Unit 16 HIV-AIDS (1).pptx

Chapter One
Infectious diseases
Pharmacotherapy:
XVI.Human Immunodeficiency
Virus Infection

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

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.

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.

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.

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
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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.

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.

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%.

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.

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.

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HIV Virology: Structure of the Virus
The phenotype (or physical appearance/structure) of HIV

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

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

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.

 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

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.

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

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.

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.

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]

HIV Life Cycle: Sites for Therapeutic Intervention.

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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)

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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.

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.

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;

Natural History of HIV Infection…
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Year 1
Predictor for:
-Disease progression
-Risk of transmission
Low set point = slower
disease progression
High set point = faster
disease progression

Patterns of HIV Disease Progression
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HIV
Infection
Long-term
Non-progressors
Rapid Progressors
Typical Progressors
<3 years
7-10 years
>10-15 yrs
Normal, Stable CD4
90 %
<5 %
<10 %

Session 2.1 Immunopathogenesis
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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.

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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

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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

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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

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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)

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Pruritic Papular Eruption…
Courtesy of Charles Steinberg MD

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Herpes Zoster
Courtesy of Tom Thacher, MD Courtesy of the Public Health Image Library/CDC

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Courtesy of Dr. R. Ojoh
Seborrheic Dermatitis (Dandruff)

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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

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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)

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Oral Candidiasis
Courtesy of Samuel Anderson, MD Courtesy of Dr. R. Ojoh

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Oral Hairy Leukoplakia
Courtesy of Dr. R. Ojoh

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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)

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WHO Stage IV…
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

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WHO Stage IV…
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

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HIV Wasting Syndrome
 Weight loss >10% body
weight
plus
 Unexplained chronic
diarrhea (>1 mo) or
 Unexplained fever (>1 mo)
plus chronic weakness

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Kaposi’s Sarcoma (KS)
 Usually, multiple dark
raised lesions
 Lesions themselves
are not itchy and
are rarely painful
Courtesy of Tom Thacher, MD

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

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.

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?

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
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Classes of Antiretrovirals
1- Reverse transcriptase (RT) inhibitors
– Nucleoside RT inhibitors (NRTI)
– Non-nucleoside RT inhibitors (NNRTI)
– Nucleotide RT inhibitors (NtNRI)
2- Protease inhibitors (PI)
3- Fusion inhibitor
4- Integrase inhibitors
5- CCR5 Inhibitor.

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.
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Ethiopian ARV Guidelines: First-line Regimens
Recommended for Adults and Adolescents
Preferred :
 TDF+FTC+EFV = Triple FDC
 ZDV+3TC+EFV = ZDV/3TC + EFV
 ZDV+3TC+NVP = Triple FDC
Alternatives:
 D4T/3TC/EFV = Double FDC (d4T/3TC) + EFV
 TDF/3TC/NVP
 D4T/3TC/NVP = Triple FDC
 ABC/3TC/EFV
 ABC/3TC/NVP
 ABC/3TC/ZDV = ZDV/3TC + ABC
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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

2013)
 Adolescents (10 to 19 years) ≥35 kg
 AZT + 3TC + EFV
 AZT + 3TC + NVP
 ABC + 3TC + EFV (or NVP)

2013)
 Children 3 years to less than 10 years and
adolescents <35 kg
 ABC + 3TC + EFV
 ABC + 3TC + NVP
 AZT + 3TC + EFV
 AZT + 3TC + NVP

2013)
 Children <3 years
 ABC (or AZT) + 3TC + LPV/r
 ABC + 3TC + NVP
 AZT + 3TC + NVP

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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

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HIV Life Cycle and Sites
for Therapeutic Drugs Intervention

66
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Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
 Lamivudine (3TC)
 Stavudine (d4T)
 Zidovudine (ZDV, AZT)
 Didanosine (ddI)
 Tenofovir (TDF)
 Abacavir (ABC)
 Emtricitabine (FTC)

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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
 Avoid use with:
 D4T (competitive antagonism)
 Other bone marrow suppressing drugs
 TMP/SMX
 Pyrimethamine

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Zidovudine…..
 Toxicity
 Nausea
 Bone Marrow Suppression
 Anemia (fatigue)
 Monitor Hgb
 Thrombocytopenia (low platelet count)
 Neutropenia (low white blood cell [neutrophils] count)
 Headache
 Myalgia
 Myopathy
 Insomnia
 Pigmentation of nail beds
 Lactic acidosis, fatty liver

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Lamivudine (3TC)
 Dosing: 150mg BID or 300mg QD
 Reduce dose with renal compromise
 Food Interactions: no food interactions
 Toxicity: very rare
 Headache
 Occasional nausea

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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
 Pancreatitis
 Hypertriglyceridemia

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Stavudine (2)
 Do NOT use with ZDV (competitive antagonism)
 Use with caution: Other ‘D’ drugs, INH, phenytoin,
ethambutol

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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)

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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

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Didanosine (3)
 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

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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

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Tenofovir Disoproxil Fumarate (2)
 Drug interactions:
 TDF increases ddI levels
 TDF reduces ATZ levels
 Toxicity
 Headache
 Nausea, diarrhea
 Renal insufficiency (rare)

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Abacavir (ABC)
 Dosing: 1 x 300mg tablet BID or 600 mg QD
 No dose adjustment for renal failure
 Toxicity
 Hypersensitivity
 Occurs within first 6 weeks of therapy
 GI intolerance
 Rash
 Flu-like symptoms

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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%)

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Emtricitabine (FTC)
 Dosing: 1 x 200mg capsule QD
 Dose should be reduced for patients with renal
compromise
 Toxicity
 Mild abdominal discomfort
 Occasional nausea

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NRTI Class Side Effects
 Nausea
 Headache
 Peripheral Neuropathy
(d4T/ddI)
 Lipoatrophy
 Pancreatitis (ddI > d4T)
 Lactic Acidosis, fatty
liver
 d4T > ddI > ZDV
 Rare with ABC, TDF,
3TC and FTC
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NRTI Mitochondrial Toxicity
 Inhibition of
mitochondrial DNA
polymerase-
  oxidative metabolism →
 ATP generation
 Implicated in lactic
acidosis with hepatic
steatosis
 Other possible
manifestations:
 Neuropathy (d4T, ddI)
 Lipoatrophy (d4T)
 Pancreatitis (ddI)
 Myopathy (ZDV)
 Cardiomyopathy (d4T, ZDV)

83
83
Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
 Nevirapine (NVP)
 Efavirenz (EFV)
 Delavirdine*
 Etravirine * (ETV)-New drug
*Not available in Ethiopia

84
84
Nevirapine (NVP)
 Dosing: 200 mg QD x 2 weeks, then 200 mg BID
 Food Interactions: None
 Pregnancy
 Prevention of perinatal transmission but use is limited
 Drug interactions (induces liver enzymes)
 Reduces plasma level of certain drugs (ethinyl estradiol,
ketoconazole, PIs, etc)
 Toxicity
 Rash (17%)
 Hepatitis (8–18%)

85
85
Nevirapine-Induced Rash
Courtesy of HIV Web Study,
www.hivwebstudy.org

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

89
89
Efavirenz (2)
Toxicity
 CNS Changes (52%) - Insomnia, nightmares,
poor concentration, mood change, dizziness,
dysequilibrium, depression, psychosis
 Rash (15-27%)
 Nausea

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

91
91
Protease Inhibitors (PI)
 Lopinavir + Ritonavir
 Atazanavir*
 Nelfinavir*
 Indinavir*
 Saquinavir-SGC*
 Ritonavir*
*
Saquinavir-
HGC*
Amprenavir*
Fosamprenavir*
Tipranavir*

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

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

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

95
95
Atazanavir/r (2)
 Pregnancy
 Potential for ATZ to cause hyperbilirubinemia in
neonates
 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

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
 Due to CYP450 3A4
Inhibition
96

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

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

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

 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

 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

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

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

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

LABORATORY GRADING OF ADVERSE EVENTS (ACTG)
105

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

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

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

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%

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

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