Acyclovir for retrovirus

http://news.bbc.co.uk/1/hi/health/8512412.stm

"A common treatment for herpes can delay the need for HIV drugs in people with both infections, say US researchers.

A study of 3,300 patients in Africa found aciclovir reduced the risk of HIV progression by 16%, The Lancet reports.

Although a "modest" effect, the researchers said the cheap treatment is a simple way of keeping people with HIV healthy for longer. "

While no-one is suggesting anything about "other" retroviruses it makes you think, doesn't it:sofa:

OTH

And here's the Summary from the Lancet

The Lancet, Early Online Publication, 15 February 2010doi:10.1016/S0140-6736(09)62038-9Cite or Link Using DOI

Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial


Original TextDr Jairam R Lingappa MD a b c , Jared M Baeten MD a b, Anna Wald MD b d f g, James P Hughes PhD e, Katherine K Thomas MS b, Andrew Mujugira MBChB a, Nelly Mugo MBChB a h, Elizabeth A Bukusi MBChB a h i, Craig R Cohen MD j, Elly Katabira MBChB k, Allan Ronald MD l, James Kiarie MBChB h, Carey Farquhar MD b d, Grace John Stewart MD b d, Joseph Makhema MBChB m, Myron Essex DVM n, Edwin Were MBChB o, Kenneth H Fife MD p, Guy de Bruyn MBBCh q, Glenda E Gray MBBCh q, James A McIntyre FRCOG q, Rachel Manongi MD s, Saidi Kapiga MD t, David Coetzee MBBCh u, Susan Allen MD v w, Mubiana Inambao MBChB v w, Kayitesi Kayitenkore MD v w, Etienne Karita MD v w, William Kanweka MD v w, Sinead Delany MD r, Helen Rees MBBChir r, Bellington Vwalika MD v w, Amalia S Magaret PhD f g, Richard S Wang MS a, Lara Kidoguchi MPH a, Linda Barnes MHA a, Renee Ridzon MD x, Lawrence Corey MD b f g, Connie Celum MD a b d, for the Partners in Prevention HSV/HIV Transmission Study Team

Summary

Background
Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of aciclovir on HIV-1 progression.

Methods
In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to aciclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per μL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per μL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per μL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.

Findings
At enrolment, the median CD4 cell count was 462 cells per μL and median HIV-1 plasma RNA was 41 log10 copies per μL. Aciclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned aciclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 084, 95% CI 071098, p=003). In those with CD4 counts ≥350 cells per μL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per μL by 19% (081, 071093, p=0002)

Interpretation
The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.

Funding
Bill & Melinda Gates Foundation.

I think a lot of us are wondeirng if it is worth tackling co-infections assuming we are also carrying a retrovirus, while we wait for the whole retrovirus thing to shake out.

Shame it's only a moderate improvement.

Go Bill, Go Melinda.

There's been other multiple studies that demonstrated that acyclovir reduced viral load of HIV in people co-infected with HIV and herpes simplex.

aquariusgirl, I think it might be better to try to tackle all the infections at once. I am worried that trying to tackle EBV, for example, while waiting for XMRV treatment might draw out the process and cause drug resistance. I posted a thread in the Antiviral section a few days ago showing that people with HIV develop resistant strains of herpes simplex about 10 fold the rate of healthy people (5% versus 0.5%). But it is hard to wait when several people have reported such positive outcomes from valtrex/valcyte. I am very tempted to try these myself. But just as many people have reported negative experiences with these drugs.

yeah, but I assumed that a lot of those folks who didn't respond to valtrex or valcyte were non responders because their immune system didn't work... because they had impaired methylation cycles, non existent natural killer cell activity ..etc...

I mean antivirals only prevent replication as I understand it, right? they don't kill the virus. Your immune system has to do that.

And when I first tested natural killer cell activity, it was 5 on a scale of 8-170. In a scenario like that, you ain't gonna get much bang for your buck with the drugs. It's better after 3 years on methylation, although I really need to run a more comprehensive immune panel.

But otoh, even if my immune system was in fighting shape, I worry about the retrovirus stirring up the other viruses and I don't want to go thru drug treatment twice.

That's assuming I even have XMRV, of course.

Good points, I don't have much of a response because my thinking is the same as yours. It seems like a guessing game at this point. Personally, I am trying a bunch of immune modulators right now, they are all supposed to help NK cell activity, maybe after a few months my immune system will be functioning enough where Acyclovir/Valtrex might make a positive impact. It is hard just to wait and do nothing.

sorry no time to link to these but should be easy to google:

The antiherpetic drug acyclovir inhibits HIV replication and selects the V75I reverse transcriptase multidrug resistance mutation McMahon MA, et al J Biol Chem. 2008 Nov 14;283(46):31289-93. Epub 2008 Sep 24.

Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues Lisco A et al, Cell Host Microbe. 2008 Sep 11;4(3):260-70.

Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. Baeten JM,et al J Infect Dis. 2008 Dec 15;198(12):1804-8.

Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. Zuckerman RA, et al J Infect Dis. 2007 Nov 15;196(10):1500-8. Epub 2007 Oct 31.

The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. Corey L et al J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):435-45.

Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. Schacker T, J Infect Dis. 2002 Dec 15;186(12):1718-25. Epub 2002 Nov 22.

Herpes simplex virus downregulates secretory leukocyte protease inhibitor: a novel immune evasion mechanism. Fakioglu E, J Virol. 2008 Oct;82(19):9337-44. Epub 2008 Jul 30.

(from http://autismcalciumchannelopathy.com/HIV_and_Autism.html see bottom of page for other references on retrovirus inhibition by various agents)

Acyclovir is activated into a reverse transcriptase inhibitor in infected tissue

could someone dig out a full version and comment? thanks in advace :Retro smile:


The antiherpetic drug acyclovir inhibits HIV replication and selects the V75I reverse transcriptase multidrug resistance mutation McMahon MA, et al J Biol Chem. 2008 Nov 14;283(46):31289-93. Epub 2008 Sep 24.

Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues Lisco A et al, Cell Host Microbe. 2008 Sep 11;4(3):260-70.

Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. Baeten JM,et al J Infect Dis. 2008 Dec 15;198(12):1804-8.

Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. Zuckerman RA, et al J Infect Dis. 2007 Nov 15;196(10):1500-8. Epub 2007 Oct 31.

The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. Corey L et al J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):435-45.

Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. Schacker T, J Infect Dis. 2002 Dec 15;186(12):1718-25. Epub 2002 Nov 22.

Herpes simplex virus downregulates secretory leukocyte protease inhibitor: a novel immune evasion mechanism. Fakioglu E, J Virol. 2008 Oct;82(19):9337-44. Epub 2008 Jul 30.

thank you for the links nastasa. I will check them out.

cfs since 1998: Yes. Exactly. A guessing game with very high stakes, because I assume my viral load carries some risk of cancer with it.

In fact, when I had a chat with an oncologist a couple of years ago and told him my NK cell numbers, he told me to go out and get checked for every cancer I could. He said not to bother with a full body CT scan though... too many false negatives.

Hmmmm I've tried acyclovir for a month, can't say it helped me. Maybe because the integration is so slow with xmrv?

Looking for something else on Pubmed, I came across this. Natasa posted the link earlier, but have we understood the full implications of this?

It's saying that acyclovir (similar to Valtrex) can make HIV mutate into a form that's resistant to standard HIV drugs.

Are there dangers in trying acyclovir or Valtrex if we have XMRV?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581555/?report=abstract

J Biol Chem. 2008 November 14; 283(46): 3128931293.
doi: 10.1074/jbc.C800188200. PMCID: PMC2581555

Copyright 2008, The American Society for Biochemistry and Molecular Biology, Inc.
The Antiherpetic Drug Acyclovir Inhibits HIV Replication and Selects the V75I Reverse Transcriptase Multidrug Resistance Mutation*
Moira A. McMahon, Janet D. Siliciano, Jun Lai, Jun O. Liu, James T. Stivers, Robert F. Siliciano, and Rahul M. Kohli1
Department of Pharmacology and Molecular Sciences and the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore Maryland 21205 and the Howard Hughes Medical Institute, Baltimore Maryland 21205
1 To whom correspondence should be addressed: Division of Infectious Diseases, Dept. of Medicine, Johns Hopkins University School of Medicine, 1830 Monument St., Baltimore MD 21205. Tel.: 410-614-9644; Fax: 410-955-3023; E-mail: rkohli2@jhmi.edu.
Received September 19, 2008
This article has been cited by other articles in PMC.
Abstract
The antiviral drug acyclovir is a guanosine nucleoside analog that potently inhibits herpes simplex virus (HSV) replication. Acyclovir treatment in patients coinfected with HSV and human immunodeficiency virus (HIV) has been observed to alter disease course and decrease HIV viral load, a finding that has been attributed to indirect effects of HSV suppression on HIV replication. Based on this hypothesis, several clinical studies have recently investigated the use of acyclovir for treatment of patients coinfected with HSV and HIV or for prophylaxis against HIV transmission. In this report, we use a single round HIV infectivity assay to show that acyclovir directly inhibits HIV infection with an IC50 of ~5 μm. The target of acyclovir in HIV-infected cells is validated as HIV reverse transcriptase (RT) by the emergence of the RT variant V75I under the selective pressure of acyclovir. The V75I mutation is part of the multidrug resistance pathway that enhances viral resistance to many of the best RT inhibitors approved for the treatment of HIV. Biochemical analyses demonstrate that acyclovir triphosphate is a chain terminator substrate for HIV RT and can compete with dGTP for incorporation into DNA. Although acyclovir may prove a useful lead for development of new HIV treatments, the selection of resistant mutants raises a cautionary note to the use of acyclovir monotherapy in patients coinfected with HSV and HIV.

Jenny

Jenny
that study you posted is concerning me. I just found out xmrv+ today so researching but was trying to pulse valtrex recently, low dose every other day because mcs, didnt get far as got interrupted after 10 days by root canal but now am run down either from dental or going off valtrex or both and in quandry what to do, esp since root canals aint good w/cfs either so its all confused my experiment to know what is increasing my o2 hunger etc now

and aquarius girl re:

"In fact, when I had a chat with an oncologist a couple of years ago and told him my NK cell numbers, he told me to go out and get checked for every cancer I could. He said not to bother with a full body CT scan though... too many false negatives"

my nkcell: nkc9 lytic unit 3 n 8-170 in jan. '09
so mine was a 3, that freaks me what the oncologist said to you. my pc didnt make any suggestions like that he is too busy, just rec'd glutamine for gut! i cant even tolerate that.
I get concerned could get barrets esophagus cus of swallow problems and things get stuck in throat and gerd.

oh, also, i just posted this somewhere else too, my cfs immune panel w/nkcell info in early 09 that was after 6months of LDN trial. my interleukins were actually normal, maybe the LDN? dont know what it means as my NKcells and elastase rnase and Igg were abnormal.

wow. i took valtrex for 3 years! maybe thats why the HIV drugs arent really working well for me.

my NK cell function was very very low too.

daffodil i dont recall your current protocol, do you have it listed somewhere, and yr xmrv+ too?
I am going to try to segue away from the valtrex til know more. it did help in some ways but increased pain too. wonder if it could already be causing rebound viral flare after such a short time of trying it.

Oh dear.
I've been taking acyclovir continuously for several years because I got frequent, more severe herpes attacks after coming down wth ME. Well if my hypothetical (hopeful) XMRV was going to go drug resistant, I guess it would have done so by now.

OTH