Is the Rate of Progression to AIDS Associated with the Severity of Primary HIV Infection?
ABSTRACT & COMMENTARY
Source: Vanhems P, et al. Severity and prognosis of acute human immunodeficiency virus Type I illness: A dose-response relationship. Clin Infect Dis 1998;26:323-329.
Vanhems and colleagues examined the relationship between the severity of the acute illness due to primary HIV-1 infection and the time to disease progression and death. A total of 259 newly HIV-infected persons, including 171 Australians and 88 Europeans, were assessed, all of whom were enrolled in four ongoing studies of primary HIV infection in either Sydney, Australia, or Geneva, Switzerland, including a placebo-controlled treatment trial of AZT.
Acute symptomatic infection occurred in 218 of 259 subjects (84%) who presented with acute symptomatic primary infection confirmed by either the presence of p24 antigen and initially negative or indeterminate ELISA (62%), two other bands on Western blot and initially negative or indeterminate ELISA (8%), or subsequent seroconversion by ELISA within one year (30%). RNA studies were not available. Forty-one of 259 subjects (16%) were initially asymptomatic and seronegative for HIV, and were enrolled within one-year of presentation based on subsequent seroconversion. Time 0 was defined as the date of laboratory confirmation of acute HIV disease or, in the case of those patients who were initially asymptomatic with negative blood tests, the midpoint between their first presentation and documentation of infection. Only those symptoms that occurred in more than 10% of patients were included in the analysis; thus, the few patients with encephalitis, esophagitis, and lymphadenopathy were excluded. Disease progression was confirmed using Centers for Disease Control clinical categories B and C. The median follow-up for the cohorts was 3.2 years (range, 0.12-10.6 years).
Most of the subjects averaged 32 years of age, were male (93%), and were homosexual (79%). The mean duration of acute illness was 25 ± 22 days. A total of 81 (31%) patients progressed to CDC category B, 63 (24%) progressed to CDC category C, and 54 (21%) patients died. The median times to these events were, respectively, 6.1, 7.3, and 8.6 years.
Multivariate analysis showed that patients who presented with multiple symptoms progressed more rapidly than asymptomatic subjects, but only patients with a total of 5-6 symptoms at initial presentation developed category C disease or died. Oral candidiasis, which occurred in 37 (14%) patients, was the strongest predictor of more rapid disease progression, with a median time to category B disease of 3.9 years (range, 2.2-5.5 years) compared with 6.6 years (range, 6.0-7.1 years) for patients without thrush (P = 0.0002). Other signs and symptoms such as fever greater than 38.5°C, pharyngitis or sore throat, skin rash, lethargy, and diarrhea were also significantly associated with more rapid disease progression (all cases, P < 0.03).
There was a suggestion, not statistically significant, that AZT administration at the time of acute infection may delay the onset of disease progression; the risk of progression in patients receiving AZT was less compared with those receiving placebo (adjusted Hazard ratio, 0.62; 95% CI, 0.31-1.27).
COMMENT BY CAROL A. KEMPER, MD
Although the patients enrolled in this study lived in geographically distinct sites, were enrolled in other clinical trials (including an assessment of AZT monotherapy in the treatment of acute HIV infection), and largely volunteered for this trial, these factors do not alter the conclusions. Whether some patients diagnosed with "acute" HIV-1 infection were correctly diagnosed, especially those who presented with thrush, is, perhaps, debatable, although documentation of seroconversion was confirmed in all of the patients. Vanhems and colleagues acknowledge this potential limitation, but indicate that only two patients who presented with thrush progressed to category B disease within 80 days.
The findings of this study are supported by at least two other studies of primary HIV infection. Swedish investigators found that patients with hyperacute primary HIV infection were more likely to progress to AIDS (58% vs 28%), develop CD4 counts less than 200/mm3 (84% vs 54%), or to die (53% vs 7%) compared with asymptomatic seroconverters (Lindbaack S, et al. BMJ 1994;309:1535-1537). Veugelers and colleagues in British Columbia found that one-half of seroconverters with sustained fever greater than 38.5°C for seven or more days progressed to AIDS within six years compared with only one-fourth of those asymptomatic converters (Veugelers PJ, et al. J Infect Dis 1997;176:112-117). Sweats, cough, and fatigue during the acute illness were not significantly associated with disease progression.
These data are helpful in identifying a subset of patients who may be more likely to benefit from aggressive initiation of antiretroviral therapy during primary infection. Such therapeutic intervention could, however, be supplanted by the broader use of "PEP for sex" (postexposure prophylaxis for high risk sexual [and needle] exposures), but this seems unlikely to occur based on the current lack of public awareness surrounding this issue, the availability of such intervention, and its cost. Thus far, only low-risk individuals with an isolated episode of high-risk activity appear interested in seeking out such potentially preventative measures, at least in the San Francisco Bay Area. Others who more regularly engage in high-risk activities, such as young gay males, adolescents, and parenteral drug users, unfortunately continue to put themselves at risk for HIV infection. These patients may prove especially difficult to identify and recruit for aggressive early intervention and prevention studies.
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