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Valtrex For Reducing Transmission of Genital Herpes- FDA Hearing: FDA panel votes 11-0 to recommend approval
Written by Jules Levin
  Yesterday May 14 at the irrepressible Holiday Inn in historic (3 strip store malls & a Holiday Inn) Gaithersburg, Maryland the FDA Anitiviral Drug Advisory Committee met for the second time in two days, this time to consider approval of GlaxoSmithKline's Valtrex (aka Valcyclovir) for use "to reduce the risk of transmission of genital herpes with the use of suppressive therapy and safer sex practices at the dose of 500 mg once daily". The Committee voted 11-0 unanimously to recommend approval to the FDA.
GSK conducted an 8 month international study for this approval and the study showed that using 500 mg of Valtrex once daily resulted in a 75% reduction in transmission of symptomatic genital herpes infection, and also showed a 48% reduction in the acquisition asymptomatic acquisition of herpes-2 documented by HSV-2 seroconversion during the study. 4 of 743 (0.5%) study participants who received Valcyclovir (Valtrex) developed symptomatic HSV-2 acquisition compared to 16 of 741 (2.2%) study participants who received placebo in the study (p-value: 0.007). This is a 75% reduction. Acquisition of asymptomatic HSV-2 occurred in 14 of 743 (1.9%) persons receiving Valtrex 500 mg once daily compared to 27 of 741 (3.6%) persons receiving placebo who acquired asymptomatic HSV-2 (p-value: 0.038). This is a reduction of 48%.
Men were less likely in the study to develop symptomatic genital herpes: 4.1% of females receiving placebo vs 1.2% of men; 0.8% of females receiving Valtrex vs 0.4% of men receiving Valtrex. Having HSV-1 may provide a protective effect from developing symptomatic genital herpes. For study participants receiving placebo having HSV-1 did not reduce the risk for transmission, 2.2% of persons who were HSV-1 negative vs 2.1% of persons who were HSV-1 positive developed symptomatic genital herpes. But for persons receiving Valtrex 0.9% of persons who were HSV-1 negative developed symptomatic genital herpes compared to 0.4% of persons who were HSV-1 positive.
Additionally, 47% of persons infected with HSV-2 had no recurrences during the 8 month study compared to only 13% of study participants who received placebo in the study.
Viral shedding was also reduced by persons taking Valtrex 500 mg once daily in the study. 82% of the study participants had viral shedding on 1 or more days compared to 49% of persons who took Valtrex at this dose who had viral shedding on 1 or more days. The mean percentage of days on which subjects shed virus when lesions were not present (asymptomatic shedding) was 7.8% in the placebo group and 2.8% in the valacyclovir group (p<0.001). HSV viral load (HSV DNA) was lower in persons taking Valtrex than in persons receiving placebo (1.7 log copies vs 4.2 log copies).
Transmission of HSV-2 can occur when a person with HSV-2 has an "outbreak", a genital sore or lesion and has sex with another individual. Viral shedding can also be a source for transmission. It appears that using a condom can be protective in reducing the risk for transmission, but transmission can still occur even if a condom is uesd. Presumably, the reduction in viral shedding and outbreaks in this study by using Valtrex daily therapy resulted in the reduced transmission of HSV-2. All of these study findings were statistically significant.
There were some interesting findings regarding condom use in the study. Condom use appeared to reduce the development of symptomatic genital herpes study participants who received placebo, and in persons using condoms and taking Valtrex no one developed symptomatic genital herpes. Study participants were counseled to use condoms during all sex acts during the study. During the study 55% of study participants said they never used condoms; 13% percent they used condoms sometimes (1-90%); and 30% said they used condoms nearly always (90-100%). It appeared that condom that condom use reduced acquisition of symptomatic HSV-2 in persons who received placebo and in persons who received Valtrex. Of note, persons who received Valtrex and said they sometimes or nearly always used condoms had no clinical endpoints during the study (signs and symptoms of HSV-2 documented by testing for virus). GSK reported that in participants receiving placebo and who reported never using condoms 2.8% developed symptomatic genital herpes, 2.0% who sometimes used condoms developed symptomatic genital herpes, and 1.4% of participants who nearly always used condoms developed symptomatic genital herpes. Bur for study participants who received Valtrex, 1% of those who never used condoms developed symptomatic genital herpes, and of note no one who sometimes used condoms (0/91) and no one who nearly always used condoms (0/211) developed symptomatic genital herpes.
The study was conducted in Australia, USA, Eastern Europe, South America, Canada, and Western Europe. 800 of the 1500 couples participating were from the USA. The primary endpoint of the study conducted by GlaxoSmithKline was the proportion of couples with symptoms of a first episode of genital HSV-2 in the susceptible partner, defined as symptomatic HSV-2 infection confirmed by culture, PCR, or HSV-2 seroconversion. 1484 couples were included in an intent-to-treat (ITT) analysis. Two-thirds of the source partners in the study were female, 90% white, mean age 36.1 years; two-thirds of susceptible partners were male, 90% white, mean age 36.3 years.
Secondary study endpoints included the effect on viral shedding and the time to first recurrence of genital herpes in the source partners. And in the susceptible partners, time to acquisition of symptomatic genital herpes infection, and proportion of couples with, and time to, overall acquisition. Additional secondary endpoints included time to first oral HSV outbreak. In susceptible partners, proporation with, and time to, HSV-2 seroconversion; proportion with, and time to, asymptomativ HSV-2 seroconversion. And proportion with clinical evidence (signs and symptoms) of a first episode of HSV-1.
The FDA raised these relevant points. The population in the study may vary from those treated in a typical practice setting in a number of ways: e.g., the study setting offered enhanced treatment of source patients with herpes recurrences and of susceptible partners with initial symptomatic episodes, but excluded non- monogamous couples, same-sex couples, and the presence of other STDs, including HIV. It is likely that patients will be treated for longer than 8 months. Therapeutic compliance may diminish when asymptomatic HSV-2-infected persons receive treatment for protecting partners, with no immediate personal benefit. The extent to which some infected persons might be less cautious about using condoms and avoiding sex when herpes outbreaks occur may blunt the public health impact of chemotherapy. In addition, more widespread use and off-label use, including transient use, of valacyclovir may lead to the development of drug resistance.
The day's discussion was an interesting one for me as this is a virus and treatment that I'm not very familiar with, so the proceedings were informative for me. The Committee met from 8am until about 3:15pm and had a number of lively discussions about the issues including the wording or labeling of the product insert, whether use of the drug should extend beyond monogomous heterosexuals to gay couples, individuals not in steady relationships, and non-monogomous couples. An additional interesting discussion included use of Valtrex for this new indication "to prevent sexual transmission of genital herpes" in HIV-infected individuals.
The Committee had a lively discussed whether the "susceptible" partner should be required to be tested for herpes 2 and 1 before the "source" partner starts a course of continuous Valtrex therapy. The source partner is the person with herpes and Valtrex would be taken by the source partner in order to prevent transmission of genital herpes to the susceptible partner. If the susceptible partner already has herpes-2 without knowing it because they had not been tested it would not be advisable for the source partner to start Valtrex for the purpose of reducing the risk of transmission. Of course, if a person ("source partner") with genital herpes has more than 1 or numerous sex partners, that opens up another discussion. The Committee also discussed whether approval of Valtrex for this new use should include these types of individuals.
Currently, Valtrex is approved for several types of use:
(1) treatment of initial genital herpes: 1000 mg twice daily for 10 days
(2) treatment of recurrent genital herpes: 500 mg twice daily for 3 days
(3) chronic suppressive treatment of recurrent genital herpes: 1000 mg once daily or 500 mg once daily (alternate dose)
I'm not sure how Valtrex is dosed for HIV+ individuals but it's my understanding that double the dose is often used because herpes-2 is more resilient in HIV+ individuals probably for several reasons including the impaired immune system. Valtrex is approved for HIV+ individuals for treatment of recurrent HSV-2 (herpes-2), but Valtrex was NOT considered yesterday for approval for use to reduce risk of transmission of genital herpes in HIV+ persons. The study conducted by GSK was in couples who were in stable monogomous heterosexual relationships; apparently because this type of study is difficult to successfully complete and the type of population chosen in which to perform this study was the easiest group of individuals. As a result the Committee was split on whether or not to apply the findings to other types of individuals such as gay couples, non-monogomous couples, and in HIV.
There was a lively discussion about using language in the product insert regarding the use of Valtrex for this new indication "to reduce transmission of sexual transmission of gential herpes" beyond monogomous heterosexual couples in stable relationships. The committee was divided on whether you could apply the study findings to individuals with other types of sexual lifestyles. Chris Mathews, MD, the Director of the Owen Clinic in San Diego, gave a good example. Female sex workers who have genital herpes. Obviously, they are not in a monogomous stable heterosexual relationship with their sex partners.
The study provided all participants with safer sex counseling and encouraged use of condoms during all sex acts. Study participants were counseled to avoid sex when signs or symptoms of an outbreak of genital herpes was present, Condoms were available free at each study site. Participants were given at study entry a booklet on safer sex. The study was conducted in heterosexual partners in a stable monogomous relationship. This was the easiest group to recruit for a large difficult-to-recruit for study. 4000 couples were screened to enter 1500 couples for the study.
The HSV-2 viral shedding study was a substudy conducted in 89 source partners from 3 US sites. They participated for 60 days. They received daily genital swabs for HSV-2 PCR, and an additional swab of lesion if present.
Time to overall acquisition of HSV-2 infection in susceptible partners was reduced in the persons receiving Valtrex compared to those receiving placebo(p=0.039). Time to symptomatic genital herpes in susceptible partners was reduced for persons receiving Valtrex compared to persons receiving placebo (p=0.008).
The Committee opinions expressed were that this drug appears fairly free of side effects. 68% of study participants reported adverse events. Headaches appear to be the most common side effect and occurred with about equal incidence in the persons receiving Valtrex (29%) and in persons receiving placebo (26%). 2% of persons receiving Valtrex and 2% of persons receiving placebo reported serious adverse events. And only 1-2% reported an adverse event leading to discontinuation. 15% of persons receiving placebo or Valtrex reported inflammation of the nasal passage (nasopharyngitis). There did not appear to be any differences in laboratory test abnormalities between persons receiving Valtrex or placebo. 16% of persons receiving placebo reported ALT greater than 2 times above the upper limit of normal (ULN), and 11% of persons receiving Valtrex reported this. Hemoglobin <0.8 times the ULN was reported in <1% of both study groups. And 1-2% reported White Blood Cells <0.75 times the lower limit of normal in both the placebo and Valtrex study arms.
In the current labeling of valacyclovir, the Warnings section includes the following: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir at doses of 8 grams per day. There were no reports of thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) in this study.
No deaths were reported. Twelve placebo and 14 valacyclovir-treated patients experienced serious adverse events. Five placebo and 12 valacyclovir source partners experienced an adverse event leading to discontinuation during double-blind therapy. Headache was the most common adverse event leading to discontinuation of study drugs.
Sixteen pregnancies occurred during the study: 8 in the valacyclovir group, 8 in the placebo group. Five pregnant subjects received valacyclovir for suspected HSV-2, four source patients and one susceptible partner. Two healthy children and two spontaneous abortions occurred among the four pregnant valacyclovir-treated source patients; the valacyclovir-treated pregnant susceptible partner elected abortion. Of the seven pregnant source partners in the placebo group, 3 delivered healthy children, 3 spontaneous and one elective abortion occurred.
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