Acute HIV Syndrome after Discontinuation of Antiretroviral Therapy in a Patient Treated before Seroconversion

15 May 1998 | Volume 128 Issue 10 | Pages 827-829

Primary HIV infection is associated with high levels of viral replication and the development of HIV-specific immune responses [1-5]. Treating patients during primary HIV infection is recommended [6], but little is known about the effects of such therapy [7-9]. We report the results of virologic and immunologic studies in a patient who began receiving antiretroviral therapy during primary HIV infection and chose to discontinue therapy after 6 months.

Case Report

Top Case Report Methods Results Discussion Author & Article Info References

A 38-year-old homosexual man presented on day 5 of an acute retroviral syndrome characterized by fever, pharyngitis, myalgia, headache, lymphadenopathy, and rash. The patient's leukocyte count was 2.6 x 10⁹/L, his platelet count was 85.0 x 10⁹/L, and his plasma HIV RNA level was 1 800 000 copies/mL. No HIV antibodies were detectable. Primary HIV infection was diagnosed. Infection was probably a result of a receptive orogenital sexual encounter that took place 13 days before presentation, when the patient had a hard-palate ulcer. Two days after presentation, HIV antibodies remained undetectable; the plasma HIV RNA level was 5 600 000 copies/mL; and therapy with standard doses of zidovudine, lamivudine, and ritonavir was started.

Because of toxicity, therapy was altered several times over the next 6 months. At 6 months, the patient chose to stop antiretroviral treatment despite being counseled about the possible outcomes of doing so. Thirty-five days later, he developed an acute illness that was indistinguishable from the acute retroviral syndrome. Results of serologic evaluation for Epstein-Barr virus, cytomegalovirus, rubella, roseola, parvovirus B19, and human herpesvirus-6 were inconsistent with acute disease. The patient chose not to reinitiate treatment, and his acute symptoms resolved during the following 10 to 14 days.

Methods

Top Case Report Methods Results Discussion Author & Article Info References

Antibodies to HIV were measured by enzyme immunoassay (Abbott Laboratories, North Chicago, Illinois) and Western blot (Genetic Systems, Seattle, Washington). Plasma HIV RNA was quantified by a branched-DNA assay (version 2.0, Chiron Diagnostics, Emeryville, California), which measured as few as 500 copies/mL. Quantitative cultures of plasma and peripheral blood mononuclear cells [1, 10] and memory cytotoxic T-lymphocyte assays [11] were performed as described elsewhere.

The funding sources had no role in gathering, analyzing, or interpreting the data or in the decision to submit the paper for publication.

Results

Top Case Report Methods Results Discussion Author & Article Info References

Our patient began receiving antiretroviral therapy before a humoral immune response was detected. Virologic and immunologic measurements were made during the treatment and post-treatment phases (Figure 1). As seen in other patients treated during primary HIV infection [7, 8], our patient's plasma HIV RNA declined to undetectable levels. In addition, plasma titers of infectious virus declined to less than 1 tissue-culture infectious dose per mL; cellular titers of infectious virus decreased to less than 0.1 infectious units per million peripheral blood mononuclear cells. Although not tested earlier, cytotoxic T-lymphocyte memory-cell activity was undetectable after 5 months of treatment (Figure 2). Also at this time, minimal CD8⁺ cell activation was detected by using previously described methods [11, 12].

View larger version (18K): [in this window] [in a new window]   Figure 1. Temporal relation among clinical symptoms, antiretroviral therapy, plasma HIV RNA levels, and CD4+ and CD8+ T-lymphocyte counts in a patient treated during primary HIV infection before HIV-specific antibodies were detectable. ARS = acute retroviral syndrome; AS = acute syndrome; HAART = highly active antiretroviral therapy; RNA = plasma HIV RNA.

 

View larger version (12K): [in this window] [in a new window]   Figure 2. Memory cytotoxic T-lymphocyte activity in blood, measured as the percentage of specific lysis at different effector-to-target ratios. Left. Results while the patient was receiving antiretroviral therapy, 169 days after the onset of the acute retroviral syndrome. Right. Results 2.5 months after therapy was stopped, 268 days after the onset of the acute retroviral syndrome. Gag = targets expressing Gag proteins; Pol = targets expressing Pol proteins; control = targets infected with wild-type vaccinia.

 

Viremia rebounded after therapy was discontinued (Figure 1). In addition, memory cytotoxic T-lymphocyte activity (Figure 2) and high levels of CD8⁺ T-lymphocyte activation (data not shown), which correlate with the presence of cytotoxic T lymphocytes [13], were detected. The presence of memory cytotoxic T-cell activity against HIV Gag and Pol (but not against control cells, which do not express HIV proteins) indicates that the donor had CD8⁺ T cells primed against HIV antigens. These memory cells provide rapid secondary responses to antigens to which the host has been sensitized.

Discussion

Top Case Report Methods Results Discussion Author & Article Info References

Although declining cytotoxic T-lymphocyte activity has been described in patients treated during primary HIV infection [7, 14], we are not aware of such observations in treated patients with chronic HIV infection. Whether absence of memory cytotoxic T-lymphocyte activity is a frequent outcome of treatment during seronegative primary HIV infection needs to be confirmed in larger studies. Nevertheless, our results suggest that HIV replication sustained for some minimal period may be needed to establish a durable CD8⁺ cell-mediated response. This observation has implications for HIV vaccination protocols because brief exposures to viral antigens may not result in the sustained immune response needed for HIV immunity. This is in contrast to observations in other viral systems [15-17].

The rebound in viremia after our patient stopped therapy was anticipated because of the cellular reservoirs of infectious HIV [18-20]. In contrast, the associated clinical syndrome was unexpected and may be explained by the emergence, at that time, of a CD8⁺ cell-mediated immune response similar to the response in newly infected persons. Further investigation is required to determine the clinical significance of this second acute syndrome and the effect of early therapy on HIV-specific immune responses.

Ms. Hausner, Mr. Majchrowicz, and Dr. Giorgi: University of California, Los Angeles, School of Medicine, 12-939 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1745.

Author and Article Information

Top Case Report Methods Results Discussion Author & Article Info References

From Cedars-Sinai Burns and Allen Research Institute and the University of California, Los Angeles, Los Angeles, California.
Acknowledgments: The authors thank Stephen Nichols, MD, for technical assistance; Jacqui Pitt, RN, for clinical assistance; Marie Reskusic for Figure preparation; and John Ferbas, PhD, for critical review of the manuscript. They also thank the patient, who cooperated with all studies and reviewed the manuscript to assure accuracy of the description of the clinical syndrome.
Grant Support: In part by the Universitywide AIDS Research Program California Multicenter AIDS Research Consortium Award and National Institutes of Health grant AI-32883.
Requests for Reprints: Eric S. Daar, MD, Division of Infectious Diseases, Cedars-Sinai Medical Center, B217, 8700 Beverly Boulevard, Los Angeles, CA 90048.
Current Author Addresses: Drs. Daar and Bai and Ms. Tamaddon: Division of Infectious Diseases, Cedars-Sinai Medical Center, B217, 8700 Beverly Boulevard, Los Angeles, CA 90048.

References

Top Case Report Methods Results Discussion Author & Article Info References

1. Daar ES, Moudgil T, Meyer RD, Ho DD. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med. 1991; 324:961-4.

2. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994; 68:4650-5.

3. Piatak M Jr, Yang LC, Luk KC, Lifson JD, Saag MS, Clark SJ, et al. Viral dynamics in primary HIV-1 infection [Letter]. Lancet. 1993; 341:1099.

4. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med. 1996; 125:257-64.

5. Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ. Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med. 1997; 337:1267-74.

6. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA Panel. JAMA. 1997; 277:1962-9.

7. Markowitz M, Cao Y, Vesanen M, Talal A, Nixon D, Hurley A, et al. Recent HIV infection treated with AZT, 3TC, and a potent protease inhibitor [Abstract]. Proceedings of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC; 1997:207.

8. Lafeuillade A, Poggi C, Tamalet C, Profizi N, Tourres C, Costes O. Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis. 1997; 175:1051-5.

9. Perrin L, Rakik A, Yerly S, Baumberger C, Kinloch-de Loes S, Pechere M, et al. Combined therapy with zidovudine and L-697,661 in primary HIV infection. AIDS. 1996; 10:1233-7.

10. Daar ES, Chernyavskiy T, Zhao JQ, Krogstad P, Chen IS, Zack JA. Sequential determination of viral load and phenotype in human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 1995; 11:3-9.

11. Ferbas J, Daar ES, Grovit-Ferbas K, Lech WJ, Detels R, Giorgi JV, et al. Rapid evolution of human immunodeficiency virus strains with increased replicative capacity during the seronegative window of primary infection. J Virol. 1996; 70:7285-9.

12. Giorgi JV, Ho HN, Hirji K, Chou CC, Hultin LE, O'Rourke S, et al. CD8+ lymphocyte activation at human immunodeficiency virus type 1 seroconversion: development of HLA-DR+ CD38+ CD8+ cells is associated with subseuent stable CD4+ cell levels. The Multicenter AIDS Cohort Study Group. J Infect Dis. 1994; 170:775-81.

13. Ho HN, Hultin LE, Mitsuyasu RT, Matud JL, Hausner MA, Bockstoce D, et al. Circulating HIV-specific CD8⁺ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol. 1993; 150:3070-9.

14. Hoen B, Harzic M, Dumon B, Lascoux C, Gomard E, Venet A, et al. Efficacy of zidovudine, lamivudine, and ritonavir combination in patients with symptomatic primary HIV infection: the ANRS 053/538 trial. Can eradication be obtained? [Abstract] 5th Conf Retro and Opportun Infect. 1998:524.

15. Selin LK, Welsh RM. Cytolytically active memory CTL present in lymphocytic choriomeningitis virus-immune mice after clearance of virus infection. J Immunol. 1997; 158:5366-73.

16. Lau LL, Jamleson BD, Somasundaram T, Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994; 369:648-52.

17. Beverley PC. Is T-cell memory maintained by crossreactive stimulation? Immunol Today. 1990; 11:203-5.

18. Cavert W, Notermans DW, Staskus K, Wletgrefe SW, Zupancic M, Gebhard K, et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science. 1997; 276:960-4.

19. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997; 387:188-91.