Is monitoring for CD4 counts still needed for the management of patients with long-term 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?

HIV RNA <50 copies/mL

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?

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

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)

• 689 ARV-naïve patients

• Viral load >5,000• No CD4 cell

count entry

Screening phase (2–4 weeks)

Treatment phase (192 weeks)

TDF = tenofovir; FTC = emtricitabine*Dosing and switch dependent on local regulatory approval and patient/investigator preference

SD = standard deviation; HBV = hepatitis B virus; HCV = hepatitis C virus

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)

Stratification factors CD4 cell count <200 cells/mm3, n (%) HIV-1 RNA, ≥100,000 copies/mL

141 (41.1)117 (34.1)

148 (42.8)120 (34.7)

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 follow-up, 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

0 20 40 60 80 100 120 140 1600

100

200

300

400

500

600

MONET: Patient with short-term CD4 decline <200

Weeks on treatment (HIV RNA <50 copies/mL)

CD4

countcells/uL

From baseline to Week 144, HIV RNA was <50 copies/mL. No change in treatment. CD4 percentage was in the range of 22-27% throughout the trial, except for a single result of 17% when the absolute CD4 count was also low.

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

HIV RNA

CD4 CD4 + RNA HIV RNA only?

BEFORE ART

ANTIRETROVIRAL TREATMENT

CD4 COUNT

HIV RNA

CD4 COUNT

CD4 CD4 + RNA HIV RNA onlyBEFORE

ARTANTIRETROVIRAL TREATMENT

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?