Jennifer A. Cross
History of present illness
A 43-year-old woman comes into your emergency room com- plaining of painful areas on her genital area. She states that they have been present for two months, but recently they have become very painful. She has had them before, but in the past they have not lasted this long. She is currently homeless and has been living under a bridge with several friends. You notice from previous hospital records that she is HIV positive and has had inconsistent follow-up. She is currently not taking any medications because “someone stole them.” She admits to marijuana use and last used one week ago. She is sexually active with one male partner and they do not use condoms.
She otherwise does not endorse any other medical problems and has had no prior surgeries.
Physical examination
General appearance: Alert woman in no acute distress that appears older than her stated age
Vital signs:
Temperature: 37.0°C Pulse: 87 beats/min
Blood pressure: 105/67 mmHg Respiratory rate: 16 breaths/min Oxygen saturation: 100% at room air Cardiovascular: Regular rate and rhythm
Respiratory: Lungs clear to auscultation bilaterally Abdomen: Soft, nondistended, nontender
Genitourinary: Large ulcerative painful lesions covering most of her right and left external labia, smaller lesions located around her anal sphincter
Laboratory studies:
HIV viral RNA:>50 000 copies Absolute CD4 count: 90μL HSV PCR: Positive
How should you manage this patient?
This patient is an HIV-positive patient with AIDS presenting with painful lesions on her vulva. The patient’s care should revolve around identifying the causative agent responsible. She should be tested for all sexually transmitted infections as she is currently sexually active and having unprotected intercourse.
In this case the patient is testing positive for herpes simplex virus (HSV) type 2 based on polymerase chain (PCR) testing.
This patient should be started on high-dose acyclovir with daily prophylactic acyclovir once the lesions resolve.
A multidisciplinary approach should be used including Infec- tious Disease and Social Services.
Persistent HSV in an HIV-positive patient
Chronic herpes simplex virus (HSV), as seen in this patient, is defined by mucocutaneous genital lesions lasting greater than one month. Such lesions are found often in the human immuno- deficiency virus (HIV)-positive population, and are commonly associated with declining CD4 counts and rising serum HIV RNA [1]. These atypical lesions have been identified since the outbreak of the HIV epidemic and were among thefirst oppor- tunistic infections identified in the acquired immune deficiency syndrome (AIDS) population, especially in heterosexual females.
Chronic HSV is an AIDS-defining illness as classified by the Centers for Disease Control and Prevention (CDC).
HSV-2 has been the subject of interest due to its global impact on health. The World Health Organization estimated the number of people living with genital herpes at 536 million worldwide in 2003. More women than men were affected, with a total of 315 million women affected globally [2]. This is especially important in the control of HIV spread due a two to threefold risk of acquiring HIV in those who are HSV-2 seropositive. HSV-2 is more prevalent in the HIV-positive population with 50–90% testing seropositive [3]. Active genital lesions and asymptomatic viral shedding have afivefold increase in risk of HIV transmission per sexual contact for individuals not on highly active antiretroviral therapy (HAART).
The pathogenesis of HSV-2 impact on HIV disease trans- mission is multifactorial. First, mucosal disruption caused by HSV-2 provides a route for transmission. HSV infection also attracts CD4-positive lymphocytes to the infected area, the same host cells used by HIV. HSV-encoded proteins often increase the expression of HIV-encoded RNA [4]. Therefore, HIV RNA levels at the mucosal surface often exceed the amount in the serum of infected persons. These factors lead to increased HIV transmission even with lower HIV RNA levels.
The presentation of HSV in most patients who are HIV positive is similar to those who are immunocompetent, with most cases causing asymptomatic infections. However, pro- longed and atypical infections can be seen including abnormal lesion locations, ulcers greater than 20 cm in diameter, and exophytic protrusions resembling malignancy or condylomas [5]. This can often lead to misdiagnosis or a delay in diagnosis.
Reactivation of lesions is common, sometimes occurring more
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
than 12 times a year, with little healing time in between outbreaks. This can cause increased scarring, secondary infec- tions with yeast or bacteria, and deep ulcerative painful lesions.
Primary infections are usually more intense with persistent lesions, fevers, chills, and even dissemination causing enceph- alitis, hepatitis, and pneumonitis [1]. There are only a few such cases in the literature as most patients are already seropositive for HSV by the time they acquire HIV.
PCR and HSV cell culture remain the gold standard for diagnosis in the United States. PCR has a higher sensitivity and specificity for detecting HSV and is preferred. Viral culture sensitivity rapidly declines with chronic, nonhealing lesions but, if used, should be obtained from the base of the lesion [6]. As most cases of HSV are subclinical, type-specific sero- logic testing can be offered to patients especially if viral cul- tures are negative and HSV is suspected clinically.
Treatment of HSV in HIV-positive patients revolves around the use of HSV antiviral therapy including acyclovir, famciclovir, and valacyclovir (Table 19.1) [6]. Treatment should start as soon as possible and should not be delayed until the return of laboratory results. Doses and treatment duration are often increased from HIV-seronegative patients.
Intravenous acyclovir 5–10 mg/kg every 8 hours can be used initially for severe infections [6]. Daily prophylactic HSV should be used in HSV-seropositive patients as it decreases the frequency and severity of outbreaks. However, antiviral therapy does not prevent asymptomatic shedding of viral par- ticles in the genital area and, thus, transmission to sexual partners is a concern [4]. Patients must be counseled on the disease process and the possibility of transmission even with- out apparent vesicles or lesions.
Drug resistance to acyclovir is rare in the immunocompe- tent population but can occur in as many as 5% of cases in HIV patients. This should be suspected for persistent lesions or an increase in lesion size after 7–10 days of appropriately
dosed antiviral therapy. Resistance can be diagnosed through plaque reduction assays, which rely on viral cultures [6]. If resistance occurs with acyclovir, it also confers resistance to valganciclovir and even famciclovir. Alternative therapies include foscarnet 40 mg/kg IV every 8 hours, or cidofovir 5 mg/kg IV given once weekly until lesions resolve. Topical agents include imiquimod and topical cidofovir. Transmission of resistance strains has not been documented in the literature.
Resistance is often limited, with the wild-type acyclovir- sensitive strain predominating in an infected individual [3].
Therefore, treatment should be geared towards daily suppres- sive acyclovir, which has been shown to decrease the incidence of resistance in the future.
Management of HIV-infected persons should be focused on recognition and treatment of genital herpes. Although daily acyclovir treatment does not decrease the amount of asymp- tomatic shedding in HSV-2 seropositive individuals, it has been shown to decrease symptomatic ulcers and alter HIV disease progression for those not on HAART [3]. This has been theor- ized by noting that HIV viral DNA is unregulated in the serum of individuals with active HSV infections. Daily acyclovir treat- ment has been shown to decrease plasma levels of HIV RNA by as much as 35% over those not on treatment and who are also HSV seropositive. Vaccine research is underway for HSV given the large impact the virus has on HIV transmission [7].
For our patient, and for those who are HIV positive, disease prevention should be offered in the form of counseling for safe sex behaviors. Consistent condom use has been shown to decrease the risk of sexually transmitted infections by 80%
[6]. It is important to inform your patient that HIV transmis- sion and genital herpes transmission can still occur even when active lesions are not present. A multidisciplinary approach is ideal for treating HIV-positive patients. It is important to take into account social factors and easy access to medical care facilities when determining treatment options.
Key teaching points
Genital herpes can affect disease progression; therefore, early initiation of antiviral therapy is imperative.
Most individuals who are herpes simplex virus (HSV) seropositive do not have active lesions and have asymptomatic genital shedding. They are still able to transmit the disease without active lesions.
Daily suppressive therapy with acyclovir decreases the frequency and severity of genital herpes outbreaks. It also decreases resistance to acyclovir in the future.
A multidisciplinary approach should be used for all HIV-positive patients.
References
1. Baeten J, Celum C.Herpes Simplex Virus and HIV-1. HIV InSite Knowledge Base, 2006. Available at
http://hivinsite.ucsf.edu/InSite?
page=kb-05-03-02#S1X.
2. Looker K, Garnett G, Schmid G.
An estimate of the global prevalence
and incidence of herpes simplex virus type 2 infection.Bull World Health Organ2008;86:
737–816.
Table 19.1 Drug regimes for HSV in HIV-positive patients*
Daily suppressive therapy Episodic treatment Acyclovir 400–800 mg PO
BID–TID Acyclovir 400 mg PO TID ×
5–10 days
Famciclovir 500 mg PO BID Famciclovir 500 mg PO BID × 5–10 days
Valacyclovir 500 mg PO BID Valacyclovir 1 g PO BID × 5–10 days
* Drug doses obtained from Centers for Disease Control and Prevention [6].
BID, twice a day; CDC, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus; HSV, herpes simplex virus; PO,per os(orally);
TID, three times a day.
3. Strick LB, Wald A, Celum C. HIV/
AIDS: Management of herpes simplex virus type 2 infection in HIV type 1-infected persons.Clin Infect Dis 2006;43(3):347–56.
4. Corey L, Wald A, Celum C, 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 Syndr2004;
35(5):435–45.
5. Patel A, Rosen T. Herpes vegetans as a sign of HIV infection.Dermatol Online J2008;14(4):6.
6. Centers for Disease Control on Prevention.Diseases Characterized by Genital, Anal, or Perianal Ulcers.
Sexually Transmitted Diseases.
Treatment Guidelines 2010. Available at http://www.cdc.gov/std/treatment/
2010/genital-ulcers.htm.
7. World Health Organization.
Initiative for Vaccine Research:
Sexually Transmitted Diseases.
Available athttp://apps.who.int/
vaccine_research/diseases/
portfolio/en/.
Case 19: Persistent HSV in an HIV-positive woman