February 2009

The Absence of CD4+ T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy:  Clinical Risk, Immunological Gaps, and Therapeutic Options
Gazzola L, et al.

Studies have shown that 15-30% of patients receiving long-term HAART have discordant responses with a poor CD4 cell count response despite full suppression of HIV replication (Immunol Lett 1999;66:207; AIDS 1998;12:745).  These patients are referred to as “immunological unresponders” and the frequency obviously depends on definition.

Clinical Correlates with Immunologic Failure:  

• Age:  Advanced age is a consistent predictor of impaired immune recovery and also appears to be associated with an enhanced risk of AIDS-related complications (AIDS 2008;22:1463; AIDS 2004;18:51).  
• CD4 cell nadir is consistently noted in previous reviews but the authors here point out that these studies are quantitative and may miss important qualitative gaps.  Paradoxically, some reports note high baseline CD4 counts are also at risk.  
• Viral hepatitis:  This association was noted in a meta-analysis (CID 2005;41:713).  Also, at least two studies have shown that high baseline CD4 cell counts correlate with poor immunologic recovery.
• Low baseline HIV viral load:  This may be counter intuitive, but was reported in at least four reviews (see Table).

These observations, based on eight reviews, are summarized in the following Table along with the frequency of immunologic nonresponders and the definition provided in these studies.

Correlates with blunted CD4 Recovery
*Variously defined as viral suppression with CD4 increase (cells/mL) of <50 at 6-12 mo (1,4,6,8), <500 at 4-5 years (2,5), <100 at 12-24 mo (3,7).                                         
 
Therapeutic Options: 

• IL-2-treated patients “is safe and efficacious” for inducing a rapid and significant reconstitution of the CD4 cell compartment with no significant impact on HIV load (CID 2008;46:1925; JID 1999;180:56).*
• IL-7:  Recent trials showed improvement in naïve and memory CD4 cells with IL-7, but the authors note that IL-7 levels are already elevated in immunologic nonresponders.
• Immunosuppressive Drugs:  The authors acknowledge reluctance which is obvious but also express interest in identifying targeted interventions to interact with specific pathways involved with immunologic nonresponse.

*However, this writing in the February 1 issue of CID preceded the two clinical trials (ESPRIT and SILCAAT) presented at the 2009 CROI indicating no clinical benefit.

HAART:  It appears that PI-based HAART is superior to EFV-based HAART in terms of the CD4 cell response (NEJM 2008;358:2095).  Subsequent reports can indicate that RAL and MCV-based HAART are also superior to EFV-based HAART; in each case, the increase in CD4 cell count in patients with comparable virologic response were statistically significantly superior, but the significance of the difference in terms of clinical relevance is unknown.  There is a consensus that some patients have a blunted CD4 cell response and that initiating therapy at a higher baseline CD4 cell count is more likely to achieve CD4 cell counts in the normal range (CID 2007;44:441).

Comment:  This review nicely summarizes the issues, but the fact is that we usually do not have a reversible cause of immunologic nonresponse.  Exceptions are selected medication effects such as TDF/ddI, steroids, and alfa interferon.  The great hopes for IL-2 were dramatically dashed at CROI.  Best solution now is early detection and treatment.