Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children
Human Herpesvirus 8 Disease
(Last updated:11/6/2013; last reviewed:11/6/2013)
- Effective suppression of HIV replication with combination antiretroviral therapy (cART) is recommended to reduce the risk of human herpesvirus 8- (HHV-8)—associated Kaposi sarcoma (AIII).
- Routine testing to identify HHV-8—seropositive, HIV-infected patients is not recommended (BIII).
- Effective suppression of HIV replication with cART is recommended for all patients with evidence of active KS and other human herpesvirus 8-associated malignant lymphoproliferative disorders (AIII).
- The use of intravenous ganciclovir or oral valganciclovir is recommended for treatment of HHV-8—associated multicentric Castleman disease (BIII) and may be a useful adjunct for treating HHV-8-associated primary effusion lymphoma (BIII).
- Appropriate chemotherapy, in combination with potent cART, should be considered for patients with visceral KS or primary effusion lymphoma (BII*).
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
†Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
Human herpesvirus 8 (HHV-8) is a transmissible DNA virus, with similarities in DNA structure to Epstein-Barr virus. HHV-8 has been causally linked to all forms of Kaposi sarcoma (KS) (HIV-related and endemic) and with two rare neoplastic conditions usually associated with HIV infection: body cavity-based lymphoma, also known as primary effusion lymphoma (a B-cell lymphoma that typically arises in body cavities such as the pleural space) and multicentric Castleman disease (non-cancerous tumors that may develop in lymph nodes in a single site or in multiple sites throughout the body). The exact mechanism by which HHV-8 infection leads to neoplastic disease has not been fully elucidated, but seroconversion to HHV-8 antibody positivity virtually always precedes development of the tumors.1
Higher plasma HHV-8 DNA titers are associated with increased risk of KS.2
The prevalence of antibodies to HHV-8 varies widely with age and geography. In the United States and Europe, 1% to 3% of the general adult population is seropositive, with higher rates (8%) among men who have sex with men (MSM).3
Among other adult men in the general population, HHV-8-seropositivity was marginally associated with duration of heterosexual activity and positively associated with the number of lifetime sex partners and co-infection with hepatitis B virus and herpes simplex virus type 2 viruses; none of these were significantly associated with risk for women. In contrast, the adult seropositivity rate in Mediterranean countries ranges from 10 to 25%. In areas where HHV-8 is endemic, such as eastern and central Sub-Saharan Africa, HHV-8 seropositivity rates as high as 80% have been reported in adults.4-8
HHV-8 is transmitted through oral and genital secretions. Immunocompetent HHV-8-infected adults frequently shed HHV-8 in their oropharyngeal secretions, with viral DNA detected in saliva on 22% of test days.9
In areas where HHV-8 infection is endemic, the seroprevalence increases quickly during the first 5 years of life (especially when other family members are HHV-8-positive), then plateaus until adolescence and young adult years. In studies from rural Tanzania and Uganda, the rate of positivity for HHV-8 was 3.7% to 16% among infants, 58% among children aged 4 to 5 years, and 49% to 89% among adults aged >45 years.10,11
The seroprevalence among infants and children increased with the number of HHV-8-positive parents and siblings in the home, indicating non-sexual transmission for pre-pubertal children, with a limited role for perinatal transmission.10-17
In the United States, among a cohort of HIV-infected and at-risk HIV-negative adolescents with a median age of 19 years, 11.2% were HHV-8 seropositive.18
The highest rates were in adolescent HIV-infected males reporting sex with males (23%). Seropositivity was associated with HIV infection, MSM, a history of syphilis, and injection-drug use.18,19
HHV-8 can be transmitted through exposure to infected blood. Adult injection-drug users have an increased rate of HHV-8 positivity.18,19
In addition, recent evidence suggests that HHV-8 may be transmitted through blood product transfusions. In one study in an area of Uganda with a high incidence of HHV-8-seropositivity, the excess risk of acquiring HHV-8 through transfusion was nearly 3% when recipients of HHV-8 antibody-positive blood were compared with those receiving HHV-8 antibody-negative blood.20
A small study suggested that maternal HHV-8 infection might increase risk for perinatal transmission of HIV, although no evidence of mother-to-child transmission of HHV-8 infection was identified among HIV-infected infants.15
Women coinfected with HHV-8 and HIV had increases in both HHV-8 and HIV viral load in serum and/or cervical fluid during pregnancy, when compared to their pre-pregnancy levels and to HHV-8 and HIV coinfected, non-pregnant women.21
For HIV-infected individuals, coinfection with HHV-8 places them at risk of KS. The risk is highest in adults (compared to children). Before the advent of combination antiretroviral therapy (cART), the overall incidence of KS in HIV-infected adults was as high as 20%. However, the rate among children was low. In the United States and England, KS represented <1% of pediatric AIDS-defining illnesses. The risk of KS is also highest in individuals with severe immunodeficiency. KS, primary effusion lymphoma, and multicentric Castleman disease can occur at any CD4 T lymphocyte (CD4) count level, but they are described most often in HIV-infected patients with more advanced immunosuppression (CD4 cell count <200 cells/mm3
The incidence of KS appeared to decline even before the widespread use of cART. The reason is unclear but may have been related to the use of other antiviral agents, such as those used to treat cytomegalovirus (CMV) (i.e., foscarnet, ganciclovir, and cidofovir), which may inhibit HHV-8.22-28
With the advent of earlier and more aggressive cART, the incidence of KS in adults has continued to decrease. In a well-characterized, HIV-infected adult cohort, the incidence fell from 33/1,000 person-years before 1996, to 5.1/1,000 person-years in 1996 to 1998 and 1.4/1,000 since 1999. Of note, the risk of KS decreased sharply after the first few months on cART and remained low for 7 to 10 years after the initiation of antiretroviral therapy.29,30
Although KS occurs primarily in adults, the incidence in children has increased substantially as a result of the HIV pandemic, particularly in Africa and because of frequent use of immunosuppressive drugs. One series reported a 40-fold increase in incidence of childhood KS in Uganda in the era of AIDS;31
a 30-fold increase was also noted recently in South Africa,32
where KS represented 5% of pediatric cancers. In a cohort of 6,530 HIV-infected children in Uganda, 1.7% were found to have a malignancy, 91% of which were KS.33
A febrile illness with mild respiratory symptoms and a maculopapular rash and a mononucleosis-like illness have been associated with primary infection in young, immunocompetent children.34,35
A similar self-limited illness has been described in adults with primary infection. Evidence suggests more significant symptomatology in immunodeficient adults with primary infection, including reports of fever, arthralgia, splenomegaly, and bone marrow suppression.36,37
KS presentation varies widely, but most patients have non-tender, purplish, indurated skin lesions. Intraoral lesions can be seen and visceral dissemination can occur, occasionally without skin lesions. Multicentric Castleman disease presents with generalized adenopathy and fever and may progress to multiorgan failure. Primary effusion lymphoma presents with symptoms related to fluid accumulation in the pleural or pericardial space or with abdominal distention. In South Africa32
the average age at the time of diagnosis of KS in HIV-infected children was 72 months; median CD4 percentage and count at the time of diagnosis were 12% and 440 cells/μL, respectively. Just over half presented with skin lesions; 30% had adenopathy and 25% had oral lesions. In a study in Mozambique, biopsy-proven KS was observed in 32 HIV-infected children (0.8% of all HIV-infected children seen between 2003–2008); mean age was 8.3 years and median CD4 percentage was 16%.38
KS affected the lymph glands in 5 children, the skin in 10 children, and was mixed in 13 children (both cutaneous and nodal in 12 children and cutaneous and lung in 1 child).38
Making the Diagnosis
Laboratory diagnosis of HHV-8 infection is most commonly based on serologic assays, such as immunofluorescence, enzyme-linked immunosorbent assay, and Western blot. However, without a standard for diagnosing HHV-8 infection, these tests range in sensitivity from 80% to ≥90% and interassay agreement is poor.39
Combination assays containing both lytic and late-phase antigens may improve detection rates. Nucleic acid-based tests, such as in situ
DNA hybridization and polymerase chain reaction (PCR), are important for tissue diagnosis. Although these tests have high levels of sensitivity, specificity and reproducibility are highly variable. Only 40% to 60% of patients with proven KS will have detectable HHV-8 DNA in their blood by PCR.
Laboratory diagnosis of KS is based on histologic examination of affected tissues.
Routine testing of children and adults for HHV-8 is not recommended; therefore, the serostatus of HIV-infected patients usually is unknown. Although the efficacy of condoms in preventing HHV-8 exposure has not been established, HIV-infected patients should use male latex condoms correctly and consistently during sexual intercourse to reduce exposure to sexually transmitted pathogens. HIV-infected injection-drug users should be counseled not to share drug-injection equipment, even if both users are already HIV-infected, because of the risk of becoming infected with HHV-8 or other blood-borne pathogens. Adolescents who are diagnosed with KS should be counseled about the possibility of transmitting HHV-8 to their sexual contacts through intercourse and, possibly, kissing.
In the future, HHV-8 testing of donated blood products before use in immunodeficient patients may be considered. In addition, routine use of leukocyte reduction for red cell transfusions may lower the transmission risk.
Infants can acquire HHV-8 perinatally or through contact with infected family members and playmates. No effective intervention is known to prevent childhood acquisition of HHV-8, although avoidance of salivary exposure (e.g, via pre-mastication of food) may theoretically prevent transmission.
Preventing First Episode of Disease
The use of cART with suppression of HIV replication has markedly decreased the incidence of KS in HIV-infected adults (AIII
). Routine testing to identify HHV-8-seropositive, HIV-infected individuals is not recommended (BIII
). Although several antiviral agents (namely, ganciclovir, foscarnet, and cidofovir) inhibit HHV-8 replication in vitro, no data exist on their use to prevent KS in patients who are HIV/HHV-8 coinfected.
Specific treatment recommendations are not included in this report because the HIV-related clinical entities associated with HHV-8, such as KS and Castleman disease, are oncologic and traditionally have been treated with cytotoxic chemotherapy. However, in HIV-infected patients with KS, effective suppression of HIV replication with cART may prevent KS progression or occurrence of new lesions. Therefore, cART is recommended for all HIV-infected patients with evidence of active KS and other HHV-8-associated malignant lymphoproliferative disorders (AIII
). Appropriate chemotherapy, in combination with potent cART, should be considered for patients with visceral KS or primary effusion lymphoma (BII*
). A retrospective analysis of 28 HIV-infected children in Mozambique treated with cART and 6 cycles of monthly paclitaxel showed that treatment was well-tolerated and resulted in complete and sustained remission of KS in 19 children.38
In HIV-infected adults with KS, HHV-8 cellular viremia and higher viral load have been associated with disease progression.40
Treatment with specific antiviral agents that have in vitro
activity against the lytic but not latent phase of HHV-8 (e.g., ganciclovir, foscarnet, cidofovir), has not been widely studied. No therapeutic effect was noted when oral valganciclovir was given to five HIV-negative adults with KS.41
In addition, the vast majority of infected cells are not undergoing lytic replication, and anti-herpesvirus medications have had little or no effect on established KS or HHV-8 cellular viremia. Studies are under way of methods that induce lytic replication or attack the episomal (latent) HHV-8 genome.42,43
In contrast to KS, in Castleman disease, many of the cells support lytic replication of HHV-8, and treatment with anti-herpesvirus drugs has led to substantial clinical improvement in some studies.43
IV ganciclovir or oral valganciclovir is recommended for treating multicentric Castleman disease (BIII
and may be a useful adjunct for treating primary effusion lymphoma (BIII
Monitoring and Adverse Events (Including IRIS)
Rapid progression of KS after initiation of cART and after a change from a failing regimen to a more potent one has been reported, representing immune reconstitution inflammatory syndrome (IRIS) associated with immunologic improvement. IRIS-related progression of KS usually appeared within 8 weeks after start of a potent cART regimen. Most patients experienced rapid progression of cutaneous lesions; however, sudden worsening of pulmonary KS, with resultant deaths, was reported in at least 4 patients. All reported fatalities were linked to pulmonary KS. In most cases, cART was continued with stabilization and then regression of lesions. In more severe cases, especially those involving visceral lesions, chemotherapy was instituted, and in combination with cART, led to regression of the KS.47,48
For patients with disease manifestations of HHV-8 infection who are treated with ganciclovir or valganciclovir, refer to the chapter on CMV infections (Monitoring and Adverse Events
) for information on treatment-associated adverse events.
Managing Treatment Failure
No recommendations exist for management of treatment failure.
Effective suppression of HIV replication with cART in HIV-infected patients with KS may prevent KS progression or occurrence of new lesions and is recommended for all individuals with evidence of active KS and other HHV-8-associated malignant lymphoproliferative disorders (AIII
Discontinuing Secondary Prophylaxis
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