Santiago, 30th June 2017

Clinical Implications of Low level viremia / failure and resistance

1st Andean Workshop on HIV & Hepatitis

Francesca Ceccherini-Silberstein

Univeristà degli Studi di Roma “Tor Vergata”Cattedra di Virologia

Almost every step of HIV replication is target of at least one drug

9 Nucleoside reverse transcriptase inhibitors (NRTIs):AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTC, TAF

9 Protease inhibitors (PIs)SQV, IDV, RTV, NFV, fAPV, LPV, ATV, TPV, DRV

5 Non-nucleoside reverse transcriptase inhibitors (NNRTIs)EFV, NVP, DLV, ETR, RPV

(1) Binding & fusion – (2) Entry – (3) Uncoating – (4) Reverse transcription – (5) Integration – (6) Transcription –(7) Translation - (8) Assembly & budding – (9) Maturation

1 Fusion inhibitor (FIs): T20

3 Integraseinhibitors (INIs)

RAL, EVG, DTG

1 Entry inhibitor: MVC

Today, thanks to the modern potent regimens, more than 90% ofpatients starting a first-line regimen achieve virological suppression

Indeed…

Proportion of patients with a VL

Definitions of Virological Failure

Confirmed HIV-VL > 50 copies/mL 6 months after starting therapy(initiation or modification) in persons that remain on ART.Depending on the HIV-VL assay, this limit could be higher or lower.European Guidelines, 2016.

The inability to achieve or maintain suppression of viralreplication to an HIV RNA level 50 copie/mL). ItalianGuidelines, 2016.

The inability to achieve or maintain viral suppression below acertain threshold. Viral failure is defined by a persistentlydetectable viral load exceeding 1000 copies/mL (twoconsecutive viral load measurements within a 3-month intervalwith adherence support between measurements) after at least6 months of using ART. WHO guidelines, 2016.

In the long-term management of HIVinfection, the stable maintenance ofundetectable HIV over the years ismore important than the mere successof the first regimen.

Factors influencing long-term viral suppression

Durability = + +Adherence

Height and duration of drug exposure

Adverse effects

Genetic Barrier

Number and type of mutations required

for resistance development

– Baseline Mutations

BaselineBurden

Number and type of mutations present

at baselineSubtype

Drug Levels –

HIV RNAHIV DNA

Convenience & tolerability

Patient Drug Virus

Svicher et al submitted

• Treatment is life-long (or at least for decades)• Therapy is successful only if maintained for decades, not for months

or a few years• Switch to new ARTs is a natural event in the course of long-term

therapies (failure, toxicity, intolerance etc)• Preservation of future therapeutic options is mandatory in this

context• Avoiding the emergence of resistance / cross resistance is, in this

frame, one of the major factors to be considered– Otherwise, a clinical price will be paid, although later than in the past….

Therapy insights today

• Our endeavour today has switched from treating the resistant virus to preventing its emergence and consolidation– Although resistant viruses are still an issue in a number of patients

• Long-term success will require major attention in this matter

Virological rebound is still a concern

Therefore………..

0 24 48 72 96

0.0

0.2

0.4

0.6

0.8

1.0

1442 12801671

24 480

17.5%

Time (weeks)

No. at risk

0.0

0.2

0.4

0.6

0.8

1.0

Prob

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Overall, by 96 weeks after achieving virological success, theprobability of virological rebound was 17.5%.

1046

96

Patients (N=1,671) followed after achieving VS regardless therapy changes or interruptions. Virological rebound definedas the first of 2 consecutive viremia values >50 copies/mL after achieving VS. VS: virological success.

1157

72

Rebound as the first of 2 consecutive HIV-RNA >50 copies/mL

Armenia D unpublished data October 2016

0 24 48 72 96

0.0

0.2

0.4

0.6

0.8

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148239

0

Prob

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p50 copies/mL after achieving VS. 500,000. HAART: highly active antiretroviral therapy. VS: virological success.

By 96 weeks after achieving virological success, patients having pre-HAARTviremia >500,000 copies/mL showed the highest probability of experiencingvirological rebound compared to other pre-HAART viremia ranges.

100-300K >500K200 copies/mL : 12%

Rebound as the first of 2 consecutive HIV-RNA >50 copies/mL: 17.5%

Armenia D unpublished data October 2016

The majority of virological rebounds showlow level viremia that represents one of themost frequent reasons of uncertainty inclinical decisions

Indeed…….

LLV & Time to next visit

Months to next visit

Ryscavage P et al., AAC2014

Definitions of virological failure

Viral blip

Ryscavage P et al., AAC2014

Low level viremia (LLV) and very low level viremia (VLLV)

Ryscavage P et al., AAC2014

>50-500 copies/ml

Residual viremia (80% of individuals had stable HIV-1viremia after 60 weeks of cART, with a median pVL of 3.1 copies/ml (range, 1 to49 copies/ml).

Shen, J Allergy Clin Immunol 2008

Ongoing virus replicationin sanctuary cellular orbody compartments due topoor drug penetration oractivity

Virus reactivation inlatently infected cells inresponse to stochasticantigenic stimulation, withpresence of HAARTensuring that new cellscannot be productivelyinfected

Two models to explain residual viraemia

It is possible that both mechanisms contribute to residual viremia

Residual Viraemia

Transient low level viremias, with plasma HIV-1 RNAlevels in the range of 50 to 400 copies/ml, have beenreported to occur in 25 to 40% of adults in whom viralreplication appeared to have been suppressed by HAART

Greub, G., A. et al. Intermittent and sustained low-level HIV viral rebound in patientsreceiving potent antiretroviral therapy. AIDS 2002Havlir, D. V., et al. Prevalence and predictive value of intermittent viremia withcombination HIV therapy. JAMA 2001Sklar, et al . Prevalence and clinical correlates of HIV viremia (‘blips’) in patients withprevious suppression below the limits of quantification. AIDS 2002Garcia et al. Episodes of low-level viral rebound in HIV-infected patients onantiretroviral therapy: frequency, predictors and outcome. AAC 2008

Time to virologic rebound according to the T0 viral load

VR: single VL>50 copies/mL VR: confirmed or last available viral load >50 copies/mL

Very low-level viremia (

Risk of virologic failure (confirmed viral load > 50 copies/ml) in the following 4 months for patients with an HIV-RNA < 3 copies/ml was 0.4% compared with a 3.2% risk for those with any value of low-level viremia (P < 0.0001; odds ratio 7.52, 95% CI from 3.8 to 15.0).

Linear relationship between the HIV-RNA level and risk of virological failure

Very low-level viremia (

Very low-level viraemia on HAART: significance and management

Doyle and Geretti, Curr Opin Infect Dis 2012

Residual viraemia (

Navarro et al. Antivir ther, 2016

HIV-RNA>200 copies/ml, PI/r-based dual therapy and PI/r monotherapy were associated with virological failure

Navarro et al. Antivir ther, 2016

What about viral blips?

Is their magnitude associated with virological failure?

Kaplan–Meier curves of time freeof virological failure for patientswith persistent virologicalsuppression and (a) very low levelviraemia (VLLV; (20–49copies/mL), (b) low-level viraemia(50–199 copies/mL) and (c) high-level blips (≥ 200 copies/mL).

Among patients who achieved full suppression at 200 copies/ml or one >200 copies/ml followed by a change of ART

Kaplan–Meier curves of time freeof virological failure for patientswith persistent virologicalsuppression and (a) very low levelviraemia (VLLV; (20–49copies/mL), (b) low-level viraemia(50–199 copies/mL) and (c) high-level blips (≥ 200 copies/mL).

Virological failure: 2 consecutive VLs >200 copies/ml or one >200 copies/ml followed by a change of ART

4.0% 1.7%

The incidence of virological failure was significantly higher in patients with transient viremic episodes > 200 copies/mL than in persistently suppressed patients

Teira et al., HIV Medicine 2016

When genotypic resistance test should be performed?

Low level viremias have been associated with selection of drug-resistant virus in several (but not all) studies

Cohen Stuart, et al. Transient relapses (“blips”) of plasma HIV RNA levels during HAART are associated with drugresistance. JAIDS 2001Greub, et al. Intermittent and sustained low-level HIV viral rebound in patients receiving potent antiretroviral therapy.AIDS 2002Gunthard, et al. Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in thesetting of potent antiviral therapy. J. Virol. 1999Hermankova, et al. HIV-1 drug resistance profiles in children and adults with viral load of

When genotypic resistance test should be performed?

In acute HIV infection

In ART-naive patients with chronic HIV infection

In patients with virologic failureDrug-resistance testing is recommended in patients on combinationART with HIV RNA levels >1,000 copies/mL (AI). In patients with HIVRNA levels >500 copies/mL but

In acute HIV infection

In ART-naive patients with chronic HIV infection

In patients with virologic failure

EACS, 2017

When genotypic resistance test should be performed?

In acute HIV infection

In ART-naive patients with chronic HIV infection

In patients with virologic failureDrug-resistance testing is recommended in patients on combinationART with HIV RNA levels >1,000 copies/mL (AI). In patients with HIVRNA levels >500 copies/mL but

8,342 genotypic requests from plasma samples of treatment experienced patients stratified by viremia and years. * Update to October 2013.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

>10000010001-1000001001-10000501-1000201-50051-200

N samples 751 551 670 798 951 836 784 553 561 581 495 442 369

Viremia ranks(copies/mL)

An increased number of GRTs have been requested over the years for patients failing with low viremia values

*

Santoro et al., update from CID 2014

GRT at low level viremia is reliable andresistance is detectable at all viremia levels!

96%

67%

88%93% 97% 99% 99%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall 51-200 201-500 501-1,000 1,001-10,000 10,001-100,000 >100,000

N Samples 12,828 769 489 444 2,435 4,845 3,846

Viremia Ranks (cps/mL)

Perc

ent o

f gen

otyp

ic s

ucce

ssOverall, the PR/RT genotyping success rate was 96%. Genotyping success was ≥88% above 200 HIV copies/mL. A reasonable chance of success was obtained

also between 50 and 200 copies/mL.

PR/RT Genotypic success rate according to different viremia ranks.Santoro et al., CID 2014

A considerable resistance is observed also at low levels of viremia

Prev

alen

ce o

f sam

ples

with

at

leas

t 1 M

RM

(%)

Viremia ranks (cps/mL)

N samples 3,895 396 287 242 1,102 1,212 656 P 100,000

73.96

52.8

70

74

86.1

76.7

63

DATASET_FULL

ID_PazienteIDSampledata_prelievoviremia_valorerangeVLdurataTA_mesiter_durataAnniN_regimiTOTPrimo_regimeNRTItotNNRTItotPitotNRTIregimenNNRTIregimenPIregimenBoostedUnboostedA62VD30ND67NE138AE138GE138KE138QE138RF116YF227CF77LG190AG190EG190SG48MG48VH221YI47AI47VI50LI50VI54AI54LI54MI54TI54VI84VK101EK101PK103NK103SK219EK219QK65RK70EK70RL100IL210WL74IL74VL76VL90MM184IM184VM230IM230LM41LM46IM46LN88DN88SP225HQ151MT215FT215YT69insT74PV106AV106MV108IV179LV32IV75IV82AV82FV82LV82SV82TY115FY181CY181IY181VY188CY188HY188LNRTI_resTOTNNRTI_resTOTPI_resTOT

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