Correspondence

Viral Load and Combination Therapy for Human Immunodeficiency Virus

N Engl J Med 1997; 336:958-961March 27, 1997

Article

To the Editor:

In their editorial, Corey and Holmes (Oct. 10 issue)1 state, “All persons with HIV [human immunodeficiency virus] infection who have CD4 cell counts below 500 cells per cubic millimeter should be encouraged to begin antiretroviral therapy.” Such an early instigation of therapy is in line with the current understanding of HIV infection and experience with other infectious diseases, but we do not yet know whether we have good enough therapies — those that have negligible long-term risks and do not jeopardize the efficacy of future therapies the patient may be given — to say that this statement is now true in practice.2

No randomized trials in asymptomatic patients have established that those treated early survive any longer than those for whom treatment is deferred. Extended follow-up of patients in one trial, the Concorde study, has shown a significantly increased risk of death among the patients treated early.3 The trials mainly involve monotherapy with zidovudine. The suggestion is that the situation is different for combination therapy. But where is the evidence that for a patient with a CD4 count of 450 cells per cubic millimeter and a low plasma virus level, it would not be better to wait before initiating therapy? On average, such patients are not at serious risk for more than five years, and there is no evidence that the efficacy of treatment lasts this long. If therapy is delayed, there may eventually be better drugs from which to choose.

In 1990, after the results of the AIDS Clinical Trials Group (ACTG) 019 study in patients with CD4 counts of less than 500 cells per cubic millimeter had been published, a patient with a CD4 count of 450 cells per cubic millimeter would have been advised to start monotherapy with zidovudine.4 We now tell such a patient that, in fact, follow-up data for up to 4.5 years since that time have shown no survival benefit from the early use of zidovudine5 and that if the patient starts using a second nucleoside drug now, the benefit will be smaller than if he or she had waited and started to use zidovudine at the same time as a second nucleoside drug.1 There is no more hard evidence now of the benefits of early therapy than there was in 1990. We need new randomized trials to determine whether the notion that was probably not true in the era of zidovudine monotherapy — that early therapy prolongs survival as compared with deferred therapy — is now true.2

Andrew N. Phillips, Ph.D.
Royal Free Hospital School of Medicine, London NW3 2PF, United Kingdom

George Davey Smith, M.D.
University of Bristol, Bristol BS8 2PR, United Kingdom

5 References

1
Corey L, Holmes KK. Therapy for human immunodeficiency virus infection -- what have we learned? N Engl J Med 1996;335:1142-1144
Full Text | Web of Science | Medline

2
Phillips AN, Smith GD, Johnson MA. Will we ever know when to treat HIV infection? BMJ 1996;313:608-610
CrossRef | Web of Science | Medline

3
Darbyshire J. Extended follow-up of four European/Australian randomised trials of zidovudine in symptomatic HIV infection. Presented at the Fifth European Conference on Clinical Aspects and Treatment of HIV Infection, Copenhagen, Denmark, September 26–29, 1995. abstract.

4
State-of-the-Art Conference on Azidothymidine Therapy for Early HIV InfectionAm J Med 1990;89:335-344
CrossRef | Web of Science | Medline

5
Volberding PA, Lagakos SW, Grimes JM, et al. The duration of zidovudine benefit in persons with asymptomatic HIV infection. JAMA 1994;272:437-442
CrossRef | Web of Science | Medline

To the Editor:

Two recent editorials1,2 mention the costs of drugs for treating HIV-infected patients, but specific costs are not given. Because there is so much discussion about the costs of these drugs, we have put together some facts on the average wholesale prices of drugs commonly prescribed in the treatment of HIV-infected patients (Table 1Table 1Costs of Commonly Used Agents and Laboratory Tests for an HIV-Infected Adult.).

Henry M. Feder, Jr., M.D.
University of Connecticut Health Center, Farmington, CT 06030-2939

Laura R. Milch, Pharm.D.
Hartford Hospital, Hartford, CT 06102

2 References

1
Horsburgh CR Jr. Advances in the prevention and treatment of Mycobacterium avium disease. N Engl J Med 1996;335:428-430
Full Text | Web of Science | Medline

2
Corey L, Holmes KK. Therapy for human immunodeficiency virus infection -- what have we learned? N Engl J Med 1996;335:1142-1144
Full Text | Web of Science | Medline

To the Editor:

Katzenstein et al. (Oct. 10 issue)1 describe the correlation of the plasma level of HIV RNA with the risk of a progression of HIV disease and with the efficacy of antiretroviral therapy. At our institution, we have been using measurements of viral load both to monitor disease progression and to assess the response to therapy. In addition, we have observed that informing patients about their viral load influences their acceptance of antiretroviral therapy. Of 12 patients with HIV infection who had refused antiretroviral therapy, 8 changed their minds and accepted it after the concept of viral load and the goal of therapy had been explained.

Patients with HIV disease who accept early medical intervention and those who refuse it have distinctly different beliefs about their health and treatment.2 The viral load is a simple concept that gives patients a better understanding of their disease status and the goal of therapy (i.e., to reduce the viral load and render it undetectable). This new strategy may increase patients' acceptance of antiretroviral therapy and perhaps their compliance with it.

Venkatasubramanian Srinivasan, M.D.
Sary Omar Beidas, M.D.
Prince George's Hospital Center, Cheverly, MD 20785

2 References

1
Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. N Engl J Med 1996;335:1091-1098
Full Text | Web of Science | Medline

2
Catt S, Stygall J, Catalan J. Acceptance of zidovudine (AZT) in early HIV disease: the role of health beliefs. AIDS Care 1995;7:229-235
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Feder and Milch's table listing the costs of medications and tests commonly used in the care of HIV-infected persons is a useful current reference.

Drs. Phillips and Smith infer that because prolonged follow-up in the Concorde trial showed higher morbidity among the patients assigned to early treatment with zidovudine than among those assigned to deferred treatment with zidovudine, there is a need to perform another Concorde-type trial comparing early with deferred combination therapy. The increase in benefit with combination therapy, as compared with zidovudine monotherapy, in ACTG 175 was large (40 to 55 percent longer survival).1 The long-term follow-up data suggesting a worse outcome in the early-zidovudine group in the Concorde trial have not yet been published; however, the available information suggests that the difference between the long-term outcomes associated with immediate zidovudine monotherapy and deferred therapy was considerably smaller.

Recent information indicates that threefold to fivefold increments in the number of copies of HIV type 1 (HIV-1) RNA in plasma are associated with significantly increased rates of disease progression. Mellors et al. reported that in persons with HIV-1 RNA levels that were less than 4530, 4530 to 13,020, 13,021 to 36,270, or more than 36,270 copies per milliliter, the median time to the progression to AIDS was 10, 7.7, 5.3, and 3.5 years and the five-year mortality rate was 5, 10, 25, and 49 percent, respectively.2 In the Pittsburgh Multicenter AIDS Cohort Study, less than 15 percent of the patients initially enrolled with CD4 cell counts of less than 500 per cubic millimeter had HIV-1 RNA levels that were lower than 4530 copies per milliliter,2 and less than 7 percent of the patients in Katzenstein et al.'s substudy of ACTG 175 had base-line plasma HIV RNA levels that were less than 5000 copies per milliliter. Thus, the great majority of patients with CD4 cell counts of less than 500 per cubic millimeter, who already have immune depletion, also have viral loads associated with an increased risk of progression to AIDS and death, and hence, in our opinion, deserve antiretroviral therapy. Although we do not have data on the benefits of combination therapy in patients with CD4 cell counts below 500 per cubic millimeter and low viral loads, we also do not have data showing that this subgroup does not benefit from such therapy.

There are many important questions about the use of combination antiretroviral therapy that have not yet been answered. Does combination therapy reduce mortality among patients with CD4 counts of 500 or more cells per cubic millimeter who have high viral loads? What should be done when the initial therapy does not achieve a reduction of 1 log or more in plasma HIV RNA levels? When should additional or alternative therapies be instituted? Until more definitive data from clinical trials provide answers to such questions in the form of consistently reproducible results, clinicians will continue to use the CD4 count, clinical information, and judgments about the probable biologic importance of plasma HIV-1 RNA levels in extrapolating from the available trial data to the care of their patients.

Lawrence Corey, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104-2092

King K. Holmes, M.D., Ph.D.
University of Washington, Seattle, WA 98195

2 References

1
Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996;335:1081-1090
Full Text | Web of Science | Medline

2
Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis of HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167-1170
CrossRef | Web of Science | Medline

Author/Editor Response

Drs. Srinivasan and Beidas suggest that the measurement of plasma HIV RNA, as discussed in our study, provides an opportunity to encourage HIV-positive persons to accept antiretroviral treatment. This suggestion reflects an increasing interest among both HIV-infected persons and their physicians in the use of viral-load monitoring to determine the need for and response to treatment. Measurement of viral load defines a clear adversary. Reduced viral replication, lower plasma HIV RNA levels, and a decreased risk of disease progression are clearly appreciated responses to antiretroviral therapies. On the other hand, how much of a reduction in plasma HIV RNA levels is necessary to provide a lasting clinical benefit and how such a reduction can be sustained still need to be determined by additional carefully designed clinical trials.

David Katzenstein, M.D.
Stanford University Medical Center, Stanford, CA 94305

for the AIDS Clinical Trials Group Study 175 Investigators

Citing Articles (1)

Citing Articles

1
Eleni Papadopulos-eleopulos, Valendar F. Turner, John M. Papadimitriou, David Causer, Helman Alphonso, Todd Miller. (1999) A Critical Analysis of the Pharmacology of AZT and its Use in AIDS. Current Medical Research and Opinion 15:s1, S1-S45
CrossRef