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Herpes Simplex Virus and HIV-1
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Introduction
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Epidemiology of HSV Infection
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Clinical Manifestations of HSV Infection
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The Importance of Asymptomatic HSV Reactivation
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HSV Diagnosis
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HSV Treatment
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Antiviral Resistance
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HSV-2 and HIV-1 Transmission and Disease Progression
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Conclusions
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References
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Tables
Table 1.Recommended Regimens for Treatment of Herpes Simplex Virus in HIV-1-Infected Individuals
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Introduction
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Herpes simplex virus (HSV) infection is a common cause of ulcerative mucocutaneous disease in both immunocompetent and immunocompromised individuals. Classically, HSV type 1 (HSV-1) is acquired in childhood and causes orolabial ulcers, whereas HSV type 2 (HSV-2) is transmitted sexually and causes anogenital ulcers. However, both oral infection with HSV-2 and particularly genital infection with HSV-1 are increasingly recognized, likely as a result of oral-genital sexual practices. The clinical presentations of the 2 virus types are indistinguishable.

The hallmarks of HSV infection are periodic symptomatic reactivation and asymptomatic viral shedding. Infection with HSV is a lifelong condition; the virus becomes permanently latent in the nerve root ganglia corresponding to the site of inoculation (the trigeminal ganglia for orolabial infection and the sacral ganglia for genital infection). HSV induces antibody and cell-mediated immune responses that modulate the severity of recurrent disease, but these are insufficient to eradicate infection. In immunocompromised individuals, such as those with HIV-1 infection, impaired immunity leads to more frequent and severe symptomatic and asymptomatic HSV reactivation.

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Epidemiology of HSV Infection
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The seroprevalences of HSV-1 and HSV-2 infections in the United States have been studied in the National Health and Nutrition Examination Survey (NHANES), a large ongoing population-based study. In NHANES III (midpoint 1991), the seroprevalences of HSV-1 and HSV-2 were 68% and 22%, respectively.(1,2) Both infections were more common among women and nonwhite participants. Poverty, less education, and markers of sexual behavior (earlier sexual debut, higher number of sexual partners) were also associated with HSV infection. Compared with earlier NHANES surveys, the seroprevalence of HSV-2 had increased 30% since the 1970s, although analyses of the recent NHANES IV survey data (1999-2004) demonstrated flattening of HSV-2 seroprevalence during the 1990s, with declining seroprevalence among youth.(3) It is estimated that 50 million persons in the United States have genital HSV infection.(4) Similar HSV prevalences have been reported in Europe, and even higher seroprevalences have been seen in many parts of the developing world.(4,5) Studies have consistently shown that the great majority of individuals with HSV infection are unaware of their status.

Among HIV-1 infected individuals, HSV-1 and HSV-2 infections are common, with prevalences that approximate or exceed those in the general population. In recent years, a number of studies have focused on the prevalence of HSV-2 among HIV-1 infected individuals, finding seroprevalences of 50-90% in some populations, significantly higher than among those without HIV-1.(6) The 2 viruses' shared route of sexual transmission may explain this finding. The highest prevalences of coinfection with HSV-2 among HIV-1-infected individuals have been seen in heterosexual women and men in sub-Saharan Africa and in men who have sex with men in the Americas.

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Clinical Manifestations of HSV Infection
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Among HIV-1 infected persons, the clinical presentation of symptomatic HSV-2 infection can vary considerably. As it does in HIV-1-uninfected persons, HSV reactivation among the HIV-1-infected typically presents with vesicular and ulcerative lesions of the oral and anogenital areas. Often, genital reactivation may go unrecognized, because lesions are early or small, are manifesting as hypersensitive erythematous papules or late granulated lesions, or, in the case of perianal lesions or internal lesions in women, are difficult to visualize. HIV-1-infected persons, however, also can have frequent or persistent HSV lesions, often with extensive or deep ulcerations, particularly among those with low CD4 counts. In one study, the frequency of genital ulcer disease consistent with reactivation of genital herpes was found to increase in a stepwise fashion with declining CD4 counts.(7) Frequent and severe recurrent oral or genital herpes can be a source of significant pain and morbidity among some HIV-1-infected persons.

Primary infection with HSV, at either the oral or genital sites, is often characterized by multiple lesions that persist for a longer period than they do during recurrent disease. Preexisting antibody to HSV-1 is associated with milder or asymptomatic primary HSV-2 infection. Primary infection may be accompanied by systemic symptoms, including fever, headache, myalgia, and aseptic meningitis. Many HIV-1-infected persons are already infected with HSV-2 at the time of HIV-1 acquisition, and cases of primary HSV-2 infection therefore are relatively uncommon among HIV-1-infected individuals. Notably, primary genital HSV-2 occurring in an HIV-1-infected person is a marker for ongoing unsafe sexual practices. When primary infection occurs among HIV-1-infected persons with advanced immunosuppression, its course tends to be prolonged and more severe.

Mucocutaneous manifestations of genital HSV reactivation in HIV-1-infected persons may be atypical in presentation, which can delay diagnosis and initiation of appropriate therapy. The differential diagnosis of genital ulceration resulting from HSV includes other sexually transmitted diseases (syphilis, chancroid, lymphogranuloma venereum), bacterial and fungal infections, contact dermatitis, recurrent varicella-zoster virus infection (shingles), and Behçet disease.

More serious and systemic manifestations of HSV infection include esophagitis, meningoencephalitis, hepatitis, pneumonitis, retinal necrosis, and disseminated infection, all of which are relatively rare, even among those with advanced HIV-1 infection.(6)

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The Importance of Asymptomatic HSV Reactivation
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Most HSV-2-infected individuals, regardless of HIV-1 serostatus, shed HSV in oral or genital secretions, and most shedding is asymptomatic. Prospective studies have shown that oral and genital shedding of HSV (both HSV-1 and HSV-2) occurs more frequently among those who are also infected with HIV-1 than among HSV-infected/HIV-1-uninfected persons.(8-10) Among HIV-1-infected persons, HSV mucosal shedding occurs more frequently, and with higher quantity of HSV, among those with lower CD4 counts.(9,11,12) However, it is important to note that many individuals with intermediate or high CD4 counts may also shed HSV-2 frequently, and there is substantial variability in the frequency and quantity of HSV-2 shedding among individuals.(12) Frequent and high-titer HSV-2 shedding, regardless of whether it is associated with symptomatic disease, likely increases the risk of HSV-2 transmission to sexual partners.

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HSV Diagnosis
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Clinical diagnosis of genital ulcer disease, even by experienced clinicians, has been shown in a number of studies to be unreliable.(13) Among HIV-1-infected persons, the potential for atypical presentations of genital HSV may further increase the chance of inaccurate diagnosis and result in a delay in the initiation of appropriate care. Polymerase chain reaction (PCR) testing of samples taken from mucocutaneous lesions yields consistently higher rates of HSV detection than does viral culture analysis and should be considered the gold standard for diagnosis of HSV infection in persons presenting with ulcerative disease.(14)

For asymptomatic individuals, type-specific serologic testing based on glycoprotein G can accurately distinguish HSV-1 and HSV-2 infections with high sensitivity and specificity.(14,15) These assays appear to perform well among persons with HIV-1 infection. Some experts have adopted routine HSV serologic testing as part of the initial evaluation of persons presenting for HIV-1 care, in order to diagnose asymptomatic or unrecognized HSV-2 infection.(6,15) Concerns about the psychological burden of a diagnosis of HSV-2 should not prohibit testing--studies have found that the effect is limited.(16) The Centers for Disease Control and Prevention (CDC) has included recommendations for the counseling of persons diagnosed with genital herpes in its Sexually Transmitted Disease Treatment Guidelines, 2006.(15)

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HSV Treatment
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The nucleoside analogues acyclovir, valacyclovir, and famciclovir inhibit HSV-1 and HSV-2 replication through specific inhibition of a virally encoded thymidine kinase. More than 2 decades of experience with acyclovir (now available in generic formulations) has demonstrated that these compounds are safe and effective for treatment of HSV reactivation. All have good oral bioavailability; topical therapy offers little clinical benefit and is not recommended. Studies among HIV-1-infected individuals have shown that these medications are well tolerated in this population and, importantly, demonstrate no interaction with antiretroviral medications used in the treatment of HIV-1. Antiviral chemotherapy provides clinical benefits both as episodic treatment of symptomatic patients and as suppressive therapy for prevention of recurrent disease.

Episodic therapy for symptomatic reactivation of genital HSV can shorten the duration of lesions (Table 1).(15) Because symptomatic outbreaks may be more severe or may respond more slowly to therapy, a longer duration of treatment is recommended for HIV-1-infected individuals. Therapy is most effective when started soon after symptoms arise; providing patients with an antiviral prescription allows them to initiate treatment at the onset of symptoms, or even during the prodromal period that can precede outbreaks. Severe outbreaks can require use of intravenous acyclovir.

Suppressive oral therapy, taken daily, effectively reduces the rate of recurrence of symptomatic genital herpes as well as the frequency of asymptomatic genital HSV shedding (Table 1). When breakthrough reactivations do occur, they tend to be short and asymptomatic. Suppressive therapy is effective among persons with HIV-1 infection, and, because symptomatic and asymptomatic HSV reactivation is common among persons with HIV-1, long-term suppressive antiviral therapy against HSV should be considered for persons coinfected with HSV-2 and HIV-1. Higher-dose treatments (eg, acyclovir 800 mg 3 times per day, and similar bioequivalent doses for famciclovir and valacyclovir) can be used for those who have frequent HSV outbreaks despite receiving standard suppressive therapy.(6)

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Antiviral Resistance
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Although acyclovir resistance was first documented more than 20 years ago, isolation of drug-resistant HSV remains rare (<1% of isolates). The usual mechanism of resistance is a mutation in the HSV thymidine kinase, typically leading to lower fitness of the virus.(17) Among HIV-1-infected persons, rates of acyclovir resistance are also generally low (<5%), but drug-resistant disease can be a significant problem for severely immunocompromised patients, in whom a poor response to escalating doses of HSV antivirals may indicate acyclovir resistance. Notably, in vitro evidence of acyclovir resistance alone does not ensure poor clinical response to standard therapy, and thus routine acyclovir sensitivity testing is not indicated. Resistance to acyclovir implies resistance to valacyclovir, and most strains are also resistant to famciclovir. Intravenous foscarnet is the drug of choice for treatment of severe resistant disease. Topical cidofovir and foscarnet also have been used successfully.(6) Most individuals likely occasionally generate resistant variants; however, these are thought to have lower viral fitness than wild-type strains and rarely persist, making recurrent acyclovir-resistant disease uncommon.(17) In most cases following instances of laboratory-documented acyclovir resistance, wild-type, acyclovir-susceptible virus reemerges in subsequent outbreaks if the previous drug-resistant outbreak has been treated successfully.(6)

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HSV-2 and HIV-1 Transmission and Disease Progression
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There is increasing evidence that genital HSV-2 is facilitating the perseverance of the global HIV-1 epidemic.(12) A recent metaanalysis concluded that HSV-2 infection increases the risk of HIV-1 acquisition approximately 3-fold in both men and women, and that primary HSV-2 infection may have an even greater effect on HIV-1 susceptibility.(18) Among those who become infected with HIV-1, HSV-2 seropositivity and genital ulcer disease resulting from HSV have been associated with significantly higher HIV-1 plasma viral loads.(19,20) A number of observational studies have found that HSV-2 reactivation, including asymptomatic shedding, also increases the concentration of HIV-1 in plasma and genital secretions.(20,21) A prospective study among heterosexual HIV-1 discordant couples in Rakai, Uganda, found that genital ulcer disease in the HIV-1-infected partner, primarily resulting from HSV-2, was associated with a 4-fold increase in the likelihood of HIV-1 transmission.(22) Thus, coinfection with HSV-2 may contribute to faster HIV-1 disease progression and heightened risk of HIV-1 transmission. Finally, as already detailed, enhanced genital HSV-2 shedding among HIV-1-infected individuals in turn likely increases the risk of HSV-2 transmission.

To date, limited data have demonstrated that HSV treatment has an impact on HIV-1 disease progression. In one small observational study, HIV-1 plasma viral load was decreased among HSV-2/HIV-1-coinfected men starting suppressive therapy with acyclovir.(20) Recent results from a randomized trial among HSV-2/HIV-1-coinfected women demonstrated that suppressive therapy with valacyclovir lowered plasma and genital HIV-1 levels.(23) A metaanalysis of 8 randomized trials from the era before the widespread availability of antiretroviral therapy (ART) found that high-dose acyclovir (≥3,200 mg per day) reduced the risk of death among HIV-1-infected persons (hazard ratio: 0.78; 95% confidence interval [CI]: 0.65-0.93),(24) which may be attributed in part to reductions in HIV-1 plasma viral load as a result of HSV-2 suppression. However, acyclovir therapy has not become the standard of care for HSV-2/HIV-1-coinfected persons, although this is being reconsidered in light of recent data on the effect of suppressive therapy on HIV-1 levels and the established effect of suppressive therapy on the rate of symptomatic HSV-2 recurrences.

There are only a few studies about the effect of ART on HSV reactivation, but available data suggest that ART decreases symptomatic HSV disease but may not reduce asymptomatic HSV shedding.(25) Thus, ART alone may not reduce the risk of HSV transmission. In addition, although ART significantly lowers plasma and genital HIV-1 levels, likely indicating reduced HIV-1 infectiousness, some individuals with fully suppressed HIV-1 plasma viral loads continue to shed HIV-1 genitally. It is unknown whether HSV suppressive therapy might further decrease HIV-1 shedding among individuals on ART. Finally, the effects of ART on the interaction between HSV and HIV-1 progression and transmission, and the role for HSV suppression in influencing HIV-1 progression and transmission in the context of ART, remain important research topics.

Several randomized trials examining anti-HSV therapy and HIV-1 transmission are ongoing. These will determine the effect of HSV suppressive therapy on HIV-1 acquisition among HSV-2-seropositive/HIV-1-seronegative individuals and on genital HIV-1 shedding, HIV-1 disease progression (among those with CD4 counts high enough that initiation of ART is not warranted), and HIV-1 transmission among HSV-2/HIV-1-coinfected individuals.(21) There is hope that HSV-2 suppressive treatment can reduce HIV-1 infectiousness and delay disease progression among the large group of HIV-1-infected individuals whose HIV-1 disease has not progressed to the stage at which initiation of ART is routinely recommended.

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Conclusions
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Most HIV-1-infected persons are also infected with HSV-1 and HSV-2, although HSV infections are often mild or asymptomatic. Symptomatic and asymptomatic HSV reactivations are common among HIV-1-infected persons and can be a cause of significant morbidity. Antiviral medications given for episodic outbreaks or as long-term suppressive treatment provide important clinical benefits to patients. Given the apparent epidemiologic synergy between HSV-2 and HIV-1, promoting awareness of HSV-2 treatment for the purpose of decreasing HIV-1 transmission and disease progression may have substantial public health benefits.

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References

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1.   Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997; 337:1105-11.
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2.   Schillinger JA, Xu F, Sternberg MR, Armstrong GL, Lee FK, Nahmias AJ, McQuillan GM, Louis ME, Markowitz LE. National seroprevalence and trends in herpes simplex virus type 1 in the United States, 1976-1994. Sex Transm Dis 2004; 31:753-60.
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3.   Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, Berman SM, Markowitz LE. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. Jama 2006; 296:964-73.
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4.   Corey L, Handsfield HH. Genital herpes and public health: addressing a global problem. Jama 2000; 283:791-4.
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5.   Weiss HA, Buve A, Robinson NJ, Van Dyck E, Kahindo M, Anagonou S, Musonda R, Zekeng L, Morison L, Carael M, Laga M, Hayes RJ. The epidemiology of HSV-2 infection and its association with HIV infection in four urban African populations. Aids 2001; 15 Suppl 4:S97-108.
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6.   Strick LB, Wald A, Celum C. Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. Clin Infect Dis 2006; 43:347-56.
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7.   McClelland RS, Lavreys L, Katingima C, Overbaugh J, Chohan V, Mandaliya K, Ndinya-Achola J, Baeten JM. Contribution of HIV-1 infection to acquisition of sexually transmitted disease: a 10-year prospective study. J Infect Dis 2005; 191:333-8.
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8.   Schacker T, Zeh J, Hu HL, Hill E, Corey L. Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men. J Infect Dis 1998; 178:1616-22.
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9.   Augenbraun M, Feldman J, Chirgwin K, Zenilman J, Clarke L, DeHovitz J, Landesman S, Minkoff H. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995; 123:845-7.
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10.   Kim HN, Meier A, Huang ML, Kuntz S, Selke S, Celum C, Corey L, Wald A. Oral herpes simplex virus type 2 reactivation in HIV-positive and -negative men. J Infect Dis 2006; 194:420-7.
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11.   Wright PW, Hoesley CJ, Squires KE, Croom-Rivers A, Weiss HL, Gnann JW, Jr. A prospective study of genital herpes simplex virus type 2 infection in human immunodeficiency virus type 1 (HIV-1)-seropositive women: correlations with CD4 cell count and plasma HIV-1 RNA level. Clin Infect Dis 2003; 36:207-11.
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12.   Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004; 35:435-45.
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13.   DiCarlo RP, Martin DH. The clinical diagnosis of genital ulcer disease in men. Clin Infect Dis 1997; 25:292-8.
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14.   Strick LB, Wald A. Diagnostics for herpes simplex virus: is PCR the new gold standard? Mol Diagn Ther 2006; 10:17-28.
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15.   Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006; 55:1-94.
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16.   Meyer JL, Crosby RA, Whittington WL, Carrell D, Ashley-Morrow R, Meier AS, Harrington RD, DiClemente R, Wald A. The psychosocial impact of serological herpes simplex type 2 testing in an urban HIV clinic. Sex Transm Infect 2005; 81:309-15.
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17.   Gupta R, Hill EL, McClernon D, Davis G, Selke S, Corey L, Wald A. Acyclovir sensitivity of sequential herpes simplex virus type 2 isolates from the genital mucosa of immunocompetent women. J Infect Dis 2005; 192:1102-7.
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18.   Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. Aids 2006; 20:73-83.
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19.   Gray RH, Li X, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, Lutalo T, Kiwanuka N, Kigozi G, Nalugoda F, Meehan MP, Robb M, Quinn TC. Determinants of HIV-1 load in subjects with early and later HIV infections, in a general-population cohort of Rakai, Uganda. J Infect Dis 2004; 189:1209-15.
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20.   Schacker T, Zeh J, Hu H, Shaughnessy M, Corey L. Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis 2002; 186:1718-25.
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21.   Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis 2005; 191 Suppl 1:S107-14.
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22.   Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, Wabwire-Mangen F, Lutalo T, Li X, vanCott T, Quinn TC. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357:1149-53.
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23.  Nagot N, Ouedraogo A, Mayaud P, et al. Effect of HSV-2 suppressive therapy on HIV-1 genital shedding and plasma viral load: a proof of concept randomized double-blind placebo controlled trial (ANRS 1285 Trial). In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver. Abstract 33LB.
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24.   Ioannidis JP, Collier AC, Cooper DA, Corey L, Fiddian AP, Gazzard BG, Griffiths PD, Contopoulos-Ioannidis DG, Lau J, Pavia AT, Saag MS, Spruance SL, Youle MS. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis 1998; 178:349-59.
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25.   Posavad CM, Wald A, Kuntz S, Huang ML, Selke S, Krantz E, Corey L. Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy. J Infect Dis 2004; 190:693-6.
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