Absence of virological changes after acute febrile illnesses in two patients with undetectable pre-illness plasma HIV-1-RNA levels
Sha, Beverly E.a; Johnson, Victoria A.b; Kendall, Michelle A.c; Haubrich, Richardd; Nokta, Mostafae; Lamb, Karanf; Zackin, Robert A.c; Nail, Clint D.b; Currier, Judith S.g
aRush Medical College, Chicago, IL, USA; bUniversity of Alabama at Birmingham School of Medicine and Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA; cHarvard School of Public Health, Boston, MA, USA; dUniversity of California, San Diego, CA, USA; eUniversity of Texas Medical Branch, Galveston, TX, USA; fAdult AIDS Clinical Trials Group Operations Center, Rockville, MD, USA; and gUniversity of California, Los Angeles, CA, USA.
Informed consent was obtained from all participants. Human experimentation guidelines of the US Department of Health and Human Services and local institutional guidelines were followed. The human subjects' consent form was reviewed and approved by the local Institutional Review Board before initiation of the study.
Sponsorship: This work was supported in part by the Adult AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, NIH (grants AI-38855 and AI-32775; contract 96VC001), and partly by the General Clinical Research Center Units funded by the National Center for Research Resources.
Received: 17 December 1999; accepted: 22 December 1999.
Repeated episodes of intercurrent infections have been postulated to be an important stimulus for the clinical progression of HIV-1 disease [1,2]. Disseminated Mycobacterium avium complex (MAC), Mycobacterium tuberculosis disease, bacterial pneumonia, and outbreaks of herpes simplex virus (HSV) have been reported to increase plasma HIV-1 levels transiently [1–7]. Previous reports have documented increases in plasma HIV-1-RNA levels in patients with uncontrolled viremia after an opportunistic infection [2,4]. The AIDS Clinical Trials Group ACTG 891 was designed to assess changes in plasma viral load and CD4 cell counts during and after an acute febrile illness in patients on potent antiretroviral therapy with initial undetectable plasma HIV-1-RNA levels.
Two patients on stable antiretroviral therapy and plasma HIV-1-RNA levels of less than 500 copies/ml (Amplicor HIV-1 Monitor test, Roche Diagnostic Systems, Branchburg, NJ, USA; limit of quantitation at 400 copies/ml) within 8 weeks of study entry enrolled in 1998. Patients remained on antiretroviral therapy throughout the study period. Plasma HIV-1-RNA samples were obtained at the time of febrile illness presentation, at 3 days, and at 1, 2, 4, 8, 16 and 24 weeks after presentation, and were assayed using the Roche Ultrasensitive Amplicor HIV-1 Monitor test (Roche Diagnostic Systems; lower limit of quantitation at 50 copies/ml) . Results are presented as the geometric mean from two separate assay runs. Immunology phenotyping for markers of immune activation and function were performed by three-color cytofluorometric analysis at entry, weeks 4, 16, and 24 .
Patient 1 was a 27-year-old man who had been on lamivudine, stavudine, and indinavir for 55.2 weeks. He had had a fever for 48 h up to 103.5°F, which was presumably viral in origin. Entry plasma HIV-1 RNA and CD4 cell count were less than 50 copies/ml and 756 cells/mm3 (40%), respectively. Patient 2 was a 52-year-old man who had been on abacavir, efavirenz, and indinavir for 39 weeks. The patient had a fever of unknown origin. He had been hospitalized five times between January and July 1998 with an unrevealing diagnostic work-up including splenectomy. His fevers resolved 20 weeks after study entry. Entry plasma HIV-1 RNA and CD4 cell count were 55 copies/ml and 134 cells/mm3 (32%), respectively.
No significant changes from entry viral load levels occurred over time. Patient 1 had plasma HIV-1 RNA levels of less than 50 copies/ml at each timepoint and patient 2 had plasma HIV-1 RNA levels of 55, < 50, < 50, 67, < 50, < 50, and 140 copies/ml at entry, day 3, and weeks 1, 2, 4, 16, and 24, respectively. CD4 cell counts and flow cytometry data are depicted in Fig. 1.
Earlier studies [1–7] have demonstrated an increase in plasma HIV-1-RNA levels during various opportunistic infections and acute illnesses. In general, those reports involved patients with elevated baseline plasma HIV-1-RNA levels. After resolution of the acute illness, the plasma HIV-1-RNA levels did not always return to baseline values, leading to the concern that intercurrent illnesses may play a role in disease progression. In 18 HIV-infected patients with bacterial pneumonia, Pneumocystis carinii pneumonia, viral syndrome, bacteremia, cellulitis, pulmonary aspergillosis, toxoplasmosis, or sinusitis, the median plasma HIV-1 load increased 7.8-fold (+0.89 log10) during illness from a median baseline 108 442 copies/ml and decreased 1.5-fold (−0.18 log10) during recovery . Changes in plasma HIV-1 RNA were significantly associated with changes in soluble TNF receptor types I and II, and soluble IL-2 receptor, suggesting that acute co-infections increase HIV-1 replication and are associated with in-vivo immune activation.
Similar results were reported in 14 patients with AIDS-associated opportunistic diseases . Twenty-seven patients developed MAC bacteremia while enrolled in a MAC prophylaxis trial. Plasma HIV-1-RNA levels increased a median of 0.4 log10 (2.5-fold increase) from a baseline of 4.8 log10 in cases, but not in controls, at the time of MAC bacteremia . In 16 patients with an acute HSV outbreak, 14 increased their plasma HIV-1 a median of 3.4-fold (+0.53 log10). None of the patients had an undetectable viral load before their HSV outbreak .
Our two patients differed from previous studies in that they were on potent antiretroviral therapy with undetectable plasma HIV-1-RNA levels before the illness and they remained on antiretroviral therapy during the acute illness. We saw no significant change in plasma HIV-1-RNA levels over time using the Roche Ultrasensitive Amplicor HIV-1 Monitor assay . Our data suggest that in the setting of adequate virological control, acute febrile illnesses have little impact on plasma viremia and the immune status of the patient. We postulate that, in this setting, acute febrile illnesses would not contribute to the progression of HIV disease. These results underscore the need to maintain antiretroviral therapy during acute infectious illnesses. Future larger-scale studies should further address the impact of intercurrent illnesses on plasma viremia and immune activation.
Dr Johnson acknowledges the core laboratory research facilities of the University of Alabama at Birmingham School of Medicine, University of Alabama at Birmingham Center for AIDS Research, and the Birmingham Veterans Affairs Medical Center. In addition, the authors would like to thank Jill Kunkel, RN, and the two patients who participated in this study.
Beverly E. Shaa
Victoria A. Johnsonb
Michelle A. Kendallc
Robert A. Zackinc
Clint D. Nailb
Judith S. Currierg
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