European AIDS Clinical Society：EACS guidelines version 9.0.
J O Kahn, B D Walker
Acute human immunodeficiency virus type 1 infection.
N Engl J Med. 1998 Jul 2;339(1):33-9. doi: 10.1056/NEJM199807023390107.
Abstract/Text
Eberhard W Fiebig, David J Wright, Bhupat D Rawal, Patricia E Garrett, Richard T Schumacher, Lorraine Peddada, Charles Heldebrant, Richard Smith, Andrew Conrad, Steven H Kleinman, Michael P Busch
Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection.
AIDS. 2003 Sep 5;17(13):1871-9. doi: 10.1097/01.aids.0000076308.76477.b8.
Abstract/Text
OBJECTIVES: The characterization of primary HIV infection by the analysis of serial plasma samples from newly infected persons using multiple standard viral assays.
DESIGN: A retrospective study involving two sets of archived samples from HIV-infected plasma donors. (A) 435 samples from 51 donors detected by anti-HIV enzyme immunoassays donated during 1984-1994; (B) 145 specimens from 44 donors detected by p24 antigen screening donated during 1996-1998.
SETTING: Two US plasma products companies.
MAIN OUTCOME MEASURES: The timepoints of appearance of HIV-1 markers and viral load concentrations during primary HIV infection.
RESULTS: The pattern of sequential emergence of viral markers in the 'A' panels was highly consistent, allowing the definition and estimation of the duration of six sequential stages. From the 'B' panels, the viral load at p24 antigen seroconversion was estimated by regression analysis at 10 000 copies/ml (95% CI 2000-93 000) and the HIV replication rate at 0.35 log copies/ml/day, corresponding to a doubling time in the preseroconversion phase of 20.5 h (95% CI 18.2-23.4 h). Consequently, an RNA test with 50 copies/ml sensitivity would detect HIV infection approximately 7 days before a p24 antigen test, and 12 days before a sensitive anti-HIV test.
CONCLUSION: The sequential emergence of assay reactivity allows the classification of primary HIV-1 infection into distinct laboratory stages, which may facilitate the diagnosis of recent infection and stratification of patients enrolled in clinical trials. Quantitative analysis of preseroconversion replication rates of HIV is useful for projecting the yield and predictive value of assays targeting primary HIV infection.
Sabine Yerly, Bernard Hirschel
Diagnosing acute HIV infection.
Expert Rev Anti Infect Ther. 2012 Jan;10(1):31-41. doi: 10.1586/eri.11.154.
Abstract/Text
Individuals with acute HIV infection (AHI) pose a greater transmission risk than most chronically HIV-infected patients and prevention efforts targeting these individuals are important for reducing the spread of HIV infection. Rapid and accurate diagnosis of AHI is crucial. Since symptoms of AHI are nonspecific, its diagnosis requires a high index of suspicion and appropriate HIV laboratory tests. However, even 30 years after the start of the HIV epidemic, laboratory tools remain imperfect and only a few individuals with AHI are identified. We review the clinical presentation of the acute retroviral syndrome, the laboratory markers and their detection methods, and propose an algorithm for the laboratory diagnosis of AHI.
Neurology. August 2016; 87 (9 Supplement 2).
J Lapins, S Lindbäck, P Lidbrink, P Biberfeld, L Emtestam, H Gaines
Mucocutaneous manifestations in 22 consecutive cases of primary HIV-1 infection.
Br J Dermatol. 1996 Feb;134(2):257-61.
Abstract/Text
Twenty-two consecutive patients presenting with symptomatic human immunodeficiency virus 1 (HIV-1) seroconversion were studied. Most of the patients had a glandular fever-like illness. All patients had fever and pharyngitis, and eight of them also suffered from ulcers of the oral, genital or anal mucosa. Uniform skin eruptions were observed in 17 of the 22 patients. The exanthem consisted of varying numbers of macular or maculopapular lesions that were oval or rounded in shape, ranging from a few millimetres to 1 cm in diameter. The lesions were distributed on the upper thorax in all cases, and were particularly profuse in the collar region. The face, forehead and scalp were involved in most cases, but the eruption was sparse or absent at the periphery of the extremities. In the majority of patients, the exanthem appeared after 2 or 3 days of fever. The exanthem developed during the first day, persisted for 5-8 days, and then cleared concurrently with the general recovery of the patients. Histopathological studies of skin punch biopsy specimens from four patients showed a sparse lymphocytic cell infiltrate distributed around vessels of the dermal superficial plexus. The infiltrates predominantly consisted of equally represented T-helper/inducer and T-suppressor/cytotoxic cells. A vacuolar aberration of basal layer cells was found in two of the four cases studied histologically. The microscopic findings correspond to the histopathological patterns seen in toxicodermia and in the interface dermatitis of morbilliform viral exanthems. The exanthem is a frequent and characteristic sign of primary HIV infection, which is further indicated if mucosal ulcers are present.
Farheen Manji, Evan Wilson, Etienne Mahe, John Gill, John Conly
Acute HIV infection presenting as hemophagocytic lymphohistiocytosis: case report and review of the literature.
BMC Infect Dis. 2017 Sep 20;17(1):633. doi: 10.1186/s12879-017-2732-y. Epub 2017 Sep 20.
Abstract/Text
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complication of an acute HIV infection, with only ten documented case reports per our literature search. We present a case of HLH secondary to acute HIV infection with a negative HIV antibody-based assay and high plasma viral load.
CASE PRESENTATION: A 45 year old male with a past medical history of well controlled hypertension presented with fever, dizziness and non-bloody diarrhea. Initial lab work revealed a new thrombocytopenia, marked renal failure and an elevated creatine kinase, ferritin, lactate dehydrogenase and D-dimer. A bone marrow biopsy revealed HLH. As part of the work up for thrombocytopenia, a rapid HIV antibody based assay was done and was negative. The sample was later routinely tested with a fourth generation antigen/antibody assay as per local protocol and was strongly positive. The plasma RNA viral load was >10,000,000 copies /mL confirming the diagnosis of an acute HIV infection. The patient was urgently started on antiretroviral therapy and recovered.
CONCLUSION: This case illustrates a diagnostic approach to HLH which is an uncommon but life threatening multisystem disease, requiring the involvement of a multidisciplinary team of experts. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. A negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.
Carolyn Chu, Peter A Selwyn
Diagnosis and initial management of acute HIV infection.
Am Fam Physician. 2010 May 15;81(10):1239-44.
Abstract/Text
Recognition and diagnosis of acute human immunodeficiency virus (HIV) infection in the primary care setting presents an opportunity for patient education and health promotion. Symptoms of acute HIV infection are nonspecific (e.g., fever, malaise, myalgias, rash), making misdiagnosis common. Because a wide range of conditions may produce similar symptoms, the diagnosis of acute HIV infection involves a high index of suspicion, a thorough assessment of HIV exposure risk, and appropriate HIV-related laboratory tests. HIV RNA viral load testing is the most useful diagnostic test for acute HIV infection because HIV antibody testing results are generally negative or indeterminate during acute HIV infection. After the diagnosis of acute HIV infection is confirmed, physicians should discuss effective transmission risk reduction strategies with patients. The decision to initiate antiretroviral therapy should be guided by consultation with an HIV specialist.
Dominique L Braun, Roger D Kouyos, Belinda Balmer, Christina Grube, Rainer Weber, Huldrych F Günthard
Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection.
Clin Infect Dis. 2015 Sep 15;61(6):1013-21. doi: 10.1093/cid/civ398. Epub 2015 May 19.
Abstract/Text
BACKGROUND: Prospectively and systematically collected data on frequency and spectrum of unexpected clinical manifestations during primary human immunodeficiency virus (HIV) infection (PHI) have not been published.
METHODS: We prospectively enrolled 290 patients with documented PHI in the Zurich Primary HIV Infection Study. Typical acute retroviral syndrome (ARS) was defined as fever plus at least 1 symptom or sign typically considered to be associated with ARS; in absence of fever, presence of 2 or more ARS symptoms or signs. Atypical ARS was defined as lack of symptoms or signs, a single symptom or sign only and absence of fever, presence of symptoms or signs that are not considered typically associated with ARS, or occurrence of an opportunistic disease. Time to diagnosis was calculated based on estimated date of infection and first positive HIV test.
RESULTS: We analyzed 290 patients (271 males). PHI manifested with typical ARS in 202 (70%) and with atypical ARS in 88 (30%) patients. Patients with atypical ARS were hospitalized 4 times more often compared with typical ARS (43% vs 11%; P < .001). The gastrointestinal tract was the most frequent organ system affected in patients with atypical manifestations. Only in 112 (38%) patients was HIV infection suspected during the first medical attendance. Patients with typical ARS were diagnosed slightly earlier compared with atypical ARS, but this difference was not significant (P = .3).
CONCLUSIONS: Unexpected clinical presentations occurred in a large fraction of patients with PHI and were associated with substantial morbidity. Universal HIV testing may be mandatory in high-risk groups.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
When To Start Consortium, Jonathan A C Sterne, Margaret May, Dominique Costagliola, Frank de Wolf, Andrew N Phillips, Ross Harris, Michele Jönsson Funk, Ronald B Geskus, John Gill, François Dabis, Jose M Miró, Amy C Justice, Bruno Ledergerber, Gerd Fätkenheuer, Robert S Hogg, Antonella D'Arminio Monforte, Michael Saag, Colette Smith, Schlomo Staszewski, Matthias Egger, Stephen R Cole
Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies.
Lancet. 2009 Apr 18;373(9672):1352-63. doi: 10.1016/S0140-6736(09)60612-7. Epub 2009 Apr 8.
Abstract/Text
BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies.
METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL.
FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL).
INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.
Mari M Kitahata, Stephen J Gange, Alison G Abraham, Barry Merriman, Michael S Saag, Amy C Justice, Robert S Hogg, Steven G Deeks, Joseph J Eron, John T Brooks, Sean B Rourke, M John Gill, Ronald J Bosch, Jeffrey N Martin, Marina B Klein, Lisa P Jacobson, Benigno Rodriguez, Timothy R Sterling, Gregory D Kirk, Sonia Napravnik, Anita R Rachlis, Liviana M Calzavara, Michael A Horberg, Michael J Silverberg, Kelly A Gebo, James J Goedert, Constance A Benson, Ann C Collier, Stephen E Van Rompaey, Heidi M Crane, Rosemary G McKaig, Bryan Lau, Aimee M Freeman, Richard D Moore, NA-ACCORD Investigators
Effect of early versus deferred antiretroviral therapy for HIV on survival.
N Engl J Med. 2009 Apr 30;360(18):1815-26. doi: 10.1056/NEJMoa0807252. Epub 2009 Apr 1.
Abstract/Text
BACKGROUND: The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.
METHODS: We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group).
RESULTS: In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001).
CONCLUSIONS: The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
2009 Massachusetts Medical Society
Elvin H Geng, C Bradley Hare, James O Kahn, Vivek Jain, Tracy Van Nunnery, Katerina A Christopoulos, Steven G Deeks, Monica Gandhi, Diane V Havlir
The effect of a "universal antiretroviral therapy" recommendation on HIV RNA levels among HIV-infected patients entering care with a CD4 count greater than 500/μL in a public health setting.
Clin Infect Dis. 2012 Dec;55(12):1690-7. doi: 10.1093/cid/cis750. Epub 2012 Sep 5.
Abstract/Text
BACKGROUND: On 1 January 2010, a large, publicly funded clinic in San Francisco announced a "universal ART" approach to initiate antiretroviral therapy (ART) in all human immunodeficiency virus (HIV)-infected persons. The effect of changing guidance on real-world patient outcomes has not been evaluated.
METHODS: We evaluated untreated adult patients (defined as going >90 days without ART use) visiting clinic from 2001 to 2011. The cumulative incidence of HIV RNA suppression (viral load, <500 copies/mL), stratified by CD4 cell count at entry and calendar dates representing guideline issuance, were estimated using a competing risk framework. A multivariate Poisson-based model identified factors associated with HIV RNA suppression 6 months after clinic entry.
RESULTS: Of 2245 adults, 87% were male, and the median age was 39 years (interquartile range, 33-45 years). In 534 patients entering clinic with a CD4 cell count of >500 cells/µL, the 1-year incidence of HIV RNA suppression was 10.1% (95% confidence interval [CI], 6.6%-14.6%) before 4 April 2005; 9.1% (95% CI, 3.6%-17.4%) from 4 April 2005 to 1 December 2007; 14.1% (95% CI, 7.5%-22.8%) from 1 December 2007 to the universal ART recommendation and 52.8% (95% CI, 38.2%-65.4%) after. After adjustment, the SFGH policy was associated with a 6-fold increase in the probability of HIV RNA suppression 6 months after clinic entry.
CONCLUSIONS: Recommendations to initiate ART in all HIV-infected patients increased the rate of HIV RNA suppression for patients enrolling in care with a CD4 cell count of >500 cells/µL and may foreshadow national trends given the March 2012 revision of national treatment guidelines to favor ART initiation for persons with CD4 cell counts of >500 cells/µL.
Eric S Daar, Christopher D Pilcher, Frederick M Hecht
Clinical presentation and diagnosis of primary HIV-1 infection.
Curr Opin HIV AIDS. 2008 Jan;3(1):10-5. doi: 10.1097/COH.0b013e3282f2e295.
Abstract/Text
PURPOSE OF REVIEW: To describe current findings concerning the clinical manifestations and diagnosis of primary HIV-1 infection.
RECENT FINDINGS: HIV-1 seroconversion can occur with a variety of clinical manifestations or without symptoms. More severe and numerous symptoms during primary HIV-1 infection predict a higher plasma HIV-1 RNA set-point and faster disease progression. While detection of primary HIV-1 infection is potentially very important for HIV-1 prevention and may offer clinical benefits, the diagnosis is often missed. Diagnosis of symptomatic individuals with antibody-negative HIV-1 infection requires recognition of the diverse signs and symptoms of this syndrome. Diagnostic tests for primary HIV-1 infection include assays for HIV-1 RNA, p24 antigen, and third generation enzyme immunoassay antibody tests capable of detecting IgM antibodies. Targeting these tests using clinical presentation alone will probably miss the diagnosis in many individuals. Consequently, increasing effort has gone into developing strategies to incorporate the use of these assays into routine HIV-1 testing algorithms.
SUMMARY: More numerous and severe primary HIV-1 infection symptoms predict more rapid disease progression. Pooled HIV-1 RNA screening and fourth generation HIV-1 enzyme immunoassay antibody tests with sensitive p24 antigen detection are beginning to be implemented in routine HIV-1 testing algorithms, but further research is needed to define optimal strategies for increasing detection of primary HIV-1 infection.
Tuan Le, Edwina J Wright, Davey M Smith, Weijing He, Gabriel Catano, Jason F Okulicz, Jason A Young, Robert A Clark, Douglas D Richman, Susan J Little, Sunil K Ahuja
Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy.
N Engl J Med. 2013 Jan 17;368(3):218-30. doi: 10.1056/NEJMoa1110187.
Abstract/Text
BACKGROUND: The relationship between the timing of the initiation of antiretroviral therapy (ART) after infection with human immunodeficiency virus type 1 (HIV-1) and the recovery of CD4+ T-cell counts is unknown.
METHODS: In a prospective, observational cohort of persons with acute or early HIV-1 infection, we determined the trajectory of CD4+ counts over a 48-month period in partially overlapping study sets: study set 1 included 384 participants during the time window in which they were not receiving ART and study set 2 included 213 participants who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load. We investigated the likelihood and rate of CD4+ T-cell recovery to 900 or more cells per cubic millimeter within 48 months while the participants were receiving viral-load-suppressive ART.
RESULTS: Among the participants who were not receiving ART, CD4+ counts increased spontaneously, soon after HIV-1 infection, from the level at study entry (median, 495 cells per cubic millimeter; interquartile range, 383 to 622), reached a peak value (median, 763 cells per cubic millimeter; interquartile range, 573 to 987) within approximately 4 months after the estimated date of infection, and declined progressively thereafter. Recovery of CD4+ counts to 900 or more cells per cubic millimeter was seen in approximately 64% of the participants who initiated ART earlier (≤4 months after the estimated date of HIV infection) as compared with approximately 34% of participants who initiated ART later (>4 months) (P<0.001). After adjustment for whether ART was initiated when the CD4+ count was 500 or more cells per cubic millimeter or less than 500 cells per cubic millimeter, the likelihood that the count would increase to 900 or more cells per cubic millimeter was lower by 65% (odds ratio, 0.35), and the rate of recovery was slower by 56% (rate ratio, 0.44), if ART was initiated later rather than earlier. There was no association between the plasma HIV RNA level at the time of initiation of ART and CD4+ T-cell recovery.
CONCLUSIONS: A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. Initiation of ART during this period is associated with an enhanced likelihood of recovery of CD4+ counts. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Christopher D Pilcher, Hsiao Chuan Tien, Joseph J Eron, Pietro L Vernazza, Szu-Yun Leu, Paul W Stewart, Li-Ean Goh, Myron S Cohen, Quest Study, Duke-UNC-Emory Acute HIV Consortium
Brief but efficient: acute HIV infection and the sexual transmission of HIV.
J Infect Dis. 2004 May 15;189(10):1785-92. doi: 10.1086/386333. Epub 2004 Apr 28.
Abstract/Text
BACKGROUND: We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual transmission of HIV.
METHODS: We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere.
RESULTS: Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8-10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%-24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD.
CONCLUSIONS: Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals.
European AIDS clinical society：European guidelines for treatment of HIV-positive adults in Europe version 8.2.
Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med [Internet]. 2018 Sep 6 [cited 2019 Jun 24];379(10):979–981. Available from: http://www.nejm.org/doi/10.1056/NEJMc1807653
