initiation of antiretroviral therapy
DESCRIPTION
Initiation of Antiretroviral Therapy. Dr Appolinaire TIAM Technical Director EGPAF-Lesotho. When to Start Therapy?. Eligibility for ART Adults and Adolescents. Criteria for initiation in a specific population. Priority population for ART initiation. Those with very low CD4 counts (TRANSCRIPT
INITIATION OF ANTIRETROVIRAL THERAPY
Dr Appolinaire TIAMTechnical Director
EGPAF-Lesotho
WHEN TO START THERAPY?
ELIGIBILITY FOR ART ADULTS AND ADOLESCENTS
WHO clinical stage CD4 available CD4 not available
4 Treat all Treat all
3 Treat all Treat all
2 CD4≤350 Do not treat
1 CD4≤350 Do not treat
3
CRITERIA FOR INITIATION IN A SPECIFIC POPULATION
Target Population Clinical condition Recommendation
Asymptomatic individuals (including pregnant women)
WHO stage 1 Start ART if CD≤350
Symptomatic individuals (including pregnant women)
WHO stage 2 Start ART if CD4≤350
WHO stage 3 or 4 Star ART irrespective of CD4 cells count
TB and Hepatitis B co-infection
Active TB disease Star ART irrespective of CD4 cells count
HBV infection requiring treatment
Star ART irrespective of CD4 cells count
4
PRIORITY POPULATION FOR ART INITIATION
• Those with very low CD4 counts (<200)
• Children• Pregnant women• TB patients• Absence of CD4 lab should not delay
ART initiation in those in need such as children aged <24months, adults or child stage 3 or 4.
5
HAART AND SURVIVAL BASED ON INITIAL CD4+ CELL COUNT
• Modeled data from ART Cohort Collaborative
• 10,855 patients included• 934 progressed to AIDS or
died• IDUs excluded from model
CD4+ < 200 vs
201-350
CD4+ < 350 vs
351-500Hazard ratio for AIDS (95% CI)
3.68 (3.01-4.51)
1.52 (1.10-2.10)
Hazard ratio for AIDS or death (95% CI)
2.93 (2.41-3.57)
1.26 (0.94-1.68)
Sterne J, et al. CROI 2006. Abstract 525.
Cumulative Probability of AIDS/Death According to CD4+ Count at Initiation
of HAART
Years Since Initiation of HAART0 1 2 3 4 5
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Prob
abili
ty o
f AID
S or
Dea
th
101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
WHEN TO START - CONSENSUS
• Symptomatic patients that WHO stage 3 or 4– Treat all
• Asymptomatic patients– CD4 Abs: ≤350/mm3– Regardless of HIV-1-RNA level
• When the patient is ready to commit
7
THE INITIAL REGIMEN
FIRST LINE FOR TREATMENT NAIVE ADULTS AND ADOLESCENTS
Target population
Preferred Option
Alternatives
Comments
Adults and adolescents (> 12 years and >35 kg)
TDF +3TC +EFV
AZTNVP
Use fixed dose combinations wherever possible
Pregnant women
AZT +3TC +EFV
TDFNVP
-TDF is acceptable in pregnancy-Do not initiate EFV in the first trimester
HIV/TB TDF +3TC +EFV
AZTboosted LPV/r
-Initiate ART as soon as possible (within the first 8 weeks) after starting ATT-Use LPV/r (ritonavir boosted, 1:1) if EFV is contraindicated
HIV/HBV TDF +3TC +EFV
NVP -HBsAg screening should be done at baseline for all patients-Use of two ARVs with anti-HBV activity required
9
Regimens When to use What to avoidTenofovir (TDF) 300 mg OD +
Lamivudine(3TC) 300 mg OD+
Efavirenz (EFV)600 mg nocte; use 400 mg if<40kg
Preferred 1st line regimen. Also preferred in patients with Hepatitis B co-infectionMay be used in adolescents > 12 years and > 35kg
Avoid TDF if renal compromise (baseline calculated creatinine Clearance is <50ml/min)
Tenofovir (TDF) 300 mg OD +
Lamivudine(3TC) 300 mg OD+
Neverapine (NVP)200 mg OD for the first 2 weeks, then 200 mg BD
NVP should be used in women who expect to become pregnantMay be used in adolescents > 12 years and > 35kg
Avoid NVP in patients on TB treatment NVP should be used with caution in women with baseline CD4 between 250-350
Zidovudine(AZT)300 mg BD +
Lamivudine(3TC) 300 mg OD+
Efavirenz (EFV)600 mg nocte; use 400 mg if<40kg
Preferred regimen for pregnant women if beyond the 1st trimester
Avoid AZT in patients with Hb<8mg/dl (use TDF); may use ABC if TDF contraindicatedAvoid EFV in first trimester of pregnancy
Zidovudine(AZT)300 mg BD +
Lamivudine(3TC) 300 mg OD+
Neverapine (NVP)200 mg OD for the first 2 weeks, then 200 mg BD
Use NVP for pregnant women still in the 1st trimester
Avoid AZT in patients with Hb<8.0 mg/dl (use aindicatedTDF); may use ABC if TDF contraindicated.
10
MODE OF ACTION11
12
SUBSTITUTION IN THE FIRST LINE
• Co-infection with TB: D-D interaction btw NVP and Rifampicin so EFZ should be substituted for NVP.
• For children<3 years of wt<10kgs, give NVP at 200mg/m2.
• Severe toxicity grade 3 or 4.
13SEVERE TOXICITIES AND POTENTIAL FIRST LINE SUBSTITUTIONSFirst-line ARV drug
Frequent toxicities 1st line substitution
TDF Renal Toxicity AZTAZT Severe anenia/neutropenia TDF or ABC
Severe GI intolerance TDF or ABCLatic acidosis TDF or ABC
D4T Lactic Acidosis TDF or ABCPN, pancreatitis, lipodystropy/metabolic syndrome.
AZT or ABC or TDF
EFZ Persistent or severe CNS toxicity NVPNVP Acute symptomatic hepatitis,
hypersensitivity reactionEFZ
SJS LPV/r ABC Hypersensitivity reaction AZT
SIDE EFFECTS
15
ADVERSE EFFECTS OF ANTIRETROVIRAL DRUGS
• Do occur commonly • Can be a potential barrier to successful
therapy• May lead to a reduction in the quality of
life• May be an important cause of non-
adherence to therapy• REMEMBER: Overall experience in the
world has shown that ARV medications are very well tolerated by the vast majority of patients!
16
OUTLINE
• Common side effect profiles of each ARV drug (grouped by class)
• Serious and rare toxicities of each ARV drug
• Recognition & Management strategies
• Brief review of long-term complications of PI’s
• Food requirements of ARV drugs• Summary / Conclusions
SIDE EFFECTS AND TOXICITIES
• Side effects are usually self-limited and not life-threatening, and usually resolve over a short period of time and with symptomatic support. Side effects usually occur early after ARV initiation.
• Toxicities are more severe, potentially life-threatening effects of ARVs and can occur at anytime.
17
POTENTIAL TOXICITIES OF NRTI CLASS
• AZT Zidovudine Retrovir™• 3TC Lamuvidine Epivir™• DDI Didanosine Videx™• D4T Stavudine Zerit™• ABC Abacavir Ziagen™
18
AZT (ZIDOVUDINE)
• Most common: – Nausea, vomiting, headaches, fatigue,
myalgias• Common:
– Macrocytosis -- not significant, but a marker for adherence
• Serious:– Anemia and neutropenia– Myositis (elevated CPK) and myopathy– Lactic Acidosis
• Other:– Darkening of skin, mucous membranes, nails
19
AZT PIGMENTATION (NAIL BEDS)20
AZT PIGMENTATION OF THE MUCOSA21
AZT PIGMENTATION(HARD AND SOFT PALATE)22
AZT ANEMIA
• Modification of AZT therapy must be considered when patients have substantial drop in HB (< 7.0 gm/dL) or more than 25% decrease from their baseline.
• AZT-induced anemia can occur as early as 2-4 weeks following initiation, but typically occurs after 4-12 weeks, but sometimes later.
23
SEVERE AZT ANEMIA
• If significant drop in HB from baseline:– STOP AZT Substitute D4T for
AZT– Transfuse if HB < 5.5 gm/dL– Do not treat with AZT again.
24
3TC (LAMIVUDINE)
• Common:– None (well-tolerated)
• Less common:– Occasional nausea, headaches,
vomiting, and diarrhea• Serious:
– Pancreatitis (very rare)
25
D4TN(STAVUDINE)
Contraindicated with AZT
• Common side effects: – Peripheral neuropathy (up to 20%)
• Uncommon:– Lethargy, myalgia, headache
• Serious:– Liver toxicity, pancreatitis (rare), lactic
acidosis (rare)
26
DDI (DIDANOSINE)
• Common:– Nausea– Bloating– Diarrhoea– Peripheral neuropathy (up to 20%)
• Serious:– Pancreatitis, optic neuritis
27
ABC (ABACAVIR)
• Common:– Hypersensitivity reaction
• Serious:– Anaphylactic reaction– Death may occur
28
RECOGNITION OF ARV DRUG INDUCEDPERIPHERAL NEUROPATHY
• ARV drugs implicated: D4T > DDI > > AZT• Need to document presence of PN at
baseline visit since HIV alone can cause significant PN, which often improves with ARV therapy.
• Typical symptoms (parasthesia, numbness)– Usually in hands / feet (“stocking-glove
distribution”)– As progresses, can cause loss of reflexes and
vibratory sense– Important to assess how PN affects activities of
daily living (walking, sleeping, working, etc.)
29
30MANAGEMENT OF ARV DRUG INDUCEDPERIPHERAL NEUROPATHY
• Mild/Moderate PN– Treat side effects and continue same regimen– Treat with amitriptyline (begin at 25 mgs),
carbamazepine, phenyton, or gabapentin.• NOTE: [Need to document presence of PN at baseline
visit since HIV alone can cause significant PN]
• Severe PN– Discontinue causative ARV drugs (D4T and/or
DDI)– May take weeks-months for symptoms to
resolve even after discontinuing causative ARV drugs
31RECOGNITION OF ARV DRUG INDUCED PANCREATITIS
• Symptoms of pancreatitis typically during first 1-6 months
• Begins with abdominal pain, nausea and vomiting
• More common with DDI, but also rarely reported with 3TC and D4T
• Elevated amylase/lipase (asymptomatic hyperamylasemia may be due to parotid/salivary gland source).
MANAGEMENT OF ARV DRUG INDUCED PANCREATITIS
• Treat abdominal pain, nausea, vomiting.
• Bowel rest with IVF’s (stop all ARVs, until pancreatitis resolves); consider imaging with abdominal ultrasound / CT scan.
• Do not re-challenge with offending ARV(s) if pancreatitis is confirmed.
32
LACTIC ACIDOSIS SYNDROME
• Entire NRTI class implicated:– Recently described / reported– Probably due to mitochondrial toxicity– Very rare– Presentation is very vague (fatigue,
nausea, vomiting, abdominal pain, weight loss, malaise, dyspneoa, and motor weakness)
33
RECOGNITION OF LACTIC ACIDOSIS SYNDROME
• Laboratory Clues:– Increased anion gap: Na – [Cl + CO2] – Increased lactic acid (check with a grey-
top tube on ice), modest elevation in SGOT/SGPT, and low HCO3
• NOTE: If your lab is not able to perform routine HCO3 on U/E, can run heparinised blood specimen on blood gas analyzer)
• Diagnosis:– Above symptoms with elevated lactate
level (> 5.0 mmol/L in adults
34
MANAGEMENT OF LACTIC ACIDOSIS SYNDROME
• High mortality rate (60%)• Consider administering bicarbonate
and vitamin supplements (riboflavin).• Discontinue all ART; administer NRTI-
sparing HAART after patient recovers. Consult HIV specialist.
• Recovery from elevated lactic acid levels may be prolonged.
35
Efavirenz (EFV)
Nevirapine (NVP)
POTENTIAL TOXICITIES OF NNRTI CLASS
37
EFV (EFAVIRENZ)
• Common (not class-related):– Central nervous system side effects
• Headaches• Light-headedness• Confusion• Sleep disturbances (abnormally vivid
dreams)– These side effects typically resolve within the first
14-21 days of treatment
38
EFV (EFAVIRENZ)
• Serious (class-related):– Skin rash; progressing to Steven’s
Johnson Syndrome – Hepatotoxicity– The above toxicities are less common
with EFV than with NVP.
39
EFV (EFAVIRENZ)
• EFV is the only ARV absolutely contra-indicated in pregnancy
• Not recommended for use in women with child-bearing potential
• Safe to administer with ATT medications
40
EFV (EFAVIRENZ)
• Other possible side effects:– Lipodystrophy (body habitus
changes)– Elevated triglycerides/cholesterol– Breast enlargement
NVP (NEVIRAPINE)
• Common:– Cutaneous
• Skin rash, reported up to 20%, usually appears in the first few weeks to months of therapy.
• Progresses to Stevens-Johnson Syndrome (SJS) in < 1.0%.
• Less Common:– Liver toxicity(more common than with
EFV)
41
MILD NVP RASH
• Moderate maculopapular rash is typically on face, trunk, and/or extremities, with or without pruritus.
• Usually appears within the first few weeks to months of therapy.
• Treat with antihistamines, topical skin creams, and NOT systemic steroids.
• Usually resolves within a few weeks.• Safe to continue NVP, but if patient is still on OD
dose, do not dose escalate until rash resolves.• Advise patient to return if rash worsens or
mucous membrane involvement appears.
42
SEVERE NVP RASH (1)
• Severe Hypersensitivity Reaction • SJS is quite rare, occurs within the first 6-8
weeks of ARV therapy, and can be fatal. • Treat with steroids and stop ALL ARV drugs
until patient recovers, and do not re-challenge with NVP.
43
SEVERE NVP RASH (2)
• Any of the following signs/symptoms suggest impending SJS:– Fever– Conjunctivitis– Extensive, moist, peeling rash– Mucous membrane involvement
(lip sores/ulcers/swelling, new vaginal lesions)
– Patient appears unwell
44
NVP-RELATED SJS45
STEVENS-JOHNSON SYNDROME47
MANAGEMENT OF NVP-INDUCED SEVERE SKIN REACTION• Discontinue ARVs and all other
medications• Treatment:
– Prednisone (40-60 mgs, taper)– Chlorpheniramine– Brufen– Paracetamol– Close observation, realizing that patient
may deteriorate over next 72-96 hours• After recovery, new ARV regimen may
substitute EFV or NFV for NVP. Do not re-challenge with NVP.
NNRTI LIVER TOXICITY
• If LFT’s up to 2x upper limit of normal values: WATCH!
• If LFT’s ≥ 5x upper limit of normal values: – Stop all medications, including ARVs,
and monitor LFTs.– When LFTs have normalized, restart
ARVs.– If previously on NVP, substitute EFV or
NFV for NVP.– If previously on EFV, substitute NFV for
EFV (do not use NVP).
50PRACTICAL CONSIDERATIONS WITH NVP TREATMENT
• LFTs should be drawn at 2 week follow-up visit after initiation of NVP.
• NVP: Need to monitor patients closely during first 6-8 weeks on ART.
• If possible, try to avoid simultaneous initiation of NVP with other drugs having potential hepatotoxicity, eg., ATT, IPT, cotrimoxazole.
• However, INH and cotrimoxazole may safely be used with NVP.
51
TOXICITIES OF PROTEASE INHIBITORS
• To be used for first/second treatment failures (cost, pill burden, interactions with TB meds, and side effects)
• Nelfinavir NFV• Ritonavir RTN• Saquinavir SQV• Indinavir IDV (PEP
only)• Lopinavir/Ritonavir LPV/r
52
LPV/R (LOPINAVIR / RITONAVIR
• Common:– Diarrhoea– Skin rash– Headache– Weakness
LONG-TERM METABOLIC COMPLICATIONS OF PI’S
• Insulin Resistance/Diabetes Mellitus – (elevated blood glucose)
• Lipodystrophy Syndrome – (body habitus changes)
• Lipid Abnormalities – (increased cholesterol/triglyceride
levels)• Osteoporosis/Avascular Necrosis
(rare)
LIPODYSTROPHY: BODY HABITUS CHANGES
• Fat accumulation (lipodystrophy*):– Neck fat pad– Breast enlargement
(gynecomastia in men)
– Visceral / central obesity
– Lipomas– *EFV and PIs
• Fat loss (lipoatrophy*):– Facial fat loss– Subcutaneous fat
loss in the extremities
– Fat loss in buttocks– *NRTIs, especially
D4T
LIPODYSTROPHY 155
LIPODYSTROPHY 256
LIPID MONITORING OF PATIENTS ON HAART
• Patients should have baseline and then 6-monthly lipid assessments if on PI-containing or EFV-containing HAART
• Check fasting glucose if diabetes is suspected.
58
FOOD REQUIREMENTS OF ARV MEDS
• Most ARV drugs may be taken with or without food.
• However, side effects may be less if taken with some food (AZT-induced nausea).
• DDI does need to be taken on empty stomach (otherwise poorly absorbed). Patient can eat 60 minutes after taking DDI.
• NFV and SQV (PI’s) should be taken with food
59
SUMMARY / CONCLUSIONS
• Adverse effects of antiretroviral agents are common and may be a cause of treatment discontinuation and non-adherence to therapy.
• Mild to moderate side effects, and those that resolved with time, may be managed with symptomatic therapy.
• Serious or disabling side effects or toxicities may necessitate discontinuation of the offending drug.
60
SUMMARY / CONCLUSIONS (2)
• It is important to EDUCATE patients about the potential adverse effects of these medications.
• It is important to be vigilant to these adverse effects when initiating therapy and also during follow-up.
• It is important to perform careful, comprehensive evaluations at baseline to see what side effects are pre-existing
TREATMENT FAILURE
BIG QUESTION….
• How seriously must we take resistance?
63
INTRODUCTION
• Drug resistance a significant obstacle in the fight against AIDS
• Resistance = poorer clinical outcomes
WHAT ABOUT TRANSMITTED RESISTANCE?
CDC Survey: DrugCDC Survey: Drug--Resistant HIV Resistant HIV Among Newly Diagnosed PatientsAmong Newly Diagnosed Patients
Prevalence of Drug Resistance (%)Prevalence of Drug Resistance (%)
1.31.33.03.0
1.71.7
7.77.7
10.710.7
2000 2000 (n=299)(n=299)
3.13.11.31.300>>2 drug class2 drug class2.82.80.80.800PIPI
8.48.42.12.10.40.4NNRTINNRTI
7.17.17.17.15.15.1NRTINRTI
14.514.58.88.85.55.5Resistance to:Resistance to:
Any drugAny drug
20032003--20042004(n=787)(n=787)
1999 1999 (n=239)(n=239)
1998 1998 (n=257)(n=257)
Bennett D, et al. 9th CROI, Seattle, 2002. Abstract 372.Bennett D, et al. 12th CROI. Boston, 2005. Abstract 674.
SO…..
• Resistance does not equal death• People rarely die on ARV’s, even with
resistant virus (Lancet 1999)
• Decreasing resistance = lengthening life of drugs/ lengthening life of patients
66
PATHOGENESIS67
HIV IS THE MOST SERIOUS INFECTIOUS DISEASE THREAT OF MODERN TIMES BECAUSE ……..
HIV’S REVERSE TRANSCRIPTASE ENZYME LACKS A PROOF-READING FUNCTION
• Allowing the virus to continually evolve and:– Evade the immune
response– Develop
antiretroviral drug resistance
69
MUTATIONS OCCUR DURING HIV REPLICATION
• Virion half-life = 30 minutes• Daily production = 10–100 billion virions
per day.• RT incorporates the wrong nucleotide
once every 10,000–30,000 nucleotides• Approximately 1 mutation per viral copy
Higher viral replication = more frequent mutations
• Every single point mutation occurs daily1. Coffin JM. Science. 1995;267:483-489.2. Wainberg MA et al. Science.1996;271:1282-1285. 3. Ho DD et al. Nature. 1995;373:123-126. 4. Wei X et al. Nature. 1995;373:117-122.
SURVIVAL AND PREDOMINANCE OF THE ‘MOST FIT’ STRAINS
• ‘Natural selection’Evolution of the virus by natural selection
• ‘Predators’ Antiretroviral drugsImmune system
DRUGS AVAILABLE…
• Nucleoside analogues – eg: AZT, ddI, d4T, 3TC
• Reverse transcriptase inhibitors eg: nevirapine, efavirenz
• Protease inhibitors – eg: Kaletra• Fusion inhibitors – T-20
72
DNA OF RESISTANT VIRUSES CAN BE ‘ARCHIVED’ AWAY IN MEMORY T LYMPHOCYTES
MUTATION
• Definition: A change in nucleic acid sequence that results in a change in amino acid sequence
AAA GAC AGT AAA AAC AGC
K(Lys)
D(Asp)
S(Ser)
K(Lys)
N(Glu)
S(Ser)
Codon
AAA GAC AGT AAA GAC AGT AGT
K(Lys)
D(Asp)
S(Ser)
K(Lys)
D(Asp)
S(Ser)
S(Ser)
PointMutation
Insertion
SilentMutation
M184V
Wild-typeamino acid(consensus)
Codon (position)PR = 1-99 amino acidsRT = 1-560 amino acids
Mutant amino acid
NOMENCLATURE75
Resistant virus
Wild type virus
The evolution of HIV resistance
Wild virus predominant, ‘chance’ resistant virus
time
Resistant virus
Wild type virus
Effective ARV’s, ineffective, non-pathogenic crippled virus
Good adherence, high drug pressure
The evolution of HIV resistance
Wild virus predominant, ‘chance’ resistant virus
time
Resistant virus
Wild type virus
Effective ARV’s, ineffective, non-pathogenic crippled virus
Decreased drug pressure as resistance develops
Good adherence, high drug pressure
The evolution of HIV resistance
Crippled but pathogenic virus
Wild virus predominant, ‘chance’ resistant virus
time
Resistant virus
Wild type virus
Effective ARV’s, ineffective, non-pathogenic crippled virus
Decreased drug pressure as resistance develops Stop all drugs
Good adherence, high drug pressure
The evolution of HIV resistance
Crippled but pathogenic virus
Wild virus predominant, ‘chance’ resistant virus
Rise of wild virus again, but large population of resistant virus
time
80
• Resistance is complex• > 200 mutations known to be
involved• Some affect more than one drug• Some reverse resistance• A critical need for reliable, practical
info on resistance
81“LOW GENETIC BARRIER” FOR ARV RESISTANCE (3TC, NNRTIS)
Number of Mutations
Rela
tive
Re
sist
ance
1 32 54
82“HIGH GENETIC BARRIER” FOR ARV RESISTANCE (AZT, D4T, DDI, KALETRA)
Number of Mutations
Rela
tive
Re
sist
ance
1 32 54
VIRAL FITNESS
• Resistant viruses may display impaired viral fitness – Impaired fitness = ↓ replication efficiency, ↓
growth
• Many drugs retain residual antiviral activity despite presence of mutations –3TC
Treatment
drug-sensitive virus
NNRTI-resistant virusdrug-sensitive virus
NNRTI-based treatment
drug-sensitive virus Crippled drug resistant virus
Non-NNRTI treatment
Good treatment
Crippled drug resistant virus
?????
“Supervirus”
Treatment
89
KNOWING THE ENEMY! RT MUTATIONS
• NNRTI resistance:– K103N – Y181C – V106M (clade C)
• Any one of these mutations will cause profound NNRTI cross-resistance
“LOW GENETIC BARRIER” FOR ARV RESISTANCE (3TC, NNRTIS)
Number of Mutations
Rela
tive
Re
sist
ance
1 32 54
91
RT MUTATIONS CONTINUED
• 3TC resistance– M184V – Causes complete resistance to 3TC– AND decreases ‘viral fitness’
“LOW GENETIC BARRIER” FOR ARV RESISTANCE (3TC, NNRTIS)
Number of Mutations
Rela
tive
Re
sist
ance
1 32 54
drug-sensitive virus Battered virus
3TC
94
RT MUTATIONS CONTINUED
• Thymidine analog mutations (TAMs)– Gradual accumulation of mutations
reduce susceptibility to AZT / d4TAND – eventually causes cross-resistance to
other NRTIs– E.g 41L, 67N, 70R, 210W, 215 Y/F,
219Q/E
“HIGH GENETIC BARRIER” FOR ARV RESISTANCE (ZDV, D4T, TDF, PIS)
Number of Mutations
Rela
tive
Re
sist
ance
1 32 54
96
RT MUTATIONS CONTINUED
• The non-thymidine mutations:– 65R mutation
• Reduced susceptibility to ABC, TDF, ddI– 74V mutation
• Reduced susceptibility to ddI, ABC
97
THE NRTI CLASS RESISTANCE MUTATIONS
• Multiple TAMs• Q151M• T69xxx• Ugly, ugly, ugly!
98
THE PROTEASE MUTATIONS
• Boosting with ritonavir to overcome the ‘genetic barrier’
• Mutations at position 82, 84, 90 cause cross-resistance to all PI
• Lopinavir-ritonavir very robust– Needs >6 mutations
99
Study 045: Influence of Baseline PI Study 045: Influence of Baseline PI Mutations on HIV RNA ReductionMutations on HIV RNA Reduction
•• 9696--week data in patients with week data in patients with prior PI failuresprior PI failures-- Lopinavir/ritonavir (n=123)Lopinavir/ritonavir (n=123)-- Atazanavir/ritonavir (n=120)Atazanavir/ritonavir (n=120)
•• Primary endpointPrimary endpoint-- TimeTime--averaged difference averaged difference
(TAD) in log(TAD) in log1010 viral load changeviral load change•• Atazanavir/rAtazanavir/r--lopinavir/rlopinavir/r
-- <4 mutations:<4 mutations:•• TAD: 0.04 (95% CI: TAD: 0.04 (95% CI: --0.23, 0.31)0.23, 0.31)
-- 4 mutations4 mutations•• TAD: 0.44 (95% CI 0.06, 0.83)TAD: 0.44 (95% CI 0.06, 0.83)
Johnson M, et al. 12th CROI. Boston, 2005. Abstract 711.
-3-2.5
-2-1.5
-1-0.5
0
WeeksWeeks0 24 48 72 960 24 48 72 96
--2.082.08
Lopinavir/ritonavirLopinavir/ritonavirAtazanavir/ritonavirAtazanavir/ritonavir
HIV RNA Reduction logHIV RNA Reduction log1010 copies/mLcopies/mL<4 Baseline PI Mutations<4 Baseline PI Mutations
--2.292.29
-3-2.5
-2-1.5
-1-0.5
0
WeeksWeeks0 24 48 72 960 24 48 72 96
--1.711.71
Lopinavir/ritonavirLopinavir/ritonavirAtazanavir/ritonavirAtazanavir/ritonavir
HIV RNA Reduction logHIV RNA Reduction log1010 copies/mLcopies/mL>>4 Baseline PI Mutations4 Baseline PI Mutations
--1.811.81
POORER VIROLOGIC RESPONSE FROM DELAYED SWITCH
Time
Accumulation of mutations
Vir
al lo
ad
Early switch
Late switch
Intermediate switch
First regimenSecond regimen
ddI
d4T
AZT
3TC
2 Nukes Non-nuke
Efavirenz/ nevirapine
Protease
Kaletra
Failure – VL>5000
ddI
d4T
AZT
3TC
2 Nukes Non-nuke
Efavirenz/ nevirapine
Protease
Kaletra
Failure – VL>5000
103
REASONS FOR FAILURE
– Non-adherence– Inadequate/inappropriate drugs– Sub-optimal drug levels– Intrinsic drug resistance
RESISTANCE PATTERNS AFTER INITIAL FAILURE OF COMMON NRTI BACKBONES
ZDV/3TCd4T/3TC M184V
TAMsZDV/3TC/ABC
ABC/3TC M184V L74V or K65R
TDF/FTC M184V K65R
Gallant JE. Top HIV Med. 2005;13:138-142.
DICHOTOMOUS PATHWAYS TO RESISTANCE
ZDV or d4T
Unknown factors
Unknown factors
Lower-level ZDV resistanceLess NRTI cross-resistance
Greater effect of M184V
Higher-level ZDV resistanceMore NRTI cross-resistance
Less effect of M184V
TAMs emerge sequentially
with ZDV- and d4T-containing regimens after
M184V
6 identified: M41L, D67N,
K70R, L210W, T215Y/F,
K219Q/E/N/R
41L210W215Y
67N70R
219Q
105
WHO REALLY NEEDS NEW DRUGS?
Mid90s
Late 00s
Early
00sLate 90s
Early
90sLate 80s
Early
80sAdapted from slides by Gallant JE and Deeks SG.
No ART
ZDV mono-
therapy
Sequential NRTI monotherapy and dual-NRTI therapy
“Sequential monotherapy” with PIs/NNRTIs
“Hit hard,
hit early”
Deferral of
therapy
Earlier initiation of therapy with
better rx
Highly adherent, aggressively treated patients led to selection of multidrug-
resistant HIV
107
NNRTIS: IMPORTANT MUTATIONS
• Most common: K103N, Y181C• These also lead to NNRTI resistance:
L100I, V106A, V108I, Y188L, G190A/S, P225H
• Other substitutions in loci close to the above may induce NNRTI resistance
108CLINICAL CONSEQUENCES OF RESISTANCE TO FIRST-GENERATION NNRTIS
• Important points about NNRTI resistance– Extensive cross-resistance between
drugs– No impairment of replication capacity or
ongoing antiviral effect once resistance develops
• Why resistance reports may be misleading– NVP failures often select for Y181C; EFV
still active phenotypically– G190A may lead to DLV
hypersusceptibility; rarely present in isolation
109CLINICAL CONSEQUENCES OF RESISTANCE TO FIRST-GENERATION NNRTIS (CONT’D)• But most studies suggest any prior NNRTI
resistance reduces subsequent response to current NNRTIs—low levels of K103N may not be detected by current assays
• Therefore, sequencing not a practical option with first-generation NNRTIs (EFV, NVP, DLV)
• NNRTIs in a failing regimen should be stopped to prevent selection of mutations that may impair response to second- generation agents
Palmer S, et al. J Clin Microbiol. 2005;43:406-413. Vingerhoets J, et al. CROI 2006. Abstract 154.
RESPONSE TO ETRAVIRINE IN PATIENTS WITH NNRTI & PI RESISTANCE (ITT:NC=F)
N = 199 HIV-infected patients with NNRTI resistance and ≥ 3 primary PI mutations
OBR alone(n = 40)
Etravirine 400 mg BID
(n = 80)
Etravirine 800 mg BID
(n = 79)-1.5
-1.0
-0.5
0
0.5
Mea
n (±
SE
) Cha
nge
in V
L (lo
g 10 c
/mL
)
Weeks
-0.14
-0.88*-1.01†
*P = .018†P = .002
► Median fold NNRTI-R Nevirapine: 61 Efavirenz: 41 Etravirine: 1.7
8 12 16 20 240 4 32 40 48
Cohen C. British HIV Association, 2006. Abstract 2.
2
EFFECT OF BASELINE RESISTANCE ON RESPONSE TO ETRAVIRINE
Number of Baseline NNRTI
Mutations (Number of Patients)
Viral Load Reduction at
Week 24(log10
copies/mL)
0 (n = 15) -1.82
1 (n = 18) -1.65
2 (n = 17) -1.00
≥ 3 (n = 29) -0.66
• Each of the following mutations, always in combination with up to 4 other mutations, was associated with a mean FC>10
– K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
– For V179E, V179F, G190S, or M230L, the additional mutations always included Y181C when the FC>10
• No single NNRTI drug resistance mutation was associated with FC>10
– Required multiple mutations (≥4)Vingerhoets J, et al. Resistance Workshop, 2006. Abstract 52.
Prevalence of Transmitted NNRTI Prevalence of Transmitted NNRTI Mutations in Newly Diagnosed PatientsMutations in Newly Diagnosed Patients
9.19.1G190AG190A
3.03.0Y188LY188L
16.016.0Y181CY181C
1.51.5V108IV108I
1.5/1.51.5/1.5V106A/MV106A/M
57.057.0K103NK103N
Transmitted NNRTI Mutations Transmitted NNRTI Mutations Among Those With NNRTI Among Those With NNRTI
Resistance (n=66)Resistance (n=66)
1.51.5L100IL100I
PrevalencePrevalence(%)(%)
4.64.6P225HP225H
•• Most prevalent mutations for: Most prevalent mutations for: -- PIs (n=22)PIs (n=22)
•• L90M (54.6%), M46I (41%), Y181C L90M (54.6%), M46I (41%), Y181C (16.0%)(16.0%)
-- NRTIs (n=56)NRTIs (n=56)•• T215 (46.6%), M41L (27%), M184V T215 (46.6%), M41L (27%), M184V
(21%), D67N (16%), T69N (12.5%), (21%), D67N (16%), T69N (12.5%), K219Q (11%)K219Q (11%)
•• Prevalence of transmitted HIV Prevalence of transmitted HIV drug resistance to drug resistance to >>2 drug 2 drug classesclasses-- Overall: 3.1% (n=24)Overall: 3.1% (n=24)
•• NNRTI + NRTI: 38%NNRTI + NRTI: 38%•• NNRTI + PI: 8%NNRTI + PI: 8%•• PI + NRTI: 29%PI + NRTI: 29%•• All 3 classes: 25%All 3 classes: 25%
Bennett D, et al. 12th CROI. Boston, 2005. Abstract 674.
112
NNRTI RESISTANCE IN SA LIKELY TO BE A SIGNIFICANT (LAB) PROBLEM
Prevalence of Transmitted NNRTI Prevalence of Transmitted NNRTI Mutations in Newly Diagnosed PatientsMutations in Newly Diagnosed Patients
9.19.1G190AG190A
3.03.0Y188LY188L
16.016.0Y181CY181C
1.51.5V108IV108I
1.5/1.51.5/1.5V106A/MV106A/M
57.057.0K103NK103N
Transmitted NNRTI Mutations Transmitted NNRTI Mutations Among Those With NNRTI Among Those With NNRTI
Resistance (n=66)Resistance (n=66)
1.51.5L100IL100I
PrevalencePrevalence(%)(%)
4.64.6P225HP225H
•• Most prevalent mutations for: Most prevalent mutations for: -- PIs (n=22)PIs (n=22)
•• L90M (54.6%), M46I (41%), Y181C L90M (54.6%), M46I (41%), Y181C (16.0%)(16.0%)
-- NRTIs (n=56)NRTIs (n=56)•• T215 (46.6%), M41L (27%), M184V T215 (46.6%), M41L (27%), M184V
(21%), D67N (16%), T69N (12.5%), (21%), D67N (16%), T69N (12.5%), K219Q (11%)K219Q (11%)
•• Prevalence of transmitted HIV Prevalence of transmitted HIV drug resistance to drug resistance to >>2 drug 2 drug classesclasses-- Overall: 3.1% (n=24)Overall: 3.1% (n=24)
•• NNRTI + NRTI: 38%NNRTI + NRTI: 38%•• NNRTI + PI: 8%NNRTI + PI: 8%•• PI + NRTI: 29%PI + NRTI: 29%•• All 3 classes: 25%All 3 classes: 25%
Bennett D, et al. 12th CROI. Boston, 2005. Abstract 674.
113
114
SOME THOUGHTS ON RESISTANCE…
• Resistance is complex• Field evolving as rapidly as the virus• Resistance ≠ MDR TB, but can
seriously limit future options• Common sense goes a long way…
115A PRACTICAL APPROACH TO A PATIENT FAILING THEIR FIRST REGIMEN
• Questions to ask when faced with a patient on ARV’s and possible drug resistance… – 1) How do you know that the person is
resistant?
116
EFV (600 mg qd)+ZDV+3TC (N=422)
EFV (600 mg qd)+IDV (1,000 mg q8h) (N=429)
IDV (800 mg q8h)+ZDV+3TC (N=415)
STUDY 006 DESIGN
• Design• Open-label, multicenter,
multinational (USA, Europe, Canada) trial
• Blinded to viral load to Week 24• 3TC-, NNRTI-, and PI-naive• Plasma HIV RNA 10,000 copies/mL• CD4 count 50 cells/mm3
117
RESULTS OF THE CPCRA 058 FIRST STUDY
• Long-Term Clinical and Immunologic Outcomes Are Similar in HIV-Infected Persons Randomized to NNRTI versus PI versus NNRTI+PI-based Antiretroviral Regimens as Initial Therapy: – MacArthur RD, Novak RM, Peng G, Chen
L, Xiang Y, Huppler Hullsiek K, Kozal MJ, van den Berg-Wolf M, Henely C, Schmetter B, Dehlinger M for the CPCRA 058 Study Team and the Terry Beirn Community Programs for Clinical Research on AIDS
118
DESIGN AND FOLLOW-UP
PI Strategy:
PI + NRTIs
(N=470)
NNRTI Strategy:
NNRTI + NRTIs
(N=463)
3-class Strategy:
PI + NNRTI + NRTI(s)
(N=464)
1,397 Participants Randomized
Median follow-up: 60 months (IQR 52-69 months)
Lost to Follow-up: 9.67%
(No study visit within 6 months of study closure for surviving participants)
119PI AND NNRTI DRUGS PRESCRIBED AT STUDY ENTRY
• PI Strategy:– Nelfinavir 61%– Ritonavir-boosted PI 26%
• NNRTI Strategy:– Efavirenz 63%– Nevirapine 36%
• 3-class Strategy:– Nelfinavir 63%– Efavirenz 52%
OUTCOMES
0.1 1 100.1 1 10
AIDS or deathor CD4+ < 200
Death
AIDS or death
Grade 4 event
AIDS or death orgrade 4 event
Discontinuation of AR due to toxicity
NNRTI vs. PI 3-class vs. 2-class
Hazard Ratio (95% CI)Event
Favors NNRTI Favors 3-classFavors PI Favors 2-class
1.07
0.95
1.02
1.15
1.28
1.06
1.01
1.15
1.04
1.02
0.93 1.58
TIME TO INITIAL VIROLOGIC FAILURE*
* HIV RNA > 1000 copies/mL at or after the 4-month visit
122GENOTYPIC MUTATIONS1DETECTED AT INITIAL VIROLOGIC FAILURE
PI NNRTI 3-class
None (%)2 54.9 46.2 47.4
Single-class (%)2 31.3 31.4 38.4
Multi-class (%)2 13.8 22.3 14.2
Number with genotype 326 264 268
1 IAS October 2004 list
2 Percent is of those with a genotype
123
CONCLUSIONS
Initiation of therapy with either an NNRTI or a PI (ritonavir-boosted or unboosted), but not both together, are good and effective strategies for long-term antiretroviral management in treatment-naïve HIV-infected persons with a wide range of baseline CD4+ cell counts and diverse demographics
124
TREATMENT FAILURE
• The decision to switch a patient to a 2nd line regimen must be made with care.
• For children: – The decision to switch a child to 2nd line therapy must be
made in consultation with a specialist at a tertiary institution.
– Cases must be reviewed and approved by a 2nd Line Committee (appointed by the MOHSW) prior to regimen change.
• For adults: – Trained clinicians are allowed to switch adults to 2nd line
regimen in consultation with specialists at tertiary institutions.
– The decision to switch to 2nd line therapy must be reviewed by the Second Line Committee prior to regimen change.
125
TREATMENT FAILURE IN CHILDREN
• Clinical Criteria for Treatment Failure– New or recurrent WHO clinical stage 3 or 4
events in a child who has been on ART > 24 weeks and with good adherence
• The following may also be considered:– Lack of or decline in growth rate in children
who show an initial response to treatment (moderate or severe unexplained malnutrition not adequately responding to standard therapy despite adequate nutritional support)
– Loss of neuro-developmental milestones or development of HIV encephalopathy,
TYPICAL RESISTANCE PATTERNS AFTER INITIAL FAILURE OF COMMON NRTI BACKBONES
AZT/3TCd4T/3TC M184V TAMsAZT/3TC/ABC
ABC/3TC M184V L74V > K65R
TDF/FTC M184V K65R
IMMUNOLOGICAL DEFINITION OF TREATMENT FAILURE IN CHILDREN
Development or return to the following age-related immunological thresholds after at least 24 weeks on ART (in a treatment-adherent child):- ≥ 2 years to < 5 years of age: CD4 < 10% or
< 200 cells/mm3
- ≥ 5 years of age: CD4 < 100 cells/mm3
Treatment failure should be suspected if any of the above clinical or immunological criteria are met and:
• The child has been receiving the regimen for at least 24 weeks (6 months)
• Poor adherence has been ruled out; excellent adherence has been documented through pill counts.
• Immune Reconstitution Inflammatory Syndrome (IRIS) has been excluded
• Poor nutrition has been ruled out
• Pulmonary or extra-pulmonary tuberculosis has been excluded
• Potential medication interactions have been excluded
SECOND LINE REGIMENS FOR CHILDREN FAILING FIRST LINE THERAPY
First Line Regimen Second Line Regimens
AZT + 3TC + NVP/EFV ABC + 3TC + LPV/rAlternative (ABC+ddI+LPV/r)
D4T + 3TC + NVP/EFV
ABC +3TC + NVP AZT +3TC + LPV/rAlternative (AZT+ddI+LPV/r)
ABC +3TC + EFV
AZT + 3TC + LPV/r ABC + 3TC + NVP/EFV
ABC + 3TC + LPV/r AZT + 3TC + NVP/EFV
DEFINITIONS OF TREATMENT FAILURE IN ADULTS AND ADOLESCENTS
Definition CommentsClinical Failure
New or recurrent WHO stage 4 event
Should be differentiated from Immune Reconsitution Inflammatory Syndrome (IRIS)Certain WHO stage 3 clinical conditions (e.g. pulmonary TB, severe bacterial infections), may be an indication of treatment failure and should be investigated.
Immunological Failure
Fall of CD4 count to pre-therapy baseline (or below); or50% fall from the on-treatment peak value (if known); orPersistent CD4 levels below 100 cells/mm3
Without concomitant infection to cause transient CD4 cell decrease; if the patient is asymptomatic and treatment failure is being defined by immunological criteria alone, consideration should be given to performing a repeat CD4 cell count before establishing the diagnosis of treatment failure
Virological Failure
Plasma viral load (VL) above 5,000 copies/ml after at least 6 months on ART
The optimal VL threshold for defining virological failure has not been determined; values of > 5,000 copies/ml are associated with clinical progression and a decline in the CD4 cell count
GUIDELINES ON SWITCHING ARVS DUE TO FAILURE OF FIRST LINE REGIMEN
Treatment Failure Criteria WHO Stage 1 Event WHO Stage 2 Event WHO Stage 3 Event WHO Stage 4 Event
Immunological failurea
(Viral load testing not available)
Do not switch regimen.
Follow patient for development of clinical signs or symptoms.
Repeat CD4 cell count in three months
Do not switch regimen. Follow patient for
evidence of further clinical progression.
Repeat CD4 cell count in three months
Consider switchingb to second-line regimen.
Recommend switchingb to second-line regimen
Immunological and virological failurea
(Viral load testing not available)
Consider switchingb to second-line regimen
Consider switchingb to second-line regimen
Recommend switchingb to second-line regimen
Recommend switchingb to second-line regimen
SECOND LINE REGIMENS FOR ADULTS FAILING ON FIRST LINE THERAPY
Targated Population Preferred Options CommentsAdults and adolescents > 12 years and > 35 kg (including pregnant women)
If d4T or AZT used in first-line
TDF + 3TC + LPV/r or ATV/r NRTI sequencing based on availability of FDCs and potential for retained antiviral activity, considering early and late switch scenariosATV/r or LPV/r are comparable and available as heat stable FDCs or co-packaged formulations
If TDF used in the first-line
AZT + 3TC + LPV/r or ATV/r
TB/HIV If rifabutin available Same regimen as recommended above for adults and adolescents
No difference in efficacy between rifabutin and rifampicinRifabutin has significantly less drug interactions with boosted PIs, permiting standard bPI dosing
If rifabutin not available
Same NRTI backbone as recommended for adults and adolescents plus LPV/r with superboosted dosing of RTVLPV/r 400mg/400mg twice daily or LPV/r 800/200mg BD
Rifampicin significantly reduces the levels of bPIs, limiting the effective options. Use of extra doses of ritonavir with selected bPIs (e.g. LPV/r) can overcome this effect but with increased risk of toxicity
Hepatitis B co-infection
AZT+TDF+3TC+LPV/r or ATV/r TDF +3TC should be maintained for anti-HBV activity and second line regimen should include other drugs with anti-HIV activity
THIRD-LINE REGIMENS
Drug ToxicityDarunavir Skin rash (10%)-DRV has a sulphonamide moiety
SJS and erythrema multiforme have been reported. Other possible side effects include: Hepatotoxicity; Diarrhoea; nausea; Headache; Hyperlipedaemia; Transaminase elevation; Hyperglycaemia; Fat maldistribution; and Possible increased bleeding episodes in patients with haemophilia
Ritonavir (RTV); as a pharmacokinetic booster
GI intolerance; nausea; vomiting; diarrhoea; Paresthesias-circumoral and extremities; Hyperlipedaemia especially hypertriglyceridaemia; Hepatitis; Asthenia; Taste perversion; Hyperglycaemia; Fat maldistribution; and Possible increased bleeding episodes in patients with haemophilia
Raltegravir (RAL)
Nausea; Headache; Diarrhoea; Pyrexia; CPK elevation
Etravirine (ETV) Rash (2% discontinuation because of rash during clinical trials); Hypersensitivity reactions characterised by rash, constitutional findings, and sometimes organ dysfunction including hepatic failure; and Nausea