Herpes Simpleks Tipe 2

01Pathophysiology

Genital herpes is caused by Herpes Simplex Virus (HSV), a double-stranded DNA virus belonging to the Herpesviridae family. There are two serotypes: HSV-1 and HSV-2. HSV-2 is classically associated with genital infection, while HSV-1 can also cause genital herpes through oral-genital contact. Both viruses can infect the genital area.

The virus enters the body through mucosal surfaces or breaks in the skin. After initial replication in epithelial cells (which produces the visible lesions), HSV travels retrograde along sensory nerve fibers to establish lifelong latency in the sacral dorsal root ganglia. This latency is the reason the infection is chronic and incurable. The virus remains dormant within neurons, evading the immune system because neuronal cells have limited MHC class I expression.

Reactivation occurs when the virus travels anterograde back down the nerve axon to the genital skin or mucosa, producing a new round of lesions. Triggers for reactivation include physical or psychological stress, other illnesses, menstruation, excessive sexual activity, alcohol use, trauma, fatigue, and immunosuppression. Importantly, reactivation can also occur without visible lesions (asymptomatic viral shedding), which is a major mechanism of transmission.

The reason primary episodes are more severe than recurrences is immunological. During a first encounter with the virus, the host has no pre-existing antibodies, so viral replication proceeds relatively unchecked. This leads to more extensive lesions, prolonged duration (12 to 21 days untreated), and systemic symptoms such as fever, malaise, and lymphadenopathy. In contrast, a non-primary first episode (first clinical genital herpes in someone who already has antibodies against the other HSV type, e.g., prior HSV-1 oral infection now presenting with HSV-2 genitally) is milder because of partial cross-reactive immunity. Recurrent episodes are the mildest, as the host already has type-matched antibodies and T-cell memory.

The connection between HSV-2 and HIV is clinically important. Genital HSV-2 infection increases the risk of acquiring HIV by two to threefold, because mucosal disruption provides a portal of entry for HIV, and local inflammation recruits CD4+ T cells (HIV target cells) to the genital tract. This is why HIV testing is recommended in all patients diagnosed with genital herpes.

02Classification and Clinical Manifestation

By Episode Type

03Diagnostic Workup

The diagnosis of genital herpes is primarily clinical. When the presentation is classic (grouped vesicles on an erythematous base in the genital region, painful, with regional lymphadenopathy), laboratory confirmation is not strictly necessary. However, when the clinical picture is atypical or ambiguous, ancillary testing is warranted.

Best initial test: Clinical examination. The classic evolution of lesions (papule to vesicle to erosion/ulcer to crust) on an erythematous base, grouped in clusters, with associated pain and inguinal lymphadenopathy, is highly suggestive.

If laboratory confirmation is needed, the preferred test is NAAT, which offers sensitivity of 90.9 to 100% with high specificity. This has largely replaced viral culture as the gold standard in many settings. NAAT can detect viral DNA even in crusted or healing lesions where culture yield drops considerably.

Viral culture remains useful and was historically the gold standard. Its main limitation is that sensitivity depends heavily on the stage of the lesion: 67 to 70% from an intact vesicle, 32% from a pustule, and only 17% from a crusted lesion. If you are going to culture, sample early and from a fresh vesicle.

Tzank test (scraping the base of a vesicle and looking for multinucleated giant cells under light microscopy) is a rapid bedside test but has a sensitivity below 40%. It cannot distinguish HSV from Varicella-Zoster Virus. It is useful as a quick triage tool when nothing else is available.

Type-specific IgG serology is useful for identifying prior infection and determining the HSV type (HSV-1 vs. HSV-2), which has implications for counseling because HSV-2 recurs genitally more frequently than HSV-1. IgM serology is not recommended because it does not reliably distinguish between primary and recurrent infection and has high false-positive rates.

PCR of cerebrospinal fluid is the test of choice for suspected HSV encephalitis or meningitis.

HIV testing should be performed in all patients with genital herpes, because HSV-2 infection increases HIV acquisition risk two to threefold due to mucosal disruption and local immune cell recruitment.

04Management and Treatment

Symptomatic care applies to all forms and includes analgesics, antipyretics, and antipruritics as needed. Antiseptic compresses or a sit bath with povidone iodine can help dry lesions, prevent secondary bacterial infection, and accelerate healing.

Primary first episode is the most severe presentation and always warrants antiviral therapy. The first-line agent is acyclovir, given orally at 5x200 mg/day or 3x400 mg/day for 7 to 10 days. Valacyclovir (the L-valyl ester prodrug of acyclovir with superior bioavailability and less frequent dosing) at 2x500 mg/day for 7 to 10 days is equally effective. Famciclovir at 3x250 mg/day for 7 to 10 days is the third option. For severe cases requiring hospitalization (extensive lesions, urinary retention, meningitis, inability to take oral medication), intravenous acyclovir at 5 to 10 mg/kg every 8 hours for 7 to 10 days is indicated.

Recurrent episodes are stratified by severity. Mild recurrences are managed with symptomatic treatment alone. Severe recurrences are treated with shorter antiviral courses, reflecting the fact that the immune system is now more capable of controlling viral replication. Options include acyclovir 5x200 mg/day for 5 days, or the highly practical "weekend regimen" of 2x800 mg/day for 2 days. Early initiation of therapy (ideally during the prodrome) is critical for efficacy.

Suppressive therapy is indicated when a patient experiences six or more recurrences per year. The goal is to reduce the frequency of outbreaks, decrease viral shedding, and improve quality of life. Treatment is continued for 6 to 12 months and then re-evaluated. First-line suppressive regimens include acyclovir 2x400 mg/day or valacyclovir 1x500 to 1000 mg/day. Suppressive therapy also reduces (but does not eliminate) the risk of transmission to sexual partners.

Immunocompromised patients (including those with HIV/AIDS) require longer treatment courses, and therapy should continue until clinical symptoms fully resolve. If the patient is at high risk for dissemination or cannot tolerate oral medication, IV acyclovir at 5 mg/kgBB every 8 hours for 7 to 14 days (or longer, up to 14 to 21 days) is indicated. If confirmed systemic infection occurs (hepatitis, pneumonia, encephalitis), escalate to acyclovir IV 3x10 to 15 mg/kgBB/day for at least 10 days.

Acyclovir resistance occurs primarily in immunocompromised patients. The alternative is foscarnet at 80 to 120 mg/kg/day IV divided in 2 to 3 doses. Renal function must be monitored closely because foscarnet is nephrotoxic. Topical alternatives include imiquimod 5%, cidofovir 1% gel, trifluridine, or foscarnet 1% topical. If resistance to both acyclovir and foscarnet develops, cidofovir IV is the third-line agent.

Pregnancy is a high-stakes scenario. Primary genital herpes in pregnancy is treated with acyclovir 5x200 mg for 10 days or valacyclovir 2x500 mg for 10 days. Recurrent episodes are treated for 5 days. IV acyclovir is given when manifestations are severe. If a pregnant woman has active genital herpes within 6 weeks of delivery, cesarean section is recommended before or within 4 hours of membrane rupture. Suppressive therapy with acyclovir 3x400 mg/day or valacyclovir 2x500 mg/day starting at 36 weeks of gestation can prevent lesions at delivery. Routine cesarean section is NOT indicated for recurrent genital herpes unless there is evidence of active viral shedding or visible genital lesions at the time of delivery.

Neonatal herpes is treated with acyclovir 20 mg/kg IV every 8 hours. Duration depends on extent: 14 days for disease limited to skin, eyes, and mouth, and 21 days for disseminated infection or CNS involvement.

Non-pharmacological measures apply across all forms:

1. Patient education about transmission, including asymptomatic viral shedding.

2. Abstinence from sexual contact with uninfected partners during prodromal symptoms or active lesions.

3. Screening for other sexually transmitted infections and HIV.

4. Partner notification.

5. Consistent use of condoms and spermicidal agents (reduces but does not eliminate transmission).

6. Circumcision reduces HSV-2 acquisition and transmission.

7. Avoidance of known triggers where possible.

8. Psychiatric referral when recurrent infections impair quality of life.

No approved vaccine for genital herpes currently exists.

Prognosis: Quo ad vitam: bonam. Quo ad functionam: bonam. Quo ad sanationam: dubia ad bonam (reflecting the chronic, recurrent nature of the disease).

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students get herpes questions wrong is by confusing the ulcer characteristics with other genital ulcer diseases. The exam loves to present a patient with a "painful genital ulcer" and ask for the most likely diagnosis. The critical discriminator is that herpes produces multiple, shallow, grouped vesicles or erosions on an erythematous base, while chancroid produces a single deep purulent ulcer, and syphilis produces a single painless ulcer with clean edges. If the vignette says "painful" and "multiple" and "vesicles," it is herpes until proven otherwise.

A second common trap is the primary vs. non-primary vs. recurrent distinction. Students often underestimate the severity of the primary episode. A vignette describing a sexually active young patient with their first-ever genital vesicular eruption accompanied by fever, myalgia, and bilateral inguinal lymphadenopathy is describing a primary first episode, not a recurrence. This matters because the treatment duration differs: 7 to 10 days for a primary episode versus 5 days or less for recurrent episodes.

A third testing point involves pregnancy management. The "next best step" question for a pregnant woman at 36 weeks with a history of recurrent genital herpes is to start suppressive acyclovir (3x400 mg/day). The cesarean section question hinges on whether there are active lesions or viral shedding at the time of delivery. Recurrent herpes alone is NOT an automatic indication for cesarean section.

Students also stumble on the IgM trap. IgM serology for HSV is not recommended because it does not reliably differentiate primary from recurrent infection and can be falsely positive. The correct serologic test is type-specific IgG for HSV-1 and HSV-2.

The acyclovir resistance pathway is tested in the context of immunocompromised patients (especially HIV/AIDS) who fail to respond to standard antiviral therapy. The next step is foscarnet (with renal monitoring), not simply increasing the acyclovir dose.

Finally, remember the HIV connection. Any time a question mentions a new diagnosis of genital herpes, the next best step in screening includes HIV testing, because HSV-2 increases HIV acquisition risk two to threefold.

The core competency being tested is the ability to: (1) recognize classic and atypical presentations of genital herpes, (2) correctly sequence the diagnostic workup (clinical first, then NAAT or culture if needed, with type-specific IgG serology for typing), (3) select the appropriate antiviral regimen and duration based on episode type and patient population, and (4) manage high-risk scenarios including pregnancy, neonatal exposure, immunocompromised hosts, and antiviral resistance.