Transcript Proposed Antiretroviral Treatment Pilot Programs in Uganda

Managing Emerging complications of HIV
Treatment
Background
 ARV has become more available in our settings
– Currently >65,000 Kenyans are estimated to be
on ARV treatment
 Antiretroviral therapy (ART) alters the nature of
HIV disease, transforming an almost uniformly
fatal illness into a chronic but stable condition.
 However its use may be complicated by a number
of factors, including side effects, drug interactions
and treatment failure.
Toxicity
 Adverse drug reactions (ADRs) are the most
common reason for treatment change or
discontinuation
– All classes of ARV drugs associated with ADRs
 Rate of toxicity is high
– 45% have clinical adverse events and 27% have
laboratory adverse events
 9% of clinical and 16% of laboratory are serious or severe
ICONA Study:
Reasons for Failure of Initial
HAART
8%
Toxicity
Failure
Nonadherence
Other
n = 25
20%
n = 61
58%
14%
n = 44
d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.
n = 182
Common side effects
 Which side effects are you seeing in your
patients?
ARV Drug Class Adverse
Effects
NRTIs
 Peripheral
neuropathy
 Pancreatitis
 Lipoatrophy
 Hepatitis
 Lactic acidosis
 Mitochondrial toxicity
NNRTIs





Rash
Fever
Nausea
Diarrhea
Hepatoxicity, CNS
PIs




Lipodystrophy
GI Intolerance
Hyperglycaemia
Lipid abnormalities
Common Adverse Effects









Peripheral Neuropathy – d4T,ddI
Hematotoxicity - AZT
Hepatotoxicity - NVP
Diarrhea – NFV
Skin rash – NVP
Lipodystrophy – PIs, NRTIs
CNS disturbance – EFV
Hypersensitivity – ABC
Hyperlipidemia-PIs, d4T
Common toxicity in our setting
 There is little information on tolerability to these
medications in African populations.
–
–
–
–
–
–
Severe rash /Steven Johnson's syndrome
Hepatotoxicity
Peripheral neuropathy
Hematological
Metabolic and morphologic complications.
Others
 pancreatitis
Distribution and Frequency of
Clinical Adverse Events among HIVInfected Patients Receiving ARV
Therapy,
Kibera ARV
Program
Adverse
Event
Any
Grade 3-4
(n=283)
(n=283)
Any adverse event
184 (65%)
18 (6%)
Neuropathy
65 (23%)
7 (3%)
Rash
58 (20%)
4 (1%)
Nausea
46 (16%)
1 (0.4%)
Asthenia
11(3.9%)
0
Diarrhea
5 (1.8%)
1 (0.4%)
4 (1%)
4 (1%)
6 (2)
6 (2)
Clinical hepatitis
Lipodystrophy
Time to First Adverse Event among HIVInfected Patients Receiving ARV Therapy,
Kibera ARV Program
Kaplan-Meier survival estimate
1.00
0.75
0.50
0.25
No adverse event at
6 months
12 months
18 months
Probability
0.47
0.26
0.17
0.00
0
n=283
12
6
Months Until First Clinical Adverse Event
n=92
n=19
18
n=14
Rash
 Most commonly due to Nevirapine, Also sometimes due to Efavirenz,
Abacavir and Cotrimoxazole
 Rash seen in up to 20% of patients, usually in the first 2-8 weeks of
use
 Associated with:
– Gender (female > male; RR 4.85-8.31)
– CD4 count/disease stage
– previous sulphur allergy (RR 5)
 Often mild to moderate , can be managed symptomatically
 Can progress to severe rash or even Stevens Johnson syndrome, in 5
-7%
Rash continued…..
 Dose- escalation decreases incidence
– Do not dose escalate if rash
 Pretreatment with steroids increases risk of
severe rash
 Stop NVP for grade 3 rash or higher
Stevens-Johnsons syndrome
Abacavir Hypersensitivity
Reaction
 Occurs in approximately 5-8% of ABC-treated
patients
 Associated with:
– female gender
– higher CD4 count
– Genetically linked to haplotype HLA-B*5701
 Multiorgan clinical syndrome including 2 or more
of the following:
– Fever, rash, GI complaints (nausea, emesis, diarrhea),
malaise, and respiratory symptoms (pharyngitis, cough,
dyspnea)
 Usually occurs within first 6 weeks of starting ABC
Abacavir hypersensitivity
Reaction cont……
Management
 Discontinue drug
(if diagnosis strongly suspected)
 NEVER re-challenge-Continued ABC
in face of HSR or reintroduction after
HSR can result in death
Hepatotoxicity
 Nevirapine is most likely to cause hepatotoxicity( other NRTI and
PIs)
–
–
–
–
Occurs in up to 10% of patients on NVP
Most common in first weeks to months
12 x more likely in women than in men
More likely at CD4 >250 in women and CD4>400 in men
 Often mild to moderate but can be severe ( potentially fatal)
 More common if underling liver disease
– Consider other causes
 Infectious hepatitis, other infections
 Other drugs (e.g. anti-TB)
 Check ALT/SGPT routinely at baseline, 4-6 weeks and at 3
months (as available)
 Check ALT/SGPT if any hepatic symptoms/signs
 Discontinue NVP for grade 3 toxicity or higher
– (transaminases> 5x normal)
Laboratory Toxicity
Anemia
(n=182)
Highest Toxicity Grade on ARVs
Normal
1
2
3
4
n (%)
n (%)
n (%)
n (%)
n (%)
174
7 (4%) 0 (0%) 1 (<1%) 0 (0%)
(96%)
Transamin
54
83
42(23%) 2 (1%)
ase
(30%)
(46%)
elevation
Among patients with >= 1 lab test after ARV initiation
(n=182)
1 (<1%)
HAART and Liver Enzyme Elevations
 Meta-analysis of 20 publications of HIV-infected patients ± HCV
coinfection
 Grade 2 or higher liver elevations noted
% LEE in HCV-Coinfected Patients by Drug Class
Patients With LEE,%
P = .025
40
P = .004
32.00
P = .009
30
18.44
20
15.96
14.67
13.62
10
5.26
0
NNRTI
PI
Mixed
BPI
Drug Class
Benhamou Y, et al. CROI 2006. Abstract 88.
NRTI
Overall
2NN: Hepatic Events With
NVP QD or BID vs EFV
All 2NN Patients
Asymptomatic grade 3/4 ALT/AST elevations
Symptomatic hepatic event
P = .0004
10
9
Hepatic Events (%)
 Initial data from 2NN
suggested ↑ incidence
of hepatotoxicity
with NVP QD or BID vs
EFV
8.6
8
7
P = .0135
6.7
5.6
6
4.8
5
3.7
4
3
2.1
2
1
0
Storfer S, et al. EACS 2005. Abstract PE9.6-2.
NVP QD
n = 210
NVP BID
n = 378
EFV
n = 379
2NN: Hepatic Events With
NVP QD or BID vs EFV
– Difference NVP QD vs BID
lost
Storfer S, et al. EACS 2005. Abstract PE9.6/2.
Non-Thai Centers
Asymptomatic grade 3/4 ALT/AST elevations
Symptomatic hepatic event
P = .055
10
9
Hepatic Events (%)
 Initial data from 2NN
suggested ↑ incidence
of hepatotoxicity
with NVP QD or BID vs
EFV
 Result later found to be
primarily due to 1 Thai
study center
P = .0233
8
7
6
6.3
6.2
5.6
4.2
5
3.2
4
2.6
3
2
1
0
NVP QD
n = 161
NVP BID
n = 334
EFV
n = 310
HCV-3 Coinfection Associated With
Greater Risk of Hepatotoxicity

N = 388 HIV/HCV-coinfected
patients in Italian cohort
– 132 had HCV genotype 3

Factors associated with ↑ risk
of grade ≥ 3 hepatotoxicity
– Male sex
– HBsAg positivity
– Baseline ALT
– HCV genotype 3
Cumulative Proportion of Patients
Free of ≥ Grade 3 Hepatotoxicity
1.0
HCV ≠ 3
0.9
0.8
0.7
P < .001
0.6
HCV-3
0.5
0.4
0.0
0.5
1.0
1.5
2.0
2.5
Time Since Entry (Years)
Torti C, et al. ICAAC 2005. Abstract H-1484.
3.0
 Management?
Hematological Toxicity
 AZT by far the most common cause
– Most likely in women, those with pre-existing anemia and low
baseline CD4 count
– Peaks at 4-12 weeks after treatment initiation
– AZT can also cause neutropenia, thrombocytopenia
 Check Hb at baseline, 4-6 weeks at 3 months, thereafter 6
monthly routinely
 Check Hb if clinical symptoms/signs of anemia
 Remember other possible causes of bone marrow
suppression
– Cotrimoxazole
Peripheral Neuropathy
 Associated with:
– NRTI therapy
– “d” drugs especially D4t, ddI,
– Duration of therapy
 Other associations:
– Lower CD4 count
– Other drugs
– Alcohol
 Incidence: 5-10%
 Can be disabling and irreversible
Peripheral neuropathy
Continued…..
 Management include:
– Prompt withdraw of these drugs enables gradual resolution of
symptoms
– Avoid use of neurotoxic drugs
– Simple analgesics, with augmentation with tricyclic
antidepressants or anticonvulsant agents when pain is severe
– Patient education
Metabolic and morphologic
complications associated with HIV
infection and ART
 Lipodystrophy
– Lipohypertropy( adipose accumulation)
 Abdominal adiposity
 Dorsocervical fat enlargement
– Lipoatrophy
 Extremities
 Face
 Buttocks
Metabolic and morphologic
disturbances continued…..
 Lactic acidosis
 Glucose metabolism
– Insulin resistance
– impaired glucose metabolism
– DM
 Dyslipidemias
– Increased triglycerides
– Decreased HDL
– Increased LDL
 Bone disease
– Osteonecrosis
– osteoporosis
Case
 35 year old male HIV positive since 1995
 Started on D4T/3TC/NFV in 1998
 CD4: 201, Wt: 62 kg
 Clinically doing well, CD4 400, VL undetectable
2002: Noticed change in facial features
2003: “Popping out” of veins on all extremities
Case
 Patient is very bothered by his changed
appearance and resulting stigmatization
– Friends recognize his facial wasting as HIV related
– He thinks people in the street are looking at him
– Feels he is being turned down for jobs
 Considering stopping his ART
 What do you do?
Lipodystrophy

First described in 1998 after introduction of PIs

Common in patients on long term ART( 30-50% in several large ,
prospective studies)

Distressing to patients and may increase stigma

Lipoatrophy
– Associated fat loss in the face and limbs with central fat
accumulation
– associated with thymidine analogs (d4T >> AZT)
– Very common after long periods on stavudine containing regimen

Lipohypertrophy
– Fat accumulation centrally with large belly and buffalo hump
– Breast enlargement
– associated with PIs
Diagnosis

Primarily on Clinical grounds

Clinical Diagnosis may be hampered by several factors
– Fat depletion in the periphery may be associated with AIDS
wasting syndrome
– Visceral fat accumulation may be associated with wait gain
that occurs shortly after starting ART
 In individuals with stable weight, assessment of lipodystrophy
relies on demonstration of maldistribution of fat following use of
ART and therefore, by necessity, requires knowledge of
premorbid fat content and distribution. May be reasonable to
document fat distribution prior to the initiation of ART by
– Weight, height, and circumferences of the arms , thighs,
waist, hips and neck
– Photographs
Late Toxicity
Management difficult; maybe irreversible
 Lipodystrophy
– Lipoatrophy (LA) associated with thymidine analogs (d4T >
AZT)
– Common after long periods on stavudine containing regimen
– Associated fat loss in the face and limbs with central fat
accumulation
– Distressing to patients and may increase stigma
The Face (and Body)
of Lipodystrophy
Diagnosis Continued…..
– Abdominal MRI or CT scan especially for
visceral fat
– Dual energy x ray absorptiometry( Dexa scan)
for peripheral fat loss. Cannot distinguish
abdominal subcutaneous and visceral fat
d4T/ddI + EFV, NFV, or both
 Both NRTI combinations
associated with early fat ↑
– Likely restoration of
HIV-related fat loss
 By Week 48 and on, subjects on
d4T/ddI had significantly more
limb fat loss than those taking
ZDV/3TC
Median Change in Limb Fat (%)

A5005s: Thymidine
Analogues Associated With
Limb
Fat
Loss
Subjects given ZDV/3TC or
15
ZDV/3TC
10
P < .001
5
n = 41
0
-5
16
32
48
64
-10
-15
-20
Dubé MP, et al. AIDS. 2005;19:1807-1818.
ddI/d4T
n = 61
ACTG 384/5005S: Limb Fat
Changes
Dubé MP, et al. Antivir Ther. 2002;7:L18. Abstract 27
Zidovudine/lamivudine
% Change in Limb Fat
 Peripheral limb fat
declined below
baseline level with
both ZDV/3TC and
ddI/d4T
 Lipoatrophy delayed
with ZDV/3TC
compared with
ddI/d4T
Stavudine/didanosine
15
10
5
0
-5
16
32
48
-10
-15
-20
Weeks
64
80
Treatment
 No clear standard Goal of therapy
– Target metabolic derangement
– Purely cosmetic
Treatment continued…..
 Withdrawal or substitution
 Potential switching options
– Switch d4T or AZT to ABC (MITOX study)[1]
 Significant and continued increase in limb fat in
patients with moderate or severe lipodystrophy
during prior d4T or AZT
– Switch d4T to TDF
 Studies ongoing
 GS 903 showed very low prevalence of
lipodystrophy with TDF vs d4T and maintenance
of normal limb fat with TDF at 144 weeks[2]
1. Carr A, et al. JAMA. 2002;288:207-215.
2. Gallant JE, et al. XV IAC, Bangkok, 2004. Abstract TuPeB4538.
GS 903: Lipodystrophy
With TDF vs d4T
Patients with
lipodystrophy (%)
*P < .001
20
18
16
14
12
10
8
6
4
2
0
19
TDF, 3TC, EFV
d4T, 3TC, EFV
*P < .001
12
4
3
1
1
Week 48
Week 96
Mean total limb fat (kg):
7.9 *
5.0
Staszewski S, et al. 10th CROI, Boston, 2003. Abstract 564b.
Gallant JE, et al. XV IAC, Bangkok, 2004. Abstract TuPeB4538.
Week 144
8.7 *
4.4
Impact of Switching From
d4T on Lipids and Limb Fat
TGs
TC
LDL HDL
0
-1
-16
-20
-40
-38
-60
-80
-72
Zhong L, et al. EACS 2005. Abstract PE9.3/5.
Mean Total Limb Fat (kg)
Mean Change in Fasting
Lipids at Week 48 (mg/dL)
 96-week open-label extension phase of 903 study
– Data from subgroup of patients given d4T for 144 weeks who
switched to open-label TDF for 48 weeks
5.02
5.0
(n = 74)
4.8
P < .001
4.6
4.60
(n = 74)
4.4
4.2
d4T
TDF
0
Wk 96
Wk 144
Wk 48
post-switch
with
self-defined lipoatrophy
on thymidine analogue
NRTI
 105 patients randomized
to replace TA with
– Tenofovir, or
– Abacavir
 Total limb fat increased
to similar extent in both
arms over 48 weeks
TDF
ABC
1200
Change in Fat Mass
by DEXA at Week 48 (g)

RAVE: Switch Thymidine Analogue
Suppressed patients
to ABC or TDF
1061
1046
1000
791
800
600
400
522
393
316
200
0
Limb
Trunk
Total Fat
Within-group change in limb fat from baseline:
TDF (P = .01), ABC (P = .001)
Moyle G, et al. CROI 2005. Abstract 44LB.
Pharmacological interventions for
lipodystrophy
 Testosterone
– Decreased levels found in HIV infected men
– Placebo controlled trial evaluating role of testosterone is ongoing within the
AACTG
– Currently only recommended for HIV –infected men with lipodystrophy who
also have hypogonadism
 Human growth hormone
– Open label trail of 30 American patients led to signifacant decraese in VAT
but is associated with severe advere events, hyperglycemia,athragias and
fluid retention
 Metformin
 Decarese in VAT that was not statistically significant
 Thiazolidinediones-Troglitazone
– Decreases VAT in diabetics , however no consistent VAT deacrese in HIV
infected
Non pharmacological
interventions
 May offer some benefit
 Exercise can be pursued at a moderate intensity without
adverse effect on HIV control
– Exercise and diet
 Useful for fat accumulation, insulin resistance and cardiovascular
disease; less so for LA
– Reduces central adiposity
– Improves glycemic control and lipid profile
– May lead to loss of peripheral subcutaneous fat
– Smoking cessation (cardiovascular risk)
Case
 46 year old male
 Presents with thrush and 12 kg weight loss
 HIV positive, CD4: 112, Wt: 52 kg
January 05: Started on D4T/3TC/NVP (30)
March 05: Feeling much better; weight 59 kg
September 05: Malaise for several weeks, no fever
or any other specific symptoms
 What to do?
Case
 Physical exam: slight hepatomegaly
 CXR normal, Hb normal
 CD4 210 (from 112)
October 05: Worsening malaise,
now with nausea, vomiting,
abdominal pain, weight loss (56 kg)
 ALT 388
 What to do?
Hyperlactataemia and
Lactic Acidosis
 Over all incidence 8-18% in HIV pts on NRTI’s
– Mostly asymptomatic
– Elevations lactate in first 6-9 months after start NRTI
– Median 9 months, range 3-20 months
 Highest risk:
– D4T>DDI>>ZDV
– DDI/D4T (pregnancy)
 Lowest risk 3TC (TDF, ABC)
 Can progress to Lactic Acidosis Syndrome
Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37
Lactic Acidosis Syndrome
 Clinical definition
– Hepatic steatosis
– Liver failure
– Profound lactic acidosis
 Biochemical definition
– Lactic acid >5.0
– Bicarbonate <20
– (pH<7.3)
Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37
Hyperlactataemia and
Lactic Acidosis
 Associated with NRTI administration
 NRTI’s have some affinity for human DNA
polymerase gamma in mitochondria
– impairing mitochondrial DNA synthesis
– resulting in mitochondrial toxicity
 Accumulation of lactate causing acidosis
Hyperlactataemia and
Lactic Acidosis
Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37
Hyperlactatemia:
Clinical Syndromes
Normal
Range
Lactate
(mmol/L)
1
2
Compensated or
asymptomatic
hyperlactatemia
– Chronic
– Normal Anion Gap
– Common
3
4
5
Decompensated or
symptomatic lactic
acidosis
– Rapidly progressive
– Increased anion gap
– Life-threatening, rare
6
When to suspect
hyperlactataemia or lactic
acidosis?
 High index of suspicion
 Gastro-intestinal complaints (onset months
after starting ART)
 Unexplained weight loss while CD4 stable
 Nausea, vomiting, abdominal pain
 Liver abnormalities
 Altered mental status
 Profound metabolic acidosis
Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37
Management of
Hyperlactataemia and
Lactic Acidosis
 Stop all NRTI’s
 Consider carefully restarting 3TC with
ZDV (or TDF or ABC) under close
supervision when patient improved
 Supportive management
Management of Adverse Drug
Effects
 Try and establish the ARV drug responsible for the adverse effect
 Consider duration of ARV use, other disease processes (e.g. hepatitis),
other treatments (including self administered)
 If it is necessary to stop ART, discontinue all ARV drugs simultaneously*
 Grade 1 or 2 reactions: continue ART under observation.
– Single drug substitution may be necessary
 Grade 3 or 4- Stop ART; manage Adverse Event and re-introduce ART.
Minimizing adverse events
 Appropriate drug and regimen selection
 Dose titration
 Monitoring and reassuring for effects that
are transient
 Appropriate timing of administration
 Pharmacological interventions
 Withdrawal of the offending drug(s)