hepatitis B
Dosed 300mg QD
Food Interactions: Can be taken with or without
food
73. 78
78
Abacavir (ABC)
Dosing: 1 x 300mg tablet BID or 600 mg QD
Food Interactions: no food interactions
No dose adjustment for renal failure
Toxicity
Hypersensitivity
Occurs within first 6 weeks of therapy
GI intolerance
Rash
Flu-like symptoms
74. 79
79
Hypersensitivity to Abacavir (2)
Observed in approximately
5% of all patients receiving
abacavir
Multi-organ system
involvement
NEVER rechallenge—May
be fatal
Most common signs and
symptoms:
Fever (>80%)
Rash (maculopapular or
urticarial) (70%)
Fatigue (>70%)
Flu-like symptoms (50%)
GI (nausea, vomiting,
diarrhea, abdominal pain)
(50%)
75. 80
80
Emtricitabine (FTC)
Dosing: 1 x 200mg capsule QD
Dose should be reduced for patients with renal
compromise
Food Interactions: no food interactions
Toxicity
Mild abdominal discomfort
Occasional nausea
Lactic acidosis, fatty liver
83. 88
88
Efavirenz (EFV)
Dosing: 600mg tablet QHS
Food Interactions
Take with low-fat meal - High-fat meals increase
absorption 50% increases side effects
Drug interactions (induces liver enzymes)
Changing from a EFV to a PI, may need to increase dose
of PI for first two weeks
85. 90
90
NNRTI Class Effects
Side effects
Rash
EFV > DLV > NVP
Hepatotoxicity manifested by elevated transaminase
Cross resistance across entire class
Essentially a one chance class of drugs
90
87. 92
92
Lopinavir/ritonavir (LPV/r)
Dosing: 250mg tabs and BID 500mg BID
Each tablet contains LPV 200 mg/RTV 50 mg
Food Interactions:
The tablet can be taken without food
Toxicity
Nausea, diarrhea
Lipid abnormalities
Hyperglycemia
Tablets can be stored at room temperature
88. 93
93
Lopinavir/ritonavir (2)
Interactions with other ARVs
EFV and NVP decrease LPV/r levels
Increase LPV/r to 4 caps bid or 3 tablets bid
LPV/r decreases fosamprenavir levels
This combination is not recommended
89. 94
94
Atazanavir/ritonavir (ATZ/r)
Dosing: 2 x 200mg capsules QD
Dosed with ritonavir 100mg QD, ATZ dose = 2 x 150mg
QD (for PI experienced patients)
Food Interactions: Take with food
Toxicity:
Nausea
Diarrhea
Elevated bilirubin
90. 95
95
Atazanavir/r (2)
Pregnancy
Potential for ATZ to cause hyperbilirubinemia in
neonates
Drug interactions
Inhibits liver enzymes
If used with RTV, decrease dose to 300 mg qd + RTV 100
mg qd
TDF decreases ATZ levels
Use boosted ATZ with TDF
Use boosted ATZ with any NNRTI
91. 96
96
PI Class Side Effects
Metabolic Disorders
Hepatotoxicities
Hyperglycemia, insulin
resistance
Lipid abnormalities
Fat redistribution
Bone Disorders
Avascular necrosis
Osteoporosis and
Osteopenia
GI intolerance
Drug interactions
Due to CYP450 3A4
Inhibition
96
92. 97
97
PIs induced Hepatotoxicity
RTV use linked to increased risk of severe
hepatotoxicity
Increased LFT’s observed with all PI’s
More common in patients with chronic viral hepatitis
(HBV, HCV)
Data do not, however, support withholding PI’s from
patients co-infected with HBV or HCV
93. Monitoring and Managing ARV Toxicities
They are major causes of drug discontinuation in the
first 3-6 months of ART initiation.
ARV Toxicities be classified in to three categories:
1. Early side effects but NOT dangerous:
a) Early and Very common:
Important to inform patients about them; But don’t
scare patient with all details;
They include headache, GI-upset, dizziness, tiredness,
etc
Often start with treatment initiation and resolve within
few weeks;
98
94. Monitoring and Managing ARV Toxicities
Most ARV drugs have such symptoms;
Shouldn’t be worried unless they persist for a long time.
E.g. CNS toxicity of EFV.
b) Early and Less common:
It is not advisable to warn patients of this side effects.
E.g. AZT induced nail discoloration; only cosmetic
concern.
99
95. Monitoring and Managing ARV Toxicities
2. Early and Serious Toxicities:
They require emergency intervention/consultation;
Patients need to be warned about them and what to do if
they occur;
Examples:
NVP and EFV: Severe rash or hepatitis can occur in the first
few weeks, and may be life-threatening;
AZT: Severe anemia which occurs within 3 months.
100
96. Monitoring and Managing ARV Toxicities
ABC hypersensitivity reaction during the first week;
D-drugs and PIs: Lactic acidosis, Peripheral neuropathies;
3. Late Side Effects:
Occur after several months or years of ART.
Most common one is lipodystrophy and/or dyslipidemia of
D-drugs and PIs.
Some serious side effects may occur late: e.g. Lactic acidosis.
101
97. Monitoring and Managing ARV Toxicities
Strategies for managing adverse drug reactions:
Step 1. Establish whether the problem is due to antiretroviral
drugs, other medications, OIs, non-HIV related clinical
conditions.
Step 2. Try to identify the responsible ARV drug.
Step 3. Assess the severity of the Adverse Event using the ACTG
adverse events grading system.
Step 4. Manage the adverse event according to severity and
also
decide whether to substitute or discontinue ARV drug.
102
98. Monitoring and Managing ARV Toxicities
Grade-1(Mild reaction):
Are bothersome but do not require changes in therapy.
Grade 2 (Moderate reaction):
Consider continuation of ART as long as feasible.
If the patient does not improve in symptomatic therapy, consider
single-drug substitution.
Grade 3 (Severe reaction):
Substitute offending drug without stopping ART.
Closely monitor using laboratory and clinical parameters.
103
99. Monitoring and Managing ARV Toxicities
Grade 4 (Severe life-threatening reaction):
Immediately discontinue all ARV drugs, manage the medical
event with symptomatic and supportive therapy;
Reintroduce ARV drugs using a modified regimen when the
patient is stabilized.
Life-threatening toxicity includes severe hepatitis,
pancreatitis, lactic acidosis or Steven-Johnson syndrome.
104
101. 106
Reasons for Changing ART
ART should not be changed unless
absolutely necessary!
ART may be changed because of:
Treatment Failure
Toxicity or intolerance
Co-morbid conditions
Non-adherence/compromised quality of
life
102. 107
Treatment Failure
Treatment failure is defined by
Clinical failure
Immunologic failure
Virologic failure
Clinical failure
New or recurrent WHO stage 4
condition
Note: Should not be confused with immune
reconstitution inflammatory syndrome
103. 108
Treatment Failure (2)
Immunologic failure
Fall of CD4 count by >50% from the on treatment peak
Return of the CD4 count to pretherapy baseline or below
Persistent CD4 levels below 100 cells/MM3
Virologic failure:
Failure to suppress viral load to undetectable
Reappearance of detectable virus after a period of
undetectability (loss of virologic control)
Less than one log (10-fold) decrease in viral load from
baseline after 8-12 weeks of ART
Plasma viral load above 10,000 copies/ml in duplicates
after six months on ART
104. 109
Clinical Indications to Change ART Due to Toxicity
Symptom Clinical Indication
Nausea Severe discomfort or minimal intake for > 3 days
Vomiting Severe vomiting of all foods/fluids in 24 hrs, orthostatic
hypotension or need of IV fluids
Diarrhea Bloody diarrhea, orthostatic hypotension or need of IV
fluids
Fever Unexplained fever of > 39.6 C
Headache Severe or requires narcotics
Allergic
Reaction
Generalized urticaria, angioedema or anaphylaxis
Peripheral
Neuropath
y
Severe discomfort, objective weakness, loss of 2-3
previously present reflexes
Fatigue Normal activity reduced > 50%
105. 110
Toxicity: Changing One Drug
Regimen: d4T/3TC/NVP
d4T-related neuropathy or pancreatitis: Switch d4T to
ZDV or TDF loose therapy
NVP-related rash or hepatotoxicity:
Switch NVP to EFZ or
Switch NVP to PI’s
Regimen: d4T/3TC/EFV
EFZ-related persistent CNS toxicity: Switch EFV to NVP
Regimen: ZDV/3TC/EFV
ZDV-related anemia or neutropenia: Switch ZDV to TDF
Regimen: TDF/3TC/EFV
TDF-related renal problem: switch TDF to ABC
