JAIDS Journal of Acquired Immune Deficiency Syndromes:
The Detection and Management of Early HIV Infection: A Clinical and Public Health Emergency
Smith, M. Kumi MPIA*; Rutstein, Sarah E. BA†; Powers, Kimberly A. PhD*,‡; Fidler, Sarah MD, PhD§; Miller, William C. MD, PhD*,‡; Eron, Joseph J. Jr MD‡,‖; Cohen, Myron S. MD‡,‖
Departments of *Epidemiology, Gillings School of Global Public Health;
†Health Policy and Management, Gillings School of Global Public Health; and
‡Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;
§Department of Medicine, Imperial College, London, United Kingdom; and
‖Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Correspondence to: Myron S. Cohen, MD, 2031 Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, NC 27517 (e-mail: firstname.lastname@example.org).
K.S. was supported by the National Institute of Allergy and Infectious Diseases T32 training grant, T32 AI0700. W.C.M., K.A.P., and S.E.R. were supported by the US National Institutes of Health grant R01 AI083059 and SER by R01 IF30MH085431. S.F. received funding from the National Institute for Health Research Imperial Biomedical Research Center (P46467), FHI360 (0800 0166/964), and the London School of Hygiene & Tropical Medicine (EPIDVH72). M.S.C. and J.J.E. received funding from the University of North Carolina Center for AIDS Research (P30 AI50410), the HIV Prevention Trials Network (UM1 AI068619), and the National Institute of Diabetes and Digestive and Kidney Diseases R37 DK049381. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
S.F. has grants/grants pending and has received payment as a speaker. K.A.P. receives salary support from the National Institutes of Health. J.J.E. is an ongoing consultant with Merck, GSK, WiiV, Gilead, BMS, and Janssen and has grants/grants pending with Merck, GSK, and BMS.
Abstract: This review considers the detection and management of early HIV infection (EHI), defined here as the first 6 months of infection. This phase is clinically important because a reservoir of infected cells formed in the individual renders HIV incurable, and the magnitude of viremia at the end of this period predicts the natural history of disease. Epidemiologically, it is critical because the very high viral load that typically accompanies early infection also makes infected individuals maximally contagious to their sexual partners. Future efforts to prevent HIV transmission with expanded testing and treatment may be compromised by elevated transmission risk earlier in the course of HIV infection, although the extent of this impact is yet unknown. Treatment as prevention efforts will nevertheless need to develop strategies to address testing, linkage to care, and treatment of EHI. Cost-effective and efficient identification of more persons with early HIV will depend on advancements in diagnostic technology and strengthened symptom-based screening strategies. Treatment for persons with EHI must balance individual health benefits and reduction of the risk of onward viral transmission. An increasing body of evidence supports the use of immediate antiretroviral therapy to treat EHI to maintain CD4 count and functionality, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission. Although we can anticipate considerable challenges in identifying and linking to care persons in the earliest phases of HIV infection, there are many reasons to pursue this strategy.
The goals of immediate antiretroviral therapy (ART) for individuals presenting with early HIV infection (EHI) are twofold: first, for the health benefits of the individual and second to reduce the risk of onward viral transmission. Use of ART to control the HIV epidemic has garnered considerable interest at the population level. The extent to which elevated transmission during EHI1—if not reached by treatment—might compromise the preventive effect is a matter of debate.2–5
The evidence to date about the feasibility of treatment as prevention targeting persons with EHI are summarized in Table 1. This review synthesizes the existing evidence on the individual-level effects of early treatment and its potential role in using ART to prevent HIV transmission. Specifically, we consider the significance of early treatment in 3 areas: the challenges of finding early infection, in moderating essential behavior change in these individuals, and considerations for treatment of those with EHI.
EARLY HIV INFECTION
Sexual transmission of HIV generally involves only 1 or a small number of viral variants infecting receptive cells.6,7 The earliest days of infection are marked by HIV replication in the mucosa, submucosa, and lymphoreticular tissues, during which viral markers can only be detected in the affected tissues but not in the plasma.8 Once HIV RNA concentration increases to 1–5 copies per milliliter in plasma, nucleic acid amplification can be used to qualitatively detect HIV, after which the sequential appearance of various viral makers define the stages of EHI for which different quantitative clinical assays can be used to monitor viral load.9 At the same time, the initial immune response includes a “cytokine storm” that in a substantial number of newly infected people produces acute retroviral syndrome10 and that can be used to mark the stages of acute infection.11
Gut T-cell depletion12 and rapid growth in the HIV DNA reservoir size13,14 take place in the earliest (first ∼25 days) after infection.15 However, elevated risk of transmissions has been shown to persist for up to 6 months after seroconversion.16 “Early HIV infection” here will therefore refer to all stages of acute infection including seroconversion and up until the establishment of early chronic infection, approximately 3–6 months after HIV acquisition.
This stage of infection is critical both clinically and epidemiologically because (1) the reservoir of infected cells is formed in the individual that render HIV incurable; (2) the magnitude of viremia at set point predicts the natural history of disease,17 and (3) the very high viral load that typically accompanies acute infection—combined with specific characteristics of recently transmitted viral variants18—can make acutely infected individuals maximally contagious to their sexual partners.9
HIV AND THE SPREAD OF INFECTION
The biological plausibility of elevated HIV transmission risk during EHI is based on the heightened viral load of persons with early infection—often on the order of 106 log copies per milliliter19—which is also mirrored in high levels of virus in the genital tract.19–21 In addition, characteristics of the transmitted virus,18 concomitant sexually transmitted infections,22 and patterns of sexual behavior among recently infected individuals23 who may be unaware of their status24 may all factor into the role that EHI plays in the spread of HIV. However, the extent to which HIV treatment as prevention programs must account for transmission during EHI is a matter of some debate.5,25
The biological plausibility that EHI may enhance transmission risk is supported in some risk groups by the findings of phylogenetic methods to define transmission clusters22,26–28 or reconstruct transmission events during EHI29 using viral sequences from recently infected persons. Results suggest that HIV transmission from persons with EHI may account for 25%–50% of all viral transmissions within certain populations.16,26,29 Some posit, however, that the failure of these methods to consider other risk factors for transmission or to distinguish between new and chronic infection may lead them to overestimate the portion of new infections attributable to EHI.30
Mathematical models also provide insight into the role of EHI in HIV epidemiology. As we have summarized previously,9,31 model estimates of the contribution of EHI to population-level transmission have varied widely, with estimates of the portion of new cases attributable to EHI ranging from 1% to 82% (Table 2), depending on epidemic stage, model structure, assumptions about sexual contact rates and patterns, and the assumed duration of high infectiousness associated with EHI. We are aware of only one model to date that has formally assessed the potential impact of prevention interventions during EHI,25 the results of which suggest that transmission prevention during both EHI and chronic infection are needed for maximal impact.
Successful use of ART during EHI to control the HIV epidemic will depend greatly on our ability to effectively screen and identify these individuals to target for intervention, although this is not yet part of routine testing strategies. Such efforts will likely demand more frequent testing, particularly among those believed to be at greater risk of HIV infection and with the use of novel tools such as self-administered HIV tests—where legally sanctioned47—paired with open access to care. The acute phase of EHI when antibodies are not yet present will remain undetected by traditional antibody tests,48–50 when diagnosis must rely on direct detection of virus using nucleic acid amplification tests or viral antigen such as p24. Give the financial, technical, and logistical barriers to widespread use of nucleic acid amplification tests, third- and fourth-generation indirect enzyme immunoassays have emerged as a strong alternative. The sensitivity of these tests to HIV antibody isotypes that emerge earlier in the course of infection (IgM and IgG), and in the case of fourth generation to p24 antigen, allow detection earlier in the course of infection with relatively good sensitivity.3–5,49,51 However, limited availability of fourth-generation enzyme immunoassays in resource poor settings and low sensitivity for detecting HIV infection before seroconversion limits their utility in many settings with high EHI prevalence.52,53
Pooling samples for batched RNA screening may be a cost-effective alternative for EHI detection in places with higher prevalence of persons with EHI,6,7,49,54–58 but laboratory-based assays remain costly, necessitate people attending for testing venipuncture, and require patient follow-up. Field evaluations of available point-of-care tests to date have reported disappointingly high false-positive and false-negative rates.1,9,59,60
In light of these shortcomings, symptom-based screening—particularly those that incorporate targeted screening—must be developed as a cornerstone of field efforts to identify persons with EHI. Candidate populations include those presenting with symptoms indicative of sexually transmitted infections2–5,61,62 or with reported high-risk behavior.6,7,11,50,62 A strengthened symptom-based screening strategy will also require retraining of clinicians and community health workers, paired with routinized point-of-care viral load testing.63
PREVENTION IN PERSONS WITH EHI
Beyond the limitations of timely and adequate identification of acutely infected individuals are the unique challenges of preventing the HIV transmission in these individuals. Behavioral interventions will demand swift and decisive strategies to reduce risk behaviors, including notification of current sexual partners, limitation of new partner acquisition, condom use, and, possibly, abstinence during the acute phase. Seeking behavior change is the most constant theme in HIV prevention, but the limited evidence available on behavior change during EHI9,64,65 bode less well for future interventions in persons with EHI.
Following the biological plausibility of reduced viremia leading to reduced HIV transmission risk,66,67 we expect that treated persons with EHI will be less likely to transmit to their partners. In the absence of a mechanism to directly observe this effect, the phylogenetic cluster study by Rieder et al on transmission dynamics in gay men in Switzerland suggests that at least 5 reconstructed transmission events were attributable to presumed transmitters who ceased early therapy.68 Although discouraging from a disease control standpoint, these findings also underscore the need for new ways to modify and measure the impact of early ART on HIV transmission in persons with EHI.
THERAPEUTIC EFFECTS OF EARLY ART
The rationale for treating individuals with EHI is based on the suppressive effect of ART on patient viral load, which consistent of 4 elements: (1) alleviation of symptoms of early infection, (2) preservation of immune function, (3) reduction in the viral reservoirs, and (4) reduction of HIV transmission during EHI.
Until more recent evidence to the contrary,15,69 early exposure to ART was considered something best avoided or at least be administered intermittently so as to minimize cumulative side effects or the development of drug resistance.16,70 Here, we summarize findings from the body of literature reporting treatment effects of ART—defined as 1 to 4 antiretroviral drugs in a regimen—administered as either consistent or intermittent courses—during all phases of EHI (Table 3).
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Early ART Alleviates Acute Syndrome Symptoms
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Acute retroviral syndrome can manifest within days to weeks after exposure, as mildly as a viral syndrome or as severely as multisystem dysfunction.18,116–118 By reducing viral levels in treated patients, ART can modify both the direct viral effect and the host immune response to the virus, thereby alleviating symptoms of acute infection.9,27,68,96 Treatment for the sole purpose of reducing these symptoms was included as an indication for treatment for individuals with EHI in a recent set of treatment guidelines in the United Kingdom.63
Effect of ART in EHI on Immune Function
There is little debate about the role of immediate ART for individuals presenting with very low initial CD4 counts or who are severely unwell,19–21,119 but there is some uncertainty about appropriate courses for those identified in EHI with only minor symptoms and high CD4 counts. Known immunological benefits of ART initiated during EHI to date fall into 2 general categories: slower disease progression and near-term improvements in HIV-specific immunological responses.
Regarding disease progression, numerous observational studies and 7 randomized clinical trials have identified associations between early ART and the slowing of the depletion of CD4+ T cells77,83–86,90–92,99,102,106,107 as well as with the facilitation of immune cell restoration.22,80,92,94 Preservation of immune cell function has also been reported23,95,100,108,112 but not universally.24,115 In many of these studies, ART exposure was very brief and longitudinal follow-up time relatively short, limiting the strength of inferences that can be drawn about early treatment.
ART during EHI has also been associated with improved HIV-specific T-cell function,5,25,73,89,96,100,110 although starting ART too early may possibly interfere with the initial HIV-specific humoral response.115 Persistent immune activation has been identified among early ART initiators,29,75,81,112,113 possibly to a lesser extent than persons starting ART during chronic infection.16,26,29,88
Taken together, these data suggest that immediate use of ART irrespective of CD4 count could be expected to confer health benefits to patients with HIV. However, the durability and magnitude of these effects are yet unknown, limiting their immediate application to clinical decisions regarding optimal management of persons with EHI. Future research efforts must take note that increasingly higher CD4 thresholds for ART initiation in guidelines will continue to narrow the gap between early and delayed therapy, necessarily limiting our ability to decisively attribute observed health effects to early therapy.30,48–50,95
Effect of ART in EHI on Virological Outcomes
In addition to improvements in surrogate markers of clinical progression, studies report potential benefits of ART during EHI on virological outcomes. The potential effect of ART on the viral set point—the level at which a patient's viral load stabilizes after seroconversion—is of great interest given its strong association with the course of disease progression.120 Two observational studies101,109 and several trials83,87,104 have examined this issue, all but one101 reporting lower viral set points among patients treated during EHI versus those who were not. The variable definitions of viral set point across these studies, defined as the viral load at points in time ranging from 7 to 72 weeks after ART cessation, and the noncomparability of controls may contribute to the inconsistency of results across observational studies.87,104,109 Nevertheless, the fact that 3 randomized clinical trials87,104,107 all demonstrated some reduction in viral set point between ART-treated and control participants suggest the presence of a substantive effect.
Although some report no effect of transient therapy on virological indicators after cessation,92,101,113 most identify a significant difference in the viral loads of the early treatment groups74,77,80,84,95,96,99,107,110,114 versus their comparators. Interruption of ART almost invariably leads to the reemergence of detectable viral replication and the progression of HIV infection, a result of the establishment of inaccessible viral reservoirs.121
Finally, very early treatment may impact the size of the latent reservoir that is established early after infection. Research in this area may be critical for future work on HIV cure,71,105 the key barrier to which is eradication of the latent pool of inaccessible reservoir cells.122 To date, results of 4 separate study groups provide the most insight. The RV254/SEARCH 010 Study Group has reported that ART during EHI may play a key role in immune restoration and preventing the seeding of the HIV reservoir in the gut mucosal tissue of 20 Thai participants.15 These findings are supported by other groups who also report reduction in the sizes of viral reservoirs—measured as levels of cell-associated HIV DNA—among individuals with EHI receiving immediate ART compared with deferred therapy,75,85,88,123 in some cases even to levels comparable with those of documented elite controllers.124 Examining perhaps the most rigorous measure of the persistent HIV reservoir, resting CD4 cell infection with replication competent virus, Archin et al observed a strong correlation between the extent of viral replication before suppressive ART and the size of the resting cell reservoir.71 The Virological and Immunological Studies in Controllers after Treatment Interruption group demonstrated that early ART could also enhance viral control of therapy irrespective of HLA type and CCR5 genotype in a subset of patients treated intermittently during early infection.72,81,125 This group showed that immediate ART initiated within 12 weeks of diagnosis and maintained for a minimum of 3.5 years before discontinuing was associated with a higher proportion of viral controllers several years after stopping ART compared with the proportion of controllers described in untreated chronic infection (from <1% to 15.6%).
These findings together with the successful elimination of HIV from 1 patient126 and the functional cure reported in an infant treated at birth127 give cautious hope to the concept of strategic use of ART to limit establishment or reestablishment of the viral reservoir and work toward HIV cure.
Other Considerations of Early ART
A successful strategy to carry out early ART for prevention purposes must address a complex interplay of factors likely to mediate its impact. The acceptability of such a strategy must, for example, help patients faithfully confront the reality of lifelong adherence from an earlier stage in the course of disease, with which we have limited experience. Our understanding of the toxicity of prolonged exposure to antivirals for even longer duration is also limited.86
The choice of ART regimens will also determine the success of treatment as prevention strategies targeting persons with EHI. Current regimens are designed for simplicity, reduced cost, tolerance, patient and clinician preference, and the genotype of transmitted virus. However, for persons with EHI, treatment choices may be informed by patients' desires to initiate therapy as soon as possible—often before resistance data are available—and the inclusion of agents known to achieve rapid decreases in plasma viral load. Selecting drugs that concentrate in the genital or gastrointestinal tracts, such as integrase inhibitors, may protect lymphocytes in these compartments that are especially vulnerable to the adverse effects of EHI and also present clear prevention advantages. Evidence that intensive drug regimens of up to 5 agents may confer benefit over standard triple therapy for individuals with EHI is still formative.96
The potential risks of earlier initiation of ART can be, in part, anticipated, given the anticipated risks of lifelong treatment for all patients with HIV. Early ART may present new challenges for effective delivery of patient care, but may also have positive impacts on patient quality of life82 and retention in care.128 But the relatively short follow-up periods, transient nature of the treatment exposure, and small sample sizes limit insight and underscore the need for further research into comparative treatment outcomes.129 Furthermore, interruption of therapy has been associated with major cardiovascular, renal, and hepatitic disease,69 outcomes that must be considered when bearing risks versus benefits of sustained therapy.
Finally, as with all treatment as prevention efforts, feasibility of future programs must anticipate logistical challenges such as drug stock-outs or unavailability of second-line regimens.130
SUMMARY AND CONCLUSIONS
The formative nature of research into ART during EHI is reflected in the lack of consensus surrounding treatment guidelines for these persons. The United States and United Kingdom are the only 2 countries known to date with specific guidelines for clinical management of disease in persons with EHI.63,130–132 In both cases, treatment is recommended, though both note caveats about the strength of evidence.
However, an increasing body of evidence supports the role of immediate ART among individuals identified with EHI to facilitate immune function, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission. We and others have anticipated the considerable difficulty in finding subjects in the earliest phases of HIV infection given the added demands of repeat HIV testing, limitations of detection using currently available technologies, and the need for enhanced provider and patient awareness of the clinical and prevention significance of EHI. These considerations notwithstanding, future HIV control efforts will need to emphasize novel and targeted methods to identify patients with EHI and provide unequivocal support for treatment to improve their quality of life and limit onward transmission of HIV.
1. Cates W, Chesney MA, Cohen MS. Primary HIV infection—a public health opportunity. Am J Public Health. 1997;87:1928–1930.
2. Epstein H. Universal voluntary HIV testing and immediate antiretroviral therapy. Lancet. 2009;373:1078–1079.
3. Wilson DP. Data are lacking for quantifying HIV transmission risk in the presence of effective antiretroviral therapy. AIDS. 2009;23:1431–1433.
4. Ruark A, Shelton JD, Halperin DT, et al.. Universal voluntary HIV testing and immediate antiretroviral therapy. Lancet. 2009;373:1078.
5. Cohen MS, Dye C, Fraser C, et al.. HIV treatment as prevention: debate and Commentary—will early infection compromise treatment-as-prevention strategies? PLoS Med. 2012;9:e1001232.
6. Keele BF, Giorgi EE, Salazar-Gonzalez JF, et al.. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A. 2008;105:7552–7557.
7. Bar KJ, Li H, Chamberland A, et al.. Wide variation in the multiplicity of HIV-1 infection among injection drug users. J Virol. 2010;84:6241–6247.
8. Estes JD, Haase AT, Schacker TW. The role of collagen deposition in depleting CD4+ T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche. Semin Immunol. 2008;20:181–186.
9. Cohen MS, Shaw GM, McMichael AJ, et al.. Acute HIV-1 infection. N Engl J Med. 2011;364:1943–1954.
10. Borrow P, Hou S, Gloster S, et al.. Virus infection-associated bone marrow B cell depletion and impairment of humoral immunity to heterologous infection mediated by TNF-alpha/LTalpha. Eur J Immunol. 2005;35:524–532.
11. Fiebig EW, Wright DJ, Rawal BD, et al.. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003;17:1871–1879.
12. Brenchley JM, Douek DC. The mucosal barrier and immune activation in HIV pathogenesis. Curr Opin HIV AIDS. 2008;3:356–361.
13. Chun TW, Engel D, Berrey MM, et al.. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A. 1998;95:8869–8873.
14. McMichael AJ, Borrow P, Tomaras GD, et al.. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010;10:11–23.
15. Ananworanich J, Schuetz A, Vandergeeten C, et al.. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One. 2012;7:e33948.
16. Brenner BG, Roger M, Routy JP, et al.. High rates of forward transmission events after acute/early HIV‐1 infection. J Infect Dis. 2007;195:951–959.
17. Lavreys L, Baeten JM, Chohan V, et al.. Higher set point plasma viral load and more-severe acute HIV type 1 (HIV-1) illness predict mortality among high-risk HIV-1-infected African women. Clin Infect Dis. 2006;42:1333–1339.
18. Ma ZM, Stone M, Piatak M, et al.. High specific infectivity of plasma virus from the pre-ramp-up and ramp-up stages of acute simian immunodeficiency virus infection. J Virol. 2009;83:3288–3297.
19. Pilcher CD, Joaki G, Hoffman IF, et al.. Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection. AIDS. 2007;21:1723–1730.
20. Pilcher CD, Tien HC, Eron JJ, et al.. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis. 2004;189:1785–1792.
21. Morrison CS, Demers K, Kwok C, et al.. Plasma and cervical viral loads among Ugandan and Zimbabwean women during acute and early HIV-1 infection. AIDS. 2010;24:573–582.
22. Pao D, Fisher M, Hué S, et al.. Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS. 2005;19:85–90.
23. Colfax GN, Buchbinder SP, Cornelisse PGA, et al.. Sexual risk behaviors and implications for secondary HIV transmission during and after HIV seroconversion. AIDS. 2002;16:1529–1535.
24. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV from persons aware and unaware that they are infected with the virus in the USA. AIDS. 2006;20:1447–1450.
25. Powers KA, Ghani AC, Miller WC, et al.. The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study. Lancet. 2011;378:256–268.
26. Lewis F, Hughes GJ, Rambaut A, et al.. Episodic sexual transmission of HIV revealed by molecular phylodynamics. PLoS Med. 2008;5:e50.
27. Yerly S, Vora S, Rizzardi P, et al.. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS. 2001;15:2287–2292.
28. Dennis AM, Hué S, Hurt CB, et al.. Phylogenetic insights into regional HIV transmission. AIDS. 2012;26:1813–1822.
29. Fisher M, Pao D, Brown AE, et al.. Determinants of HIV-1 transmission in men who have sex with men: a combined clinical, epidemiological and phylogenetic approach. AIDS. 2010;24:1739–1747.
30. Brown AE, Gifford RJ, Clewley JP, et al.. Phylogenetic reconstruction of transmission events from individuals with acute HIV infection: toward more-rigorous epidemiological definitions. J Infect Dis. 2009;199:427–431.
31. Miller WC, Rosenberg NE, Rutstein SE, et al.. Role of acute and early HIV infection in the sexual transmission of HIV. Curr Opin HIV AIDS. 2010;5:277–282.
32. Jacquez JA, Koopman JS, Simon CP, et al.. Role of the primary infection in epidemics of HIV infection in gay cohorts. J Acquir Immune Defic Syndr. 1994;7:1169–1184.
33. Pinkerton SD, Abramson PR. Implications of increased infectivity in early-stage HIV infection application of a Bernoulli-process model of HIV transmission. Eval Rev. 1996;20:516–540.
34. Koopman JS, Jacquez JA, Welch GW, et al.. The role of early HIV infection in the spread of HIV through populations. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14:249–258.
35. Kretzschmar M, Dietz K. The effect of pair formation and variable infectivity on the spread of an infection without recovery. Math Biosci. 1998;148:83–113.
36. Coutinho FA, Lopez LF, Burattini MN, et al.. Modelling the natural history of HIV infection in individuals and its epidemiological implications. Bull Math Biol. 2001;63:1041–1062.
37. Xiridou M, Geskus R, De Wit J, et al.. Primary HIV infection as source of HIV transmission within steady and casual partnerships among homosexual men. AIDS. 2004;18:1311–1320.
38. Pinkerton SD. How many sexually-acquired HIV infections in the USA are due to acute-phase HIV transmission? AIDS. 2007;21:1625–1629.
39. Prabhu VS, Hutchinson AB, Farnham PG, et al.. Sexually acquired HIV infections in the United States due to acute-phase HIV transmission: an update. AIDS. 2009;23:1792–1794.
40. Goodreau SM, Cassels S, Kasprzyk D, et al.. Concurrent partnerships, acute infection and HIV epidemic dynamics among young adults in Zimbabwe. AIDS Behav. 2012;16:312–322.
41. Hayes RJ, White RG. Amplified HIV transmission during early-stage infection. J Infect Dis. 2006;193:604–605; author reply 605–606.
42. Eaton JW, Hallett TB, Garnett GP. Concurrent sexual partnerships and primary HIV infection: a critical interaction. AIDS Behav. 2011;15:687–692.
43. Pinkerton SD. Probability of HIV transmission during acute infection in Rakai, Uganda. AIDS Behav. 2008;12:677–684.
44. Abu-Raddad LJ, Longini IM. No HIV stage is dominant in driving the HIV epidemic in sub-Saharan Africa. AIDS. 2008;22:1055–1061.
45. Salomon JA, Hogan DR. Evaluating the impact of antiretroviral therapy on HIV transmission. AIDS. 2008;22(suppl 1):S149–S159.
46. Hollingsworth TD, Anderson RM, Fraser C. HIV-1 transmission, by stage of infection. J Infect Dis. 2008;198:687–693.
47. Napierala-Mavedzenge S, Gaydos CA, Makombe SD. The uptake and accuracy of oral kits for HIV self-testing in high HIV prevalence setting: a cross-sectional feasibility study in Blantyre, Malawi. PLoS Med. 2011;8:e1001102.
48. Zetola NM, Pilcher CD. Diagnosis and management of acute HIV infection. Infect Dis Clin North Am. 2007;21:19–48, vii.
49. Patel P, Mackellar D, Simmons P, et al.. Detecting acute human immunodeficiency virus infection using 3 different screening immunoassays and nucleic acid amplification testing for human immunodeficiency virus RNA, 2006-2008. Arch Intern Med. 2010;170:66–74.
50. Stekler JD, Swenson PD, Coombs RW, et al.. HIV testing in a high-incidence population: is antibody testing alone good enough? Clin Infect Dis. 2009;49:444–453.
51. Eshleman SH, Khaki L, Laeyendecker O, et al.. Detection of individuals with acute HIV-1 infection using the ARCHITECT HIV Ag/Ab Combo assay. J Acquir Immune Defic Syndr. 2009;52:121–124.
52. Chetty V, Moodley D, Chuturgoon A. Evaluation of a 4th generation rapid HIV test for earlier and reliable detection of HIV infection in pregnancy. J Clin Virol. 2012;54:180–184.
53. Karris MY, Anderson CM, Morris SR, et al.. Cost savings associated with testing of antibodies, antigens, and nucleic acids for diagnosis of acute HIV infection. J Clin Microbiol. 2012;50:1874–1878.
54. Quinn TC, Brookmeyer R, Kline R, et al.. Feasibility of pooling sera for HIV-1 viral RNA to diagnose acute primary HIV-1 infection and estimate HIV incidence. AIDS. 2000;14:2751–2757.
55. Fiscus SA, Pilcher CD, Miller WC, et al.. Rapid, real-time detection of acute HIV infection in patients in Africa. J Infect Dis. 2007;195:416–424.
56. Westreich DJ, Hudgens MG, Fiscus SA, et al.. Optimizing screening for acute human immunodeficiency virus infection with pooled nucleic acid amplification tests. J Clin Microbiol. 2008;46:1785–1792.
57. Kerndt PR, Dubrow R, Aynalem G, et al.. Strategies used in the detection of acute/early HIV infections. The NIMH Multisite Acute HIV Infection Study: I. AIDS Behav. 2009;13:1037–1045.
58. Hutchinson AB, Patel P, Sansom SL, et al.. Cost-effectiveness of pooled nucleic acid amplification testing for acute HIV infection after third-generation HIV antibody screening and rapid testing in the United States: a comparison of three public health settings. PLoS Med. 2010;7:e1000342.
59. Rosenberg NE, Kamanga G, Phiri S, et al.. Detection of acute HIV infection: a field evaluation of the determine® HIV-1/2 Ag/Ab combo test. J Infect Dis. 2012;205:528–534.
60. Pavie J, Rachline A, Loze B, et al.. Sensitivity of five rapid HIV tests on oral fluid or finger-stick whole blood: a real-time comparison in a healthcare setting. PLoS One. 2010;5:e11581.
61. Powers KA, Poole C, Pettifor AE, et al.. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect Dis. 2008;8:553–563.
62. Miller WC, Leone PA, McCoy S, et al.. Targeted testing for acute HIV infection in North Carolina. AIDS. 2009;23:835–843.
63. Gazzard BG, Anderson J, Babiker A, et al.. British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med. 2008;9:563–608.
64. Steward WT, Remien RH, Higgins JA, et al.. Behavior change following diagnosis with acute/early HIV infection—a move to serosorting with other HIV-infected individuals. The NIMH Multisite Acute HIV Infection Study: III. AIDS Behav. 2009;13:1054–1060.
65. Pettifor A, MacPhail C, Corneli A, et al.. Continued high risk sexual behavior following diagnosis with acute HIV infection in South Africa and Malawi: implications for prevention. AIDS Behav. 2011;15:1243–1250.
66. Quinn TC, Wawer MJ, Sewankambo N, et al.. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000;342:921–929.
67. Cohen MS, Chen YQ, McCauley M, et al.. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505.
68. Rieder P, Joos B, von Wyl V, et al.. HIV-1 transmission after cessation of early antiretroviral therapy among men having sex with men. AIDS. 2010;24:1177–1183.
69. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al.. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–2296.
70. Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary. Lancet. 2000;355:2147–2152.
71. Archin NM, Vaidya NK, Kuruc JD, et al.. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A. 2012;109:9523–9528.
72. Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al.. Distribution of the HIV reservoir in patients spontaneously controlling HIV infection after treatment interruption. Presented Mar 5-8, 2012 at the 19th International AIDS Conference, Seattle, WA.
73. Cellerai C, Harari A, Stauss H, et al.. Early and prolonged antiretroviral therapy is associated with an HIV-1-specific T-cell profile comparable to that of long-term non-progressors. PLoS One. 2011;6:e18164.
74. Desquilbet L, Goujard C, Rouzioux C, et al.. Does transient HAART during primary HIV-1 infection lower the virological set-point? AIDS. 2004;18:2361–2369.
75. Evering TH, Mehandru S, Racz P, et al.. Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection. PLoS Pathog. 2012;8:e1002506.
76. Fidler S, Fraser C, Fox J, et al.. Comparative potency of three antiretroviral therapy regimes in primary HIV infection. AIDS. 2006;20:247–252.
77. Fidler S, Fox J, Touloumi G, et al.. Slower CD4 cell decline following cessation of a 3 month course of HAART in primary HIV infection: findings from an observational cohort. AIDS. 2007;21:1283–1291.
78. Gay C, Dibben O, Anderson JA, et al.. Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy. PLoS One. 2011;6:e19617.
79. Gianella S, von Wyl V, Fischer M, et al.. Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA. Antivir Ther. 2011;16:535–545.
80. Goujard C, Emilie D, Roussillon C, et al.. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial. AIDS. 2012;26:1895–1905.
81. Goujard C, Girault I, Rouzioux C, et al.. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir Ther. 2012;17:1001–1009.
82. Grijsen ML, Koster GT, van Vonderen M, et al.. Temporary antiretroviral treatment during primary HIV-1 infection has a positive impact on health-related quality of life: data from the Primo-SHM cohort study. HIV Med. 2012;13:630–635.
83. Grijsen ML, Steingrover R, Wit FW, et al.. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial. PLoS Med. 2012;9:e1001196.
84. Hecht FM, Wang L, Collier A, et al.. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. 2006;194:725–733.
85. Hocqueloux L, Prazuck T, Avettand-Fenoel V, et al.. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS. 2010;24:1598–1601.
86. Hoen B, Cooper DA, Lampe FC, et al.. Predictors of virological outcome and safety in primary HIV type 1-infected patients initiating quadruple antiretroviral therapy: QUEST GW PROB3005. Clin Infect Dis. 2007;45:381–390.
87. Hogan CM, Degruttola V, Sun X, et al.. The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals. J Infect Dis. 2012;205:87–96.
88. Jain V, Hartogensis W, Bacchetti P, et al.. ART initiation during acute/early HIV infection compared to later ART initiation with improved immunologic and virologic parameters during suppressive ART. Presented Feb 27 - Mar 2, 2011 at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA.
89. Jansen CA, De Cuyper IM, Steingrover R, Jurriaans S, Sankatsing SU, Prins JM, et al.. Analysis of the effect of highly active antiretroviral therapy during acute HIV-1 infection on HIV-specific CD4 T cell functions. AIDS. 2005;19:1145–1154.
90. Kaufmann DE, Lichterfeld M, Altfeld M, et al.. Limited durability of viral control following treated acute HIV infection. PLoS Med. 2004;1:e36.
91. Kinloch-De Loes S, Hirschel BJ, Hoen B, et al.. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med. 1995;333:408–413.
92. Koegl C, Wolf E, Hanhoff N, et al.. Treatment during primary HIV infection does not lower viral set point but improves CD4 lymphocytes in an observational cohort. Eur J Med Res. 2009;14:277–283.
93. Lampe FC, Porter K, Kaldor J, et al.. Effect of transient antiretroviral treatment during acute HIV infection: comparison of the Quest trial results with CASCADE natural history study. Antivir Ther. 2007;12:189–193.
94. Le T, Wright EJ, Smith DM, et al.. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368:218–230.
95. Lodi S, Meyer L, Kelleher AD, et al.. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch Intern Med. 2012;172:1252–1255.
96. Markowitz M, Jin X, Hurley A, et al.. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis. 2002;186:634–643.
97. Mehandru S, Poles MA, Tenner-Racz K, et al.. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 2006;3:e484.
98. Moir S, Buckner CM, Ho J, et al.. B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy. Blood. 2010;116:5571–5579.
99. Niu MT, Bethel J, Holodniy M, et al.. Zidovudine treatment in patients with primary (acute) human immunodeficiency virus type 1 infection: a randomized, double-blind, placebo-controlled trial. DATRI 002 Study Group. Division of AIDS Treatment Research Initiative. J Infect Dis. 1998;178:80–91.
100. Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, Whelan JA, et al.. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A. 2000;97:3382–3387.
101. Pantazis N, Touloumi G, Vanhems P, et al.. The effect of antiretroviral treatment of different durations in primary HIV infection. AIDS. 2008;22:2441–2450.
102. Prazuck T, Lafeuillade A, Hocqueloux L, et al.. Can HAART at early acute HIV infection benefit the immune-virology outcome despite subsequent treatment cessation? Presented Feb 3-6, 2008 at the 15th Conference on Retroviruses and Opportunistic Infections; 2008, Boston, MA.
103. Rosenberg ES, Altfeld M, Poon SH, et al.. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523–526.
104. Rosenberg ES, Graham BS, Chan ES, et al.. Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection. PLoS One. 2010;5:e10555.
105. Sáez-Cirión A, Bacchus C, Hocqueloux L, et al.. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9:e1003211.
106. Seng R, Goujard C, Desquilbet L, et al.. Rapid CD4+ cell decrease after transient cART initiated during primary HIV infection (ANRS PRIMO and SEROCO cohorts). J Acquir Immune Defic Syndr. 2008;49:251–258.
107. SPARTAC Trial Investigators. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med. 2013;368:1–11.
108. Steingrover R, Pogany K, Fernandez Garcia E, et al.. HIV-1 viral rebound dynamics after a single treatment interruption depends on time of initiation of highly active antiretroviral therapy. AIDS. 2008;22:1583–1588.
109. Steingrover R, Garcia EF, van Valkengoed IG, et al.. Transient lowering of the viral set point after temporary antiretroviral therapy of primary HIV type 1 infection. AIDS Res Hum Retroviruses. 2010;26:379–387.
110. Streeck H, Jessen H, Alter G, et al.. Immunological and virological impact of highly active antiretroviral therapy initiated during acute HIV-1 infection. J Infect Dis. 2006;194:734–739.
111. Tilling R, Kinloch S, Goh L-E, et al.. Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection. AIDS. 2002;16:589–596.
112. Vinikoor MJ, Cope A, Gay CL, et al.. Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T cell activation. J Acquir Immune Defic Syndr. 2013. [Epub ahead of print].
113. Volberding P, Demeter L, Bosch RJ, et al.. Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment. AIDS. 2009;23:1987–1995.
114. Wyl V, Gianella S, Fischer M, et al.. Early antiretroviral therapy during primary HIV-1 infection results in a transient reduction of the viral setpoint upon treatment interruption. PLoS One. 2011;6:e27463.
115. Younes SA, Trautmann L, Yassine-Diab B, et al.. The duration of exposure to HIV modulates the breadth and the magnitude of HIV-specific memory CD4 T cells. J Immunol. 2007;178:788–797.
116. Clark SJ, Shaw GM. The acute retroviral syndrome and the pathogenesis of HIV-1 infection. Semin Immunol. 1993;5:149–155.
117. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med. 1998;339:33–39.
118. McKellar MS, Cope AB, Gay CL, et al.. Acute HIV-1 infection in the Southeastern United States: a cohort study. AIDS Res Hum Retroviruses. 2013;29:121–128.
119. Socías ME, Sued O, Laufer N, 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.
120. Henard S, Jeanmaire E, Nguyen Y, et al.. Is total community viral load a robust predictive marker of the efficacy of the TasP strategy? J Acquir Immune Defic Syndr. 2012;61:400–402.
121. Chun TW, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure. AIDS. 2012;26:1261–1268.
122. Pierson T, McArthur J, Siliciano RF. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol. 2000;18:665–708.
123. Pires A, Hardy G, Gazzard B, et al.. Initiation of antiretroviral therapy during recent HIV-1 infection results in lower residual viral reservoirs. J Acquir Immune Defic Syndr. 2004;36:783–790.
124. Buzon M, Mclaren P, Seiss K, et al.. Reduced HIV-1 reservoir size after 10 years of sup-pressive antiretroviral therapy in patients initiating treatment during primary infection. Presented Dec 6-9, 2011 at the Fifth International Workshop on HIV Persistence During Therapy; 2011; St Maarten, The Netherlands.
125. Saez-Cirion A, Hocqueloux L, Avettand-Fenoel V, et al.. Long-term HIV-1 control after interruption of treatment initiated at the time of primary infection is associated to low cell-associated HIV DNA levels: ANRS VISCONTI Study. Presented Feb 27 - Mar 2, 2011 at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA.
126. Hütter G, Nowak D, Mossner M, et al.. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692–698.
127. Persaud D, Gay H, Ziemniak C, et al.. Functional HIV cure after very early ART of an infected infant. Presented Mar 3-6, 2013 at the 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA.
128. Rebeiro P, Althoff KN, Buchacz K, et al.. Retention among North American HIV-infected persons in clinical care, 2000-2008. J Acquir Immune Defic Syndr. 2012. [Epub ahead of print].
129. University of Minnesota Clinical and Translational Science Institute. START - Strategic timing of Antiretroviral treatment. University of Minnesota Clinical and Translational Science Institute. Available at: http://insight.ccbr.umn.edu/start/
. Accessed April 18 2013.
130. World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents. 2011:1–156.
131. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/guidelines
. Accessed February 12, 2013.
132. Thompson MA, Aberg JA, Cahn P, et al.. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010;304:321–333.
early/acute HIV infection; HIV transmission; treatment as prevention; antiretroviral therapy
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