Herpes Simplex Virus and HIV-1

HIV InSite Knowledge Base Chapter

November 2006
Jared M. Baeten, MD, PhD, University of Washington, Seattle
Connie Celum, MD, MPH, University of Washington, Seattle

Introduction
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.

Epidemiology of HSV Infection

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 populationbased 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.

Clinical Manifestations of HSV Infection

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-1infected 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 Behet
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)

The Importance of Asymptomatic HSV Reactivation

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.

HSV Diagnosis
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)

HSV Treatment
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 HIV1. 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)

Antiviral Resistance

Although acyclovir resistance was first documented more than 20 years ago, isolation of drugresistant 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-1infected 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, acyclovirsusceptible virus reemerges in subsequent outbreaks if the previous drug-resistant outbreak has
been treated successfully.(6)

HSV-2 and HIV-1 Transmission and Disease Progression

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 4fold 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-2seropositive/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.

Conclusions
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.

References
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.
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.
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.
4. Corey L, Handsfield HH. Genital herpes and public health: addressing a global problem.
Jama 2000; 283:791-4.
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.
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.
7. McClelland RS, Lavreys L, Katingima C, Overbaugh J, Chohan V, Mandaliya K, NdinyaAchola 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.
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.
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.
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.
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.

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.
13. DiCarlo RP, Martin DH. The clinical diagnosis of genital ulcer disease in men. Clin Infect
Dis 1997; 25:292-8.
14. Strick LB, Wald A. Diagnostics for herpes simplex virus: is PCR the new gold standard?
Mol Diagn Ther 2006; 10:17-28.
15. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006.
MMWR Recomm Rep 2006; 55:1-94.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.