0
Editorials |

When To Start Therapy for HIV Infection: A Swinging Pendulum in Search of Data FREE

H. Clifford Lane, MD; and James D. Neaton, PhD
[+] Article and Author Information

From National Institute of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD; and University of Minnesota; Minneapolis, MN 55414.


Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: H. Clifford Lane, MD, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 10 Center Drive, MSC 1894, National Institutes of Health, Bethesda, MD 20892-1894; e-mail, clane@niaid.nih.gov.

Current Author Addresses: Dr. Lane: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, MSC 1894, Bethesda, MD 20892-1894.

Dr. Neaton: University of Minnesota, Room 220, 2221 University Avenue SE, Minneapolis, MN 55414.


Ann Intern Med. 2003;138(8):680-681. doi:10.7326/0003-4819-138-8-200304150-00018
Text Size: A A A

Among the fundamental questions that need to be addressed regarding the treatment of patients with HIV infection are the strategy questions of when to start therapy, what therapy to start, and when to change therapy. The current inability to eradicate HIV, which has led to a need for long-term therapeutic strategies, and the increased recognition of long-term drug toxicities have made these questions compelling. Unfortunately, the answers remain unclear.

Over the past 7 years, in the absence of definitive evidence, several professional societies and governmental entities have provided guidelines for the initiation of antiretroviral therapy (ART). These organizations have suggested guidelines that deal with a wide range of issues—from the treatment of all patients with viral loads greater than 10 000 copies/mL (1) to the more recent recommendation to definitely begin therapy only in patients with CD4+ T-cell counts less than 0.200 × 109 cells/L. Guidelines for the best approach to patients with CD4+ T-cell counts between 0.200 and 0.350 × 109 cells/L remain uncertain (2). As stated in the most recent edition of the guidelines from the U.S. Department of Health and Human Services and the Henry J. Kaiser Family Foundation (3), “While randomized clinical trials provide strong evidence for treating patients with <200 CD4+ T cells/mm3, the optimal time to initiate antiretroviral therapy among asymptomatic patients with CD4+ T-cell counts > 200 cells/mm3 is not known.” Unfortunately, this swing in the pendulum of expert opinion from early, aggressive therapy to a more cautious approach was not concluded from data derived from randomized trials with clinical outcomes. It was due to the influence of data from observational studies, case reports, and short-term trials that showed unexpected toxicities associated with treatment and little evidence that earlier intervention had any impact on progression to AIDS (49).

The study by Palella and colleagues in this issue (10) attempts to swing the pendulum back toward earlier intervention. This analysis of data from 1994 to 2002 from the Centers for Disease Control and Prevention–sponsored HIV Outpatient Study (HOPS) observational cohort divided patients into groups based on CD4+ T-cell count (0.201 to 0.350 × 109 cells/L, 0.351 to 0.500 × 109 cells/L, and 0.501 to 0.750 × 109 cells/L). The investigators compared mortality rates of patients who began ART in their initial CD4+ T-cell group with those of patients who deferred therapy until their CD4+ T-cell count declined to a lower group. For patients with initial CD4+ T-cell counts between 0.201 and 0.350 × 109 cells/L, initiating therapy at this time rather than waiting until CD4+ T-cell counts declined to less than 0.201 × 109 cells/L was associated with reduced mortality (15.4 vs. 56.4 deaths/1000 person-years, respectively; P < 0.001).

The work of Palella and colleagues is unique compared with other recent reports on this topic (47) because the authors compared survival for participants who began ART in a specific CD4+ group with that of participants in the same group who deferred treatment until their CD4+ T-cell counts declined to a lower CD4+ group. In contrast, other studies typically classified participants by CD4+ T-cell count at the time of initiation of treatment and thus compared risk for AIDS or death on the basis of CD4+ group at the time of initiation of therapy. By “starting the clock” at the same time for those who initiated and those who deferred therapy, Palella and colleagues overcame one of the problems of using observational data to decide when to start ART. However, like the other reports, these comparisons may be subject to confounding. Although Palella and colleagues adjusted for many potentially confounding variables (age, sex, race, insurance status, viral load at time of first ART, receipt of highly active antiretroviral therapy [HAART], and CD4+ T-cell count at time of first observation within each subgroup), the decision to start treatment probably involved several additional factors related to prognosis.

As the authors point out, another important limitation relates to statistical power. Overall, a total of only 53 end points (deaths) occurred during the follow-up period. Even for the subgroup that formed the basis for their main conclusion, the 399 participants in the 0.201 to 0.350 × 109 cells/L subgroup, the distribution of the 33 end points, once adjusted for known confounding variables, did not achieve statistical significance (hazard ratio, 0.57; P = 0.16). To directly address the question of whether to defer therapy in patients with CD4+ T-cell counts greater than 0.200 × 109 cells/L would require a randomized trial of considerable size. For example, a study of treatment-naive patients with CD4+ T-cell counts greater than 0.250 × 109 cells/L, randomly assigned to immediate or deferred therapy, would require 650 events to show a 20% difference in mortality between groups with 80% power. At a rate of progression of 1% per year, 65 000 patient-years of follow-up or a study of 6500 patients for 10 years would be required. While studies of this size exist in other areas (1112), they are the exception in HIV research.

We applaud Palella and colleagues' novel approach to observational data; however, because of potential confounding factors and limited power, their data are unlikely to change current recommendations about when to initiate therapy. These data do, however, generate new uncertainty in this area and may motivate the design and conduct of trials that will contribute to this important debate. As one views the global epidemic of HIV infection and the vast numbers of untreated patients, one also sees opportunities to perform studies that involve large sample sizes and that require long-term follow-up. The questions regarding treatment strategy are equally pressing and important for developed and developing countries. In developing countries, these questions can be addressed in a way that is consistent with the ethical principles of clinical research (1314) and that helps to develop the infrastructure required for delivery of state-of-the art care to patients with HIV infection. Our enthusiasm to test the newest class of drugs, such as entry or integrase inhibitors, must be balanced by a need to define better strategies for the use of existing drugs.

H. Clifford Lane, MD

National Institute of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, MD 20892

James D. Neaton, PhD

University of Minnesota; Minneapolis, MN 55414

References

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. PubMed
CrossRef
 
Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, et al..  Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002; 288:222-35. PubMed
 
Dybul M, Fauci A, Bartlett J, Kaplan J, Pau A.  Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med. 2002; 137:381-433.
 
Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, et al..  Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA. 2001; 286:2568-77. PubMed
 
Chen R, Westfall A, Cloud G, Chatham A, Acosta E, Raper J, et al.  Long-term survival after initiation of antiretroviral therapy [Abstract]. Chicago: 8th Conference on Retroviruses and Opportunistic Infections; 2001: Abstract 341.
 
Sterling TR, Chaisson RE, Moore RD.  HIV-1 RNA, CD4 T-lymphocytes, and clinical response to highly active antiretroviral therapy. AIDS. 2001; 15:2251-7. PubMed
 
Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F, et al..  Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002; 360:119-29. PubMed
 
Mallon PW, Cooper DA, Carr A.  HIV-associated lipodystrophy. HIV Med. 2001; 2:166-73. PubMed
 
Miller KD, Masur H, Jones EC, Joe GO, Rick ME, Kelly GG, et al..  High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med. 2002; 137:17-25. PubMed
 
Palella FJ Jr, Deloria-Knoll M, Chmiel JS, Moorman AC, Wood KC, Greenberg AE, et al..  Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+cell strata. Ann Intern Med. 2003; 138:620-6.
 
Collins R, MacMahon S.  Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet. 2001; 357:373-80. PubMed
 
Califf RM, DeMets DL.  Principles from clinical trials relevant to clinical practice: Part I. Circulation. 2002; 106:1015-21. PubMed
 
Emanuel EJ, Wendler D, Grady C.  What makes clinical research ethical? JAMA. 2000; 283:2701-11. PubMed
 
Killen J, Grady C, Folkers GK, Fauci AS.  Ethics of clinical research in the developing world. Nat Rev Immunol. 2002; 2:210-5. PubMed
 

Figures

Tables

References

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. PubMed
CrossRef
 
Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, et al..  Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002; 288:222-35. PubMed
 
Dybul M, Fauci A, Bartlett J, Kaplan J, Pau A.  Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med. 2002; 137:381-433.
 
Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, et al..  Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA. 2001; 286:2568-77. PubMed
 
Chen R, Westfall A, Cloud G, Chatham A, Acosta E, Raper J, et al.  Long-term survival after initiation of antiretroviral therapy [Abstract]. Chicago: 8th Conference on Retroviruses and Opportunistic Infections; 2001: Abstract 341.
 
Sterling TR, Chaisson RE, Moore RD.  HIV-1 RNA, CD4 T-lymphocytes, and clinical response to highly active antiretroviral therapy. AIDS. 2001; 15:2251-7. PubMed
 
Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F, et al..  Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002; 360:119-29. PubMed
 
Mallon PW, Cooper DA, Carr A.  HIV-associated lipodystrophy. HIV Med. 2001; 2:166-73. PubMed
 
Miller KD, Masur H, Jones EC, Joe GO, Rick ME, Kelly GG, et al..  High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med. 2002; 137:17-25. PubMed
 
Palella FJ Jr, Deloria-Knoll M, Chmiel JS, Moorman AC, Wood KC, Greenberg AE, et al..  Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+cell strata. Ann Intern Med. 2003; 138:620-6.
 
Collins R, MacMahon S.  Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet. 2001; 357:373-80. PubMed
 
Califf RM, DeMets DL.  Principles from clinical trials relevant to clinical practice: Part I. Circulation. 2002; 106:1015-21. PubMed
 
Emanuel EJ, Wendler D, Grady C.  What makes clinical research ethical? JAMA. 2000; 283:2701-11. PubMed
 
Killen J, Grady C, Folkers GK, Fauci AS.  Ethics of clinical research in the developing world. Nat Rev Immunol. 2002; 2:210-5. PubMed
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Journal Club
Topic Collections
PubMed Articles
Macrophages and HIV-1: dangerous liaisons. Mol Immunol 2005;42(2):195-212.
When to start antiretroviral therapy: a swinging pendulum? Top HIV Med 2008 Jun-Jul;16(2):82-8.

Want to Subscribe?

Learn more about subscription options

Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)