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Antiretroviral therapy switch : When to switch/ What to switch to ?
Dr Ameet Dravid
Antiretroviral therapy : when to start?
DHHS guidelines 2013
HIVMAI Guidelines 2012
NACO GUIDELINES 2012Classification ofHIV-associated clinical disease
WHO STAGE CD4 NOT AVAILABLE
CD4 AVAILABLE
Asymptomatic 1 Do not treatTreat 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 2012Preferred 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 optionsStavudine (d4T) + 3TC/FTC + NVP/EFVPi’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 toxicityDRUG REGIMEN OFFENDING DRUG DRUG TOXICITY DRUG SWITCH
Zidovudine + Lamivudine + Nevirapine
Zidovudine Anemia Change to Stavudine or TenofovirGI intolerance
Skin and nail hyperpigmentation
Lactic acidosis
Tenofovir + Emticitabine+Efavirenz
Tenofovir Fanconi syndrome Change to Zidovudine or AbacavirRenal dysfunction
Osteomalacia Decreased BMD
Stavudine + Lamivudine+Nevirapine
Stavudine Lipoatrophy Change to Tenofovir
Peripheral neuropathy
Pancreatitis
Lactic acidosis
DM, Dyslipidemia
Antiretroviral drug toxicityDRUG REGIMEN OFFENDING DRUG DRUG TOXICITY DRUG SWITCH
Zidovudine + Lamivudine + Nevirapine
Nevirapine Rash Change to EfavirenzHepatitis
Stevens johnson syndrome
Tenofovir + Emticitabine+Efavirenz
Efavirenz Rash, Hepatitis Change to Nevirapine in case of CNS
symptoms, change to ATV/r in case of rash
Drowsiness, abnormal dreams
Impaired concentration
Abacavir + Lamivudine + Efavirenz
Abacavir Hypersensitivity 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)
Resistant virus
Insufficient drug level
Social/personal issues
Regimen issues
Toxicities
Poor potency
Wrong dose
Host genetics
Poor absorption
Drug pharmacokinetics
Transmitted resistance
Drug interactions
Poor adherence
Viral replication in thepresence of drug
Causes of ARV Treatment Failure
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
NNRTI NEVIRAPINE K103N,Y181C
EFAVIRENZ K103N,Y181C
NRTI LAMIVUDINE M184V
EMTRICITABINE
Dynamics of resistance development
DRUG COMPONENTS RESISTANCE MUTATION
NEVIRAPINE K103N,Y181C
ZIDOLAM N/ DUOVIR N LAMIVUDINE M184V
ZIDOVUDINE TAM’s
EFAVIRENZ K103N,Y181C
TRUSTIVA/VIRADAY 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
Zaccarelli M, et al. AIDS. 2005;19:1081-1089.
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
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 :
INVESTIGATIONSHaemoglobin 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 :
INVESTIGATIONSHaemoglobin 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
NNRTI NEVIRAPINE K103N,Y181C
EFAVIRENZ K103N,Y181C
NRTI LAMIVUDINE M184V
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 :
INVESTIGATIONSHaemoglobin 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 :
INVESTIGATIONSDATE 1/4/2005 10/8/2007 27/12/2008
CD4 83 100 53
CD8 1586 2101 1455
PVL Not done Not done Not done
INVESTIGATIONSHaemoglobin 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 Time to initiate antiretroviral therapy
< 50 cells /mm3 within 2 weeks
50 – 200 cells/mm3 (low Karnofsky score, body mass index, haemoglobin, or
albumin, organ system dysfunction)
2-4 weeks
50 – 200 cells/mm3 (no severe markers)
Within 8-12 weeks
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
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
NON-THYMIDINE ANALOGS TENOFOVIR K65R
ABACAVIR L74V,K65R
DIDANOSINE L74V,K65R
NNRTI NEVIRAPINE K103N,Y181C
EFAVIRENZ K103N,Y181C
NRTI LAMIVUDINE M184V
EMTRICITABINE
Genotypic resistance testing reportDRUG 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 :
INVESTIGATIONSHaemoglobin 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 :
INVESTIGATIONSHaemoglobin 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
NON-THYMIDINE ANALOGS TENOFOVIR K65R
ABACAVIR L74V,K65R
DIDANOSINE L74V,K65R
NNRTI NEVIRAPINE K103N,Y181C
EFAVIRENZ K103N,Y181C
NRTI LAMIVUDINE M184V
EMTRICITABINE
Genotypic resistance testing reportDRUG 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 :
INVESTIGATIONSHaemoglobin 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/mm3
• 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
INVESTIGATIONSHaemoglobin 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.
THANK YOU