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Effects of Famciclovir and Valacyclovir
our experience is necessary for detection of transient recurrences on Herpes Simplex Virus Type 1 Infection, Latency,
of infectious virus. We question the statement that no “re- and Reactivation in Mice: How Dissimilar Are
bound” of infectious virus was seen, since samples were tested Study Results?
intermittently (days 2, 4, 7, 9, and 11 after infection) and beforethe acute infection was completely cleared. Indeed, some of ourresults would look similar to those published by LeBlanc et al.
[1] if our data had been recorded only on alternate days.
To the Editor—LeBlanc et al. [1] assessed the effects of fam-
Fourth, LeBlanc et al. state in their introductory text that ciclovir and valacyclovir on herpes simplex virus (HSV) type Thackray et al. [2–5] claim that “famciclovir is better than 1 infection, latency, and reactivation in mice but did not dem- valacyclovir in terminating ganglionic HSV infection and onstrate superiority of famciclovir over valacyclovir on the es- thereby limits subsequent reactivation” [1, p. 594]. We did not tablishment of HSV latency in mice. Furthermore, they assert claim that either compound was superior in terminating gan- in both the Introduction and Discussion sections of their article glionic HSV infection; however, we reported a reduction in the that their results “differ notably from the serial comparative amount of detectable latent virus measured by disaggregation, mouse studies of famciclovir and valacyclovir” [1, p. 598] pub- long-term culture of whole ganglia, in situ hybridization for lished by my colleagues and me [2–5]. We wish to draw attention latency-associated transcripts, and reduced rates of reactivation to 4 important points that we believe explain the declared dis- by explant culture [4]. In all cases, the reduction was greater crepancy between studies in our 2 laboratories.
for famciclovir, but neither compound resulted in the “termi- First, we infected a strain of moderate virulence (HSV-1 SC16) into the skin of the murine ear pinna, at a dose of 105 For these reasons, we contend that the assertion by LeBlanc pfu per mouse. The experiments described by LeBlanc et al. [1] et al. that their data differ from ours should be judged cau- involved bilateral application of 106 pfu of the neurovirulent tiously. We see little justification for the proposal that the McKrae strain of virus to the scarified corneas. We believe that “McKrae-induced infection and disease closely resemble that the latter method of inoculation would favor direct uptake of seen in humans” [1, p. 598]. Indeed, this may not be a good virus from the inoculum into the axons and rapid transfer to model in which to compare the effects of nucleoside analogues the ganglionic neurons. This then would lead to the establish- on establishment of latency. We believe that further studies in ment of unamplified latency within 24 h, as described by Sim- a variety of laboratory-infection models are urgently required mons et al. [6]. A significant number of neurons would, there- in order to fully interpret clinical data and to optimize treat- fore, contain latent HSV before the commencement of therapy ment strategies using the 2 oral prodrugs, valacyclovir and on postinfection day 1. We would anticipate the effects of ther- apy under such conditions to be minimal. Furthermore, subtledifferences between the 2 drugs may have been obscured.
Second, the experiments by LeBlanc et al. [1] resulted in 100% mortality, with deaths occurring on postinoculaton days 4 and Alana M. Thackray and Hugh J. Field
Centre for Veterinary Science, Cambridge University, 5, suggesting that a severe neurologic infection was established very quickly in this model. Because there were no survivors inthe untreated group, there were no positive control animals withwhich to compare therapy with either drug. By contrast, our References
experiments showed ∼50% mortality without treatment (which 1. LeBlanc RA, Pesnicak L, Godleski M, Straus SE. The comparative effects of usually occurred 6–10 days after infection). Mortality was re- famciclovir and valacyclovir on herpes simplex virus type 1 infection, la- duced to 0 when treatment with either drug was started within tency, and reactivation in mice. J Infect Dis 1999; 180:594–9.
2 days after infection. Under these conditions, survivors were 2. Thackray AM, Field HJ. Differential effects of famciclovir and valaciclovir available for comparison with treatment groups [2–5].
on the pathogenesis of herpes simplex virus in a murine infection model Third, LeBlanc et al. state, “In contrast to prior studies that including reactivation from latency. J Infect Dis 1996; 173:291–9.
3. Thackray AM, Field HJ. Comparison of effects of famciclovir and valaciclovir used the ear pinna model [2, 5], we did not observe a rebound on pathogenesis of herpes simplex virus type 2 in a murine infection model.
of virus titers after cessation of valacyclovir therapy” [1, p.
Antimicrob Agents Chemother 1996; 40:846–51.
596–7]. This statement appears to be at variance with the results 4. Thackray AM, Field HJ. Famciclovir and valaciclovir differ in the prevention reported by LeBlanc et al., since positive virus titers in trigem- of herpes simplex virus type 1 latency in mice: a quantitative study. An- inal ganglia and brains are evident on day 11, the last day on timicrob Agents Chemother 1998; 42:1555–62.
5. Field HJ, Tewari D, Sutton D, Thackray AM. Comparison of efficacies which samples were tested for infectious virus. Therefore, the of famciclovir and valaciclovir against herpes simplex virus type 1 in a infection was not cleared by the end of the observation period, murine immunosuppression model. Antimicrob Agents Chemother 1995;
and, in any case, the animals were not tested daily, which in 6. Simmons A, Slobedman B, Speck P, Arthur J, Efstathiou S. Two patterns of ing ganglionic infection” [2], by which we meant the presence persistence of herpes simplex virus DNA sequences in the nervous systems of infectious virus in the tissue. Despite their claim to the con- of latently infected mice. J Gen Virol 1992; 73:1287–91.
trary, Thackray and Field [4, 5] reported that famciclovir was Reprints or correspondence: Dr. Alana M. Thackray, Centre for Veterinary superior in reducing the amount of both infectious and latent Science, Cambridge University, Madingley Road, Cambridge, CB3 OES, United virus in ganglia and in “preventing the establishment of la- tency” (Discussion in [4]; Introduction and Discussion in [5]).
We agree that each animal model has its own advantages The Journal of Infectious Diseases
2000; 181:1517–8
and disadvantages. We believe, from our own data, that fam- ᭧ 2000 by the Infectious Diseases Society of America. All rights reserved.
ciclovir and valacyclovir are equivalent for the acute treatment of HSV infections and will continue to believe so until a well-designed clinical trial proves otherwise.
Rona A. LeBlanc and Stephen E. Straus
Medical Virology Section, Laboratory of Clinical Investigation, To the Editor—Thackray and Field [1] raise 4 points that they
National Institutes of Health, Bethesda, Maryland believe explain why our recent study [2] failed to document thevirologic superiority of famciclovir over valacyclovir that theydescribed in several reports and numerous abstracts.
References
First, the route of infection did differ, as we acknowledged in our Discussion section [2]. They argue, however, that infec- 1. Thackray AM, Field HJ. Effects of famciclovir and valacyclovir on herpes tion of the cornea (as opposed to the ear pinna in their model simplex virus type 1 infection, latency, and reactivation in mice: how dis- similar are study results? [letter]. J Infect Dis 2000; 181:1517–8.
system) would favor direct uptake of virus into the axons, elim- 2. LeBlanc RA, Pesnicak L, Godleski M, Straus SE. The comparative effects of inating the opportunity a drug started 24 h later might have famciclovir and valacyclovir on herpes simplex virus type 1 infection, la- to limit viral amplification in the ganglia. We believe that any tency, and reactivation in mice. J Infect Dis 1999; 180:594–9.
such aspect of our model system is overstated. In our studies, 3. Field HJ, Tewari D, Sutton D, Thackray AM. Comparison of efficacies of virus titers in tissues continued to rise for some days after the famciclovir and valacyclovir against herpes simplex virus type 1 in a mu- rine immunosuppression model. Antimicrob Agents Chemother 1995; 39:
start of treatment (figure 3 in [2]). Thus, there remained ample opportunity for viral replication to be affected by the drugs.
4. Thackray AM, Field HJ. Differential effects of famciclovir and valacyclovir Nonetheless, we failed to observe any differential benefit of on the pathogenesis of herpes simplex virus in a murine infection model famciclovir. Moreover, Thackray and colleagues [3–5] reported including reactivation from latency. J Infect Dis 1996; 173:291–9.
experiments in which they delayed treatment even further and 5. Thackray AM, Field HJ. Famciclovir and valacyclovir differ in the prevention of herpes simplex virus type 1 latency in mice: a quantitative study. An- still observed superiority of famciclovir.
timicrob Agents Chemother 1998; 42:1555–62.
Second, Thackray and Field [1] are concerned about the virus inoculum that we used, because it was associated with universal Reprints or correspondence: Dr. Stephen E. Straus, National Center for Com- mortality in the absence of treatment. It is true that no positive plementary and Alternative Medicine, National Institutes of Health, 31 CenterDr., Room 5B41, Bethesda, MD 20892 ([email protected]).
controls remained with which to compare the effects of treat- The Journal of Infectious Diseases
2000; 181:1518
ment on latency and reactivation; however, untreated animals ᭧ 2000 by the Infectious Diseases Society of America. All rights reserved.
survived long enough for us to observe that famciclovir and valacyclovir were equivalent in virologic outcome measures ofthe acute infection.
Third, with regard to a rebound of virus titers, we disagree that there is a “variance with the results published” [1]. It has Questions about Results Reported with Potent
been our experience that the time points chosen are more than Antiretroviral Therapy for Human Immunodeficiency
sufficient to track the spread of herpes simplex virus (HSV) Virus Type 1 Infection
from the eye to the trigeminal ganglia and into the brain. Withthe chosen time points, we saw the spread of virus throughthese tissues. Moreover, we detected no differences in the effect To the Editor—Zaunders et al. [1] report the clearance rates of
of either drug during the testing period. Obviously, for a true plasma human immunodeficiency virus (HIV) type 1 RNA and rebound to occur, the initial infection first must be cleared.
peripheral blood HIV-1 DNA levels, the phenotypic profiles of Clearance was beginning to occur by the final time point, post- CD4 and CD8 lymphocytes, and anti–HIV-1 antibody levels infection day 11. In an immunosuppression model, Field et al.
in patients treated for 52 weeks with antiretroviral therapy [3] tested ear and brain samples on intermittent days and still (combination of zidovudine, lamivudine, and indinovir). Ther- apy was begun during primary HIV-1 infection (PHI). Results Fourth, we claimed equivalence of both drugs in “terminat- were compared with results for HIV-1–uninfected subjects, un- treated patients with PHI, and patients with established HIV- chain reaction (PCR) kit. However, according to the manufac- 1 infection. The data reported raise several questions.
turer, “the Amplicor HIV-1 Monitor test is not intended to be First, by week 8 a similar decrease in peripheral blood HIV used as a screening test for HIV or as a diagnostic test to DNA levels was observed in both treated and untreated pa- confirm the presence of HIV infection” (Roche Diagnostic Sys- tients. What was the reason for the decrease in untreated pa- tems, [Branchburg, NJ], 06/96, 13-08088-001). Researchers at tients, and why was there no difference in the decreases in the the University of Massachusetts School of Medicine found that “plasma viral load tests were neither developed nor evaluated Second, reverse-transcriptase inhibitors prevent reverse tran- for the diagnosis of HIV infection. . . . Their performance in pa- scription (RT) of HIV RNA into HIV DNA, whereas protease tients who are not infected with HIV is unknown,” and their inhibitors render newly produced virions noninfectious. Fur- use leads to “misdiagnosis of HIV infection” [4, p. 37]. One thermore, according to the most recent model of HIV-1 patho- British virologist noted, “Those laboratories which undertake genesis reported by Ho et al. [2] and Wei et al. [3], productively HIV screening and confirmation assays understand fully the infected lymphocytes have a half-life of ∼1.6 days. However, technical problems associated with PCR and other amplifica- Zaunders et al. [1] found continued expression of viral antigens.
tion assays and it is precisely for those reasons that PCR is In this case, one would expect the HIV DNA to increase or at NOT used as a confirmatory assay (as discussions with any least to remain stable in the untreated patients with PHI and competent virologist would have informed them)” [5, p. 38].
to decrease rapidly in treated patients. What is the explanation Thus, if it is possible that Zaunders et al. did not detect HIV for their findings that treatment “had little direct effect on HIV- RNA, could this explain the lack of correlation between HIV 1 DNA burden” [1, p. 326] and that “no significant difference in the number of copies per microgram of PBMC [peripheralblood mononuclear cells] DNA was observed between treated Eleni Papadopulos-Eleopulos,1 Valendar F. Turner,2
and untreated PHI patients at baseline or at weeks 8, 24, or John M. Papadimitriou,3 Helman Alfonso,4
Barry Page,1 and David Causer1
Third, the antiretroviral drugs used by Zaunders et al. affect Departments of 1Medical Physics and 2Emergency Medicine, Royal Perth Hospital, and 3Department of Pathology, University of Western neither transcription of proviral DNA nor translation of HIV Australia, Perth, Australia; 4Department of Research, Universidad RNA into proteins (i.e., expression of viral RNA and proteins).
Metropolitana, Barranquilla, Colombia In other words, they decrease HIV RNA indirectly by decreas-ing HIV-1 DNA viral burden. How then did treatment lead to References
a decline of HIV RNA from 6.0 log copies/mL at baseline to 0 copies/mL after week 36 while having “little” effect on HIV- 1. Zaunders JJ, Cunningham PH, Kelleher AD, et al. Potent antiretroviral ther- apy of primary human immunodeficiency virus type 1 (HIV-1) infection: Fourth, when discussing their findings with regard to the partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia. J Infect Dis 1999; 180:
phenotypic profiles of the CD8 lymphocytes, Zaunders et al.
wrote, “The persistence of HIV-1 DNA together with increased 2. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M.
CD8 T lymphocyte turnover and activation indicate continued Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.
expression of viral antigens [1, p. 320].” How is it possible to Nature 1995; 373:123–6.
have continuous expression of HIV proteins in the absence of 3. Wei X, Ghosh SK, Taylor M, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373:117–22.
4. Rich JD, Merriman NA, Mylonakis E, et al. Misdiagnosis of HIV infection Fifth, if there was continuous expression of viral antigens, by HIV-1 plasma viral load testing: a case series. Ann Intern Med 1999;
why did only 2 patients treated with highly active antiretroviral therapy (HAART) develop “typical antibody responses to HIV- 5. Chrystie IL. Screening of pregnant women: the case against. Practising Mid- 1, as determined by serial Western blots” [1, p. 325]? Was there, wife 1999; 2:38–9.
at any stage of the study, a difference between the Western blot Reprints or correspondence: Dr. Eleni Papadopulos-Eleopulos, Dept. of Med- profiles of HAART-treated and -untreated patients with PHI? ical Physics, Royal Perth Hospital, Wellington St., Perth, Western Australia 6001, Sixth, given that the aim of the study was to compare treat- Australia ([email protected]).
ment between patients with PHI and “HIV-1–uninfected sub- The Journal of Infectious Diseases
2000; 181:1518–19
᭧ 2000 by the Infectious Diseases Society of America. All rights reserved.
jects, untreated PHI patients, and patients with established HIV-1 infection, [1, p. 320]” why, with the exception of thelymphocyte profiles, were no data presented on the HIV-1–un-infected subjects and the patients with established HIV-1 Finally, for the measurement of the HIV RNA, Zaunders et To the Editor—Our results [1] showed that, although there was
al. [1] used the Roche Amplicor quantitative RT polymerase a 4–5 log decrease in plasma human immunodeficiency virus (HIV) type 1 RNA concentrations after the start of treatment upper limit of quantitation of the assay, which was the case for primary HIV-1 infection (PHI), there was a !1 log effect with all initial specimens assayed in our study. It therefore is on the level of cell-associated HIV-1 DNA. The fall in HIV-1 highly unlikely that the HIV-1 RNA results obtained are due DNA was not significantly different from that in untreated patients. Further experiments are required in order to investi-gate the dynamics of production and turnover of cells con- John J. Zaunders,1 Philip H. Cunningham,1
taining HIV-1 DNA in vivo before we can understand why the Gilbert R. Kaufmann,3 and David A. Cooper1–3
regimen used had little effect on this reservoir.
1Centre for Immunology and 2HIV Medicine Unit, St. Vincent’s The probable reason for maintenance of the level of cell- Hospital, and 3National Centre in HIV Epidemiology and Clinical associated HIV-1 DNA, despite large decreases in plasma HIV- Research, University of New South Wales, Darlinghurst, Australia 1 RNA, is the generation of a large pool of long-lived, restingCD4 T lymphocytes containing integrated HIV-1 DNA at thevery early stages of PHI [2]. The decay rate of this reservoir References
appears to be extremely slow, despite highly active antiretroviral 1. Zaunders JJ, Cunningham PH, Kelleher AD, et al. Potent antiretroviral ther- apy of primary human immunodeficiency virus type 1 (HIV-1) infection: Furthermore, activation of these latently infected cells leads partial normalization of T lymphocyte subsets and limited reduction of to production of viral proteins [3–5]. Therefore, it is entirely HIV-1 DNA despite clearance of plasma viremia. J Infect Dis 1999; 180:
feasible for low-level synthesis and presentation of viral anti- 2. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early estab- gens to occur, despite the presence of inhibitors of viral reverse lishment of a pool of latently infected, resting CD4(ϩ) T cells during transcriptase and protease. Also, the reduction of plasma HIV- primary HIV-1 infection. Proc Natl Acad Sci USA 1998; 95:8869–73.
1 RNA in the patients studied was not absolute; very low-level 3. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for signals were observed in some samples from some patients but HIV-1 in patients on highly active antiretroviral therapy. Science 1997;
remained below the 50 copies/mL sensitivity of the polymerase 4. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-com- chain reaction (PCR). Others have shown that, when such low- petent HIV despite prolonged suppression of plasma viremia. Science level RNA is present in the plasma, RNA can be detected in 1997; 278:1291–5.
lymphoid tissue [6]. Retention of p24 in lymph nodes has been 5. Chun TW, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent shown after HAART, even when RNA has been eliminated [7].
reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997; 94:13193–7.
The reduction of antibody levels in some patients as a result 6. Gunthard HF, Wong JK, Ignacio CC, et al. Human immunodeficiency virus of HAART has also been reported in other studies [8–10]. The replication and genotypic resistance in blood and lymph nodes after a reason for the fall in antibody concentrations is unknown but year of potent antiretroviral therapy. J Virol 1998; 72:2422–8.
could be related to the lack of HIV-1–specific CD4 T lympho- 7. Tenner-Racz K, Stellbrink HJ, van Lunzen J, et al. The unenlarged lymph nodes of HIV-1–infected, asymptomatic patients with high CD4 T cell cytes needed to generate a normal immune response, or it may counts are sites for virus replication and CD4 T cell proliferation. The simply result from a decrease in the concentration of viral an- impact of highly active antiretroviral therapy. J Exp Med 1998; 187:
tigens. A similar decrease in antigen-specific CD8 T lympho- cytes is also observed after the start of HAART [11]. We did 8. Lafeuillade A, Poggi C, Tamalet C, Profizi N, Tourres C, Costes O. Effects not show our results for Western blot analysis and p24 antibody of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis 1997; 175:
concentrations for untreated patients with PHI, because the development of reactivity is widely reported in the literature 9. Markowitz M, Vesanen M, Tenner-Racz K, et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency The measurement of HIV-1 RNA was applied to samples virus type 1 infection on viral replication and antiviral immune responses.
from patients who had been diagnosed as having HIV-1 infec- J Infect Dis 1999; 179:527–37.
10. Morris L, Binley JM, Clas BA, et al. HIV-1 antigen–specific and –nonspecific tion on the basis of longitudinal, repeatedly reactive, licensed B cell responses are sensitive to combination antiretroviral therapy. J Exp HIV-1 antibody tests and immunoblot reactivity typical of early Med 1998; 188:233–45.
seroconversion events. In the absence of HIV antibody reac- 11. Ogg GS, Jin X, Bonhoeffer S, et al. Decay kinetics of human immunodefi- tivity, subjects were enrolled on the basis of reactivity deter- ciency virus–specific effector cytotoxic T lymphocytes after combination mined by use of an EIA for HIV-1 p24 antigen, confirmed by antiretroviral therapy. J Virol 1999; 73:797–800.
12. Tindall B, Cooper DA. Primary HIV infection: host responses and interven- neutralization, and a licensed qualitative HIV-1 DNA PCR, tion strategies. AIDS 1991; 5:1–14.
together with clinical assessment of exposure and symptoms.
In each case, subsequent specimens were obtained and assessedfor the further development of virus-specific antibodies.
Reprints or correspondence: Dr. John Zaunders, Centre for Immunology, St. Vincent’s Hospital, Victoria St., Darlinghurst, NSW 2010, Australia HIV-1 RNA is never used as a screening test. Reported false- positive RNA test results for HIV-seronegative persons are gen- The Journal of Infectious Diseases
2000; 181:1519–20
erally at a low level and rarely 11000 copies/mL. HIV RNA ᭧ 2000 by the Infectious Diseases Society of America. All rights reserved.
measurements observed during PHI, however, often exceed the

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