(Last updated: April 8, 2015; last reviewed: April 8, 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
|a Early infection represents either acute or recent infection.|
Definitions: Acute HIV-1 infection is the phase of HIV-1 disease immediately after infection that is characterized by an initial burst of viremia; although, anti-HIV-1 antibodies are undetectable, HIV-1 RNA or p24 antigen are present. Recent infection generally is considered the phase up to 6 months after infection during which anti-HIV-1 antibodies are detectable. Throughout this section, the term “early HIV-1 infection” is used to refer to either acute or recent HIV-1 infection.
An estimated 40% to 90% of patients with acute HIV-1 infection will experience symptoms of acute retroviral syndrome, such as fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms.1-6 However, because the self-limiting symptoms are similar to those of many other viral infections, such as influenza and infectious mononucleosis, primary care clinicians often do not recognize acute HIV-1 infection. Acute infection can also be asymptomatic. Table 11 provides practitioners with guidance to recognize, diagnose, and manage acute HIV-1 infection.
Diagnosing Acute HIV Infection
Health care providers should maintain a high level of suspicion of acute HIV-1 infection in patients who have a compatible clinical syndrome—especially in those who report recent high-risk behavior (see Table 11).7 Patients may not always disclose or admit to high-risk behaviors or perceive that their behaviors put them at risk for HIV-1 acquisition. Thus, even in the absence of reported high-risk behaviors, signs and symptoms consistent with acute retroviral syndrome should motivate consideration of a diagnosis of acute HIV-1 infection.
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).
Treating Early HIV-1 Infection
Clinical trial data regarding the treatment of early HIV-1 infection is limited. Many patients who enrolled in studies to assess the role of ART in early HIV-1 infection (outlined below) were identified as trial participants because they presented with signs or symptoms of acute infection. With the introduction of HIV screening tests that include assays for HIV-1 RNA or p24 antigen and wider HIV screening in healthcare systems, the number of asymptomatic patients identified with early infection may increase. The natural history of HIV-1 disease in these patients may differ from that in individuals with symptomatic infections, thus further studies on the impact of ART on the natural history of asymptomatic acute HIV-1 infection are needed. The initial burst of high level viremia in infected individuals usually declines shortly after acute infection (e.g., within 2 months); however, a rationale for treatment during recent infection (e.g., 2–6 months after infection) remains, because during this transition period the immune system may not yet have maximally contained viral replication in the lymphoid tissue.10 Several trials have addressed the question of the long-term benefit of potent treatment regimens initiated during early HIV-1 infection. The potential benefits and risks of treating HIV-1 during this stage of disease are discussed below.
Potential Benefits of Treatment During Early HIV-1 Infection
Preliminary data indicate that treatment of early HIV-1 infection with combination ART improves laboratory markers of disease progression.11-15 The data, though limited, indicate that treatment of early HIV-1 infection may also reduce the severity of acute disease; lower the viral set point,16-18 which can affect the rate of disease progression if therapy is stopped; reduce the size of the viral reservoir;19 and decrease the rate of viral mutation by suppressing viral replication and preserving immune function.20 Because early HIV-1 infection is often associated with high viral loads and increased infectiousness,21 and ART use by HIV-1-infected individuals reduces transmission to serodiscordant sexual partners,22 treatment during early HIV-1 infection is expected to substantially reduce the risk of HIV-1 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-1 infection.23,24 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-1 infection.
Potential Risks of Treatment During Early HIV-1 Infection
The potential disadvantages of initiating therapy during early HIV-1 infection include more prolonged exposure to ART without a known long-term clinical benefit. This prolonged exposure to ART could result in drug toxicities, development of drug resistance if the patient is non-adherent to the regimen, and adverse effects on the patient’s quality of life due to earlier initiation of lifelong therapy that requires strict adherence.
Clinical Trial Data on Treatment During Early Infection
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 still maintain lower viral loads and higher CD4 T lymphocyte (CD4) counts while off ART for prolonged periods of time. This objective was of interest when these studies were initiated but is now less relevant because treatment is recommended for virtually all HIV-1-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-1 infection to either defer therapy or immediately initiate ART for 36 weeks and then stop treatment.16 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 the greater proportion of participants meeting the 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 undergo treatment for 24 or 60 weeks and then stop.17 Significantly lower viral loads were observed 36 weeks after treatment interruption in the patients who had been treated early. These patients also took longer to reach a CD4 count threshold of <350 cells/mm3 for restarting ART. 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.
The SPARTAC Trial included patients with acute and recent infection randomized to either defer therapy or received ART for 12 or 48 weeks and then stop.18 In this trial, the time to reach CD4 <350 cells/mm3 or initiate 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 between the participants who received 12 weeks of ART and those who deferred treatment during early infection.
The strategies tested in these studies are of limited relevance today given that treatment interruption is not recommended. The study results may not fully reflect the natural history of HIV-1 disease in persons with asymptomatic acute infection because most patients in these trials were enrolled on the basis of identified early symptomatic HIV-1 infections. Nevertheless, the results do demonstrate that some immunologic and virologic benefits may be associated with the treatment of early HIV-1 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 when therapy is 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-1 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-1-infected patients (see Initiating Antiretroviral Therapy in Treatment Naive Patients), ART should be offered to all patients with early HIV-1 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-1 infection in clinical studies to further evaluate the natural history of this stage of HIV-1 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.
Treating Early HIV-1 Infection During PregnancyBecause early HIV-1 infection is associated with a high risk of perinatal transmission, all HIV-1-infected pregnant women should start combination ART as soon as possible to prevent perinatal transmission of HIV-1 (AI).25
Treatment Regimen for Early HIV-1 Infection
Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least 1 antiretroviral drug in 6% to 16% of patients.26-28 In one study, 21% of isolates from patients with acute HIV-1 infection demonstrated resistance to at least 1 drug.29 Therefore, before initiating ART in a person with early HIV-1 infection, genotypic antiretroviral (ARV) drug resistance testing should be performed to guide selection of a regimen (AII). If the decision is made to initiate therapy during early infection, 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 that has the greatest potential to optimize virologic response once therapy is initiated (AII).
The goal of therapy during early HIV-1 infection is to suppress plasma HIV-1 RNA to undetectable levels (AIII). Because data are insufficient to draw firm conclusions regarding specific drug combinations to use in this stage of HIV-1 infection, 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, a pharmacologically boosted protease inhibitor (PI) should be used because resistance to these agents emerges slowly and clinically significant transmitted resistance 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 selection of the ARV regimen. Given the increasing use of daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) in HIV-negative individuals,30-32 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 pharmacologically boosted PI and TDF/FTC remains a reasonable option pending resistance testing results (see What to Start).
Testing for plasma HIV-1 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-1 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).
Duration of Therapy for Early HIV-1 Infection
The optimal duration of therapy for patients with early HIV-1 infection is unknown. Recent studies of early HIV-1 infection have evaluated starting and then stopping treatment as a potential strategy.16-18 Although these studies showed some benefits associated with this strategy, a large randomized controlled trial of patients with chronic HIV-1 infection found that treatment interruption was harmful in terms of increased risk of AIDS and non-AIDS events,33 and that the strategy was associated with increased markers of inflammation, immune activation, and coagulation.34 For these reasons and the potential benefit of ART in reducing the risk of HIV-1 transmission, the Panel does not recommend discontinuation of ART in patients treated for early HIV-1 infection (AIII).
|Suspicion of Acute HIV-1 Infection:
|a In some settings, behaviors that increase the risk of HIV-1 infection may not be recognized or perceived as risky by the health care provider or the patient or both. Thus, even in the absence of reported high-risk behaviors, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of a diagnosis of acute HIV-1 infection.|