The Downside of Daily Antiviral Therapy

Gold, et al. (1988)--Fig 1 to Table 1

I recently had an exchange with someone who queried me on the blog.  Upon reflection, I thought that this was an exchange that should be front and center because it touches upon an important issue.

Although >90% of doctors in the USA would be inclined to put their herpes patients on prophylactic (daily) valtrex, famvir, or acyclovir for life to “keep their herpes symptoms under control,” the ugly truth for me (having some understanding of how the biological system behaves) is that daily antivirals should tend to undercut an infected person’s immunity to the virus hence (1) making them dependent on the antivirals for any type of control and (2) setting them up for a lifetime of higher-than-average symptoms when their antibody response to HSV-1 or HSV-2 crashes after 6 months of daily antiviral treatment.

The exchange is below.  The relevant Figure 1 from Gold, et al (1988) is shown above along with Table 1 which conveys that the data shown in the Figure is representative of what happens in most patients.  For me, these data highlight the need for an effective therapeutic HSV-2 vaccine.

  • Bill H.

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Dr. Halford,

This has become the most useful resource I have for understanding how realistically we may one day eradicate herpes, and where to set expectations on therapies. Thank you for taking the time to write.

However, this came as quite a shock: “Prophylactic valtrex is bad medicine that weakens the immune response to HSV, and thus ensures a lifetime of dependence on the drug.” I want to be clear about what you mean as I take the prescribed daily 500mg to presumably suppress outbreaks (I have had none since taking it, but have had hsv for <1 year). Do you mean the therapeutic/daily use of the drug? Or are you referring to those who might think taking it will prevent acquiring hsv? Can you please elaborate? Obviously this would not be great news for the many of us who take valtrex on advice from our doctors.

I should note that from a laymen’s perspective the logic seems to make sense. If you suppress the virus, the immune system will take it “less seriously.” I have no idea if that has any basis in medicine. Thinking along those lines when I had my initial outbreak, I attempted to do some research to determine if taking Valtrex immediately after acquiring hsv may decrease your immune response in the long run. I found a few studies that seemed to indicate no difference but I’m interested in any insight you have on these matters.

  • Tom

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Hi Tom,

Please forgive my delayed response to this important question. First off, please allow me to point you to the raw data. The relevant studies of which I am aware were both published in 1988 and should have been a red flag to everyone that prophylactic antiviral drugs were problematic. The relevant studies are:

1. Gold D, Ashley R, Solberg G, Abbo H, Corey L. 1988. Chronic-dose acyclovir to suppress frequently recurring genital herpes simplex virus infection: effect on antibody response to herpes simplex virus type 2 proteins. J Infect Dis. 158:1227-34.    http://www.ncbi.nlm.nih.gov/pubmed/2848900
To Read Paper, click link below….
https://liveherpesvaccine.files.wordpress.com/2016/06/gold-et-al-1988.pdf)

2. Erlich KS, Hauer L, Mills J. 1988. Effects of long-term acyclovir chemosuppression on serum IgG antibody to herpes simplex virus. J Med Virol. 26:33-9.  http://www.ncbi.nlm.nih.gov/pubmed/3183633
To Read Paper, click link below….
https://liveherpesvaccine.files.wordpress.com/2016/06/erlich-et-al-1988.pdf).

What the study of Gold, et al (1988) convincingly showed was that patients who go on prophylactic acyclovir (and presumably valtrex or famvir) experience a significant decrease in their antibody response to HSV-2.  At the time, this should have raised concerns about whether or not the prophylactic drugs erode the body’s natural ability to combat HSV-2 infection.  In particular, if one reads the study of Gold, et al (1988), Figure 1 demonstrates that patients taking daily acyclovir for 6 or 12 months exhibit a marked decrease in their antibody response to HSV-2 proteins.  In contrast, patients taking a placebo for 6 or 12 months show a steady level of antibody to HSV-2, which remains constant over time because subclinical and/or symptomatic HSV-2 reactivation events keep the immune system engaged such that HSV-2-specific B cells remain stimulated to produce HSV-2-specific antibodies at a rate that is in balance with the natural decay rate of antibodies (i.e., half-life = 21 days).  The results are convincing, and are consistent with how the biological systems that are “persistent infections” generally behave.

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Recently, it has become more apparent that HSV-specific antibodies play a critical role in rapid immune control of HSV-1 and HSV-2 infections (Halford, et al, 2015; Royer, et al., 2016; Iijima and Iwasaki, 2016).

Halford WP, Geltz J, Messer RJ, Hasenkrug KJ.  2015.  Antibodies Are Required for Complete Vaccine-Induced Protection against Herpes Simplex Virus 2.  PLoS One. 2015 10:e0145228  http://www.ncbi.nlm.nih.gov/pubmed/26670699

Royer DJ, Gurung HR, Jinkins JK, Geltz JJ, Wu JL, Halford WP, Carr DJ.  2016.  A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity.  J Virol. 90:5514-29  http://www.ncbi.nlm.nih.gov/pubmed/27030264

Iijima and Iwasaki.  2016.  Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature. 533:552-6.  http://www.ncbi.nlm.nih.gov/pubmed/27225131

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Therefore, any prophylactic antiviral drug regimen that reduces the antibody response to HSV-1 or HSV-2 should make people’s immune systems less competent to control HSV infection, and thus increasingly vulnerable to more frequent outbreaks and/or nerve pain (caused by a non-protective immune response to subclinical HSV reactivation in the ganglia).

The study of Erlich, et al (1988) offers a parallel conclusion.  Therefore, it is possible that the most responsible way for patients to use valtrex or acyclovir is by episodically taking these drugs as needed to curb the duration of outbreaks so that their body’s immune system might learn to fight the virus better in the in-between times when they are not having full-blown outbreaks.

Against that background, Rational Vaccines (http://rationalvaccines.com/) is proposing that an effective therapeutic HSV-2 vaccine might completely eliminate the need for antiviral drugs such as valacyclovir, famvir, and acyclovir, which suffer from the serious limitations of (1) poor solubility / absorption from the intestines to the bloodstream (i.e., poor bioavailability) and (2) failure to meaningfully limit HSV shedding to the point where HSV transmission rates are curbed and decrease over time.  If these drugs actually worked well, then the herpes problem should have started dissipating in the year 2000.  That is, if antiviral drugs were highly effective at controlling HSV replication, then HSV shedding and transmission rates should have decreased precipitously when these drugs became widely available.   However, on all fronts, current antiviral drugs against HSV are marginally effective, and thus here we are in the year 2016 with over one million people per week continuing to be newly infected with HSV-1 or HSV-2.

A therapeutic HSV vaccine regimen that actually works for patients, combined with effective prophylactic HSV vaccines, represent real medicine that will be sufficient to end the silent herpes epidemic once and for all.

  • Bill H.

16 thoughts on “The Downside of Daily Antiviral Therapy

  1. Mike says:

    Thank you for your excellent work…its really a treat to have such an excellent resource, you do a great job.

    Quick question on this background data. To my eye, the immunoblots (which are really the lynchpin of the hypothesis that daily acyclovir can have deleterious effect on the immune response) are not very convincing. It appears that the placebo patient has a significantly higher basal immune response (at timepoint E). Can it really be said tha the decrease at t=12mos is due to the drug vs. this markedly different starting point?

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    • Herpes Vaccine Research says:

      Hi Mike,

      First, I would bear in mind that the analyses performed in these studies were performed on many individuals in each group……not just the two shown in the blot. Second, the absolute levels of antibody in the two individuals is largely irrelevant. The main point is that individuals infected with HSV-1 or HSV-2 tend to maintain a fairly constant level of antibody directed against a fairly constant subset of viral proteins over time. However, when individuals go on daily antiviral suppressive therapy, the overall antibody response in individuals tends to contract by 2- to 8-fold, which is not normal. Fast forward to 2016 (28 years later), I believe that there are now better tools to perform this type of study that are far more quantitative. However, bottom line, many experts have observed these types of results in humans and I have observed something similar in mice (http://www.ncbi.nlm.nih.gov/pubmed/9375008)…..so I do agree with the general conclusions offered by Gold, et al 1988 and Erlich, et al 1988.

      – Bill H.

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    • Herpes Vaccine Research says:

      Hi Richard,

      I am a researcher, not a medical professional. Hence, I am not comfortable getting down to the specifics of an antiviral dosing regimen. Happy to discuss scientific principles, but I have to draw the line somewhere and make it clear that I am not a physician or nurse practitioner.

      – Bill H.

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  2. Vil says:

    Hi, Firstly thank you for your research into this.
    Just wanting your advice after reading your view on anti viral meds.
    I was prescribed them to prevent out break. I was taken one every few days (forgetful).
    Anyways, didnt feel like it helped at all even though I only took every few days. Not really keen on going back on them as per your post.
    I am in severe pain from my weekly outbreaks. Also, the nerve pain is severe.
    Anything you would suggest to help with preventing outbreaks while i’m waiting for possible vaccine 😦

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    • Herpes Vaccine Research says:

      Hi Vil,

      Sorry to hear of your situation. If you want to see if the antivirals would help your pain, you would have to take them for 2 – 4 weeks and give them a chance to work. However, in speaking to herpes sufferers, it is my impression that while valtrex, famvir, and acyclovir may reduce the duration of surface outbreaks, it is unclear that these antiviral drugs help much with nerve pain. Numerous people have told me their nerve pain gets worse when they are on antiviral drugs despite the fact that the same antivirals shorten the duration of their surface symptoms and cut lesion healing time by 50%.

      I am hopeful a therapeutic HSV vaccine is forthcoming, and I am even more hopeful that it will dramatically reduce the severity of the daily herpes-associated neuralgia / nerve pain that some people have been living with for years. Happy to share more when the time is right.

      – Bill H.

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  3. LiveVaccinePlease says:

    Dr. Halford,
    I’ll start by parroting the majority here by saying we are incredibly appreciative of all the work you are doing to bring both a more effective antibody test and a viable HSV vaccine into the world. The fact that you’re willing to also entertain our questions and keep this blog up to date shows a quality as a human that most of us aren’t even seeing from the doctors we are paying to treat us.
    Prior to availability of a vaccine, what would your recommendation be for those of us in discordant relationships? The advice I’ve read from every expert I know of (i.e. Terri Warren, Anna Wald, Hunter Handsfield) seems to be that daily antivirals are the most reasonable way to reduce the risk of transmission in long term discordant couples. Given that it could be some time before something else is available I don’t really see how it would be reasonable to go off daily antivirals (and stay married, especially when trying to have kids). Short of abstinence until a vaccine is available is there an option I’m missing?
    By this same logic, wouldn’t people on HIV medication dial down their dose to keep the virus simmering and showing copies to the immune system? I thought that was a recipe for drug resistance?
    Anyway, thank you again for you insights, good luck with the vaccine efforts and ABVIC, and please keep the blog posts coming. Seeing the splash page for RVx made my day.

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    • Herpes Vaccine Research says:

      Hi Live Vaccine Please,

      Let me start by paraphrasing the key elements of your questions:

      1. Prior to availability of a vaccine, what would your recommendation be for those of us in discordant relationships? The advice I’ve read from every expert is that daily antivirals are the most reasonable way to reduce the risk of transmission in long term discordant couples.

      2. I don’t really see how it would be reasonable to go off daily antivirals. Is there some option I’m missing?

      3. By this same logic, wouldn’t people on HIV medication dial down their dose to keep the virus simmering and showing copies to the immune system? I thought that was a recipe for drug resistance?

      ———————-

      While antiviral drugs are effective for some people to control their herpes symptoms, this is not the case for everyone. Part of what I was calling out on my post on antiviral drugs is the myth believed by most MDs that anti-herpesviral drugs should be a uniform solution to controlling every patient’s symptoms. This is simply not the case. For many people, antiviral drugs such as acyclovir or valacyclovir are ineffective because they are not absorbed out of the intestines and into the bloodstream where they must reach to be delivered to the relevant virus-infected tissues in the body.

      The second element of my post is that if one considers the antibody response to HSV-2 as being relevant to how the body naturally controls the infection, then I think my general advice would be that episodic use of acyclovir or valayclovir (i.e., taken as needed) leaves open the possibility to keep the body’s immune system involved in holding HSV-2 down. Thus, the only practical advice I am offering is that in the case of recurrent herpes, episodic use of antivirals might make more sense.

      Against all of that background, I am not advocating that people who are happy taking antiviral drugs every day should change their ways. If it works for you, then do it. I was simply pointing out that the available evidence indicates that the daily consumption of antiviral drugs will, on average, weaken a person’s antibody response to HSV-2 such that the efficacy of the antiviral drugs may wane over time (because the positive effects of these antivirals requires that the host immune response clean up what the antivirals miss).

      Regarding the HIV analogy you offer, it is really apples versus oranges……one has nothing to do with the other. HSV-2 is rarely a fatal infection if left untreated with antivirals, whereas HIV infection is uniformly fatal if left untreated. Second, there are hundreds of anti-HIV drugs that inhibit HIV replication in at least 4 different ways (NRTIs, NNRTIs, protease inhibitors and integrase inhibitors). Combinations of these drugs knock down HIV levels in the bloodstream by >1,000-fold. In contrast, valtrex reduces HSV-2 shedding by 2-fold. Long story short: HIV antiviral drugs are essential to survive the infection and they actually work remarkably well. If antivirals against HSV were equally as effective, then the herpes problem would have started declining decades ago when the antivirals were deployed. However, anti-herpesviral drugs are only marginally effective and thus are not nearly as effective as anti-HIV antiviral drugs.

      Anyway, I am not telling the world to abandon valacyclovir, famciclovir, or acyclovir. Rather, what I am saying is that these drugs that were developed in the 1970s are only marginally effective. In the absence of a better option, taking valtrex as needed or daily may be your best option. However, I hope that we can all agree that we can do much better and should not settle for the half-measure of acyclovir-based antivirals. I hope that Rational Vaccines can make therapeutic HSV-1 and HSV-2 vaccines available sooner rather than later.

      – Bill H.

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  4. Jim says:

    Dear Dr. Halford

    Please could I ask if there is a difference between reduced immunity as a consequence of taking acyclovir as your information suggests and the concept of viral resistance? I often see discussion of viral resistance in various articles and I believe they refer to acyclovir involvement in this. However, the article http://jid.oxfordjournals.org/content/169/6/1338.short which I don’t fully understand, suggests “…showed no trend toward development of resistance” and so my question would be, is viral resistance a different concept to that which you are raised and therefore a different problem altogether? Thank you.

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    • Lissy says:

      Thanks for this article Dr. Halford, as you know I felt that had I never taken it, I’d never developed that neuropathy.

      Do you think it’s possible for the immune system to ever bounce back and respond appropriately upon quitting antivirals or those of this w this issue, stuck w the consequences of taking antivirals?

      I started doing the newer UBI treatment once a week w a vitamin C bag and a shot of all Bs w supporting supplements and have seen massive improvement. I for the first time in almost two years,i don’t have some sort of irritation, itching, bumps or an OB of some kind persisting daily. One can only assume that this has helped my immune system and I’ll continue using this until I can hopefully one day get your vaccine, as it’s not cheap to do this weekly and UBI is not covered by insurance. They claim is has almost like a therapeutic vaccine effect, not sure just how accurate that assessment is.

      Hope all is well and take care.

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  5. tvguy123 says:

    Question in regards to this. Hypothetically speaking, if someone was to be on suppression therapy for 6-12 months and had just got off to receive your live attenuated vaccine, could that potentially pose a problem considering the now weakened immune system? Would it be wise to wait months/years to build some immunity before being vaccinated with a live virus?

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  6. Angie says:

    Hello Dr. Halford,

    Question concerning this. If you had the virus for a few years (say 4-7 years) and was not on any antivirals during that time, would it be safe to assume the body has created the most antibodies it’s ever probably going to make for this virus until an effective vaccine can help?. If so, would it be less risky to be on the antivirals without a huge fear of the negative consequences you mentioned?

    Thank you for your dedication to finding a way to defeat this virus which is now infecting so many people to the point it should be classified an epidemic. You are a great person for taking this on and I hope you have total success! I will continue to follow and try to support as much as I can. Thank you again!

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    • Herpes Vaccine Research says:

      Hi Angie,

      If you have been coping fine for 4 – 7 years without antiviral drugs, then I would not rock the boat and keep doing what works. If for some reason you felt like your outbreaks were getting worse, then you could use antiviral drugs at the start of an outbreak to keep the duration as short as possible. All I was saying in my post is that daily antiviral drugs for months to years at a time has a potential downside that is not widely appreciated by the MDs who write the prescriptions. Episodic antiviral drugs taken as needed do not pose the same problem.

      – Bill H.

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  7. TVEC says:

    Hi Bill,

    I’m wondering, say I took daily antivirals for 6 months and my antibody levels dropped as you describe above. If I stopped taking the antivirals at 6 months, would you expect the antibody levels to bounce back after a certain period of time?

    Also, if the effect of antivirals on antibody levels was strong, then wouldn’t there be many cases of patients stopping daily antiviral therapy and subsequently experiencing severe/frequent outbreaks? Is this something that is seen in the clinic?

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  8. Jim says:

    I can concur with this, that after past suppressive treatment with acyclovir for a period of approximately one year, which I used primarily to reduce post-herpetic neuralgia from GHSV1, rather than outbreaks, the subsequent viral activity which began shortly after terminating that treatment, was extremely severe, almost to the point of becoming systemic and caused me to need to recommence suppression again. The viral activity which ensued, had a much greater effect on various other areas, such as combinations of paraesthesia and numbness in the fingers, feet, forehead, knees and pressure in the abdomen.

    Subsequent to this episode, I used valacyclovir instead, since it enabled me far better control of PHN symptoms and again – every time I made an attempt to withdraw from valacyclovir, viral activity began within a 24 to 48-hour period. I regarded this as being indicative that my own immunity had been weakened by suppressive treatment.

    I’m not sure if the articles clarify however, if one is able to rebuild that lost immunity, if managing to avoid taking anti-virals. Additionally, I wonder if alternative natural anti-virals would have this similar detrimental effect as does the acyclovir family of medications, such as constant use of L-Lysine and others. This I find an interesting question.

    I have been treating myself with acyclovir, valacyclovir and various natural methods since 2011, since here in Thailand it is difficult to find knowledgeable and well-informed medical professionals in this area. We all welcome the work you are doing and the approach you are taking, Dr. Halford. Many of us are extremely supportive of your efforts. Jim

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  9. markL says:

    I know about the rapid saliva test strip for HIV. No matter what direction the doctors go, daily or outbreak, wouldnt there be strong market incentive for a shedding test strip? To me that seems like something so many would want to know for a certainty when in prodrome shedding..

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