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  17th CROI
Conference on Retroviruses
and Opportunistic Infections
San Francisco CA
February 16-19, 2010
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Older Age, Lower CD4 Nadir, NNRTI Use Predict Slow CD4 Recovery in ATHENA
  17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
Dutch ATHENA cohort members with a CD4 count under 200 when they entered the cohort had more new cardiovascular and non-AIDS cancer diagnoses than people with higher initial CD4 counts [1]. Older age, lower nadir (lowest-ever) CD4 count, and use of a nonnucleoside (NNRTI)-based regimen predicted incomplete recovery from a sub-200 CD4 count after 2 years of fully suppressive therapy.
Several earlier studies traced links between lower CD4 counts and cardiovascular disease or non-AIDS cancers, including lower current CD4 count [2-5], lower first CD4 count [6], and more time spent with fewer than 500 CD4s [4]. D:A:D study investigators found that lower CD4 counts independently predict death from non-AIDS cancers [7].
Steven van Lelyveld and ATHENA colleagues studied 3071 antiretroviral-naive adults starting treatment from 1998 onward. Everyone reached a viral load below 500 copies within 9 months of starting and did not interrupt treatment for more than 2 weeks. The investigators excluded anyone with a viral load over 500 copies in the first 18 to 24 months of therapy, pregnant women, people who combined didanosine and tenofovir, and people taking immunosuppressive drugs. The ATHENA team assessed cohort members for time from study entry to occurrence of a combined endpoint including any cardiovascular event, AIDS or non-AIDS malignancy, AIDS, or death.
The study group included 206 people with an initial CD4 count under 200, 646 with 200 to 350 CD4s at entry, 1414 with 350 to 500 CD4s, and 811 with 500 or more CD4s. Overall median age was 41 years, while median baseline and nadir CD4 counts were 425 and 160. While 58% of cohort members were taking an NNRTI regimen, 32% were taking a PI. Most cohort members, 59%, smoked, but only 8% had a family history of heart disease.
Several factors predicted failure to boost CD4 tallies above 200 in the first 2 years of suppressive antiretroviral therapy: older age (odds ratio 1.04 per year, P < 0.0001), lower nadir CD4 count (P < 0.0001), male gender (P = 0.046), lower viral load when starting antiretrovirals (P = 0.009), and starting with an NNRTI versus a protease inhibitor (P = 0.0002).
During 10,956 patient-years of follow-up 2048 people added at least 100 CD4 cells. People who entered the cohort with a CD4 count under 200 took a significantly longer time to gain 100 CD4s (P < 0.0001).
The ATHENA team determined that 198 people met the combined clinical endpoint during follow-up. Significantly more people who entered ATHENA with fewer than 200 CD4s met this endpoint (P < 0.0001). Cardiovascular disease developed in 58 people during the study, and again those with an initial CD4 count under 200 had a significantly higher risk of heart disease (P = 0.02). Non-AIDS malignancies developed in 36 people. The investigators discerned nonsignificant trends for shorter time to a non-AIDS cancer in people with a first CD4 count under 200 versus 350 to 500 (P = 0.07) or over 500 (P = 0.11).
Compared with people who still had fewer than 200 CD4s during the first 2 years of suppressive therapy, those with 200 to 350 had a 33% lower risk of reaching the combined endpoint (nonsignificant, adjusted hazard ratio [AOR] 0.67, 95% confidence interval [CI] 0.40 to 1.10), while those with 350 to 500 CD4s had a 43% lower risk (AOR 0.57, significant at 95% CI 0.36 to 0.97) and those with more than 500 CD4s had a 54% lower risk (AOR 0.46, 95% CI 0.27 to 0.77).
The ATHENA investigators caution that further analysis in combined cohorts is needed to confirm these findings because of the relatively small number of new heart disease and non-AIDS cancers in their cohort.
1. van Lelyveld S, Gras L, Kesselring A, et al. Incomplete immune recovery on HAART is associated with significantly more cardiovascular events and a trend towards more non-AIDS-related malignancies in Dutch ATHENA cohort. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 714.
2. Grunfeld C, Delaney JAC, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009;23:1841-1849.
3. Smith C, the D:A:D Study Group. Association between modifiable and non-modifiable risk factors and specific causes of death in the HAART era: the data collection on adverse events of anti-HIV drugs study. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 145.
4. Bruyand M, Thiebaut R, Lawson-Ayayi S, et al; Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA). Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis. 2009;49:1109-1116.
5. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22:841-848.
6. Bedimo RJ, McGinnis KA, Dunlap M, Rodriquez-Barradas MC, Justic AC. Incidence of non-AIDS-defining malignancies in HIV-infected versus noninfected patients in the HAART era: impact of immunosuppression. JAIDS. 2009;52:203-208.
7. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 2008;22:2143-2153.