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Antiretroviral therapy switch : When to
switch/ What to switch to ?
Dr Ameet Dravid
Antiretroviral therapy : when to start?
Antiretroviral therapy switch
DHHS guidelines 2013
HIVMAI Guidelines 2012
NACO GUIDELINES 2012
Classification of
HIV-associated
clinical disease

WHO STAGE

CD4 NOT
AVAILABLE

Asymptomatic

1

CD4 AVAILABLE

Do not treat
Treat if CD4 <350

Mild symptoms

2

Do not treat

Advanced
symptoms

3

Treat

Consider treatment
if CD4 <350
and initiate ART
before CD4
drops below 200

Severe/advanced
symptoms

4

Treat

Treat irrespective of
CD4 count
Antiretroviral therapy : what to start?
NACO GUIDELINES 2012
 Preferred regimen (2NRTI’s + 1 NNRTI)
 AZT + 3TC + NVP (Zidovudine + Lamivudine +
Nevirapine )
 Alternative regimen (2NRTI’s + 1 NNRTI)
 AZT + 3TC + EFV (Zidovudine + Lamivudine +
Efavirenz)
 TDF + 3TC + NVP/EFV (Tenofovir + Lamivudine +
Nevirapine/Efavirenz )
 Other options
 Stavudine (d4T) + 3TC/FTC + NVP/EFV
 Pi’s not recommended for first line therapy
HIVMAI guidelines 2012
Commonly used 1st line ART regimens in India
NAME OF DRUG

TRADE NAME

Zidovudine + Lamivudine + Nevirapine

Duovir-N/Lazid-N/Virocomb N

Stavudine+ Lamivudine + Nevirapine

Triomune-30/Emtri 30/Virolans 30

Zidovudine + Lamivudine + Efavirenz

Duovir + Efavir

Stavudine+ Lamivudine + Efavirenz

Lamivir-S(30 )+ Efavir

Tenofovir + Lamivudine + Efavirenz

Tenolam E/Dinmek/Trioday

Tenofovir + Emtricitabine + Efavirenz

Trustiva/Vonavir/Viraday
Monitoring patients on antiretroviral therapy
Antiretroviral switching
• Drug toxicity
• Drug drug interactions
• Simplification of regimens (change to once daily
regimens)
• Pregnancy (Efavirenz to Nevirapine)
• Cost
• Proactive
• Antiretroviral therapy failure
Antiretroviral drug toxicity
DRUG REGIMEN

OFFENDING DRUG

DRUG TOXICITY

DRUG SWITCH

Zidovudine + Lamivudine +
Nevirapine

Zidovudine

Anemia

Change to Stavudine
or Tenofovir

GI intolerance
Skin and nail
hyperpigmentation
Lactic acidosis

Tenofovir +
Emticitabine+Efavirenz

Tenofovir

Fanconi syndrome
Renal dysfunction

Change to Zidovudine
or Abacavir

Osteomalacia
Decreased BMD

Stavudine +
Lamivudine+Nevirapine

Stavudine

Lipoatrophy
Peripheral neuropathy
Pancreatitis
Lactic acidosis
DM, Dyslipidemia

Change to Tenofovir
Antiretroviral drug toxicity
DRUG REGIMEN

OFFENDING DRUG

DRUG TOXICITY

DRUG SWITCH

Zidovudine + Lamivudine +
Nevirapine

Nevirapine

Rash

Change to Efavirenz

Hepatitis
Stevens johnson
syndrome

Tenofovir +
Emticitabine+Efavirenz

Efavirenz

Rash, Hepatitis
Drowsiness, abnormal
dreams
Impaired concentration

Abacavir + Lamivudine +
Efavirenz

Abacavir

Hypersensitivity

Change to Nevirapine
in case of CNS
symptoms, change to
ATV/r in case of rash
Change to Tenofovir
if Creat clearance > 50
ml/min or else use
Zidovudine
Antiretroviral drug drug interactions
• Nevirapine to Efavirenz in patients with Tuberculosis due to
use of Rifampicin.
• HIV/HCV co infection : change to Tenofovir + Lamivudine +
Efavirenz
• HIV and cancer : avoid Zidovudine with chemotherapy due to
myelosuppressive side-effects of both.
• HIV and CMV : avoid co-administration of Zidovudine with
Valganciclovir
• HIV and cryptococcal meningitis : avoidance of Tenofovir with
Amphotericin B.
Antiretroviral drug drug interactions
• Antiretroviral regimens not recommended :
• Tenofovir + Lamivudine + Nevirapine : high
chance of virologic failure.
• Stavudine + Didanosine
• Stavudine + Zidovudine
• Tenofovir + Abacavir
• Tenofovir + Didanosine
Antiretroviral treatment failure
•
•

•
•
•

Virologic failure :
inability to achieve or maintain suppression of viral
replication to HIV-1 RNA levels < 50 copies/mL
2 consecutive tests indicating HIV-1 RNA > 400 copies/mL
after 24 weeks or > 50 copies/mL at 48 weeks
Immunologic failure
Inability of CD4 count to increase > 100 cells/mm3 in 1st year of
ART
Fall in CD4 count from peak level by > 50 %
Clinical failure
AIDS defining illness occurring more than 3-6 months after
starting antiretroviral therapy
Difference between viral rebound and viral blip

•
•
•
•

Viral blip :
defined as a single, low-level plasma HIV-1 RNA level
of 50-1000 copies/mL) that is immediately preceded
and followed by an undetectable HIV-1 RNA
false elevations of HIV-1 RNA related to erroneous
laboratory findings or to release of archived virus
from activated cells.
not associated with the development of resistance
mutations
temporally linked to nonadherence to therapy
Recommended methods for determining
virologic failure
• HIV-1 viral load measurements should be done by
any one of the following US FDA recommended
tests:
• Roche Cobas Amplicor
• Branched DNA method
• Nucleic acid sequence based assay (NASBA)
Causes of ARV Treatment Failure
Social/personal issues
Regimen issues

Poor potency
Wrong dose

Toxicities

Host genetics
Poor adherence

Poor absorption
Drug pharmacokinetics
Transmitted resistance

Insufficient drug level

Drug interactions
Viral replication in the
presence of drug
Resistant virus
ART resistance testing. AETC National Resource Center.
1st line Antiretroviral therapy treatment failure
•
•
•
•
•

•
•
•
•

Should be confirmed by 2 plasma viral load reports (plasma viral load >
400 copies/ml) after 6 months on 1st line ART.
2nd line ART should not be started on immunologic (CD4)/clinical evidence
alone.
Genotypic resistance testing should ideally be recommended while
patient is on failing 1st line antiretroviral regimen.
Reason for 1st line ART failure and cost of 2nd line antiretroviral regimen
should be discussed in detail.
Adding at least two (preferably three) fully active agents to an optimized
background antiretroviral regimen can provide significant antiretroviral
activity
Boosted PI regimens well studied, expected to be effective
Backbone of 2 NRTI’s can be decided from resistance testing report
Goal of 2nd line ART is to re-suppress plasma viral load to undetectable
levels.
Highly drug resistant HIV
Assessing treatment failiure
• Genotypic resistance testing
• Phenotypic resistance testing
• Virtual phenotype
Genotypic resistance testing
• Identifies mutations within reverse transcriptase and
protease genes that have been associated with impaired
virologic response
• Readily available
• Quick turnaround time (1-2 weeks)
• Confers short-term virologic benefits
• Useful for mixtures of wild type and drug resistant virus
• Genotype testing is suitable for straightforward situations,
such as testing for drug-resistant virus in treatment-naive
subjects or evaluating resistance in a patient with viral
rebound after their first regimen
Common reverse transcriptase inhibitor resistance
(NRTI/NtRTI/NNRTI) mutations
TYPE OF DRUG

DRUGS INCLUDED

SIGNATURE MUTATIONS

THYMIDINE ANALOGS

ZIDOVUDINE

41L, 67N,70R,210W,215Y,219Q

(TAM’s)

STAVUDINE

41L, 67N,70R,210W,215Y,219Q

NON-THYMIDINE ANALOGS

TENOFOVIR

K65R

ABACAVIR

L74V,K65R

DIDANOSINE

L74V,K65R

NEVIRAPINE

K103N,Y181C

EFAVIRENZ

K103N,Y181C

LAMIVUDINE

M184V

NNRTI

NRTI

EMTRICITABINE
Dynamics of resistance development
DRUG

K103N,Y181C

LAMIVUDINE

M184V

ZIDOVUDINE

TAM’s

EFAVIRENZ
TRUSTIVA/VIRADAY

RESISTANCE MUTATION

NEVIRAPINE
ZIDOLAM N/ DUOVIR N

COMPONENTS

K103N,Y181C

EMTRICITABINE

M184V

TENOFOVIR

K65R
Higher Mortality and Disease Progression in
MDR HIV
• Drug-resistant virus associated with poorer prognosis
and higher mortality
• Factors correlating with increased risk of death
– Lower CD4+ cell count
― Higher viral load
– Treatment history with greater number of anti-HIV agents
– Earlier diagnosis of MDR HIV
Class-Wide Resistance Mutations
Parameter, %

0

1

2

3

P Value

All-cause death

8.9

11.7

13.4

27.1

.0286

AIDS-related death

6.1

9.9

13.4

21.5

.0299

New AIDS event or death

16.0

17.7

19.3

35.9

.0155

Zaccarelli M, et al. AIDS. 2005;19:1081-1089.
CASE 1
•
•
•
•
•

Mr A.B
Resident of Phaltan, married with two kids
Farmer by occupation
Occasional Smoker
Was diagnosed HIV-1 positive in March 2008 when
he suffered from disseminated TB
• Pt was put on 4 drug ATT, Septran and responded
well
• Investigations done were as follows :
INVESTIGATIONS
Haemoglobin

12.3 g/dl

T. Bil

1 mg/dl

TLC

6500 cells/mm3

D. Bil

0.3 mg/dl

Lymphocyte count

2500 cells/mm3

I.Bil

0.7 mg/dl

Platelet count

189,000

AST/ALT

34/34

BUN

20 mg/dl

CD4

132 cells/mm3

Creat

1 mg/dl

CD8

987 cells/mm3

HBsAg

Positive

XRC P/A

Lower zone infiltrates

VDRL

negative

USG Abdomen

Mesentric
lymphadenopathy
Further course
• Pt was started on Zidovudine/Lamivudine in July
2008 along with ATT
• Pt was shifted to
Zidovudine/Lamivudine/Nevirapine in October 2008
by his physician on completion of his ATT
• Pt took treatment extremely regularly over the next
6 months although he was having AZT induced
gastritis and myalgia
• He presented to Noble Hospital, Pune in April 2009
• His investigations revealed :
INVESTIGATIONS
Haemoglobin

10.1 g/dl

T. Bil

1.1 mg/dl

TLC

6500 cells/mm3

D. Bil

0.3 mg/dl

Lymphocyte count

1600 cells/mm3

I.Bil

0.8 mg/dl

Platelet count

549,000

AST/ALT

84/114

BUN

32 mg/dl

CD4

32 cells/mm3

Creat

1.2 mg/dl

PVL+

123,000 copies/ml

HBsAg

Positive

XRC P/A

WNL

VDRL

negative

USG Abdomen

WNL
QUESTIONS
• What will be your next step ?
• Pt has failed 1st line therapy change to second
line therapy immediately
• Continue same treatment
• Do a genotypic resistance testing pending
which shift the pt to 2nd line ART
• Refer the pt to a ID specialist
Further course
• Plasma viral load is reconfirmed and the value
is 125,000 copies/ml
• Pt was willing to submit his plasma sample for
Genotypic HIV-1 resistance testing
• Pt is counseled about need for second line
ART regimen and was willing for the same
QUESTIONS
• What are the precautions to be taken while
sending plasma sample of pt for genotypic
resistance testing ?
• Resistance testing should be done when pt is
on failing ART regimen or within 4 weeks of
discontinuation
• Might not detect resistance mutations when
viral load is very low i.e < 5000 copies/ml
• Might not detect minority variants
Genotypic resistance testing
• HIV-1 subtype C
• NRTI : M184V
• NNRTI : K103N
• PI : None
Common reverse transcriptase inhibitor resistance
(NRTI/NtRTI/NNRTI) mutations
TYPE OF DRUG

DRUGS INCLUDED

SIGNATURE MUTATIONS

THYMIDINE ANALOGS

ZIDOVUDINE

41L, 67N,70R,210W,215Y,219Q

(TAM’s)

STAVUDINE

41L, 67N,70R,210W,215Y,219Q

NON-THYMIDINE ANALOGS

TENOFOVIR

K65R

ABACAVIR

L74V,K65R

DIDANOSINE

L74V,K65R

NEVIRAPINE

K103N,Y181C

EFAVIRENZ

K103N,Y181C

LAMIVUDINE

M184V

NNRTI

NRTI

EMTRICITABINE
QUESTIONS
• Would you keep lamivudine/Emtricitabine in
second line ART regimen ?
• What would be the preferred second line ART
regimen in above pt ?
Further course
• Pt was started on
Tenofovir/Emtricitabine/Lopinavir/Ritonavir
as second line regimen
• He tolerated the regimen well and
investigations done in December 2009 were
as follows :
• CD4 count : 323 cells/mm3
• Plasma viral load < 400 copies/ml
• Serum Creatinine – 1.2 mg/dl
CASE 2
•
•
•
•
•

Mr X.Y
Resident of Pune, married with 3 kids
Police constable by occupation
Heavy drinker and chain smoker
Was diagnosed HIV-1 positive in May 2003 when he
went for routine health check
• Investigations done were as follows :
INVESTIGATIONS
Haemoglobin

9.3 g/dl

T. Bil

1.3 mg/dl

TLC

10500 cells/mm3

D. Bil

1 mg/dl

Lymphocyte count

3500 cells/mm3

I.Bil

0.6 mg/dl

Platelet count

413,000

AST/ALT

83/31

BUN

32 mg/dl

CD4

66 cells/mm3

Creat

0.6 mg/dl

CD8

432 cells/mm3

HBsAg

Negative

XRC P/A

WNL

VDRL

negative

USG Abdomen

WNL
Further course
• Pt was started on Zidovudine/Lamivudine/Nevirapine in May
2003
• Pt took treatment extremely regularly but developed AZT
induced anemia in November 2003
• Pt was shifted to Stavudine/Lamivudine/Nevirapine which he
continued to take till July 2010
• During episodes of binge drinking pt used to skip ART
• Pt also gave history of taking drugs once daily instead of twice
daily when on official duty
• His self reported adherence was around 75 %
• He presented to Ruby Hall Clinic, Pune in July 2010 with h/o
high grade fever,anorexia,wt. loss since 20 days
• His past investigations revealed :
INVESTIGATIONS
DATE

1/4/2005

10/8/2007

27/12/2008

CD4

83

100

53

CD8

1586

2101

1455

PVL

Not done

Not done

Not done
INVESTIGATIONS
Haemoglobin

10.7 g/dl

T. Bil

1.3 mg/dl

TLC

14300 cells/mm3

D. Bil

1 mg/dl

Lymphocyte count

6700 cells/mm3

I.Bil

0.3 mg/dl

Platelet count

549,000

AST/ALT

96/31

BUN

32 mg/dl

CD4

4 cells/mm3

Creat

0.6 mg/dl

Plasma viral load

111,000 copies/ml

HBsAg

Negative

VDRL

negative

XRC P/A

WNL

USG Abdomen

WNL

HRCT chest

Mediastinal necrotic
lymphadenopathy

CT abdomen

Splenic microabcesses
FINAL DIAGNOSIS
• 1ST LINE ART FAILURE WITH DISSEMINATED
TUBECULOSIS
QUESTIONS
• What will be the drugs to be included in
antitubercular regimen of this patient ?
• When will you initiate second line
antiretroviral therapy in this pt ?
• What dose of rifabutin is recommended to be
used with Lopinavir-Ritonavir ?
Timing of ART initiation in patients with
tuberculosis
CD4 count
< 50 cells /mm3

Time to initiate antiretroviral
therapy
within 2 weeks

50 – 200 cells/mm3 (low Karnofsky

2-4 weeks

score, body mass index, haemoglobin, or
albumin, organ system dysfunction)

50 – 200 cells/mm3 (no severe
markers)
200 – 500 cells/mm3

Within 8-12 weeks

> 500 cells/mm3

Within 8-12 weeks

Tubercular meningitis
irrespective of CD4 count

Delay ART till meningitis under
control

Within 8-12 weeks
Recommendations for Coadministering
Antiretroviral Drugs with RIFABUTIN
DRUG WITH WHICH RIFABUTIN IS
CO-ADMINISTERED

DOSE OF RIFABUTIN

EFAVIRENZ

450-600 mg/day

NEVIRAPINE

300 mg/day

RITONAVIR BOOSTED DARUNAVIR

150 mg daily

RITONAVIR BOOSTED ATAZANAVIR

150 mg daily

RITONAVIR BOOSTED LOPINAVIR

150 mg daily
Genotypic resistance testing report
• NRTI : M41L, D67N, M184V, T215Y, K219Q
• NNRTI : Y181C, H221Y, Y318F
• PI : none
Common reverse transcriptase inhibitor resistance
(NRTI/NtRTI/NNRTI) mutations
TYPE OF DRUG

DRUGS INCLUDED

SIGNATURE MUTATIONS

THYMIDINE ANALOGS

ZIDOVUDINE

41L, 67N,70R,210W,215Y,219Q

STAVUDINE

41L, 67N,70R,210W,215Y,219Q

TENOFOVIR

K65R

ABACAVIR

L74V,K65R

DIDANOSINE

L74V,K65R

NEVIRAPINE

K103N,Y181C

EFAVIRENZ

K103N,Y181C

LAMIVUDINE

M184V

NON-THYMIDINE ANALOGS

NNRTI

NRTI

EMTRICITABINE
Genotypic resistance testing report
DRUG

MUTATION SCORE

DRUG

MUTATION SCORE

ZIDOVUDINE

68

NELFINAVIR

0

STAVUDINE

62

INDINAVIR

0

LAMIVUDINE

68

ATAZANAVIR

0

TENOFOVIR

25

LOPINAVIR

0

ABACAVIR

45

DARUNAVIR

0

DIDANOSINE

52

SAQUINAVIR

0

NEVIRAPINE

90

EFAVIRENZ

40
QUESTIONS
• What are Thymidine analog mutation (TAM)
pathways and why are they important?
• 41L, 67N,70R,210W,215Y,219Q
• 41,210,215 pathway
• 67,70,219 pathway
QUESTIONS
• What will be the second line ART regimen
chosen for this pt ?
• What are the recommended PI regimens for
second line therapy ?
Further course
• Pt was started on
Tenofovir/Emtricitabine/Lopinavir/Ritonavir
as second line regimen
• He tolerated the regimen well and
investigations done in Jan 2011 were as
follows :
• CD4 count : 493 cells/mm3
• Plasma viral load < 400 copies/ml
• Serum Creatinine – 0.8 mg/dl
CASE 3
•
•
•
•
•

Mr G.B
Resident of Dhule, married
Businessman by occupation
Tobacco chewer
Was diagnosed HIV-1 positive in April 2009 when he
went to a dermatologist regarding recurrent penile
ulcers and oral apthous ulcers
• Investigations done were as follows :
INVESTIGATIONS
Haemoglobin

11.1 g/dl

T. Bil

0.5 mg/dl

TLC

4600 cells/mm3

D. Bil

0.2 mg/dl

Lymphocyte count

1600 cells/mm3

I.Bil

0.3 mg/dl

Platelet count

138,000

AST/ALT

84/34

BUN

27 mg/dl

CD4

132 cells/mm3

Creat

1.3 mg/dl

CD8

1148 cells/mm3

HBsAg

NEGATIVE

XRC P/A

WNL

VDRL

negative

USG Abdomen

WNL
Further course
•
•

•

•
•
•
•

Pt was started on Stavudine/Lamivudine/Nevirapine in January 2009
Pt developed severe itching and erythematous rash within 15 days of
starting treatment and took tablets alternate day for 20 days and then
stopped them altogether
Pt presented to local physician in April 2009 who shifted him to
Tenofovir/Emtricitabine/Efavirenz which he continued to take till
December 2009
Pt took the treatment extremely regularly and had no side-effects
His self reported adherence was around 95 %
He presented in January 2010 with h/o weight loss of 5 kgs over 1 month
His investigations revealed :
INVESTIGATIONS
Haemoglobin

8.7 g/dl

T. Bil

1.3 mg/dl

TLC

10300 cells/mm3

D. Bil

0.3 mg/dl

Lymphocyte count

5700 cells/mm3

I.Bil

1 mg/dl

Platelet count

143,000

AST/ALT

23/31

BUN

32 mg/dl

CD4

14 cells/mm3

Creat

0.6 mg/dl

Plasma viral load

141,000 copies/ml

HBsAg

Negative

Serum Cryptococcal
Antigen

negative

XRC P/A

WNL

USG Abdomen

WNL

HRCT chest

WNL

CT abdomen

WNL
Genotypic resistance testing report
• NRTI : K65R, K70T, M184V
• NNRTI : V90I, L100I, K103N, V108IV
• PI : none
Common reverse transcriptase inhibitor resistance
(NRTI/NtRTI/NNRTI) mutations
TYPE OF DRUG

DRUGS INCLUDED

SIGNATURE MUTATIONS

THYMIDINE ANALOGS

ZIDOVUDINE

41L, 67N,70R,210W,215Y,219Q

STAVUDINE

41L, 67N,70R,210W,215Y,219Q

TENOFOVIR

K65R

ABACAVIR

L74V,K65R

DIDANOSINE

L74V,K65R

NEVIRAPINE

K103N,Y181C

EFAVIRENZ

K103N,Y181C

LAMIVUDINE

M184V

NON-THYMIDINE ANALOGS

NNRTI

NRTI

EMTRICITABINE
Genotypic resistance testing report
DRUG

MUTATION SCORE

DRUG

MUTATION SCORE

ZIDOVUDINE

-12

NELFINAVIR

0

STAVUDINE

15

INDINAVIR

0

LAMIVUDINE

90

ATAZANAVIR

0

TENOFOVIR

28

LOPINAVIR

0

ABACAVIR

42

DARUNAVIR

0

DIDANOSINE

35

SAQUINAVIR

0

NEVIRAPINE

110

EFAVIRENZ

110
QUESTIONS
• What will be the second line ART regimen
chosen for this pt ?
• What is the commonest side-effect of
Atazanavir- ritonavir ?
Further course
• Pt was started on
Zidovudine/Lamivudine/Tenofovir/Atazanavir/
Ritonavir as second line regimen
• He tolerated the regimen well and investigations
done in Sept 2010 were as follows :
• CD4 count : 189 cells/mm3
• Plasma viral load < 400 copies/ml
• Serum Creatinine – 0.6 mg/dl
• T.Bil – 4.3
• I.Bilirubin – 3.7
• SGPT/SGOT- 39/37
CASE 4
•
•
•
•
•

Mr S.J
Resident of Akluj, married
Farmer by occupation
Non- addict
Was diagnosed HIV-1 positive in June 2004 when he
was admitted for pile banding surgery at Solapur
• Investigations done were as follows :
INVESTIGATIONS
Haemoglobin

7.1g/dl

T. Bil

0.8 mg/dl

TLC

4500 cells/mm3

D. Bil

0.5 mg/dl

Lymphocyte count

2200 cells/mm3

I.Bil

0.3 mg/dl

Platelet count

643,000

AST/ALT

14/34

BUN

34 mg/dl

CD4

201 cells/mm3

Creat

0.7 mg/dl

CD8

1029 cells/mm3

HBsAg

negative

XRC P/A

WNL

VDRL

negative

USG Abdomen

WNL
Further course
•
•
•
•
•
•
•
•
•
•
•
•

Pt was started on Zidovudine/Lamivudine/Nevirapine in July 2004
Pt continued treatment till January 2008
His self reported adherence was around 80 %
He used to take multiple gaps in treatment especially during visits to other
villages for work
He was also unhappy with the gastritis and myalgia he developed on
consuming ART tablets.
Pt’s CD4 count done in January 2008 was 219 cells/mm 3
He was shifted to Tenofovir/Emtricitabine/Efavirenz by local physician in
January 2008
He took treatment extremely regularly till July 2008
His repeat CD4 count done was 159 cells/mm3
Pt was disappointed by falling CD4 count and stopped all drugs
He presented to Noble Hospital, Pune in May 2009
Pt was asymptomatic on presentation
INVESTIGATIONS
Haemoglobin

9.6g/dl

T. Bil

0.9 mg/dl

TLC

2300 cells/mm3

D. Bil

0.6 mg/dl

Lymphocyte count

1200 cells/mm3

I.Bil

0.3 mg/dl

Platelet count

419,000

AST/ALT

54/44

BUN

21 mg/dl

CD4

78 cells/mm3

Creat

0.5 mg/dl

CD8

1349 cells/mm3

HBsAg

negative

XRC P/A

WNL

Cryptococcal
Antigen

negative

USG Abdomen

WNL
QUESTIONS
• What will be your next step ?

• What will be the second line ART regimen
chosen for this pt ?
Further course
• Pt was started on
Stavudine/Lamivudine/Tenofovir/Atazanavir/
Ritonavir as second line regimen
• He tolerated the regimen well and investigations
done in Feb 2010 were as follows :
• CD4 count : 514 cells/mm3
• Plasma viral load < 400 copies/ml
• Serum Creatinine – 0.9 mg/dl
Take home message
•
•
•
•

•

Antiretroviral therapy switching occurs because of multiple reasons
Drug toxicity, ART resistance, cost reduction and ART simplification are
the major causes of drug switching in India.
Individual drug substitution to circumvent drug toxicity or reduce regimen
cost should be done only after confirming viral suppression.
Virologic failure needs to be identified early by doing at least yearly
plasma viral load in patients on ART. Non identification of failure can lead
to accumulation of drug resistance mutations and reduced capability of
second line regimens to suppress the virus.
Causes of virologic failure need to be scrupulously identified otherwise
second line regimens will also be compromised.
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Antiretroviral therapy switch

  • 1. Antiretroviral therapy switch : When to switch/ What to switch to ? Dr Ameet Dravid
  • 2. Antiretroviral therapy : when to start?
  • 6. NACO GUIDELINES 2012 Classification of HIV-associated clinical disease WHO STAGE CD4 NOT AVAILABLE Asymptomatic 1 CD4 AVAILABLE Do not treat Treat if CD4 <350 Mild symptoms 2 Do not treat Advanced symptoms 3 Treat Consider treatment if CD4 <350 and initiate ART before CD4 drops below 200 Severe/advanced symptoms 4 Treat Treat irrespective of CD4 count
  • 7. Antiretroviral therapy : what to start?
  • 8. NACO GUIDELINES 2012  Preferred regimen (2NRTI’s + 1 NNRTI)  AZT + 3TC + NVP (Zidovudine + Lamivudine + Nevirapine )  Alternative regimen (2NRTI’s + 1 NNRTI)  AZT + 3TC + EFV (Zidovudine + Lamivudine + Efavirenz)  TDF + 3TC + NVP/EFV (Tenofovir + Lamivudine + Nevirapine/Efavirenz )  Other options  Stavudine (d4T) + 3TC/FTC + NVP/EFV  Pi’s not recommended for first line therapy
  • 10. Commonly used 1st line ART regimens in India NAME OF DRUG TRADE NAME Zidovudine + Lamivudine + Nevirapine Duovir-N/Lazid-N/Virocomb N Stavudine+ Lamivudine + Nevirapine Triomune-30/Emtri 30/Virolans 30 Zidovudine + Lamivudine + Efavirenz Duovir + Efavir Stavudine+ Lamivudine + Efavirenz Lamivir-S(30 )+ Efavir Tenofovir + Lamivudine + Efavirenz Tenolam E/Dinmek/Trioday Tenofovir + Emtricitabine + Efavirenz Trustiva/Vonavir/Viraday
  • 11. Monitoring patients on antiretroviral therapy
  • 12. Antiretroviral switching • Drug toxicity • Drug drug interactions • Simplification of regimens (change to once daily regimens) • Pregnancy (Efavirenz to Nevirapine) • Cost • Proactive • Antiretroviral therapy failure
  • 13. Antiretroviral drug toxicity DRUG REGIMEN OFFENDING DRUG DRUG TOXICITY DRUG SWITCH Zidovudine + Lamivudine + Nevirapine Zidovudine Anemia Change to Stavudine or Tenofovir GI intolerance Skin and nail hyperpigmentation Lactic acidosis Tenofovir + Emticitabine+Efavirenz Tenofovir Fanconi syndrome Renal dysfunction Change to Zidovudine or Abacavir Osteomalacia Decreased BMD Stavudine + Lamivudine+Nevirapine Stavudine Lipoatrophy Peripheral neuropathy Pancreatitis Lactic acidosis DM, Dyslipidemia Change to Tenofovir
  • 14. Antiretroviral drug toxicity DRUG REGIMEN OFFENDING DRUG DRUG TOXICITY DRUG SWITCH Zidovudine + Lamivudine + Nevirapine Nevirapine Rash Change to Efavirenz Hepatitis Stevens johnson syndrome Tenofovir + Emticitabine+Efavirenz Efavirenz Rash, Hepatitis Drowsiness, abnormal dreams Impaired concentration Abacavir + Lamivudine + Efavirenz Abacavir Hypersensitivity Change to Nevirapine in case of CNS symptoms, change to ATV/r in case of rash Change to Tenofovir if Creat clearance > 50 ml/min or else use Zidovudine
  • 15. Antiretroviral drug drug interactions • Nevirapine to Efavirenz in patients with Tuberculosis due to use of Rifampicin. • HIV/HCV co infection : change to Tenofovir + Lamivudine + Efavirenz • HIV and cancer : avoid Zidovudine with chemotherapy due to myelosuppressive side-effects of both. • HIV and CMV : avoid co-administration of Zidovudine with Valganciclovir • HIV and cryptococcal meningitis : avoidance of Tenofovir with Amphotericin B.
  • 16. Antiretroviral drug drug interactions • Antiretroviral regimens not recommended : • Tenofovir + Lamivudine + Nevirapine : high chance of virologic failure. • Stavudine + Didanosine • Stavudine + Zidovudine • Tenofovir + Abacavir • Tenofovir + Didanosine
  • 17. Antiretroviral treatment failure • • • • • Virologic failure : inability to achieve or maintain suppression of viral replication to HIV-1 RNA levels < 50 copies/mL 2 consecutive tests indicating HIV-1 RNA > 400 copies/mL after 24 weeks or > 50 copies/mL at 48 weeks Immunologic failure Inability of CD4 count to increase > 100 cells/mm3 in 1st year of ART Fall in CD4 count from peak level by > 50 % Clinical failure AIDS defining illness occurring more than 3-6 months after starting antiretroviral therapy
  • 18. Difference between viral rebound and viral blip • • • • Viral blip : defined as a single, low-level plasma HIV-1 RNA level of 50-1000 copies/mL) that is immediately preceded and followed by an undetectable HIV-1 RNA false elevations of HIV-1 RNA related to erroneous laboratory findings or to release of archived virus from activated cells. not associated with the development of resistance mutations temporally linked to nonadherence to therapy
  • 19. Recommended methods for determining virologic failure • HIV-1 viral load measurements should be done by any one of the following US FDA recommended tests: • Roche Cobas Amplicor • Branched DNA method • Nucleic acid sequence based assay (NASBA)
  • 20. Causes of ARV Treatment Failure Social/personal issues Regimen issues Poor potency Wrong dose Toxicities Host genetics Poor adherence Poor absorption Drug pharmacokinetics Transmitted resistance Insufficient drug level Drug interactions Viral replication in the presence of drug Resistant virus ART resistance testing. AETC National Resource Center.
  • 21. 1st line Antiretroviral therapy treatment failure • • • • • • • • • Should be confirmed by 2 plasma viral load reports (plasma viral load > 400 copies/ml) after 6 months on 1st line ART. 2nd line ART should not be started on immunologic (CD4)/clinical evidence alone. Genotypic resistance testing should ideally be recommended while patient is on failing 1st line antiretroviral regimen. Reason for 1st line ART failure and cost of 2nd line antiretroviral regimen should be discussed in detail. Adding at least two (preferably three) fully active agents to an optimized background antiretroviral regimen can provide significant antiretroviral activity Boosted PI regimens well studied, expected to be effective Backbone of 2 NRTI’s can be decided from resistance testing report Goal of 2nd line ART is to re-suppress plasma viral load to undetectable levels. Highly drug resistant HIV
  • 22. Assessing treatment failiure • Genotypic resistance testing • Phenotypic resistance testing • Virtual phenotype
  • 23. Genotypic resistance testing • Identifies mutations within reverse transcriptase and protease genes that have been associated with impaired virologic response • Readily available • Quick turnaround time (1-2 weeks) • Confers short-term virologic benefits • Useful for mixtures of wild type and drug resistant virus • Genotype testing is suitable for straightforward situations, such as testing for drug-resistant virus in treatment-naive subjects or evaluating resistance in a patient with viral rebound after their first regimen
  • 24. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q (TAM’s) STAVUDINE 41L, 67N,70R,210W,215Y,219Q NON-THYMIDINE ANALOGS TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NNRTI NRTI EMTRICITABINE
  • 25. Dynamics of resistance development DRUG K103N,Y181C LAMIVUDINE M184V ZIDOVUDINE TAM’s EFAVIRENZ TRUSTIVA/VIRADAY RESISTANCE MUTATION NEVIRAPINE ZIDOLAM N/ DUOVIR N COMPONENTS K103N,Y181C EMTRICITABINE M184V TENOFOVIR K65R
  • 26. Higher Mortality and Disease Progression in MDR HIV • Drug-resistant virus associated with poorer prognosis and higher mortality • Factors correlating with increased risk of death – Lower CD4+ cell count ― Higher viral load – Treatment history with greater number of anti-HIV agents – Earlier diagnosis of MDR HIV Class-Wide Resistance Mutations Parameter, % 0 1 2 3 P Value All-cause death 8.9 11.7 13.4 27.1 .0286 AIDS-related death 6.1 9.9 13.4 21.5 .0299 New AIDS event or death 16.0 17.7 19.3 35.9 .0155 Zaccarelli M, et al. AIDS. 2005;19:1081-1089.
  • 27. CASE 1 • • • • • Mr A.B Resident of Phaltan, married with two kids Farmer by occupation Occasional Smoker Was diagnosed HIV-1 positive in March 2008 when he suffered from disseminated TB • Pt was put on 4 drug ATT, Septran and responded well • Investigations done were as follows :
  • 28. INVESTIGATIONS Haemoglobin 12.3 g/dl T. Bil 1 mg/dl TLC 6500 cells/mm3 D. Bil 0.3 mg/dl Lymphocyte count 2500 cells/mm3 I.Bil 0.7 mg/dl Platelet count 189,000 AST/ALT 34/34 BUN 20 mg/dl CD4 132 cells/mm3 Creat 1 mg/dl CD8 987 cells/mm3 HBsAg Positive XRC P/A Lower zone infiltrates VDRL negative USG Abdomen Mesentric lymphadenopathy
  • 29. Further course • Pt was started on Zidovudine/Lamivudine in July 2008 along with ATT • Pt was shifted to Zidovudine/Lamivudine/Nevirapine in October 2008 by his physician on completion of his ATT • Pt took treatment extremely regularly over the next 6 months although he was having AZT induced gastritis and myalgia • He presented to Noble Hospital, Pune in April 2009 • His investigations revealed :
  • 30. INVESTIGATIONS Haemoglobin 10.1 g/dl T. Bil 1.1 mg/dl TLC 6500 cells/mm3 D. Bil 0.3 mg/dl Lymphocyte count 1600 cells/mm3 I.Bil 0.8 mg/dl Platelet count 549,000 AST/ALT 84/114 BUN 32 mg/dl CD4 32 cells/mm3 Creat 1.2 mg/dl PVL+ 123,000 copies/ml HBsAg Positive XRC P/A WNL VDRL negative USG Abdomen WNL
  • 31. QUESTIONS • What will be your next step ? • Pt has failed 1st line therapy change to second line therapy immediately • Continue same treatment • Do a genotypic resistance testing pending which shift the pt to 2nd line ART • Refer the pt to a ID specialist
  • 32. Further course • Plasma viral load is reconfirmed and the value is 125,000 copies/ml • Pt was willing to submit his plasma sample for Genotypic HIV-1 resistance testing • Pt is counseled about need for second line ART regimen and was willing for the same
  • 33. QUESTIONS • What are the precautions to be taken while sending plasma sample of pt for genotypic resistance testing ? • Resistance testing should be done when pt is on failing ART regimen or within 4 weeks of discontinuation • Might not detect resistance mutations when viral load is very low i.e < 5000 copies/ml • Might not detect minority variants
  • 34. Genotypic resistance testing • HIV-1 subtype C • NRTI : M184V • NNRTI : K103N • PI : None
  • 35. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q (TAM’s) STAVUDINE 41L, 67N,70R,210W,215Y,219Q NON-THYMIDINE ANALOGS TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NNRTI NRTI EMTRICITABINE
  • 36. QUESTIONS • Would you keep lamivudine/Emtricitabine in second line ART regimen ? • What would be the preferred second line ART regimen in above pt ?
  • 37. Further course • Pt was started on Tenofovir/Emtricitabine/Lopinavir/Ritonavir as second line regimen • He tolerated the regimen well and investigations done in December 2009 were as follows : • CD4 count : 323 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 1.2 mg/dl
  • 38. CASE 2 • • • • • Mr X.Y Resident of Pune, married with 3 kids Police constable by occupation Heavy drinker and chain smoker Was diagnosed HIV-1 positive in May 2003 when he went for routine health check • Investigations done were as follows :
  • 39. INVESTIGATIONS Haemoglobin 9.3 g/dl T. Bil 1.3 mg/dl TLC 10500 cells/mm3 D. Bil 1 mg/dl Lymphocyte count 3500 cells/mm3 I.Bil 0.6 mg/dl Platelet count 413,000 AST/ALT 83/31 BUN 32 mg/dl CD4 66 cells/mm3 Creat 0.6 mg/dl CD8 432 cells/mm3 HBsAg Negative XRC P/A WNL VDRL negative USG Abdomen WNL
  • 40. Further course • Pt was started on Zidovudine/Lamivudine/Nevirapine in May 2003 • Pt took treatment extremely regularly but developed AZT induced anemia in November 2003 • Pt was shifted to Stavudine/Lamivudine/Nevirapine which he continued to take till July 2010 • During episodes of binge drinking pt used to skip ART • Pt also gave history of taking drugs once daily instead of twice daily when on official duty • His self reported adherence was around 75 % • He presented to Ruby Hall Clinic, Pune in July 2010 with h/o high grade fever,anorexia,wt. loss since 20 days • His past investigations revealed :
  • 42. INVESTIGATIONS Haemoglobin 10.7 g/dl T. Bil 1.3 mg/dl TLC 14300 cells/mm3 D. Bil 1 mg/dl Lymphocyte count 6700 cells/mm3 I.Bil 0.3 mg/dl Platelet count 549,000 AST/ALT 96/31 BUN 32 mg/dl CD4 4 cells/mm3 Creat 0.6 mg/dl Plasma viral load 111,000 copies/ml HBsAg Negative VDRL negative XRC P/A WNL USG Abdomen WNL HRCT chest Mediastinal necrotic lymphadenopathy CT abdomen Splenic microabcesses
  • 43. FINAL DIAGNOSIS • 1ST LINE ART FAILURE WITH DISSEMINATED TUBECULOSIS
  • 44. QUESTIONS • What will be the drugs to be included in antitubercular regimen of this patient ? • When will you initiate second line antiretroviral therapy in this pt ? • What dose of rifabutin is recommended to be used with Lopinavir-Ritonavir ?
  • 45. Timing of ART initiation in patients with tuberculosis CD4 count < 50 cells /mm3 Time to initiate antiretroviral therapy within 2 weeks 50 – 200 cells/mm3 (low Karnofsky 2-4 weeks score, body mass index, haemoglobin, or albumin, organ system dysfunction) 50 – 200 cells/mm3 (no severe markers) 200 – 500 cells/mm3 Within 8-12 weeks > 500 cells/mm3 Within 8-12 weeks Tubercular meningitis irrespective of CD4 count Delay ART till meningitis under control Within 8-12 weeks
  • 46. Recommendations for Coadministering Antiretroviral Drugs with RIFABUTIN DRUG WITH WHICH RIFABUTIN IS CO-ADMINISTERED DOSE OF RIFABUTIN EFAVIRENZ 450-600 mg/day NEVIRAPINE 300 mg/day RITONAVIR BOOSTED DARUNAVIR 150 mg daily RITONAVIR BOOSTED ATAZANAVIR 150 mg daily RITONAVIR BOOSTED LOPINAVIR 150 mg daily
  • 47. Genotypic resistance testing report • NRTI : M41L, D67N, M184V, T215Y, K219Q • NNRTI : Y181C, H221Y, Y318F • PI : none
  • 48. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q STAVUDINE 41L, 67N,70R,210W,215Y,219Q TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NON-THYMIDINE ANALOGS NNRTI NRTI EMTRICITABINE
  • 49. Genotypic resistance testing report DRUG MUTATION SCORE DRUG MUTATION SCORE ZIDOVUDINE 68 NELFINAVIR 0 STAVUDINE 62 INDINAVIR 0 LAMIVUDINE 68 ATAZANAVIR 0 TENOFOVIR 25 LOPINAVIR 0 ABACAVIR 45 DARUNAVIR 0 DIDANOSINE 52 SAQUINAVIR 0 NEVIRAPINE 90 EFAVIRENZ 40
  • 50. QUESTIONS • What are Thymidine analog mutation (TAM) pathways and why are they important? • 41L, 67N,70R,210W,215Y,219Q • 41,210,215 pathway • 67,70,219 pathway
  • 51. QUESTIONS • What will be the second line ART regimen chosen for this pt ? • What are the recommended PI regimens for second line therapy ?
  • 52. Further course • Pt was started on Tenofovir/Emtricitabine/Lopinavir/Ritonavir as second line regimen • He tolerated the regimen well and investigations done in Jan 2011 were as follows : • CD4 count : 493 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 0.8 mg/dl
  • 53. CASE 3 • • • • • Mr G.B Resident of Dhule, married Businessman by occupation Tobacco chewer Was diagnosed HIV-1 positive in April 2009 when he went to a dermatologist regarding recurrent penile ulcers and oral apthous ulcers • Investigations done were as follows :
  • 54. INVESTIGATIONS Haemoglobin 11.1 g/dl T. Bil 0.5 mg/dl TLC 4600 cells/mm3 D. Bil 0.2 mg/dl Lymphocyte count 1600 cells/mm3 I.Bil 0.3 mg/dl Platelet count 138,000 AST/ALT 84/34 BUN 27 mg/dl CD4 132 cells/mm3 Creat 1.3 mg/dl CD8 1148 cells/mm3 HBsAg NEGATIVE XRC P/A WNL VDRL negative USG Abdomen WNL
  • 55. Further course • • • • • • • Pt was started on Stavudine/Lamivudine/Nevirapine in January 2009 Pt developed severe itching and erythematous rash within 15 days of starting treatment and took tablets alternate day for 20 days and then stopped them altogether Pt presented to local physician in April 2009 who shifted him to Tenofovir/Emtricitabine/Efavirenz which he continued to take till December 2009 Pt took the treatment extremely regularly and had no side-effects His self reported adherence was around 95 % He presented in January 2010 with h/o weight loss of 5 kgs over 1 month His investigations revealed :
  • 56. INVESTIGATIONS Haemoglobin 8.7 g/dl T. Bil 1.3 mg/dl TLC 10300 cells/mm3 D. Bil 0.3 mg/dl Lymphocyte count 5700 cells/mm3 I.Bil 1 mg/dl Platelet count 143,000 AST/ALT 23/31 BUN 32 mg/dl CD4 14 cells/mm3 Creat 0.6 mg/dl Plasma viral load 141,000 copies/ml HBsAg Negative Serum Cryptococcal Antigen negative XRC P/A WNL USG Abdomen WNL HRCT chest WNL CT abdomen WNL
  • 57. Genotypic resistance testing report • NRTI : K65R, K70T, M184V • NNRTI : V90I, L100I, K103N, V108IV • PI : none
  • 58. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q STAVUDINE 41L, 67N,70R,210W,215Y,219Q TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NON-THYMIDINE ANALOGS NNRTI NRTI EMTRICITABINE
  • 59. Genotypic resistance testing report DRUG MUTATION SCORE DRUG MUTATION SCORE ZIDOVUDINE -12 NELFINAVIR 0 STAVUDINE 15 INDINAVIR 0 LAMIVUDINE 90 ATAZANAVIR 0 TENOFOVIR 28 LOPINAVIR 0 ABACAVIR 42 DARUNAVIR 0 DIDANOSINE 35 SAQUINAVIR 0 NEVIRAPINE 110 EFAVIRENZ 110
  • 60. QUESTIONS • What will be the second line ART regimen chosen for this pt ? • What is the commonest side-effect of Atazanavir- ritonavir ?
  • 61. Further course • Pt was started on Zidovudine/Lamivudine/Tenofovir/Atazanavir/ Ritonavir as second line regimen • He tolerated the regimen well and investigations done in Sept 2010 were as follows : • CD4 count : 189 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 0.6 mg/dl • T.Bil – 4.3 • I.Bilirubin – 3.7 • SGPT/SGOT- 39/37
  • 62. CASE 4 • • • • • Mr S.J Resident of Akluj, married Farmer by occupation Non- addict Was diagnosed HIV-1 positive in June 2004 when he was admitted for pile banding surgery at Solapur • Investigations done were as follows :
  • 63. INVESTIGATIONS Haemoglobin 7.1g/dl T. Bil 0.8 mg/dl TLC 4500 cells/mm3 D. Bil 0.5 mg/dl Lymphocyte count 2200 cells/mm3 I.Bil 0.3 mg/dl Platelet count 643,000 AST/ALT 14/34 BUN 34 mg/dl CD4 201 cells/mm3 Creat 0.7 mg/dl CD8 1029 cells/mm3 HBsAg negative XRC P/A WNL VDRL negative USG Abdomen WNL
  • 64. Further course • • • • • • • • • • • • Pt was started on Zidovudine/Lamivudine/Nevirapine in July 2004 Pt continued treatment till January 2008 His self reported adherence was around 80 % He used to take multiple gaps in treatment especially during visits to other villages for work He was also unhappy with the gastritis and myalgia he developed on consuming ART tablets. Pt’s CD4 count done in January 2008 was 219 cells/mm 3 He was shifted to Tenofovir/Emtricitabine/Efavirenz by local physician in January 2008 He took treatment extremely regularly till July 2008 His repeat CD4 count done was 159 cells/mm3 Pt was disappointed by falling CD4 count and stopped all drugs He presented to Noble Hospital, Pune in May 2009 Pt was asymptomatic on presentation
  • 65. INVESTIGATIONS Haemoglobin 9.6g/dl T. Bil 0.9 mg/dl TLC 2300 cells/mm3 D. Bil 0.6 mg/dl Lymphocyte count 1200 cells/mm3 I.Bil 0.3 mg/dl Platelet count 419,000 AST/ALT 54/44 BUN 21 mg/dl CD4 78 cells/mm3 Creat 0.5 mg/dl CD8 1349 cells/mm3 HBsAg negative XRC P/A WNL Cryptococcal Antigen negative USG Abdomen WNL
  • 66. QUESTIONS • What will be your next step ? • What will be the second line ART regimen chosen for this pt ?
  • 67. Further course • Pt was started on Stavudine/Lamivudine/Tenofovir/Atazanavir/ Ritonavir as second line regimen • He tolerated the regimen well and investigations done in Feb 2010 were as follows : • CD4 count : 514 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 0.9 mg/dl
  • 68. Take home message • • • • • Antiretroviral therapy switching occurs because of multiple reasons Drug toxicity, ART resistance, cost reduction and ART simplification are the major causes of drug switching in India. Individual drug substitution to circumvent drug toxicity or reduce regimen cost should be done only after confirming viral suppression. Virologic failure needs to be identified early by doing at least yearly plasma viral load in patients on ART. Non identification of failure can lead to accumulation of drug resistance mutations and reduced capability of second line regimens to suppress the virus. Causes of virologic failure need to be scrupulously identified otherwise second line regimens will also be compromised.

Notas do Editor

  1. ARV, antiretroviral.   This slide reviews the causes for antiretroviral treatment failure. There are many factors that affect treatment failure and they are primarily associated with insufficient drug levels. If drug levels are not sufficient, viral replication occurs in the presence of the drug, thereby permitting emergence of resistant virus and subsequent treatment failure.   Poor adherence is one cause of insufficient drug levels, but poor adherence has a negative connotation that implies the patient has done something wrong. Frequently, there are social or personal issues that may be out of the patient’s control. For example, if their state of residence closes the AIDS Drug Assistance Program, patients may have difficulty obtaining their medication. There may also be regimen issues, including tolerability problems that do not reach the level of toxicity. In addition, toxicity issues involving serious adverse effects may interrupt therapy.   However, there are other reasons for insufficient drug levels. For example, the clinician may choose a regimen with low potency. Alternatively, the wrong dose may be prescribed or dispensed and even though the patient may be perfectly adherent, this suboptimal dose may be the cause for treatment failure. There might be differences in host genetics that affect drug metabolism. Likewise, there might be issues affecting drug absorption. We have also mentioned drug pharmacokinetics and drug-drug interactions.   Transmitted resistance is another factor affecting the ability to achieve sufficient drug level. If the patient is infected with an NNRTI-resistant virus, for example, any level of efavirenz will be insufficient. This results in viral replication in the presence of the drug and may lead to emergence of further drug resistance even to other classes of drugs. However, if the patient does not take his or her medication, he or she is unlikely to develop a resistant virus but treatment failure would still occur.
  2. A study of 623 individuals who had genotype resistance testing during antiretroviral failure demonstrated a heightened risk of death with viral drug resistance. These highly experienced patients had a median 24 months of HAART before genotype testing, and a median of 3 failed regimens. Approximately half of these patients (50.9%) had at least 1 class-wide resistance mutation according to genotype results, and 24 (3.9%) had resistance to all 3 classes. Over 48 months of observation from the time of genotype resistance testing, 28 new AIDS events were documented and 38 deaths occurred, of which 29 were AIDS related. The incidence of death in patients with 0, 1, 2, or 3 class-wide resistance mutations was found to be 3.50, 2.79, 3.97, and 11.90 per 100 person-years of follow-up, respectively. Multivariate statistical analysis correlated triple-class resistance with an increased risk of death (hazard ratio [HR], 5.34; 95% CI, 1.76- 16.24; P &lt; .01); AIDS-related death (HR, 4.14; 95% CI, 1.17-14.68; P = .03); and new AIDS diagnosis or death (HR, 5.36; 95% CI, 2.16-13.32; P &lt; .01). Other factors associated with increased morbidity and mortality were higher current HIV-1 RNA level and pregenotype AIDS diagnosis. Higher CD4+ cell count at the time of genotype resistance testing significantly reduced the risk of death.