The severity and the duration of acute human immunodeficiency virus (HIV) infection (AHI) are associated with a faster rate of progression to AIDS, but the prognostic value of the length of incubation time of AHI (IncAHI), defined as the time between HIV infection and AHI, on progression to AIDS has not been assessed. We explored this issue prospectively in 70 individuals with documented AHI and a known date of HIV infection. The median IncAHI was 21.5 days (range, 5-70 days), and the median duration of AHI was 15.5 days (range, 3-67 days). The adjusted relative hazard of progression to AIDS or to a CD4+ count 15.5 days, compared with those with shorter duration. Both IncAHI and duration of AHI were independent predictors of progression. This suggests that early pathogenic events before the onset of AHI influence the rate of HIV disease progressio

Brassard, Joelle

Cooper, David A.

Hirschel, Bernard

Perrin, Luc

Phillips, Andrew N.

Vanhems, Philippe

Vizzard, Jeanette

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334CONCISE COMMUNICATIONIncubation Time of Acute Human Immunodeficiency Virus (HIV) Infectionand Duration of Acute HIV Infection Are Independent Prognostic Factorsof Progression to AIDSPhilippe Vanhems,1 Bernard Hirschel,2Andrew N. Phillips,3 David A. Cooper,4Jeanette Vizzard,4 Joelle Brassard,5 and Luc Perrin21Laboratory of Epidemiology and Public Health, INSERM U271,Universite´ Claude Bernard, and Epidemiology Unit, Edouard HerriotHospital, Lyon, France; 2Division of Infectious Diseases, UniversityHospital, Geneva, Switzerland; 3Royal Free Centre for HIV Medicineand Department of Primary Care and Population Sciences, Royal Freeand University College Medical School, London, United Kingdom;4National Centre in HIV Epidemiology and Clinical Research,Sydney, Australia; 5Institute of Social and Preventive Medicine,University of Montreal, Montreal, CanadaThe severity and the duration of acute human immunodeficiency virus (HIV) infection(AHI) are associated with a faster rate of progression to AIDS, but the prognostic value ofthe length of incubation time of AHI (IncAHI), defined as the time between HIV infectionand AHI, on progression to AIDS has not been assessed. We explored this issue prospectivelyin 70 individuals with documented AHI and a known date of HIV infection. The medianIncAHI was 21.5 days (range, 5–70 days), and the median duration of AHI was 15.5 days(range, 3–67 days). The adjusted relative hazard of progression to AIDS or to a CD4+ count! /mL was 4.23 (95% confidence interval [CI], 1.40–12.73; ) for the patients3200 3 10 P = .01with an IncAHI !21.5 days, compared with those with longer IncAHI, and was 3.53 (95%CI, 1.09–11.36; ) for the patients with a duration of AHI 115.5 days, compared withP = .03those with shorter duration. Both IncAHI and duration of AHI were independent predictorsof progression. This suggests that early pathogenic events before the onset of AHI influencethe rate of HIV disease progression.Acute human immunodeficiency virus type 1 (HIV-1) infec-tion (AHI) is a heterogeneous syndrome [1, 2]. Patients withmore severe symptoms during AHI and an AHI lasting 115days tend to progress faster toward AIDS [3, 4]. Data on theprognostic value of the incubation of AHI (IncAHI), definedas the time between HIV infection and AHI, are lacking.The objective of this investigation was to determine whetherthe time from HIV infection until the onset of AHI is an in-Received 10 November 1999; revised 18 April 2000; electronically pub-lished 19 June 2000.Presented in part: 6th Conference on Retrovirus and Opportunistic Com-plications, Chicago, 31 January–4 February, 1999 (poster 73).Financial support: Swiss Federal Office of Public Health through fundingof the Swiss HIV Cohort Study (project 256) and Swiss National AIDSProgram (grant 3200.56.059.98). The National Centre in HIV Epidemiologyand Clinical Research is supported by the Australian National Council onAIDS through the Commonwealth AIDS Research Grants Committee.Informed consent was obtained from patients.Reprints or correspondence: Dr. Philippe Vanhems, Laboratoire d’Epi-de´miologie et de Sante´ Publique, Universite´ Claude Bernard Lyon 1, 8,av. Rockefeller, 69373 Lyon Cedex 08, France (philipva@lyon-sud.univ-lyon1.fr).The Journal of Infectious Diseases 2000;182:334–7q 2000 by the Infectious Diseases Society of America. All rights reserved.0022-1899/2000/18201-0046$02.00dependent factor of progression to AIDS or toward a CD41count ! /mL after adjustment for duration of AHI.3200 3 10MethodsThis prospective study included a total of 70 patients with AHIfor whom a date of HIV infection was known. These patients area subgroup of a larger cohort of Swiss and Australian individualsdescribed in detail elsewhere [1]. This cohort was initiated to studythe clinical features of AHI and the comparison of the rates ofdisease progression by severity of AHI. The patients selected forthis investigation were those with symptomatic AHI and with adate of HIV exposure reported in the data-collection form. Theonset of AHI was before the end of 1987 in 6 patients, between1988 and 1991 in 19 patients, and between 1992 and December 31,1995 in 45 patients. Patients were asked about the date of infectionat the time they presented with symptoms of AHI. The number ofsexual partners within the last year was 1 for 57 patients (81.4%),2 for 5 patients (7.1%), and 12 for the remainder (11.4%). Thepresumed route of HIV infection was self-reported; a total of 47individuals (67%) reported infection by unprotected homosexualintercourse, 6 (8.5%) by unprotected receptive oral sex, 11 by het-erosexual intercourse (15.7%), 2 after syringe exchange (3%), 1 afterblood transfusion (1.4%), and 3 by another route not reported. TheJID 2000;182 (July) Time From Infection to Acute Syndrome Predicts Progression to AIDS 335Figure 1. Probability of being free of clinical AIDS or not havinga CD41 cell count ! /mL for individuals with incubation of3200 3 10acute human immunodeficiency virus (HIV) infection 121.5 days (solidline) or !21.5 days (dashed line).serostatus of patients’ partners was available for 11 individuals. In2 cases (3%), the partner had AIDS, and in 9 cases (13%) he wasasymptomatic. The date of exposure was based on the patient’sbest estimate. IncAHI was defined as the time elapsed between thedate of HIV infection and the date of AHI onset. The clinicalfeatures of AHI were recorded on standardized collection forms inthe 2 centers (in Geneva and Sydney) [1]. Clinical and laboratoryfollow-up procedures were similar in both centers [1].The laboratory criteria of AHI were (1) the presence of p24antigenemia ( ) in patients with negative or indeterminate EIAn = 58serology, (2) 2 bands on Western blots, one of which correspondedto the env gene (gp 160, gp 120, gp 41; ) with a negative EIAn = 3serology, and (3) a negative HIV-1 EIA test followed by a positiveHIV-1 EIA test within 6 months (median, 85 days; range, 4–188days; ). HIV infection was confirmed in all patients by Westernn = 9blots. CD41 cell counts were conducted in laboratories affiliatedwith either university center. The laboratories in Geneva and Syd-ney are national reference centers, and quality control testing isdone regularly. T cell subsets were measured by flow cytometry inboth locations.Groups were compared by the x2 test or Fisher’s exact test forcategorical variables and by Student’s t test for continuous vari-ables after logarthimic transformation, if necessary. Multiple linearregression was used for calculate the association between IncAHIand duration of AHI, after adjustment for confounders. The end-point was AIDS according to the 1993 definition by the Centersfor Disease Control and Prevention or a first CD41 count! /mL. Progression was calculated by the Kaplan-Meier3200 3 10method, with the onset of AHI as time 0 and censoring at the lastvisit or at June 30, 1995, to exclude the confounding effect of theuse of highly active antiretroviral therapy. Comparison of survivaldistribution was based on the log-rank test. The Cox proportionalhazard model was used to estimate the adjusted relative hazard(ARH) of disease progression. No patient was considered lost tofollow-up, defined as 1 year without knowledge of vital status. Pvalues !.05 were considered statistically significant. Analysis wasconducted with SPSS version 6.0 (SPSS, Chicago).ResultsThe patients, 91% of whom were men, had a mean age of30.6 years. Thirty-one patients were from Geneva and 39 fromSydney. The mean IncAHI was 25.8 days, with a median of21.5 days (range, 5–70 days), and did not differ by center( ). The mean duration of AHI was 16.8 days, with aP = .15median of 15.5 days (range, 3–67 days). The most commonsymptoms at AHI were fever (91%), lethargy (84%), skin rash(76%), headache (69%), myalgia (67%), arthralgia (41%), anddiarrhea (27%). No difference in symptom frequency or theproportion of hospitalized patients (23%) was observed ac-cording to IncAHI greater than or less than 21.5 days.Adjusted regression analysis did not identify independentvariables associated with IncAHI ( for duration of AHI;P = .77for age; for gender; for route of infec-P = .33 P = .50 P = .36tion; for the center [Geneva vs. Sydney]).P = .17The duration of follow up was 24.3 months for patients withIncAHI below the median (21.5 days; group 1) and 24.2 monthsfor patients with IncAHI above the median (group 2; ).P = .9Antiretroviral treatment was prescribed in a similar proportionin the 2 groups ( ) at AHI (48%) and during follow upP = 1.00(60% for group 1 and 51% for group 2; ). The meanP = .47interval between AHI and the start of antiretroviral therapywas 6.2 months for group 1 and 5.5 months for group 2( ). The regimens prescribed at AHI for patients in groupP = .841 was single nucleoside reverse transcriptase inhibitor for 15patients (43%), a combination of 2 nucleoside reverse tran-scriptase inhibitors for 1 patient (6%), and a combination ofnucleoside reverse transcriptase inhibitor and acyclovir for 1patient (6%); the regimens prescribed at AHI in group 2 werea single nucleoside reverse transcriptase inhibitor for 15 patients(43%), a combination of nucleoside reverse transcriptase in-hibitor and acyclovir for 1 patient (6%), and a combination ofnucleoside reverse transcriptase inhibitor and nonnucleoside re-trotranscriptase inhibitor for 1 patient (6%). The proportion ofpatients treated within 3 months after AHI was similar betweenthe two centers (58% for Geneva and 41% for Sydney; P =), and the total duration of antiretroviral was also similar.16between the two centers (mean of 4.6 months for Geneva andmean of 4.1 months for Sydney; ). The proportion ofP = .5patients who received primary Pneumocystis carinii prophylaxiswas similar in both groups ( ). A total of 13 patients inP = .32group 1 and 8 patients in group 2 reached the end point duringthe follow-up. Six AIDS events occurred in group 1 (2 chronicherpes simplex ulcerations 11 month, 2 cryptosporidiosis, 1AIDS dementia complex, and 1 cytomegalovirus infection), and336 Vanhems et al. JID 2000;182 (July)Table 1. Adjusted relative hazard of progression to AIDS or to aCD41 cell count ! /mL.3200 3 10VariableAdjusted relativehazard (95% CI) PIncAHI !21.5 days 4.23 (1.40–12.73) .01Duration of AHI >15.5 days 3.53 (1.09–11.36) .03Antiretroviral treatment at AHI 0.28 (0.08–.94) .04Primary Pneumocystsi carinii pneumoniaprophylaxis 0.50 (0.13–1.84) .30Route of HIV infectionHomosexual intercourse vs. others 0.25 (0.02–2.16) .20Center (Geneva vs. Sydney) 0.40 (0.11–1.30) .12NOTE. All the variables of the table were in the model equation. Age wasnot associated with progression ( ) and not included in the model. ModelP = .69characteristics: 22 log likelihood, 83.556; x2, 24.513; 6 df; . CI, confi-P = .0004dence interval; IncAHI, incubation of acute human immunodeficiency virus (HIV)infection.2 AIDS events occurred in group 2 (1 Mycobacterium aviumcomplex infection and 1 chronic herpes simplex ulceration 11month). By use of the Kaplan-Meier analysis, the median ofprogression to AIDS or to a CD41 cell count ! /mL3200 3 10was 3.82 years (95% confidence interval [CI], 3.13–4.50) ingroup 1 and 5.05 years (95% CI, 1.80–8.28) in group 2 (P =; figure 1). One patient received protease inhibitors 243 days.03after AHI for a period of 92 days; this individual was in group1 and did not have AIDS during follow-up. Survival analysiswithout this patient remained unchanged. By use of the Kaplan-Meier method, the median of progression to AIDS or to a CD41cell count ! /mL was 3.55 years (95% CI, 2.93–4.17)3200 3 10for individuals with a duration of AHI greater than the median(15.5 days) and 5.04 years (95% CI, 4.30–5.78) for those witha duration of AHI less than the median ( ).P = .005We calculated the ARH of progression using the proportionalhazard model after adjustment for the length of AHI and forpotential confounders (table 1). The multivariate model iden-tified both IncAHI and duration of AHI as independent prog-nostic factors of disease progression. Similar analysis withIncAHI and AHI as continuous variables identified only a longIncAHI (AHR, 0.95; 95% CI, 0.91–0.99; ) as protectiveP = .03effect on disease progression. Among patients free of antire-troviral treatment at AHI, the mean of CD41 within 1 monthafter onset was 467/mL (SD, 271) for group 1 patients (n =) and 604/mL (SD, 228) for group 2 patients ( ;14 n = 21 P =) and the mean of CD41 at 2 months after onset was 637/.12mL (SD, 263) for group 1 patients ( ) and 695/mL (SD,n = 19325) for group 2 patients (a; ). The use of antiretroviralP = .52therapy at AHI had a protective effect in this observationalcohort.DiscussionThe objective of this study was to identify the independentprognostic value of the IncAHI and duration of AHI. Previ-ously, early prognostic studies were done mostly at the onsetof AHI and/or at the time of HIV seroconversion, but fewinvestigations of IncAHI have been conducted. The questionof the validity of the reported date of HIV infection is centraland was ascertained on 3 grounds. First, the information wascollected prospectively, which reduced memory bias. Second,the duration between infection and the onset of AHI was similarto that in studies elsewhere [2, 5–8], in which IncAHI rangedfrom 1 to 8 weeks. For example, IncAHI lasted 11–28 days forGaines et al. [5], 5–29 days (mean, 15 days) for Schacker et al.[2], 2–3 weeks for Quin [6], and 3–6 weeks for Clark et al. [7].Third, our results are consistent with data obtained from health-care workers who developed AHI after needle-stick injuries [9].In that case, the IncAHI reported was 14–28 days for Marcuset al. [10], 25 days for Oksenhendler et al. [11], and 16 daysfor Pratt et al. [12]. Although we cannot have total confidencein individual measures of the IncAHI, we think it unlikely thatlack of precision would bias our results. For a bias to occur,patients destined to progress faster toward AIDS would haveto systematically recall a presumed date of infection that waslater than the real date of infection. The occurrence of such asystematic error does not seem plausible to us.IncAHI was associated with progression toward AIDS in ourcohort independently of duration of AHI. Because this resultwas obtained among individuals who reached a small numberof outcomes, confirmatory studies are needed with larger co-horts. Pedersen et al. showed that duration of acute HIV in-fection was associated with a faster progression to AIDS [3].The rapid rate of disease progression observed in our cohortwas related to the absence of asymptomatic HIV seroconver-tors. Our study was conducted among patients who, except for1, received what is now regarded as suboptimal therapy, becauseno protease inhibitors were administered until the end of follow-up. This provided the opportunity to study the natural historyof disease progression without the confounding factor of highlyactive antiretroviral therapy.The present investigation suggests that initial pathogeneticmechanisms could influence the rate of disease progression,even before the onset of AHI. The mechanisms influencing thelength of IncAHI are not well understood. Because no specificanti-HIV immune response can be measured during that period,differences in the replicative capacities of HIV, in the interactionof HIV and mucosal surfaces or in the reaction of the innateimmune system to HIV, could presumably play a role [13]. Ashort IncAHI could mean that the virus has faster access tothe target cells. Investigations on the transition period betweenIncAHI and onset of AHI could yield essential information onthe respective contribution of the viral replication [14] and im-munological response [15] that determine the prognosis. Theimpact of virus replication and its relationship to host geneticfactors also need to be investigated.This study suggests both IncAHI and duration of AHI wereassociated with the prognosis. These results confirm the keyplace of early events on late prognosis of HIV infection.JID 2000;182 (July) Time From Infection to Acute Syndrome Predicts Progression to AIDS 337AcknowledgmentsWe wish to thank B. Anderson, D. Baker, A. Beveridge, M. Bloch,N. Doong, C. Duncombe, R. Finlayson, V. Furner, B. Genn, J. Gold,J. Kidd, R. McFarlane, M. McMurchie, A. McNulty, H. Michelmore,A. Pethebridge, D. Quan, and M. Robertson (Sydney); J. Kaldor andthe late B. Tindall, at the National Centre in HIV Epidemiology andClinical Research (Sydney); and J. F. Balavoine, A. Christina, C. Junet,V. Sendersky, J. Wintsch (Geneva), and S. Kinloch-de Loe¨s (London).The members of the Swiss HIV Cohort Study are M. Bateguay (co-chair of the scientific board), E. Bernasconi, Ph. Bu¨rgisser, M. Egger,P. Erb (chairman of the “Laboratories” group), W. Fierz, M. Flepp(chairman of the “Clinics” group), P. Francioli (president of the SwissHIV Cohort Study, Centre Hospitalier Universitaire Vaudois, CH-1011Lausanne), H. J. Furrer, P. Grob, B. Hirschel (co-chair of the scientificboard), L. Kaiser, B. Ledergerber, R. Lu¨thy, R. Malinverni, L. Matter,M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, W. Pichler, J.-C. Pif-faretti, M. Rickenbach, P. Sudre, J. Schupbach, A. Telenti, and P.Vernazza.References1. Vanhems P, Allard R, Cooper DA, et al. Acute human immunodeficiencyvirus type 1 disease as a mononucleosis-like illness: is the diagnosis toorestrictive? Clin Infect Dis 1997;24:965–70.2. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemi-ologic features of primary HIV infection. Ann Intern Med 1996;125:257–64.3. Pedersen C, Lindhardt BO, Jensen BJ, et al. Clinical course of primary HIVinfection: consequences for subsequent course of infection. BMJ 1989;299:154–7.4. 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Incubation Time of Acute Human Immunodeficiency Virus (HIV) Infection and Duration of Acute HIV Infection Are Independent Prognostic Factors of Progression to AIDS

Incubation Time of Acute Human Immunodeficiency Virus (HIV) Infection and Duration of Acute HIV Infection Are Independent Prognostic Factors of Progression to AIDS

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