gram and abstracts of the 5th International Workshop on HIV Drug Resistance (Whistler, British Columbia). 1996. 6. Strack PR, West Frey M, Rizzo CJ, et al. Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc Natl Acad Sci U S A 1996; 93:9571–6. Reprints or correspondence: Dr. Dean L. Winslow, Div. of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, 300 Pasteur Dr., Grant Bldg., Rm. S-169, Palo Alto, California 94304 (
[email protected]). Clinical Infectious Diseases 2009; 49:165–6 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4901-0024$15.00 DOI: 10.1086/599619
Reply to Winslow
Acknowledgments Potential conflicts of interest. A.C. is an employee of Monogram BioSciences. P.G. and A.Z.: no conflicts. Philip Grant,1 Eoin Coakley,2 and Andrew Zolopa1 1
Division of Infectious Diseases, Stanford University, Palo Alto, and 2Monogram Biosciences, South San Francisco, California
References 1. Winslow DL. Replication capacity of HIV-1 in the presence of resistance-associated substitutions in protease [letter]. Clin Infect Dis 2009; 49:165–6 (in this issue). 2. Petropoulos CJ, Parkin NT, Limoli KL, et al. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000; 44:920–8. 3. Malet I, Roquebert B, Dalban C, et al. Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients. J Infect 2007; 54:367–74. 4. Goetz M, Leduc R, Kostman J, et al. HIV replicative capacity is an independent predictor of disease progression in persons with untreated chronic HIV infection [abstract WEPDB07]. In: Program and abstracts of he 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. (Sydney, Australia). Geneva: International AIDS Society, 2007. 5. Skowron G, Spritzler JG, Weidler J, et al. Replication capacity in relation to immunologic and virologic outcomes in HIV-1–infected
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treatment-naive subjects. J Acquir Immune Defic Syndr 2009; 50:250–8. 6. Maguire MF, Guinea R, Griffin P, et al. Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro. J Virol 2002; 76:7398–406. 7. Huang W, Gamarnik A, Limoli K, Petropoulos CJ, Whitcomb JM. Amino acid substitutions at position 190 of human immunodeficiency virus type 1 reverse transcriptase increase susceptibility to delavirdine and impair virus replication. J Virol 2003; 77:1512–23. 8. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344:472–80. Reprints or correspondence: Dr. Philip Grant, Div. of Infectious Diseases and Geographic Medicine, 300 Pasteur Dr., Grant Bldg., Rm. S-101, Stanford, CA 94306 (
[email protected]). Clinical Infectious Diseases 2009;49:166 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4901-0025$15.00 DOI: 10.1086/599620
Fatality Despite Appropriate Treatment for Babesiosis To the Editor—Since our article [1] was published in Clinical Infectious Diseases in January 2009, the treating physicians have provided additional information about one of the reported deaths (patient 8). This patient received therapy for presumptive severe Plasmodium falciparum malaria and for possible babesiosis with exchange transfusion, quinidine, and clindamycin. Because of the initial high level of parasitemia (10%–12%), pathologists considered both parasites, and the physicians chose treatment effective for both. The patient’s parasitemia level decreased to !0.5%, but she died. Results positive for Babesia species were determined after the patient’s death. This case highlights the fact that initial testing may not clearly distinguish Plasmodium infection from Babesia infection. Because of that uncertainty, the patient was wisely treated simultaneously for both pathogens. Acknowledgments Potential conflicts of interest. All authors: no conflicts.
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To the Editor—We agree with Dr. Winslow [1] that the mechanism for immunologic benefit with incompletely suppressive regimens is likely to be complex. The relative contribution to immunologic stability of residual antiretroviral activity, reduced fitness, and/or a protease inhibitor (PI)–specific effect—possibly mediated by an anti-apoptotic effect with PIs, as was suggested by Winslow [1]—has not been fully defined. It is important to note that the PhenoSense HIV assay, which is used to measure human immunodeficiency virus (HIV) drug resistance and replication capacity within gag-pol, incorporates not only the reverse-transcriptase and protease but also the C-terminal portion of gag, including 2 protease cleavage sites, NC-p7/p1 and p1/p6, as well as the PTAAP motif and other important regulatory elements [2]. Changes to this particular portion of gag have been observed in the setting of protease resistance [3]. Reduced replication capacity, as measured by this methodology, has defined clinical correlates. It has been associated with slower disease progression in treatment-naive individuals and with differences in the recovery of CD4+ cell counts in the setting of successful combination therapy [4, 5]. In the setting of multidrug resistance (MDR), as in this study, a reduced replication capacity likely represents an expression of the multiplicity of changes in reverse-transcriptase, protease,
and N-terminal gag, which have arisen in the setting of nucleoside reverse-transcriptase inhibitor, nonnucleoside reverse-transcriptase inhibitor, and/or PI exposure [6, 7]. We agree that changes outside of this region of gag may be relevant to the recovery of fitness in patients with drugresistant infection. However, the rapid recrudescence of wild-type virus with treatment interruption in patients with multidrug-resistant infection suggests a favorable fitness of wild-type virus over the resistant mutants. Also, among patients with treatment interruption, greater increases in HIV-1 RNA have been correlated with greater increases in replication capacity [8]. Therefore, in sum, the replication capacity can be seen as a reasonable surrogate or proxy for in vivo viral fitness and has the advantage that it is readily available to the clinician.
Diane M. Gubernot,1 Robert P. Wise,1 and Stanley M. Spinola2 1
Center for Biologics Evaluation and Research, US Food and Drug Administration, Rockville, Maryland; and 2Department of Medicine, Indiana University, Indianapolis References 1. Gubernot DM, Lucey CT, Lee KC, Conley GB, Holness LG, Wise RP. Babesia infection through blood transfusion: reports received by the US Food and Drug Administration, 1997–2007. Clin Infect Dis 2009; 48:25–30. Reprints or correspondence: Dr. Diane Gubernot, FDA-CBER, 1401 Rockville Pike, HFM-394, Rockville, MD 20852-1448 (
[email protected]).
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Clinical Infectious Diseases 2009; 49:166–7 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4901-0026$15.00 DOI: 10.1086/599621
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