Primary human immunodeficiency virus. (Review Article).

ABSTRACT: The term "primary HIV infection" refers to the period from initial infection with the human immunodeficiency virus to complete seroconversion. It is a period of extreme infectiousness. The occurrence and severity of symptoms during primary HIV infection correlate with the rapidity of clinical and immunologic decline. Treatment of patients during primary infection may improve immune preservation and reconstitution. In this review article, we present information that will help clinicians understand, recognize, and diagnose primary HIV infection. The current approach to management of primary HIV infection is based more on expert opinion than clinical trial results, though ongoing clinical trials should provide more information about this syndrome.

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PRIMARY HIV INFECTION is the period from initial infection with HIV to complete seroconversion. Patients may be symptomatic or asymptomatic during this period. Symptomatic primary HIV infection is a transient illness associated with high titer HIV replication, usually followed by a robust and expansive immunologic response to the invading virus. (1) It is also known as acute HIV syndrome, acute HIV illness, seroconversion illness, or acute retroviral syndrome. Although an incidence as low as 10% has been reported in retrospective studies of intravenous drug abusers, (2,3) its true incidence in unselected populations is probably greater than 50%. (4,5) The disparity in reported frequencies may be due to differences in the definition, study methodology and data analysis. Symptomatic primary HIV infection has been described in all populations at risk for HIV infection: homosexual men, heterosexual men and women, recipients of contaminated blood, recipients of organs from infected donors, intravenous drug abusers , and persons acquiring HIV from occupational exposure to contaminated body fluids. (6)

Although the proportion of patients who seek medical attention for symptomatic primary HIV infection is unknown, it is likely that most such contact is with a primary care clinician because the symptoms mimic those of more common illnesses. Unfortunately, the diagnosis is often missed. Symptomatic primary HIV infection was recognized in only 5 of 19 high-risk patients who were enrolled in HIV surveillance programs and who had serologic testing for HIV every 4 to 6 months. (7) It is likely that more cases are missed under routine clinic conditions. Health care providers who miss the diagnosis of symptomatic primary infection are likely to perform tests for illnesses with similar presentations, such as infectious mononucleosis. (8) Indeed, the first report in which symptomatic primary HIV infection was described as mononucleosis involved a patient who was infected with what was then known as HTLV-III. (9)

Recognition of primary HIV infection is important for the following reasons.

First, most published studies show that patients with symptomatic primary infection have a relatively aggressive clinical course with earlier onset of immunodeficiency and acquired immunodeficiency syndrome (AIDS) than in those with asymptomatic HIV seroconversion, (10-13) though this was not always observed. (14) It also appears that the severity of the seroconversion illness may predict the subsequent course of HIV infection. Among patients with illness longer than 2 weeks, 78% had AIDS-related diagnoses within 3 years as compared with 10% of patients whose primary HIV syndrome lasted less than 2 weeks. (15)

Second, symptomatic primary HIV infection may be a period when initiation of treatment allows immune preservation and reconstitution. (14,16-21) Rosenberg et al (22) recently published data from 8 patients who initiated highly active antiretroviral therapy (HAART) during primary HIV infection and achieved undetectable viral loads. After 358 to 1,081 days of HAART, treatment was interrupted. Although all 8 patients had viral rebound (after a mean of 17 days), only 5 of them had viremia, with >5,000 copies/mL. After reinstituting therapy, all 5 patients achieved undetectable HIV-RNA levels again, and treatment was interrupted for the second time (after a median of 16 weeks of additional treatment). At the time of publication, 5 of the original 8 patients were off therapy (a mean of 2.7 years after initial infection), with HIV-RNA <500 copies/mL.

Third, patients seem to be more infectious during primary HIV infection, (23) probably because of higher levels of viremia. Data from studies of vertical, (24) sexual, (25) and hematogenous (26) acquisition of HIV show a positive correlation between the likelihood of HIV transmission and the level of viremia. Also, the virus present during primary infection may be well adapted to transmission, since it has recently been transmitted and thus was likely selected as well suited for generating new infection. (27) The risk of acquiring HIV (per contact) during symptomatic primary infection may be as much as 500-fold greater than the risk during the period of prolonged clinical latency. (23) According to one mathematic model, as many as half of the new cases of HIV infection are acquired from patients with primary infection. (28) Thus, it is important to identify newly infected patients to allow early introduction of preventive measures that can limit spread of the disease. Primary infection may be thought of as a window during which HIV prevention efforts could be particularly effective. (29)

Fourth, research focused on patients with symptomatic primary infection may provide insight into effective immune responses to HIV and perhaps elucidate mechanisms of immune system collapse that precede the development of AIDS.

IMMUNOLOGY

Human immunodeficiency virus primarily infects [CD4.sup.+] T lymphocytes. Soon after a new infection, virus rapidly concentrates in lymphoid tissue. (30) During primary infection, there is [CD4.sup.+] T lymphopenia and decreased T-lymphocyte function related to the loss of functionally mature, dividing [CD4.sup.+] T cells, which are the target cells for HIV infection and replication. (31) There is also an expansion of [CD4.sup.+] T lymphocytes leading to an inversion of the CD4:CD8 ratio. (32) Curtailment of the high level of HIV viremia and p24 antigenemia seen during primary infection is thought to be the consequence of the development of cellular and humoral immune responses combined with virus sequestration in lymphoid tissues. The rapid decline in HIV viremia is temporally correlated with development of HIV-specific [CD8.sup.+] cytotoxic T-lymphocyte (CTL) responses (33-35) and perhaps antibody-dependent cellular cytotoxicity. (36) The immune response to HIV leads to a drop in viral load, but viral eradi cation does not occur. One possible reason for the failure of the immune response to eradicate HIV is antigenic exhaustion of the HIV-specific CTL responses. Moreover, HIV-specific CTLs appear to preferentially accumulate in peripheral blood rather than lymph nodes where a significant proportion of viral replication occurs. (36) After the drop in viral load, there is resolution of the symptoms of primary infection, followed by a prolonged period of clinical latency in most patients.

CLINICAL FEATURES

Symptoms of primary HIV infection develop days to weeks after the virus is acquired. It is important for the clinician to ask about any history of potential HIV exposure during the preceding month, such as unprotected intercourse, occupational exposure, or needle sharing. The absence of any potential HIV risk factors lessens the likelihood of the diagnosis, though it is important to appreciate that sexual and substance use histories may not be readily volunteered. Symptoms are thought to be related to immune response to HIV and tend to peak at about the same time as the viral load. When a person acquires HIV, there is an initial viral doubling time of 10 hours, and peak viremia occurs about 21 days after reported HIV exposure. (37) Duration of symptoms is usually less than 2 weeks, though in rare instances it may be as long as 10 weeks. (7)

Some of the symptoms of primary HIV infection are similar to those of infectious mononucleosis, and primary HIV infection has been described as a mononucleosis-like illness. However, there maybe protean manifestations of primary HIV infection, and defining it as a mononucleosis-like illness is too restrictive. Vanhems et al (38) found typical mononucleosis-like illness in only 15.6% of 218 patients. The most frequent symptoms of primary HIV infection in most series are fever, rash, lymphadenopathy, sore throat, fatigue, headache, and myalgia (Table). (2-4,8,14,39-42) Some patients may experience weight loss, retro-orbital pain, or depression. (4,38) Other symptoms such as nonproductive cough, abdominal pain, and rhinorrhea do not appear to distinguish patients with symptomatic primary infection from control subjects. (4) Lymphadenopathy most commonly affects cervical lymph nodes, though axillary, epitrochlear, and inguinal nodes may also be involved. In rare instances, oral thrush and other opportunistic infe ctions develop due to transient immunosuppression. (43, 44)

Differential diagnosis of symptomatic primary HIV infection includes infectious mononucleosis, cytomegalovirus mononucleosis, toxoplasmosis, rubella, secondary syphilis, drug reactions, primary herpes simplex, and viral hepatitis. Primary HIV infection should be considered in patients suspected of having any of these conditions. Some clinical patterns may be useful in differentiating primary HIV infection from other syndromes. In a patient with mononucleosis-like illness, features suggestive of infectious mononucleosis rather than HIV include the presence of hepatomegaly, splenomegaly, and >50% relative lymphocytosis or >10% atypical lymphocytosis. Abnormal liver enzymes may occur in infectious mononucleosis or primary HIV infection. Cutaneous eruptions, usually macular, are common in symptomatic primary HIV infection (Figure), though they are transient and may be missed. Less commonly, papules and urticaria are seen. The trunk is most commonly involved, followed by the head, lower limbs, and upper limbs. (40 ) The rash generally appears after a few days of fever and clears concurrently with general recovery from the acute illness. (45) Biopsy is nonspecific and thus nondiagnostic. (45,46) Other clues to the diagnosis include oral and/or genital ulcers and objective neurologic signs including aseptic meningitis and/or meningeoencephalitis. (47)

LABORATORY FEATURES

The laboratory diagnosis of primary HIV infection is challenging. When it is considered, the practitioner should communicate with the laboratory to expedite the diagnosis. There may be clues to the diagnosis from routine laboratory testing. Thrombocytopenia, which is probably related to the formation of antiplatelet antibodies, (48) is a relatively frequent hematologic abnormality during primary HIV infection, occurring in up to 45% of patients. (1) Other hematologic abnormalities are also common. In one study, 91.3% of patients with primary HIV infection had one or more abnormalities on complete blood count, such as thrombocytopenia, anemia, leukopenia, neutropenia, lymphopenia, monocytosis, leukocytosis, and thrombocytosis. Lymphocytosis was rare. (40) Rarely, patients may present with increased immature neutrophils, erroneously suggesting a diagnosis of bacterial sepsis. (49) Suspected primary HIV infection should prompt testing designed to detect the virus (HIV-1 RNA) or its antigen (p24). An HIV antibody test should also be obtained, though it will be uniformly negative during early infection. Assays for p24 antigen are widely available, relatively inexpensive, and highly specific. The sensitivity and specificity of p24 antigen assay were recently determined to be 88.7% and 100.0%, respectively. (42) However, in the experience of one of us (C.B.H.), p24 antigen testing has been less sensitive, with positive results in fewer than 50% of patients who had primary HIV infection. Testing for HIV-1 RNA by polymerase chain reaction or branch DNA assay is twofold to threefold more expensive than p24 antigen assay. When rapid turnaround of HIV RNA testing is needed (such as suspected primary HIV infection), a call to the laboratory can usually lead to the test results being available within 48 to 72 hours. The HIV-1 RNA level (viral load) is typically high during primary infection. The test becomes positive as early as 10 days after acquisition of the virus and peaks between days 20 and 30. (50,51) The HIV RNA test h as a sensitivity of about 100%, but it is specific in only 97.4% of cases. (42) Clinicians and patients should be aware of the potential for false-positive results when ordering HIV-1 RNA tests to diagnose primary HIV infection. A false-positive result should be suspected when symptoms are suggestive of primary HIV infection but HIV-1 RNA levels are low (usually <2,000 copies/mL). (52) Other findings in patients with false-positive results of HIV-1 RNA tests include normal CD4:CD8 ratio and persistently negative (up to 1 year after development of symptoms) HIV antibody tests. In these patients, repeated HIV-1 RNA testing is usually negative. An HIV antibody test is used to distinguish patients whose HIV-1 RNA or p24 antigen tests are positive due to primary HIV infection from those who have positive tests due to chronic HIV infection. The HIV antibody is invariably negative or indeterminate during primary infection except at the latest period of symptoms. In contrast, it is positive in patients who have chron ic HIV infection.

TREATMENT

Current treatment recommendations (53,54) are largely based on theoretical considerations and expert opinion because of a paucity of data from clinical trials. In carefully worded documents, the International AIDS Society--USA Panel and the Panel on Clinical Practices for the Treatment of HIV Infection gave reserved support to selective treatment of patients with symptomatic primary infection. Both stress that decisions should be made only after detailed discussions have been held with the patient about potential benefits and risks of treatment. Referral to clinical trials is encouraged.

One of the potential benefits of early treatment is immune preservation and reconstitution. Treatment during primary HIV infection appears to restore the balance between naive and memory CD[4.sup.+] T cells, a result seen less often when therapy is started during chronic infection. Also, there are improvements in lymphoproliferative responses to candidiasis and tetanus among patients treated during primary HIV infection, (15) and CD[4.sup.+] T-cell- mediated HIV-1 specific immune responses may be preserved and augmented. (16-18) Neutralizing antibodies appear more quickly in treated patients than in untreated patients. (19) These responses may lead to improved virologic control. Yerly et al (20) compared HIV RNA levels in patients in whom treatment was initiated at different stages of HIV infection: during primary infection, chronic infection without immune suppression, and chronic infection with immune suppression. After 6 to 30 months, 75%, 32%, and 8% of patients respectively had viral load levels less tha n 3 copies/mL. This improved virologic control may be associated with reduction in the rate of viral transmission and mutation. Treatment during primary infection was recently shown to reduce the likelihood of transmitting resistant strains of HIV. (21)

These apparent benefits should be weighed against potential disadvantages. By the time symptoms of primary infection develop, treatment may already be too late to prevent the accumulation of a large pool of infectious virus in CD[4.sup.+] T lymphocytes or the lymphoid follicular dendritic cell network. (55-57) Furthermore, it has been suggested that removal of HIV antigen before the evolution of a complete immune response may impair future immune control. Darr et al (58) reported a case in which primary HIV infection recurred when antiretroviral medications were stopped in a patient with treatment-induced viral suppression.

Little is known about optimal treatment protocols. Zidovudine (ZDV) monotherapy is inferior to HAART. In one study, 6 months of ZDV monotherapy led to initial improvement in CD4 count but after treatment was discontinued, CD4 decline was more rapid in the ZDV-treated group than in the placebo ann. (59) In comparative studies, ZDV monotherapy had minimal effect on viral replication and CD4 recovery as compared with HAART. (57) Currently, most antiretroviral combinations used for primary HIV infection are similar to those used in patients with chronic infection and include 3 or 4 drug combinations. Preliminary studies have also been conducted on immune modulating agents such as cyclosporine (60) and hyaroxyurea. (61,62) No consensus regarding the best regimens has been reached.

Considerable experience with HIV management is required to select appropriate antiretroviral regimens. The potential for acquisition of resistant viruses further complicates the issue. The role of resistance testing in primary HIV infection is unclear. (63) Clinical trials in progress may help to clarify this situation. Current guidelines suggest that resistance testing should be considered before initiating therapy. (64)

Because of the complexities of treating these patients, it is recommended that expert consultation be obtained as soon as the diagnosis of primary HIV infection is made. The availability of comprehensive services including social workers, pharmaceutical assistance, psychologic counseling, and patient education is crucial to a successful management strategy.

CONCLUSION

The primary care physician is the key health care professional for detecting primary HIV infection. Knowledge of the likely presentation coupled with a thoughtful approach to laboratory diagnosis will improve opportunities for diagnosis and preventive measures. Avenues for the proper training of primary care clinicians should be created in medical schools, residency programs, midlevel practitioner training programs, and continuing medical education programs. The role of antiretroviral therapy is evolving, and most available data suggest some benefit. Treatment should be selected preferably in concert with experts who have experience with primary HIV infection. The ultimate impact of such management may benefit public health as well as the newly infected individual.

TABLE.

Frequency of Symptoms of Primary Human Immunodeficiency Virus Infestion.

Symptom(s)                      Frequency

Fever (mean temperature,        >80%
  39.4[degrees]C [102.9
  [degrees]F])
Arthralgia or myalgia, rash,    40% to 80%
  lymphadenopathy, sore
  throat, fatigue, headache
Oral ulcers and/or genital      10% to 40%
  ulcers, >5 kg weight loss,
  nausea, vomiting or diarrhea

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RELATED ARTICLE: KEY POINTS

* Primary human immunodeficienty virus (HIV) infection is a period of extreme infectiousness.

* Illnesses such as infectious mononucleosis, viral syndromes, rubella, drug reaction, and secondary syphilis have similar symptoms.

* The correct application of diagnostic tests (HIV RNA, p24 antigen, and HIV antibody) is essential for confirmation of primary HIV.

From the Early Intervention Clinic, Lincoln Health Center, and the Division of infectious Diseases and AIDS Research and Treatment Center, Durham, NC.

Reprint requests to Babafemi O. Taiwo, MD, Lincoln Health Center, 1301 Fayetteville St, Durham, NC 27707.