Acute Retroviral Syndrome: A Challenge for Primary Care

Primary HIV infection refers to the earliest stages of infection, or the interval from initial infection to seroconversion (when antibody to HIV is detectable). During this stage, many patients have symptoms of acute HIV seroconversion illness, are viremic with very high HIV RNA levels, and have negative or indeterminate findings on HIV antibody tests.

The acute retroviral syndrome (ARS), or "seroconversion illness," is an important issue for primary care, urgent care, and emergency department providers because infected persons are likely to initially present in these settings. This is in contrast to the experience of specialists in HIV care and providers in HIV treatment programs who generally do not see a person with primary HIV infection, unless he or she is referred with this diagnosis already established.

CHALLENGES
Because the symptoms are nonspecific, ARS is a diagnostic and treatment challenge (Table 1).^1,2 Although many patients seek medical care for symptoms of ARS, the diagnosis is often missed at initial presentation and called "flu" or some other nonspecific illness. Many clinicians may still not be familiar with the signs and symptoms of ARS and do not consider this in the differential diagnosis; as a result, the appropriate testing is often not done.

Symptoms consistent with ARS develop in up to 75% of persons who become infected with HIV. Symptoms typically appear in days to weeks after exposure.³ However, these symptoms may be overlooked or may not come to medical attention if they are relatively minor or self-limited. This symptomatic phase may persist for as long as 2 to 4 weeks, although any lymphadenopathy may last longer.

ARS needs to be included in the differential diagnosis when examining at-risk persons presenting with symptoms resembling flu, mononucleosis, or a nonspecific viral illness. Accordingly, the medical history must be modified to include recent sexual, occupational, or injection drug risk behaviors in patients who present with symptoms consistent with acute HIV infection. This includes asking specific and direct questions, such as, “Have you had sexual or needle contact with anyone with HIV recently?”

During the symptomatic phase of HIV seroconversion, the HIV antibody test is likely to be negative or indeterminate. After infection with HIV, it takes a median of 25 days before the HIV antibody enzyme immunoassay test results become positive, but in some persons, it may take up to several months before seroconversion.³

For patients who have symptoms consistent with seroconversion illness and a recent history of possible HIV exposure, an HIV RNA test should be performed in addition to the standard screening HIV antibody test.⁴ State or local regulations concerning written informed consent for HIV testing apply in this case as well. Since some laboratories do not perform HIV RNA tests without a confirmed positive antibody test result, it is important to include the diagnosis of ARS (International Classification of Diseases-9 code V08) on the requisition.

The diagnosis of ARS, or seroconversion illness, will likely require 2 patient visits. If rapid HIV testing is available, it can be done on the first visit. The HIV RNA test result, with blood drawn during that same visit, will probably take longer, so patients will need to return for those results and additional discussion.

Patients with negative antibody test results but high HIV RNA levels (greater than 100,000 copies/mL) can be considered to be infected with HIV, although the screening antibody test should be repeated later to confirm seroconversion.

A low HIV RNA level (less than 1000 copies/mL) usually indicates a false-positive result at this stage because levels are typically very high (often above 1 million copies/mL) in acute infection. Antibody testing should be repeated in 4 to 6 weeks in patients who have indeterminate HIV antibody test results, low HIV RNA levels, and no clear HIV risk factors for or symptoms of primary HIV infection. Indeterminate results rarely indicate evolving seroconversion in persons without significant risk factors.

Table 2 summarizes the interpretation of HIV antibody and viral load tests to establish or rule out the diagnosis of ARS.

TREATMENT
It is reasonable to consider starting potent antiretroviral therapy in persons with acute HIV infection, but the final decision needs to be discussed with the person and is best managed by an experienced HIV provider. Limited data suggest that treatment initiated during the first 2 weeks of primary HIV infection may preserve HIV-specific immune function, which would otherwise be lost as HIV infection progresses. However, the longer-term immunological, virological, or clinical benefits of early treatment are yet to be defined.^5,6

For patients who choose to start therapy during primary HIV infection, the choice of drug therapy and patient monitoring is similar to that for the treatment of chronic HIV infection.⁷ The initial goal of therapy in primary HIV infection should be to suppress the number of HIV RNA copies to undetectable levels.

The decision to treat primary infection should also be weighed against the likelihood of patient adherence to treatment and the risk of short- and long-term toxicities in patients with newly diagnosed HIV infection. Consultation with an HIV expert should be done for recommendations on treatment. Referral to a clinical trial should be considered if available.

PUBLIC HEALTH VERSUS INDIVIDUAL IMPLICATIONS
Since the HIV RNA level in acute HIV infection is extremely high, the risk of transmitting infection to others by sexual, blood, or needle contact may be increased in persons with acute infection. Marks and associates⁸ estimated that about 25% of HIV-infected persons who are unaware of their infection account for more than 50% of new HIV infections in the United States every year.

A report from the Quebec Primary HIV Infection cohort (1998 to 2005) helps quantify further the public health importance of identifying primary infection.⁹ This longitudinal study looked at so-called forward transmission of HIV infection by persons who were within 6 months of seroconversion. The investigators found that viruses from 49% (293 of 593) of persons were involved in 75 chains, or “clusters,” of HIV transmission, ranging from 2 to 17 new infections in each cluster. Maximum periods for onward transmission in clusters were 15.2 months.

The Quebec researchers concluded that early infection accounted for approximately half of onward transmissions in this urban study and that therapy at early stages of disease may prevent onward HIV transmission.

At the individual level, Marks and associates¹⁰ studied the behaviors of persons who knew their HIV status and those who were unaware. The prevalence of unprotected anal or vaginal intercourse was 68% lower in persons who were aware of their HIV status than in those who were unaware. The likely conclusion is that persons who are aware of their HIV status make efforts to reduce the risk of transmission to others.

From the individual perspective, the sooner an HIV-infected patient accesses medical care, the better. Identifying patients with ARS is another opportunity to reverse the ongoing trend of late diagnosis of HIV infection.¹¹

In a study from the CDC that included more than 4000 patients from 16 states, 45% received their HIV diagnosis within 12 months of a diagnosis of advanced HIV disease (ie, “late testers”).¹¹ Interestingly, the group of late testers in this study had a median of 4 encounters with the health care system (eg, physician office, clinic, emergency department) but had not been tested for HIV in the 2 years before their HIV diagnosis, highlighting the extent of missed opportunities for testing.^11,12

SUMMARY
Identifying persons with primary HIV infection is another component of earlier HIV testing and very much within the realm of primary care. Persons who test late in the course of HIV infection are not able to benefit fully from subsequent antiretroviral therapy or from prophylaxis for opportunistic infections, and in these persons, the disease is more likely to progress to AIDS.

With the availability of rapid HIV testing and recent CDC recommendations for “routinizing” HIV testing in primary care settings, we need to lower the bar for those who should be tested and include efforts to identify persons with ARS. While most primary care providers will likely respond by beginning to routinely screen patients between the ages of 13 and 64, this is a good time to begin to increase providers’ awareness and improve their recognition of ARS. In the end, it’s all about improving outcomes for our patients.

References:

References1. Pilcher CD, Fiscus SA, Nguyen TQ, et al. Detection of acute infections during HIV testing in North Carolina. N Engl J Med. 2005;352:1873-1883.
2. Pilcher CD, Eron JJ, Galvin S, et al. Acute HIV revisited: new opportunities for treatment and prevention [published correction appears in J Clin Invest. 2006; 116:3292]. J Clin Invest. 2004;113:937-945.
3. Schacker T, Collier AC, Hughes J, et al. Clinical and epidemiologic features of primary HIV infection [published correction appears in Ann Intern Med. 1997; 126:174]. Ann Intern Med. 1996;125:257-264.
4. Hecht FM, Busch MP, Rawal B, et al. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS. 2002;16:1119-1129.
5. Smith DE, Walker BD, Cooper DA, et al. Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence? AIDS. 2004; 18:709-718.
6. Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited durability of viral control following treated acute HIV infection. PLoS Med. 2004;1:e36.
7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
Department of Health and Human Services. January 29, 2008;1-128. http://www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed May 14, 2008.
8. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV from persons aware and unaware that they are infected with the virus in the USA. AIDS. 2006;20:1447-1450.
9. Brenner BG, Roger M, Routy JP, et al; Quebec Primary HIV Infection Study Group. High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis. 2007;195:951-959.
10. Marks G, Crepaz N, Senterfitt JW, Janssen RS. Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs. J Acquir Immune Defic Syndr. 2005;39:446-453.
11. Centers for Disease Control and Prevention. Late versus early testing of HIV-16 sites, US, 2000-2003. JAMA. 2003;290:455-457.
12. Branson BM, Handsfield HH, Lampe MA, et al; Centers for Disease Control and Prevention. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR. 2006;55(RR-14):1-17.

 

Internet Resources
University of California San Francisco, HIV InSite. http://hivinsite.ucsf.edu/InSite?page=kbr-03-01-11#S3.0X. Accessed May 14, 2008.

AIDS Education and Training Center (AETC). www.aids-ed.org/aidsetc?page=cm-108_testing. Accessed May 14, 2008.

Clinical Trials Information, AIDS Clinical Trials Information Service (ACTIS). www.aidsinfo.nih.gov/clinicaltrials. Telephone (800)-HIV-0440. Accessed May 14, 2008.