Acute HIV Infection

Chinese Version

Updated August, 2009

Vivian Levy, M.D.

Stanford University, Division of Infectious Diseases

San Mateo Medical Center, Clinical Trials and Research

222 West 39^th Avenue

San Mateo, CA 94403

Phone: (650)573-2385, Fax: (650) 573-2474

E-mail: vlevy@stanford.edu

Robert M. Grant, M.D., M.P.H

Associate Investigator

Gladstone Institute of Virology and Immunology

Associate Professor of Medicine

University of California, San Francisco

PO Box 419200

San Francisco, CA 94141-9100

Phone:(415)695-3809, Fax:(415)826-8449

E-mail: rgrant@itsa.ucsf.edu

Diagnosis of Acute HIV Infection

               Acute HIV infection, defined as the time from virus entry to completion of detectable antibody responses to HIV, is a unique opportunity for therapeutic intervention in selected patients. Acute infection is followed by early stage infection, the interval between seroconversion and the establishment of the viral load set point, which usually occurs 6-12 months after infection (25).

               About 40% to 90% of persons with newly acquired HIV infection will have symptoms of an acute viral infection, such as fever, rash, and myalgias (Table 1) (19, 24, 36, 40, 46). The syndrome may last from a few days to more than 10 weeks, but usually lasts less than two weeks. Acute HIV infection should be considered in persons presenting with these symptoms 2-6 weeks after a possible HIV exposure. (24, 40) or with this acute retroviral syndrome accompanied by a sexually transmitted disease (48).

               HIV infection is followed by a series of events with variable timing (4, 35). The initial post-exposure period, which occurs after infection but before the development of viremia, typically lasts 4-20 days. Because plasma HIV RNA can be detected for about 3-4 days before HIV p24 antigen, plasma viremia is the most sensitive means of diagnosing acute HIV infection (22). Although false-positive plasma HIV RNA levels can occur, the levels are usually lower (<3000 copies/ml) than in true positives (19) where peak viremia can reach levels of several million viral copies.

               Less sensitive serologic assays can be used to confirm the diagnosis of HIV infection. Although enzyme immunoassay (EIA) tests used for blood screening can detect antibodies about one week after the initial appearance of plasma viremia, they may not be available in all laboratories. The more widely available EIA tests typically become positive one to two weeks after plasma viremia. Western blot serological assays begin to develop detectable bands about two weeks after plasma viremia.

Guideline:  Aberg JA, et al.  Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America.  Clin Infect Dis 2009;49:651-681. 

Benefits of Treatment During Acute HIV Infection

               Currently, there is no evidence from human studies that antiretroviral therapy begun during acute infection decreases clinical progression or alters the clinical course of HIV compared with effective therapy begun later in disease. There are several potential benefits to instituting treatment during acute HIV infection: (1) reducing the symptoms associated with acute infection, (2) delaying progression to advanced immunodeficiency, (3) preserving HIV-specific immunity, (4) limiting the development of HIV diversity, and (5) decreasing the likelihood of HIV transmission when viral titers are high.

Schulze Zur Wiesch J, et al. Sustained Virological Response after Early Antiviral Treatment of Acute Hepatitis C Virus and HIV Coinfection. Clin Infect Dis 2009;49:466–472.

Reducing the Symptoms Associated with Acute Infection    

               The syndrome of acute HIV infection is usually self-limited and often escapes identification during clinical evaluation. However, some people with primary infection continue to experience symptoms for several months. These symptoms, including fever, rash, headache, and even oral thrush, can be prevented by antiretroviral therapy (3, 26). The subset of acutely infected persons with more severe or prolonged acute symptoms and persons with higher viral loads 6-12 months following resolution of the acute infection (higher viral set points) are more likely to be rapid HIV progressors (8, 13, 31).

Delaying Progression to Advanced Immunodeficiency

               Cohort studies have suggested viral loads in acutely treated subjects rebound to lower levels than in untreated subjects (16, 39). Two other cohort studies of seroconverters treated during acute infection found viral set points were not significantly lower compared with seroconverters from earlier natural history cohorts (14, 33).

Preservation of Immune Responses         

               HIV-specific cell-mediated immune responses may be preserved in subjects treated prior to seroconversion (37, 39). Within six months of infection, CD4+ cells lose their ability to proliferate in response to HIV antigens (42). This is most likely because activated cells are infected and killed by viral replication and T cell activation (12). Antiretroviral therapy begun after chronic HIV viremia can restore immune responses to a wide variety of antigens but cannot re-establish anti-HIV proliferative responses, probably because clones of CD4+ T cells that recognize HIV antigens are exhausted (1, 2, 12, 44).

               HIV-specific CD8+ cytotoxic T lymphocytes detectable early after infection are strongly associated with control of viremia in acute and established infection (29). Epitopes targeted during acute infection often differ from those recognized during chronic infection (28). HIV specific CD4+ and CTL proliferative responses were found in both treated and untreated subjects during the first 18 months of infection but were markedly increased in treated subjects who maintained virologic control (27).

Limiting Viral Evolution           

               The natural history of HIV evolution indicates that an initially homogenous virus population diversifies during the course of infection (9, 10, 41, 53). If the extent of viral diversity can be limited early in infection, variants with the ability to escape from host immunity or antiretroviral therapy are theoretically less likely to emerge.

Decreasing Transmission    

               Recently infected persons may be particularly infectious, in part because of the high viral loads observed in primary viremia and because they may continue the risky behavioral patterns that led to their infection (38, 52). Treatment clearly decreases transmission from mothers to newborns (5). It also has been demonstrated in observational studies to decrease rates of sexual transmission (34), perhaps because viral load in genital secretions is markedly suppressed during therapy (18, 47).

Possible Risks of Early Treatment

               There is no evidence that earlier treatment is associated with a higher likelihood of virus eradication (32). The mutational capacity of a rapidly replicating virus in acute HIV infection makes adherence critical to the success of acute HIV treatment. Reduced adherence or prolonged use of certain drug combinations may promote HIV drug resistance and limit drug options for future therapy. In addition to risks of antiretroviral resistance, there is a risk of serious toxicities with current therapy ("Complications of Antiretroviral Therapy").

Transmitted Drug Resistance       

               About 10% of recently infected persons in North America and Europe exhibit primary resistance to at least one drug class, and about 5% are infected with viruses having genotypic evidence of resistance to at least two drug classes (17, 30, 43). Primary resistance poses a difficult clinical problem because the antiretroviral history of the source of infection is often unavailable. Resistance testing prior to initiating therapy should be done in North America and Europe, where the highest rates of primary drug resistance have been reported (11, 23, 49) . Clinicians should consider initiating therapy at once in these cases and revising the regimen when resistance test results are available.

               Genotypic testing is likely to be the most sensitive method of detecting resistance because, unlike phenotypic tests, it can identify minority populations and transitional mutations. For example, T215C and T215D are common mutations resulting from T215Y and T215F back mutation. These mutations do not cause phenotypic resistance but suggest that T215Y or T215F may have been transmitted (15, 51).

               Primary drug resistance may lengthen the time required to attain viral suppression or even prevent a response to treatment and lead to the development of additional drug resistance (20, 21). Subjects may eventually achieve virologic suppression, probably as a result of agents in the combination regimen to which the virus remains susceptible (30, 50). Primary resistance to multiple classes of drugs might best be managed by delaying therapy in order to identify the "set-point" or steady-state level of viremia. In some untreated subjects with a multidrug-resistant infection, the viral load after primary viremia is low and therapy may not be necessary.

Review Article:  Hirsch MS, et al.  Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA Panel.  Clin Infect Dis 2008;47:266-285.

Selection of Antiretroviral Drugs During Acute HIV Infection          

               There are no clinical trials of different HAART regimens in patients with acute HIV infection. Therefore most clinicians follow the guidelines outlined in the chapter on treating the previously untreated patient.

               However, considering the increasing risk of transmitted drug resistance, it would not be unreasonable to choose one of the more aggressive regimens such as two NRTIs and a dual PI or three NRTIs and an NNRTI. Caution should be taken when beginning treatment for acute infection with an NNRTI. Class resistance to NNRTIs is suspected to be the most common type of primary drug resistance. Among NNRTIs, nevirapine is likely not an appropriate choice for empiric treatment of acute infection as it is associated with a higher incidence of serious hepatic and cutaneous toxicities compared to efavirenz (11). Nevirapine hepatic toxicity is more likely to occur in women with CD4+ T cell counts > 250 cells/mm³ and men with CD4+ T cell counts > 400 cells/mm³ pre-nevirapine use (7, 11). If susceptibility test results become available the treatment regimen can either be simplified or modified according to the results of these tests. The institution of antiretroviral therapy during acute HIV infection does not commit the patient to lifelong therapy; although treatment may be continued indefinitely if well tolerated. Therapy may be discontinued after adequate viral suppression has been achieved until guidelines warrant its reinstitution. Most clinicians who elect to treat acute HIV infection will extend the treatment for the first 6 months after seroconversion (25).

Treatment Interruptions Following the Treatment of Acute HIV Infection

               Intermittent interruption of therapy is not currently recommended practice, but is an active area of investigation. Treatment interruptions may serve to enhance HIV immune responses by providing bursts of viral antigen followed by viral suppression with drugs that spare the proliferating CD4+ cells from direct and indirect viral-mediated destruction (39). Treatment interruptions, however, may render HIV-specific CD4+ T cells vulnerable to the infection and destruction by HIV (12). Finally, it is possible that drug resistance will emerge more rapidly in subjects with repeated cycles of interrupted therapy.

Tables and Figures

Table 1. Symptoms and Findings Associated with Acute HIV Infection

*Based on data from 588 patients in five studies (6, 19, 36, 40, 45).

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