Paziente con fallimento a basso numero di

copie (50-400)

Patogenesi delle basse viremieL. Sarmati - Roma

Viremia a basso numero di copie50-400 - definizione

Low Level Viremia (LLV) defined as values of plasma HIV-RNA between 50 and 400 copies/ml (while on therapy)

(A viral blip was defined as an HIV RNA value of 50 to 999 copies/mL preceded and followed by values <50 copies/mL.)

0

10

20

30

40

50

60

70

80

90

100

<2 <5 <10 <15 <20 <30 <40 <50 >50 >100 >500

Detection of viral load by ultrasensitive method in 420 patients with <50 HIV-RNA copies/ml

% o

f pa

tient

s

HIV-RNA copies/ml of plasma

2012

Transient

low level

viremia

(50 to 500

copies/ml)

10%

Very low level

viremia 20%Residual

viremia

40%

Undetect

30%

……….. According to current treatment guidelines there is little distinction between this definition of LLV and virologic failure even for treatment-experienced patients (which questions whether distinguishing between LLV and virologic failure is, in fact, clinically relevant)………..

Calvin Cohen

HIV Clin Trials 2009

Isolated blips (..transiently …HIV RNA <400 copies/mL) are not predictive of virologic failure

The association between persistently LLV(HIV RNA <200 copies/mL) and virologic failure is

conflicting. ….. This guidelines and the ACTG.. define virologic failure as a confirmed viral load >200

copies/mL

2016

Virological failure: incomplete virological response after commencingtreatment or evidence of confirmed virological rebound to >200 copies/mL.

Hofstra LM, et al 2014

Low-level viremia is often preceded by positive VL results; in 50% of these patients HIV-RNA was detected in all VL determinations in the preceding year, compared to only 3% of patients with a sustained suppressed VL (p<.0001)

16 patients ART with low-level viremia (persistent VL of 50–1000 copies/mL); 77 with a blip, 79 controls (<50 copies/mL since start therapy)

Claudie Laprise et al. Clin Infect Dis. 2013;57:1489-1496

Cumulative incidence of virologic failure defined as a human immunodeficiency virus load of >1000 RNA copies/mL) over 3 years, ccording to 6-month viral load persistence status stratified by periods of persistence evelopment. Abbreviation: LLV, low-level viremia.

Ongoing replication/ production of virus particles from reservoir

Inflammation and impact on immune status

Adherence to ARV and emerging of resistance

Viremia a basso numero di copie50-400 – patogenesi

Tobin NH, et al. JOURNAL OF VIROLOGY 2005

All children and adolescents in Seattle Children’s Hospital with HIV-1 plasma RNA <50 c/ml after 1 year of suppressive HAART.>1 or more episode of intermittent LLV (HIV-1 RNA between 50 and 400). Multiple LLV. Virologic failure: 2 consecutive RNA of 400 c/ml or a single RNA of 1,500 c/ml.

LLV in 21/37 (57%) sequenziamento e l’analisi filogenetica su 8/11: 6 identical sequences of PBMC preterapia, 3 drug resistant strain

(i) production of virus particles from long-lived cells infected months to years prior to initiation of HAART and (II) low-level viral replication with selection of new mutants with outgrowth of HIV-1 resistant to antiretroviral agents.

Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4+ T Cell Activation during Antiretroviral Treatment Gannella S., J Virol. 2014

HIV Type 1 Accumulates in Influenza-Specific T Cells in Subjects Receiving Seasonal Vaccination in the Context of Effective Antiretroviral Therapy .Jones& Ostrowski, AIDS RESEARCH AND HUMAN RETROVIRUSES 2012

• Inflammation and impact on immune status

Viremia a basso numero di copie50-400 – conseguenze

Study Patients and characteristics Association withLLV persistence

Mavigner et al. 2009* 23 pts, vl<50 poor immunological thosewith 1-10 cps HIV-RNA

YES

Hatano H, 2012 190 pts, CD38/HLA-DR CD4+ and vl 50-150 NO

Taiwo et al 2013 1861 pts (ACTG A384, ALLRT), pre-postCD38/HLA-DR on CD8+ and vl 50-400 cps

NO

Zheng L et al 2014 527 pts, CD38/HLA-DR CD8+ and vl 51-200 (26 pts)

YES

Saison J et al 2014 87 pts vl 40-49, CD38/HLADR CD8+ NO

*Mavigner PloS One 2009, 4: e7658, Hatano JID 2012, Taiwo et al J AIDS 2013, 63, 101, ZenghJAIDS 2014, 67, 153, Saison J Clin Exp Immu 2014, 176, 401

Immunologic outcomes stratified by treatment response. (a) % of activated (CD38/HLA-DR) CD4 and CD8 T cells in patients with suppressed, intermittent, and persistent viremia.

. (b) The magnitude of the HIV-specific (Gag, Pol, Env, Nef, Tat and Rev) CD8 T-cell responses among patients with durable suppression of viremia compared to patients with intermittent viremia, stratified by the plasma HIV RNA level at the time of the ELISPOT assay. Significant differences (P < 0.05) between those with durable suppression and the other patient groups are indicated (*P < 0.05; **P < 0.01).

13

Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia

Karlsson, AC et al, AIDS 2004.

Chad J. Achenbach et al. 2014

Hypothetical time course of CSF viral blips, neuroinflammation, and neuronal

injury

Chen MF Curr Opin HIV AIDS 2014

• Adherence to ARV and Emerging of resistance

Viremia a basso numero di copie50-400 – conseguenze

Christina Konstantopoulos et al. CID 2015

37/128 REACH participants were found to have an episode of LLV after at least 3 months of virologic suppression. In multivariable Cox proportional hazard analysis, ART adherence over the past 3 months was associated with risk of LLV (P = .050).

Research on Access to Care in the Homeless cohort

January 2014

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 drug resistance. JAIDS 2001.

Greub, et al. Intermittent and sustained low-level HIV viral rebound in patients receiving potent antiretroviral

therapy. AIDS 2002

Gunthard, et al. Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular

reservoirs in the setting of potent antiviral therapy. J. Virol. 1999.

Nettles, et al. Intermittent HIV-1viremia (blips) and drug resistance in patients receiving HAART. JAMA

2005.

Sklar, et al . Prevalence and clinical correlates of HIV viremia (‘blips’) in patients with previous suppression

below the limits of quantification. AIDS 2002.

Kieffer, et al. Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without

evolution in treated adults with undetectable HIV loads. J. Infect Dis. 2004.

Mackie N et al. Detection of HIV-1 antiretroviral resistance from patients with persistently low but detectable

viraemia. J Virol Methods 2004; 119:73–81

Mackie NE, Phillips AN, Kaye S, et al. Antiretroviral drug resistance in HIV-1-infected patients with low-level

viremia. J Infect Dis 2010; 201:1303–1307

Delaugerre, et al. Selection of Drug-resistance Mutations at Low Level of HIV-1 Viral Replication in ART-

treated Patients. CROI 2012, Paper # 347.

Gonzalez-Serna A et al. Performance of HIV-1 Drug Resistance Testing at Low Level Viraemia and

Its Ability to Predict Future Virologic Outcomes and Viral Evolution in Treatment-Naive Individuals. CID

2014.

Santoro MM et al. Reliability and Clinical Relevance of the HIV-1 Drug-Resistance Test in Patients

with Low Viremia Levels. CID 2014

Antivir Ther. 2015

54 soggetti/virus studiati prima di ARV e dopo LLV sia nei siti genetici di DRM che non-DRM. Persistent LLV was defined as at least two VLs > 50 and < 1000 copies/mLover a 24-week . 20/54 (37%) developed DRM

Greater HIV-1 evolution from the pre-ART to the final sequence of LLV in subjects who developed DRMs compared to subjects who did not develop DRM driven

Among subjects with emergent DRM, those with DRM detected at VL > 200 copies/mLhad much greater sequence changes compared to those with DRM detected at VL < 200 copies/mL.

The magnitude of LLV was the primary driver of evolutionary rate at DRM as well as non-DRM sites

0.001

0.01

0.1

1

10

100

1000

10000

100000

1000000

0 5 10 15

Time on ART (years)

Limit of detection (50 c/ml)

Start

HAART

Residual viremia

0.001

0.01

0.1

1

10

100

1000

10000

100000

1000000

Replication-competent viruses Defective viruses

HIV-DNA load

Low Level viremia

Loredana Sarmati, Current HIV Research, 2015

Current available observational evidence indicates that patients with blips exceeding 500 copies/mL and patients with persistent viral loads above 50 copies/mLhave a higher risk of virologic failure.

In these patients it is more likely that viral replication occurred with subsequent risk of selection of drug resistant variants (therefore a regimen switch after assessing present drug resistance should be highly considered).

Viremia a basso numero di copie(50-400) – conclusioni

Statement 1

Uptoday, LLV pathogenesis of is not completely defined. Mechanisms of active replication and emptying of reservoirs both seem to contribute to its development. However, the correlation between persistent LLV and virologic failure lays for the presence of active viral replication at the base of this phenomenon

Viremia a basso numero di copie

50- 400: patogenesi

Statement 2The presence of LLV is not always associated with

virologic failure, however some studies associated LLV with the emergence of drug resistance mutation and this phenomenon was positively associated with higher HIV-1 RNA levels during LLV

Viremia a basso numero di copie

50- 400: patogenesi

Statement 3A direct correlation between immune activation and development of LLV was not recognized while there is an evidence of a correlation between LLV and the increase/persistence of immune activation and reduction in the number of CD4 lymphocytes

Viremia a basso numero di copie

50- 400: patogenesi