Primary HIV Infection
- 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 sexually transmitted with 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.
- Sx occur in up to 50-90% of pts within 1-4 wks of infection. Typically "flu-like" illness similar to other viral syndromes (e.g. influenza, mononucleosis) with low-grade fever, malaise, and headache. 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).
- 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 high VL. In some studies, up to 50% of transmission estimated to be from individuals in acute infection period.
- US Preventive Services Task Force 2013 HIV screening recommendations: all individuals aged 15-65, 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. (NOTE: Alere Determine HIV-1/2 Ag/Ab Combo Rapid test has been approved by the FDA (8-2013) but performance is only somewhat better than third-generation immunoassay tests making it a poor choice for diagnoses of acute HIV).
- 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.
- Data are mostly indirect but favor ART in acute and early HIV infection for the following reasons:
- Median time from acute infection to CD4 < 500 in CASCADE study was 1.2 years.
- ART reduces mortality up to and perhaps higher than a CD4 count of 500 (mostly from non opportunistic illness causes) (START Trial).
- 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.
- Situations in which starting ART during acute infection is clearly urgently indicated: highly symptomatic acute infection (with or without neurological disease).
- Situation in which ART should be deferred: need to manage other pressing issues (substance use, depression, etc) or unwillingness of patient to initiate ART.
- Potential risks of early treatment: (1) toxicity, (2) resistance. However, delaying ART will provide a median of approximately 1.5 years off ART before lifelong therapy and current ART has considerably reduced toxicity. For most patients these are not reasons to defer therapy.
- Psychological needs can be considerable, assess patients and offer referrals to support groups, peer educators, counselors, and psychologists as appropriate.
- If starting ART before baseline genotype results available, use 2 NRTIs plus a boosted PI, as transmitted resistance unlikely.
- If viral load very high (> 1 million, some experts would initiate with a four drug ART regimen such as DRV/r,DTG, TDF/FTC)
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.
- Obtain resistance test (genotype) to determine if drug-resistance mutations are present.
- 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
- 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
- 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.
- 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.
- 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 5/28/2016.
Comment: Recommendations for treating all patients with HIV infection.
- 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]
- 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]
- 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.
- 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).
- 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
- 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
- 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
- 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).
- 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
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