Catherine KoberMargaret Johnson

Martin FisherCaroline Sabin

On behalf of UK-CHICBHIVA/BASHH Manchester 2010

Non-uptake of HAART among patients with a CD4 count <350 cells/mm3 - UK

Collaborative HIV Cohort (CHIC)

BACKGROUND Since the introduction of highly active antiretroviral therapy (HAART)

in 1996, treatment guidelines have evolved in terms of the CD4 count at which HAART should be initiated

Current British HIV Association (BHIVA) guidelines (2008) recommend that all patients with a confirmed CD4 count <350 cells/mm3 are offered HAART

In previous UK CHIC analyses, based on data up to 2003, only 50-60% of patients with a CD4 count <200 cells/mm3 and 10-15% with a CD4 count of 200-350 cells/mm3 initiated HAART in the following 6 months

BACKGROUND

BACKGROUND To determine whether since the last UK-CHIC analysis, in 2004, the

proportion of patients commencing HAART after a confirmed CD4 count < 350 cells/mm3 has improved

To identify factors associated with initiation (or not) of HAART after confirmed CD4 decline to <350 cells/mm3

AIMS

BACKGROUND Patients > 18 years of age in UK-CHIC included if:

Confirmed (2 consecutive) CD4 counts <350 At least 1 day of subsequent follow-up No previous ART

HAART: any regimen including a PI, NNRTI, abacavir or enfuvirtide

First analysis: all patients in UK-CHIC (1996 onwards)

Second analysis: patients with first confirmed CD4 <350 after 2004 More than 6 months of follow-up At least 1 clinic visit in 2007-2009

METHODS

BACKGROUND Characteristics at time of first confirmed CD4<350 (baseline) and

over follow-up were compared to identify factors associated with delayed HAART uptake

Demographic factors: gender, risk group, ethnicity Clinical: previous AIDS diagnosis Laboratory: CD4 count, viral load, frequency of CD4 monitoring

(as surrogate of clinical attendance)

Analyses used proportional hazards regression with fixed (sex, age, risk group, ethnicity, AIDS, baseline CD4) and time-updated (frequency of CD4 measurement, % of CD4<350) covariates

ANALYSIS

17,153 patients presented with their first confirmed low CD4 count <350cells/mm3 between 1996 and 2008

Of this group 14,780 (86.2%) of patients initiated HAART a median of 5.1 months after the first confirmed low CD4 count

RESULTS

Uptake of HAART in patients with a confirmed CD4 count <350 cells/mm3, stratified by calendar year

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1996-1997 1998-1999 2000-2001 2002-2003 2004-2005 2006-2008

Year of first confirmed CD4 <350cells/mm3

Init

iati

on

of

HA

AR

T

Never started, >6 mo follow-up

Started subsequently

Started in first 6 months

Never started, but <6 mo follow-up

17,153 patients presented with their first confirmed low CD4 count <350cells/mm3 between 1996 and 2008

Of this group 14,780 (86.2%) of patients initiated HAART a median of 5.1 months after the first confirmed low CD4 count

RESULTS

Uptake of HAART in patients with a confirmed CD4 count <350 cells/mm3, stratified by calendar year

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1996-1997 1998-1999 2000-2001 2002-2003 2004-2005 2006-2008

Year of first confirmed CD4 <350cells/mm3

Init

iati

on

of

HA

AR

T

Never started, >6 mo follow-up

Started subsequently

Started in first 6 months

Never started, but <6 mo follow-up

17,153 patients presented with their first confirmed low CD4 count <350cells/mm3 between 1996 and 2008

Of this group 14,780 (86.2%) of patients initiated HAART a median of 5.1 months after the first confirmed low CD4 count

RESULTS

Uptake of HAART in patients with a confirmed CD4 count <350 cells/mm3, stratified by calendar year

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1996-1997 1998-1999 2000-2001 2002-2003 2004-2005 2006-2008

Year of first confirmed CD4 <350cells/mm3

Init

iati

on

of

HA

AR

T

Never started, >6 mo follow-up

Started subsequently

Started in first 6 months

Never started, but <6 mo follow-up

17,153 patients presented with their first confirmed low CD4 count <350cells/mm3 between 1996 and 2008

Of this group 14,780 (86.2%) of patients initiated HAART a median of 5.1 months after the first confirmed low CD4 count

RESULTS

Uptake of HAART in patients with a confirmed CD4 count <350 cells/mm3, stratified by calendar year

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1996-1997 1998-1999 2000-2001 2002-2003 2004-2005 2006-2008

Year of first confirmed CD4 <350cells/mm3

Init

iati

on

of

HA

AR

T

Never started, >6 mo follow-up

Started subsequently

Started in first 6 months

Never started, but <6 mo follow-up

11,534 patients satisfied the following criteria: first confirmed low CD4 count <350cells/mm3 between 1996 and 2008 At least 6 months follow-up At least one attendance during 2007-2009 (when BHIVA guidelines

available advising treatment commenced for all patients with CD4<350cells/mm3

657 (5.6%) of patients had still not commenced HAART by the time they were last seen

Patient remaining off HAART: had a median last available CD4 count 320 (IQR 258, 390) cells/mm3 Among this subgroup, last CD4 count was:

RESULTS - Patients remaining under follow-up in 2007-2009

CD4 count (cells/mm3) No. of patients

<50 15 (3.6%)

50-99 8 (1.9%)

100-149 20 (4.8%)

150-199 36 (7.2%)

200-249 69 (16.6%)

250-299 113 (27.2%)

300-349 155 (37.3%)

Characteristics of patients started on HAART:

more likely to have experienced a previous AIDS diagnosis 15.1% vs 4.6% p=0.0001

had a lower first confirmed CD4 count <350cells/mm3 median value 216 (IQR 99, 290) vs 300 (IQR 260, 324) p=0.0001

had a longer duration of follow-up (months) after their low CD4 count

median 62.5 (IQR 31.4, 101.1) vs 24.1 (IQR 12.7, 45.3) p=0.0001

attended clinic more frequently total number of CD4 count measurements following confirmed low

count - median 21 (IQR 12, 33) vs 10 (IQR 5, 19) p=0.0001 mean time interval (days) between consecutive CD4 measures

following confirmed low count – median 96 (IQR 77, 119) vs 114 (IQR 86, 161) p=0.0001

RESULTS - Patients remaining under follow-up in 2007-2009

Graph showing the percentage of patients commenced on HAART by their last clinic visit in 2007-2009 stratified by year in which their first low CD4 count was recorded. All patients had >6 months follow-up

RESULTS - Patients remaining under follow-up in 2007-2009

Percentage of patients who had or had not started HAART prior to their last visit

in 2007-2009 - Year of first confirmed CD4 <350cells/mm3

70%

80%

90%

100%

1996/1997 1998/1999 2000/2001 2002/2003 2004/2005 2006-2008

Not started HAART

Started HAART

RESULTS - Patients with first low CD4 in 2004-2008

5613 patients were identified as having had a confirmed low CD4 <350 cells/mm3 from 2004-2008

Of these, 534 (9.5%) had not started HAART by the time of their last clinic visit in 2007-2009

Median baseline CD4 for the whole cohort was 230 [IQR 117, 300] cells/mm3

HAARTStarted Not started p-value

Number of patients 5079 534Female sex 1343 (26.4) 118 (22.1) 0.03Risk group MSM 2493 (49.1) 316 (59.2)

IDU 102 (2.0) 13 (2.4)Heterosexual 1978 (38.9) 144 (27.0)

Other/not known 506 (10.0) 61 (11.4) 0.0001Ethnicity White 2601 (51.2) 295 (55.2)

Black African 1532 (30.2) 106 (19.9)Other 635 (12.5) 75 (14.0)

Not known 311 (6.1) 58 (10.9) 0.0001Age (years) at confirmed low CD4 count

Median (IQR) 36 (31, 42) 34 (29, 41) 0.0001

Previous AIDS 546 (10.8) 22 (4.1) 0.0001First confirmed CD4 count <350 (cells/mm3)

Median (IQR) 220 (106, 290) 300 (261, 325) 0.0001

Follow-up time (months) after confirmed low count

Median (IQR) 29.2 (15.4, 43.2) 19.6 (10.7, 32.7) 0.0001

Time (days) between first and second CD4 <350 cells/mm3

Median (IQR) 43 (21, 85) 79 (30, 126) 0.0001

Total number of CD4 count measurements following confirmed low count

Median (IQR) 12 (7, 18) 9 (5, 16) 0.0001

% of these CD4 measures that were <350 cells/mm3

Median (IQR) 60 (35, 93) 50 (31, 80) 0.0001

Mean time interval (days) between consecutive CD4 measures following confirmed low count

Median (IQR) 86 (67, 109) 108 (80, 149) 0.0001

RESULTS - Patients with first low CD4 in 2004-2008 - Baseline covariates:

AdjustedFactor RH (95% CI) p-valueAverage of last two CD4 measurements /50 cells/mm3 higher 0.56 (0.54, 0.57) 0.0001Number of CD4 counts after confirmed low value that are <350 cells/mm3

/count 1.16 (1.14, 1.18) 0.0001

Sex/risk group MSM 1.08 (0.98, 1.20) 0.13Male heterosexual - -

Female heterosexual 1.10 (1.00, 1.21) 0.04IDU 0.69 (0.56, 0.87) 0.001

Male Other 0.82 (0.72, 0.94) 0.005Female Other 0.76 (0.64, 0.91) 0.003

Ethnicity White 1 -Black African 0.85 (0.72, 0.99) 0.03

Other 1.06 (0.97, 1.15) 0.23Not known 0.76 (0.62, 0.93) 0.008

Previous AIDS 1.01 (0.92, 1.11) 0.83Age /10 years older 1.11 (1.07, 1.14) 0.0001First confirmed low CD4 count /50 cells/mm3 higher 1.22 (1.18, 1.25) 0.0001Calendar year of confirmed low count 2004 1 -

2005 1.16 (1.06, 1.26) 0.0012006 1.37 (1.26, 1.50) 0.00012007 1.62 (1.48, 1.78) 0.00012008 2.31 (2.08, 2.55) 0.0001

RESULTS - Patients with first low CD4 in 2004-2008

Results of multivariable proportional hazards regression analysis of factors associated with uptake of HAART (Fixed + time-updated covariates)

After controlling for fixed and time-updated covariates, independent predictors for initiation of HAART included: Older age of patient (RH /10 years older 1.11 [1.07, 1.14]) A lower average CD4 count when considering the last two

measurements taken (RH /50 cells/mm3 higher 0.56 [0.54, 0.57]) A greater number of CD4 counts <350 cells/mm3 (RH /count 1.16 [1.14,

1.18]) Risk group: Female heterosexuals (RH 1.10 [1.00, 1.21]) were more

likely to start

Intravenous drug users remained less likely to start HAART (RH 0.69 [0.56, 0.87])

The association with the baseline CD4 count was reversed in the final analysis (RH /50 cells/mm3 higher 1.22 (1.18, 1.25)

RESULTS - Patients with first low CD4 in 2004-2008

Discussion

Patients presenting with first low CD4 count <350cells/mm3 between 1996 and 2008

No real change in percentage of patients commencing therapy within the first 6 months after their low confirmed count over the years

58.2% of patients commenced treatment within 6 months in 1998-1999 compared with 61% in 2006-2008

A significant minority (5.6%) patients remain HAART naïve having presented with their first low CD4 count between 1996 and 2008

0.7% of patients remain HAART naïve having been diagnosed in 1996/199711.8% of patients remain HAART naïve having been diagnosed in 2006-2008

Possible reasons for this - Clinician factors: feel no rush to start, especially if CD4 count just less than 350cells/mm3

Patient factors: takes >6 months to prepare/persuade patients that it is time to start. ?more reluctance to start straight away since guidelines changed to recommend life-long therapy (with no treatment breaks)

Limitations

Unable to determine whether HAART was offered and declined or whether HAART was not offered

Unable to determine whether co-morbidity (e.g. MTB or other OI) may have driven decision not to recommend HAART

Unable to determine if HAART was subsequently commenced at a non UK-CHIC site

Despite clear guidance regarding appropriate CD4 count below which to commence HAART, there remains a small but significant proportion of patients with a CD4 below this level who are treatment naïve.

Whilst it is not possible to state reasons for this, certain demographic groups are disproportionately affected

If there is a further shift towards earlier initiation of treatment (as in USA) these trends may become even more marked

Conclusion

Within UK-CHIC: Analysis of those with CD4 >400 and >500 at diagnosis, with

Kaplan Meier of proportion remaining HAART naïve (as in Stohr 2007) with comparison by calendar year

Analysis by treatment centre (anonymised) to tease out clinician versus patient factors

With other cohorts: Comparison to other countries (?especially USA)

Outside of UK-CHIC: Greater understanding of barriers to initiation within guidelines RCT of intervention for “treatment refusers”

Possible Future Analyses