HIV/AIDS Update
Dr. Norbert Gilmore
Immunodeficiency Service
Montreal Chest Institute
Royal Victoria Hospital
HIV-1 Lifecycle
Genetic Diversity of HIV
• High genetic variability
– Multiple introductions of diverse simian viruses into
humans
– Genetic diversity from high error rate of reverse
transcriptase
• Two main viral types with 2 initial epicentres:
– HIV-1 (Central Africa)
– HIV-2 (West Africa)
• Two different sources:
– Chimpanzees (Pan troglodytes)
– Sooty mangabeys (Cercocebus atys)
Subtypes of HIV-1 Group M
• A: Central Africa
• B: North America,
Europe, Australia
• C: Brazil, India,
southern Africa, China
• D: Central Africa
• E: Thailand, Central
African Republic,
China
• F: Brazil, Romania,
Zaire
• G: Zaire, Gabon,
Taiwan
• H: Zaire, Gabon
• O: Cameroon, Gabon
• N: Cameroon
Table 1: Distribution of HIV-1 Subtypes in Canada
Subtype
Frequency
Percentage
A
25
2.1
A/B
1
0.1
A/C
1
0.1
A/E*
5
0.4
A/G
3
0.3
B
1076
92.2
C
52
4.5
D
4
0.3
Total
1167
10
Health Canada’s LCDC defines an AIDS case as a person with a disease
characterized by:
•at least one indicator disease diagnosed definitively; and
•an HIV positive test result or absence of specific causes for
underlying immunodeficiency.
Adults and children estimated to be living
with HIV/AIDS as of end 1999
North America
900 000
Caribbean
360 000
Latin America
1.3 million
Eastern Europe
Western Europe & Central Asia
520 000 420 000 East Asia & Pacific
North Africa
530 000
South
& Middle East
& South-East Asia
220 000
5.6 million
sub-Saharan
Africa
24.5 million
Total: 34.3 million
00001-E-1– 27 June 2000
Australia
& New Zealand
15 000
End-1999 global HIV/AIDS estimates
Children and adults
l
People living with HIV/AIDS
34.3 million
l
New HIV infections in 1999
5.4 million
l
Deaths due to HIV/AIDS in 1999
2.8 million
l
Cumulative number of deaths due to HIV/AIDS
00001-E-11– 27 June 2000
18.8 million
Number of positive test reports by year of test.
Year of test
1985-1994
Number
Reported to
CIDPC
33087
1995
2998
1996
2785
1997
2541
1998
2328
1999
2239
2000
2119
2001
2172
Total
50259
Surrogate markers
• CD4 lymphocytes: assess magnitude of injury to
immune system, treatment and prophylaxis,
N=500-1400
• CD8 lymphocytes: role in disease process to
control infection but less well understood
• CD4/CD8 ratio: N-1.1-3.5, progression leads to
inversion of ratio
• p24 Ag: detects infection before Ab: used in acute
infection
T Lymphocytes
• Develop in the thymus
• essential role is to recognize foreign
material in cells of host
• CD4(“T4”): most are helper cells that help
B cells divide & produce Ab
• CD8(“T8”): most are cytotoxic cells that
destroy virally infected cells
Surrogate markers
• Quantitative viral loads: PCR, bDNA,
NASBA; used for FU, treatment decisions
and prognosis;
• Qualitative PCR: if antibody testing not
reliable (eg.newborns), expensive and not
generally available
Clinical Manifestations of HIV
Infection
•
•
•
•
Transmission
Acute (primary) HIV Infection
Asymptomatic HIV Infection
Symptomatic HIV Infection (thrush,
diarrhea)
• AIDS: Opportunistic Infections, Cancers,
Neurologic Disease
HIV Transmission
• Blood transmission (contaminated
transfusions, needle sharing, needle-stick)
• vertical transmission (mother to child)
• sexual transmission (75% infections
worldwide)
Immunopathogenesis of HIV
• Acute Infection: wide dissemination of
HIV into lymphoid tissue with
establishment of chronic persistent infection
• loss of CD4+ cells and immunodeficiency
• HIV reservoirs in resting CD4+ cells
• Cellular activation and proinflammatory
cytokines can induce HIV replication in
latent cells
PRIMARY INFECTION
PATHOGENESIS AND TIMING
Acute (primary) HIV Illness
• 50-90% pts acutely infected with HIV will
develop symptoms
• often not recognized because symptoms resemble
“flu” or common illnesses
• may occur without symptoms
• preliminary trials suggest that treatment with
combination therapy may improve clinical
outcome and slow progression by suppressing
initial burst of viral replication and altering set
point
CD4+ Cell
Count
> 500
cells/mm3
< 500
cells/mm3
Organism
Common Manifestations
HIV
Primary HIV infection
HIV
HIV
Persistent generalized lymphadenopa
thy
Aseptic meningitis
HIV
Idiopathic thrombocytopenia purpura
Streptococcus pneumoniae,
Haemophilus influenza
Mycobacterium tuberculosis
Community-acquired pneumonia
Candida species
Herpes simplex virus
Oropharyngeal and vaginal
candidiasis
Orogenital herpes
Varicella zoster virus
Dermatomal zoster (shingles)
Epstein-Barr virus
Cryptosporidium parvum
Oral hairy leukoplakia, non-Hodgkin's
lymphoma
Self-limited diarrhea
HHV-8 (KSHV)
Kaposi's sarcoma
Pulmonary tuberculosis
< 200 cells/mm3
< 100 cells/mm3
Pneumocystis carinii
Pneumonia
Cryptosporidium parvum
Chronic diarrhea
Toxoplasma gondii
Encephalitis
Microsporidia
Diarrhea
Candida species
Esophagitis
Cryptococcus neoformans
Meningitis
M tuberculosis
Disseminated or extrapulmonary TB
Herpes simplex virus
Disseminated or aggressive herpes
Varicella zoster virus
Disseminated herpes zoster
Epstein-Barr virus
Primary central nervous system lymphoma
Mycobacterium avium complex
Disseminated M avium complex
Cytomegalovirus
Retinitis, GI disease, encephalitis
HIV
Wasting syndrome, dementia, myelopathy
Resistance Testing
• Genotype: measures gene mutations to
predict resistance, 1-2 wks, expert
interpretation
• Phenotype: growth of HIV in lab in
presence of HIV drugs, 4 wks, more
expensive
Medical Evaluation of an HIV
Positive Individual
• Identifying Data
• Reason for Visit
• Route of Transmission: sexual, IDU,
transfusion, vertical
• Medications: HIV (present and past), nonHIV, allergies and intolerance, alternative
• Social: drugs, alcohol, cigs; relationships;
finances; work; transport; mandate/will
Medical Evaluation
• Past History: HIV related and AIDS
defining (OI, Ca, neuro); non-HIV; TB,
syphilis, condyloma, hepatitis A/B/C,
herpes
• Immunizations: Pneumovax, hepatitis A/B,
Fluviral, tetanus
• Sexual: partners, practices, contraception
• Travel and country of origin
• Functional Inquiry
Medical Evaluation
• Physical Examination: ht & wt, fundi, oral
cavity, lymph nodes, chest, abdo, skin,
rectal and genital (incl Pap), mental status
• Laboratory: baseline (CBC, liver, kidney);
staging (CD4 and viral load); microbiology
(PPD, CMV, hepatitis B/C, toxo, VDRL);
other (according to history)
Assessment of the HIV Infected
Patient
• Evaluate patients for antiretroviral therapy
• Evaluate patients for prophylaxis (PCP,
MAC, herpes, CMV)
• Immunizations (hepatitis, tetanus,
Pneumovax)
• Treatment of acute and comorbid conditions
• Evaluate psychosocial factors
Indications for HIV Therapy
• Any patient with advanced HIV (AIDS or
symptomatic disease eg. thrush or unexplained
fever)
• any patient with a CD4 cell count <200
• consider if CD4 cell count 200-350
• consider if viral load >30,000(bDNA) or >55,000
(PCR)
• defer if CD4>350 and viral load <30,000(bDNA)
or <55,000(PCR)
• acute HIV infection
• during pregnancy
Goals of Therapy
•
•
•
•
•
maximal and durable suppression of viral load
restoration of immune function
improved quality of life
reduction of HIV morbidity and mortality
70-90% pts undetectable at 6-12 mos in research
setting; 50% in city clinic
• eradication of HIV is currently not possible due to
latent cells with long half life
Considerations in HIV Therapy
• Treatment regimens: 2 NRTI’s + (PI or
NNRTI or NRTI)
• Future treatment options and sequencing of
drugs; class sparing regimens
• predictors of virologic success (low baseline
viraemia and high baseline CD4 count
• class and drug specific side effects
• compliance/adherence
• pharmacokinetics and drug interactions
• comorbidity (eg. HCV, renal failure)
Antiretroviral Options 2002
Nucleoside
RTI
Zidovudine (AZT,
Retrovir)
Lamivudine (3TC, Epivir)
Stavudine (d4T, Zerit)
Zalcitabine (ddC)
Didanosine (ddI, Videx)
Abacavir (Ziagen)
Nonnucleoside
RTI
Delaverdine
(Rescriptor)
Neverapine
(Viramune)
Efaverenz (Sustiva)
Nucleotide
RTI
Tenofovir
(Viread)
Protease
Inhibitor
Nelfinavir (Viracept)
Indinavir (Crixivan)
Ritonavir (Norvir)
Saquinavir hgc
(Invirase)
Saquinavir sgc
(Fortovase)
Amprenavir (Agenerase)
Lopinavir (Kaletra)
atazanavir
How should pts be monitored?
• CD4 and viral load 1month after treatment
change/initiation and then every 3-4 months
• more frequent if non-compliant, clinical
symptoms or progression
• monitor for side effects
Why do pts fail treatment?
•
•
•
•
lack of compliance
viral resistance
malabsorption
drug-drug interactions
Issues in HIV Vaccine
Development
• genetic variability
• establishing appropriate animal models
• establishing long lasting, protective
immunity
• role of antibodies at mucosal surfaces in
preventing sexual transmission
• eliminating reservoirs of HIV infected cells
HAART Associated Adverse
Clinical Events
• Lactic acidosis/hepatic steatosis (NRTI)
• hyperglycemia/diabetes mellitus (PI,
NNRTI)
• Fat Maldistribution/Lipodystrophy
• hyperlipidemia
• osteopenia/osteoporosis
Lipodystrophy
• Fat redistribution, lipid and glucose
metabolism (50-60%)
• Fat depletion (extremities, face,
buttock,venomegaly); and fat accumulation
(abdo, neck and breasts)
• lack of case definition
• fat redistribution does not always correlate
with lipid abnormalities
Metabolic & Morphologic
Changes
METABOLIC CHANGES
• Glucose Metabolism
– insulin resistance
– impaired glucose
tolerance
– diabetes (rare)
• Lipid Metabolism
–  triglycerides
–  total cholesterol
–  LDL
MORPHOLOGIC CHANGES
• Fat Accumulation
– Abdominal obesity
– Buffalo hump
– lipomatosis
– breast enlargement
• Fat Loss
– appendices
– face
– buttocks
Components of
Lipodystrophy Syndrome
Lipid
abnormalities
Dysregulation
of glucose
metabolism
Fat
accumulation
Fat
atrophy
• 1 syndrome or several?
• 1 etiology or multifactorial?
Physical Manifestations
of HIV-Associated LD
1
1
2
1
Reprinted with permission from: 1New England Journal of Medicine (1998:339;1296). Copyright 1998, Massachusetts
Medical Society; 2International Journal of STD and AIDS (1198;9:596). Copyright 1998, Royal Society of Medicine
Lipodystrophy
• Direct versus indirect effect of therapy (endocrine
alterations, adipocyte survival, cytokines)?
• Counsel patients about benefit of AR therapy
versus risks and monitor fasting lipids and glucose
• Treatment options: PI sparing?, therapy switch,
lipid lowering agents, hypoglycemics (metformin),
growth hormone, liposuction
Women and HIV
•
•
•
•
Increasing rates
less information than men
 frequency: thrush, bact pneumonia, PML
More HPV and more intraepithelial cervical
neoplasia; Pap/colpo every 6 months
• more severe PID
• menstrual disorders common
• similar progression to men if same care
HIV and Pregnancy
• Offer all pregnant women HIV testing
• Generally treat mother; if >14 wks continue
treatment, if <14 wks consider Rx
interruption
• AZT transmission from 25.5 to 8.3%
• Single dose Nevirapine
• most infections occur at time of delivery
Conclusions
• HIV is a chronic disease featuring ongoing viral
replication despite a robust cellular and humoral
immune response during primary infection
• Eradication is currently not feasible
• HIV is a treatable disease but current drugs have
limitations including toxicities
• treatment of HIV includes treatment of comorbid
conditions and coordination between multiple
health care treaters
Conclusions (2)
• Drug interactions need to be considered
• Adherence is a key factor in treatment failure and
must be maintained at a high level over long
periods of time
• HIV is a multisystem disease with numerous
psychosocial implications and factors
• Care is best delivered by a health care professional
experienced in the treatment of HIV
Reference
• DHHS Guidelines for the Use of
Antiretroviral Agents in HIV Infected
Adults and Adolescents (www.hivatis.org)