Correspondence
Early Treatment of HIV Infection
N Engl J Med 1995; 333:1782-1783December 28, 1995
- Article
To the Editor:
In an editorial on the studies of early treatment of human immunodeficiency virus (HIV) infection by Kinloch-de Loës et al.1 and Volberding et al.,2 Dr. Ho (Aug. 17 issue)3 cites a study showing that the plateau concentration of viral RNA after primary HIV type 1 (HIV-1) infection predicts the clinical outcome. He suggests that “treatment at the time of seroconversion may lower the initial viral plateau (`set point') and thereby improve the subsequent clinical course.” Kinloch-de Loës et al. state that “the administration of antiviral therapy at the time of primary HIV infection is intended to decrease the viral load, which may . . . reduce the rate of the clinical progression of disease, and improve survival.” After six months, however, the viral loads were identical in the zidovudine and placebo groups, although the zidovudine recipients had higher CD4+ lymphocyte counts and fewer opportunistic infections. A study of zidovudine in 28 patients with later stages of disease, reported by Ruffault et al., showed that the patients in whom the disease progressed had higher plasma virus levels, both during and at the end of follow-up, than the patients without progression, but also had higher levels at base line.4
It is clear that the viral load is a predictor of disease progression. What we desperately need to show is that modulation of the plasma viral load by therapy during the late stages of infection improves the clinical outcome. People may infer that reducing the viral load after the primary infection has been demonstrated to ameliorate the course of HIV-1 disease. In fact, many physicians already use measurements of the plasma HIV-1 RNA level to monitor therapy long after the primary infection. There is as yet no scientifically valid basis for this approach.
The cost of a test to determine the plasma HIV-1 RNA level is approximately $250. The test would have to be performed at about three-month intervals, for a total cost of $1,000 yearly. Since there are between 1 and 2 million HIV-1–infected persons in the United States, the overall cost of monitoring the HIV RNA viral load could be $1 billion to $2 billion per year. It would be unconscionable to introduce this practice without substantial evidence of its benefit. The appropriate study could be accomplished within 18 months. Until that study has been performed, it is almost always unjustified to measure HIV-1 RNA levels outside a research study.
4 ReferencesW. Jeffrey Fessel, M.D.
Permanente Medical Group, San Francisco, CA 941151
Kinloch-de Loes S ,Hirschel BJ ,Hoen B , et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 1995;333:408-413
Full Text | Web of Science | Medline2
Volberding PA ,Lagakos SW ,Grimes JM , et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. N Engl J Med 1995;333:401-407
Full Text | Web of Science | Medline3
Ho DD . Time to hit HIV, early and hard. N Engl J Med 1995;333:450-451
Full Text | Web of Science | Medline4
Ruffault A ,Michelet C ,Jacquelinet C , et al. The prognostic value of plasma viremia in HIV-infected patients under AZT treatment: a two-year follow-up study. J Acquir Immune Defic Syndr 1995;9:243-248
Web of Science
To the Editor:
Ho states that the relative homogeneity of HIV during the earliest stage of disease favors the elimination of the virus before the development of potential escape mutants. This argument seems to be inconsistent with the random and independent accumulation of mutations in the pol region of HIV, as compared with the env region. It is the hypervariable regions of the latter gene that have typically been sequenced for studies of HIV heterogeneity, and it is these sequences that presumably come under the strongest selective pressure from antibodies and cell-entry requirements. Although the pol gene products may also come under selective pressure, is it clear that they are more homogeneous very early in the course of the disease than during the prolonged asymptomatic phase, with respect to the mutations known to confer a resistance to zidovudine? How can this be explained in the light of the hundreds of billions of virions produced during the first few weeks of infection, coupled with the mutation rate of 1 to 10 per 10,000 base pairs?
David H. Schwartz, M.D., Ph.D.
Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205-1901To the Editor:
The report by Kinloch-de Loës et al. on the use of zidovudine to treat primary HIV infection is exciting. As would be expected, the degree of viremia in the early stage of infection was considerably higher than at any other time. Moreover, the data in Figure 3 of the report show a persistent reduction in p24 antigen levels in the patients who received zidovudine and a more modest reduction in the HIV RNA levels. The authors conclude that antiretroviral therapy given during the primary infection may slow the onset of AIDS, presumably by reducing the initial viral burden.1 Although early treatment may prove important for the prognosis, it could have far greater public health benefits.
Mathematical models suggest that 56 to 92 percent of cases of HIV transmission may result from transmission during acute infection.2 The viral burden in genital secretions is probably high during this time, and the high-risk sexual behavior that initially allowed the acquisition of HIV usually continues unabated. Thus, reducing transmission from persons with early infection may be the best way to reduce the spread of HIV. Although zidovudine does not eliminate HIV from genital secretions, antiretroviral drugs may reduce the level of virus below the concentration required for efficient transmission.
The primary HIV infection appears to be a key target for both treatment and prevention. But finding, recruiting, and treating patients with acute infection will present a difficult challenge.
At the societal level, we must continue to move social norms in safer directions (e.g., delaying the initiation of sexual intercourse, reducing the rate of change in partners, and increasing the use of condoms). Reducing the synergistic effect of concurrent sexually transmitted diseases on the transmission of HIV3 with the use of presumptive treatment based either on individual signs or symptoms or on prevalence levels in populations may also reduce infectivity during the primary HIV infection. It is time to develop strategies focused on early HIV infection to help slow the spread of this virus.
3 ReferencesWillard Cates, Jr., M.D., M.P.H.
Family Health International, Research Triangle Park, NC 27709Myron S. Cohen, M.D.
University of North Carolina School of Medicine, Chapel Hill, NC 275991
Henrard DR ,Phillips JF ,Muenz LR , et al. Natural history of HIV-1 cell-free viremia. JAMA 1995;274:554-558
CrossRef | Web of Science | Medline2
Jacquez JA ,Koopman JS ,Simon CP ,Longini IM Jr . Role of primary infection in epidemics of HIV infection in gay cohorts. J Acquir Immune Defic Syndr 1994;7:1169-1184
Web of Science | Medline3
Wasserheit JN . Epidemiological synergy: interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis 1992;19:61-77
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Fessel that repeated monitoring of HIV-1 RNA plasma levels has not been demonstrated to be clinically beneficial. Our study had a totally different purpose, which was to assess the clinical and laboratory effects of zidovudine in patients with primary HIV infection. Our results do not suggest that quantitation of viremia should be used routinely in HIV infection.
We appreciate the comments made by Drs. Cates and Cohen. We believe that the diagnosis of primary HIV infection allows for counseling and may decrease the spread of the infection. As Cates and Cohen suggest, zidovudine may reduce the transmission of the virus to the sexual partners of patients with acute infection by decreasing viremia, although we were not able to show a dramatic effect on viremia in the zidovudine group, as compared with the placebo group. Combined therapy with two antiretroviral drugs, however, may be more effective in controlling viremia.1 As a consequence, in our clinical practice, we offer a combination of two antiviral drugs to patients presenting with primary HIV infection.
1 ReferencesSabine Kinloch-de Loës, M.D.
Luc Perrin, M.D.
Bernard Hirschel, M.D.
Geneva University Hospital, SwitzerlandAuthor/Editor Response
Dr. Fessel is apparently unaware of recent findings from multiple studies (AIDS Clinical Trials Group Protocols 116B/117 and 175 plus a Veterans Affairs Cooperative Study) that demonstrate the link between lowering the viral load and reducing adverse clinical events. As for the cost, the current cost of a plasma HIV-1 RNA test is actually closer to $100 per assay than $250, and the cost will decrease further when the demand increases. Moreover, measurements of viral load are likely to render obsolete many surrogate markers, some of which are quite costly to measure.
With respect to Dr. Schwartz's comment, I will simply restate the indisputable. It is easier to treat a homogeneous viral population than one that is heterogeneous. HIV-1 infection typically begins with a relatively homogeneous population, which diversifies with time. Ergo, it is easier to treat patients with HIV infection early in the course of infection.
Finally, I agree wholeheartedly with the views expressed by Drs. Cates and Cohen.
David D. Ho, M.D.
Aaron Diamond AIDS Research Center, New York, NY 10016
