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ing algorithms (decision tree and support vector machine) for HIV-1 genotypic drug- ity is associated with better virological re- Algorithms Need to IncludeHypersusceptibility- resistance interpretation, but neither al- sponses. In addition, hypersusceptibility- persusceptibility. We recently developed a linear statistical model for HIV-1 genotyp- clinical significance has not been firmly To the Editor—Tozzi et al. [1] recently
ic drug-resistance interpretation [5]. Our reported a retrospective study investigat- with hypersusceptibility to nonnucleoside interpretation algorithms have, to date, ig- reverse-transcriptase inhibitors (NNRTIs) nored the issue of hypersusceptibility. In existence of at least 1 hypersusceptibility- ceptibility and better virological responses, we suggest that these mutations be includ- with a better, although transient, virolog- inhibitors (PIs) and reverse-transcriptase ed in genotypic algorithms and in rules for ical outcome in patients treated with efa- inhibitors used in our study. Included in choosing combination therapy regimens.
Further work should be done to investigate the clinical significance of mutations that are reported to confer hypersusceptibility come across several articles reporting on Kai Wang, Ram Samudrala,
and John E. Mittler
served a positive correlation between phe- tations Group [2] includes a footnote that and virological responses to regimens that possibly associated with hypersusceptibil- include efavirenz; also, using a multivar- ity to some nucleoside reverse-transcrip- iate analysis similar to our linear model, 1. Tozzi V, Zaccarelli M, Narciso P, et al. Mutations bility-associated mutations in its main ta- analyzed genotypic, phenotypic, and clin- in HIV-1 reverse transcriptase potentially as- ble. Using the algorithm-specific interface ical data on mutations associated with hy- sociated with hypersusceptibility to nonnucleo-side reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban [3], we could not find a “hypersuscepti- observational cohort. J Infect Dis 2004; 189:
ble” category in the rules for either the creased susceptibility to delavirdine and 2. Johnson VA, Brun-Ve´zinet F, Clotet B, et al.
Drug resistance mutations in HIV-1. Top HIV causes slight increases in susceptibility to Med 2003; 11:215–21.
all three NNRTIs” (p. F45). Haubrich et 3. Rhee SY, Gonzales MJ, Kantor R, Betts BJ, does contain a few hypersusceptibility an- al. [8], Katzenstein et al. [9], and Mellors ciency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003;
reported by Tozzi et al. is listed as con- ferring hypersusceptibility to efavirenz or and virological responses. These articles 4. Beerenwinkel N, Daumer M, Oette M, et al.
Geno2pheno: estimating phenotypic drug re- sistance from HIV-1 genotypes. Nucleic Acids are associated with hypersusceptibility to Res 2003; 31:3850–5.
• JID 2004:190 (1 December) • 2055
5. Wang K, Jenwitheesuk E, Samudrala R, Mittler mutation associated with hypersusceptibil- 4. Katzenstein DA, Bosch RJ, Hellmann N, et al.
JE. Simple linear model provides highly ac- Phenotypic susceptibility and virological out- curate genotypic predictions of HIV-1 drug come in nucleoside-experienced patients re- resistance. Antivir Ther 2004; 9:343–52.
reverse-transcriptase inhibitor mutations ceiving three or four antiretroviral drugs. AIDS 6. Shulman N, Zolopa AR, Passaro D, et al. Phe- 2003; 17:821–30.
notypic hypersusceptibility to non-nucleoside 5. Tozzi V, Zaccarelli M, Narciso P, et al. Mutations reverse transcriptase inhibitors in treatment- in HIV-1 reverse transcriptase potentially as- experienced HIV-infected patients: impact on sion in genotypic algorithms for choosing sociated with hypersusceptibility to nonnucleo- virological response to efavirenz-based ther- side reverse-transcriptase inhibitors: effect on apy. AIDS 2001; 15:1125–32.
some caveats should be kept in mind.
response to efavirenz-based therapy in an urban 7. Whitcomb JM, Huang W, Limoli K, et al. Hy- observational cohort. J Infect Dis 2004; 189:
persusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phe- notypic and genotypic correlates. AIDS 2002;
Reprints or correspondence: Dr. Valerio Tozzi, National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 8. Haubrich RH, Kemper CA, Hellmann NS, et al. The clinical relevance of non-nucleoside The Journal of Infectious Diseases
2004; 190:2056
reverse transcriptase inhibitor hypersuscepti- ᮊ 2004 by the Infectious Diseases Society of America. All bility: a prospective cohort analysis. AIDS 2002;
rights reserved. 0022-1899/2004/19011-0024$15.00 9. Katzenstein DA, Bosch RJ, Hellmann N, Wang clinical trials of phenotypic assays [3, 4].
N, Bacheler L, Albrecht MA. Phenotypic sus- ceptibility and virological outcome in nucleo- side-experienced patients receiving three or four
antiretroviral drugs. AIDS 2003; 17:821–30.
eficial effect on virological response is 10. Mellors J, Vaida F, Benett K, Hellmann N, DeGruttola V, Hamme S. Efavirenz hypersus- To the Editor—In their excellent article,
ceptibility improves virologic response to mul- tations in the reverse-transcriptase gene tidrug salvage regimens in ACTG 398 [abstract 45]. In: Program and abstracts of the 9th Con- and the virological response to efavirenz- ference on Retroviruses and Opportunistic In- fections. Seattle: Foundation for Retrovirology respect to achieving an undetectable viral and Human Health, 2002:69.
success of rescue therapy when the rescue Reprints or correspondence: Dr. John E. Mittler, Dept. of Mi- crobiology, University of Washington, Box 358070, Seattle, WA tectable due to a lack of virological re- persusceptibility to efavirenz. It is a rea- The Journal of Infectious Diseases
2004; 190:2055–6
sonable interpretation. However, it would ᮊ 2004 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2004/19011-0023$15.00 the need to closely monitor virus load if cussed the possible effect of adherence.
My colleagues and I, as well as others, To the Editor—Wang et al. [1], on the
Valerio Tozzi
National Institute for Infectious Diseases Lazzaro gested that mutations associated with hy- does not harbor resistance mutations [2– 5]. Thus, in the study by Tozzi et al., the included in genotypic drug-resistance in- 1. Wang K, Samudrala R, Mittler JE. HIV-1 ge- notypic drug-resistance interpretation algo- choosing combination therapy regimens.
rithms need to include hypersusceptibility-as- I agree with their suggestion. The Inter- sociated mutations [letter]. J Infect Dis 2004;
at least in part, by better adherence. Ad- 2. Johnson VA, Brun-Ve´zinet F, Clotet B, et al.
Drug resistance mutations in HIV-1. Top HIV Med 2003; 11:215–21.
tease inhibitor (PI)–based therapy does 3. Haubrich RH, Kemper CA, Hellmann NS, et al. The clinical relevance of non-nucleoside re- verse transcriptase inhibitor hypersusceptibil- dovudine, stavudine, and/or tenofovir.
ity: a prospective cohort analysis. AIDS 2002;
verse-transcriptase inhibitors, but this as- 2056 • JID 2004:190 (1 December) • CORRESPONDENCE

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