(Last updated:14/9/2015; last reviewed:8/4/2015)
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
Definitions: Acute HIV infection is the phase of HIV disease immediately after infection during which the initial burst of viremia in newly infected patients occurs; anti-HIV antibodies are undetectable at this time while HIV RNA or p24 antigen are present. Recent infection generally is considered the phase up to 6 months after infection during which anti-HIV antibodies are detectable. Throughout this section, the term “early HIV infection” is used to refer to either acute or recent HIV infection.
An estimated 40% to 90% of patients with acute HIV infection will experience symptoms of acute retroviral syndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms.1-6 Primary care clinicians, however, often do not recognize acute HIV infection because the self-limiting symptoms are similar to those of many other viral infections, such as influenza and infectious mononucleosis. Acute infection can also be asymptomatic. Table 10 provides practitioners with guidance to recognize, diagnose, and manage acute HIV infection.
Diagnosis of Acute HIV Infection
Health care providers should maintain a high level of suspicion of acute HIV infection in patients who have a compatible clinical syndrome—especially in those who report recent high-risk behavior (Table 10 ).7 Patients may not always disclose or admit to high-risk behaviors or they may not perceive that their behaviors put them at risk for HIV acquisition. Thus, signs and symptoms consistent with acute retroviral syndrome should motivate consideration of a diagnosis of acute HIV infection even in the absence of reported high-risk behaviors.
Acute HIV-1 infection is usually defined as detectable HIV-1 RNA or p24 antigen in serum or plasma in the setting of a negative or indeterminate HIV-1 antibody test result.7,8 Combination immunoassays that detect HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen are now approved by the Food and Drug Administration (FDA), and the most recent Centers for Disease Control and Prevention testing algorithm recommends them as the preferred assay to use for HIV screening, including for possible acute HIV-1 infection. Specimens that are reactive on this initial assay should be tested with an immunoassay that differentiates HIV-1 and HIV-2 antibodies.9 Specimens that are reactive on the initial assay and have either negative or indeterminate antibody differentiation test results should undergo testing using an FDA-approved quantitative or qualitative HIV-1 RNA test; a negative HIV-1 RNA test result indicates that the original Ag/Ab test result was a false positive. Detection of HIV-1 RNA indicates that acute HIV-1 infection is highly likely,9 and that antiretroviral therapy (ART) may be warranted (see Treatment for Early HIV-1 Infection). HIV-1 infection should be confirmed by subsequent testing to document HIV antibody seroconversion.
Some health care facilities may still be following HIV testing algorithms that recommend initial testing with an assay that only tests for the presence of HIV antibody. In such settings, when acute HIV-1 infection is suspected in a patient with a negative or indeterminate HIV antibody result, a quantitative or qualitative FDA-approved HIV-1 RNA test should be performed (AII). A presumptive diagnosis of acute HIV-1 infection can be made on the basis of a negative or indeterminate HIV antibody test result and a positive HIV-1 RNA test result, in which case, ART may be warranted (see Treatment for Early HIV-1 Infection). Providers should be aware that a low-positive quantitative HIV-1 RNA level (e.g., <10,000 copies/mL) may represent a false-positive result because HIV-1 RNA levels in acute infection are generally very high (e.g.,>100,000 copies/mL).5,6 Therefore, when a low-positive quantitative HIV-1 RNA result is obtained, the HIV-1 RNA test should be repeated using a different specimen from the same patient.6 In this setting, the diagnosis of HIV-1 infection should be confirmed by subsequent documentation of HIV antibody seroconversion (see Table 11).
October 2017 - Feedback
When acute HIV-1 infection is suspected and an anti-HIV antibody and/or antibody/antigen combo test is negative or the western blot is indeterminate, other suitable test options include a nucleic acid test for HIV. However, proviral DNA tests are not widely available in Australia and HIV viral load assays are not registered for use as a diagnostic test in this setting. False negative proviral DNA and false positive or negative HIV RNA tests can occur. Repeating anti-HIV antibody testing is likely to resolve the diagnosis in a shorter time period than ordering additional types of tests unless the turnaround time for nucleic acid tests is rapid.
- Potential Benefits of Treatment During Early HIV Infection. Preliminary data indicate that treatment of early HIV infection with combination ART improves laboratory markers of disease progression.13-17 The data, though limited, indicate that treatment of early HIV infection may also decrease the severity of acute disease; lower the viral set point,18-20 which can affect disease progression rates in the event therapy is stopped; reduce the size of the viral reservoir;21 and decrease the rate of viral mutation by suppressing viral replication and preserving immune function.22 Because early HIV infection often is associated with high viral loads and increased infectiousness,23 and ART use by HIV-infected individuals reduces transmission to serodiscordant sexual partners,24 treatment during this stage of infection is expected to substantially reduce the risk of HIV transmission. In addition, although data are limited and the clinical relevance unclear, the profound loss of gastrointestinal lymphoid tissue that occurs during the first weeks of infection may be mitigated by initiating ART during early HIV infection.25,26 Many of the potential benefits described above may be more likely to occur with treatment of acute infection, but they also may occur if treatment is initiated during recent HIV infection.
- Potential Risks of Treatment During Early HIV Infection. The potential disadvantages of initiating therapy during early HIV infection include more prolonged exposure to ART without a known long-term clinical benefit. This could result in drug toxicities, development of drug resistance, and adverse effects on an individual’s quality of life due to earlier initiation of lifelong therapy that requires strict adherence.
Several randomized controlled trials have studied the effect of ART during acute and recent infection to assess whether initiating early therapy would allow patients to stop treatment and maintain lower viral loads and higher CD4 counts while off ART for prolonged periods of time. This objective was of interest when these studies were initiated but is less relevant in an era in which treatment is recommended for virtually all HIV-infected patients and treatment interruptions are not recommended (see Initiating Antiretroviral Therapy in Treatment-Naive Patients).
The Setpoint Study (ACTG A5217 Study) randomized patients with recent but not acute HIV infection to either defer therapy or immediately initiate ART for 36 weeks and then stop.18 The primary study end point was a composite of meeting criteria for ART or re-initiation of ART and viral load results at week 72 in both groups and at week 36 in the deferred treatment group. The study was stopped prematurely by the Data and Safety Monitoring Board because of an apparent benefit associated with early therapy that was driven mostly by greater proportion of participants meeting criteria for ART initiation in the deferred treatment group (50%) than in the immediate treatment group (10%). Nearly half of the patients in the deferred treatment group needed to start therapy during the first year of study enrollment.
The Randomized Primo-SHM Trial randomized patients with acute (~70%) or recent (~30%) infection to either defer ART or to undergo treatment for 24 or 60 weeks and then stop.19 Significantly lower viral loads were observed 36 weeks after treatment interruption in the patients who had been treated early. These patients also experienced a longer time before the need to initiate therapy, primarily on the basis of reaching a CD4 count of <350 cells/mm3. The median time to starting treatment was 0.7 years for the deferred therapy group and 3.0 and 1.8 years for the 24- and 60-week treatment arms, respectively. The time to reaching a CD4 count of <500 cells/mm3 was only 0.5 years in the deferred group.
Finally, the SPARTAC Trial included patients with acute and recent infection randomized to either defer therapy or to undergo treatment for 12 or 48 weeks and then stop.20 In this case, the time to CD4 <350 cells/mm3 or initiation of therapy was significantly longer in the group treated for 48 weeks than in the deferred treatment group or the group treated for 12 weeks. However, no difference was observed comparing persons who received 12 weeks of ART with those who deferred treatment during early infection.
The strategies tested in these studies are of limited relevance in the current treatment era in which treatment interruption is not recommended. The study results may not fully reflect the natural history of HIV disease in persons with asymptomatic acute infection because most patients in these trials were enrolled on the basis of identified early symptomatic HIV infections. Nevertheless, the results do demonstrate that some immunologic and virologic benefits may be associated with the treatment of early HIV infection. Moreover, all the findings suggest, at least in the population recruited for these studies, that the time to initiating ART after identification of early infection is quite short when the threshold for ART initiation is 350 CD4 cells/mm3, and nonexistent when therapy is advised for all individuals regardless of CD4 cell count as currently recommended in these guidelines. These observations must be balanced with the risks of early treatment, risks that are largely the same as those of therapy initiated in chronically infected asymptomatic patients with high CD4 counts. Consequently, the health care provider and the patient should be fully aware that the rationale for initiating therapy during early HIV infection is based on theoretical benefits and the extrapolation of data from the strategy trials outlined above. These potential benefits must be weighed against the risks. For these reasons, and because ART is currently recommended for all HIV-infected patients (see Initiating Antiretroviral Therapy in Treatment Naive Patients), ART should be offered to all patients with early HIV infection (BII). However, patients must be willing and able to commit to treatment and providers, on a case-by-case basis, may elect to defer therapy for clinical and/or psychosocial reasons. Providers also should consider enrolling patients with early HIV infection in clinical studies to further evaluate the natural history of this stage of HIV infection and to further define the role of ART in this setting. Providers can obtain information regarding such trials at www.clinicaltrials.gov or from local HIV treatment experts.
Treatment for Early HIV Infection During Pregnancy
Because early HIV infection is associated with a high risk of perinatal transmission, all HIV-infected pregnant women should start combination ART as soon as possible to prevent perinatal transmission of HIV (AI).27
Treatment Regimen for Early HIV Infection
Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least 1 antiretroviral in 6% to 16% of patients.28-30 Up to 21% of isolates from contemporary patients with acute HIV infection demonstrated resistance to at least 1 drug.31 Therefore, before initiation of ART in a person with early HIV infection, genotypic antiretroviral drug resistance testing should be performed to guide the selection of a regimen (AII). If the decision to initiate therapy during early infection is made, especially in the setting of acute infection, treatment initiation should not be delayed pending resistance testing results. Once results are available, the treatment regimen can be modified if warranted. If therapy is deferred, resistance testing still should be performed because the results will help guide selection of a regimen to optimize virologic response once therapy is initiated (AII).
The goal of therapy during early HIV infection is to suppress plasma HIV RNA to undetectable levels (AIII). Because data to draw firm conclusions regarding specific drug combinations to use in this stage of HIV infection are insufficient, ART should be initiated with one of the combination regimens recommended for patients with chronic infection (AIII) (see What to Start). If therapy is started before the results of drug resistance testing are available, because resistance to RTV-boosted protease inhibitors (PIs) emerge slowly and clinically significant transmitted resistance to PIs is uncommon (AIII). If available, the results of ARV drug resistance testing or the ARV resistance pattern of the source person’s virus should be used to guide the selection of the ARV regimen. Given the recent approval of daily tenofovir DF/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP),32-34 early infection may be diagnosed in some patients while they are taking TDF/FTC as PrEP. In this setting, resistance testing should be performed; however, because PI resistance is unlikely, use of a RTV-boosted PI with TDF/FTC remains a reasonable option pending resistance testing results (see What to Start).
Testing for plasma HIV RNA levels, CD4 cell counts, and toxicity monitoring should be performed as described in Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy (i.e., HIV RNA at initiation of therapy, after 2 to 8 weeks, then every 4 to 8 weeks until viral suppression, and thereafter, every 3 to 4 months) (AII).
The optimal duration of therapy for patients with early HIV infection is unknown. Recent studies of early HIV infection have evaluated the potential for starting and then stopping treatment.18-20 Although these studies showed some benefits associated with this strategy, a large randomized controlled trial of patients with chronic HIV infection found that treatment interruption was harmful in terms of increased risk of AIDS and non-AIDS events,35 and that the strategy was associated with increased markers of inflammation, immune activation and coagulation.36 For these reasons and because of the potential benefit of ART in reducing the risk of HIV transmission, the Panel recommends against discontinuation of ART in patients treated for early HIV infection (AIII).
Table 11. Identifying, Diagnosing, and Managing Acute and Recent HIV-1 Infection
Click here to view this table as an image
b Plasma HIV RNA can be measured by a variety of quantitative assays, including branched DNA (bDNA) and reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays as well as by a qualitative transcription-mediated amplification assay (APTIMA, GenProbe).
- Tindall B, Cooper DA. Primary HIV infection: host responses and intervention strategies. AIDS. 1991;5(1):1-14. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1812848.
- Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review of pathogenesis and early treatment intervention in humans and animal retrovirus infections. J Infect Dis. 1993;168(6):1490-1501. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8245534.
- Kinloch-de Loes S, de Saussure P, Saurat JH, Stalder H, Hirschel B, Perrin LH. Symptomatic primary infection due to human immunodeficiency virus type 1: review of 31 cases. Clin Infect Dis. 1993;17(1):59-65. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8353247.
- Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med. 1996;125(4):257-264. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8678387.
- Daar ES, Little S, Pitt J, et al. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network. Ann Intern Med. 2001;134(1):25-29. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11187417.
- Hecht FM, Busch MP, Rawal B, et al. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS. 2002;16(8):1119-1129. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12004270.
- Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17; quiz CE11-14. Available at http://www.ncbi.nlm.nih.gov/pubmed/16988643.
- Pilcher CD, Christopoulos KA, Golden M. Public health rationale for rapid nucleic acid or p24 antigen tests for HIV. J Infect Dis. 2010;201(1):S7-15. Available at http://www.ncbi.nlm.nih.gov/pubmed/20225950.
- Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014. Accessed March 19, 2015.
- Branson BM. The future of HIV testing. J Acquir Immune Defic Syndr. Dec 2010;55 Suppl 2:S102-105. Available at http://www.ncbi.nlm.nih.gov/pubmed/21406978.
- Branson BM, Stekler JD. Detection of acute HIV infection: we can't close the window. J Infect Dis. Feb 15 2012;205(4):521-524. Available at http://www.ncbi.nlm.nih.gov/pubmed/22207652.
- Pantaleo G, Cohen OJ, Schacker T, et al. Evolutionary pattern of human immunodeficiency virus (HIV) replication and distribution in lymph nodes following primary infection: implications for antiviral therapy. Nat Med. 1998;4(3):341-345. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9500610.
- Hoen B, Dumon B, Harzic M, et al. Highly active antiretroviral treatment initiated early in the course of symptomatic primary HIV-1 infection: results of the ANRS 053 trial. J Infect Dis. 1999;180(4):1342-1346. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10479169.
- Lafeuillade A, Poggi C, Tamalet C, Profizi N, Tourres C, Costes O. Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis. 1997;175(5):1051-1055. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9129065.
- Lillo FB, Ciuffreda D, Veglia F, et al. Viral load and burden modification following early antiretroviral therapy of primary HIV-1 infection. AIDS. 1999;13(7):791-796. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10357377.
- Malhotra U, Berrey MM, Huang Y, et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J Infect Dis. 2000;181(1):121-131. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10608758.
- Smith DE, Walker BD, Cooper DA, Rosenberg ES, Kaldor JM. Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence? AIDS. 2004;18(5):709-718. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15075505.
- 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(1):87-96. Available at http://www.ncbi.nlm.nih.gov/pubmed/22180621.
- 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(3):e1001196. Available at http://www.ncbi.nlm.nih.gov/pubmed/22479156.
- The SPARTAC Trial Investigators. Short-Course Antiretroviral Therapy in Primary HIV Infection. N Engl J Med. 2013;368(3):207-217. Available at http://www.ncbi.nlm.nih.gov/pubmed/23323897.
- Strain MC, Little SJ, Daar ES, et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis. 2005;191(9):1410-1418. Available at http://www.ncbi.nlm.nih.gov/pubmed/15809898.
- Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. S2000;407(6803):523-526. Available at http://www.ncbi.nlm.nih.gov/pubmed/11029005.
- Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis. 2005;191(9):1403-1409. Available at http://www.ncbi.nlm.nih.gov/pubmed/15809897.
- Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. Available at http://www.ncbi.nlm.nih.gov/pubmed/21767103.
- Mehandru S, Poles MA, Tenner-Racz K, et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004;200(6):761-770. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15365095.
- Guadalupe M, Reay E, Sankaran S, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol. 2003;77(21):11708-11717. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14557656.
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
- Wheeler WH, Ziebell RA, Zabina H, et al. Prevalence of transmitted drug resistance associated mutations and HIV-1 subtypes in new HIV-1 diagnoses, U.S.-2006. AIDS. 2010;24(8):1203-1212. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20395786.
- Kim D, Wheeler W, Ziebell R, al e. Prevalence of transmitted antiretroviral drug resistance among newly-diagnosed HIV-1-infected persons, US, 2007. Paper presented at: 17th Conference on Retroviruses and Opportunistic Infections; 2010; San Francisco, CA.
- Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis. 2005;192(6):958-966. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16107947.
- Yanik EL, Napravnik S, Hurt CB, et al. Prevalence of transmitted antiretroviral drug resistance differs between acutely and chronically HIV-infected patients. J Acquir Immune Defic Syndr. 2012;61(2):258-262. Available at http://www.ncbi.nlm.nih.gov/pubmed/22692092.
- Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. Available at http://www.ncbi.nlm.nih.gov/pubmed/21091279.
- Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. Available at http://www.ncbi.nlm.nih.gov/pubmed/22784037.
- Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423-434. Available at http://www.ncbi.nlm.nih.gov/pubmed/22784038.
- Strategies for Management of Antiretroviral Therapy Study G, El-Sadr WM, Lundgren J, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283-2296. Available at http://www.ncbi.nlm.nih.gov/pubmed/17135583.
- Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203. Available at http://www.ncbi.nlm.nih.gov/pubmed/18942885.