eMedicine Specialties > Infectious Diseases > HIV

Early Symptomatic HIV Infection

Author: Robert J Carpenter, DO, Fellow in Infectious Diseases, Infectious Diseases Clinic, Naval Medical Center San Diego
Coauthor(s): Braden R Hale, MD, MPH, Assistant Clinical Professor, Department of Internal Medicine, University of California at San Diego; Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Naval Medical Center at San Diego; Kirk M Chan-Tack, MD, Fellow, Division of Infectious Disease, University of Maryland School of Medicine; John Bartlett, MD, Chief of Division of Infectious Diseases, Chief of HIV Care Service, Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine
Contributor Information and Disclosures

Updated: Jun 9, 2009

Introduction

Background

The clinical effects of human immunodeficiency virus (HIV) infection are diverse, ranging from an acute retroviral syndrome associated with primary HIV infection to a prolonged asymptomatic state to advanced HIV disease. Experts regard HIV disease as beginning at the time of primary (acute) HIV infection and progressing through numerous stages of chronic infection.

Acute HIV infection is defined as the period between exposure to the virus and completion of the initial immune responses. This period varies but generally lasts 2-3 months. During this time, the antibody test may be negative for HIV, but the serum viral load (the amount of HIV virus in the blood) is detectable and can be quite high (millions of copies per milliliter).

In most infected individuals, active virus replication and progressive immunologic impairment occur throughout the course of HIV infection, even during the clinically latent stage. Chronic HIV disease can be divided empirically based on the degree of immunodeficiency into (1) early stage (ie, CD4 T-cell count >500/µL), (2) intermediate stage (ie, CD4 T-cell count 200-500/µL), and (3) advanced stage (ie, CD4 T-cell count <200/µL).

Approximately 70% of patients with HIV infection develop symptoms during the acute infection period,¹ although some reports of symptomatic acute HIV infection are likely associated with a reporting bias, and the actual frequency may be lower. Symptoms associated with HIV seroconversion are nonspecific and may be attributed to a viral syndrome such as influenza virus infection.

Complex changes occur in the immune system during the acute infection period, including rapid depletion of CD4 cells. Anti-HIV antibodies are produced, and cytotoxic CD8 lymphocytes destroy HIV-infected cells. Unfortunately, the response is imperfect, and latent reservoirs of HIV infection are established throughout the body.

Chronic HIV infection begins after antibodies to the virus have fully developed and the initial immune response is complete. HIV disease with active virus replication usually progresses during this asymptomatic period, and the rate of disease progression correlates directly with HIV RNA levels. Individuals with high levels of HIV RNA progress to symptomatic HIV disease faster than patients with low levels of HIV RNA. Some individuals develop symptoms or organ dysfunction during chronic infection due to direct effects of the virus rather than a defect in cell-mediated immunity. Some infected persons who are otherwise asymptomatic develop persistent generalized lymphadenopathy (PGL) during this time. With few exceptions, CD4 cell counts decline progressively during this asymptomatic period, at an average rate of approximately 50 cells/µL/y.

Acquired immunodeficiency syndrome (AIDS) is the condition that results from long-term (chronic) HIV infection and is defined by an absolute CD4 cell count of less than 200 cells/µL and specific opportunistic infections or malignancies. The interval between acute HIV infection and AIDS is highly variable, with a median time of approximately 10 years. In many infected individuals, an opportunistic disease is the first manifestation of HIV infection. When the CD4 cell count falls to below approximately 200 cells/µL, the resulting state of immunodeficiency places the individual at high risk for opportunistic infections and neoplasms (clinically apparent HIV disease).

Pathophysiology

Acute HIV infection (also known as seroconversion) is defined as the period between exposure to the virus and completion of the initial immune responses (when an antibody test becomes positive for HIV). After infection, HIV is able to replicate at an exponential rate using CD4 cells. The following is a simplified outline of events that occur during acute HIV infection:²

• Day 0: The individual is exposed to HIV, and infection begins.
• Day 8: The virus is detectable in blood using polymerase chain reaction (PCR); however, antibody test findings are negative. The amount of virus in the blood more than doubles every day. The CD4 cell count (and total WBC count) begins to drop as the viral load increases.
• Week 2-4: Early antibodies to HIV may be detected; however, they have a low affinity for viral antigens and have little effect on the virus itself. Newer antibody assays may detect these antibodies. The viral load peaks and begins to decline as the immune system begins to battle the virus with antibodies and CD8 cytotoxic cells. (Although persons infected with HIV may transmit the infection to another person at any time, they are highly infectious during the period of acute infection when genital shedding of HIV virus peaks [at approximately week 3-4 of acute infection]. Because the individual may be asymptomatic during this period, he or she may have no knowledge that he or she is infected and may therefore not be using appropriate safer-sex precautions. This represents an epidemiologic challenge in controlling the HIV pandemic.)
• Week 10-24: The HIV viral load drops to its lowest point, also known as the set point, which is different in each person. Antibodies now have higher affinity for viral antigen; therefore, antibody tests become positive for HIV. Seroconversion is now complete, and chronic HIV infection begins.

Frequency

United States

• In 2006, a study of people requesting HIV testing at a sexually-transmitted diseases (STD) clinic in San Francisco found 136 new HIV infections of 3,789 people tested. Eight percent of those with HIV infection were acutely infected (antibody findings negative, antigen findings positive). This study found that acute HIV infections were associated with having a known HIV-positive partner within the past 12 months and a history of hepatitis B, syphilis, and chlamydia infection in the past 2 years.³
• A larger, prospective study of 109,250 people seeking HIV testing in North Carolina found 606 new HIV infections, 4% of which were acute infections (antibody findings negative, antigen findings positive). Seventy percent of the acute HIV infections were in people who were tested at STD clinics.⁴
• Clearly, the prevalence of acute HIV infection varies and depends on geography, as well as demographics of the population tested.

Mortality/Morbidity

Acute HIV infection has a range of presentations. Morbidity varies depending on the condition. Mortality associated with acute HIV infection is uncommon.

Race

Early symptomatic HIV infection has no reported racial predilection.

Sex

Both sexes are affected with the constellation of symptoms that define the syndrome of acute HIV infection.

Age

Early symptomatic HIV infection can affect individuals of any age.

Clinical

History

Acute human immunodeficiency virus (HIV) infection manifests as numerous signs and symptoms and can affect multiple systems. The most common presentations include asymptomatic infection, fever, chills, malaise, fatigue, swollen lymph nodes, sore throat, and myalgias.²

• Approximately 30% of individuals with acute HIV infection are asymptomatic but are highly infectious; this represents an epidemiologic challenge in controlling the HIV pandemic.
• Constitutional: Patients with acute HIV infection may experience fever, chills, malaise or fatigue, night sweats, anorexia, and weight loss.
• Lymphatics: Swollen lymph nodes are common, especially in the groin, head, and neck.
• Nose and throat: Patients may experience sore throat, with or without ulcers or thrush.
• Gastrointestinal: Nausea, emesis, diarrhea, and transaminitis may develop.
• Musculoskeletal: Joints may be asymmetrically swollen and tender; myalgias are also common.
• Neurologic: Personality changes, headache, and painful or stiff neck can be seen during acute HIV infection.

Physical

Physical findings of acute HIV infection are nonspecific and may mimic those of other viral infections, such as influenza virus infection. In addition, many of these findings resolve without medical intervention. The most common findings include fever and chills, lymphadenopathy, pharyngitis, anemia, thrombocytopenia, and rash.

• Fever and chills
• Lymphadenopathy: During the examination, the nodes are generally discrete and freely mobile and may be tender.
• Oral lesions
  • Pharyngitis is a common finding.
  • Thrush manifests as a white exudate, often with an erythematous mucosa. Thrush develops most commonly on the soft palate. Early lesions can also be found along the gingival border. The diagnosis is made based on clinical appearance or direct examination of a scraping for pseudohyphal elements, which are characteristic of candidiasis (typically with Candida albicans). Severe cases of thrush can involve the esophagus, with resultant dysphagia or odynophagia.
  • Oral hairy leukoplakia manifests as filamentous white lesions, generally along the lateral borders of the tongue.
  • Herpes simplex virus (HSV) causes lesions. Oral and genital lesions are most common, but perianal and periungual lesions are also observed. Herpetic lesions resemble a cluster of vesicles on an erythematous base.
  • Reactivation of herpes zoster (shingles) is characterized by lesions due to varicella-zoster virus (VZV) that may extend over several dermatomes. Widespread cutaneous dissemination may occur, but visceral involvement has not been reported.
  • Aphthous ulcers are shallow and painful and usually affect the posterior oropharynx.
• Hematologic
  • Anemia may be present, and the physical examination may reveal pallor.
  • In thrombocytopenia associated with acute HIV infection, as in other forms of thrombocytopenia, bleeding is rare, unless the platelet count falls to below 10,000 cells/µL. If this occurs, bleeding gums, extremity petechiae, and easy bruising are common presentations.
• Dermatologic: Rash may develop and is usually maculopapular, primarily on the trunk and/or proximal extremities.
• Neurologic
  • Aseptic meningitis may manifest as headache, photophobia, and frank encephalitis. Cranial nerve involvement may be observed. Cranial nerve VII is affected predominantly; sometimes, nerves V and/or VIII are also affected.
  • Findings of acute inflammatory demyelinating polyneuropathy include weakness, areflexia, and minimal sensory changes.
  • Patients with mononeuritis multiplex develop multifocal asymmetric cranial or peripheral nerve lesions, including facial or laryngeal palsy, wristdrop or footdrop, and other neuropathic symptoms. Early in the course of HIV infection, mononeuritis multiplex is usually limited to a single nerve or a few nerves and resolves spontaneously without treatment.
  • Myopathy is characterized by proximal muscle weakness as the primary clinical finding.
  • Encephalopathy or encephalitis can also be seen in acute HIV infection.

Causes

• Persistent generalized lymphadenopathy: This is often the earliest symptom of HIV infection after primary infection. Because of marked follicular hyperplasia in response to HIV infection, the lymph nodes have very high viral concentrations. Persistent generalized lymphadenopathy may be observed at any point in the spectrum of immune dysfunction and is not associated with an increased likelihood of developing AIDS.
• Oral lesions
  • Thrush: This can result from Candida infection and oral hairy leukoplakia, presumably due to Epstein-Barr virus (EBV) infection. Thrush is usually a sign of fairly advanced immunologic decline, generally occurring in individuals with CD4 cell counts of 200-500 cells/µL.
  • HSV lesions: The finding of HSV lesions can also reflect deteriorating immune function in patients infected with HIV.
  • Aphthous ulcers of the posterior oropharynx: These affect 10-20% of patients infected with HIV. Their etiology is unknown. These ulcers can be very painful and can cause dysphagia if left untreated.
• Hematologic
  • Anemia
    • All other causes of anemia should be excluded systematically before concluding that anemia is due to HIV infection.
    • Upon disease progression, individuals with HIV infection develop a moderate-to-severe hypoproliferative anemia.
    • The most common form of anemia observed in patients infected with HIV has the characteristics of anemia of chronic disease.
    • Anemia may be a complication of opportunistic infections and/or may be due to marrow damage from the virus or from drug toxicity (eg, zidovudine, also known as azidothymidine [AZT]).
  • Thrombocytopenia
    • Thrombocytopenia may also be an early manifestation of HIV infection. Approximately 3% of patients infected with HIV with CD4 cell counts greater than 400 cells/µL have platelet counts of less than 150,000 cells/µL. Of patients who have CD4 cell counts less than 400 cells/µL, 10% also have platelet counts of less than 150,000 cells/µL.
    • HIV-associated thrombocytopenia is rarely a serious clinical problem. In most cases, platelet counts remain greater than 50,000 cells/µL and the condition can be treated conservatively.
    • Idiopathic thrombocytopenia in persons with HIV infection is very similar to the thrombocytopenia observed in individuals with idiopathic thrombocytopenic purpura (ITP). Antibodies against HIV (anti-GP160/120) have been shown to also bind to platelets (anti-GPIIb/IIIa).⁵ Because these data point to an immunologic basis for thrombocytopenia in persons infected with HIV, most of the treatments used are immune-based.
    • Another mechanism for HIV-induced thrombocytopenia is a direct effect of HIV on megakaryocytes, evidenced by a defect and subsequent decrease in platelet production.
    • In patients infected with HIV, thrombocytopenia has also been reported as a consequence of classic thrombotic thrombocytopenic purpura (TTP). This clinical syndrome, consisting of fever, thrombocytopenia, hemolytic anemia, and neurologic and renal dysfunction, is a rare complication of early HIV infection.
• Neurologic
  • Aseptic meningitis: This can be observed in all but the very late stages of HIV infection. This suggests that aseptic meningitis in the setting of HIV infection is an immune-mediated disease. Aseptic meningitis due to HIV infection usually resolves spontaneously within 2-4 weeks. Signs and symptoms may persist long-term in some patients.
  • Acute inflammatory demyelinating polyneuropathy: Through unknown mechanisms, HIV infection can mimic Guillain-Barré syndrome.
  • Mononeuritis multiplex: A necrotizing arteritis of peripheral nerves, mononeuritis multiplex is another autoimmune peripheral neuropathy observed in patients infected with HIV.
  • Myopathy: AZT can cause myopathy; this is often reversible once the drug is discontinued. HIV infection can also cause myopathy by direct damage to the muscle cells. The exact mechanism has not yet been elucidated.
• Dermatologic: Reactivation of herpes zoster (shingles): Observed in 10-20% of patients infected with HIV infection, shingles indicates a modest decline in immune function and is often the first clinical indication of immunodeficiency.

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