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Signs or symptoms of acute HIV infection in a cohort undergoing community-based screening.

The detection of acute HIV infection (AHI) is critical to HIV prevention and treatment strategies (1). Clinical diagnosis of AHI is difficult, however, because the signs and symptoms that occur during seroconversion are frequently not recognized as an indicator of AHI (2-4). Although screening programs that rely on point-of-care HIV antibody testing will reliably identify persons with established infection, these tests fail to detect AHI (1,5). The Centers for Disease Control and Prevention began addressing this problem by updating recommendations for the laboratory diagnosis of HIV in healthcare settings to include initial fourth generation HIV-1 p24 antigen-based immunoassays (6). However, previous studies indicate that sensitivity of p24 antigen detection for AHI might not exceed 80% (7). In addition, most testing programs in nonhealthcare settings continue to rely on routine antibody testing alone, with specific testing for AHI conducted only for persons with signs or symptoms.

Although previous studies focused on retrospective evaluation of AHI symptoms in persons diagnosed with early seropositive HIV infection (8,9) or cases identified by symptom-based AHI screening, the actual proportion of persons with AHI who are symptomatic at the time of testing remains unknown. We investigated the proportion of persons with AHI who have ongoing or recent signs or symptoms at the time of their diagnostic test in a cohort undergoing community-based universal AHI screening.

The Study

We analyzed AHI signs and symptoms in 90 patients given a diagnosis of AHI during 2007-2014. As part of this confidential HIV testing program, routine, individual donation, HIV nucleic acid amplification testing (NAT) has been provided to all rapid antibody-negative participants since June 2007 (samples for NAT are obtained at the time of rapid antibody testing) (7,10,11). AHI was defined as having a negative or indeterminate HIV antibody test result in the presence of detectable HIV-1 RNA, corresponding to Fiebig stages I-II, with a mean estimated date of infection within the previous 10 days (95% CI 7-14 days) (12). Dates of infection were estimated for all recently infected patients using previously published criteria on the basis of serologic and virologic test results (13).

At each patient's first visit after documentation of AHI diagnosis (median 4 days, interquartile range [IQR] 3-6 days after AHI testing), we obtained blood samples for CD4 and viral load testing and collected detailed information regarding occurrence, duration, and start and stop dates for 11 signs and symptoms associated with AHI (5,14). Participants were also asked to specify any other symptoms. In addition, patients who participated during 2007-2011 were asked if they had sought medical attention for any signs or symptoms. Typical AHI (i.e., [greater than or equal to] 2 signs/symptoms) was defined according to criteria described by Braun et al. (14).

For statistical analysis, SPSS version 21 (SPSS, Inc., Chicago, IL, USA) was used. For analysis on signs or symptoms compatible with AHI, signs or symptoms that started [greater than or equal to] 5 days before the estimated date of infection (i.e., before the 7-14 day 95% CI) were excluded. The University of California San Diego's Human Research Protections Program approved the study protocol, consent process, and all study-related procedures.

All 90 participants were male and self-identified as men who have sex with men (MSM). Median age was 29 (range 18-67) years. Half (50%) of participants reported white race; 29% reported Hispanic ethnicity. Median number of male partners reported for the previous 12 months was 20 (IQR 14-31). A total of 72 (80%) patients had signs or symptoms associated with AHI that occurred within 2 weeks before undergoing NAT; of these 72 patients, 47 (52% of the study population) had ongoing signs or symptoms, while signs or symptoms had resolved by the time of testing for 25 (28% of the study population). Twelve (13%) reported signs or symptoms starting after testing, while 6 (7%) reported the absence of signs or symptoms (Table 1). A total of 66 patients (73% of the study population) reported headache, pharyngitis, or myalgia occurring during the 14 days before AHI testing.

Overall, 69 patients (77%) reported signs or symptoms that met criteria of compatibility with AHI (Table 2). Onset of signs or symptoms compatible with AHI occurred at a median of 5 days (IQR 0-8, range -4 to 15 days) after the estimated date of infection. Neither viral load nor CD4 count correlated with duration or actual number of signs or symptoms.

Data on whether a patient sought medical attention because of signs or symptoms were available for 42 (47%) of 90 patients; of these, 12 (29%) reported that they sought medical attention because of their signs or symptoms and 30 (71%) did not. Significantly higher viral loads were observed for those who sought medical attention compared with those who did not (median 6.1 [IQR 5.7-6.7] log copies/mL vs. 4.7 [IQR 3.4-5.5] log copies/mL; p<0.01).

Overall, 70 (78%) of the 90 patients fulfilled criteria for having typical AHI and 20 (22%) did not (of the latter, 14 had only 1 sign or symptom, and 6 were asymptomatic). Patients with typical AHI had significantly higher viral loads compared with patients without (p<0.01). A total of 61 (85%) of 72 patients with signs or symptoms before NAT testing fulfilled criteria for having typical AHI. In addition, 40 (85%) of 47 patients who had ongoing signs or symptoms at the time of AHI testing fulfilled criteria for having typical AHI at that time.

Conclusions

We characterized signs or symptoms relative to the date of AHI diagnosis among persons seeking HIV testing in a program offering universal AHI screening. Two findings are notable: 1) 52% of participants reported ongoing signs or symptoms at the time of AHI testing, and 2) 80% reported signs or symptoms occurring within 2 weeks before undergoing testing.

These findings may have major clinical implications for community-based settings that restrict AHI testing to persons with ongoing signs or symptoms. This practice may be relatively insensitive in settings where MSM undergo HIV screening frequently (11). Our results show that expansion of AHI screening to include those with signs or symptoms during the 2 weeks before the test may increase the yield of AHI diagnoses by more than half.

Although our results may allow for estimation of sensitivity of signs and symptoms for AHI in persons seeking HIV testing, specificity of signs and symptoms remains unknown (in this study, signs and symptoms were not assessed in those who tested negative, and no control group was available). Estimates on frequency of signs and symptoms in HIV-negative persons (i.e., specificity) ranged widely in previous studies. Although in one study a specificity of 65% was estimated for influenza illness-like symptoms (15), specificities ranging from 38% to 91% for recent symptoms were estimated in another study (5). Limitations of those studies include the fact that exact time frames for occurrence of signs or symptoms (e.g., ongoing at the time of testing or occurring within the last 14 days) have not been evaluated, which makes comparison of results difficult. A limitation in our study is that all cases of AHI occurred among MSM. Therefore, our results may not be applicable to populations other than MSM, although previous studies have reported that clinical features of AHI may not differ by sex and age of patients (4).

In summary, HIV diagnostic testing strategies that limit AHI testing to patients with ongoing signs or symptoms may fail to identify many persons with AHI. In contrast, HIV NAT provided for MSM who report signs or symptoms during the preceding 2 weeks (representing 80% of AHI diagnoses) may increase the yield of AHI diagnoses by more than half.

DOI: http://dx.doi.org/10.3201/eid2203.151607

Author affiliations: Medical University of Graz, Graz, Austria (M. Hoenigl); University of California San Diego, San Diego, California, USA (M. Hoenigl, N. Green, M. Camacho, S. Gianella, S.R. Mehta, D.M. Smith, S.J. Little); Veterans Affairs Healthcare System, San Diego (S.R. Mehta, D.M. Smith)

This work was supported by funding from the Max Kade Foundation (through a Max Kade postdoctoral research grant), the International Research Fellowship in NeuroAIDS (R25-MH081482), the US Department of Veterans Affairs, and the National Institutes of Health (grant nos. AI043638, AI074621, AI106039, MH100974, AI108351, and AI093163).

M.H. served on the speakers' bureau of Merck, Inc. M.S. has received grant funding from ViiV Healthcare and has served as a consultant for Gen-Probe, Inc. and Testing Talent Services, Inc. S.J.L. received research grants from Gilead Sciences, Inc.

Dr. Hoenigl has been an Infectious Diseases Fellow at the Medical University of Graz, Austria, for 5 years and is currently working as a postdoctoral scholar at the Antiviral Research Center of the University of California, San Diego. His primary research interests are acute HIV infection, HIV prevention, mycology, and multidrug-resistant gram-negative bacterial infections.

References

(1.) Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505. http://dx.doi.org/10.1056/NEJMoa1105243

(2.) Sorias ME, Sued O, Laufer N, Lazaro ME, Mingrone H, Pryluka D, et al. Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters. J Int AIDS Soc. 2011;14:40. http://dx.doi.org/10.1186/1758-2652-14-40

(3.) Walensky RP, Rosenberg ES, Ferraro MJ, Losina E, Walker BD, Freedberg KA. Investigation of primary human immunodeficiency virus infection in patients who test positive for heterophile antibody. Clin Infect Dis. 2001;33:570-2. http://dx.doi.org/ 10.1086/321903

(4.) Vanhems P, Routy JP, Hirschel B, Baratin D, Vora S, Maenza J, et al. Clinical features of acute retroviral syndrome differ by route of infection but not by gender and age. J Acquir Immune Defic Syndr. 2002;31:318-21. http://dx.doi.org/10.1097/ 00126334-200211010-00007

(5.) Hecht FM, Busch MP, Rawal B, Webb M, Rosenberg E, Swanson M, et al. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS. 2002;16:1119-29. http://dx.doi.org/10.1097/00002030-200205240-00005

(6.) Centers for Disease Control and Prevention (CDC). National HIV Testing Day and new testing recommendations. MMWR Morb Mortal Wkly Rep. 2014;63:537.

(7.) Hoenigl M, Graff-Zivin J, Little SJ. Costs per diagnosis of acute HIV infection in community-based screening strategies: a comparative analysis of four screening algorithms. Clin Infect Dis. 2015;pii:civ912. http://dx.doi.org/10.1093/cid/civ912

(8.) Little SJ, McLean AR, Spina CA, Richman DD, Havlir DV Viral dynamics of acute HIV-1 infection. J Exp Med. 1999;190:841-50. http://dx.doi.org/10.1084/jem.190.6.841

(9.) Schacker TW, Hughes JP, Shea T, Coombs RW, Corey L. Biological and virologic characteristics of primary HIV infection. Ann Intern Med. 1998;128:613-20. http://dx.doi.org/10.7326/ 0003-4819-128-8-199804150-00001

(10.) Hoenigl M, Weibel N, Mehta SR, Anderson CM, Jenks J, Green N, et al. Development and validation of the San Diego Early Test Score to predict acute and early HIV infection risk in men who have sex with men. Clin Infect Dis. 2015;61:468-75. http://dx.doi.org/10.1093/cid/civ335

(11.) Hoenigl M, Anderson CM, Green N, Mehta SR, Smith DM, Little SJ. Repeat HIV-testing is associated with an increase in behavioral risk among men who have sex with men: a cohort study. BMC Med. 2015;13:218. http://dx.doi.org/10.1186/s12916-015-0458-5

(12.) Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003;17:1871-9. http://dx.doi.org/10.1097/00002030-200309050-00005

(13.) Le T, Wright EJ, Smith DM, He W, Catano G, Okulicz JF, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368:218-30. http://dx.doi.org/10.1056/NEJMoa1110187

(14.) Braun DL, Kouyos RD, Balmer B, Grube C, Weber R, Gunthard HF. Frequency and spectrum of unexpected clinical manifestations of primary HIV-1 infection. Clin Infect Dis. 2015; 61:1013-21. http://dx.doi.org/10.1093/cid/civ398

(15.) Juusola JL, Brandeau ML, Long EF, Owens DK, Bendavid E. The cost-effectiveness of symptom-based testing and routine screening for acute HIV infection in men who have sex with men in the USA. AIDS. 2011;25:1779-87. http://dx.doi.org/10.1097/ QAD.0b013e328349f067

Address for correspondence: Martin Hoenigl, Antiviral Research Center, Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 200 W Arbor Dr, Mail Code 8208, San Diego, CA 92103, USA; email: mhoenigl@ucsd.edu
Table 1. Comparison of AHI stage, characteristics of signs
or symptoms, CD4+ cell count, and viral load between persons
with signs or symptoms before and at the time of NAT versus
persons without, San Diego, California, USA, 2007-2014 *

Characteristic                 Total no.     Symptoms before
                                persons      NAT ([dagger])

No. persons                       90               72
Overall no. signs/symptoms     5 (3-7);          5 (4-7)
  in those symptomatic,         n = 84
  median (IQR)
Duration of symptoms, d,       9 (5-13);       10 (6-13);
  median (IQR)                  n = 79           n = 67
CD4+ cell count, cells/      435 (298-597)    435 (302-586)
  [micro]L, median (IQR)
Viral load, [log.sub.10]     5.4 (4.5-6.3)    5.8 (4.8-6.4)
  RNA, median (IQR)

Characteristic               Asymptomatic    p value      Ongoing
                              before NAT                 symptoms
                                                          at NAT

No. persons                       18                        47
Overall no. signs/symptoms     5 (2-6);        NS         6 (4-8)
  in those symptomatic,         n = 12
  median (IQR)
Duration of symptoms, d,       4 (3-7);       <0.01     11 (8-14);
  median (IQR)                  n = 12                    n = 43
CD4+ cell count, cells/        LO LO CO        NS      424 (299-592)
  [micro]L, median (IQR)
Viral load, [log.sub.10]     4.5 (3.2-5.0)    <0.01    5.6 (4.8-6.4)
  RNA, median (IQR)

Characteristic                Absence of     p value
                               symptoms
                                at NAT

No. persons                       43
Overall no. signs/symptoms     5 (3-6);        NS
  in those symptomatic,         n = 37
  median (IQR)
Duration of symptoms, d,       6 (3-9);       <0.01
  median (IQR)                  n = 36
CD4+ cell count, cells/      445 (295-610)     NS
  [micro]L, median (IQR)
Viral load, [log.sub.10]     5.0 (3.8-6.1)    0.07
  RNA, median (IQR)

* AHI, acute HIV infection; IQR, interquartile range; NAT,
nucleic acid amplification testing; NS, not significant.

([dagger]) Most frequently observed signs or symptoms that occurred
during the 14 days before NAT or were ongoing at the time of NAT
were fatigue (53 persons, 59% of the study population), fever
(51,57%), myalgia (48, 53%), headache (41,46%), night sweats (35,
39%), pharyngitis (32, 36%), and gastrointestinal symptoms (29, 32%).

Table 2. Signs or symptoms occurring in 69 persons with
AHI, San Diego, California, USA, 2007-2014 *

Characteristic              Signs/symptoms

                            Compatible with    Resolved     Ongoing
                            AHI ([dagger])    before NAT    at NAT

No. persons                       69              16          41
  reporting symptoms
Duration of symptoms,          8 (5-11)        7 (4-8)     11 (7-13)
  d, median (IQR)
No. (%) persons with            64 (93)        15 (94)      36 (86)
  typical AHI

Signs or symptoms, no. (%)

  Fever                         53 (77)        11 (69)      34 (83)
  Myalgia                       48 (70)        13 (81)      28 (68)
  Fatigue                       48 (70)         13(81)      29 (71)
  Headache                      42 (61)        10 (63)      27 (66)
  Night sweats                  38 (55)         5 (31)      26 (63)
  Pharyngitis                   34 (49)         9 (56)      17 (41)
  GI symptoms                   29 (42)         3 (19)      22 (54)
    ([double dagger])
  Rash                          19 (28)         6 (38)      12 (29)
  Weight loss ([section])       15 (22)         2 (13)      12 (29)
  Arthralgia                    14 (20)         3 (19)      8 (20)

Characteristic              p value   Signs/symptoms

                                         Persons
                                         seeking
                                         medical
                                        attention

No. persons                                 10
  reporting symptoms
Duration of symptoms,        <0.01      13 (10-17)
  d, median (IQR)
No. (%) persons with          NS         10 (100)
  typical AHI

Signs or symptoms, no. (%)

  Fever                       NS          9 (90)
  Myalgia                     NS          8 (80)
  Fatigue                     NS          9 (90)
  Headache                    NS          8 (80)
  Night sweats               0.04         7 (70)
  Pharyngitis                 NS          4 (40)
  GI symptoms                0.02         5 (50)
    ([double dagger])
  Rash                        NS          5 (50)
  Weight loss ([section])     NS          6 (60)
  Arthralgia                  NS          4 (40)

Characteristic              Signs/symptoms   p value

                             Persons not
                               seeking
                               medical
                              attention

No. persons                       22
  reporting symptoms
Duration of symptoms,         10 (4-11)       0.01
  d, median (IQR)
No. (%) persons with           18 (82)         NS
  typical AHI

Signs or symptoms, no. (%)

  Fever                        16 (73)         NS
  Myalgia                      12 (55)         NS
  Fatigue                      13 (59)         NS
  Headache                     11 (50)         NS
  Night sweats                  9 (41)         NS
  Pharyngitis                  11 (50)         NS
  GI symptoms                   7 (32)         NS
    ([double dagger])
  Rash                          5 (23)         NS
  Weight loss ([section])       3 (14)        0.01
  Arthralgia                    1 (5)         0.02

* AHI, acute HIV infection; GI, gastrointestinal; IQR,
interquartile range; NAT, nucleic acid amplification
testing; NS, not significant.

([dagger]) Defined as having started [less than or
equal to] 4 days before estimated date of infection
or after the estimated date of infection.

([double dagger]) General GI symptoms (e.g., nausea,
vomiting, and diarrhea).

([section]) Weight loss >2.5 kg.
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Title Annotation:DISPATCHES
Author:Hoenigl, Martin; Green, Nella; Camacho, Martha; Gianella, Sara; Mehta, Sanjay R.; Smith, Davey M.; L
Publication:Emerging Infectious Diseases
Geographic Code:1U9CA
Date:Mar 1, 2016
Words:2805
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