Valacyclovir May Reduce HIV Viral Load Even in People Without Herpes

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The antiviral drug valacyclovir (Valtrex and generics), used to treat herpes simplex virus type 2 (HSV), led to a decrease in HIV viral load even among individuals who did not have genital herpes, according to a small study reported in the March 3 advance edition of Clinical Infectious Diseases.

Prior studies have found that treating herpes with acyclovir or its pro-drug valacyclovir is associated with a reduction in HIV viral load, though not in the risk of HIV transmission. Experts have suggested this may be due to HSV infection increasing inflammation and accumulation of immune cells vulnerable to HIV.

Now, however, Christophe Vanpouille and Leonid Margolis from theNational Institute of Child Health and Human Development and colleagues have shown that the reduction in HIV viral load occurs even in people who are not coinfected with HSV-2, the virus that typically causes genital herpes.

In this study 18 HIV-positive but HSV-2-negative participants were randomly assigned to receive 500 mg twice-daily acyclovir for 12 weeks followed by placebo for 12 weeks, or else placebo and acyclovir in the reverse order. The researchers found that HIV viral load fell by an average of 0.37 log during valacyclovir treatment.

"These data indicate that the effects of valacyclovir on HIV-1 replication are not related to the suppression of HSV-2-mediated inflammation and are consistent with a direct effect of acyclovir on HIV-1 replication," they concluded.

Below is an edited excerpt from a National Institutes of Health press release describing the study and its findings in more detail.

Anti-herpes Drug May Help Control HIV, NIH Study Finds

Valacyclovir, a drug commonly used to control the virus that causes genital herpes, appears to reduce the levels of HIV in patients who do not have genital herpes, according to a study by researchers from the National Institutes of Health, Case Western Reserve University, Cleveland, Emory University, Atlanta and Lima, Peru.  

The study of 18 patients is the first to show that the drug does not require the presence of herpes simplex virus 2 (HSV-2) to suppress HIV in patients. The researchers hope to confirm their results in a larger study.

"These findings are very encouraging," said senior author Leonid Margolis, PhD, head of the Section on Intercellular Interactions at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). "If valacyclovir’s effectiveness against HIV can be confirmed in a larger cohort, it could be added to the mix of drugs used to suppress the virus, and might prove especially helpful in cases in which HIV has developed resistance to other drugs."

The study, published online today in Clinical Infectious Diseases, was supported by NIH’s Bench to Bedside Program, which funds research teams seeking to translate basic scientific findings into medical practice. The first authors of this paper are Christophe Vanpouille and Andrea Lisco, both with NICHD. Other authors are Michael Lederman (senior author) and Benigno Rodriguez of Case Western Reserve University and Case Medical Center and Hospitals; Leda Bassit, Robert Kauffman, and Raymond F. Schinazi (senior author), Emory University School of Medicine and Veterans Administration Medical Center in Atlanta; and Jorge Sanchez, of The Civic Association for Health and Education in Lima. 

These results follow a 2008 study by the same research team, which showed that acyclovir suppresses HIV in laboratory cultures of human tissues that were infected with various kinds of herpes viruses. Valacyclovir is referred to as a prodrug for acyclovir because it’s structurally similar to acyclovir, and is converted to acyclovir in the body. For the current study, the researchers used valacyclovir because it remains in the blood longer than acyclovir and so would not need to be taken as often.

Earlier studies have shown that acyclovir reduces HIV levels in patients coinfected with HIV and HSV-2, the virus that causes genital herpes. However, this effect has been attributed to the drug’s anti-HSV-2 activity. The decrease in immune activity results in fewer active immune cells for HIV to infect. 

In contrast, the laboratory results of the research team indicated that the drug likely reduced HIV levels by interfering directly with HIV’s reproductive machinery and did not require the presence of HSV-2. HSV-2 chemically alters acyclovir, by attaching chemical groups known as phosphates to it. It is this altered form of the drug that suppresses HSV-2. The researchers believe this form also interferes with HIV’s ability to reproduce. In their earlier study, the researchers found that many other kinds of herpes viruses can also attach phosphate groups to acyclovir. Dr. Margolis noted that these other herpes viruses are widespread and that most people harbor at least one of them.

"We wanted to find out whether such a mechanism could operate in the cells of patients with HIV," Dr. Margolis said.

The researchers enrolled 18 HIV-infected patients in their study, none of whom were infected with HSV-2, and treated them with valacyclovir. For 12 weeks, half of the enrolled patients took valacyclovir twice a day while the other half received a placebo. After two weeks, the placebo group received valacyclovir while the group originally treated with the drug switched to the placebo.

The researchers found that when the patients took valacyclovir, their blood HIV levels declined significantly. Typically, HIV patients take a cocktail of several anti-HIV drugs because a single drug is not enough to suppress the virus. Multiple HIV medications also hinder the virus’ ability to develop resistance to the drugs. 

The researchers conducted a genetic analysis and found that the HIV in the study volunteers did not develop resistance to valacyclovir. But because HIV has a history of becoming resistant to the drugs used to treat it, the researchers do not discount the possibility that the virus could develop resistance to valacyclovir with longer treatment. Given the ability of the drug to lower HIV levels, however, the researchers believe that valacyclovir could one day be added to the cocktail of drugs given to HIV-infected people.

"Larger randomized trials and cost effectiveness analyses could be warranted to further explore the potential of [valacyclovir] in the context of HIV-1 infection, in particular in combination with other antivirals," the study authors wrote.

3/25/15

Reference

C Vanpouille, A Lisco, J-C Grivel, L Margolis, et al. Valacyclovir Decreases Plasma HIV-1 RNA in HSV-2 Seronegative Individuals: A Randomized Placebo-Controlled Crossover Trial. Clinical Infectious Diseases. March 3, 2015 (Epub ahead of print).

Other Sources

National Institutes of Health. Anti-herpes Drug May Help Control HIV, NIH Study Finds. Press release. March 13, 2015.

Case Western Reserve University. Common Herpes Medication Reduces HIV-1 Levels, Independent of Herpes Infection. Press release. March 13, 2015.