Am Fam Physician. 1999 Aug 1;60(2):413-417.
In this issue of American Family Physician, Perlmutter and colleagues1 carefully discuss the diagnosis and treatment of persons newly infected with human immunodeficiency virus (HIV-1). Certain aspects of this topic merit additional comment.
As clinicians, our first responsibility in assessing the acutely ill patient is to diagnose life-threatening conditions and initiate appropriate therapy. However, acute HIV-1 infection is not life-threatening. Nevertheless, failure to consider the diagnosis makes it impossible to order the definitive diagnostic laboratory tests—plasma HIV-1 measurements and HIV-1 serologies.2 Without the results of these specific tests, the clinician will not be able to make the proper diagnosis, raising many questions.
Does a failure to consider an HIV diagnosis compromise our patients' future clinical course? Furthermore, do we compromise their future clinical course by failing to promptly identify the pathogen and initiate appropriate antiviral therapy? Or, are we exposing these patients to therapies with significant short- and long-term toxicities without clear evidence of long-term benefit? Moreover, will early intervention even endanger the future therapeutic response in these patients if a drug-resistant virus develops as a result of intermittent adherence to treatment?
Failure to identify a patient who is newly infected with HIV-1 may result in a permanently lost opportunity. Current guidelines support early treatment based on virologic, immunologic and public health considerations.3 Rosenberg and coworkers4 have demonstrated that treating primary HIV-1 infection allows for the maintenance of T-helper cell responses to HIV-1–specific antigens, whereas these responses are more difficult to demonstrate in similarly treated, chronically infected persons. Given the knowledge that a small, slowly decaying latent infectious reservoir is established very early in the course of HIV-1 infection, the maintenance of these immune responses may be critical if the ultimate goal of immune control of HIV-1 is to be achieved.
Why are these immune responses thought to be so critical? Perhaps, the characterization of patients with long-term HIV-1 infection and the absence of immunologic progression (long-term non-progressors [LTNPs]) has given us a clue to the importance of HIV-1–specific immune responses. These patients as a group are characterized by high levels of CD4 cell proliferation to HIV-1–specific antigens and robust HIV-1–specific cytotoxic T cell responses, as well as a modest viral burden.5,6 Although LTNPs make up at most only 5 percent of the HIV-1–infected population, they have provided us with an important model which may be achieved with early intervention.7
Based on a series of interventional clinical trials that provided insight into HIV-1 replication dynamics in vivo, a two-compartment model of HIV-1 replication was proposed in which some infected cells decay rapidly (half-life of one day) and some decay slowly (half-life of two to four weeks).8,9 We hypothesized that if virus replication could be completely suppressed and no other compartment exists, then HIV-1 would be “eradicated” in 30 to 36 months of continuous antiretroviral therapy. However, with the identification of a longer-lived latent population (minimal half-life of six months), eradication with antiviral therapy alone becomes less likely.10
Nevertheless, early therapy can clearly limit the size of this latent pool by controlling the repetitive rounds of virus replication characterizing the chronic asymptomatic phase of HIV-1 infection. We have recently demonstrated that early therapy can result in profound suppression of virus replication and preservation of the host immune system.11 Also, hypothetically, the long-term results of this suppression are unknown but, with therapy, less virus and more potent immune responses may allow for subsequent immune control of HIV-1 infection.
The public health consequences of undiagnosed HIV-1 infection are significant. Despite reductions in HIV-1–associated morbidity and mortality,12 new infections continue to occur at alarming rates, particularly in adolescents and women. Failure to inform patients that they may transmit this infection either sexually or through intravenous drug use can only further aggravate this trend. Though immediate diagnosis does not guarantee responsible behavior, early initiation of therapy and reductions of viremia to extremely low levels will likely reduce transmissibility of the pathogen.
Early therapy has risks as well as benefits. The toxicities of therapy along with the complexity of the current regimens make patient adherence a critical issue. Intermittent pill-taking may result in the emergence of drug-resistant variants.13 However, even though the current therapies have a long way to go before they can be considered “ideal,” withholding therapies because of these considerations abolishes the benefit of early diagnosis and treatment.
Untreated HIV-1 infection is characterized by high-level ongoing virus replication that ultimately results in immunodeficiency. The therapeutic advances in the past five years have clearly made it possible to reduce and maintain viral replication to minimal levels. The prospect of achieving a virologic remission (that is, control of replication in the absence of antiviral therapy) remains a daunting challenge. However, if this goal is to be achieved, the newly infected patient with a minimally impaired immune system and a minimal viral burden is certain to be the most likely successful candidate.
Dr. Markowitz is assistant professor at Rockefeller University and clinical director of Aaron Diamond AIDS Research Center, New York, N.Y.
Address correspondence to Martin Markowitz, M.D., Rockefeller University, New York, N.Y. 10016.
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2. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med. 1996;125:257–64.
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5. Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Eng J Med. 1995;332:209–16.
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10. Perelson A, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature. 1997;387:188–91.
11. Markowitz M, Vesanen M, Tenner-Racz K, Cao Y, Binley JM, Talall A, et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis. 1999;179:527–37.
12. Palella F, Delaney K, Moorman A, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced HIV infection. N Engl J Med. 1998;338:853–8.
13. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS. 1999;13:F35–42.
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