Transcript HIV Antiretrovirals

Session B: HIV Antiretrovirals
Pre-departure Orientation
23 January 2007
Royce C. Lin, MD
Assistant Clinical Professor of Medicine
University of California, San Francisco
Director, AIDS Consult Service
Deputy Director, ASPIRE
Positive Health Program. HIV/AIDS Division
San Francisco General Hospital
GOALS
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Review Kenyan ART guidelines
Discuss WHO 2006 guidelines
Review individual ARV agents
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Review principles of therapy switch
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Toxicity
Side effects
Monitoring considerations
For side effects
For adverse events
Case Studies
Available ANTIRETROVIRALS: U.S.
NRTI (nucleoside analogs)
Protease Inhibitor
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Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Zalcitabine
Tenofovir
ABC
DDI
FTC
3TC
D4T
ZDV
DDC
TDF
Amprenavir
Atazanavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Darunavir
NNRTI (non-nucleosides)
Fusion Inhibitor
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Integrase Inhibitors
Delavirdine
Efavirenz
Nevirapine
DLV
EFV
NVP
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Enfuvirtide
APV
ATV
FPV
IDV
LPV
NFV
RTV
SQV
TMC-114
T-20
Selecting HAART regimen: US
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Full access to all antiretroviral agents
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Which specific combo depends on
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Existing comorbidities, lab abnormalities
Genotype (transmitted resistance)
Patient preferences
Once-daily dosing; pill burden considerations
Wide variation in combos prescribed
Benefits: tailor-fit; option to switch
Selecting HAART regimen: RLS
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Limited access to all antiretroviral agents
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Generally, one-size-fits all:
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Cheap generics make ART ‘roll-out’ possible
Algothrithmic approach enable rapid scale-up
But this results in limited options, essentially….
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Triomune for all, unless:
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Contraindication to any component
Treatment of active TB
Pregnancy considerations
Treatment-limiting SAE/toxicity
Constructing an Antiretroviral
Regimen for Initial Therapy:
a US-based approach
Royce C. Lin, MD
Assistant Clinical Professor
Constructing a HIV
Antiretroviral regimen
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Key principle: 3 active drugs
2 NRTI + NNRTI or PI
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“Nuc” backbone + either PI or NNRTI
AKA: Two scoops rice + chicken or beef
Choosing a regimen
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Step 1: Decide: NNRTI or PI
Step 2: Pick a NRTI ”backbone”
Choose components based on toxicity
Take into account side effect, pill burden, patient
preference, and cost
Summary: DHHS Guidelines 2006
Chicken
Beef
Two Scoops
Guidelines for the Use of Antiretrovirals in HIV-1 infected Adults and Adolescents
10 October 2006, Department of Health and Human Services, USA
WHO 2006 Guidelines: Summary Table
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited
Settings: Toward Universal Access. World Health Organisation 2006 Revision.
WHO 2006 Guidelines: Summary Table
Majority: D4T + 3TC + NVP in FDC
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited
Settings: Toward Universal Access. World Health Organisation 2006 Revision.
Recommended first-line regimens in TZ
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d4T+3TC+NVP, (All in one tablet: Fixed Dose
Combination (FDC):
I
Triomune 40 twice daily (> 60 kg body weight).
Triomune 30 twice daily (< 60 kg body weight).
NB: For new patients use Nevirapine only once a day
(half dose) for first 2 weeks by giving 1triomune in the
evening and d4t and 3TC separate tablets in the morning
II
AZT+3TC+NVP
Zidovudine and Lamivudine and Nevirapine, each
twice daily
NB: For new patients use Nevirapine only once a day
(half dose) for first 2 weeks
Recommended first-line regimens in TZ, continued
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III d4T+3TC+EFV
Stavudine and Lamivudine twice daily and Efavirenz
600 mg once daily at night
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IV AZT+3TC+EFV
Zidovudine and Lamivudine twice daily and Efavirenz
once daily at night.
Indications to change antiretroviral therapy
within first line regime are to be determined by
prescribing doctor: (see next slide)
Recommended second-line regimens in Kenya
 ABC + ddI + LPV/r
Abacavir and Lopinavir/ritonavir two times a
day and Didanosine once a day on empty
stomach
ABC + TDF + LPV/r
Learning ARVs for Kenya
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Goals
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Monitoring for SAFETY
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ARVs have many toxicities
Toxicity depend on ARV class
Some ARVs have fatal toxicities
Switching therapy
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Some clients cannot tolerate their ART regimen
 Side effects
 Toxicity
 Failure
Knowing how a HIV regimen is put together allows
you to make intelligent and safe changes.
How to learn ARVS
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Divide individual ARVs into 3 classes
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NRTI
NNRTI
PI
Learn the “class effects”
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Each class of ARVs have common toxicities
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If you can remember which class an ARV
belongs to, you can remember which toxicities to
watch for
Learn individual drugs
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Learn any other unique properties of each drug.
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Knowing each drug well is one of the most
important parts of being a good HIV care and
treatment provider!
NRTI
Nucleoside/tide Reverse
Transcriptase Inhibitors
(mimics Adenosine, Thymidine, Guanine, or Cytosine)
NRTI: class effects
• All may cause:
– Mitochondrial toxicity
– Lactic acidosis
– Pancreatitis
– Peripheral Neuropathy
– Lipodystrophy
– Hepatotoxicity
NRTI tips
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How to recognize a NRTI
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3 letters or numbers
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Generic name usually end in “ine”
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AZT, 3TC, DDI, D4T, ABC, TDF
Zidovudine, lamividine, didanosine, stavudine
NRTI Exceptions: abacavir, tenofovir end in “vir”
but are NRTIs
NNRTI Exceptions: nevirapine, delavirdine are
NNRTI but end in “ine”
NRTI = “Backbone” of ART
 Foundation of most ART combinations
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“Two scoops of rice” plus chicken or beef
Two NRTI (rice) PLUS
 Chicken (NNRTI) or
 Beef (PI)
NRTIs
DISADVANTAGES
ADVANTAGES
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Essential part of any
ART combination
Less drug-drug
interactions
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Individual drugs with
unique side
effects/toxicities
Class effect:
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Availability in resourcelimited settings
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Lactic acidosis
Mitochondrial toxicity
Peripheral neuropathy
Lipodystrophy
Hepatotoxicity
3TC (lamivudine/Epivir)
• Toxicity
– Few
– Hepatitis B exacerbation
• Side Effects
– Few; class effect
• Dosing
– 150mg bid or
– 300mg qd
– Renal dosing available
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Special Considerations
– Hepatitis B
D4T (stavudine/Zerit)
• Toxicity
– Lipoatrophy
– Peripheral neuropathy
– Pancreatitis
– Lactic acidosis
• Side Effects
– Gen well-tolerated
• Dosing
– 40mg bid (if >60kg)
– 30mg bid (if <60kg)
Malar Wasting of Lipoatrophy
AZT (zidovudine/Retrovir)
• Toxicity
– Anemia
– Neutropenia
– Thrombocytopenia
– Myopathy
• Side Effects
– Nausea/vomiting
– Headache
– Dizziness
• Dosing
– 300mg bid
DDI (didanosine/Videx)
• Toxicity
– Lactic acidosis
– Peripheral neuropathy
– Pancreatitis
– Lipodystrophy
• Side Effects
– GI
• Dosing
– If EC, 400mg QD (<60kg:
250mg qd)
– If reg tabs, 200mg bid
(<60kg:125 bid/250qd)
– Empty stomach
ABC (abacavir/Ziagen)
• Toxicity
– FATAL hypersensitivity
• Rash
• Fever
• GI (nausea/vomiting)
• Respiratory (SOB)
• Hypotension
• Death on re-challenge
– Class effect
• Side Effects
– Nausea, other GI
• Dosing
– 300mg bid or 600mg qd
– Co-formulated with 3TC as
Epzicom
TDF (tenofovir/Viread)
• Toxicity
– Renal failure
• Renal Tubular Necrosis
• Hypophosphatemia
– Hepatitis B exacerbation
• Side Effects
– Gen well-tolerated
• Dosing
– 300mg QD
– Avoid in borderline renal
dysfunction
– Fanconi’s syndrome (rare)
– Renal dosing necessary
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Special Considerations
– Hepatitis B
NNRTI
NON-nucleoside Reverse
Transcriptase Inhibitors
(blocks RT directly, NOT a nucleoside-analogue)
NNRTI: class effects
• All may cause:
– Rash
– Hepatotoxicity
NNRTIs
DISADVANTAGES
ADVANTAGES
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Ease (low pill burden)
Tolerability
Less metabolic effects
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fat maldistribution,
dyslipidemia
Availability in resourcelimited settings
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Prone to resistance
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single mutation
Cross resistance among
NNRTIs
Rash; hepatotoxicity
Potential drug
interactions (CYP450)
NVP (nevirapine/Viramune)
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Toxicity
– Hepatotoxicity (can be fatal)
• Cases of fulminant hepatitis 
death
• Usually within 6 wks
• Not in PMTCT
• Increased risk in women
– 12-fold risk: women, CD4>250
– 4-fold risk: men, CD4>400
– Rash (can be fatal)
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• Stevens-Johnson (erythema
multiforme major)
• Toxic epidermal necrolysis
• Mild rash COMMON
Side Effects
• Well-tolerated
Dosing
• Lead-in dosing: 200mg daily x 2
weeks, then 200mg bd
EFV (efavirenz/Sustiva)
• Toxicity
– Rash
– Hepatitis
– Teratogenic
• Not for use in women of
childbearing potential
• Side Effects
– CNS
• Insomnia/Somnolence
• Vivid dreams
• “Spacey”, poor
concentration
• Gen. ↓ after 1-2 wks
• Dosing
– 600 mg qd
PI
Protease Inhibitors
(binds/disables viral protease enzyme)
PI: class effects
• All may cause:
– Hyperlipidemia
– Hyperglycemia
– Fat redistribution
– CYP 3A4 inhibitors
– multiple drug-drug interactions
Protease Inhibitors
ADVANTAGES
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High potency
Longest prospective
data (durability)
 Esp. in advanced AIDS
Less susceptible to
resistance from virus
“Salvage” therapy when
NNRTI fails
DISADVANTAGES
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Metabolic complications
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fat maldistribution,
dyslipidemia, insulin
resistance
Drug interactions
(CYP3A4)
High cost
Limited availability
Ritonavir (RIT/Norvir)
• Toxicity
• Hepatotoxicity
• Hyperlipidemia
• Hyperglycemia/ insulin
resistance
• Drug-drug interactions!
• Potent inhibition CYP3A4
• Increases levels of other PIs
• Must check interactions
• Side Effects
– GI
• Nausea/vomiting
• Diarrhea
• Abdominal pain
• Dosing
• “boosting” 100-200mg qd
KAL (lopinavir+rit/Kaletra)
• Toxicity
• Hyperlipidemia
• Hyperglycemia/ insulin
resistance
• Drug-drug interactions
• Side Effects
– GI
• Nausea/vomiting
• Diarrhea
• Abdominal pain
• Dosing
• 3 tabs bid (400/100mg)
• Other
• Most potent ARV
• Hard to develop resistance
(>5 major PI-associated
mutations ↓ efficacy)
Constructing a HIV
Antiretroviral regimen
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2 NRTI + NNRTI or PI
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Exception: 3 NRTI in special circumstances only
Choose components based on toxicity
Take into account side effect, pill burden,
patient preference, and cost
Always need 3 active drugs!
AZT
3TC(or FTC)
+
D4T
(or DDI)
ABC
NRTI
Backbone
TDF
AVOID
D4T
AZT
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+
Competitive
Inhibition
Levels ↓
ddI
+
 Excessive
toxicity
D4T
ddC
Putting it all together
Cases in Treatment with ART
Algorithm for selecting first line treatment
1st line regimen
I. d4T + 3TC + NVP
Replace d4T with AZT
due to:
• Peripheral neuropathy
and NO anaemia
Replace NVP with EFV
due to:
• Hepatoxicity
• NVP intolerance
• TB patient on rifampicin
II. AZT + 3TC + NVP
III. d4T + 3TC + EFV
Modified 1st line regimen
Replace d4T with AZT
due to:
• Peripheral neuropathy
and NO anaemia
Replace NVP with EFV
due to:
• Hepatoxicity
• NVP intolerance
• TB patient
IV. AZT + 3TC + EFV
Case 1: Switching for complications
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34 yo Kenyan woman
WHO IV, CD4 45
HIV wasting, chronic diarrhea
Exam: cachexia, conjunctival pallor
Labs:
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HgB 7
WBC 1.2
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(40% PMN, 59% lymph, 1% eos)
Plt 140k
Remaining normal
OK to start Kenyan first-line therapy?
What if you are in South Africa?
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First-line is efavirenz/3TC/AZT
Case 2: Switching for Complications
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45 yo man
WHO III, CD4 170
Prurigo, onychomycosis, and oral
hairy leukoplakia and treated thrush
Pre-ART labs: all normal
Started on Triomune
4-months later, hospitalized for
severe abdominal pain, nausea,
vomiting, dehydration, inability to
tolerate oral solids/liquids
Differential diagnosis?
What is your work-up?
Case 2
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Hospital labs:
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Clinical course:
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CBC, chemistry, LFT nl
Lipase 600
ART stopped
Hydration, electrolyte support
Discharged 3 days later
When the patient returns, would you resume
ART? If so, with what combination?
Case 3
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45 yo Ugandan woman
In 2002 ago was WHO III
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Social: administrative assistant
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Weight loss (75kg  66kg)
Recurrent thrush, vaginal candidiasis
Zoster with post-herpetic neuralgia
Limited income, can spend up to 25,000 TSH on
medications
Advised to purchase generic Triomune
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Started Triomune October 2002
4 months later, weight 66kg  70kg
8 months later, no more recurrence of
thrush
1 yr later, weight 74kg
3 yrs later, weight 74 kg
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Complains “I am starting to like a man….I think I
look strange in the face”
Fat loss in thighs and face.
Otherwise feels well.
Case 7: Switching for complications
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33 yo Tanzanian woman
Spouse also HIV+
WHO Stage III, CD4 180
Sexually active, cannot afford
condoms
Complains of chronic cough for 2
months
Exam: thrush
Labs: all within normal parameters
CXR: “clear”
OK to start Triomune?
Case 7
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Started on Triomune
Tolerated well, no problems
3 weeks later
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Differential diagnosis?
Exam:
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Cough increased
Fever
Weight loss
Rales in RLL and LUL
CXR: R apical infiltrate and LLL diffuse opacity, hilar
lymphadenopathy not seen on prior CXR
Labs: WNL
Course of Action?
Case 7
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Diagnostics
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Sputum for AFB
Given Amoxicillin
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AFB smear+
What should you do now?
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No improvement
Start anti-TB therapy?
Continue Triomune?
Stop Triomune?
Replace Triomune?
Drug interaction:
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Rifampin decrease NVP
Use EFV+3TC+D4T
Must provide birth control while on EFV
Change in AUC: Interaction between RIF+ARV
RIF levels
ARV levels
Nevirapine
unchanged
↓ 58%
Efavirenz
unchanged
↓ 26%
Ritonovir
unchanged°
↓ 35%
Saquinavir
NR*
↓ 70%sgc 80%hgc
Indinavir
NR*
↓ 90%
Nelfinavir
NR*
↓ 82%
Amprenavir
NR*
↓ 81%
AIDS Read 10(2):102-108, 2000. Adapted with permission from Burman WJ et al. Clin Infect Dis. 1999.
Rifampicin + Efavirenz
• YES. But optimal dosage unclear.
• Rifampin decreases EFV 28%
• Unclear if dose adjustment needed
– Spanish study: ↑EFV from 600mg to
800mg overcomes PK1
– Descriptive studies supporting both 600
and 800 mg dose2,3
1.
2.
3.
Lopez-Cortes L, Valderas R, Viciana P, et al. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected
patients with tuberculosis. Clinical Pharmacokinetics 2002; 41 (9):681-690.
Lopez-Cortes L,et al. Efficacy, safety, and pharmaco-kinetics of efavirenz (EFV) 800 mg qd co-adminstrated with rifampin (R)
in HIV-infected patients with tuberculosis, 2nd IAS Conference on HIV Pathogenesis and Treatment, Paris, France, July 1316, 2003. Vol. 8.
Patel A, et al. To study the safety and antiretroviral efficacy of concomitant use of rifampicin and efavirenz in antiretroviralnaive tuberculosis co-infected HIV-1patients in India, 10th Conference on Retroviruses and Opportunistic Infections, Boston,
Massachusetts, February 10-14, 2003.
Rifampicin + Nevirapine
• UNCLEAR. More data needed.
• Rifampin decreases NVP 31% to 58%
• Little clinical data
– Small Spanish cohort (n=32): 74% with
virologic suppression at 15 months1
• More studies needed
– Esp. in resource-limited settings
1. Oliva J, Moreno S, Sanz J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. Aids
2003; 17:637-8.
Rifampicin + PI’s
• NOT RECOMMENDED
• Rifampicin decrease protease inhibitor
levels 70-90%
• Rifampicin induces hepatic enzyme cytochrome
P450 3A4
• Results in MARKED INCREASE in metabolism of
protease inhibitors
• Few clinical studies on PI + rifampicin
– Kaletra (lopinavir/ritonavir): variable Cmin.
– Saquinavir/ritonavir tried
PI’s in TB: Additive Toxicity
– SQV/rit 1600/200 has been tried1
• High dose PI “boosted” with ritonavir
– Ritonavir used to increase PI levels by inhibiting
CYP3A4
• 3/20 with viral rebound, all with low Cmin
– High hepatotoxicity with RIF + SAQ/RIT
• Reported February 2005 in Dear Doctor letter
• Phase I study: RIF 600mg + SAQ 1000mg + RIT
100mg
• 11/28 (39.3%) developed hepatotoxicity
– Transaminases up to 20x upper limit normal
• Ritonavir + rifampin  additive hepatotoxicity
1.
Veldkamp AI, et al. Ritonavir enables combined therapy with rifampin and saquinavir. Clin Infect Dis 1999; 29:1586.
Summary Points
• HIV potentiates TB. TB accelerates HIV
• Treating HIV-TB coinfection is complex
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Many clinical questions remain
Rifampicin decreases levels of PI and NNRTI
NRTI levels unchanged.
Additive toxicity with some ARVs and TB therapy
• ARV recommendation in TB therapy
– EFV 600mg or 800mg is best option
– NVP not well studied, levels decreased somewhat
– PIs levels decreased significantly
» Additive toxicity
» Beware of hepatotoxicity, failure due to insufficient levels
Algorithm for selecting first line treatment
1st line regimen
I. d4T + 3TC + NVP
Replace d4T with AZT
due to:
• Peripheral neuropathy
and NO anaemia
Replace NVP with EFV
due to:
• Hepatoxicity
• NVP intolerance
• TB patient on rifampicin
II. AZT + 3TC + NVP
III. d4T + 3TC + EFV
Modified 1st line regimen
Replace d4T with AZT
due to:
• Peripheral neuropathy
and NO anaemia
Replace NVP with EFV
due to:
• Hepatoxicity
• NVP intolerance
• TB patient
IV. AZT + 3TC + EFV
Summary
 Understand Toxicity of Individual ARV
 If symptoms develop, consider each individual
ARV and what it can cause
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Also consider non-ART related causes
 Therapy switch
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For Toxicity of Complication of ART
OK to switch within class
• NVP  EFV
• D4T  AZT or ABC
• NVP should NOT be switched for D4T, AZT, DDI,
ABC!