Managing Emerging complications of HIV Managing Emerging complications of HIV TreatmentTreatment

Background Background

ARV has become more available in our settingsARV has become more available in our settings– Currently >65,000 Kenyans are estimated to be Currently >65,000 Kenyans are estimated to be

on ARV treatmenton ARV treatment Antiretroviral therapy (ART) alters the nature of Antiretroviral therapy (ART) alters the nature of

HIV disease, transforming an almost uniformly HIV disease, transforming an almost uniformly fatal illness into a chronic but stable condition. fatal illness into a chronic but stable condition.

However its use may be complicated by a number However its use may be complicated by a number of factors, including side effects, drug interactions of factors, including side effects, drug interactions and treatment failure.and treatment failure.

Toxicity Toxicity

Adverse drug reactions (ADRs) are the most Adverse drug reactions (ADRs) are the most common reason for treatment change or common reason for treatment change or discontinuationdiscontinuation– All classes of ARV drugs associated with ADRsAll classes of ARV drugs associated with ADRs

Rate of toxicity is highRate of toxicity is high– 45% have clinical adverse events and 27% have 45% have clinical adverse events and 27% have

laboratory adverse eventslaboratory adverse events 9% of clinical and 16% of laboratory are serious or severe9% of clinical and 16% of laboratory are serious or severe

14%

20%

8%

58%

Toxicity

Failure

Nonadherence

Other

n = 25

n = 61

n = 44

n = 182

ICONA Study: ICONA Study: Reasons for Failure of Initial Reasons for Failure of Initial

HAARTHAART

d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.

Common side effectsCommon side effects

Which side effects are you seeing in your Which side effects are you seeing in your patients?patients?

ARV DrugARV Drug ClassClass Adverse Adverse EffectsEffects

NRTIsNRTIs Peripheral Peripheral

neuropathyneuropathy PancreatitisPancreatitis Lipoatrophy Lipoatrophy HepatitisHepatitis Lactic acidosisLactic acidosis Mitochondrial toxicityMitochondrial toxicity

NNRTIsNNRTIs Rash Rash FeverFever NauseaNausea DiarrheaDiarrhea Hepatoxicity, CNSHepatoxicity, CNS

PIsPIs LipodystrophyLipodystrophy GI IntoleranceGI Intolerance HyperglycaemiaHyperglycaemia Lipid abnormalitiesLipid abnormalities

Common Adverse EffectsCommon Adverse Effects Peripheral Neuropathy – d4T,ddIPeripheral Neuropathy – d4T,ddI Hematotoxicity - AZTHematotoxicity - AZT Hepatotoxicity - NVPHepatotoxicity - NVP Diarrhea – NFVDiarrhea – NFV Skin rash – NVPSkin rash – NVP Lipodystrophy – PIs, NRTIsLipodystrophy – PIs, NRTIs CNS disturbance – EFVCNS disturbance – EFV Hypersensitivity – ABCHypersensitivity – ABC Hyperlipidemia-PIs, d4THyperlipidemia-PIs, d4T

Common toxicity in our settingCommon toxicity in our setting

There is little information on tolerability to these There is little information on tolerability to these medications in African populations.medications in African populations.

– Severe rash /Steven Johnson's syndromeSevere rash /Steven Johnson's syndrome– HepatotoxicityHepatotoxicity– Peripheral neuropathy Peripheral neuropathy – HematologicalHematological– Metabolic and morphologic complications.Metabolic and morphologic complications.– OthersOthers

pancreatitispancreatitis

Distribution and Frequency of Distribution and Frequency of Clinical Adverse Events among HIV-Clinical Adverse Events among HIV-

Infected Patients Receiving ARV Infected Patients Receiving ARV Therapy, Kibera ARV ProgramTherapy, Kibera ARV Program Adverse EventAdverse Event AnyAny

(n=283)(n=283)

Grade 3-4Grade 3-4

(n=283)(n=283)

Any adverse eventAny adverse event 184 (65%)184 (65%) 18 (6%)18 (6%)

NeuropathyNeuropathy 65 (23%)65 (23%) 7 (3%)7 (3%)

RashRash 58 (20%)58 (20%) 4 (1%)4 (1%)

NauseaNausea 46 (16%)46 (16%) 1 (0.4%)1 (0.4%)

AstheniaAsthenia 11(3.9%)11(3.9%) 00

DiarrheaDiarrhea 5 (1.8%)5 (1.8%) 1 (0.4%)1 (0.4%)

Clinical hepatitisClinical hepatitis 4 (1%)4 (1%) 4 (1%)4 (1%)

LipodystrophyLipodystrophy 6 (2)6 (2) 6 (2)6 (2)

Kaplan-Meier survival estimate

Months Until First Clinical Adverse Event0 6 12 18

0.00

0.25

0.50

0.75

1.00

Time to First Adverse Event among HIV-Time to First Adverse Event among HIV-Infected Patients Receiving ARV Therapy, Infected Patients Receiving ARV Therapy,

Kibera ARV ProgramKibera ARV Program

No adverse event at Probability

6 months 0.47

12 months 0.26

18 months 0.17

n=283 n=92 n=19 n=14

RashRash Most commonly due to Nevirapine, Also sometimes due to Efavirenz, Most commonly due to Nevirapine, Also sometimes due to Efavirenz,

Abacavir and Cotrimoxazole Abacavir and Cotrimoxazole

Rash seen in up to 20% of patients, usually in the first 2-8 weeks of useRash seen in up to 20% of patients, usually in the first 2-8 weeks of use Associated with:Associated with:

– Gender (female > male; RR 4.85-8.31)Gender (female > male; RR 4.85-8.31)– CD4 count/disease stageCD4 count/disease stage– previous sulphur allergy (RR 5)previous sulphur allergy (RR 5)

Often mild to moderate , can be managed symptomaticallyOften mild to moderate , can be managed symptomatically

Can progress to severe rash or even Stevens Johnson syndrome, in 5 -Can progress to severe rash or even Stevens Johnson syndrome, in 5 -7%7%

Rash continued…..Rash continued…..

Dose- escalation decreases incidenceDose- escalation decreases incidence– Do not dose escalate if rash Do not dose escalate if rash

Pretreatment with steroids increases risk of Pretreatment with steroids increases risk of severe rashsevere rash

Stop Stop NVP for grade 3 rash or higherNVP for grade 3 rash or higher

Stevens-Johnsons syndromeStevens-Johnsons syndrome

Abacavir Hypersensitivity Abacavir Hypersensitivity ReactionReaction

Occurs in approximately 5-8% of ABC-treated patientsOccurs in approximately 5-8% of ABC-treated patients Associated with:Associated with:

– female genderfemale gender– higher CD4 counthigher CD4 count– Genetically linked to Genetically linked to haplotype HLA-B*5701haplotype HLA-B*5701

Multiorgan clinical syndrome including 2 or more of the Multiorgan clinical syndrome including 2 or more of the following:following:– Fever, rash, GI complaints (nausea, emesis, diarrhea), Fever, rash, GI complaints (nausea, emesis, diarrhea),

malaise, and respiratory symptoms (pharyngitis, cough, malaise, and respiratory symptoms (pharyngitis, cough, dyspneadyspnea))

Usually occurs within first 6 weeks of starting ABCUsually occurs within first 6 weeks of starting ABC

Abacavir hypersensitivity Abacavir hypersensitivity Reaction cont……Reaction cont……

Management Management Discontinue drug Discontinue drug (if diagnosis strongly suspected)(if diagnosis strongly suspected)

NEVER re-challenge-NEVER re-challenge-Continued ABC Continued ABC in face of HSR or reintroduction after in face of HSR or reintroduction after HSR can result in deathHSR can result in death

HepatotoxicityHepatotoxicity Nevirapine is most likely to cause hepatotoxicity( other NRTI and PIs)Nevirapine is most likely to cause hepatotoxicity( other NRTI and PIs)

– Occurs in up to 10% of patients on NVPOccurs in up to 10% of patients on NVP– Most common in first weeks to monthsMost common in first weeks to months– 12 x more likely in women than in men12 x more likely in women than in men– More likely at CD4 >250 in women and CD4>400 in men More likely at CD4 >250 in women and CD4>400 in men

Often mild to moderate but can be severe ( potentially fatal)Often mild to moderate but can be severe ( potentially fatal) More common if underling liver diseaseMore common if underling liver disease

– Consider other causesConsider other causes Infectious hepatitis, other infectionsInfectious hepatitis, other infections Other drugs (e.g. anti-TB)Other drugs (e.g. anti-TB)

Check ALT/SGPT routinely at baseline, 4-6 weeks and at 3 months (as Check ALT/SGPT routinely at baseline, 4-6 weeks and at 3 months (as available)available)

Check ALT/SGPT if any hepatic symptoms/signs Check ALT/SGPT if any hepatic symptoms/signs Discontinue NVP for grade 3 toxicity or higherDiscontinue NVP for grade 3 toxicity or higher

– (transaminases> 5x normal)(transaminases> 5x normal)

Laboratory ToxicityLaboratory Toxicity

Highest Toxicity Grade on ARVsHighest Toxicity Grade on ARVs

Normal Normal

n (%)n (%)

1 1

n (%)n (%)

2 2

n (%) n (%)

3 3

n (%) n (%)

4 4

n (%)n (%)

Anemia Anemia (n=182)(n=182)

174 174 (96%)(96%)

7 (4%)7 (4%) 0 (0%)0 (0%) 1 (<1%)1 (<1%) 0 (0%)0 (0%)

TransaminTransaminase ase elevation elevation (n=182)(n=182)

54 54 (30%)(30%)

83 83 (46%)(46%)

42(23%)42(23%) 2 (1%)2 (1%) 1 (<1%)1 (<1%)

Among patients with >= 1 lab test after ARV initiation

HAART and Liver Enzyme ElevationsHAART and Liver Enzyme Elevations Meta-analysis of 20 publications of HIV-infected patients Meta-analysis of 20 publications of HIV-infected patients ±± HCV coinfection HCV coinfection

Grade 2 or higher liver elevations notedGrade 2 or higher liver elevations noted

Drug Class

Pat

ien

ts W

ith

LE

E,%

NNRTI0

10

32.00

18.44 15.9620

30

40

13.62

5.26

14.67

PI Mixed BPI NRTI Overall

P = .004

P = .025

P = .009

% LEE in HCV-Coinfected Patients by Drug Class

Benhamou Y, et al. CROI 2006. Abstract 88.

2NN: Hepatic Events With 2NN: Hepatic Events With NVP QD or BID vs EFV NVP QD or BID vs EFV

Initial data from 2NN Initial data from 2NN suggested suggested ↑ incidence ↑ incidence of hepatotoxicity of hepatotoxicity with NVP QD or BID vs with NVP QD or BID vs EFVEFV

Storfer S, et al. EACS 2005. Abstract PE9.6-2.

0

1

2

3

4

5

6

7

8

NVP QD NVP BID EFV

Hep

atic

Eve

nts

(%

)

6.7

8.6

4.85.6

3.7

2.1

n = 210 n = 379n = 378

P = .0004

P = .0135

Asymptomatic grade 3/4 ALT/AST elevations

Symptomatic hepatic event

All 2NN Patients

9

10

2NN: Hepatic Events With 2NN: Hepatic Events With NVP QD or BID vs EFV NVP QD or BID vs EFV

Storfer S, et al. EACS 2005. Abstract PE9.6/2.

0

1

2

3

4

5

6

7

8

NVP QD NVP BID EFV

Hep

atic

Eve

nts

(%

)

5.66.2

4.2

6.3

3.22.6

n = 161 n = 310n = 334

P = .055

P = .0233

Asymptomatic grade 3/4 ALT/AST elevations

Symptomatic hepatic event

Non-Thai Centers

9

10

Initial data from 2NN Initial data from 2NN suggested ↑ incidence suggested ↑ incidence of hepatotoxicity of hepatotoxicity with NVP QD or BID vs with NVP QD or BID vs EFVEFV

Result later found to be Result later found to be primarily due to 1 Thai primarily due to 1 Thai study center study center – Difference NVP QD vs BID Difference NVP QD vs BID

lostlost

HCV-3 Coinfection Associated With HCV-3 Coinfection Associated With Greater Risk of HepatotoxicityGreater 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

0.9

1.0

0.8

0.7

0.6

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0.4

Time Since Entry (Years)

Cum

ulat

ive

Pro

port

ion

of P

atie

nts

Fre

e of

≥ G

rade

3 H

epat

otox

icity

P < .001

HCV ≠ 3

HCV-3

Torti C, et al. ICAAC 2005. Abstract H-1484.

Management?Management?

Hematological ToxicityHematological Toxicity

AZT by far the most common causeAZT by far the most common cause– Most likely in women, those with pre-existing anemia and low Most likely in women, those with pre-existing anemia and low

baseline CD4 countbaseline CD4 count– Peaks at 4-12 weeks after treatment initiationPeaks at 4-12 weeks after treatment initiation– AZT can also cause neutropenia, thrombocytopeniaAZT can also cause neutropenia, thrombocytopenia

Check Hb at baseline, 4-6 weeks at 3 months, thereafter 6 Check Hb at baseline, 4-6 weeks at 3 months, thereafter 6 monthly routinely monthly routinely

Check Hb if clinical symptoms/signs of anemiaCheck Hb if clinical symptoms/signs of anemia Remember other possible causes of bone marrow Remember other possible causes of bone marrow

suppressionsuppression– CotrimoxazoleCotrimoxazole

Peripheral NeuropathyPeripheral Neuropathy Associated with:Associated with:

– NRTI therapyNRTI therapy– ““d” drugs especially D4t, ddI, d” drugs especially D4t, ddI, – Duration of therapyDuration of therapy

Other associations:Other associations:– Lower CD4 countLower CD4 count– Other drugsOther drugs– AlcoholAlcohol

Incidence: 5-10%Incidence: 5-10% Can be disabling and irreversibleCan be disabling and irreversible

Peripheral neuropathy Peripheral neuropathy Continued…..Continued…..

Management include:Management include:– Prompt withdraw of these drugs enables gradual resolution of Prompt withdraw of these drugs enables gradual resolution of

symptomssymptoms– Avoid use of neurotoxic drugsAvoid use of neurotoxic drugs– Simple analgesics, with augmentation with tricyclic Simple analgesics, with augmentation with tricyclic

antidepressants or anticonvulsant agents when pain is severeantidepressants or anticonvulsant agents when pain is severe– Patient educationPatient education

Metabolic and morphologic Metabolic and morphologic complications associated with HIV complications associated with HIV

infection and ARTinfection and ART Lipodystrophy Lipodystrophy

– Lipohypertropy( adipose accumulation)Lipohypertropy( adipose accumulation) Abdominal adiposityAbdominal adiposity Dorsocervical fat enlargementDorsocervical fat enlargement

– LipoatrophyLipoatrophy ExtremitiesExtremities Face Face ButtocksButtocks

Metabolic and morphologic Metabolic and morphologic disturbances continued….. disturbances continued…..

Lactic acidosisLactic acidosis Glucose metabolismGlucose metabolism

– Insulin resistanceInsulin resistance– impaired glucose metabolismimpaired glucose metabolism– DMDM

DyslipidemiasDyslipidemias– Increased triglyceridesIncreased triglycerides– Decreased HDL Decreased HDL – Increased LDLIncreased LDL

Bone disease Bone disease – OsteonecrosisOsteonecrosis– osteoporosisosteoporosis

Case Case

35 year old male HIV positive since 199535 year old male HIV positive since 1995 Started on D4T/3TC/NFV in 1998Started on D4T/3TC/NFV in 1998 CD4: 201, Wt: 62 kgCD4: 201, Wt: 62 kg

Clinically doing well, CD4 400, VL Clinically doing well, CD4 400, VL undetectableundetectable

2002: Noticed change in facial features2002: Noticed change in facial features

2003: “Popping out” of veins on all extremities2003: “Popping out” of veins on all extremities

Case Case Patient is very bothered by his changed Patient is very bothered by his changed

appearance and resulting stigmatizationappearance and resulting stigmatization– Friends recognize his facial wasting as HIV Friends recognize his facial wasting as HIV

relatedrelated– He thinks people in the street are looking at himHe thinks people in the street are looking at him– Feels he is being turned down for jobsFeels he is being turned down for jobs

Considering stopping his ARTConsidering stopping his ART

What do you do?What do you do?

LipodystrophyLipodystrophy First described in 1998 after introduction of PIsFirst described in 1998 after introduction of PIs

Common in patients on long term ART( 30-50% in several large , Common in patients on long term ART( 30-50% in several large , prospective studies) prospective studies)

Distressing to patients and may increase stigmaDistressing to patients and may increase stigma

LipoatrophyLipoatrophy– Associated fat loss in the face and limbs with central fat accumulationAssociated fat loss in the face and limbs with central fat accumulation– associated with thymidine analogs (d4T >> AZT)associated with thymidine analogs (d4T >> AZT)– Very common after long periods on stavudine containing regimenVery common after long periods on stavudine containing regimen

LipohypertrophyLipohypertrophy– Fat accumulation centrally with large belly and buffalo humpFat accumulation centrally with large belly and buffalo hump– Breast enlargementBreast enlargement– associated with PIsassociated with PIs

DiagnosisDiagnosis Primarily on Clinical groundsPrimarily on Clinical grounds

Clinical Diagnosis may be hampered by several factorsClinical Diagnosis may be hampered by several factors– Fat depletion in the periphery may be associated with AIDS Fat depletion in the periphery may be associated with AIDS

wasting syndromewasting syndrome– Visceral fat accumulation may be associated with wait gain Visceral fat accumulation may be associated with wait gain

that occurs shortly after starting ARTthat occurs shortly after starting ART

In individuals with stable weight, assessment of lipodystrophy In individuals with stable weight, assessment of lipodystrophy relies on demonstration of maldistribution of fat following use of relies on demonstration of maldistribution of fat following use of ART and therefore, by necessity, requires knowledge of ART and therefore, by necessity, requires knowledge of premorbid fat content and distribution. May be reasonable to premorbid fat content and distribution. May be reasonable to document fat distribution prior to the initiation of ART bydocument fat distribution prior to the initiation of ART by– Weight, height, and circumferences of the arms , thighs, Weight, height, and circumferences of the arms , thighs,

waist, hips and neckwaist, hips and neck– PhotographsPhotographs

Late ToxicityLate Toxicity

Management difficult; maybe irreversibleManagement difficult; maybe irreversible LipodystrophyLipodystrophy

– Lipoatrophy (LA) associated with thymidine analogs (d4T > Lipoatrophy (LA) associated with thymidine analogs (d4T > AZT)AZT)

– Common after long periods on stavudine containing regimenCommon after long periods on stavudine containing regimen– Associated fat loss in the face and limbs with central fat Associated fat loss in the face and limbs with central fat

accumulationaccumulation– Distressing to patients and may increase stigmaDistressing to patients and may increase stigma

The Face (and Body) The Face (and Body) of of

LipodystrophyLipodystrophy

Diagnosis Continued…..Diagnosis Continued…..– Abdominal MRI or CT scan especially for Abdominal MRI or CT scan especially for

visceral fatvisceral fat– Dual energy x ray absorptiometry( Dexa scan) Dual energy x ray absorptiometry( Dexa scan)

for peripheral fat loss. Cannot distinguish for peripheral fat loss. Cannot distinguish abdominal subcutaneous and visceral fat abdominal subcutaneous and visceral fat

n = 41

A5005s: Thymidine A5005s: Thymidine Analogues Associated With Analogues Associated With

Limb Fat Loss Limb Fat Loss Subjects given ZDV/3TC or Subjects given ZDV/3TC or d4T/ddI + EFV, NFV, or bothd4T/ddI + EFV, NFV, or both

Both NRTI combinations Both NRTI combinations associated with early fat associated with early fat ↑↑– Likely restoration of Likely restoration of

HIV-related fat lossHIV-related fat loss By Week 48 and on, subjects on By Week 48 and on, subjects on

d4T/ddI had significantly more d4T/ddI had significantly more limb fat loss than those taking limb fat loss than those taking

ZDV/3TCZDV/3TC

-20

-15

-10

-5

0

5

10

15

16 32 48 64M

edia

n C

han

ge

in L

imb

Fat

(%

) ddI/d4T ZDV/3TC

P < .001

n = 61

Dubé MP, et al. AIDS. 2005;19:1807-1818.

ACTG 384/5005S: Limb Fat ACTG 384/5005S: Limb Fat ChangesChanges

Peripheral limb fat Peripheral limb fat declined below declined below baseline level with baseline level with both ZDV/3TC and both ZDV/3TC and ddI/d4TddI/d4T

Lipoatrophy delayed Lipoatrophy delayed with ZDV/3TC with ZDV/3TC compared with compared with ddI/d4TddI/d4T

Dubé MP, et al. Antivir Ther. 2002;7:L18. Abstract 27

16 32 48 64 80

-20

-15

-10

-5

0

5

10

15

Weeks

Zidovudine/lamivudine

Stavudine/didanosine

% C

han

ge

in

Lim

b F

at

TreatmentTreatment

No clear standard-No clear standard- Goal of therapyGoal of therapy

– Target metabolic derangementTarget metabolic derangement– Purely cosmeticPurely cosmetic

Treatment continued…..Treatment continued….. Withdrawal or substitutionWithdrawal or substitution Potential switching optionsPotential switching options

– Switch d4T or AZT to ABC (MITOX study)Switch d4T or AZT to ABC (MITOX study)[1][1]

Significant and continued increase in limb fat in patients Significant and continued increase in limb fat in patients with moderate or severe lipodystrophy during prior d4T with moderate or severe lipodystrophy during prior d4T or AZTor AZT

– Switch d4T to TDFSwitch d4T to TDF Studies ongoingStudies ongoing GS 903 showed very low prevalence of lipodystrophy GS 903 showed very low prevalence of lipodystrophy

with TDF vs d4T and maintenance of normal limb fat with TDF vs d4T and maintenance of normal limb fat with TDF at 144 weekswith TDF at 144 weeks[2][2]

1. Carr A, et al. JAMA. 2002;288:207-215. 2. Gallant JE, et al. XV IAC, Bangkok, 2004. Abstract TuPeB4538.

Mean total limb fat (kg): 7.9 * 5.0 8.7 * 4.4

1

4

1

12

3

19

02468

101214161820

Pat

ien

ts w

ith

lip

od

ystr

op

hy

(%)

Week 48 Week 96 Week 144

*P < .001

*P < .001

TDF, 3TC, EFVd4T, 3TC, EFV

Staszewski S, et al. 10th CROI, Boston, 2003. Abstract 564b. Gallant JE, et al. XV IAC, Bangkok, 2004. Abstract TuPeB4538.

GS 903: Lipodystrophy GS 903: Lipodystrophy With TDF vs d4TWith TDF vs d4T

Impact of Switching From Impact of Switching From d4T on Lipids and Limb Fatd4T on Lipids and Limb Fat

96-week open-label extension phase of 903 study96-week open-label extension phase of 903 study– Data from subgroup of patients given d4T for 144 weeks who Data from subgroup of patients given d4T for 144 weeks who

switched to open-label TDF for 48switched to open-label TDF for 48 weeksweeks

Zhong L, et al. EACS 2005. Abstract PE9.3/5.

Mea

n C

han

ge

in F

asti

ng

L

ipid

s at

Wee

k 48

(m

g/d

L) TGs TC LDL HDL

-80

-60

-40

-20

0

-72

-38

-16

-1

Mea

n T

ota

l L

imb

Fat

(kg

)

0

4.2

4.4

Wk 96 Wk 144 Wk 48post-switch

P < .0014.6

4.8

5.05.02

(n = 74)

4.60(n = 74)

d4T TDF

RAVE: Switch Thymidine Analogue RAVE: Switch Thymidine Analogue to ABC or TDFto ABC or TDF Suppressed patients with Suppressed patients with

self-defined lipoatrophy self-defined lipoatrophy on thymidine analogue on thymidine analogue NRTINRTI

105 patients randomized 105 patients randomized to replace TA withto replace TA with

– Tenofovir, orTenofovir, or

– AbacavirAbacavir Total limb fat increased to Total limb fat increased to

similar extent in both similar extent in both arms over 48 weeksarms over 48 weeks

Moyle G, et al. CROI 2005. Abstract 44LB.

Ch

ang

e in

Fat

Mas

s b

y D

EX

A a

t W

eek

48 (

g)

393

522

1061

316

791

1046

0

200

400

600

800

1000

1200

Limb Trunk Total Fat

TDFABC

Within-group change in limb fat from baseline: TDF (P = .01), ABC (P = .001)

Pharmacological interventions for Pharmacological interventions for lipodystrophylipodystrophy

Testosterone Testosterone – Decreased levels found in HIV infected menDecreased levels found in HIV infected men– Placebo controlled trial evaluating role of testosterone is ongoing within the Placebo controlled trial evaluating role of testosterone is ongoing within the

AACTGAACTG– Currently only recommended for HIV –infected men with lipodystrophy who Currently only recommended for HIV –infected men with lipodystrophy who

also have hypogonadismalso have hypogonadism Human growth hormoneHuman growth hormone

– Open label trail of 30 American patients led to signifacant decraese in VAT Open label trail of 30 American patients led to signifacant decraese in VAT but is associated with severe advere events, hyperglycemia,athragias and but is associated with severe advere events, hyperglycemia,athragias and fluid retentionfluid retention

MetforminMetformin Decarese in VAT that was not statistically significantDecarese in VAT that was not statistically significant Thiazolidinediones-TroglitazoneThiazolidinediones-Troglitazone

– Decreases VAT in diabetics , however no consistent VAT deacrese in HIV Decreases VAT in diabetics , however no consistent VAT deacrese in HIV infectedinfected

Non pharmacological Non pharmacological interventionsinterventions

May offer some benefitMay offer some benefit Exercise can be pursued at a moderate intensity without Exercise can be pursued at a moderate intensity without

adverse effect on HIV controladverse effect on HIV control– Exercise and dietExercise and diet

Useful for fat accumulation, insulin resistance and cardiovascular Useful for fat accumulation, insulin resistance and cardiovascular disease; less so for LAdisease; less so for LA

– Reduces central adiposity Reduces central adiposity – Improves glycemic control and lipid profileImproves glycemic control and lipid profile

– May lead to loss of peripheral subcutaneous fatMay lead to loss of peripheral subcutaneous fat

– Smoking cessation (cardiovascular risk)Smoking cessation (cardiovascular risk)

Case Case 46 year old male46 year old male Presents with thrush and 12 kg weight lossPresents with thrush and 12 kg weight loss HIV positive, CD4: 112, Wt: 52 kgHIV positive, CD4: 112, Wt: 52 kg

January 05: Started on D4T/3TC/NVP (30)January 05: Started on D4T/3TC/NVP (30)March 05: Feeling much better; weight 59 kgMarch 05: Feeling much better; weight 59 kg September 05: Malaise for several weeks, no September 05: Malaise for several weeks, no

fever or any other specific symptomsfever or any other specific symptoms

What to do?What to do?

Case Case

Physical exam: slight hepatomegalyPhysical exam: slight hepatomegaly CXR normal, Hb normalCXR normal, Hb normal CD4 210 (from 112)CD4 210 (from 112)

October 05: Worsening malaise, October 05: Worsening malaise, now with nausea, vomiting, now with nausea, vomiting, abdominal pain, weight loss (56 kg)abdominal pain, weight loss (56 kg)

ALT 388ALT 388

What to do?What to do?

Hyperlactataemia andHyperlactataemia andLactic AcidosisLactic Acidosis

Over all incidence 8-18% in HIV pts on NRTI’sOver all incidence 8-18% in HIV pts on NRTI’s– Mostly asymptomaticMostly asymptomatic– Elevations lactate in first 6-9 months after start Elevations lactate in first 6-9 months after start

NRTINRTI– Median 9 months, range 3-20 monthsMedian 9 months, range 3-20 months

Highest risk:Highest risk:– D4T>DDI>>ZDVD4T>DDI>>ZDV– DDI/D4T (pregnancy)DDI/D4T (pregnancy)

Lowest risk 3TC (TDF, ABC)Lowest risk 3TC (TDF, ABC) Can progress to Lactic Acidosis SyndromeCan progress to Lactic Acidosis Syndrome

Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

Lactic Acidosis SyndromeLactic Acidosis Syndrome

Clinical definitionClinical definition– Hepatic steatosisHepatic steatosis– Liver failureLiver failure– Profound lactic acidosisProfound lactic acidosis

Biochemical definitionBiochemical definition– Lactic acid >5.0Lactic acid >5.0– Bicarbonate <20Bicarbonate <20– (pH<7.3)(pH<7.3)

Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

Hyperlactataemia and Hyperlactataemia and Lactic AcidosisLactic Acidosis

Associated with NRTI administrationAssociated with NRTI administration

NRTI’s have some affinity for human NRTI’s have some affinity for human DNA polymerase gamma in DNA polymerase gamma in mitochondriamitochondria– impairing mitochondrial DNA synthesisimpairing mitochondrial DNA synthesis– resulting in mitochondrial toxicityresulting in mitochondrial toxicity

Accumulation of lactate causing acidosisAccumulation of lactate causing acidosis

Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

Hyperlactataemia and Lactic Acidosis

Compensated or Compensated or asymptomatic asymptomatic hyperlactatemiahyperlactatemia

– ChronicChronic– Normal Anion GapNormal Anion Gap– CommonCommon

Decompensated or Decompensated or symptomatic lactic symptomatic lactic acidosisacidosis

– Rapidly progressiveRapidly progressive– Increased anion gapIncreased anion gap– Life-threatening, rareLife-threatening, rare

1 53

Lactate (mmol/L)

42 6

Symptoms Aci

dosi

s

Normal

Range

Hyperlactatemia:Hyperlactatemia:Clinical SyndromesClinical Syndromes

When to suspect When to suspect hyperlactataemia or lactic hyperlactataemia or lactic

acidosis?acidosis? High index of suspicionHigh index of suspicion Gastro-intestinal complaints (onset months after Gastro-intestinal complaints (onset months after

starting ART)starting ART) Unexplained weight loss while CD4 stableUnexplained weight loss while CD4 stable Nausea, vomiting, abdominal painNausea, vomiting, abdominal pain Liver abnormalitiesLiver abnormalities Altered mental statusAltered mental status Profound metabolic acidosisProfound metabolic acidosis

Ogedegbe. Lancet Infect. Dis. 2003; 3:329-37

Management of Management of Hyperlactataemia and Hyperlactataemia and

Lactic AcidosisLactic Acidosis Stop all NRTI’sStop all NRTI’s

Consider carefully restarting 3TC Consider carefully restarting 3TC with ZDV (or TDF or ABC) under with ZDV (or TDF or ABC) under close supervision when patient close supervision when patient improvedimproved

Supportive managementSupportive management

Management of Adverse Drug Management of Adverse Drug EffectsEffects

Try and establish the ARV drug responsible for the adverse effect Try and establish the ARV drug responsible for the adverse effect

Consider duration of ARV use, other disease processes (e.g. hepatitis), Consider duration of ARV use, other disease processes (e.g. hepatitis), other treatments (including self administered)other treatments (including self administered)

If it is necessary to stop ART, discontinue all ARV drugs simultaneously*If it is necessary to stop ART, discontinue all ARV drugs simultaneously*

Grade 1 or 2 reactions: continue ART under observation.Grade 1 or 2 reactions: continue ART under observation.– Single drug substitution may be necessarySingle drug substitution may be necessary

Grade 3 or 4- Stop ART; manage Adverse Event and re-introduce ART. Grade 3 or 4- Stop ART; manage Adverse Event and re-introduce ART.

Minimizing adverse eventsMinimizing adverse events Appropriate drug and regimen selectionAppropriate drug and regimen selection Dose titrationDose titration Monitoring and reassuring for effects that Monitoring and reassuring for effects that

are transientare transient Appropriate timing of administrationAppropriate timing of administration Pharmacological interventionsPharmacological interventions Withdrawal of the offending drug(s)Withdrawal of the offending drug(s)