Poor CD4 Cell Recovery on Antiretroviral Therapy Is Linked to Late Treatment, Leads to Adverse Outcomes

		SUMMARY: People with HIV who do not experience significant CD4 cell recovery with antiretroviral therapy (ART) -- even though they achieve viral load suppression -- are at risk for a host of complications including cardiovascular disease and cancer, according to an analysis of the Dutch ATHENA cohort presentation at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last week in San Francisco. In related news, researchers with the DART trial in Africa found that starting treatment late increased the likelihood of inadequate CD4 cell gains.

By Liz Highleyman

Despite achieving full suppression of plasma HIV RNA, an estimated 5% to 10% of patients have incomplete immune recovery, a phenomenon know as discordant response.

ATHENA

Steven van Lelyveld and colleagues looked at the relationship between incomplete immune recovery and the occurrence of cardiovascular events, cancer, and other adverse outcomes, which they hypothesized might be due to ongoing immune deficiency.

The analysis included 3071 participants in ATHENA, a national observational study of people with HIV/AIDS in the Netherlands. Selected patients had started ART since 1998, achieved virological suppression (< 500 copies/mL) within 9 months of treatment initiation, maintained suppression for at least 2 years, and had undetectable viral load during the prior 6 months. Pregnant women and people taking immunosuppressive drugs were excluded.

Most participants (about 80%) were men, the mean age was 41 years, and sex between men was the most frequent HIV risk factor. The median CD4 cell count at baseline was fairly high, at 425 cells/mm3, but the nadir (lowest-ever) level was 160 cells/mm3. Nearly 60% were taking non-nucleoside reverse transcriptase inhibitors (NNRTIs) and about one-third were on protease inhibitors. As in many European cohorts, smoking was common (about 60%).

Participants were allocated to 4 groups according to immune recovery, as indicated by CD4 cell counts after 2 years on treatment: < 200 (6.6%), 200-350 (21.0%), 350-500 (46.0%), and > 500 (26.4%) cells/mm3. For comparison, the normal range for healthy HIV negative adults is around 500-1500 cells/mm3.

Results

	A total of 2048 patients experienced CD4 cell gains of at least 100 cells/mm3.
	Patients with incomplete immune recovery after 2 years were significantly older than those with larger CD4 cell gains.
	198 total endpoint events occurred during follow-up, including new cardiovascular events, new malignancies, AIDS-defining events, and death.
	Combined endpoint events were significantly more likely to occur in people with < 200 cells/mm3.
	58 participants developed cardiovascular disease during follow-up.
	Here too, people with a baseline CD4 count < 200 cells/mm3 had a significantly elevated risk.
	36 participants developed non-AIDS malignancies.
	There was a trend toward a link between being in the lowest CD4 cell category and shorter time to non-AIDS malignancies, but this did not reach statistical significance.
	After taking into account confounding factors including sex and age, adjusted hazard ratios relative to the < 200 cells/mm3 group for the combined endpoints were:
	0.67 for people with 200-350 cells/mm3; 0.57 for those with 350-500 cells/mm3; 0.46 for those with > 500 cells/mm3.
	Incomplete immune recovery after 2 years on suppressive ART was significantly associated with older age, male sex, lower nadir CD4 count, lower HIV RNA at ART initiation, and starting with a NNRTI rather than a protease inhibitor.

DART

The second study looked at the link between poor CD4 cell recovery and adverse outcomes in a resource-limited setting.

The DART trial enrolled 3316 previously untreated HIV positive adults in Uganda and Zimbabwe with a low median CD4 count of 86 cells/mm3.

Participants started 1 of 3 ART regimens, using zidovudine/lamivudine (Combivir) plus either tenofovir (Viread)(74%), nevirapine (Viramune)(16%), or abacavir (Ziagen)(9%). Participants were randomly assigned to be followed using either laboratory and clinical monitoring or only clinically-driven monitoring, switching to second-line ART when they either fell below 100 cells/mm3 or develop WHO stage 4 disease.

Results

	After a median 5 years of follow-up, 69% of patients ever achieved a confirmed CD4 count >250 cells/mm3 on their first-line regimen, 46% reached 350 cells/mm3, and 19% reached >500 cells/mm3.
	Patients on first-line therapy took a median 1.8 years to reach >250 cells/mm3, 3.9 years to reach 350 cells/mm3, and more than 6 years to reach >500 cells/mm3.
	Among participants who stayed on their first-line regimen for 1 year before switching:
	10% still had a CD4 count <99 cells/mm3 or less; 38% had 100-199 cells/mm3; 39% had 200-349 cells/mm3; 10% had 350-499 cells/mm3; 2% had 500 cells/mm3.
	By 5 years after ART initiation, the proportion reaching >500 cells/mm3 had increased, but still remained relatively low at 21%.
	20% of patients with a CD4 count < 100 cells/mm3 after 1 year, and 55% with 100-199 cells/mm3, subsequently reached >250, the level at which AIDS-related opportunistic infections become very uncommon.
	However, the rate of CD4 count change from week 24 to 48 did not predict who would or would not eventually reach >250.

"Patients initiating ART with very low CD4 counts struggle to achieve sufficient immune restoration within 2 to 3 years though responses continue to improve over time," the researchers concluded.

They added that people with a CD4 count < 125 cells/mm3 after week 48 on ART are not likely to ever reach >250 cells/mm3 on the first-line regimen.

The investigators stated that these findings "highlight the importance of expanded earlier diagnosis and treatment initiation" in resource limited settings. They also raised the prospect of switching people with limited CD4 cell recovery -- even if they have suppressed viral load -- to second-line regimens associated with larger CD4 cell gains, including protease inhibitors rather than NNRTIs, and potentially maraviroc (Selzentry).

Study 1: University Medical Center Utrecht, Netherlands; Stichting HIV Monitoring, Amsterdam, Netherlands.

Study 2: Medical Research Council/Uganda Virus Research Institute, Entebbe, Uganda; Medical Research Council Clinical Trials Unit, London, UK; Joint Clinical Research Center, Kampala, Uganda; University of Zimbabwe, Harare, Zimbabwe; Infectious Diseases Inst, Makerere University, Mulago, Uganda; Imperial College London, UK.

2/23/10

References

S van Lelyveld, L Gras, A Kesselring, and others. Incomplete Immune Recovery on HAART Is Associated with Significant More Cardiovascular Events and a Trend Towards More Non-AIDS Related Malignancies in Dutch ATHENA Cohort. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 714).

P Munderi, AS Walker, C Kityo, and others. Immune Restoration over 5 Years on ART among Patients Initiating Treatment with Advanced Immune Deficiency in the DART Trial in Uganda and Zimbabwe. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 110.