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  • Expert Commentary
  • June 14, 2010

Recommendations for Initiating Antiretroviral Therapy Reflect Need for Further Research

The December 2009 version of the Department of Health and Human Services (DHHS) treatment guidelines for human immunodeficiency virus (HIV) infection in adolescents and adults provides an important synthesis of recent data regarding the use of highly active antiretroviral therapy (HAART) (1).

While the DHHS updated other aspects of the guidelines, the most salient changes for many providers and patients are those related to the timing of the initiation of antiretroviral therapy. In applying these guidelines to clinical practice, it is critical to recognize areas of uncertainty embodied by the divided votes of the panelists. Thus, for most asymptomatic persons with 350 to 500 CD4+ cells/μL, 55% of panelists favored a strong recommendation (AII) (see Appendix A below for the recommendation rating scheme) and 45% a moderate recommendation (BII) in favor of initiating antiretroviral therapy; for persons with >500 CD4+ cells/μL, 50% of panelists favored a moderate recommendation (BIII) and 50% an optional recommendation (CIII). In important exceptions to these split votes, the panelists were unified in recommending the initiation of antiretroviral therapy regardless of the CD4+ cell count for asymptomatic persons who are pregnant (AI), have HIV-associated nephropathy (AII), or are co-infected by hepatitis B virus (AIII).

For more than two decades, the thresholds for initiating antiretroviral therapy have swung back and forth between lower and higher CD4+ counts. When HAART first became available, treatment recommendations expanded to include persons with >500 CD4+ cells/μL (2). However, it later became apparent that available antiretroviral therapy was not curative, that therapy would likely need to be lifelong, and that exceptionally high levels of medication adherence were necessary to prevent the development of extensive antiretroviral resistance. In addition, it was noted that serious medical disorders (e.g., lipodystrophy, metabolic syndrome, peripheral neuropathy, lactic acidosis, and cardiovascular disease) were frequent complications of therapy. These observations, combined with the relatively low rates of HIV-related complications in treatment-naïve persons with higher CD4+ counts, led to more conservative treatment guidelines that largely limited antiretroviral therapy to persons whose CD4+ count had fallen to <200 to 350 cells/μL (3).

Recently, a number of factors led the pendulum to swing back in favor of treating persons with higher CD4+ counts. The availability of newer, more potent, and better-tolerated therapeutic agents and classes has lessened concerns about antiretroviral resistance and toxicities. Increased rates of disease due to comorbidities, such as non–acquired immune deficiency syndrome (AIDS) malignancies, vascular complications, and liver disease in HIV-infected persons with 350 to 500 CD4+ cells/μL as compared to patients with higher CD4+ cell counts, are now well recognized (4-6). Finally, outcomes in cohorts of treatment-naïve HIV-infected patients support starting antiretroviral therapy with higher CD4+ counts. In one analysis (7), decreased survival was found both in persons who deferred therapy until the CD4+ count was <350 cells/μL as well as in persons who deferred therapy until the CD4+ count was <500 cells/μL. Another report (8) found that deferring combination therapy until a CD4+ cell count of 251 to 350 cells/μL was associated with higher rates of AIDS and death than starting therapy in the range of 351 to 450 cells/μL.

These considerations provide the basis for the new treatment recommendations. However, for clinicians and researchers considerable uncertainty remains. As with all nonrandomized trials, differences in rates of access to medical care, pre-existent medical and psychiatric comorbidities, patient behaviors related to health-seeking activities, alcohol consumption/abuse, injection-drug and other substance use, smoking, and adherence to therapy may bias the outcomes of the cohort studies (7-9). In addition, findings supporting specific thresholds for early therapy derive from studies in developed countries and may not fully reflect the risks and benefits of antiretroviral therapy in developing country settings, where persons with 200 to 350 cells/μL have higher rates of HIV-related complications and access to antiretroviral regimens and drugs used in the developed world remains uneven or nonexistent (10).

In summary, while randomized clinical trials clearly demonstrate benefit for starting HAART for persons with <350 CD4+ cells/μL, it is important to recognize that the recommendations for the initiation of HAART at higher CD4+ cell counts have a weaker evidentiary basis. Although recent cohort analyses provide insight and support for the recommendations, as pointed out in the guideline, the possibility that unmeasured confounders influenced the results cannot be ruled out. Furthermore, as also stated in the guideline, "When discussing starting antiretrovirals at higher CD4 cell counts (>500 cells/mm3), clinicians should inform patients that data on the clinical benefit of starting treatment at such levels is not conclusive. There is a need for further ongoing research (both with randomized clinical trials and cohort studies) to assess the short- and long-term clinical and public health benefits, and cost-effectiveness of starting therapy at higher CD4 counts" (1).

As always, it should be understood that these guidelines reflect the evidence available at the time of development. Of note, a prospective, randomized trial, which seeks to determine the benefits of initiating antiretroviral therapy at a CD4+ cell count >500 cells/μL versus deferring therapy until the CD4+ declines to <350 cells/μL, is now underway (11). If successfully completed, this study will provide tremendous insight regarding the benefits of early antiretroviral therapy. Meanwhile, in the absence of further evidence, clinicians will need to carefully consider the strengths and weaknesses of the available data regarding the initiation of treatment for persons with >350 CD4+ cells/μL.

Appendix A

Rating Scheme for Recommendations

Strength of Recommendation

  1. Strong recommendation for the statement
  2. Moderate recommendation for the statement
  3. Optional recommendation for the statement

Quality of Evidence for Recommendation

  1. One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
  2. One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
  3. Expert opinion


Matthew Bidwell Goetz, MD
Professor of Clinical Medicine, David Geffen School of Medicine at UCLA
Chief, Infectious Diseases, VA Greater Los Angeles Healthcare System
Los Angeles, CA


The views and opinions expressed are those of the author and do not necessarily state or reflect those of the National Guideline Clearinghouse™ (NGC), the Agency for Healthcare Research and Quality (AHRQ), or its contractor, ECRI Institute.

Potential Conflicts of Interest

Dr. Goetz declared no potential conflicts of interest with respect to this expert commentary.


  1. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. External Web Site Policy (PDF Help). Access Date: December 1, 2009.
  2. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society - USA Panel. JAMA. 1997; 277:1962-9.
  3. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Access Date: February 4, 2002.
  4. Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006; 166:1632-41.
  5. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008; 22:2409-18.
  6. Monforte A, Abrams D, Pradier C, Weber R, Reiss P, Bonnet F, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 2008; 22:2143-53.
  7. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009; 360:1815-26.
  8. Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009; 373:1352-63.
  9. Sax PE, Baden LR. When to start antiretroviral therapy—ready when you are? N Engl J Med. 2009; 360:1897-9.
  10. Wood R, Lawn SD. Should the CD4 threshold for starting ART be raised? Lancet. 2009; 373:1314-6.
  11. Strategic Timing of Antiretroviral Treatment (START) - NCT00867048. External Web Site Policy. Access Date: April 25, 2010.

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