Transcript Perspective on the use of ARV in developing countries

Antiretroviral Therapy
Perspectives for Developing Countries
Christopher Mathews, MD
University of California, San Diego
Survival Time from 1st Owen Clinic Visit, n=4854
yrentry 1999
1.00
yrentry 1998
yrentry 1997
yrentry 1996
0.75
yrentry 1995
0.50
yrentry 1994
yrentry 1993
yrentry 1992
0.25
yrentry 1991
yrentry 1990
0.00
1
2
3
4
5
Years
6
7
8
9
10
Time to Undetectable VL, by Year of Entry, Owen Clinic, n=701
Proportion with pVL>400 copies
1.00
0.75
0.50
1995-96
1999
1998
0.25
1997
0.00
0
1
2
Follow-up time (years)
3
4
(Perrin & Telenti. Science 1998;280:1871-1873)
Licensure of Antiretroviral Agents
by Year
1987:
1988:
1989:
1990:
1991:
1992:
1993:
1994:
1995:
zidovudine
didanosine
zalcitabine
stavudine
lamivudine
saquinavir
1996: ritonavir
indinavir
nevirapine
1997: nelfinavir
delavirdine
1998: efavirenz
abacavir
1999: amprenavir
2000: lopinavir/ritonavir
2001: tenofovir
WHO Antiretroviral Guidelines
Primary targets are national treatment advisory
boards and senior-level policymakers
Outline a public health approach to enable
treatment of 3 million individuals in the next 3
years
WHO placed ARVs on Essential Drug List in
April 2002
– “they should be available at all times in adequate
amounts, appropriate dosage forms, at a price
individuals and communities can afford…”
(http://www.who.int/HIV_AIDS/first.html)
Feasibility and Will to Use ARVs
UN General Assembly Special Session (article
15) recognized that access to medication is
integral to the human right to health
Global Fund to Fight AIDS, Tuberculosis, and
Malaria” – target $7-10 billion/year
Of $174 million approved for coming year, 67%
assigned to HIV
21 of 28 countries awarded Global Fund grants
specifiy purchase of ARVs as central aim
Factors affecting success
Drug acquisition costs
Facility and personnel infrastructure
Minimizing side effects
Preventing rapid evolution of drug
resistance
Recognizing indirect benefit of treatment
on transmission probability – “Therapy as
Prevention”
Affordable prices
Annual cost per person for triple therapy in Africa
(US$)
$12,000
$10,000
Drug Access Initiative
$8,000
$6,000
Domestic production
$4,000
Accelerated access
initiative
February-April 2001 offers
$2,000
$0
1991
1993
1995
1997
1999
2001
2003
WHO Staging System for HIV Infection
and Disease in Adults and Adolescents
Clinical Stage I:
1.
Asymptomatic
2.
Persistent generalized
lymphadenopathy (PGL).
Performance scale 1: Asymptomatic, normal
activity.
WHO Staging System for HIV Infection
and Disease in Adults and Adolescents
Clinical Stage II:
3.
Weight loss, < 10 % of body weight.
4.
Minor mucocutaneous manifestations (seborrheic
dermatitis, prurigo, fungal nail infections, recurrent oral
ulcerations, angular cheilitis).
5.
Herpes Zoster, within the last 5 years.
6.
Recurrent upper respiratory tract infections (i.e.,
bacterial sinusitis).
And/or Performance scale 2: symptomatic, normal activity.
WHO Staging System for HIV
Infection and Disease in Adults and
Adolescents: Clinical Stage III
7. Weight loss, > 10 % of
body weight.
8. Unexplained chronic
diarrhoea, > 1 month.
9. Unexplained prolonged
fever (intermittent or
consant), > 1 month.
10.
Oral candidiasis
(thrush).
11.
Oral hairy
leukoplakia.
12.
Pulmonary
tuberculosis, within the
past year.
13.
Severe bacterial
infections (i.e.,
pneumonia, pyomyositis).
And/or Performance
scale 3: bed-ridden, <
50% of the day during the
last month.
WHO Staging System for HIV Infection and
Disease in Adults and Adolescents: Clinical
Stage IV
14. HIV wasting syndrome, as
defined by CDC1.
15. Pneumocystis carinii
pneumonia.
16. Toxoplasmosis of the brain.
21. Any disseminated endemic
17. Cryptosporidiosis with
24.
18.
19.
20.
21.
diarrhoea, > 1 month.
Cryptococcosis,
extrapulmonary
Cytomegalovirus (CMV)
disease of an organ other than
liver, spleen or lymph nodes.
Herpes simplex virus (HSV)
infection, mucocutaneous > 1
month, or visceral any
duration.
Progressive multifocal
leukoencephalopathy (PML).
23.
25.
26.
27.
28.
29.
mycosis (i.e. histoplasmosis,
coccidioidomycosis).
Candidiasis of the
oesophagus, trachea, bronchi
or lungs.
Atypical mycobacteriosis,
disseminated.
Non-typhoid Salmonella
septicaemia.
Extrapulmonary tuberculosis.
Lymphoma.
Kaposi’s sarcoma (KS
HIV encephalopathy, as
defined by CDC2.
And/or Performance scale 4:
bed-ridden, > 50 % of the day
during the last month.
CDC Classification of HIV Infection
(1993)
Clinical
Categories
A
B
C
CD4
Categories
>500
A-1
B-1
C-1
200-500
A-2
B-2
C-2
<200
A-3
B-3
C-3
Table A
Recommendations for Initiating Antiretroviral Therapy in Adults
and Adolescents with Documented HIV Infection
If CD4 Testing Available:

WHO Stage IV disease irrespective of CD4 cell count

WHO Stage I, II or III3 with CD4 cell counts <200/mm3
(1)
If CD4 Testing Unavailable:

WHO Stage IV disease irrespective of total lymphocyte
count

WHO Stage II or III (3) disease with a total lymphocyte
count <1000-1200/mm3 – (2)
1The
precise CD4 level above 200/mm3 at which to start ARV treatment
has not been established but the presence of symptoms and the rate of
CD4 cell decline (if measurement available) should be factored into the
decision making.
2A total
lymphocyte count of <1000-1200/mm3 can be substituted for the
CD4 count when the latter is unavailable and HIV-related symptoms
exist. It is less useful in the asymptomatic patient. Thus, in the absence
of CD4 cell testing, asymptomatic HIV infected patients (WHO Stage I)
should not be treated because there is currently no other reliable marker
available in severely resource constrained settings.
3Treatment
is also recommended for patients with advanced WHO Stage
III disease including recurrent or persistent oral thrush and recurrent
invasive bacterial infections irrespective of CD4 cell or total lymphocyte
count.
When to change therapy?
Intolerance leading to poor adherence
Drug toxicity
Occurrence of active tuberculosis
Pregnancy
Treatment failure
– Clinical
Disease progression on therapy, not due to immunologic
reconsitution syndrome
– Immunologic:
Drop >30% CD4 from peak
Return to baseline or below
– Virologic
Continued detectable viremia
Cytochrome P-450, HIV-1 Protease
Inhibitors and NNRTIs
Enzyme
Substrates
Inducers
Inhibitors
Ritonavir
1A2
Ritonavir
Delavirdine
Efavirenz
Ritonavir
Delavirdine
Efavirenz
Ritonavir
2C9
2C19
2D6
Delavirdine
3A4
Saquinavir
Indinavir
Ritonavir
Nelfinavir
Nevirapine
Delavirdine
Efavirenz
Lopinavir
Nevirapine
Efavirenz
Indinavir
Ritonavir
Nelfinavir
Lopinavir
Delavirdine
Efavirenz
Abacavir Hypersensitivity
Syndrome
Incidence about 5%
Onset within 6 weeks of initiation
Definition:
– A fever > 100.9 F and one of the following:
Nausea greater than baseline
Malaise greater than baseline
With or without rash
Stop the drug and do not re-challenge
Metabolic Abnormalities
Associated with HIV Protease
Inhibitor Therapy
Peripheral lipodystrophy (Carr et al. AIDS
1998;12:F51-8)
Hypertriglyceridemia
Hypercholesterolemia & decreased HDL
Hyperinsulinemia & glucose intolerance
Accelerated atherosclerosis (Henry et al.
Lancet 1998;351:1328)
Dorsal fat pads (“Buffalo humps”)
Peripheral Lipodystrophy
Variable definitions and prevalence (5-60%)
Characteristics
– Change in body habitus
– Increase abdominal girth with visceral fat
deposition (Miller et al. Lancet 1998;351:871-5)
– Loss of appendicular fat, with thinning of legs
and prominent veins
– Breast hypertrophy in women
Treatment Adherence
(Altice & Friedland. Ann Intern Med 1998;129:503-505)
“…compared with therapies for other
chronic diseases, which are often
forgiving of lapses in adherence, HIV
therapy is unforgiving.”
Nonadherence may mean:
– Not taking medication at all
– Taking reduced amounts
– Not taking doses at prescribed frequencies
or intervals
– Not matching medication to food
requirements
SS
% Patients with HIV RNA
<400 c/mL
Correlation Between Optimal
Therapeutic Response and Adherence
to Protease Inhibitor Therapy
100%
80%
60%
40%
20%
0%
>95
90-94.9
80-89.9
70-79.9
<70
% Adherence
Paterson D, et al. Ann Inter Med. 2000;133:21-30.
Definitions
Genotype
Virus nucleotide sequence from which a
protein’s
amino acids can be deduced
– Mutations reported as change in the deduced amino
acid sequence, e.g., Met184Val
– Specific mutations confer phenotypic resistance
– The phenotype is always derived from the genotype
Phenotype
Relative growth of the virus in the presence
of different drug concentrations
– Usually reported as the drug concentration that
inhibits virus replication by 50% (IC50), or the fold
increase in IC50
IAS-USA Recommendations for
Use of HIV Drug Resistance Assays
Clinical characteristics
Recommendation
Rationale
Primary HIV infection
Consider testing
Established HIV
infection
Consider testing
First regimen failure
Recommend testing
Multiple regimen
failures
Recommend testing
Pregnancy
Recommend testing
Hirsch. JAMA 2000;283:2417.
Detect transmission of drugresistant virus; modify therapy to
optimize response and maintain
HIV-specific immune responses
Detect prior transmission of drugresistant HIV although this may
not always be possible with
current tests
Document drug(s) to which there
is resistance
Optimize the number of active
drugs in the next regimen;
exclude drugs to which response
is unlikely
Optimize maternal treatment and
prophylaxis for the neonate
Types of Drug Resistance Assays:
Strengths and Weaknesses
Strengths
Availability
Turnaround time 2 weeks
Mutations may precede
phenotypic resistance
Lower cost
Measures susceptibility
directly
Results are easier to
interpret
Fast results (2 weeks)
Moderate cost
Weaknesses
GENOTYPE
Requires expert interpretation
Measures susceptibility indirectly
Insensitive for detecting minor species
Does not assess interactions among
mutations
Does not address drug levels
PHENOTYPE
Restricted availability
Turnaround time 2–4 weeks
Insensitive for detecting minor species
Clinically significant cutoff values may not
be defined for some drugs
More expensive
VIRTUAL
PHENOTYPE
Measures susceptibility indirectly
Insensitive for detecting interactions
between mutations
Phenotype Sample Report From ViroLogic