Correspondence

Structured Treatment Interruption for Patients with Human Immunodeficiency Virus Infection

N Engl J Med 2003; 349:2268-2269December 4, 2003

Article

To the Editor:

The study by Lawrence et al. (Aug. 28 issue)1 demonstrates that continued treatment with an optimized antiretroviral regimen is superior to an interruption in treatment for patients with multidrug-resistant human immunodeficiency virus (HIV) infection. In my view, this study raises some important ethical issues. No study, at any time, has demonstrated the superiority of treatment interruption over conventional anti-HIV therapy. Moreover, because of concern about clinical progression and HIV resistance, treatment interruption has consistently been discouraged in current and previous guidelines.2 Therefore, the authors' hypothesis of a 33 percent reduction in the incidence of progression of disease or death in the treatment-interruption group lacks (and lacked in 2000, when the study began) adequate and necessary support.

Bernardino Roca, M.D., Ph.D.
Hospital General, 12004 Castellon, Spain
brocav@meditex.es

2 References

1. 1

   Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003;349:837-846
   Full Text | Web of Science | Medline

2. 2

   Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Rockville, Md.: AIDSinfo, July 14, 2003. (Accessed November 10, 2003, at http://aidsinfo.nih.gov/guidelines/archive.asp.)
   

To the Editor:

In his Perspective article on interruptions of HIV therapy, Hirschel1 pertinently points out the effect of HIV genome variability on viral resistance and treatment failure. However, the dramatic statement that every possible mutation will arise at each position of this genome every day must be interpreted with caution. This correct affirmation does not imply that every possible HIV genome will emerge every day, as some readers might falsely conclude. Indeed, nonsense mutations and loss of fitness will prevent the emergence of many, if not most, mutated genomes. In addition, considering a length of about 9200 bases, the total number of possible different HIV RNA molecules is 4⁹²⁰⁰, or approximately 8.95×10⁵⁵³⁸, corresponding to a mass of 4.65×10⁵⁵¹⁸ kg, which far exceeds the estimated mass of our galaxy (about 4×10⁴² kg). Thus, only an infinitesimal fraction of all possible viral genomes can be generated daily among HIV-infected people worldwide, because of both biologic and physical constraints.

Henri Agut, M.D., Ph.D.
Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France
henri.agut@psl.ap-hop-paris.fr

1 References

1. 1

   Hirschel B. Beware of drug holidays before HIV salvage therapy. N Engl J Med 2003;349:827-828
   Full Text | Web of Science | Medline

Author/Editor Response

We designed this study on the basis of several pilot studies suggesting that reversion to wild-type virus during an interruption of antiretroviral treatment was associated with an improved response to subsequent therapy. These results were initially presented at scientific conferences in 1999 and 2000 and were subsequently published.1-3

We hypothesized that a less resistant viral population would reemerge in the absence of drug pressure. The purpose of the current study was to determine whether therapeutic intensification after genotypic reversion is associated with improved virologic and immunologic responses and delayed disease progression. Because of the initial risk associated with a structured interruption of treatment, a 33 percent reduction in disease progression was chosen as the minimal difference that would warrant adoption of this strategy.

We agree that a structured interruption of treatment should be approached with caution. On the basis of our results, treatment interruption should be avoided in patients with advanced disease and treatment failure due to multidrug-resistant HIV. Antiretroviral treatment guidelines are continually changing, and randomized clinical trials like ours help to ensure that clinical decisions are based on definitive scientific evidence.

Jody Lawrence, M.D.
University of California, San Francisco, San Francisco, CA 94110
jtlawrence@php.ucsf.edu

Kathy Huppler Hullsiek, Ph.D.
University of Minnesota, Minneapolis, MN 55414

John D. Baxter, M.D.
University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Camden, NJ 08103

3 References

1. 1

   Miller V, Sabin C, Hertogs K, et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 2000;14:2857-2867
   CrossRef | Web of Science | Medline

2. 2

   Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001;344:472-480
   Full Text | Web of Science | Medline

3. 3

   Izopet J, Massip P, Souyris C, et al. Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen. AIDS 2000;14:2247-2255
   CrossRef | Web of Science | Medline

Author/Editor Response

A galaxy made entirely of HIV: not a place where I'd like to live! Henri Agut suggests tighter wording to prevent combinatorial excess — and I agree with him.

Bernard Hirschel, M.D.
Geneva University Hospital, CH-1211 Geneva 14, Switzerland
bernard.hirschel@hcuge.ch