Download (lamivudine or emtricitabine) +

Approccio terapeutico nel
paziente “naive”
Ivano Mezzaroma
Dipartimento di Medicina Clinica
UOC Immunologia Clinica
Università di Roma “La Sapienza”
Roma, 24 marzo 2006
Initiation of Therapy
Guidelines for the Use of Antiretroviral
Agents in Adults and Adolescents
October 2005
Goals of Antiretroviral Therapy
(ART)
 Eradication of HIV?
Not possible with currently available
antiretroviral medications
ART Goals & Tools to Achieve
Them
 Improvement of quality of
life
 Reduction of HIV-related
morbidity and mortality
 Restoration and/or
preservation of
immunologic function
 Maximal and durable
suppression of viral load
 Selection of ARV regimen
 Preservation of future
treatment options
 Rational sequencing of
therapy
 Maximizing adherence
 Use of resistance testing
in selected clinical
settings
Before Initiating ART







Confirm HIV results
Complete H&P
CBC, chemistry profile
CD4 cell count
Plasma HIV RNA measurement
Consider resistance testing
Assess “readiness” for treatment and
adherence
Before Initiating ART:
Additional Tests




RPR or VDRL
PPD
Chest X ray
Hepatitis A,B,C
serology
 Toxoplasma IgG
 Fasting glucose and
lipids
 Gynecologic exam
with pap smear
 Testing for chlamydia
and gonorrhea
 Ophthalmology exam
(CD4+ T cell count
<100 cells/µL)
Considerations in Initiating ART:
Asymptomatic HIV
 Willingness of patient to begin and the
likelihood of adherence
 Degree of immunodeficiency (CD4+ T
cell count)
 Plasma HIV RNA
 Risk of disease progression
 Potential benefits and risks of therapy
Considerations in Initiating
ART: Chronically HIV-Infected
Patient, Asymptomatic
 Strong evidence of decreased mortality and
morbidity with ART if CD4 <200 cells/µL or
symptomatic
 Theoretical benefit of treatment at higher CD4
 Few data establish clinical benefit for treatment
if CD4 >200 cells/µL; optimal point to initiate
ART is unknown
 Individualize treatment decisions
Indications for ART in the
Chronically HIV-Infected Patient
Treat all (regardless of viral load):
 Symptomatic (AIDS, severe symptoms)
 Asymptomatic, CD4 count <200 cells/µL
Indications for ART in the
Chronically HIV-Infected Patient
Offer treatment, after discussion of pros
and cons:
 Asymptomatic, CD4 count 200-350 cells/µL
Indications for ART in the
Chronically HIV-Infected Patient
Defer Treatment:
Asymptomatic, CD4 count >350 cells/µL
 If HIV RNA >100,000 copies/mL, may
consider treatment
Benefits and Risks of
Deferred Therapy
BENEFITS
 Avoid negative effects on
quality of life
 Avoid drug-related toxicity
 Preserve future drug
options
 Delay development of drug
resistance
 Decrease total time on
medications
RISKS
 Possibility of irreversible
immune system
depletion
 Increased possibility of
progression to AIDS
 Possible increased risk
of HIV transmission
Current Antiretroviral Medications
PI
NRTI








Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Zalcitabine
Tenofovir
ABC
DDI
FTC
3TC
D4T
ZDV
DDC
TDF
NNRTI
 Delavirdine
 Efavirenz
 Nevirapine
DLV
EFV
NVP








Amprenavir
Atazanavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
 soft gel
 hard gel
 tablet
 Tipranavir
APV
ATV
FPV
IDV
LPV
NFV
RTV
SQV
SGC
HGC
INV
TPV
Fusion Inhibitor
 Enfuvirtide
T-20
The Move Toward Lower Pill Burdens
Regimen
1996
Zerit/Epivir/Crixivan
1998
Retrovir/Epivir/Sustiva
2002
Combivir (AZT/3TC)/EFV
2003
Viread/Emtriva/Sustiva
2004
Truvada/Sustiva
2004
Kivexa/Sustiva
Dosing
10 pills, Q8H
5 pills, BID
3 pils, BID
3 pills, QD
 2 pills, QD
 2 pills, QD
Daily pill
burden
HAART Studies with >65%
Response (VL<50)
COMBINE (NVP+ZDV/3TC)
2NN (NVP BID+d4T+3TC)
ZODIAC (EFV+ABC QD+3TC)
M98-863 (LPV/r+d4T+3TC)
ZODIAC (EFV+ABC+3TC)
CNA30024 (EFV+ZDV+3TC)
2NN (NVP QD+d4T+3TC)
2NN (EFV+d4T+3TC)
CNA30024 (EFV+ABC+3TC)
M02-418 (LPV/r+FTC+TDF QD)
FTC301 (EFV+FTC+ddI QD)
DMP266-043 (EFV+D4T+3TC)
CLASS (EFV+ABC+3TC)
ANRS 12-04 (EFV+ddI+3TC)
M97-720 (LPV/r+d4T+3TC)
Dart 1 (EFV+ddI-EC+3TC)
GS903 (EFV+d4T+3TC)
GS903 (EFV+TDF+3TC)
ANRS 091 (EFV+ddI+FTC)
0
40
50
60
70
80
90
100
% with VL < 50 at week 48
Bartlett JA, et al. CROI, 2005, Abstract 586.
Fattori importanti nella
monosomministrazione
 Fattori farmaco-correlati (caratteristiche
intrinseche):
- concentrazione plasmatica
- legame alle proteine
- concentrazione nel sito di azione
 Fattori estrinseci:
- tempo di assorbimento
- velocità di eliminazione
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmax
maximum concentration
correlates with some short-term
side effects, e.g. nausea
8
6
4
AUC
area under the curve
overall drug exposure
2
0
2
4
6
8
10
12
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmin
minimum, or trough concentration
occurs at the end of the dosing interval
correlates with anti-HIV effect
8
6
4
2
0
2
4
6
8
10
12
Half-lives of HIV Drugs
70
*
60
50
* * *
40
*
* *
* *
24h
30
20
12h
10
Intracellular
Plasma
Moore at al. AIDS. 1999;13:2239. Kewn. AAC. 2002;136:45; Hawkins.2004; Rome, Italy.
ATVr
LPVr
fAPVr
SQVr
IDVr
NFV
EFV
NVP
FTC
TDF
ddI
3TC
ABC
D4t
ZDV
0
Missing Drug Doses With
Different Half-lives (“Unbalanced”)
Day 1
Missed Dose
Day 2
Drug concentration
Hypothetical
and not
representative
of specific
agents.
MONOTHERAPY
IC90
Zone of potential
replication
0
12
IC50
24
Time (h)
36
48
“Balanced” ART: PK Symmetry
Missed Dose
Day 2
Drug Concentration
Day 1
Window for
replication
vs
synergy/additive
activity
IC90
IC50
0
12
24
Time
(hours)
36
48
From in vitro to in vivo?
Accumulation
Synergy
Active metabolites
Protein binding
Viral diversity
P-glycoprotein
Sanctuaries
What else?
Initial Treatment for Previously
Untreated Patients: Choosing
Regimens
 Three categories:
 1 NNRTI + 2 NRTIs
 1 PI + 2 NRTIs
 3 NRTIs
 Few clinical endpoints to guide choices
 Advantages and disadvantages to each type
of regimen
 Individualize regimen choice
Antiretroviral Components in
Initial Therapy: NNRTIs
ADVANTAGES
 Less fat
maldistribution and
dyslipidemia than in
PI-based regimens
 PI options preserved
for future use
DISADVANTAGES
 Resistance - single
mutation
 Cross-resistance
among NNRTIs
 Rash; hepatotoxicity
 Potential drug
interactions (CYP450)
Antiretroviral Components in
Initial Therapy: PIs
ADVANTAGES
 Longest prospective
data
 NNRTI options
preserved for future
use
DISADVANTAGES
 Metabolic complications
(fat maldistribution,
dyslipidemia, insulin
resistance)
 Greater potential for drug
interactions (CYP450),
especially with ritonavir
Antiretroviral Components in
Initial Therapy: NRTIs
ADVANTAGES
 Established backbone
of combination therapy
 Minimal drug
interactions
 PI & NNRTI preserved
for future use
DISADVANTAGES
 Lactic acidosis and hepatic
steatosis reported with
most NRTIs (rare)
 Triple NRTI regimens show
inferior virologic response
compared with EFV- and
IDV-based regimens*
* Triple NRTI regimen of abacavir + lamivudine + zidovudine to be used
only when a preferred or alternative NNRTI- or PI-based regimen
cannot or should not be used as first-line therapy.
Initial Treatment:
Preferred Regimens
NNRTI-Based
Efavirenz*
+ (lamivudine or emtricitabine)
+ (zidovudine or tenofovir)
# pills
/day
2-5
PI-Based
Lopinavir/ritonavir (Kaletra)
+ (lamivudine or emtricitabine)
+ zidovudine
8-10
*Avoid in pregnant women and women with high pregnancy potential.
Initial Treatment:
Alternative Regimens (1)
NNRTI-Based
Efavirenz*
+ (lamivudine or emtricitabine)
+ (abacavir or didanosine or stavudine)
 Nevirapine**
+ (lamivudine or emtricitabine)
+ (zidovudine or stavudine or didanosine or
abacavir or tenofovir)
pills/day
2-4
3-6
*Avoid in pregnant women and women with high pregnancy potential.
**Because of higher rates of hepatotoxicity, nevirapine should not be initiated in
women with pre-nevirapine CD4 counts >250cells/mm3 or men with CD4+ T
cell counts >400 cells/mm3, unless the benefit clearly outweighs the risk.
Initial Treatment:
Alternative Regimens (2)
PI-Based
 Atazanavir
+ (lamivudine or emtricitabine)
+ (zidovudine or stavudine or abacavir or
didanosine) or (tenofovir + ritonavir 100 mg/d)
 Lopinavir/ritonavir (Kaletra)
+ (lamivudine or emtricitabine)
+ (stavudine or abacavir or tenofovir or
didanosine)
# pills
/day
3-6
7-10
Initial Treatment:
Alternative Regimens (3)
PI-Based
 Fosamprenavir or fosamprenavir/ritonavir or
indinavir/ritonavir or nelfinavir or saquinavir (hardor soft-gel capsule)/ritonavir
+ (lamivudine or emtricitabine)
+(zidovudine or stavudine or abacavir or tenofovir
or didanosine)
# pills
/day
5-16
Initial Treatment:
Alternative Regimens (4)
NRTI-Based
Abacavir + lamivudine + zidovudine*
# pills
/day
2-6
* To be used only when a preferred or alternative NNRTI- or PIbased regimen cannot or should not be used as first-line
therapy.
Antiretroviral Medications: Not
Recommended in Initial
Treatment (1)
High rate of virologic
failure
 Didanosine + tenofovir +
Inferior antiviral activity
 Delavirdine
 Zidovudine + zalcitabine
 Saquinavir (unboosted)
High incidence of
toxicities
 Stavudine + didanosine
 Ritonavir used as sole PI
NNRTI
Antiretroviral Medications: Not
Recommended in Initial
Treatment (2)
 Amprenavir
High pill burden/
Dosing inconvenience  Amprenavir/ritonavir
 Indinavir (unboosted)
 Saquinavir (unboosted)
 Nelfinavir + saquinavir
Lack of data in initial
treatment
 Tipranavir
 Enfuvirtide
Antiretroviral Medications:
Should not be offered at any time
 Regimens not recommended:
 Monotherapy (except possibly in prevention of
perinatal HIV transmission)
 Dual NRTI therapy
 3-NRTI regimen of abacavir + tenofovir +
lamivudine
 3-NRTI regimen of didanosine + tenofovir +
lamivudine
Antiretroviral Medications:
Should not be offered at any time
 Antiretroviral components not recommended:
 Didanosine + stavudine
 Stavudine + zidovudine
 Emtricitabine + lamivudine
 Zalcitabine + stavudine; zalcitabine +
didanosine; zalcitabine + lamivudine
Antiretroviral Medications:
Should not be offered at any time
 Antiretroviral components not recommended:
 Efavirenz in pregnancy and in women with high
potential for pregnancy*
 Nevirapine initiation in women with CD4 >250
cells/mm3 or men with CD4 >400 cells/mm3
* Women with high pregnancy potential are those who are
trying to conceive or who are not using effective and consistent
contraception.
Antiretroviral Medications:
Should not be offered at any time
 Antiretroviral components not recommended:
 Atazanavir + indinavir
 Amprenavir + fosamprenavir
 Amprenavir oral solution in pregnancy, in children
<4 years, in renal or hepatic failure, or in patients
treated with metronidazole or disulfiram
 Amprenavir oral solution + ritonavir oral solution
 Saquinavir hard-gel capsule (Invirase) as single PI
Sequenziamento NRTI/NtRTI
•

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
Potenza
Dosaggio once-daily
Tossicità
Convenienza
Coinfezioni
Resistenza al baseline
Profilo di resistenza dopo
fallimento virologico
Mutazioni in HIV-1 RT comunemente
associate con resistenza agli NRTIs
Farmaci
RT: comuni mutazioni di resistenza
Abacavir
K65R, L74V, Y115F, M184V
Didanosina
K65R, L74V
Lamivudina
E44A/D, V118I, M184I/V
Stavudina
M41L, E44A/D, D67N, K70R, V118I, L210W, T215Y/F, K219Q/E
Tenofovir DF
K65R
Zalcitabina
K65R, T69D, L74V, M184V
Zidovudina
Mutazioni degli
analoghi timidinici
(TAMs)
M41L, E44A/D, D67N, K70R, V118I, L210W, T215Y/F, K219Q/E
Resistenza
multinucleosidica
M41L, D67N, K70R, L210W, T215Y/F, and K219Q
Q151M resistance complex: A62V, V75I, F77L, F116Y, Q151M
69XXX insertion: in genere associate con le TAMs
Dicotomia nella evoluzione delle
TAMs
Zidovudina o Stavudina
215Y
TAM pathway I 41L
215Y
210W
70R
TAM pathway II
67N
70R
219Q/E
Elevato livello di resistenza ad AZT e d4T
Più cross-resistenza tra NRTI
Più basso livello di resistenza ad AZT e d4T
Comune nella duplice terapia con NRTI
( AZT/ddC o AZT/ddI)
Comune con la monoterapia con AZT
Meno cross-resistenza agli NRTI
Resistenza multinucleosidica (MNR)
 5 distinti mutazioni: A62V, V75I, F77L, F116Y
e Q151M
 Il complesso Q151 MNR conferisce ampia
cross-resistenza a molteplici NRTI (ma non a
TDF)
 L’inserzione T69 (in combinazione con le
TAM) conferisce resistenza a NRTIs + TDF
The Choice of the NRTI Backbone
2004
Prediction
By the end of the year, virtually all dual-NRTI
backbones prescribed for initial therapy will
consist of 1 of 3 fixed-dose coformulations:
AZT/3TC
ABC/3TC
TDF/FTC
Gallant, Bangkok 2004
Choice of NRTI Backbone
AZT/3TC
• Years of clinical
ABC/3TC
experience
• Well tolerated
• Prevention of K65R or
• 1 pill QD, no food
L74V
restrictions
• Gradual and sequential
• No mitochondrial toxicity emergence of TAMs
• L74V>K65R: no TDF
• BID dosing, 2 pills/day
cross-resistance
• TAMs broad→ cross• Better CD4+ cell count
resistance
response than AZT/3TC
• GI side effects
• ABC HSR, with potential
• Hematologic toxicity
confusion when
• Mitochondrial toxicity
combined with NNRTI
• More patient education
required
• Failure with M184V →
↓ susceptibility ABC &
3TC
TDF/FTC
• Longest intracellular
half-lives
• Well tolerated
• 1 pill QD, no food
restrictions
• No mitochondrial
toxicity
• M184V →↑
susceptibility to TDF
• TDF: nephrotoxicity?
• FTC:
hyperpigmentation
• K65R: cross-resistance
to
ABC, ddI
NRTI sequencing option
AZT+3TC
ABC+3TC
TDF+3TC/FTC
selection
selection
selection
very low risk if with PI/r
184V
TAMs
184V
74V
184V
65R
resistance
3TC/FTC (AZT, All NRTIs)
options
ddI, d4T? TDF? ABC?
resistance
ABC, ddI, 3TC/FTC
options
TDF, AZT (d4T)
resistance
3TC/FTC, ABC, ddI (TDF)
options
AZT, d4T? TDF?
Sequenziamento degli NNRTI
 Impiego degli NNRTI in combinazione con altri
agenti attivi, all’interno di regimi la cui efficacia
antivirale è stata stabilita
 Opzione realistica con gli NNRTIs di seconda
generazione (TMC125, ecc.)
 Opzioni terapeutiche dopo fallimento con NNRTI:
 Regimi a base di PI
 Regimi con più NRTI (pochi dati clinici)
Sequenziamento dei regimi con PI
 Obiettivi dei regimi iniziali con PI




Elevata potenza antivirale
Ridurre la probabilità di un fallimento
Ridurre la possibilità di emergenza di resistenza
Mantenimento della suscettibilità ai successivi regimi di
salvataggio con PI
 Altre considerazioni per la terapia sequenziale con PI





Convenienza
Tolerabilità
Numero di compresse
Facilità di aderenza
Profilo di tossicità
Regimi sequenziali con PI
 Il clinico deve essere prudente quando vengono
pianificati regimi di salvataggio con PI dopo
fallimento con PI boosting
 Il fallimento ad un regime basato sui PI dovrebbe
essere trattato aggressivamente per evitare
l’accumulo di mutazioni secondarie che possono
ulteriormente aumentare la cross-resistenza.
 TPV/RTV o TMC114/RTV + ENF: risultati
incoraggianti
Potential Advantages of Fixed-Dose
Formulations
 Reduced pill burden
 Increased adherence
 Improved patient satisfaction
 Reduced risk of dosing errors
Approved Fixed-Dose NRTIs
 Zidovudine/lamivudine
BID
 Abacavir/lamivudine
QD
 Tenofovir/emtricitabine
QD
 Zidovudine/lamivudine/abacavir
BID
Fixed-Dose Antiretrovirals:
Future Developments
 Tenofovir/emtricitabine/efavirenz
 First formulation to combine treatment in 2
different antiretroviral drug classes
 Will be the first 1 pill/day combination regimen
 Expected in 2006
ART-Associated Adverse
Effects








Lactic acidosis/hepatic steatosis
Hepatotoxicity
Hyperglycemia
Fat maldistribution
Hyperlipidemia
Increased bleeding in hemophiliacs
Osteonecrosis, osteopenia, osteoporosis
Rash
Adverse Effects: NRTIs
 All NRTIs:
 Lactic acidosis and hepatic steatosis
(higher incidence with stavudine)
 Lipodystrophy (higher incidence with
stavudine)
Adverse Effects: NRTIs
 Abacavir - hypersensitivity reaction
 Didanosine* - GI intolerance, pancreatitis,
peripheral neuropathy (PN)
 Stavudine* - PN, pancreatitis
 Tenofovir - headache, GI intolerance, renal
impairment
 Zalcitabine - PN
 Zidovudine - headache, GI intolerance, bone
marrow suppression
*Pregnant women may be at increased risk for lactic acidosis and
liver damage when treated with stavudine + didanosine. This
combination should be avoided in pregnant women, if possible.
Adverse Effects: NNRTIs
 All NNRTIs:
 Rash
 Drug-drug interactions
 Nevirapine – hepatotoxicity (may be severe
and life-threatening), rash including
Stevens-Johnson syndrome
 Efavirenz - neuropsychiatric, teratogenic in
primates (FDA Pregnancy Class D)
Adverse Effects: PIs
 All PIs:
 Hyperlipidemia
 Insulin resistance and diabetes
 Lipodystrophy
 Elevated liver function tests
 Possible increased bleeding risk in
hemophiliacs
 Drug-drug interactions
Adverse Effects: PIs
 Amprenavir and fosamprenavir - GI intolerance,
rash
 Atazanavir - hyperbilirubinemia, PR interval
prolongation
 Indinavir - nephrolithiasis, GI intolerance
 Lopinavir/ritonavir - GI intolerance
 Nelfinavir - diarrhea
 Ritonavir - GI intolerance, hepatitis
 Tipranavir – GI intolerance, rash, hyperlipidemia,
liver toxicity
Adverse Effects: Fusion
Inhibitors
 Enfuvirtide – injection-site reactions,
hypersensitivity reaction, increased risk of
bacterial pneumonia
ARV-Associated Adverse
Effects: Lactic Acidosis/
Hepatic Steatosis
 Possibly due to mitochondrial toxicity
 Associated with NRTIs (especially d4T, ddI, ZDV)
 Clinical presentation variable: have high index of
suspicion
 Lactate >2-5 mmol/dL plus symptoms
 Treatment: discontinue ARVs, supportive care
ARV-Associated Adverse
Effects: Lactic Acidosis/
Hepatic Steatosis (continued)
 Rare, but high mortality*
* Pregnant women may be at increased risk for lactic
acidosis and liver damage when treated with stavudine
+ didanosine. This combination should be avoided in
pregnant women, if possible.
ARV-Associated Adverse
Effects: Hepatotoxicity
 Severity variable: usually asymptomatic, may
resolve without treatment interruption
 May occur with any NNRTI or PI:
 Nevirapine: risk of severe hepatitis in first 18 weeks of use
(monitor LFT), increased risk in chronic hepatitis B/C,
women, and high CD4 count at initiation of nevirapine
(>250 cells/µL in women, >400 in men)
 PI: especially RTV, RTV/SQV; increased risk in hepatitis
B/C, ETOH, other hepatotoxins
ARV-Associated Adverse
Effects: Hyperglycemia
 Insulin resistance, hyperglycemia, and
diabetes associated with all PIs, especially
with chronic use
 Mechanism not well understood
 Insulin resistance, relative insulin
deficiency
 Consider regular screening via fasting
glucose
ARV-Associated Adverse Effects:
Fat Maldistribution
Lipodystrophy:
 No uniform definition
 Mechanism not understood
 peripheral fat wasting more associated with NRTIs
(especially stavudine)
 central fat accumulation perhaps more associated
with PIs
 May be associated with dyslipidemia, insulin
resistance, lactic acidosis
 Treatment: switching to other agents may slow
progression; insufficient data to guide specific therapy
ARV-Associated Adverse Effects:
Hyperlipidemia
 Elevations in total cholesterol, LDL, and
triglycerides
 Associated with all PIs (except ATV), d4T, EFV
 Mechanism unknown
 Consequences uncertain: concern for
cardiovascular events, pancreatitis
 Monitor regularly
 Treatment: consider ARV switch; lipid-lowering
agents (caution with PI + certain statins)
ARV-Associated Adverse
Effects: Bone Abnormalities
 Osteonecrosis (AVN)
 Mechanism unknown
 Associated with PIs; increased in
corticosteroid treatment, alcohol abuse,
hemoglobinopathies, hyperlipidemia,
hypercoagulable states
 Treatment: surgical treatment for severe
disease
ARV-Associated Adverse
Effects: Rash
 Most common with NNRTIs, especially nevirapine
 Most cases mild to moderate, occurring in first 6
weeks of therapy; occasionally serious (e.g.,
Stevens-Johnson syndrome)
 No benefit of prophylactic steroids or antihistamines
(increased risk with steroids)
 NRTIs: especially abacavir (consider
hypersensitivity syndrome)
 PIs: especially amprenavir, fosamprenavir,
tipranavir
Drug Interactions with ARVs: Dose
Modification or Cautious Use






Lipid-lowering agents
Antimycobacterials, especially rifampin*
Psychotropics - midazolam, triazolam
Ergot alkaloids
Antihistamines - astemizole
Anticonvulsants
*Of available NNRTIs and PIs, rifampin may be used only with fulldose ritonavir or with efavirenz
Drug Interactions with ARVs:
Dose Modification or Cautious
Use
 Oral contraceptives (may require second
method)
 Methadone
 Erectile dysfunction agents
 Herbs - St. John’s wort
Drug Interactions with ARVs:
Dose Modification or Cautious
Use




Efavirenz or nevirapine with PIs
Atazanavir + tenofovir
Didanosine + tenofovir
Didanosine + stavudine
Drug Interactions – TDF, ABC, AZT
Agent
(Product Package Insert and Recent Clinical Data)
Systemic PK Interactions
TDF
ABC
AZT
None
AUC of 3TC  15%
None
FTC
ddI
ABC
None
Avoid; (ddI 250 mg)
None
No Data
No Data
AZT
None
AUC of AZT  10%
d4T
TDF
IDV
LPV
RTV
SQV
FPV/r
ATV
None
None
None
None
Adjust to ATV/R 300/100
No Data
None
None
?  clearance ABC
No Data
No Data
None
None
NFV
None
No Data
TPV
EFV
None
None
No Data
No Data
3TC
None
 AUC of TDF 32%
None
No Data
None
Avoid
None
None
?  clearance AZT
AUC of AZT 25%
None
AUC of APV  13%
None
AUC of AZT 35%
No Data
None
NRTI Interactions —
Common Comitant Medications
Systemic PK Interaction
Agent
TDF
ABC
AZT
Methadone
None
Methadone Cl 
22%
AUC of AZT  43%
Alcohol
No Data
AUC of ABC 
by 41%
No Data
Oral
Contraceptives
None
No Data
No Data
Ribavirin
None
No Data
Avoid
Rifampin
None
No Data
AUC of AZT 47%
Source: EU SmPCs May 2005.
Overlapping Toxicities
 Peripheral neuropathy
 didanosine, isoniazid, stavudine, zalcitabine
 Bone marrow suppression
 cidofovir, dapsone, hydroxyurea, ribavirin, TMPSMZ, zidovudine
 Hepatotoxicity
 nevirapine, efavirenz, isoniazid, macrolides, NRTIs,
PIs
 Pancreatitis
 didanosine, pentamidine, ritonavir, stavudine, TMPSMZ
Special Issues
Guidelines for the Use of
Antiretroviral Agents in
Adults and Adolescents
published October 2005
Acute Retroviral Syndrome:
Signs and Symptoms - I






Fever
Lymphadenopathy
Pharyngitis
Rash
Myalgia or arthralgia
Diarrhea
96%
74%
70%
70%
54%
32%
Acute Retroviral Syndrome:
Signs and Symptoms - II






Headache
Nausea and Vomiting
Hepatosplenomegaly
Weight Loss
Thrush
Neurological Symptoms
32%
27%
14%
13%
12%
12%
Acute Retroviral Syndrome:
Neurological Symptoms
 Meningoencephalitis or aseptic meningitis
(uncommon)
 Peripheral neuropathy or radiculopathy
 Facial palsy
 Guillain-Barré syndrome
 Brachial neuritis
 Cognitive impairment or psychosis
Acute HIV Infection:
Laboratory Testing
 Detectable HIV RNA with negative or
indeterminate HIV antibody test
 Low-positive HIV RNA (<10,000
copies/mL) may be false positive
 If diagnosis is made by HIV RNA testing,
confirmatory serologic testing should be
performed subsequently
Acute HIV Infection: Treatment
 Limited outcome data from clinical trials;
therapy based largely on theoretic
considerations
Acute HIV Infection: Treatment
Possible benefits:
Possible risks:
 Decrease the severity of
acute disease
 Alter the viral “set point”
 Reduce the rate of
mutation
 Preserve immune
function
 Reduce risk of viral
transmission
 Drug-related toxicity
 Earlier emergence of
drug resistance
 Limitation of future
treatment options
 Potential need for
indefinite treatment
 Adverse effects on quality
of life
Injection Drug Users
 Transmission via injection drug use is
second most common transmission route
in the U.S. (the first in western Europe)
 Injection drug users (IDU)
 Often have multiple comorbidities,
 Increased morbidity and mortality,
 Decreased access to HIV care
 Are less likely to receive ARV
Injection Drug Users
Efficacy of HIV treatment
 In IDU who are not actively using, efficacy
similar to other populations
 Active drug use may interfere with adherence
and ARV success
 In some patients, substance abuse treatment
may be required for ARV success
 Many other support mechanisms may be
effective
Injection Drug Users
Drug toxicities and interactions
 IDU may have more ARV-related adverse effects
 Methadone may interact significantly with ARV
 NRTI: no significant effects on methadone levels; AZT
levels increased
 NNRTI: EFV and NVP decrease methadone levels
 PI: APV, NFV, LPV decrease methadone levels;
methadone decreases APV levels
 Buprenorphine: limited data on interactions with
ARV
HBV/HIV Co-Infection
 Higher rates of HBe antigenemia, higher
Hepatitis B (HBV) DNA levels, higher rates of
HBV-associated liver disease
 Unclear if HBV increases HIV progression
 HBV therapy recommended:
 active HBV replication
 HBeAg+ or elevated HBV DNA
 microinflammation
 ALT >2x ULN or histology showing moderate
disease activity or fibrosis
HBV/HIV Co-Infection: Treatment
 Interferon alfa 2a or 2b
 Duration and efficacy unclear in HIV/HBV coinfection
 Nucleoside/nucleotide analogs
 Appear to be highly active against HBV
 Lamivudine (3TC), tenofovir (TDF), and
emtricitabine (FTC) also active against HIV
 Potential flare in HBV when discontinued
HBV/HIV Co-Infection: Treatment
 Nucleoside/nucleotide analogs
 Lamivudine: FDA-approved for treatment of HBV.
Resistance frequently develops.
 Adefovir: FDA-approved for treatment of HBV.
Active against lamivudine-resistant strains. No
anti-HIV activity at doses used for HBV treatment.
 Tenofovir: Limited data available. Active against
lamivudine-resistant strains.
 Emtricitabine: Limited data; similar to lamivudine,
cross resistance to lamivudine.
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to treat HIV, not HBV:
 Consider withholding 3TC, TDF, and FTC for
future use
 Avoid using these as a single drug with antiHBV activity
 Need to treat HIV & HBV:
 Consider using 3TC, TDF, or FTC
 Consider using 3TC or FTC, + TDF, to avoid
resistance
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to treat HBV, not HIV:
 Consider adefovir or interferon
 Avoid 3TC, TDF, and FTC
 use these only as components of fully-suppressive
ART, unless preexisting HIV resistance
 Need to discontinue 3TC, TDF, or FTC:
 Consider adefovir
 Flares of HBV possible; monitor closely
HCV/HIV Co-Infection
 Higher rates of progressive liver disease in HIV/
Hepatitis C (HCV co-infection
 Unclear if HCV increases HIV progression
 Poor prognosis; unclear if HIV treatment
improves morbidity and mortality for untreated
HCV
 Higher rates of ARV-associated hepatotoxicity
HCV/HIV Co-Infection
Treatment indicated:
 Detectable plasma HCV RNA and bridging or
portal fibrosis on liver biopsy
 Consider other factors such as:




stage and stability of HIV disease
other co-morbidities
probability of adherence
possible contraindications to HCV medications
HCV/HIV Co-Infection: Treatment
Pegylated interferon + ribavirin for 48 weeks
 Low rates of sustained virologic response
in genotype 1
 Limited data on patients with CD4 <200
cells/mm³
HCV/HIV Co-Infection: Treatment
Potential for drug-drug interactions and additional
toxicity in HIV/HCV:
 Avoid use of DDI with ribavirin (neuropathy,
pancreatitis, lactic acidosis)
 Avoid use of AZT with ribavirin, if possible
(anemia)
 Monitor closely for hepatotoxicity due to ARV
 Monitor closely for neutropenia (due to
interferon) and anemia (due to ribavirin);
hematopoetic growth factors