is hhv 8 contagious?

In the general population of the United States and other developed countries, nonsexual transmission appears to be infrequent. HHV-8 appears to be transmissible, although less frequently, via exposure to blood.

The human herpesvirus (HHV) belong to the herpesvirus family which is a group of viruses that can infect both animals and humans. Over 130 species of herpesvirus are known, but only eight of these are known to infect humans. These, collectively, are known as human herpesvirus, or HHV.

The herpesvirus family are DNA viruses, which means that they have DNA rather than RNA as their genetic material (the HIV virus, for example, is an RNA virus). Other DNA viruses that affect humans are adenoviruses, different types of which can cause the common cold, conjunctivitis and bronchitis, as well as human papillomaviruses, various strains of which can cause warts, genital warts, cervical cancer, and anal cancer. 1 It is important to note that, although these are all DNA viruses, they are not otherwise related to one another.

Human herpesviruses are contagious, which means that they are passed from person to person. Because they do not live for long outside the human body, they are usually passed on by direct contact with bodily fluids, rather than infected objects. Human herpesviruses can be passed on by: 2 3

Newborn babies can be infected in the womb or during birth.

The human herpesvirus family is the source of many common diseases, including chickenpox, shingles, mononucleosis, cold sores and genital herpes. Infections caused by human herpesvirus tend to remain latent, which means they stay in the host even after the primary infection has resolved and can reactivate later.

Only eight members of the herpesvirus are known to infect humans, which is why they are known as human herpesviruses. 4 Some of these viruses have more than one name. The eight herpesviruses that infect humans are: 2 ref4 5

Because referring to these viruses can become confusing due to the similarity of the names, this document will use the alternative names. For example, human herpesvirus 1 will be called herpes simplex virus 1 or HSV-1, and human herpesvirus 4 will be called Epstein-Barr Virus or EBV.

Human Herpes Virus 1 and 2 are also known as Herpes Simplex Virus 1 and 2. They are extremely common, with HSV-1 being present in 90 percent of adults and HSV-2 being present in between ten and 30 percent of adults. 2 HSV-1 is usually associated with herpes labialis, but can sometimes cause genital herpes, while HSV-2 is usually associated only with genital herpes.

Most people are infected with HSV-1 during early childhood, and symptoms are mild; some children may not show any symptoms at all. 5 HSV-1 is spread by saliva and/or respiratory secretions, but HSV-2 is almost always spread by genital contact. People usually contract HSV-2 later in life than they contract HSV-1. However, in the U.S.A., Europe and some parts of the western Pacific, it is becoming more common to contract HSV-1 for the first time during sexual activity as a teenager or adult, which is leading to an increase in the number of cases of genital herpes caused by HSV-1. 6

Read more about Herpes Simplex »

Herpes labialis, also known as oral herpes, cold sores or fever blisters, is caused by HSV-1. It is characterized by recurrent outbreaks of painful blisters on the lips and is highly contagious. People with an active outbreak of herpes labialis, i.e who have an active cold sore, should avoid kissing or oral sex. Stress, illness or weather conditions may trigger the appearance of cold sores.

Herpes labialis is not usually very serious, although people with weak immune systems are more at risk of complications.

Read more about Herpes Labialis »

Genital herpes is characterized by itchy painful blisters on the genitals and in the genital region. It is usually caused by HSV-2 and is almost always sexually transmitted. For this reason, anyone with an active blister caused by genital herpes should refrain from sexual activity until the blister has healed. Like cold sores, outbreaks of genital herpes can be triggered by stress, illness or weather conditions.

Read more about Genital Herpes ».

Most babies who are born to mothers who have HSV-1 or HSV-2 are not at all affected by it, but if the mother contracts HSV for the first time during the third trimester of pregnancy, the chances of the baby experiencing complications is increased. HSV infection in very young babies, or newborns, is known as neonatal herpes.

The majority of cases of neonatal herpes happen when the baby is exposed to the virus in the birth canal during delivery. 7 The affected baby usually begins to show symptoms during the first month of life.

There are three main subcategories of neonatal herpes: 7

Skin infection, in which a rash forms on the skin and around the eyes and mouthEncephalitis, inflammation of the brain which can cause problems such as seizuresDisseminated infection, in which the virus spreads throughout the body and affects various organs

Symptoms of neonatal herpes include: 7 8

Neonatal herpes is rare, but is considered an emergency, and medical attention should be sought as soon as symptoms appear.

The varicella zoster virus, also known as VZV, herpes zoster and sometimes simply as zoster, causes the common childhood disease chickenpox, when it infects a person for the first time and, when reactivated later in life, causes the painful skin condition known as shingles.

Although chickenpox is a common disease, its incidence is falling due to effective widespread vaccination campaigns in most developed countries. Nevertheless, it is a common childhood condition, with outbreaks periodically happening at kindergartens and elementary schools. It is also common for the siblings, parents or caregivers of an affected child to contract the virus, especially if they have not been vaccinated. The condition tends to be more severe among teenagers and adults, but relatively mild in children.

The most distinctive symptom of chickenpox is an itchy, blister-like rash. Other symptoms include fever, headache and body aches, which often appear before the rash develops. The outlook in cases of chickenpox is usually good, and most people recover without particular treatment. Complications can develop, but these are not common. Potential complications include pneumonia, secondary bacterial infections, and, more rarely, encephalitis.

Read more about Varicella Zoster (Chickenpox) »

After the primary varicella zoster infection has resolved, the varicella virus remains dormant in the body for life. It can be reactivated later in life by stress or illness. Older adults and those with weakened immune systems may be more at risk of developing shingles.

When the virus reactivates, it travels up the nerve in which it has lain dormant to the surface of the skin, causing painful lesions. These are usually restricted to an area of the skin served by a particular nerve, known as a dermatome, leading to a characteristic stripe pattern of lesions.

Read more about the Signs of Shingles »

Shingles is very uncomfortable and may become complicated if it affects the ears or eyes, or if a secondary bacterial infection affects the lesions and leads to a skin infection.

Shingles is treated with antiviral medications and pain management medications, and most people recover well within two weeks. Some, however, experience ongoing pain and discomfort in the affected area; this is known as post-herpetic neuralgia.

Read more about Shingles »

It is estimated that about 90% of the world’s entire population carries the Epstein-Barr virus (EBV). Most people contract the virus in childhood, when symptoms of infection are mild and often go unnoticed.

The Epstein-Barr virus remains in the body for life. Periodically, people with EBV shed the virus in their bodily fluids and tissues. When this happens, people who come into contact with their saliva or respiratory droplets may contract the virus. It is possible to have EBV and not know it.

Although most people who contract EBV remain asymptomatic for life, some may develop a condition known as infectious mononucleosis, which is also called glandular fever or simply mono. This is more common in people who encounter EBV for the first time during adolescence or early adulthood.

The main features of this condition are fatigue and a severe sore throat. The fatigue associated with infectious mononucleosis can last up to six months in extreme cases, but usually resolves after three months. Most people recover well, but complications can develop. These include encephalitis, a ruptured spleen and extremely enlarged tonsils.

Cytomegalovirus, like other members of the human herpesvirus family, is commonly found worldwide. In most people, the virus lies dormant in the body once the original infection has cleared up and can be reactivated by stress or illness.

Infection with cytomegalovirus (CMV) is extremely common, and it is estimated that between 60 and 90 percent of all adults have had CMV at some time in their lives. Usually, the virus is contracted during childhood, though it is also possible to be infected for the first time as an adult. 9 In adolescents and adults, CMV infection may cause CMV mononucleosis, which is similar to EBV mononucleosis. In healthy people, CMV infection is often asymptomatic or has only mild, non-specific symptoms such as fever, malaise and swollen lymph glands.

Most people who have CMV will have no ill-effects, but people with weakened immune systems may experience serious complications. Likewise, babies born to mothers who are infected with CMV for the first time during pregnancy may develop congenital cytomegalovirus infection, 10 which can be very serious.

Read more about Cytomegalovirus Infection »

Human herpesvirus 6 is quite commonly found in the human population, affecting between 25 and 95 percent of many populations. Most people contract HHV-6 by the age of three years, 11 and in the majority of cases, the infection is asymptomatic. 12 By far the most common strain of HHV-6 is HHV-6B, which is implicated in the vast majority of all HHV-6 infections, including the common childhood condition roseola infantum. HHV-6A is much less common and is usually found in people with weakened immune systems, ref12 for example people affected by HIV infection or chemotherapy.

HHV-6 is spread from person to person by contact with respiratory secretions from coughing or sneezing. 13 Like all strains of human herpesvirus, HHV-6 causes a primary infection, such as roseola infantum, and then stays latent in the body, where it can be reactivated by stress or other illness. 11 In some adults who experience a primary infection of HHV-6, a mononucleosis-like condition can develop. 12

It is much more common for HHV-6 reactivation to happen in people with weakened immune systems than those with normal immune systems. 12 When the virus reactives, it can affect any organ, including the heart, lungs, kidneys and brain. If the brain is involved, complications such as otitis media, hepatitis and encephalitis may occur. ref12

In most cases, HHV-6 infection is an uncomplicated condition that clears up on its own. 12 Laboratory tests are not usually needed to diagnose a primary infection, but are sometimes used to identify HHV-6 reactivation in people with weakened immune systems. ref12

There is no specific treatment for HHV-6 infection 14 but some evidence shows that antivirals such as ganciclovir, cidofovir and foscarnet may be useful in some cases. 11 Antivirals should be used in cases of HHV-6 primary infection or reactivation in people with compromised immune systems.

Roseola infantum is a common childhood condition, caused by infection with HHV-6, that causes high fever, irritability, loss of appetite and a rash. It is most common in children between the ages of six months and two years, but can affect adults, though symptoms tend to be mild in both cases. It is the primary infection caused by human herpesvirus 6, in the same way that chickenpox is the primary infection of HHV-3, the chickenpox virus. HHV-7 can also sometimes cause roseola infantum.

A common complication of roseola infantum is febrile seizures,** which can sometimes require hospitalization, but are usually passing and not an indication of epilepsy. It is rare for an adult or a child to have roseola more than once, but this can happen if the affected person is immunosuppressed.

Read more about Roseola Infantum »

HHV-7, like HHV-6, affects upwards of 90 percent of all adults worldwide. 15 Infection with HHV-7 usually occurs in childhood or infancy, 16 and is usually asymptomatic. The conditions caused by this human herpesvirus are generally less well-understood overall than those caused by some of the other strains of the virus.

In children, primary infection with HHV-7 can cause a fever, on its own or in combination with other symptoms in a condition that resembles roseola infantum. While HHV-7 is less likely to reactivate than some other human herpesviruses, it can reactivate in people with weakened immune systems, especially among people who have recently received organ transplants. 15 Infections caused by HHV-7 are not generally very serious in people with healthy immune systems 16

HHV-8, also known as KSHV, or Kaposi’s Sarcoma Herpesvirus, is not as common as the other strains of HHV discussed here. In the U.S., it is estimated that less than five percent of the total population carry HHV-8, with most cases concentrated among men who have sex with men and intravenous drug users. However, HHV-8 is much more common in sub-Saharan Africa, where it is not necessarily associated with drug use or men who have sex with men. In sub-Saharan Africa, most people with HHV-8 contract the virus during childhood, 17 with some regions reporting prevalences of between 30 and 80 percent. 18 HHV-8 is spread by contact with respiratory droplets and nasal secretions, ref17 19 and may be sexually transmitted.

Most people who contract HHV-8 do not show symptoms, 19 but some young children and immunocompetent adults may develop symptoms such as: 17 18

Immunosuppressed people who contract HHV-8 may experience the symptoms listed above, as well as enlarged lymph glands, enlarged spleen and a blood disorder known as pancytopenia. This last is a condition in which levels of red blood cells, white blood cells and platelets all drop, 17 leading to fatigue, anemia, bruising and a weakened immune system.

November 8, 2000

Most people do not think of kissing as a way of spreading serious sexually transmitted diseases. But kissing between men may be what spreads human herpes virus 8 (HHV-8), the cause of Kaposi’s sarcoma, according to researchers at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle.

The findings are published in the article, “Mucosal Shedding of Human Herpes Virus 8 in Men,” in the Nov. 9 New England Journal of Medicine.

Kaposi’s sarcoma is a tumor that usually appears as purplish raised blotches on the skin or in the mouth. It can also form inside internal body cavities, such as the abdomen and chest. This cancer has been recognized for centuries among people living in Southern Europe, the Middle East and Africa, but became more frequent in the United States and Western Europe in the early 1980s. At that time, an epidemic of Kaposi?s sarcoma in homosexual men was what heralded the arrival of the AIDS epidemic.

Kaposi’s sarcoma most often occurs in people with compromised or suppressed immune systems. That is why it attacks people with AIDS. That is also why it is also sometimes found in people who have received organ transplants — they take medications to suppress their immune system in order to reduce the risk that the body will reject the new, foreign organ. The cancer can usually be treated effectively with chemotherapy, though occasionally, it can spread to internal organs and prove fatal.

HHV-8 was first characterized in 1994 by researchers at Columbia University who found it to be associated with Kaposi’s sarcoma. HHV-8 is the latest recognized addition to a family of human herpes viruses that include those responsible for oral and genital herpes, chickenpox and infectious mononucleosis. Although previous studies had indicated that in the United States HHV-8 was more common among people with many sexual partners, the exact mechanism of transmission remains unclear. In addition, in Africa and in Southern Europe, the virus is found in children as well as adults, suggesting that non-sexual spread can occur.

“When we think of STDs, we traditionally think of infections which are spread through sexual contact. It turned out that HHV-8 has been very hard to find in genital secretions. One of the reasons people started looking at the mouth is because Kaposi’s sarcoma often shows up first as lesions in the mouth,” says Dr. John Pauk, the lead author, who conducted the study during his fellowship in infectious diseases at the UW School of Medicine. He is now in private practice. “We found the virus in the mouth more often and in higher amounts than in genital secretions.”

So far, the virus has been very difficult to grow in the laboratory and techniques to detect the virus have relied on detection of the viral DNA in the laboratory of Dr. Meei-Li Huang, research scientist at Fred Hutchinson Cancer Research Center. These findings are strengthened by studies performed by Dr. Scott Brodie, research assistant professor in the Department of Laboratory Medicine and director of molecular virology laboratories at the UW School of Medicine. Dr. Brodie showed that HHV-8 replicates in the cells that line the mouth.

Among men who have sex with men in Seattle, the virus was found in about 40 percent of the men with HIV infection and about 20 percent of men without HIV.

The study analyzed 112 men who have sex with men and found three independent risk factors for infection with HHV-8: * A history of sex with a partner who has Kaposi’s sarcoma.* A history of deep kissing – the exchange of saliva – with an HIV-positive partner.* The use of amyl nitrite capsules (known as ‘poppers’) or inhaled nitrites. Researchers are not sure why this drug, taken to enhance the sexual experience, showed up as a risk factor in their study.

Despite the large percentage of men in Seattle who were infected with HHV-8, Kaposi’s sarcoma is less common now than in the early days of the AIDS epidemic. This may be largely due to the success in treating patients with AIDS using drugs that halt the damage done to the body?s immune system.

“Currently, the number of people who go from infection with HHV-8 to any clinical syndrome is very low. Even if you become infected with HHV-8, your risk of developing cancer is very slim,” Pauk said. Most people infected with HHV-8 are without symptoms.

The public health ramifications of this study remain unclear. Researchers are not telling people to modify their sexual practices. But they are suggesting that men who have sex with men, especially those with HIV infection, should be aware of the risks that might be associated with deep kissing. “‘Safer sex’ messages have focused on exposure to genital secretions. The issue that this paper raises is that kissing can also be a risk for a virus,” said one of the paper’s authors, Dr. Anna Wald. She is director of the UW Virology Research Clinic and an assistant professor of allergy and infectious diseases in the UW School of Medicine and of epidemiology in the School of Public Health and Community Medicine.

The other co-authors on this paper include Dr. Lawrence Corey of the UW and a member of the clinical research division of Fred Hutchinson Cancer Research Center; Dr. David Koelle, Dr. Connie Celum and Stacy Selke of the UW; and Dr. Timothy Schacker of the University of Minnesota.

The UW Virology Research Clinic is undertaking more studies to examine HHV-8 transmission and infections. Researchers are particularly looking for couples of gay men who can be followed over time. For more information, call the clinic at (206) 720-4340.

The seroprevalence of human herpesvirus-8 (HHV-8)—also known as Kaposi sarcoma-associated herpesvirus (KSHV)—varies worldwide and is estimated to be 1% to 5% in the general U.S. population1,2 compared with 10% to 20% in certain Mediterranean countries and 30% to 80% in parts of sub-Saharan Africa.3 In the United States, men who have sex with men (MSM) and persons with HIV infection are at increased risk for HHV-8 infection. Among MSM without HIV infection, the seroprevalence ranges from 13% to 20% and HHV-8 seroprevalence increases to 30% to 35% among MSM with HIV infection.4-6 Injection drug use may also be a risk factor for HHV-8 seropositivity,7 although this association has not been consistently observed.8

HHV-8 is etiologically associated with all forms of Kaposi sarcoma (KS) including classic, endemic, transplant-related, and AIDS-related, as well as rare neoplastic disorders (primary effusion lymphoma and solid organ variants) and the lymphoproliferative disorder known as multicentric Castleman’s disease (MCD). Although the precise pathogenesis for these tumors remains unclear, infection with HHV-8 precedes their development.9 Patients who are HHV-8 seropositive and exhibit HHV-8 viremia are at increased risk (approximately nine-fold) for developing KS relative to those without HHV-8 viremia.10 HHV-8 viremia typically accompanies symptomatic episodes of multicentric Castleman’s disease.11

The overall prevalence of KS in the U.S. was as high as 30% among patients with AIDS prior to the advent of effective antiretroviral therapy (ART).12 The incidence of KS rose steeply in the United States between 1981 and 1987 and subsequently gradually declined.13 Reasons for this reduction in KS incidence prior to the widespread availability of ART include the deaths of patients with advanced AIDS who were most susceptible to KS, and the increasing use by individuals with HIV individuals of antiviral drugs that may have had activity against HHV-8 (zidovudine for the treatment of HIV; ganciclovir, foscarnet, and cidofovir use for treatment of CMV disease).14 Supporting the latter hypothesis, observational studies indicate that patients receiving ganciclovir or foscarnet (but not acyclovir) develop KS at a reduced rate.15-18 A more marked reduction in KS incidence occurred beginning in 1996, shortly after the introduction of protease inhibitor-containing ART in the U.S. Despite these declines, KS is among the most common cancers among the AIDS population in the U.S.,19 and HIV infection increases the risk of KS several thousand fold even in the ART era.20 Notably, KS is a common cancer in many countries in sub-Saharan Africa,21 fueled in part by the HIV pandemic, and incidence has not declined in regions of sub-Saharan Africa where ART coverage is increasing but incomplete.22,23 PEL and MCD remain rare relative to KS.24,25

KS and PEL are described most frequently among individuals with HIV exhibiting advanced immunosuppression (CD4 T lymphocyte cell counts <200 cells/mm3), although they may occur at any CD4 cell count. Recent reports of KS occurring at higher CD4 cell counts in the United States26,27 suggest that clinicians caring for patients with HIV should be vigilant for the clinical manifestations of KS in patients at risk of HHV-8 infection, regardless of CD4 cell count. MCD may arise at any CD4 cell count.

Most individuals latently infected with HHV-8 are asymptomatic.28 Immunocompetent children and organ transplant recipients infected with HHV-8 may develop a primary infection syndrome consisting of fever, rash, lymphadenopathy, bone marrow failure, and occasional rapid progression to KS.29,30 KS manifestations vary widely, but most patients have nontender, hyperpigmented, macular or nodular skin lesions. Oral lesions occur in approximately one-third of patients31 and are predictors of pulmonary involvement and less favorable treatment outcomes.32-34 Lymphatic involvement is also common and may lead to debilitating lower extremity edema. Involvement of internal viscera occurs in up to 50% of cases and may be difficult to diagnose. Patients with visceral involvement may be asymptomatic, or manifest with shortness of breath, painless rectal bleeding or melena, and other non-specific pulmonary and gastrointestinal symptoms.35-40

PEL characteristically presents with effusions isolated within the pleural, pericardial, or abdominal cavities,41 but mass lesions and “extracavitary” disease within skin, hematopoietic organs, and the gastrointestinal tract have been described.42-44 MCD routinely manifests with systemic symptoms including fever and night sweats, and findings on examination including generalized adenopathy, fever and hepatosplenomegaly.24,45 MCD may mimic other inflammatory conditions including sepsis, with hypotension, clinical evidence of a systemic inflammatory response, and progression to multi-organ failure.24,46,47

Another HHV-8- associated condition, the KSHV inflammatory cytokine syndrome (KICS), has been more recently described.48-50 Patients with this syndrome display MCD-like inflammatory symptoms, but do not have pathological findings of MCD. Patients with KICS are frequently critically ill and demonstrate marked elevations in IL-6 and IL-10, as well as high plasma HHV-8 viral loads. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or PEL, and there may be significant clinical overlap between these conditions.

The diagnoses of KS, MCD, and PEL depend on cytologic and immunologic cell markers, as well as histology. Clinical diagnosis alone is not sufficient for KS, and tissue examination is needed to confirm the diagnosis.51,52 Confirmation of these diagnoses is achieved through immunohistochemical staining of tumors with antibodies recognizing the HHV-8-encoded latency-associated nuclear antigen (LANA).53,54 While not commercially available, diagnoses may also be confirmed utilizing polymerase chain reaction (PCR) to identify HHV-8 DNA within tumor tissue.53,54 Use of serologic testing for HHV-8 antibodies is currently not indicated for either diagnostic testing or routine screening for HHV-8-related illnesses due to lack of standardization and poor sensitivity and specificity of these assays.55 In addition, use of PCR to quantify HHV-8 in the peripheral blood has no established role in the diagnosis of KS, MCD, or PEL.11

The mode(s) of transmission of HHV-8 remains unclear, but epidemiologic and virologic data suggest that saliva is a source of infectious virus and may be an important route of transmission. Asymptomatic HHV-8 infection is often associated with HHV-8 shedding in the saliva and occasional shedding in genital secretions.4,28,56 In a study of 50 HHV-8-infected MSM in the U.S., HHV-8 was detected by PCR in the saliva of 39% of participants and on more than 35% of days on which samples were obtained.4 HHV-8 shedding is also common among persons in sub-Saharan Africa. Among HHV-8-infected adults without KS in Uganda, 22% had HHV-8 DNA detected in saliva and 3% in genital secretions; HHV-8 was also detected in saliva of 68% of commercial sex workers in Kenya.57,58 Based on these observations, viral shedding may result in HHV-8 transmission to uninfected partners through behaviors associated with exposure to saliva or genital secretions. HHV-8 transmission through blood transfusion has been reported in Uganda, where HHV-8 is endemic;59 however, studies from the U.S. and Western Europe have not found evidence to support HHV-8 transmission through blood transfusion.60,61

Recommendations to prevent exposure to HHV-8 do not yet exist; screening patients for HHV-8 serostatus or behavioral modifications to limit potential exposures have not been validated and are not currently recommended.

Despite observational evidence supporting a role for anti-HHV-8 therapy in preventing the development of KS, the toxicity of current anti-HHV-8 treatments outweighs the potential use for prophylaxis (AIII). Because strong risk factors for the development of KS in HIV-positive individuals include both low CD4-positive T cell count62 and uncontrolled viremia,63 early initiation of ART is likely to be the most effective measure for the prevention of KS (AII). Although epidemiologic data are somewhat conflicting, there are no antiretroviral agents which have proven clearly superior for the prevention of KS.60-65 Therefore, specific classes of ART for prevention of KS or other HHV-8-associated illnesses are not recommended (AII).

KS: Chemotherapy, in combination with ART, should be administered to patients with visceral involvement (AI) and is likely to be a useful adjunctive therapy in individuals with disseminated cutaneous KS (BIII).64-67 Liposomal doxorubicin and paclitaxel exhibit comparable response rates and progression-free survival, although liposomal doxorubicin exhibits less high-grade toxicity relative to paclitaxel and is, therefore, generally preferred as first-line therapy (AI).64 Paclitaxel has proven effective with relapse following treatment failure with liposomal doxorubicin.67 Importantly, concurrent use of corticosteroids in patients with KS should be either avoided or used with caution and under close observation, given the potential for exacerbation of life-threatening disease, as well as an association between the use of corticosteroids and development of KS (AIII).68-70 KS arising in the setting of organ transplantation is related to the use of corticosteroids and other non-targeted immunosuppressives, especially in geographic areas of high HHV-8 seroprevalence.71 Transplant-associated KS may be effectively treated or avoided with use of immunosuppressive regimens which include drugs that inhibit the mammalian target of rapamycin (mTOR) such as rapamycin and sirolimus.71-73

The antiviral agents ganciclovir, foscarnet, and cidofovir exhibit in vitro activity against HHV-8.74,75 Available data indicate that antivirals have limited efficacy for the treatment of KS (ganciclovir and cidofovir)76,77 and HHV-8-associated hemophagocytosis (foscarnet).78,79 Therefore, antiviral agents with activity against HHV-8 are not recommended for KS treatment (AII).

PEL: Chemotherapy, in combination with ART, should be administered to patients with PEL (AIII), although, given its rarity, there are limited data available from longitudinal observational series or prospective randomized clinical trials. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in combination with ART has demonstrated some benefit, albeit still limited, for PEL, and the combination of infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) demonstrated superior survival relative to CHOP in one pooled analysis (BII).80,81 Rituximab may be considered for rare CD20-positive cases of PEL (CIII), and dose-adjusted EPOCH (DA-EPOCH) may be beneficial for some patients (CIII).82,83 Antiviral agents, including valganciclovir or zidovudine, may also be used as adjunctive therapies, but available data are limited for this approach and additive toxicities may limit their utility (CIII).84-86

MCD: There are no standardized treatments for MCD, but several treatment regimens have been utilized. The use of either IV ganciclovir or oral valganciclovir are options for treatment of MCD (CII). A 3-week course of twice-daily IV ganciclovir or oral valganciclovir was associated with remissions in MCD in one report,87 and a combination of valganciclovir and high-dose zidovudine has led to durable clinical remissions (CII).88 Rituximab has also emerged as an important adjunctive treatment for MCD (CII),89,90 although up to one-third of patients receiving rituximab may have subsequent exacerbations or emergence of KS.91,92 For patients with concurrent diagnoses of KS and MCD, use of both rituximab and liposomal doxorubicin is recommended (BII).45 Therapeutic monoclonal antibodies targeting either interleukin-6 (IL-6) or the IL-6 receptor have also proven effective for some patients with MCD and may be utilized in some situations (BII).93-95 At this time, there is insufficient evidence to recommend monitoring IL-6 levels for diagnostic or prognostic purposes. Although corticosteroids are potentially effective as an adjunctive therapy for MCD, they should be used with caution or avoided, especially in patients with concurrent KS, given potential for exacerbation of life-threatening KS (AIII).68-70

Detailed recommendations for the treatment of HHV-8 malignancies (including chemotherapy and radiation therapy) are beyond the scope of these guidelines. Treatment should be undertaken in consultation with an experienced specialist with appropriate guidance from both oncology and infectious disease specialists (AIII). Preferred ART to be given concurrently with chemotherapy for HHV-8 malignancies should be chosen to minimize drug-drug interactions and additive toxicities.

Early initiation of ART may prevent incident KS and PEL.74,96 ART that suppresses HIV replication should be administered to all patients with HIV and KS (AII), PEL (AIII), or MCD (AIII), although insufficient evidence exists to support using one ART regimen over another.

Immune reconstitution inflammatory syndrome (IRIS) may occur among HHV-8-infected patients initiating ART.

KS: KS-IRIS is characterized by either first presentation of KS (“unmasking”), or paradoxical worsening of pre-existing KS following ART initiation, and can be associated with significant morbidity and mortality.97 Studies in the U.S. and Europe reveal that KS is the most commonly reported form of IRIS, occurring in 6% to 34% of KS patients with HIV who are initiating ART.98,99 In sub-Saharan Africa, exacerbations of KS compatible with KS-IRIS have been reported in 18% to 61% of adults initiating ART treatment.100-102 Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log10 copies/mL, detectable pre-treatment plasma HHV-8, and initiation of ART alone without concurrent chemotherapy.97 Treatment of KS-IRIS includes systemic chemotherapy and supportive measures. Steroids are strongly discouraged for management of KS-IRIS, as corticosteroid therapy has been associated with exacerbation of pre-existing KS in persons with HIV (AIII).70,103

PEL: No data exist on the frequency with which initiation of ART complicates the course of primary effusion lymphoma.

MCD: A small number of patients with HIV-associated MCD have experienced clinical decompensation upon initiation of ART.104,105

Although neither the incidence nor predictors of HHV-8-associated IRIS are well-described, suppression of HIV replication and immune reconstitution are key components of therapy, and initiation of ART should not be delayed (AIII).

Effective suppression of HIV replication with ART in patients with HIV and KS may prevent KS progression or occurrence of new lesions. Because KS is an AIDS-defining cancer, ART is indicated for all patients with active KS (AII). Suppression of HIV replication to prevent recurrence is also recommended for patients with MCD (AIII) as well as those with malignant lymphoproliferative disorders (AIII).

The seroprevalence of HHV-8 infection among pregnant women with HIV varies by geographic area, ranging from 1.7% among U.S.-born and 3.6% among Haitian-born women in New York City to 11.6% among pregnant women from 4 other U.S. cities.106 Pregnancy does not appear to affect the prevalence of antibodies to HHV-8 or the antibody levels,107 although levels of HHV-8 DNA in the peripheral blood may increase late in pregnancy.108 HHV-8 seropositivity does not appear to influence pregnancy outcome. Routine screening for HHV-8 by PCR or serology is not indicated for pregnant women with HIV (AIII). Antiviral therapy for HHV-8 infection in pregnancy is not recommended (AIII). Given the rarity of KS, PEL, and MCD in pregnancy and the potential toxicity of the drugs used for treatment, when these conditions occur in pregnancy, they should be managed with consultations between the obstetrician, infectious disease specialist, and oncologist. With limited disease, treatment may be deferred until after delivery.109