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Primary HIV Infection and the Acute Retroviral Syndrome: The Urgent Need for Recognition

The new widespread availability of HIV viral-load testing, along with potent new antiviral therapeutic regimens, has created the opportunity for very early detection and treatment of acute HIV infection. It is critical that clinicians rapidly recognize primary HIV infection and consider the therapeutic options available during this early stage of disease. Recent evidence is a basis for hope that very early therapy will improve prognosis and perhaps even eradicate HIV.

Natural History of Acute Retroviral Syndrome

The period between initial exposure to and infection by HIV and the development of an HIV-specific antibody response is generally defined as primary HIV infection. Natural history during this stage of infection is characterized by both an enormous viremia and a vigorous immune response.¹ During the peak period of viremia a rapid decline in CD4 cell count occurs. In six subjects studied by Cooper et al., all subjects had an initial decrease in total lymphocyte count. The lowest median CD4 and CD8 counts occurred nine days after the onset of clinical illness. Cooper also described a second phase of response to acute HIV infection, notable for an inversion of the CD4 to CD8 ratio. In the six subjects studied, the median inversion of CD4 to CD8 ratio occurred 16 days after the onset of clinical symptoms and the median value of the inverted ratio was 0.70. This inversion of ratio was secondary to an increase in the number of CD8 cells relative to CD4 lymphocytes and was temporally associated with the development of lymphadenopathy.

A third phase of lymphocyte dynamics was noted to occur a median of 33 days after the onset of the clinical syndrome. The hallmark of this stage was an absolute increase in the number of circulating CD8 lymphocytes, resulting in an even greater inversion of the CD4 to CD8 ratio and probably reflecting a vigorous cytotoxic T-lymphocyte response. This response is hypothesized to be responsible for the decline in number of circulating virions. As infection abated, the ratio tended to reverse itself, mostly due to a rebound in the number of circulating CD4 lymphocytes and a decrease in CD8 lymphocytes. Nevertheless, the total number of CD4 cells usually did not return to baseline preinfection level, circulating CD8 lymphocytes remained at a higher level, and the ratio stayed inverted.²

During the period of peak viremia and immunological activity, patients often develop symptoms characteristic of a mononucleosis-like illness. As the immune system activates, HIV-specific cytotoxic T-lymphocyte activity increases,³ and eventually the amount of circulating virus declines until the host and virus develop an equilibrium and a "viral set point" is established. The development of high-level viremia accompanied by immunological activation in the presence of clinical manifestations constitutes the acute retroviral syndrome. This period of viremia and infection slowly evolves into what was formerly called a "clinically latent" period that begins with the generation of an HIV-specific antibody response. Seroconversion has been reported to occur from eight days to ten weeks after the onset of acute illness.⁴

Spectrum of Presentations

The spectrum of clinical presentation during this stage of disease varies broadly from completely asymptomatic infection to severe illness requiring admission to the hospital. Typically, symptoms develop within 5 to 30 days after exposure; median duration of symptoms is 14 days. Schacker et al. at the University of Washington examined 46 patients with documented primary infection to define its clinical and epidemiologic presentation.⁵ Eighty-nine percent of the studied patients reported symptoms associated with HIV seroconversion.

The symptoms most commonly reported by patients are fever, sore throat, fatigue, weight loss, and myalgia. Common physical findings include fever, lymphadenopathy, a macular erythematous rash, and orthostatic hypotension. Several oral manifestations, including exudative pharyngitis, thrush, and oral ulcerations, are frequent during primary infection. Genital or rectal ulceration, peripheral neuropathy,⁵ occasional meningoencephalitis,⁶ and thrombocytopenia⁷ have been reported. The differential diagnosis of this syndrome includes Epstein-Barr virus infection, cytomegalovirus (CMV) infection, influenza, acute toxoplasmosis, rubella, and syphilis.

Interestingly, 17 of the 46 patients reviewed by the University of Washington group were studied during the period before HIV-specific antibody responses were detected. Sixteen of the 17 reported having an acute retroviral syndrome, and 15 sought medical attention. These data suggest that a large proportion of patients seek medical attention during acute retroviral infection.

Importance of Early Recognition

However, it is of great concern that many cases of primary infection are not being recognized because the diagnosis is not considered. Furthermore, 23 of the 46 patients studied by the University of Washington group were participants in a routine surveillance program that performed HIV testing every six months. Of the 23 patients reviewed, 20 reported a history of symptoms associated with acute retroviral illness and 19 of them were evaluated medically while these symptoms were occurring, but a diagnosis of primary HIV infection was considered in only 5 of 19 patients (26%).⁵

Although data are limited, a strong case can be made for starting antiretroviral therapy as soon as possible after a patient is diagnosed with acute retroviral syndrome. The rationale is as follows:

First, some have argued that acute curtailment of viral production will help the immune system clear virus, resulting in a lower "viral set point" than if initial viral infection went unabated.

Second, there is the theoretical advantage that by dramatically limiting viral production during the period of tremendous viremia and immune activation, fewer of the lymphocytes proliferate in direct response to the virus will become infected and subsequently disappear.

Recent Data

Perhaps the best preliminary evidence to date suggesting that early, aggressive treatment is advantageous was presented at the 4th Conference on Retroviruses and Opportunistic Infections by Markowitz et al. from the Aaron Diamond AIDS Institute in New York City. This study (which is still in progress) examined 24 patients found to be within 90 days of HIV infection and placed on triple-drug therapy, including AZT (200 mg TID), lamivudine (150 mg BID) and either ritonavir (600 mg BID) or indinavir (800 mg TID). All subjects compliant with the three-drug regimens have achieved and maintained an undetectable plasma viral load. The patients have been on therapy from 4 to 16 months. Preliminary data from this group suggest that virus is absent from lymphoid tissue. Several of these subjects have also undergone biopsy of GALT (gastrointestinal-associated lymphoid tissue), and both culture and in-situ hybridization for HIV RNA indicate no viral activity is present in these biopsy tissues.⁸

The only study published on the effect of antiviral therapy during primary infection was a multicenter, double-blind, placebo-controlled trial that enrolled 77 patients with primary HIV infection and randomized them to AZT (250 mg BID) or placebo for six months. The AZT-treated group had fewer minor opportunistic infections and a small increase in mean CD4 cell count.⁹ This trial report did not mention the long-term impact of AZT treatment during primary infection or the emergence of AZT resistance.

Duration of Treatment

There are no clinical trial data to guide duration of therapy initiated during primary HIV infection. The mathematical model of viral kinetics proposed by Alan Perelson and David Ho suggests there is a rapid "first phase" decline in plasma viral number, followed by a much slower "second phase" decline in long-lived sources such as macrophages and lymphoid tissue.¹⁰ By these models, the earliest the concept of "viral eradication" could be entertained for these patients is after two to three years of therapy. It is most important to note that, although based on clinical data, these models are theoretical estimates that have not yet been confirmed.

Recommendations

We propose the following guidelines for an initial diagnostic and therapeutic approach when a patient presents with possible acute HIV infection.

1. Maintain a high level of suspicion even in the absence of known risk factors.

2. Perform a thorough history and physical exam, paying attention to details and dates of high-risk exposure, and known signs and symptoms of acute retroviral syndrome.

3. Perform a qualitative HIV-DNA assay, if available. Otherwise a quantitative test of viral load should be performed. Because neither of these tests is approved by the FDA for diagnosis, they must be followed with antibody testing. A baseline HIV-1 antibody test should also be performed at the initial visit.

4. If a qualitative DNA assay is positive, perform a baseline T-cell subset analysis and a quantitative viral load measurement, then commence aggressive antiretroviral therapy as soon as possible. Regimens should include two nucleoside analogs in combination with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor.

5. When possible, the three drugs in a three-drug regimen should be started simultaneously. Given the large viral burden and rapidity with which HIV replicates during primary infection, resistance can theoretically develop if medications are started in a step-wise manner.

6. To assure a rapid lowering of viral burden, monitor viral load at four weeks and then monthly until a stable viral set point is reached -- the goal is below detection.

7. Within six weeks after onset of primary infection, perform an HIV-1 antibody test to confirm the diagnosis; repeat until positive.

8. Counsel patients about the spread of HIV and to notify individuals with high-risk exposure to the patient.

9. Many experts believe that at least six months of triple-drug therapy, followed by either two- or three-drug combinations should be administered, but at this time we lack data to guide these decisions.

10. Given the complexity and uncertainty of therapy for primary HIV infection, patients should be referred when possible to an AIDS center or experienced AIDS practitioner and be offered participation in any available clinical trials.

View this table: [in a new window]   Table 1. Recognizing and Treating Acute Retroviral Syndrome

 

Conclusion

Both effective methods of detection and promising therapy exist for primary HIV infection. Clinicians caring for patients at risk for acquiring HIV infection are strongly encouraged to maintain a high level of suspicion of HIV, in order to detect and diagnose the acute retroviral syndrome. Although there is a paucity of clinical trial data on which to base decisions, preliminary data suggest that aggressive combination therapy as soon as infection is detected may offer the most promising prognosis to date in HIV infection.

— Eric Rosenberg, MD, and Deborah Cotton, MD, MPH

Dr. Rosenberg is a senior infectious diseases fellow at Massachusetts General Hospital. Dr. Cotton is Editor of AIDS Clinical Care. Referrals: rosenberg.eric@mgh.harvard.edu or 617-724-3923.

Published in Journal Watch HIV/AIDS Clinical Care March 1, 1997

Citation(s):

1. Daar E et al. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med 1991 324 961-964.

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2. Cooper DA et al. Characterization of T lymphocyte responses during primary infection with human immunodeficiency virus. J Infect Dis 1988 157 889-896.

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3. Koup RA et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994 68 4650-4655.

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4. Cooper DA et al. Antibody response to human immunodeficiency virus after primary infection. J Infect Dis 1987 155 1113-1118.

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5. Schacker T et al. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996 125 257-264.

• Original article (Subscription may be required)
• Medline abstract (Free)

6. Ho D et al. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to acquired immunodeficiency syndrome. N Engl J Med 1985 313 1493-1497.

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7. Cooper DA et al. Acute AIDS retrovirus infection: Definition of a clinical illness associated with seroconversion. Lancet 1985 1 537-540.

• Medline abstract (Free)

8. Markowitz M et al. Recent HIV infection treated with AZT, 3TC, and a potent protease inhibitor. 4th Conference on Retroviruses and Opportunistic Infections. Washington DC, January 22-26 1997 .

9. Kinloch-De Loes et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 1995 333 408-413.

• Original article (Subscription may be required)
• Medline abstract (Free)

10. Perelson AS et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996 271 1582-1585.

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