A poster at IAS2009 by Nick Paton and the INSIGHT SMART Study Group presented long-term follow-up data from the SMART study on biomarkers associated with mortality. [1] This analysis extended an earlier nested case-controlled study of the association between biomarkers and mortality.

The earlier study identified all 85 patients who had died up to 11 January 2006, ie the date that enrollment into SMART was stopped. Each death was matched to two controls by country, age, gender and randomisation date. The study evaluated four inflammatory markers, hsCRP (C-reactive protein measured using the highly sensitive test), interleukin-6 (IL-6), Serum amyloid A and serum amyloid P. It also examined three coagulation markers, D-dimer, PA1-1 and Prothombin fragment 1+2 (F1.2). Three markers, hs-CRP, IL-6 and D-dimer, were found to have a statistically significant association with mortality on both adjusted and unadjusted odd ratios.

Table 1: Case-controlled odd ratios by baseline biomarker levels

The extended analysis reported at IAS2009 included all deaths up to 11 July 2007 in order to determine whether the association between these biomarkers and mortality persists. There were 167 deaths in the SMART cohort up to that point, 85 before the protocol modification (to offer all patients continuous treatment) and 82 post-modification. For this analysis, the deaths were however divided into early (<=2 years after randomisation, n = 95) or late (>2 years, n = 71). Two cases were matched to each death as in the baseline study. The baseline values of two of the three biomarkers (IL-6 and D-dimer) continued to be statistically significant predictors of late deaths and there was a trend for CRP to be a predictor of late deaths (see Table 2).

Table 2: Baseline biomarker levels and risk of death

* 4th/1st quartile

Greater predictors of risk than other factors

Table 3 shows some of the other risk factors for deaths that have been found in SMART (note that where p-values show non-significance, the factor can still be significant when the early and late groups are counted together).

Table 3: Risk factors associated with mortality in SMART

The authors noted that IL-6, hs-CRP and D-dimer are associated with greater risk of mortality than smoking and diabetes and about an equivalent risk of prior cardiovascular disease. They conclude that interventions to decrease inflammatory and coagulation pathway activation may be of long-term benefit for people with HIV.

COMMENT

The association between mortality and hs-CRP, IL-6 and D-dimer is significant, even after long-term follow-up and the termination of the structured treatment interruption arm. This highlights the importance of further research on whether anti-inflammatory medicines will have an additional role in HIV management of high-risk patients.

It would be interesting to know the association between these biomarkers and mortality is in the uninfected population. If they are similarly prognostic, then the question is how much of the associations seen in SMART are HIV-specific.

The role of early HAART in mitigating the association with mortality also needs to be determined.

References

1. Paton N. Association between activation of inflammatory and coagulation pathways and mortality during long-term follow up in SMART. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-22 July 2009, Cape Town. Oral abstract MOPEA034.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3388

People who are newly diagnosed with HIV, commonly expect to delay HAART for 5-8 years. However, the UK Register of Seroconverters has previously reported that at least a quarter of patients may need to start treatment within two years of infection. In a review of this cohort published in AIDS in January 2008, the median time from seroconversion to HAART initiation was 5.0 years but the IQR was 2.1 to > 10 years. The 25th percentile of time to starting HAART was 2.0, 2.0, 2.0 and 1.4 years in 1998-1999, 2000-2001, 2002-2003 and 2004-2006, respectively. [1]

This was also a conservative analysis as it excluded patients who started treatment within six months of infection due to complications during seroconversion. This analysis related to the period when UK guidelines recommended starting treatment before the CD4 count dropped below 200 cells/mm³.

At the IAS meeting, two studies from the CASCADE cohort of European seroconverters (which includes the UK data) provided further information on time to progression.

A European analysis, presented by Sara Lodi from the UK’s MRC, looked at time to CD4 counts dropping to below 500 cells/mm³, in order to inform policy should guidelines broaden to this higher threshold. [2]

Of over 11,700 adults (age >15 years) who seroconverted after 1992, over half (57%) reached CD4 <500 cells/mm³ during a median of 20 months (95%CI: 19.6, 20.5), with 29% censored at initiation of antiretroviral therapy. The proportion of patients with CD4 counts above 500 at 6, 12, 24 and 36 months after seroconversion was approximately 92%, 72%, 43% and 30%, respectively.

From these results, the authors concluded that 50% of patients would require treatment within 20 months of seroconversion, if future guidelines change the CD4 initiation threshold to 500 cells/mm³.

Increasing age at seroconversion was associated with faster progression (HR, 95%CI: 1.06,1.03-1.09 per 10-year increment). For example, 50% of the patients aged 15-20 still had counts >500 cells/mm³ after two years compared to only 35% of patients who were older than 40 at diagnosis. Unadjusted median times for those aged < 20, 20-29, 30-39, and 40+ years were 25.5, 21.9, 19.8 and 17.6 months, respectively.

No association was found with gender, transmission group and acute infection. Although numbers of patients with sub-type A, C and D were very low, there was an indication that progression may have been faster compared with sub-type B.

A second study from the CASCADE group, presented by Andrea de Luca, reinforced the finding that older age is associated with a shorter time to starting treatment, but also that older age was associated with better virological response (suppression to <50 copies/mL viral load). [3]

Of over 7100 patients who seroconverted after 1993 that were included in the analysis, just under half (48%) initiated antiretroviral treatment. Median time to starting treatment was 3.32, 3.15, 2.64 and 2.08 years for patients aged 15-29, 30-39, 40-49 and 50+ years respectively.

Later calendar period and seroconversion illness, but not age, were found to be independent predictors of CD4 count at ARV initiation. Increasing age was associated with better viral response (HR (95%CI)= 1.17 (1.06, 1.29); 1.30 (1.15, 1.47); and 1.25 (1.07, 1.47) for 30-39, 40-49 and 50+, respectively, compared to 15-29 year olds at seroconversion).

Data on progression rates in an African cohort were presented from the French ANRS 1220 Primo-CI cohort 1997-2008, in patients from Abidjan, Côte d’Ivoire. [4]

This study had a similar design, though it was a much smaller cohort (of 254 adults enrolled, 112 had baseline CD4 >500 cells/mm³). Baseline characteristics of these 112 patients followed included 65% men, median age was 28 years (IQR 25-34), median time from estimated seroconversion was 7 months and median CD4 cell count was 677 cells/mm³ (IQR 591-800). Median duration of follow-up was 7.1 years (IQR 4.2-9.3; 790 person-years).

The probability of reaching CD4 <500 cells/mm³ (the guideline for starting PCP prophylaxis) was 0.58, 0.70, and 0.78, at 2, 4 and 5 years, respectively. The probability of reaching CD4 <350 cells/mm³ was 0.22, 0.47, and 0.49, at 2, 4 and 5 years, respectively. Baseline CD4 count and haemoglobin were associated with a CD4 decrease below 500.

The study concluded that, in this cohort, half of patients reached CD4 <350 within five years of infection. They also reported higher morbidity and mortality at CD4 counts between 350 and 500 (compared to higher CD4 counts). Mortality was 0.9 per 100 patient years and incidence of WHO stage III/IV events was 0.5.

COMMENT

Highlighting the significant interpatient variability in the time to starting treatment would give newly diagnosed patients a more realistic understanding of the chance that the optimal time to start may well be within two years. The probability is likely to be over 25% for any setting where the recommended CD4 threshold is now 350 rather than 200.

The association with older age at infection support the BHIVA guidelines recommendation to consider earlier treatment in older patients.

References:
1. Ewing F et al. Survival following HIV infection of a cohort followed up from seroconversion in the UK. AIDS, 2 January 2008, Volume 22, Issue 1; p 89-95. doi: 10.1097/QAD.0b013e3282f3915e. Free text access.
http://journals.lww.com/aidsonline/toc/2008/01020
2. Lodi S et al. Time to reaching CD4≤500 for individuals followed-up since HIV seroconversion. 5th IAS, 2009, Cape Town. Poster abstract MOPEB050.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3043
3. de Luca A et al. Timing of cART initiation and subsequent virologic response by age for individuals followed up since HIV seroconversion. 5th IAS, 2009, Cape Town. Poster abstract CDB075.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3169
4. Minga A et al. Evolution to the need of care in HIV-1 seroconverters adults with CD4+ cell count above > 500/mm?. The ANRS 1220 Primo-CI cohort1997-2008, Abidjan, Côte d’Ivoire. Poster abstract CDD026.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1949