Primary HIV Infection

Christopher Hoffmann, M.D., M.P.H.

PATHOGENS

  • HIV-1 and HIV-2 (HIV-2 predominantly found in West Africa; also Mozambique and India).
  • HIV-1 divided into 3 groups: M (Main) group (worldwide distribution); O (Outlier) group (primarily West Africa), and N (Non-O, Non-M) group (Cameroon).
  • M group further divided into subtypes or clades designated A-K.
  • HIV-1 group M subtype B is predominant cause of HIV-1 infection in U.S.
  • Majority of HIV is sexually transmitted. MSM the major mode in U.S. Heterosexual sex is the major mode globally. Injection drug use and mother-to-child transmission are also important modes of infection.
  • A "primary HIV-like" syndrome can occur after discontinuation of ART in 5% of individuals.

CLINICAL

  • Use of PrEP is important to consider in diagnostic testing for primary HIV.
  • Primary HIV can be further classified by the presence of serum markers (referred to as the Fieberg stages of primary HIV infection): eclipse phase: infection without detectable HIV RNA (VL) in the serum; I: detectable HIV RNA; II: detectable HIV p24 & HIV RNA; III: detectable HIV IgM & p24 & HIV RNA; IV: indeterminate Western blot (no longer used clinically); V: positive Western blot (no longer used clinically), correlates with positive HIV IgG on ELISA.
  • Acute HIV (positive HIV RNA and generally negative IgM or IgG) extends to about 30 days after infection
  • Use of PrEP (TDF/FTC or CAB) will lower the HIV RNA level, may attenuate or eliminate symptoms, and (documented for CAB) lead to very delayed seroconversion. HIV RNA testing is essential for HIV diagnosis among individuals on CAB PreP.
  • Sx occur in up to 20-90% of pts within 1-4 wks of infection (lower proportion with symptoms in community cohorts versus hospital cohorts). Primary HIV can be asymptomatic or only present with malaise. Typically "flu-like" illness similar to other viral syndromes (e.g. influenza, mononucleosis) with low-grade fever, malaise, and headache. Malaise may be the only symptom. Additional symptoms may include lymphadenopathy, anorexia, and weight loss. Mucosal ulcers are common also, including esophageal ulcers; symptoms may mimic GERD or peptic ulcer disease and be miss-diagnosed. Duration is usually 1 - 4 wks (median 2 weeks). A large international prospective study reported symptoms in only 50% with acute HIV.
  • Hx: fever +/- myalgias, arthralgias, rash, headache, pharyngitis, lymphadenopathy, oral or genital ulcers, thrush.
  • Severity of presentation and number of Sx associated with peak HIV RNA level (VL) (and whether or not PrEP was being used - even intermittently).
  • Exam: maculopapular rash that may extend to palms and soles (20-67%), pharyngeal erythema, oral ulcerations, oropharyngeal candidiasis, lymphadenopathy, and splenomegally (each 10-60%).
  • Most common lab abnormalities: thrombocytopenia, leukopenia, elevated liver enzymes, atypical lymphocytes. CD4 may be acutely suppressed, usually rises to near normal after acute illness.
  • Rate of CD4 decline to AIDS (< 200) from 2 to >20 yrs (without ART). Rate related to VL, multiple other factors are likely important.
  • All individuals with acute HIV infection progress to chronic disease.
  • Risk of transmission highest during acute/early period because of very high VL. In some studies, up to 50% of transmission estimated to be from individuals in acute infection period.

DIAGNOSIS

  • US Preventive Services Task Force 2019 HIV screening recommendations: all individuals aged 15-65, pregnant individuals, and younger adolescents and older adults based on risk factors.
  • HIV testing/screening algorithm (provision CDC recommendations 12/2012)
    • Fourth-generation lab-based immunoassay test with testing for anti-HIV IgG and IgM and HIV p24 antigen (e.g. Architect HIV Ag/Ab Combo Assay). This test decreases the window period from acute infection to laboratory screening diagnoses down to a few days. Use HIV RNA testing for patients receiving CAB PrEP.
    • If fourth-generation assay is positive: second- or third-generation immunoassay to confirm and distinguish between HIV-1 and HIV-2 (e.g. Multispot HIV-1/HIV-2 rapid test)
      • Positive second/third-generation test: HIV diagnosis has been made.
      • Negative second/third-generation test: nucleic acid amplification (NAT) test (HIV RNA assay). If NAT positive: acute HIV diagnosed; if negative either the fourth generation was a false positive or patient has acute HIV-2 infection (review geography of potential exposure).
  • Fourth-generation laboratory-based immunoassay test overall reported sensitivity 99.9%, specificity: 98.8%. Sensitivity for acute HIV: 83%. (Sensitivity of fourth-generation rapid Ag/Ab for acute infection similar to third-generation tests). False negative during first 2 weeks of infection.
  • VL: sensitivity 100%, specificity 97%. False positive rates as high as 1%, but usually associated with low levels (< 1000). Viral RNA can be detected as early as 9 days after infection and may be detected prior to positive fourth-generation immunoassay. Not recommended for screening due to cost, but useful in the right clinical situation when fourth-generation test is negative and clinical suspicion of HIV remains high. VL reaches peak of 100,000-10,000,000. Levels decrease spontaneously without treatment by 2 to 3 logs approx 2 wks after onset of Sx.
  • CD4 may be acutely decreased in primary HIV infection (rarely < 200)
  • Co-infection with STDs common (30%). Test for gonorrhea, Chlamydia, syphilis, and HSV. Note: incubation from syphilis infection to secondary syphilis is 2 - 24 wks. A negative treponemal test at time of diagnosis of acute HIV does not rule out co-infection. Retest 3-6 months later.
  • PrEP and HIV testing: individuals taking PrEP (oral of injectable) and continuing to take it (or have tail of injected PrEP) after becoming HIV infected may have a blunted antibody response. This can lead to false-negative testing with the fourth-generation test. For patients on injectable PrEP, the CDC recommends both the forth-generation HIV test and a HIV RNA test.

TREATMENT

General Considerations

  • Initiate ART as soon as possible:
    • Immediate ART reduces permanent impact on immune function
    • Immediate ART reduces long-term neurologic impact of HIV infection
    • ART reduces mortality even at higher CD4 counts
    • Studies of immune markers have suggested improved CD4 reconstitution and immune function with early ART initiation
    • Treating HIV decreases transmission
    • Interruption of ART after ART initiation should be avoided based on SMART and other studies. Some studies of ART in early/acute HIV assessed a short course of ART, but it did not appear to prevent eventual immune decline and may carry similar risks of interrupting ART later in the disease course (see Treatment Interruption). In addition, ART now recommended for all patients with chronic HIV infection, regardless of CD4 count.
  • Psychological needs can be considerable, assess patients and offer referrals to support groups, peer educators, counselors, and psychologists as appropriate.
  • Generally INSTI containing ART is preferred (BIK or DTG) because of more rapid reduction in HIV RNA level.
  • Obtain HIV RNA, HIV genotype (RT and PI is recommended, include INSTI if prior CAB PrEP exposure), HBsAg, HCV Ab, CD4 count, syphilis test, CBC, CMP, pregnancy test at the time of ART initiation. Can adjust ART imediately based on results.
  • Plan on follow-up (telephonic or in-person) soon after ART initiation (1 week may be ideal).

Transmitted Drug Resistance

  • In Europe 3-11% and in North America around 14% of transmitted HIV has 1 or more resistance mutations with NNRTI mutations most common.
  • Transmitted INSTI resistance remains rare
  • Obtain resistance test (genotype) to determine if drug-resistance mutations are present.

FOLLOW UP

  • Obtain CD4 at time of Dx to stage infection and level of immune suppression. Repeat every 3-6 mos until >350 or undetectable VL. CD4 drawn during PHI may be lower than CD4 setpoint following resolution of acute syndrome.
  • If ART initiated, obtain VL at initiation and repeat after 2-8 wks. Decrease of 1 log by 2-8 wks expected if regimen efficacious. Complete suppression (undetectable VL) expected by 16-20 wks. Once undetectable, repeat VL every 3-4 mos to evaluate effectiveness and durability of therapy. Can extend 6 monthly VL testing for most patients.

Basis for recommendation

  1. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807.  [PMID:26192873]

    Comment: Seminal study showing mortality benefit with ART initiation with CD4 count >500 versus >350

  2. Centers for Disease Control and Prevention (CDC). Detection of acute HIV infection in two evaluations of a new HIV diagnostic testing algorithm - United States, 2011-2013. MMWR Morb Mortal Wkly Rep. 2013;62(24):489-94.  [PMID:23784012]

    Comment: Provisional CDC recommendations for HIV testing using 4th generation tests.

  3. Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368(3):218-30.  [PMID:23323898]

    Comment: Comparison of CD4 reconsitution with early versus delayed ART. Median CD4 count at diagnosis of acute infection was 495. For those who did not initiate ART, there was an increase in CD4 count followed by a gradual decline returning to the CD4 count at study entry within 12-14 months.

  4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use ofantiretroviral agents in HIV-1-infected adults and adolescents. Department of Health andHuman Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Section accessed 1/6/2023.

    Comment: Recommendations for treating all patients with HIV infection.

References

  1. Takata H, Kakazu JC, Mitchell JL, et al. Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8+ T cells. EBioMedicine. 2022;84:104253.  [PMID:36088683]
  2. Chéret A, Bauer R, Meiffrédy V, et al. Once-daily dolutegravir versus darunavir plus cobicistat in adults at the time of primary HIV-1 infection: the OPTIPRIM2-ANRS 169 randomized, open-label, Phase 3 trial. J Antimicrob Chemother. 2022;77(9):2506-2515.  [PMID:35762503]

    Comment: Demonstration of faster achievement of undetectable VL with DTG.

  3. Ambrosioni J, Petit E, Liegeon G, et al. Primary HIV-1 infection in users of pre-exposure prophylaxis. Lancet HIV. 2021;8(3):e166-e174.  [PMID:33316212]

    Comment: Clear review of primary HIV infection, especially among individuals receiving PrEP.
    Rating: Important

  4. Robb ML, Eller LA, Kibuuka H, et al. Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand. N Engl J Med. 2016.  [PMID:27192360]
  5. Panichsillapakit T, Smith DM, Wertheim JO, et al. Prevalence of Transmitted HIV Drug Resistance Among Recently Infected Persons in San Diego, CA 1996-2013. J Acquir Immune Defic Syndr. 2016;71(2):228-36.  [PMID:26413846]
  6. Lodi S, Phillips A, Touloumi G, et al. Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds <200, <350, and <500 Cells/mm³: assessment of need following changes in treatment guidelines. Clin Infect Dis. 2011;53(8):817-25.  [PMID:21921225]

    Comment: Analysis from CASCADE on time to reaching various CD4 cut-offs after acute HIV infection.
    Rating: Important

  7. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-26.  [PMID:19339714]

    Comment: NA-ACCORD study of decreased mortality with initiation of ART at higher CD4 count (500 vs 350).
    Rating: Important

  8. Yerly S, von Wyl V, Ledergerber B, et al. Transmission of HIV-1 drug resistance in Switzerland: a 10-year molecular epidemiology survey. AIDS. 2007;21(16):2223-9.  [PMID:18090050]

    Comment: Transmission of resistant HIV

  9. Poggensee G, Kücherer C, Werning J, et al. Impact of transmission of drug-resistant HIV on the course of infection and the treatment success. Data from the German HIV-1 Seroconverter Study. HIV Med. 2007;8(8):511-9.  [PMID:17944684]

    Comment: Transmission of resistant HIV

  10. Kelley CF, Barbour JD, Hecht FM. The relation between symptoms, viral load, and viral load set point in primary HIV infection. J Acquir Immune Defic Syndr. 2007;45(4):445-8.  [PMID:17514014]

    Comment: Analysis of associations between VL and Sx during primary HIV

  11. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren J, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283-96.  [PMID:17135583]

    Comment: Major structured treatment interruption trial that demonstrated increased mortality in interruption arm (other smaller studies have had similar findings).
    Rating: Important

  12. Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis. 2005;191(9):1403-9.  [PMID:15809897]

    Comment: Risk of sexual transmission by time after infection

Last updated: January 9, 2023