Is monitoring for CD4 counts still needed
for the management of patients with longterm HIV RNA suppression?
Andrew Hill,
Liverpool University, UK
Background
1. CD4 counts show which asymptomatic patients should be started on
antiretroviral treatment (<350 or <500 cells/µL in different guidelines)
2. People with low CD4 counts on ARV treatment need prophylaxis for
opportunistic infections – higher risk of AIDS
3. HIV RNA is much more sensitive than CD4 count, as a measure of treatment
failure.
4. HIV RNA also provides information on the risk of HIV transmission, drug
resistance and poor adherence
5. If a patient has CD4 counts above 200 cells/µL and HIV RNA <50 copies/mL,
what is the use of continued CD4 testing?
6. Can we monitor with HIV RNA alone during long-term antiretroviral treatment?
Will the CD4 counts always stay above 200 cells/uL,
while the HIV RNA is suppressed?
HIV RNA <50 copies/mL
Immuno-Virological discordance –
Do we still need CD4 testing?
HIV RNA <50 copies/mL
Methods
1. In the ARTEMIS trial, 689 antiretroviral treatment-naïve patients were
randomised to tenofovir/emtricitabine plus either darunavir/ritonavir (DRV/r)
800/100 mg once daily (n=343) or lopinavir/ritonavir (LPV/r) (n=346).
2. HIV RNA was evaluated using the Roche Amplicor Ultrasensitive assay.
3. CD4 counts were measured at baseline and every 12-16 weeks to Week 192.
4. The number of patients with CD4 counts above 200 copies/mL and HIV RNA
<50 copies/mL at Week 48 was assessed.
5. For these patients, we assessed whether CD4 counts fell below 200 cells/uL
from Week 48 to Week 192 on two consecutive visits, while HIV RNA
suppression was maintained.
ARTEMIS study design
Screening phase
(2–4 weeks)
• 689 ARV-naïve
patients
• Viral load >5,000
• No CD4 cell
count entry
Treatment phase (192 weeks)
DRV/r 800/100mg qd
+ TDF 300mg and FTC 200mg (n=343)
LPV/r 400/100mg bid or 800/200mg qd*
+ TDF 300mg and FTC 200mg (n=346)
TDF = tenofovir; FTC = emtricitabine
*Dosing and switch dependent on local regulatory approval and patient/investigator preference
Baseline demographics and disease
characteristics
DRV/r
(n=343)
LPV/r
(n=346)
Baseline demographics
Female, n (%)
Mean age, years (SD)
Caucasian, n (%)
Black, n (%)
Hispanic, n (%)
Asian, n (%)
104 (30.3)
35.5 (9.23)
137 (40.1)
80 (23.4)
77 (22.5)
44 (12.9)
105 (30.3)
35.3 (9.22)
153 (44.5)
71 (20.6)
77 (22.4)
38 (11.0)
Disease characteristics
Mean baseline log10 HIV-1 RNA, copies/mL (SD)
Median CD4 cell count, cells/mm3 (range)
HBV/HCV co-infection, n (%)
4.86 (0.64)
228 (4–750)
43 (12.5)
4.84 (0.60)
218 (2–714)
48 (13.9)
141 (41.1)
117 (34.1)
148 (42.8)
120 (34.7)
Stratification factors
CD4 cell count <200 cells/mm3, n (%)
HIV-1 RNA, ≥100,000 copies/mL
SD = standard deviation; HBV = hepatitis B virus; HCV = hepatitis C virus
ARTEMIS: responders and non-responders
 There were 520 / 689 patients with HIV RNA <50 copies/mL and CD4 counts
above 200 cells/uL at Week 48
 At Week 48 the response rate was 262/343 (76%) in the DRV/r arm and
258/346 (75%) in the LPV/r arm.
 482/520 patients (93%) had follow up data on CD4 counts and HIV RNA for
Weeks 49-192.
ARTEMIS: responders and non-responders
____________________________________________________________________________________
Baseline characteristic
Responders
Non-responders
n=520
n=169
____________________________________________________________________________________
Age, years (median, IQR)
34 (28-42)
34 (28-40)
Sex (% male)
70%
68%
Race (% Caucasian)
43%
41%
Baseline CD4 count (median, IQR)
247 (171-341)
135 (55-248)
Log10 BL HIV RNA (median, IQR)
4.8 (4.4–5.2)
4.9 (4.6–5.4)
Progression to AIDS before Week 48
5 (1.0%)
19 (11.2%) *
____________________________________________________________________________________
* p=0.001, Fisher’s exact test.
ARTEMIS: lowest CD4 counts from Week 49-192, for
patients with HIV RNA <50 copies/mL at Week 48
(no HIV RNA elevations >400 during follow up)
_________________________________________________________________________
CD4 count
Lowest CD4 count on two consecutive visits, Week 49-192
At Week 48
<200
200<349
350-499
>=500
_________________________________________________________________________
200-349 (n=137)
4 (3%)
95 (69%)
35 (26%)
3 (2%)
350-499 (n=174)
1 (0.6%)
15 (9%)
109 (62%)
49 (28%)
>=500 (n=138)
0
0
21 (15%)
117 (85%)
_________________________________________________________________________
ARTEMIS: lowest CD4 counts from Week 49-192, for
patients with HIV RNA <50 copies/mL at Week 48
(with HIV RNA elevations >400 during follow up)
_________________________________________________________________________
CD4 count
Lowest CD4 count on two consecutive visits, Week 49-192
At Week 48
<200
200<349
350-499
>=500
_________________________________________________________________________
200-349 (n=17)
2 (12%)
13 (77%)
1 (6%)
1 (6%)
350-499 (n=10)
0
1 (10%)
8 (80%)
1 (10%)
>=500 (n=6)
0
2 (33%)
2 (33%)
2 (33%)
_________________________________________________________________________
ARTEMIS: AIDS defining events during follow-up
 Among the 482 responder patients with data to Week 192, 6 (1.2%)
progressed to AIDS between Weeks 49-192.
 Only 1 of these patients had a confirmed reduction in CD4 count below 200
cells/uL at the time of AIDS diagnosis (lymphoma). This patient had CD4
counts above 200 cells/uL in the visit before lymphoma was diagnosed.
 The other 5 patients had CD4 counts above 200 cells/uL at the time of
diagnosis of new AIDS events (Pulmonary TB and oesophageal candidiasis).
HIV RNA <50 copies/mL
Limitations of the ARTEMIS trial analysis
 Patients can take longer than 48 weeks to show rises in CD4 count above 200
cells/uL by Week 48
 There is limited statistical power to evaluate progression to AIDS
 Patients could discontinue the trial after virological failure – limited follow up on
second-line treatments
US Veteran Affairs Study
 1820 patients in the Washington Veteran Affairs cohort study, on antiretroviral
treatment (1998-2011)
 Patients with HIV RNA <200 copies/mL and CD4 counts >=300 cells/uL had a
97.1% probability of maintaining durable CD4 >=200 cells/uL for four years.
 When non-HIV causes of lymphopenia were excluded, the probability rose to
99.2%.
 The results supported less frequent monitoring of CD4 during viral suppression
Gale et al. CID 2013 online
MONET trial - lowest CD4 counts during 144 week followup, in the MONET Trial (HIV RNA <50 c/mL at baseline)
1
Lowest CD4 counts during three-year follow up, for patients with HIV RNA <50 copies/mL at baseline
in the MONET trial
Mean of screening
Lowest CD4 counts over three years:
and baseline CD4 counts
<200
200-350
350-500
>500 cells/µL
<200 cells/µL (n=1)
1 (100%)
0
0
0
200-350 cells/µL (n=22)
1 (4.5%)
17 (77.3%)
4 (18.2%)
0
350-500 cells/µL (n=60)
1 (1.7%)
7 (11.7%)
46 (76.7%)
6 (10.0%)
>500 cells/µL (n=148)
0
2 (1.4%)
20 (13.5%)
126 (85.1%)
______________________________________________________________________________________
Stephan et al. JAIDS 2012, 61: e73-e75
MONET: Patient with short-term CD4 decline <200
From baseline to Week 144, HIV RNA was <50 copies/mL.
No change in treatment. CD4 percentage was in the range of 2227% throughout the trial, except for a single result of 17% when
the absolute CD4 count was also low.
600
500
400
CD4
count
cells/uL
300
200
100
0
0
20
40
60
80
100
120
140
160
Weeks on treatment (HIV RNA <50 copies/mL)
Stephan et al. JAIDS 2012, 61: e73-e75
Royal Free cohort, London
Follow-up of 166 patients on antiretroviral therapy with HIV RNA <50 copies/mL
and CD4 counts above 500 cells/µL
Only five of the 166 patients (3%) showed a decline in CD4 count <350 cells/µL
during 47 weeks of follow up. All were isolated reductions:
_________________________________________________________________________
Patient Baseline
Low visit
Follow up visit
_________________________________________________________________________
1
532
262
374
2
740
330
705
3
650
331
792
4
560
347
392
5
642
349
404
_________________________________________________________________________
Phillips et al. AIDS 2002, 16: 1073-1075
German ClinServ Cohort
Risk of AIDS measured for patients with HIV RNA <50 copies/mL but CD4 count
still below 200 cells/µL while on antiretroviral treatment. 5038 patient-years of
follow up. The risk of AIDS events was very low for patients with at least two
years of HIV RNA suppression, even if the CD4 count was below 200 cells/µL
Zoufaly et al. J Infect Dis 2011, 203: 364-371
BEFORE ART
CD4
HIV RNA
CD4 COUNT
ANTIRETROVIRAL TREATMENT
CD4 + RNA
HIV RNA only?
BEFORE ART
CD4
HIV RNA
CD4 COUNT
CD4 + RNA
ANTIRETROVIRAL TREATMENT
HIV RNA only
Conclusions
 In the ARTEMIS and MONET trials, there was no added benefit to testing for
CD4 counts for patients whose CD4 counts were above 200 cells/µL and who
had full HIV RNA suppression after 48 weeks of first-line treatment.
 Continued full HIV RNA suppression could therefore be used as an alternative
surrogate marker for sustained elevations in CD4 count.
Questions still to be answered:
 If HIV RNA rebounds on treatment, when should we re-start CD4 counting?
HIV RNA >10,000? (PLATO cohort).
 Does this strategy of stopping CD4 testing need to be evaluated in larger
cohort studies?