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HIV Medicine 2007
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2. Acute HIV-1 Infection
Acute HIV-1 infection presents in 40 - 90 % of cases as a transient symptomatic illness, associated with high levels of HIV-1 replication and an expansive virus-specific immune response. With 14,000 new cases per day worldwide, it is an important differential diagnosis in cases of fever of unknown origin, maculopapular rash and lymphadenopathy.
The diagnosis of acute infection is missed in the majority of cases, as other viral illnesses ("flu") are often assumed to be the cause of the symptoms, and there are no HIV-1-specific antibodies detectable at this early stage of infection. The diagnosis therefore requires a high degree of clinical suspicion, based on clinical symptoms and history of exposure, in addition to specific laboratory tests (detection of HIV-1 RNA or p24 antigen and negative HIV-1 antibodies) confirming the diagnosis.
An accurate early diagnosis of acute HIV-1 infection is important, as infection of sexual partners can be prevented and patients may benefit from therapy at this early stage of infection (see below).
During acute HIV-1 infection, the virus replicates extensively
in the absence of any detectable adaptive immune response, reaching levels of over 100 million
copies HIV-1 RNA/ml. It is during this initial cycle of viral replication that important pathogenic
processes are thought to occur. These include the seeding of virus to a range of tissue reservoirs
and the destruction of CD4+ T-lymphocytes, in particular within the lymphoid tissues of the gut. The
very high levels of HIV-1 viremia are normally short-lived, indicating that the host is able to
generate an immune response that controls viral replication. Over the following weeks, viremia
declines by several orders of magnitude before reaching a viral setpoint. This setpoint, following
resolution of the acute infection, is a strong predictor of long-term disease progression rates
During acute HIV-1 infection, the virus replicates extensively in the absence of any detectable adaptive immune response, reaching levels of over 100 million copies HIV-1 RNA/ml. It is during this initial cycle of viral replication that important pathogenic processes are thought to occur. These include the seeding of virus to a range of tissue reservoirs and the destruction of CD4+ T-lymphocytes, in particular within the lymphoid tissues of the gut. The very high levels of HIV-1 viremia are normally short-lived, indicating that the host is able to generate an immune response that controls viral replication. Over the following weeks, viremia declines by several orders of magnitude before reaching a viral setpoint. This setpoint, following resolution of the acute infection, is a strong predictor of long-term disease progression rates (Mellors 1995).
Several factors can influence viral replication during acute infection and the establishment of a viral setpoint. These include the fitness of the infecting virus, host genetic factors and host immune responses. While antibodies against HIV-1 with neutralizing capacities are rarely detectable during primary HIV-1 infection, a number of studies have demonstrated a crucial role of HIV-1-specific cellular immune responses for the initial control of viral replication during this stage of infection. A massive, oligoclonal expansion of CD8+ T-cell responses has been described during acute HIV-1 infection (Pantaleo 1994), and the appearance of HIV-1-specific CD8+ T cells has been temporally associated with the initial decline of viremia (Koup 1994, Borrow 1994). These CD8+ T-cells have the ability to eliminate HIV-1-infected cells directly by MHC class I-restricted cytolysis or indirectly by producing cytokines, chemokines or other soluble factors, thus curtailing the generation of new viral progeny (Yang 1997). The biological relevance of HIV-1-specific cytotoxic T cells (CTL) in acute HIV-1 infection was highlighted in recent in-vivo studies demonstrating a dramatic rise of SIV viremia and an accelerated clinical disease progress in macaques after the artificial depletion of CD8+ T-cells (Schmitz 1999, Jin 1999). Additional evidence for the antiviral pressure of HIV-1-specific CTLs during primary HIV-1 infection has been provided by the rapid selection of viral species with CTL epitope mutations that were detected within a few weeks after HIV-1 and SIV infection in humans and rhesus macaques, respectively (Allen 2000, O'Connor 2002, Price 1997).
During acute HIV-1 infection, the number of CD4+ T-cells decline, occasionally to levels that allow the development of opportunistic infections at that time (Gupta 1993, Vento 1993). Even though the CD4+ T-cell count rebounds with the resolution of primary infection, it rarely returns to baseline levels in the absence of antiretroviral therapy. In addition to the decline in CD4+ T-cell counts, qualitative impairments of CD4+ T-cell function are perhaps the most characteristic abnormalities detected in HIV-1 infection. The impairment of HIV-1-specific CD4+ T-cell function occurs very early in acute infection (Rosenberg 1997, Altfeld 2001, Lichterfeld 2004), potentially due to the preferential infection of virus-specific CD4+ T-cells by the virus (Douek 2002). This is followed by a functional impairment of CD4+ T-cell responses to other recall antigens, as well as a reduced responsiveness to novel antigens (Lange 2003). The impairment of HIV-1-specific CD4+ T-helper cell function in acute HIV-1 infection subsequently results in a functional impairment of HIV-1-specific CD8+ T-cells (Lichterfeld 2004).
In addition to host immune responses, host genetic factors play an important role in both susceptibility and resistance to HIV-1 infection and speed of disease progression following infection. The most important of these is a deletion in the major coreceptor for entry of HIV-1 into CD4+ T-cells, a chemokine receptor called CCR5 (Samson 1996). Homozygotes for this 32 base pair deletion (CCR5delta32) do not express the receptor at the cell-surface and can only be infected with HIV strains that are able to use other coreceptors, such as CXCR4. Thus, although CCR5delta32 homozygotic individuals show a significant degree of resistance to HIV-1 infection (Samson 1996), a number of cases of infection with CXCR4-using HIV-1 strains have been described (O'Brien 1997, Biti 1997). Heterozygotes for the deletion exhibit significant lower viral setpoints and slower progression to AIDS. In addition to mutations in the chemokine receptor genes, a number of HLA class I alleles have been described to be associated with both, lower viral setpoints and slower disease progression, including HLA-B27 and -B57 (O'Brien 2001, Kaslow 1996). Recent studies demonstrated that individuals expressing HLA-B57 presented significantly less frequently with symptomatic acute HIV-1 infection and exhibited a better control of viral replication following acute infection (Altfeld 2003). These data demonstrate that host genetic factors can influence the clinical manifestations of acute HIV-1 infection and have an important impact on subsequent viral setpoints and the speed of disease progression.
After an incubation period of a few days to a few weeks after exposure to HIV, most infected individuals present with an acute flu-like illness. Acute HIV-1 infection is a very heterogeneous syndrome and individuals presenting with more severe symptoms during acute infection and a longer duration of the acute infection syndrome tend to progress more rapidly to AIDS (Vanhems 1998, Vanhems 2000, Sinicco 1993, Pedersen 1989, Keet 1993, Lindback 1994). The clinical symptoms of acute HIV-1 infection were first described in 1985 as an illness resembling infectious mononucleosis (Cooper 1985). The most common symptoms (see Table 1) are fever, maculopapular rash, oral ulcers, lymphadenopathy, arthralgia, pharyngitis, malaise, weight loss, aseptic meningitis and myalgia (Kahn 1998). In one study (Hecht 2002), fever (80 %) and malaise (68 %) had the highest sensitivity for clinical diagnosis of acute HIV-1 infection, whereas loss of weight (86 %) and oral ulcers (85 %) had the highest specificity. In this study, the symptoms of fever and rash (especially in combination), followed by oral ulcers and pharyngitis had the highest positive predictive value for diagnosis of acute HIV-1 infection. In another study (Daar 2001), fever, rash, myalgia, arthralgia and night sweats were the best predictors for acute HIV-1 infection.
The symptomatic phase of acute HIV-1 infection lasts between 7 - 10 days, and rarely longer than 14 days. The nonspecific nature of the symptoms poses a great challenge to the clinician and underlines the importance of a detailed history of exposure.
The diagnosis of acute HIV-1 infection is based on the detection of HIV-1 replication in the absence of HIV-1 antibodies, as these are not yet present at this early stage of infection. Different tests are available for diagnosis of acute HIV-1 infection. The most sensitive tests are based on detection of plasma HIV-1 RNA.
In one study (Hecht 2002), all assays for HIV-1 RNA that were tested (branched chain DNA, PCR and GenProbe) had a sensitivity of 100 %, but occasionally (in 2 - 5 % of cases) led to false positive results. False positive results from these tests are usually below 2,000 copies HIV-1 RNA per ml plasma, and therefore far below the high titers of viral load normally seen during acute HIV-1 infection (in our own studies on average 13 x 106 copies HIV-1 RNA/ml with a range of 0.25 - 95.5 x 106 copies HIV-1 RNA/ml). Repetition of the assay for HIV-1 RNA from the same sample with the same test led to a negative result in all false positive cases. Measurement of HIV-1 RNA from duplicate samples therefore results in a sensitivity of 100 % with 100 % specificity. In contrast, detection of p24 antigen has a sensitivity of only 79 % with a specificity of 99.5 - 99.96 %. The diagnosis of acute HVI-1 infection must be subsequently confirmed with a positive HIV-1 antibody test (seroconversion) within the following weeks.
During acute HIV-1 infection, there is frequently a marked decrease of CD4+ T-cell count, which later increases again, but usually does not normalize to the initial levels. In contrast, the CD8+ T-cell count rises initially, which may result in a CD4/CD8 ratio of < 1. Infectious mononucleosis is the most important differential diagnosis. Hepatitis, influenza, toxoplasmosis, syphilis and side effects of medications may also be considered.
Figure 1: Algorithm for the diagnosis of acute HIV-1 infection
In summary, the most important step in the diagnosis of acute HIV-1 infection is to include it in the differential diagnosis. The clinical suspicion of an acute HIV-1 infection then merely requires performance of an HIV-1 antibody test and possibly repeated testing of HIV-1 viral load, as shown in the algorithm in Figure 1 (adapted from (Hecht 2002).
The goal of antiretroviral therapy during acute HIV-1 infection is to shorten the symptomatic viral illness, reduce the number of infected cells, preserve HIV-1-specific immune responses and possibly lower the viral set point in the long term. Several studies in recent years have shown that treatment of acute HIV-1 infection allows long-term viral suppression, leads to preservation and even increase of HIV-1-specific T-helper cell responses and allows for the conservation of a very homogeneous virus population.
First pilot studies in patients who were treated during acute HIV-1 infection and subsequently went through structured treatment interruptions show that the HIV-1-specific immune response could be boosted in these patients (Rosenberg 2000). Most patients were subsequently able to discontinue therapy and experienced at least temporal control of viral replication, with viral set points remaining below 5,000 copies/ml for more than 3 years in some patients. However, in the majority of individuals in this study (Kaufmann 2004), as well as in other studies assessing viral control following treated primary infection (Markowitz 1999), viral load rebounded during longer follow-up, requiring the initiation of therapy.
The long-term clinical benefit of early initiation of therapy has not been demonstrated yet. It is also not known how long the period between acute infection and initiation of therapy can be without losing immunological, virological and clinical benefit. In view of all these unanswered questions, patients with acute HIV-1 infection should be treated in controlled clinical trials (Yeni 2002). If this is not possible, the option of standard first-line treatment should be offered and discussed. It is important during counseling to clearly indicate the lack of definitive data on clinical benefit of early initiation of antiretroviral therapy and to address the risks of antiretroviral therapy and treatment interruptions, including drug toxicity, development of resistance, acute retroviral syndrome during viral rebound and HIV-1 transmission and superinfection during treatment interruptions.1. Allen TM, O'Connor DH, Jing P, et al. Tat- specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 2000,407:386-390. http:// amedeo.com/lit.php?id=11014195 2. Altfeld M, Kalife ET, Qi Y, et al. HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1. PLoS Med. 2006 Oct;3(10):e403. http://amedeo.com/lit.php?id= 17076553 3. Altfeld M, Addo MM, Rosenberg ES, et al. Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection. AIDS. 2003 Dec 5;17(18):2581-91. http://amedeo.com/lit.php?id=14685052 4. Biti R, Ffrench R, Young J, Bennetts B, Stewart G, Liang T. HIV-1 infection in an individual homozy-gous for the CCR5 deletion allele. Nat Med 1997,3:252-253. 5. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994,68:6103-6110. http://amedeo.com/lit.php?id=8057491 6. Cooper DA, Gold J, Maclean P, et al. Acute AIDS retrovirus infection. Definition of a clinical illness associated with seroconversion. Lancet 1985,1:537-540. http://amedeo.com/lit.php?id=2857899 7. Daar ES, Little S, Pitt J, et al. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network. Ann Intern Med 2001,134:25-29. http://amedeo.com/ lit.php?id=11187417 8. Douek DC, Brenchley JM, Betts MR, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002,417:95-98. http://amedeo.com/lit.php?id=11986671 9. Gupta KK. Acute immunosuppression with HIV seroconversion. N Engl J Med 1993,328:288-289. 10. 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. http://amedeo.com/lit.php?id=12004270 11. Hecht FM, Wang L, Collier A, et al. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. 2006 Sep 15;194(6):725-33. http://amedeo.com/lit.php?id=16941337 12. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. New England Journal of Medicine 1998,339:33-39. 13. Kaslow RA, Carrington M, Apple R, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996,2:405-411. http://amedeo.com/ lit.php?id=8597949 14. Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited Durability of Viral Control following Treated Acute HIV Infection. PLOS Medicine, November 2004. in press. 15. Keet IP, Krijnen P, Koot M, et al. Predictors of rapid progression to AIDS in HIV-1 seroconverters. Aids 1993,7:51-57. http:// amedeo.com/lit.php?id=8095146 16. Kinloch-de Loes S. Treatment of acute HIV-1 infection: Is it coming of Age? J Infect Dis. 2006 Sep 15;194(6):721-4. http:// amedeo.com/lit.php?id= 16941336 17. Koup RA, Safrit JT, Cao Y, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. Journal of Virology 1994,68:4650-4655. http://amedeo.com/lit.php?id=8207839 18. Lange CG, Lederman MM, Medvik K, et al. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. Aids 2003,17:2015-2023. http://amedeo.com/lit.php?id=14502004 19. Lichterfeld M, Kaufmann DE, Yu XG, et al. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med. 2004 Sep 20;200(6):701-12. http://amedeo.com/lit.php?id=15381726 20. Markowitz M, Vesanen M, Tenner-Racz K, et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis 1999,179:527-537. 21. Mellors JW, Kingsley LA, Rinaldo CR, Jr., et al. Quantitation of HIV-1 RNA in plasma predicts out-come after seroconversion. Ann Intern Med 1995,122:573-579. http://amedeo.com/lit.php?id=7887550 22. O'Brien SJ, Gao X, Carrington M. HLA and AIDS: a cautionary tale. Trends Mol Med 2001,7:379-381. http://amedeo.com/lit.php?id=11530315 23. Pantaleo G, Demarest JF, Soudeyns H, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 1994,370:463-467. http://amedeo.com/lit.php?id=8047166 24. Pedersen C, Lindhardt BO, Jensen BL, et al. Clinical course of primary HIV infection: consequences for subsequent course of infection. Bmj 1989,299:154-157. http://amedeo.com/lit.php?id=2569901 25. Price DA, Goulder PJ, Klenerman P, et al. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A 1997,94:1890-1895. http://amedeo.com/ lit.php?id=9050875 26. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000,407:523-526. http://amedeo.com/lit.php?id=11029005 27. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997,278:1447-1450. http://amedeo.com/ lit.php?id=9367954
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