Use of Antiviral Drugs to Prevent Herpesvirus Transmission
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《新英格兰医药杂志》
One of the main lessons of antiviral-drug therapy is that the drugs that inhibit viral replication are frequently more effective at preventing viral disease than they are at treating established disease. Acyclovir, for example, when taken on a daily basis, will prevent outbreaks of recurrent genital herpes infection, but when it is taken early to treat an episode of recurrent genital herpes, the result is a shortening of the course of disease by only one day — a marginal clinical benefit.1 Ganciclovir, the mainstay of therapy for cytomegalovirus (CMV) disease, has a similar effect. This drug was first used in a human in 1984 to treat an episode of life-threatening CMV pneumonia after bone marrow transplantation. Its use resulted in a decrease in the amount of virus isolated from the lung secretions but did not improve the clinical outcome of the CMV pneumonia, which led to the patient's death. Since then, we have made little progress in the treatment of CMV pneumonia with any combination of antiviral drugs in patients who have undergone bone marrow transplantation. We have, however, learned to prevent serious CMV disease in immunocompromised transplant recipients and in patients infected with the human immunodeficiency virus (HIV) by using ganciclovir to inhibit CMV replication before the development of CMV pneumonia and CMV retinitis.2
The report by Corey et al.3 in this issue of the Journal records another important advance in the use of antiviral drugs. Corey et al. found that once-daily valacyclovir decreases the risk of sexual transmission of herpes simplex virus type 2 (HSV-2) between discordant couples (couples in which one partner is HSV-2–positive and the other is HSV-2–negative). In this well-designed, placebo-controlled, multicenter trial involving a large number of couples, the couples in both groups were counseled regarding safer sex practices, such as the use of condoms, to help prevent acquisition of HSV-2. The rate of condom use was similar in the two groups. Over the eight-month period of observation, the rate of acquisition of HSV-2 among the susceptible partners of the valacyclovir-treated participants, as compared with the susceptible partners of the placebo-treated participants, was reduced by 48 percent, and the incidence of clinically symptomatic HSV-2 infection was reduced by 75 percent.
Among the HSV-2–positive participants (i.e., source partners), valacyclovir significantly reduced the frequency with which HSV DNA was detected by polymerase-chain-reaction analysis of genital-swab samples (2.9 percent of the days, vs. 10.8 percent of the days in the placebo group). These results have enormous clinical implications and have led the Food and Drug Administration to approve a new indication for valacyclovir: the prevention of sexual transmission of HSV infection. The current article provides very careful documentation of the use of an antimicrobial drug to prevent the transmission of sexually transmitted disease.3
The researchers were careful to test for potential transmission of acyclovir-resistant HSV to the susceptible partners. No resistance to acyclovir was detected, but the number of isolates measured was small. Fortunately, even though the use of acyclovir to treat and prevent genital herpes has grown by a factor of six in the past decade, resistance to acyclovir in immunocompetent patients is a small problem and is not growing. In a study sponsored by the Task Force on Herpes Simplex Virus Resistance and the Centers for Disease Control and Prevention to determine the prevalence of acyclovir resistance in the United States, HSV was isolated from the genital secretions of 2088 patients attending sexually transmitted disease clinics.4 Ninety percent of the isolates were identified as HSV-2, but only 0.2 percent of them were resistant to acyclovir. Resistance was highly associated with oral and topical use of acyclovir. Of the HSV isolates from 226 patients who were positive for HIV type 1 (HIV-1), 5.3 percent were resistant to acyclovir. There also has been no clear demonstration of the transmission of acyclovir-resistant HSV between sexual partners, although the source of one case of recurrent genital herpes caused by an acyclovir-resistant strain of HSV-2 in an immunocompetent person was not clearly established.5
In both developed and developing countries, HSV is the leading cause of ulcers in the genital area. In the United States, 22 percent of adults are positive for HSV-2 antibody.6 The base-line prevalence among women 15 to 29 years old who attend sexually transmitted disease clinics in Uganda is 61 percent7; the prevalence among female commercial sex workers in India is 89 percent.8 There is a clear association between the prevalence of genital ulcers caused by HSV-2 and the explosion in the heterosexual transmission of HIV-1 in the Southern Hemisphere. Among patients attending three sexually transmitted disease clinics in Pune, India, newly acquired HSV-2 infection was associated with an adjusted hazard ratio of 3.81 for acquisition of HIV-1 infection, and the authors suggested that prevention of HSV-2 infection might reduce the risk of HIV-1 infection.8 In one study, HIV-1 was detected in specimens from genital swabs on 67 percent of the days that genital ulcers were present in patients coinfected with HSV-2 and HIV-1, and HIV-1 RNA levels in the genital specimens were very high (at 10,000 copies per milliliter of swab in 75 percent of the samples).9
The current report provides the scientific basis for a future intervention study with daily acyclovir to determine whether suppressing HSV-2 replication will diminish the risk of HIV-1 transmission.3 The trial, as outlined by Wald and Corey,10 would enroll persons who are positive for HSV-2 and HIV-1 in order to determine whether daily acyclovir reduces the risk of HIV-1 transmission to an HIV-1–negative sexual partner. The trial would be carried out in healthy persons with high CD4+ cell counts who do not fit current World Health Organization guidelines for the use of antiretroviral therapy. Such a trial is being initiated in the developing world with the support of the Bill and Melinda Gates Foundation.
Generic acyclovir is inexpensive (therapy with 400-mg tablets given twice per day costs 20 cents per day, or about $73 per year), it is unlikely to induce resistance with prolonged use, and it is the safest of the antiviral drugs. The urgency of such trials is enormous, because they promise to separate the complex issues of confounding sexual behavior from questions about whether HSV-2 really is causal in HIV-1 transmission. Millions could benefit if the use of acyclovir is proven to decrease the transmission of HIV-1 by preventing HSV-2 genital ulcers. The time for ethically designed interventional studies is now.
Source Information
From the Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston.
References
Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med 1992;327:782-789.
Crumpacker CS. Ganciclovir. N Engl J Med 1996;335:721-729.
Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11-20.
Reyes M, Shaik NS, Graber JM, et al. Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 2003;163:76-80.
Kost RG, Hill EL, Tigges M, Straus SE. Recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 1993;329:1777-1782.
Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-1111.
Grosskurth H, Gray R, Hayes R, Mabey D, Wawer M. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet 2000;355:1981-1987.
Reynolds SJ, Risbud AR, Shepherd ME, et al. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis 2003;187:1513-1521.
Schacker T, Ryncarz AJ, Goddard J, Diem K, Shaughnessy M, Corey L. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 1998;280:61-66.
Wald A, Corey L. How does herpes simplex virus type 2 influence human immunodeficiency virus infection and pathogenesis? J Infect Dis 2003;187:1509-1512.(Clyde S. Crumpacker, M.D.)
The report by Corey et al.3 in this issue of the Journal records another important advance in the use of antiviral drugs. Corey et al. found that once-daily valacyclovir decreases the risk of sexual transmission of herpes simplex virus type 2 (HSV-2) between discordant couples (couples in which one partner is HSV-2–positive and the other is HSV-2–negative). In this well-designed, placebo-controlled, multicenter trial involving a large number of couples, the couples in both groups were counseled regarding safer sex practices, such as the use of condoms, to help prevent acquisition of HSV-2. The rate of condom use was similar in the two groups. Over the eight-month period of observation, the rate of acquisition of HSV-2 among the susceptible partners of the valacyclovir-treated participants, as compared with the susceptible partners of the placebo-treated participants, was reduced by 48 percent, and the incidence of clinically symptomatic HSV-2 infection was reduced by 75 percent.
Among the HSV-2–positive participants (i.e., source partners), valacyclovir significantly reduced the frequency with which HSV DNA was detected by polymerase-chain-reaction analysis of genital-swab samples (2.9 percent of the days, vs. 10.8 percent of the days in the placebo group). These results have enormous clinical implications and have led the Food and Drug Administration to approve a new indication for valacyclovir: the prevention of sexual transmission of HSV infection. The current article provides very careful documentation of the use of an antimicrobial drug to prevent the transmission of sexually transmitted disease.3
The researchers were careful to test for potential transmission of acyclovir-resistant HSV to the susceptible partners. No resistance to acyclovir was detected, but the number of isolates measured was small. Fortunately, even though the use of acyclovir to treat and prevent genital herpes has grown by a factor of six in the past decade, resistance to acyclovir in immunocompetent patients is a small problem and is not growing. In a study sponsored by the Task Force on Herpes Simplex Virus Resistance and the Centers for Disease Control and Prevention to determine the prevalence of acyclovir resistance in the United States, HSV was isolated from the genital secretions of 2088 patients attending sexually transmitted disease clinics.4 Ninety percent of the isolates were identified as HSV-2, but only 0.2 percent of them were resistant to acyclovir. Resistance was highly associated with oral and topical use of acyclovir. Of the HSV isolates from 226 patients who were positive for HIV type 1 (HIV-1), 5.3 percent were resistant to acyclovir. There also has been no clear demonstration of the transmission of acyclovir-resistant HSV between sexual partners, although the source of one case of recurrent genital herpes caused by an acyclovir-resistant strain of HSV-2 in an immunocompetent person was not clearly established.5
In both developed and developing countries, HSV is the leading cause of ulcers in the genital area. In the United States, 22 percent of adults are positive for HSV-2 antibody.6 The base-line prevalence among women 15 to 29 years old who attend sexually transmitted disease clinics in Uganda is 61 percent7; the prevalence among female commercial sex workers in India is 89 percent.8 There is a clear association between the prevalence of genital ulcers caused by HSV-2 and the explosion in the heterosexual transmission of HIV-1 in the Southern Hemisphere. Among patients attending three sexually transmitted disease clinics in Pune, India, newly acquired HSV-2 infection was associated with an adjusted hazard ratio of 3.81 for acquisition of HIV-1 infection, and the authors suggested that prevention of HSV-2 infection might reduce the risk of HIV-1 infection.8 In one study, HIV-1 was detected in specimens from genital swabs on 67 percent of the days that genital ulcers were present in patients coinfected with HSV-2 and HIV-1, and HIV-1 RNA levels in the genital specimens were very high (at 10,000 copies per milliliter of swab in 75 percent of the samples).9
The current report provides the scientific basis for a future intervention study with daily acyclovir to determine whether suppressing HSV-2 replication will diminish the risk of HIV-1 transmission.3 The trial, as outlined by Wald and Corey,10 would enroll persons who are positive for HSV-2 and HIV-1 in order to determine whether daily acyclovir reduces the risk of HIV-1 transmission to an HIV-1–negative sexual partner. The trial would be carried out in healthy persons with high CD4+ cell counts who do not fit current World Health Organization guidelines for the use of antiretroviral therapy. Such a trial is being initiated in the developing world with the support of the Bill and Melinda Gates Foundation.
Generic acyclovir is inexpensive (therapy with 400-mg tablets given twice per day costs 20 cents per day, or about $73 per year), it is unlikely to induce resistance with prolonged use, and it is the safest of the antiviral drugs. The urgency of such trials is enormous, because they promise to separate the complex issues of confounding sexual behavior from questions about whether HSV-2 really is causal in HIV-1 transmission. Millions could benefit if the use of acyclovir is proven to decrease the transmission of HIV-1 by preventing HSV-2 genital ulcers. The time for ethically designed interventional studies is now.
Source Information
From the Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston.
References
Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med 1992;327:782-789.
Crumpacker CS. Ganciclovir. N Engl J Med 1996;335:721-729.
Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11-20.
Reyes M, Shaik NS, Graber JM, et al. Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 2003;163:76-80.
Kost RG, Hill EL, Tigges M, Straus SE. Recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 1993;329:1777-1782.
Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-1111.
Grosskurth H, Gray R, Hayes R, Mabey D, Wawer M. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet 2000;355:1981-1987.
Reynolds SJ, Risbud AR, Shepherd ME, et al. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis 2003;187:1513-1521.
Schacker T, Ryncarz AJ, Goddard J, Diem K, Shaughnessy M, Corey L. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 1998;280:61-66.
Wald A, Corey L. How does herpes simplex virus type 2 influence human immunodeficiency virus infection and pathogenesis? J Infect Dis 2003;187:1509-1512.(Clyde S. Crumpacker, M.D.)