Pemeriksaan Viral Load pada

Pasien dalam Terapi ARV dan

Konsep U = U

Evy Yunihastuti
Departemen Ilmu Penyakit Dalam FKUI/RSCM
Unit Pelayanan Terpadu HIV RSCM
TasP =
Treatment as
Prevention
• Lower microbial load = lower
infectivity
• First concept: AZT to prevent
perinatal transmission

Undetectable (plasma HIV RNA) =

Untransmissible (HIV to others)
 Goal of AntiretroviralC Treatment
Asymptomatic AIDS After ART
106 106
HIV RNA

CD4 lymphocyte count (cells per mm3)

HIV RNA
105 CD4 blood 105

HIV RNA copies per mL plasma

HIV RNA copies per mL plasma

CD4 blood
CD4 GIT
CD4 GIT 500
104 104

103 103
Normal

102 102
Limit of detection of commercial assays
10 0 10
9 12 1 2 3 4 5 6 7 8 9 10 11 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11
ks
Maximal durable of suppression
Years Weeks Years
Quasispecies diversity
Restoration of immune function
Viral suppression = undetectable viral load
• Undetectable: depends on lower limit of detection of viral
load testing
• HIV RNA < 40 copies/mL
• HIV RNA < 34 copies/mL
• HIV RNA < 20 copies/mL
CorrelationofPlasmaHIVRNA&HIVTransmissioninSexually
DiscordantCouples
Rakai, Uganda Thailand

Quinn et al., N Engl JMed, 2000; 342:921-929 Tovanabutra et al., JAIDS, 2002; 9:275-283-929.
Current antiretroviral therapy can not eradicate HIV
HIV infection is characterized by Antiretroviral therapy (ART) is capable of However, the virus
high levels of circulating viruses suppressing HIV to undetectable levels rebounds after
in the blood cessation of therapy

START STOP

ART
Circulating virus

Blips
Limit of detection

Time

Antiretroviral therapy is a long-life treatment

 Death of
mucosal
memory
CD4+ T cell

HIV reservoir Kahn JO, Walker BD. N Engl

J Med. 1998;339:33-39.
Phase of viral load decreasing

Patrick Ryscavage et al. Antimicrob. Agents Chemother. 2014

 INSPIRING : Virologic and Immunologic Results
in the ITT-E Population Through Week24

Modified FDA snapshot analysis (ITT-E)

Proportion of Participants With HIV-1
RNA <50 copies/mL, % (95% CI)
100
89 (79, 98)
81 (72, 90)
80
Percentage, %

60

40 DTG(n=69)
EFV(n=44) Median change from
20 Baseline CD4+ cell
count (Q1, Q3) at
0 Week 24: DTG, 146
cells/mm3 (71, 214);
-20 EFV 93 cells/mm3
-4 0 4 8 12 16 20 24 28 (47, 178)

Week
Dooley et al. CROI 2018
 HPTN 052 – Early vs.
Late ART for Sero-
Discordant HIV+ Partner

• Multinational randomized
controlled trial
• HIV+ partner with CD4 >350,
randomized to initiate or deferART

• 1,763 discordant couples enrolled

• Early ARTsignificantly reduced HIV
transmission to partner
• All transmissions occurred in those
who did not have viralsuppression
(either within 6 months of ARTor
had virologic failure)
Cohen et al NEJM 2011.
 HPTN 052 – Early vs. Total HIV-1 Transmission Events: 39
Late ART for Sero-
Discordant HIV+ Partner
Unlinked or TBD
Linked
Transmissions: 11
Transmissions: 28

Immediate Delayed
ART: 1 ART: 27

p < 0.001
One infection in immediate arm was soon after HAART

• 96% reduction in HIV transmission

Cohen et al NEJM 2011.

 • Prospective observational study from 14 European countries
• 1,166 HIV serodiscordant couples where HIV+ partner on
suppressive ART(HIV RNA< 200copies/mL)
• No condom use throughout observation period

The
Partner
Study

Rodger AJ, et al. JAMA 2016; 316(2): 171-61

 Opposite No linked infections

attract study 3 infections occurring during study contracted

from outside partners
• Any sex with outside partner: 40%
• international, prospective
cohort • Any CLAI with outside partner: 17%
• MSM serodiscordant couples
when HIV-infected partner on
ART and virologically
suppressed (N = 343 couples;
591 CYFU; 16,889 acts of CLAI)
• For HIV-infected partner, HIV-1
RNA undetectable for 95% of
CYFU

Bavinton BR. Lancet HIV 2018; 5: e438–47

 Linked HIV transmissions and incidence during
periods when CLAI was reported, viral load less
Opposite
20·0% of the couple-years of follow-up. Within-couple
than 200 copies per mL and PrEP not used

attract study
Linked Couple-years CLAI acts Upper limit of
CLAI was reported in 53·9% of the couple-years of trans- of follow-up one-sided
follow-up and the upper CI limit for within-couple missions 95% CI for
transmission for these periods was 1·16 per 100 couple- HIV incidence
years of follow-up. Only 5·8 couple-years of follow-up Overall 0 232·2 12 447 1·59
and 239 CLAI acts were not protected by condoms, daily Sexual position for CLAI
PrEP, or viral suppression (1·0% of the total couple-years Insertive CLAI 0 202·2 8081 1·82
of follow-up). Of 239 CLAI acts reported, 219 were when Receptive CLAI with withdrawal 0 102·6 1958 3·60
viral loads of HIV-positive partners were more than Receptive CLAI with ejaculation 0 66·7 2408 5·53
1000 copies per mL. Periods before an STI was diagnosed STIs*
in either partner accounted for 13·1% of couple-years of Any STI diagnosed (either partner) 0 21·1 948 17·48
follow-up, whereas periods in which the HIV-positive Any STI diagnosed (HIV-positive partner) 0 15·4 745 23·97
partner commenced ART since the last visit accounted Urethral STI diagnosed (HIV-positive partner)† 0 2·4 90 155·94
for 4·6% of couple-years of follow-up. Any STI diagnosed (HIV-negative partner) 0 8·95 381 41·23
Periods when within-couple CLAI was reported, viral Rectal STI diagnosed (HIV-negative partner)‡ 0 5·3 162 69·27
loads of HIV-positive partners were less than 200 copies Commencement of ART
per mL, and daily PrEP was not used by HIV-negative Started ART since last visit 0 6·1 145 60·07
partners accounted for 232·2 couple-years of follow-up Did not start ART since last visit 0 226·1 12 302 1·63
(39·5% of the total couple-years of follow-up). No linked
HIV transmissions were reported (table 5). Data are according to sexual behaviour, diagnosis of sexually transmitted infection (STI), and antiretroviral therapy
(ART). No linked transmissions occurred. CLAI=condomless anal intercourse. *STIs included were active syphilis, rectal
and urethral gonorrhoea, and rectal and urethral chlamydia. †Urethral STIs included were urethral gonorrhoea and
Discussion urethral chlamydia. ‡Rectal STIs included were rectal gonorrhoea and rectal chlamydia.
In this cohort study of serodiscordant male homosexual
Bavinton
Table 5: Linked HIV transmissions and incidence during BR. CLAI
periods when Lancet
was HIV 2018;
reported, 5:load
viral e438–47
less
couples, we found no phylogenetically linked HIV
than 200 copies per mL and PrEP not used
A Fauci 2018
 Virological response after ART

Early virologic failure

Virologic rebound
Viral load (failure)

1000 copies/mL

Persistent
low level viremia
40 copies/mL
Virologic blip
Virologic suppressed

Time
 Can we use CD4 for defining
C failure?
Asymptomatic AIDS After ART
106 106
HIV RNA

CD4 lymphocyte count (cells per mm3)

HIV RNA
105 CD4 blood 105

HIV RNA copies per mL plasma

HIV RNA copies per mL plasma

CD4 blood
CD4 GIT
CD4 GIT 500
104 104

103 103
Normal

102 102
Limit of detection of commercial assays
10 0 10
9 12 1 2 3 4 5 6 7 8 9 10 11 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11
ks Years Weeks Years
Quasispecies diversity
Antiretroviral failure

Resistance CD4 drop

Viral load
Non-
Adherence
Clinical
1 2 3 4 5

Started
HAART Time after treatment
 between these groups (P , 0.001), with the complete with an incr
responders having the best survival and the nonresponders complete res
having the worst survival (Fig. 2). 1.90 (95% CI

CD4 and viral load discordance

In multivariable analysis adjusted for age, clinical stage a HR of 2.00
and CD4 cell count at HAART initiation, occurrence of an a HR of 5.48
responses we
(Wald test P
independentl
for an increa
0.96). Having
• 20-40% on ART months of the
1.18 to 3.02)
• virologic-only responder variable inclu
the proportio
• immunologic-only The Co
responder in Table 3. A
correspondin
longer statist
immunologic
defining eve
HR for age
smaller samp
In a su
NNRTI-based
FIGURE 2. Kaplan–Meier curves of probability of survival a significant i
Tuboi, et al. JAIDS, 2007. Tuboi, et al. IAIDS 2010 (likelihood ra
according Mortality rate: ORof1.03
to categories (0.85 to 1.25),
immunologic and1.83 (1.36 to re-
virologic
sponses at2.45),
6 months in 7160
1.88 (1.32 patients
to 2.68) vs 3.72 in ART-LINC
(2.77 to 4.99). of IeDEA the hazard of
 CD4 decrease after viral supression
Ford N et al. Journal of the International AIDS Society 2015, 18:20061
http://www.jiasociety.org/index.php/jias/article/view/20061 | http://dx.doi.org/10.7448/IAS.18.1.20061

Number of CD4
Study Country patients declines (95% CI)

Philipps UK 166 0.15 (0.14, 1.31)

Stephan Multiple 230 0.11 (0.10, 0.95)

Girard Multiple 449 0.06 (0.05, 0.49)

Whitlock

Reynolds
UK

Uganda
141

1553
1.78 (0.26, 4.63)

0.51 (0.21, 0.93)

Overall incidence 0,35%
Ford

Davies
South Africa

South Africa
7250

5984
0.11 (0.04, 0.21)

0.64 (0.46, 0.86)

(IK 95% 0.18-0.55)
Chow Australia 744 0.02 (0.02, 0.22)

Duncan UK 392 0.90 (0.20, 2.08)

Kitizo Kenya 209 2.61 (0.90, 5.20)

Ahn Asia 1538 1.27 (0.77, 1.89)

Overall 0.35 (0.16, 0.55)

0 2 4 6
Percentage Ford N et al. Journal of the International AIDS Society 2015, 18:20061

Figure 2. Pooled proportion of virologically suppressed patients experienced an unexplained, confirmed CD4 decline.

analysis because CD4 declines were based on a single measure suppressed on ART are rare and mainly transient events, or
[4]. This estimate did not change if studies that reported explained by non-HIV factors. This suggests that, for patients
evel viremia 200-499 was
LLV
Low level viremia (50-1000) associated
did not impact on rates of AIDS o
ncreased risk ofIncreased
virologic failure
risk of virological failure in the future
Not increasing risk of AIDS progression or death

The Antiretroviral Therap

The Antiretroviral Therapy Cohort Collaboration (ART-CC) AIDS 2015 29:373-383
The Antiretroviral Therapy Cohort Collaboration (ART-CC) AIDS 2015 29:373-383
AIDS 2015 29:373-383
Pemantauan viral load

Rekomendasi
Pemeriksaan viral load rutin dilakukan
pada bulan ke 6 dan ke 12 setelah
memulai ARV dan berikutnya setiap 12
bulan (rekomendasi sesuai kondisi,
kualitas bukti sangat rendah).

PNPK HIV 2019

Apakah pemeriksaan cd4 sudah tidak
dibutuhkan lagi?
• Saat diagnosis HIV
• Menentukan indikasi profilaksis primer infeksi oportunistik
(kotrimoksasol)
• Menentukan saat menghentikan profilaksis infeksi oportunistik
• Membantu menentukan kecurigaan infeksi oportunistik
• Menentukan saat menghentikan pengobatan maintenance (profilaksis
sekunder) infeksi oportunistik:
• Kriptokokus: flukonazol hingga CD4 > 200 selama 3-6 bulan
• Toksoplasma ensefalitis: kotrimoksasol, pirimetamin klindamisin hingga CD4 > 200
selama 3-6 bulan
• CMV: setidaknya 3-6 bulan dan lesi telah inaktif dan jumlah CD4 > 100 selama 3-6
bulan
TasP =
Treatment as
Prevention