See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/340091513

Kaposi’s sarcoma-associated herpesvirus related malignancy in India, a rare

but emerging member to be considered

Article  in  VirusDisease · March 2020

DOI: 10.1007/s13337-020-00573-3

CITATIONS READS

2 139

4 authors:

Piyanki Das Nabanita Roy Chattopadhyay

Visva Bharati University Visva Bharati University
16 PUBLICATIONS   86 CITATIONS    16 PUBLICATIONS   79 CITATIONS   

SEE PROFILE SEE PROFILE

Koustav Chatterjee Tathagata Choudhuri

Institute of Life Sciences Visva Bharati University
14 PUBLICATIONS   78 CITATIONS    61 PUBLICATIONS   2,718 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

KSHV and Reactivation View project

Xeno transplantation View project

All content following this page was uploaded by Tathagata Choudhuri on 21 August 2020.

The user has requested enhancement of the downloaded file.

VirusDis.
https://doi.org/10.1007/s13337-020-00573-3
REVIEW ARTICLE
Kaposi’s sarcoma-associated herpesvirus related malignancy
in India, a rare but emerging member to be considered
Piyanki Das1 • Nabanita Roy Chattopadhyay1 • Koustav Chatterjee1
Tathagata Choudhuri1
Received: 2 February 2020 / Accepted: 5 March 2020
 Indian Virological Society 2020
Abstract Kaposi’s sarcoma-associated herpesvirus
(KSHV) is associated with viral malignancy, related to
HIV-AIDS. With a wide geographical discrimination in its
occurrence, Asian countries shows low to moderate
prevalence with higher occurrence in some particular areas.
India is one of the largest countries in Asia, having various
geographical and cultural variations where KSHV has been
considered as an unthinkable entity to cause any of its
associated disease. India has been reported as a low
prevalent zone for KSHV malignancy till date. Also there
are no reports so far, describing the occurrence pattern of
this malignancy. So this review approaches towards figur-
ing out the tendency of prevalence pattern of this malig-
nancy and associated risk factors found to be present in
Indian population. From this study it is revealed that,
KSHV related malignancy is a relatively newly reported
and emerging disease in India and may exist in hidden
pockets throughout India in association with tuberculosis.
India shows prevalence in HIV-associated Kaposi’s sar-
coma in regions where socially discriminated LGBT
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13337-020-00573-3) contains sup-
plementary material, which is available to authorized users.
& Tathagata Choudhuri
tathagata.choudhuri@visva-bharati.ac.in
Piyanki Das
piyankidas.rs@visva-bharati.ac.in
Nabanita Roy Chattopadhyay
mailnabanita@gmail.com
Koustav Chatterjee
koustavchatterjee.rs@visva-bharati.ac.in
1
Department of Biotechnology, Siksha-Bhavana, Visva-
Bharati, Santiniketan, West Bengal 731235, India
•
(lesbian, gay, bisexual, and transgender) groups, unpro-
tected sexual behavior and heterosexuality are the impor-
tant risk factors for sexually transmitted viral diseases.
Anti-retro viral therapy is not sufficient to combat the virus
and may act adversely. On a note regarding the clinical
representations of Kaposi’s sarcoma, oral, mucosal, pleural
and abdominal involvements are observed in worst cases
and these can be considered as the main manifesting cri-
teria for this malignancy among Indians.
Keywords KSHV
India
HIV
TB
Risk factors
Introduction
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a
geographically confined pathogenic member of herpes
virus family. KSHV is associated to different malignancies
like, Kaposi’s sarcoma (KS), primary effusion lymphoma
(PEL), HHV-8-associated multicentriccastleman’s disease
(MCD) and KSHV inflammatory cytokine syndrome
[31, 62]. KSHV, the ninth reported member of Herpesvi-
ralis order, taxonomically belongs to the Herpesviridae
family and subfamily Gammaherpesvirinae, is a double
stranded DNA virus, also known as the Human gamma-
herpesvirus 8 (HHV-8). KSHV possess a biphasic life
cycle (latent and lytic phase) both of which are associated
with different malignancies. During its latency, the viral
genome is maintained in an episome form inside host
nucleus and latency associated nuclear antigen (LANA) is
the key player which helps to maintain the latency and also
regulate the transcriptional activity of several host genes.
During lytic cycle KSHV produce successful infective viral
particles. There are several cellular homologues has been
produced by KSHV during the both phases of its life cycle,
123

which helps the virus to survive, replicate and modulate the
host cell machineries which leads to oncogenesis [67].
KSHV related cancers are not very ubiquitous in nature
and this virus shows uneven distribution throughout the
world [47]. The majority of reports for KSHV infection
comes from developed countries like USA, Sweden, Nor-
way, and other parts of Europe whereunder-developed
countries were reported to have low prevalence except
Africawhich is considered as the main origin of this viral
malignancy. The epidemiological justification for the dis-
crete nature of occurrence of this viral malignancy
throughout the world has not been revealed well due to lack
of population based study and patient sample availability.
The main zones of occurrence of this malignancy are the
African and Mediterranean continents whereas Asian
countries come under moderate to low prevalence zones
[14]. Southern Asian countries, mainly China, Japan and
Cambodia show moderate to high prevalence (ranging
from 10 to 56%). China is the most studied zone in Asia,
where Taiwan and Xinjiang regions show maximum
KSHV seropositivity. China shows variations in KSHV
prevalence depending on its diverse cultural, ethnic, and
life style patterns [18, 61, 72]. Other south Asian countries
like, Srilanka, Thiland, Vietnam and Malaysia shows low
prevalence of KSHV [1]. Notably, Cambodia represents
prevalence of about 50% among both men and women with
average age group of 13. This prevalence is highly local-
ized and can be characterized with distinctive poor
socioeconomic and hygienic conditions among the rural
populations. Thus this area can be said as the high risk zone
of Asia for KSHV malignancy [50].
Middle, middle-east and west Asian countries show
moderate to low prevalence of KSHV based on different
indicative factors for example, ethnic variations of Jewish
inhabitants in Israel show higher incidence as 9.9% for
overall and 22% for HCV-infected subjects, and infection
transmits mainly from spouse to spouse and mother to
child. Similarly Ethiopian migrants in Israel show a high
frequency, 22%, of KSHV infection. Interestingly,
Endogenous inhabitants and students of pre-marital age
show significantly lower infection of this virus [38, 51]. A
recent report shows thatKSHV prevalence also associated
with multiple myeloma as found in Jordan [25]. This
indicates a much intense role of this virus in cancers,
though not all varieties of cancers are studied yet for the
presence of KSHV. Blood donors in Turkey and organ
transplant patients in Iran and Saudi Arabia shows low
(5.3%) to moderate (18–25%) KSHV prevalence [4, 5, 27].
Of note, blood donation and organ transplantation both
involves mixing of blood in donors and recipients. There-
fore, it can be conferred that such mixing actually is
responsible for transfer of KSHV to donor from recipient.
123
P. Das et al.
The status of the donor and recipients, therefore, must be
checked.
This discrepancy of occurrence, even within a continent,
is due to several factors like, difference in the sensitivity of
assay methods applied for detection of KSHV, ethnicity
and different genetic factors among population, poor
socioeconomic conditions, HIV-AIDS, cancers, homosex-
uality, intravenous drug use, and organ transplantation etc
which might control the pathogenesis. Therefore if the
infectionpattern of KSHV among Asian population cannot
be understood well then it will remain ignored and might
be evolved and appeared as sudden epidemic outbreak in
due course of time [71]. India is the most diversified
country in Asia in terms of its huge geographical variation
and ethnicities next to China. Though it doesn’t come
under prevalent zone of KSHV related malignancies but
several reports are coming out in recent days from different
parts of India indicating its emerging nature. Thus this
review aims to figure out the pattern of KSHV related
malignancy in India which might help to understand the
total scenario and therefore concerns regarding KSHV
associated diseases among Indians can be addressed
properly.
India shows prevalence in AIDS related Kaposi’s
sarcoma
AIDS and KSHV are much related and different types of
KSHV related malignancies are mostly associated with
HIV [49]. Parallely in HIV associated cancers, KS and PEL
are much common and approximately 4% of HIV related
non-hodgkin’s lymphoma is PEL [49]. A study shows
481.54 people per 100,000 HIV positive ones harbour
Kaposi’s sarcoma [36]. According to the current epidemi-
ology, Kaposis’ sarcoma is of four different types, classical
form, transplant-associated, African or the endemic form,
and AIDS-related or epidemic form [22]. Considering the
impact of the co-existence of HIV-1 and KSHV, there are
several reports suggesting the molecular interactive role of
both the viruses in the pathogenesis of diseases. Both
KSHV and HIV-1 can increase the susceptibility of host
cell for infection, increase viral replication, enhances
infectivity of the virus, angiogenesis process and modula-
tion of host–pathogen signaling pathways in a bidirectional
talk between them. This cross talk happens between KSHV
and HIV-1 by direct interaction of different latency as well
as lytic associated KSHV proteins and HIV-1 associated
Tat (transcriptional activator), LTR (Long terminal region),
and CD4? T cells [63]
If we globally review the time trend of the occurrence of
HIV-AIDS and Kaposis’ sarcoma then it can be said that
HIV have been found to occur in pre 1980s and Kaposis’
Kaposi’s sarcoma-associated herpesvirus related malignancy in India, a rare but emerging…
sarcoma appeared after 1980s. Both of these became con-
temporary emerged as a sudden occurrence and became
epidemic [54]. After the occurrence of both of these enti-
ties with their epidemic emergence in the African and
Mediterranean countries, they have started to appear in
Asian continents too. But in such countries AIDS became
the epidemic one, whereas reports of the KSHV associated
malignancies are less. Similar pattern was observed in
India also, the first reported case of HIV from India came
from Chennai, Tamil Nadu in 1986 [60] and the first report
of KSHV malignancy was in 1993 [56]. During the periods
of HIV and KSHV occurrence, the prevalence of HIV was
increased and India became the third largest HIV epidemic
region in world and an HIV dominated country in Asia
[32]. But in terms of KSHV, as it is not widely revealed, it
has been denoted as a rare entity in India based on a few
case reports only. HIV-AIDS was unthinkable for Indian
population, when it became epidemic in USA few years
ago before any single case was reported in India. Actually,
the first case report of HIV-AIDS in India was revealed in
an article of BBC news, and this virus was detected by
chance for the sake of research only. After that population
based study begun and it was found to be epidemic one.
Keeping this in mind, there is a fair chance that KSHV
associated malignancies may also start a sudden emergence
as would be shown in reports, because very low population
based studies among the risk groups and general population
have been available in public domain. Without detailed
population-based detection study for KSHV, it cannot be
said with confidence that this virus is rarely found in Indian
people.
Considering KSHV associated malignancy pattern
specifically in India, reports of HIV associated KSHV
malignancies have been revealed from different regions of
Indian sub-continent. From 1993 to 2019, about 25 cases of
Kaposi’s sarcoma have been reported. On average, there is
one report of KS is found each year and all of those cases
were seropositive for HIV infection also, specifically
HHV-1 infection [10]. Currently HIV is approximately
0.22% prevalent among Indian adults and 2.1 million
people are living with HIV [45]. As mentioned above,
India shows prevalence of AIDS associated Kaposi’s sar-
coma compared to the other forms. It indicates that, HIV
infected groups are at high risk of HHV-8 infections also.
Thus survivors of HIV infections have high risk of getting
KSHV infection and conversely, detection of KSHV
infection can be considered as the initial representation of
HIV infection in Indian scenario [53, 66, 70].
Non HIV associated Kaposi’s sarcoma is rarely found
throughout the world and the same pattern is followed in
India also. Some reports claim it to be associated with
female patients, but some others report for male patients
also [26, 28, 34]. Primary effusion lymphoma (PEL) is
another malignancy associated with HHV-8. It is a kind of
body cavity effusion based non-Hodgkin’s lymphoma
(NHL) associated with KSHV and HIV. HIV associated
non-Hodgkin’s lymphoma is common in India but associ-
ation of KSHV with it, is reported in one case report only.
Interestingly, there is a rare form of PEL, denoted as extra
cavitary primary effusion lymphoma has found to be
associated with KSHV and HIV. Castleman’s diseases have
also been reported from India but KSHV association has
not been reported for that, thus the probability of KSHV
association with multi centric castleman’s diseases cannot
be stated [2, 21, 42]. But all these other forms of KSHV
malignancies are very rare compared to KS from India.
After reviewing the pattern of KSHV in India, it is
confirmed that the emergence of KSHV started along with
or better said, later to HIV emergence, HIV-AIDS became
the main focused area in Indian populations but its asso-
ciation with KSHV malignancies are not revealed well.
HIV patients in India are treated with single directional
approach not considering other risk factors like KSHV,
associated with it. To reveal the real story about this virus
and providing better survival opportunities to the AIDS
patients in India, a longitudinal study based on screening
among HIV positive high risk groups must be done, but to
have a definite and compact idea about its spread and
emerging pattern, independent focus on KSHV is needed
along with its unusual forms of malignancies.
If we consider the molecular interaction of HIV and
KSHV, it is quite clear that interaction of these two entities
plays important role in the oncogenic progression.
Tuberculosis is the main co-existing agent apart
from HIV
Tuberculosis (TB) is the most common opportunistic
infection in India. According to Indian government’s TB
report published in 2018, India ranks second in HIV-as-
sociated TB and accounts for 10% of cases worldwide. KS
patients from India have been reported with previous his-
tory of tuberculosis which has been reactivated from the
latent state during HIV associated KS, where incomplete
TB treatment acts as influencing factor. Conversely
Tuberculosis may also develop during the period of HIV
infection and subsequent development of KS [52]. The
HIV-KS-TB patients are reported of to be provided with
combined treatment of 1st line or 2nd line anti-tuberculosis
and antiretroviral therapy (ART). Prolonged application of
ART may result in the development of a clinical compli-
cation known as immune reconstitution inflammatory
syndrome (IRIS) in which the body may restore the pre-
vious subclinical condition or may deteriorates the present
pathogenic condition. This rare clinical condition may be
123

one of the causes of association of TB with HIV associated
KS among Indian patients [37, 41].
Association of TB in HIV patients is a common scenario
worldwide, but its association with KSHV is not reported
as a common incident. Interestingly association of tuber-
culosis with KSHV has been found in HIV negative indi-
viduals also, indicating its solo role in KSHV malignancy
without the involvement of HIV infection [12, 15]. Also
different types of tuberculosis have been reported to be
associated with KSHV, like abdominal and pulmonary
tuberculosis and involvement of this visceral manifestation
is a worst scenario for KSHV malignancy in India [15].
The exact pathological role of TB in development of
KSHV infection and pathogenesis needs further research.
A recent study in Africa shows high mortality of HIV
patients is associated with high KSHV viral load with
suspected TB but without any microbiological confirma-
tion of the bacteria. As KS symptoms are so much similar
with TB, association of KSHV is suspected in case of TB
and vice versa and which may also increases the chances of
misunderstanding and confusion, which should be avoided
with proper detection in every case [11]. TB is a real threat
to India and KSHV has been reported as a co-existing
factor with almost all the HIV patients in India [56].
Therefore in Indian perspective of KSHV malignancy, TB
must be considered as a risk factor and TB-AIDS-KS may
be classified as a new form of Kaposi’s sarcoma.
Sexual behavior of the patients with their socio-
economic conditions play an important role
with LGBT populations being in real threat
Though the percentage of women is high for HIV positivity
in India, but the same is not true for KSHV malignancy.
Though not concluded in Indian scenario, it is reported
worldwide that KSHV infection predominates in males. It
is suspected that hormones play an important role for this
gender discrepancy in KS [69]. Interestingly, a recent
report shows that HIV positive male patients have been
identified with HHV-8 infection, and the major route of
transmission of this virus is heterosexual [44]. Though
KSHV malignancies are common in homosexual men,
heterosexuality dominates among Indians. The main route
of transmission is by high risk sexual behaviors like
unprotected insertive, receptive and anal intercourse, where
the patients belong to sex worker, driver, business persons
and laborers by profession who are exposed to public
interactions and engaged with multiple sexual partners.
Few intravenous drug users are reported and in case of
married women, their husbands are reported to be addicted
to intravenous drugs [35]. Only few cases of blood trans-
fusion recipients are reported to harbor KSHV [52]. As
123
P. Das et al.
most people have denied or refused the discussion about
their sexual behavior it creates lack of information and the
complete scenario remains covered in dark. Therefore, any
discussion must be confidential and be performed by
trained counselor in this regard. Considering the increasing
occurrence of KSHV related malignancies, importance
should be given emphasizing the detection of KSHV,
considering the socio economic condition, age, sexual
status, occupational status etc. The main reason for this is,
in maximum cases reported from India, scientifically
specific and proper report for HHV-8 detection in the
patient sample is not done because of the social and
financial limitations [70].
It has been noticed that HIV-KSHV patients mainly
come from a socioeconomic background, which is not well
accepted socially in India. In this regard, a distinct group of
population i.e. LGBT group (Lesbian, gay, bisexual and
transgender population) are socially discriminated and it is
found that this group of population shows high risk of HIV-
AIDS and sexually transmitted diseases, hence comes
under high risk groups of KSHV malignancies. The prob-
lem is, this group of population is ill reported in terms of
health issues and treatment facilities due to their social
status which is not prioritized by the government. Though
transgender has been legalized as third gender in India,
much more legal actions and education is needed in this
field so that their health issues could be reported well [64].
The physicians, NGO and drug detention centers should
come forward for this. Research programmes focused on
the human rights of these people along with the medical
interventions should be carried out which will reveal the
cohort of KSHV malignancy among AIDS concerned
LGBT groups in India [29, 59].
Geographical scenario, environmental factors
along with parasitic infection makes a great deal
with KSHV
The occurrence of KSHV related malignancies and its
seropositivity seemed to appear in a cohort forming man-
ner. Within a highly prevalent continent also, it seems to be
geographically isolated in particular areas [47]. KSHV
malignancy reports in India are mainly reported from
western cost, mainly Mumbai, Chennai, Gujrat, and Kar-
nataka. Few cases are reported in north and north-east
India, Delhi and Manipur also. 26.06–33.3% KSHV
seropositive HIV-1 positive male patients were detected
from north India [3, 44, 56]. In south India the seroposi-
tivity rate is 4.5%. No case report has been found from
eastern part of India but this zone might bear a high risk as
it is highly cancer prone area and also located in close
proximity with the east and south East Asian continents
Kaposi’s sarcoma-associated herpesvirus related malignancy in India, a rare but emerging…
where KSHV found to be frequent. The south and south
western parts of India are in close proximity with coastal
regions of central and east Africa and flooded with immi-
gration, trade interactions and travelling therefore are in
very high risk of having KSHV infection as the central and
east Africa, which are two of the highest prevalent zone of
KSHV malignancies.
Along with afore discussed risk factors, several reports
suggest some environmental factors responsible for KSHV
infection. Volcanic clay soil containing aluminum and iron
as major components contribute to the prevalence of KS
infections among rural Africans [46, 57, 58]. In India also,
black and red soils are reported in regions of KSHV
infections. Specifically, the states of south western parts,
where KSHV related malignancies have been reported
mostly, the soil is black and red type. Black soil is mainly
made up of volcanic rocks and lava, whereas the red soil is
named so for its high iron content. Though the exact role of
aluminium, or iron, or volcanic rocks overall, is not justi-
fied in any report of KSHV infection and/or malignancy,
the geographic conditions cannot be overruled as all min-
eral nutrients eventually come from soil and physical
exposure to such kind of soil may also play certain role in
the KSHV related malignancy. These environmental fac-
tors may be co-related as the enhancing factors for KSHV
malignancy, but extensive studies are required for that.
KS has also been reported to be associated with blood
sucking insects or arthropods which mainly are those
related to malaria. This type of infection weakens the host
immune system and can contribute for having KSHV
infections. Moreover the insect bite causes a puncture in
skin and the blood capillary underneath; therefore and the
application of human saliva in the insect bite area in child
is a usual home remedy used for getting relief of itching,
which might transmit this viral spread through that tiny
puncture [7, 68]. Epidemiological study shows that Sub-
Saharan Africa which is prevalent zone for KSHV infection
is also endemic for malaria. Proportionate KSHV
seropositivity and malarial vector density has been found
from Italy. There are several study shows the molecular
link of malarial infection and KSHV oncogenesis. Subse-
quent malarial infection leads to anemia and impaired B/T
cell immunity which leads to KSHV tumorigenesis by
enhancing the reactivation and replication of the virus.
Quinine which is the main medicine for malaria has been
reported for its immune suppressive function which pro-
voke KSHV to replicate. The anemic condition can reac-
tivate KSHV by tissue hypoxia. Malarial parasite infected
RBC (IRBC) express pfEMP-1 (Plasmodium falciparum
erythrocyte membrane protein 1) and binds with specific
domain of CD-36 host endothelial cell receptor, this
binding is essential for the virulence of the parasite.
Interestingly a recombinant peptide derived from CD36
pfEMP receptor, when cross links with CD36 receptor, it
can activate KSHV lytic reactivation. Thus it is clear that
malarial infection plays a molecular impact on KSHV
reactivation [16, 24]. On this note, it must be considered
that a wide part of India is surrounded by the Indian ocean
and this sub-continents have been well reported for the
prevalence of infectious diseases like malaria, chikun-
gunya, encephalitis and dengue from ancient time to cur-
rent century [43, 57]. The total geographical distribution of
KSHV associated malignancy has been described in Fig. 1.
Clinicopathological conditions
The case reports of KS patients from India clinically pre-
sented with cutaneous violaceous patches, plaques, nodules
and blanching or non-blanching lesions over different body
parts; mainly over the trunk, including upper and lower
limbs, chest, face and genital organs. In most of the cases,
lesions appears on the trunk in the beginning for the onset
of the disease, and later, spread over the upper and lower
extremities, or sometimes reverse [17, 40, 55, 66]. The
lesions appear with a Christmas tree pattern or sometimes
with cobble stone appearance. They might be tender or
non-tender to touch with purple, pink or bluish in colour
and with 0.2–7 cm in diameter for each [8, 10].
In Indian perspective of KS, oral, facial and mucosal
involvement is very common and can appear as the solo
clinical presentation of the malignancy. Indian patients
show origin of lesions initially in hard palate of mouth or in
the oral mucosa, then in soft palate gingiva and lastly in
dorsal tongue as reported till date. Indian study reports
61.5% cases of involvement of both cutaneous and oral
mucosa and 38.46% of only cutaneous involvement [6, 48].
Interestingly presence of KS nodules on the eyelid has been
found [30]. Thus oral as well as facial lesions or nodules
can be used as an primary identifying factor for detecting
KSHV related malignancy [6, 30].
Apart from the above symptoms common fever, joint
pain, diarrhea, weight loss etc. are found as other common
symptoms associated with KS. Routine blood profiles like
the hemogram analysis and serum biochemistry shows no
remarkable change but CD4 count has been found to be
low in some cases with damaged renal function and low
hemoglobin percentage [10, 17]. Previously it is described
that KSHV reactivation has been reported to cause anemic
condition. Biopsies from lesions and their histological
reports show spindle cell proliferation with slit like con-
gested capillaries [52]. Abnormalities like, pleural effusion,
chest fibrosis, post inflammatory changes in lungs, fatty
liver with multiple lesion, hepatitis B positivity, liver
edema on GI tract, lesion in spleen etc. are the indicative
features of metastasis [13, 56, 70]. KS has been found to be
123

Fig. 1 Geographical distribution of KSHV related malignancy in India
a vascular neoplasm, thus with the progression of the dis-
eases, involvement of vascular endothelial linings, lym-
phatic channels, lymph nodes, gastrointestinal tract and
genitalia indicates towards the metastatic tendency with
symptoms like lymphadenitis, lymphadenopathy and lym-
phatic edema [33]. Notably pulmonary involvement is
associated with the most aggressive cases with massive
pleural effusion [8].
Several interacting infectious agents have been found
along with KS whereas tineacorporis and malignant
schwannoma in right palm in the same limb of KS
appearance has been found as a co-associated pathological
conditions among Indians [9, 23]. Molluscumcontagiosum,
with past tuberculosis history in a HIV positive patient has
been found to be associated with KS showing several small
to large central umbelicated facial lesions [65]. There is
also a case report of thrombocytopenia to be associated
with Kaposi’s sarcoma [55]. VDRL (venereal diseases
research laboratory) test has been found normal, whereas
123
P. Das et al.
hepatitis B antigen reactivity has been found positive in
some cases of KS [3, 10].
These findings indicate a clear clinical pattern of KSHV
malignancy along with its related pathological co-factors
(Fig. 2).
Retroviral therapy is not enough to make
up the malignancy
Combined ART and highly active antiretroviral (HAART)
therapies, along with 1st line chemotherapeutic drugs (like
liposomal doxorubicin), are used as the local therapeutic
strategy against KSHV malignancy in India. Intravenous
paclitaxel has also been administered but as 2nd line drug
for its adverse effects [19]. Other treatment modalities
include intralesional vincristine, bleomycin, alpha-inter-
feron etc. [8]. It has been observed in almost all the cases
that when individuals suffering from HIV associated KS,
Kaposi’s sarcoma-associated herpesvirus related malignancy in India, a rare but emerging…

Fig. 2 Clinical pattern of

KSHV associated malignancy in
India showing the diseases
manifestation along with the
risk factors

have been applied with HAART treatments the KS lesions
have appeared to be decreased. Thus direct antiviral effects
of the chemotherapeutic drugs on regression of KS inci-
dence can be linked and early detection of KSHV with
initiation of HAART is required in that case. Though
HAART shows positive results, it should be noted that
relapse of KS has been observed in several cases after few
months of completion of treatment [10]. As HHV-8 persist
in latent phase inside the host cell and modulates the cel-
lular signaling to cause oncogenesis, drug induced KSHV
reactivation mechanisms within the host cell must be kept
in mind for new therapeutic approaches for hitting the viral
latency and therefore, to combat relapse. Only anti-retro-
viral therapy (ART) or HAART is not sufficient enough for
treating KS completely.

123

Concluding remarks
This review intended to embrace the total scenario of
HHV-8 related malignancies in Indian sub-continent. It
describes the pattern of KSHV malignancy among Indian
population, as new emerging member which may exist as
hidden pockets. It aims towards revealing this neglected
malignancy in-terms of HIV-TB-KSHV association and its
considerable determining factors which gives a new sight
to analyze this entity in detail irrespective of its statistics of
occurrence so far (Supplementary fig. I). Through the
detailed discussion on the published reports, it is clear that
incidence of AIDS associated malignancy specifically
KSHV associated ones must be anticipated in Indian per-
spective with new trends for the AIDS patient survival
management should be planned. KSHV malignancies
should be concerned parallely and along with HIV, tuber-
culosis, and Non-Hodgkins lymphoma and other co-exist-
ing factors in Indian patients. TB associated KSHVcan be
classified as a distinct type of KSHV related malignancy
where application of ART has been found as possible risk
factor for relapse.
As it has been observed from the above study that,
Indian KSHV associated malignancy is co-infected with
various pathogens, mainly HIV-1, TB and also there are
high chance of co-existence and risk of malarial parasitic
infection, the impact of this association in KSHV onco-
genesis must be analyzed well. Several reports suggest that
co-infection may exert beneficial as well as harmful effect
in disease progression. Though high risk of mortality is
expected in HIV-TB or HIV-KSHV co-infection, there are
several other deleterious effects reported like, increased
viral load leading to increased chance of transmission, drug
interaction and impairment in diagnosis etc. Role of TB is
not explored in KSHV malignancy, but bacteria can
potentially increases viral infectivity in low viral load
condition by binding to multiple virion and adherence to
host cell. Moreover bacteria can limit abortive viral
infection by inducing recombination between two different
virus [20, 39]. Co-infection biology must be an important
part for analyzing KSHV malignancy in India otherwise
KSHV co-infection with HIV-TB will remain as orthodox
phenomena.
Though publication biasness is a considerable factor
affecting proper documentation and registration, these are
needed along with survival and prognosis data. Sometimes,
the same patient has been found to be registered and
reported differently, by different healthcare profession-
als/centers, which may create confusion [17, 70].
Along with the well reported southern parts, the eastern
and northeastern parts of India should be kept under
immense observation, because these parts have been
123
P. Das et al.
known for specific ethnicity and have been exposed to
several rare and infectious diseases along with various
cancers, specifically AIDS and the life style has a great
impact over their disease susceptibility.
This is the high time to think about the virus in terms of
its pathogenesis, detection, interaction with host and its
specific treatment modalities apart from the available ones
which are not promising to control its spread. Awareness
programmers must be needed to concern public and health
experts about these particularly rare diseases, their
emerging patterns and risk factors. The campaign should
focus on proper management considering the socioeco-
nomic conditions and sexual backgrounds among high and
as well as low risk groups, and it should try to provide an
open counseling based discussion among the socially iso-
lated populations with unusual sexual characteristics.
Researchers must focus on development of easy detec-
tion methods based on opportunities, which are economi-
cally favorable and can use genetic and molecular factors
associated with this ill-undiagnosed viral oncogenesis
associated with known epidemic diseases like HIV and TB
in India, which is currently not possible due to financial
constraints. The latency associated protein LANA/ORF73
(latency associated nuclear antigen) and lytic associated
viral replicative protein K8.1 are the major markers for
KSHV detection. Detection methods should identify these
markers from KSHV DNA from patient samples like
blood, serum, saliva and tissue biopsy. Viral load can be
determined by analyzing K8.1 in RTPCR and other anti-
body based assay targeting those markers may be used for
confirmation of the malignancy status [38] In search of the
development of this malignancy in India, immunosup-
pression, sexual behavior, geographical and environmental
factors and interactive infectious agents can be easily
pointed out to be associated with the disease. But con-
cerning the genetic justification, common markers like
HLA (human leukocyte antigen) allotype variation and
interleukin-6 polymorphism should also be considered.
Immunohistochemistry based assay or polymerase chain
reaction for viral DNA/RNA are the confirmatory methods
for KSHV presence, therefore all the HIV seropositive
patients should be kept under clinical investigation with
those methods performed on them. Diagnostic labs, hos-
pitals etc. must be equipped with those methods for early
detection. In terms of treatment facilities, the physicians
and healthcare experts should be conscious enough about
providing the better treatment opportunities as well as
proper and consistent follow up treatments of the patients is
needed to get a complete track report of this malignancy.
The gradual but limited exploration of KSHV among
Indian populations indicates a hidden existence in some
pockets of India and presenting a high-risk of its sudden
Kaposi’s sarcoma-associated herpesvirus related malignancy in India, a rare but emerging…
emergence and thus it must be considered as a rare but not
to be ignored fetal entity.
Acknowledgements We would like to thank Mr. LaltuHazra,
regarding his general laboratory help and CSIR for their financial
assistance byCSIR SRF fellowship (Council of Scientific and Indus-
trial Research, Govt. of India, Senior Research Fellowship).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
References
1. Ablashi D, Chatlynne L, Cooper H, et al. Seroprevalence of
human herpesvirus-8 (HHV-8) in countries of Southeast Asia
compared to the USA, the Caribbean and Africa. Br J Cancer.
1999;81(5):893–7. https://doi.org/10.1038/sj.bjc.6690782.
2. Acharya VK, Rai S, Shirgavi S, Pai RR, Anand R. Multicentric
castleman’s disease: ‘‘A rare entity that mimics malignancy’’.
Lung India Off Organ Indian Chest Soc. 2016;33(6):689–91.
https://doi.org/10.4103/0970-2113.192864.
3. Agarwala MK, George R, Sudarsanam TD, Chacko RT, Thomas
M, Nair S. Clinical course of disseminated Kaposi sarcoma in a
HIV and hepatitis B co-infected heterosexual male. Indian Der-
matol Online J. 2015;6(4):280–3. https://doi.org/10.4103/2229-
5178.160271.
4. Al-Dayel A, Guella A, Alzahrani AJ, et al. Increased sero-
prevalence of human herpes virus-8 in renal transplant recipients
in Saudi Arabia. Nephrol Dial Transplant. 2005;20(11):2532–6.
https://doi.org/10.1093/ndt/gfi058.
5. Altuglu I, Yolcu A, Ocek ZA, Yazan Sertoz R, Gokengin D.
Investigation of human herpesvirus-8 seroprevalence in blood
donors and HIV-positive patients admitted to Ege University
Medical School Hospital, Turkey. Mikrobiyoloji bulteni.
2016;50(1):104–11.
6. Arul AS, Kumar AR, Verma S, Arul AS. Oral Kaposi’s sarcoma:
sole presentation in HIV seropositive patient. J Nat Sci Biolmed.
2015;6(2):459–61. https://doi.org/10.4103/0976-9668.160041.
7. Ascoli V, Senis G, Zucchetto A, et al. Distribution of ‘promoter’
sandflies associated with incidence of classic Kaposi’s sarcoma.
Med Vet Entomol. 2009;23(3):217–25. https://doi.org/10.1111/j.
1365-2915.2009.00811.x.
8. Behera B, Chandrashekar L, Thappa DM, Toi P, Vinod KV.
Disseminated Kaposi’s sarcoma in an HIV-positive patient: a rare
entity in an Indian patient. Indian J Dermatol. 2016;61(3):348.
https://doi.org/10.4103/0019-5154.182466.
9. Bhagat U, Sharma A, Marfatia YS. Violaceous papulonodular
lesions in an AIDS case. Indian J Sex Transm Dis AIDS.
2008;29:51–3.
10. Bhatia R, Shubhdarshini S, Yadav S, Ramam M, Agarwal S.
Disseminated Kaposi’s sarcoma in a human immunodeficiency
virus-infected homosexual Indian man. Indian J Dermatol
Venereol Leprol. 2017;83(1):78–83. https://doi.org/10.4103/
0378-6323.193612.
11. Blumenthal MJ, Schutz C, Barr D, et al. The contribution of
Kaposi’s sarcoma-associated herpesvirus to mortality in hospi-
talized human immunodeficiency virus-infected patients being
investigated for tuberculosis in South Africa. J Infect Dis.
2019;220(5):841–51. https://doi.org/10.1093/infdis/jiz180.
12. Castro A, Pedreira J, Soriano V, et al. Kaposi’s sarcoma and
disseminated tuberculosis in HIV-negative individual. Lancet.
1992;339(8797):868.
13. Chandan K, Madnani N, Desai D, Deshpande R. AIDS-associated
Kaposi’s sarcoma in a heterosexual male—a case report. Der-
matol Online J. 2002;8(2):19.
14. Chatlynne LG, Ablashi DV. Seroepidemiology of Kaposi’s sar-
coma-associated herpesvirus (KSHV). Semin Cancer Biol.
1999;9(3):175–85. https://doi.org/10.1006/scbi.1998.0089.
15. Chen YJ, Shieh PP, Shen JL. Orificial tuberculosis and Kaposi’s
sarcoma in an HIV-negative individual. Clin Exp Dermatol.
2000;25(5):393–7.
16. Conant K, Kaleeba J. Dangerous liaisons: molecular basis for a
syndemic relationship between Kaposi’s sarcoma and P. falci-
parum malaria. Front Microbiol. 2013. https://doi.org/10.3389/
fmicb.2013.00035.
17. Dhote A, Umap P, Shrikhande A. Fine needle cytology of
Kaposi’s sarcoma in heterosexual male. Int J Res Med Sci.
2014;2(2).
18. Dilnur P, Katano H, Wang ZH, et al. Classic type of Kaposi’s
sarcoma and human herpesvirus 8 infection in Xinjiang, China.
Pathol Int. 2001;51(11):845–52.
19. Dongre A, Montaldo C. Kaposi’s sarcoma in an HIV-positive
person successfully treated with paclitaxel. Indian J Dermatol
Venereol Leprol. 2009;75(3):290–2. https://doi.org/10.4103/
0378-6323.51254.
20. Erickson AK, Jesudhasan PR, Mayer MJ, Narbad A, Winter SE,
Pfeiffer JK. Bacteria facilitate enteric virus co-infection of
mammalian cells and promote genetic recombination. Cell Host
Microbe. 2018;23(1):7788.e5. https://doi.org/10.1016/j.chom.
2017.11.007.
21. Gatphoh ED, Zamzachin G, Devi SB, Punyabati P. AIDS related
malignant disease at regional institute of medical sciences. Indian
J Pathol Microbiol. 2001;44(1):1–4.
22. Goncalves PH, Ziegelbauer J, Uldrick TS, Yarchoan R. Kaposi
sarcoma herpesvirus-associated cancers and related diseases. Curr
Opin HIV AIDS. 2017;12(1):47–56. https://doi.org/10.1097/
COH.0000000000000330.
23. Gopala A, V Ramana Reddy G. Kaposi’s sarcoma in a follow-up
patient of malignant schwannoma after seroconversion. Indian J
Surg. 2004;66:110–2.
24. Gowda NM, Wu X, Kumar S, Febbraio M, Gowda DC. CD36
contributes to malaria parasite-induced pro-inflammatory cyto-
kine production and NK and T cell activation by dendritic cells.
PLoS ONE. 2013;8(10):e77604. https://doi.org/10.1371/journal.
pone.0077604.
25. Ismail SI, Mahmoud IS, Salman MA, Sughayer MA, Mahafzah
AM. Frequent detection of human herpes virus-8 in bone marrow
of Jordanian patients of multiple myeloma. Cancer Epidemiol.
2011;35(5):471–4. https://doi.org/10.1016/j.canep.2010.10.006.
26. Jakob L, Metzler G, Chen K-M, Garbe C. Non-AIDS associated
Kaposi’s sarcoma: clinical features and treatment outcome. PLoS
ONE. 2011;6(4):e18397. https://doi.org/10.1371/journal.pone.
0018397.
27. Jalilvand S, Shoja Z, Mokhtari-Azad T, Nategh R, Ghare-
hbaghian A. Seroprevalence of Human herpesvirus 8 (HHV-8)
and incidence of Kaposi’s sarcoma in Iran. Infect Agents Cancer.
2011;6:5. https://doi.org/10.1186/1750-9378-6-5.
28. Jan RA, Koul PA, Ahmed M, Shah S, Mufti SA, War FA. Kaposi
sarcoma in a non HIV patient. Int J Health Sci. 2008;2(2):153–6.
29. Jethwani KS, Mishra SV, Jethwani PS, Sawant NS. Surveying
Indian gay men for coping skills and HIV testing patterns using
the internet. J Postgrad Med. 2014;60(2):130–4. https://doi.org/
10.4103/0022-3859.132315.
123

30. Joshi U, Ceena DE, Ongole R, et al. AIDS related Kaposi’s
sarcoma presenting with palatal and eyelid nodule. J Assoc Phys
India. 2012;60:50–3.
31. Karass M, Grossniklaus E, Seoud T, Jain S, Goldstein DA.
Kaposi sarcoma inflammatory cytokine syndrome (KICS): a rare
but potentially treatable condition. Oncologist. 2017;22(5):623–5.
https://doi.org/10.1634/theoncologist.2016-0237.
32. Karim QA. Current status of the HIV epidemic & challenges in
prevention. Indian J Med Res. 2017;146(6):673–6. https://doi.org/
10.4103/ijmr.IJMR_1912_17.
33. Kharkar V, Gutte RM, Khopkar U, Mahajan S, Chikhalkar S.
Kaposi’s sarcoma: a presenting manifestation of HIV infection in
an Indian. Indian J Dermatol Venereol Leprol. 2009;75(4):391–3.
https://doi.org/10.4103/0378-6323.53137.
34. Kodra A, Walczyszyn M, Grossman C, Zapata D, Rambhatla T,
Mina B. Case report pulmonary Kaposi sarcoma in a non-HIV
patient. F1000Research. 2015;4:1013. https://doi.org/10.12688/
f1000research.7137.1.
35. Kumarasamy N, Solomon S, Yesudian PK, Sugumar P. First
report of Kaposi’s sarcoma in an AIDS patient from Madras.
India. Indian J Dermatol. 1996;41(1):23–5.
36. Liu Z, Fang Q, Zuo J, Minhas V, Wood C, Zhang T. The world-
wide incidence of Kaposi’s sarcoma in the HIV/AIDS era. HIV
Med. 2018;19(5):355–64. https://doi.org/10.1111/hiv.12584.
37. Manion M, Uldrick T, Polizzotto MN, et al. Emergence of
Kaposi’s sarcoma herpesvirus-associated complications follow-
ing corticosteroid use in TB-IRIS. Open Forum Infect Dis.
2018;5(10):ofy217. https://doi.org/10.1093/ofid/ofy217.
38. Margalith M, Chatlynne LG, Fuchs E, et al. Human herpesvirus 8
infection among various population groups in southern Israel.
J Acquir Immune Defic Syndr. 2003;34(5):500–5.
39. McArdle AJ, Turkova A, Cunnington AJ. When do co-infections
matter? Curr Opin Infect Dis. 2018;31(3):209–15. https://doi.org/
10.1097/QCO.0000000000000447.
40. Mehta S, Garg A, Gupta LK, Mittal A, Khare AK, Kuldeep CM.
Kaposi’s sarcoma as a presenting manifestation of HIV. Indian J
Sex Transm Dis AIDS. 2011;32(2):108–10. https://doi.org/10.
4103/0253-7184.85415.
41. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated
immune reconstitution inflammatory syndrome: case definitions
for use in resource-limited settings. Lancet Infect Dis.
2008;8(8):516–23. https://doi.org/10.1016/s1473-
3099(08)70184-1.
42. Modak D, Ganguly RR, Haldar SN, Samanta PS, Pramanik N,
Guha SK. Castlemans disease in HIV infected patient from
eastern India. J Assoc Phys India. 2008;56:547–8.
43. Mukherjee S. Emerging infectious diseases: epidemiological
perspective. Indian J Dermatol. 2017;62(5):459–67. https://doi.
org/10.4103/ijd.IJD_379_17.
44. Munawwar A, Sharma SK, Gupta S, Singh S. Seroprevalence and
determinants of Kaposi sarcoma-associated human herpesvirus 8
in Indian HIV-infected males. AIDS Res Hum Retroviruses.
2014;30(12):1192–6. https://doi.org/10.1089/aid.2014.0184.
45. Paranjape RS, Challacombe SJ. HIV/AIDS in India: an overview
of the Indian epidemic. Oral Dis. 2016;22(S1):10–4. https://doi.
org/10.1111/odi.12457.
46. Pelser C, Dazzi C, Graubard BI, Lauria C, Vitale F, Goedert JJ.
Risk of classic Kaposi sarcoma with residential exposure to
volcanic and related soils in Sicily. Ann Epidemiol.
2009;19(8):597–601. https://doi.org/10.1016/j.annepidem.2009.
04.002.
47. Perez-Alvarez S, Benavente Y, de Sanjose S, et al. Geographic
variation in the prevalence of Kaposi sarcoma-associated her-
pesvirus and risk factors for transmission. J Infect Dis.
2009;199(10):1449–56. https://doi.org/10.1086/598523.
123
P. Das et al.
48. Potsangbam G, Surchandra Sharma S, Singh TJ, et al. Intra-le-
sional injection of vinblastine in a pedunculated oral Kaposi’s
sarcoma in a patient of AIDS. JIACM. 2007;8(1):99–100.
49. Qin J, Lu C. Infection of KSHV and interaction with HIV: the
bad romance. Adv Exp Med Biol. 2017;1018:237–51. https://doi.
org/10.1007/978-981-10-5765-6_15.
50. Sarmati L, Andreoni M, Suligoi B, et al. Infection with human
herpesvirus-8 and its correlation with hepatitis B virus and hep-
atitis C virus markers among rural populations in Cambodia. Am
J Trop Med Hyg. 2003;68(4):501–2.
51. Sarov B, Davidovici B, Boshoff C, et al. Seroepidemiology and
molecular epidemiology of Kaposi’s sarcoma-associated her-
pesvirus among jewish population groups in Israel. JNCI J Natl
Cancer Inst. 2001;93(3):194–202. https://doi.org/10.1093/jnci/93.
3.194.
52. Sehgal VN, Verma P, Sharma S. HIV/AIDS Kaposi sarcoma: the
Indian perspective. Skinmed. 2013;11(6):375–7.
53. Sharma RK, Bhardwaj S. Kaposi sarcoma presenting as an index
sign of HIV infection in an Indian. JK Sci. 2012;14(3):158–60.
54. Sharp PM, Hahn BH. Origins of HIV and the AIDS pandemic.
Cold Spring Harbor Perspect Med. 2011;1(1):a006841-a41.
https://doi.org/10.1101/cshperspect.a006841.
55. Shenoy VV, Joshi SR, Duberkar D, Kadam KN, Shedge RT,
Lanjewar DN. Kaposi’s sarcoma with thrombocytopenia in a
heterosexual Asian Indian male. J Assoc Phys India.
2005;53:486–8.
56. Shroff HJ, Dashatwar DR, Deshpande RP, Waigmann HR. AIDS-
associated Kaposi’s sarcoma in an Indian female. J Assoc Phys
India. 1993;41(4):241–2.
57. Simonart T. Iron: a target for the management of Kaposi’s sar-
coma? BMC Cancer. 2004;4(1):1. https://doi.org/10.1186/1471-
2407-4-1.
58. Simonart T. Role of environmental factors in the pathogenesis of
classic and African-endemic Kaposi sarcoma. Cancer Lett.
2006;244(1):1–7. https://doi.org/10.1016/j.canlet.2006.02.005.
59. Sinha A, Goswami D, Haldar D, Mallik S, Bisoi S, Karmakar P.
Sexual behavior of transgenders and their vulnerability to HIV/
AIDS in an Urban Area of Eastern India. Indian J Public Health.
2017;61(2):141–3. https://doi.org/10.4103/ijph.IJPH_248_14.
60. Solomon S, Solomon SS, Ganesh AK. AIDS in India. Postgrad
Med J. 2006;82(971):545–7. https://doi.org/10.1136/pgmj.2006.
044966.
61. Su CC, Lai CL, Tsao SM, et al. High prevalence of human her-
pesvirus type 8 infection in patients with pulmonary tuberculosis
in Taiwan. Clin Microbiol Infect. 2015;21(3):266.e5–7. https://
doi.org/10.1016/j.cmi.2014.10.015.
62. Sunil M, Reid E, Lechowicz MJ. Update on HHV-8-associated
malignancies. Curr Infect Dis Rep. 2010;12(2):147–54. https://
doi.org/10.1007/s11908-010-0092-5.
63. Thakker S, Verma SC. Co-infections and pathogenesis of KSHV-
associated malignancies. Front Microbiol. 2016;7:151. https://
doi.org/10.3389/fmicb.2016.00151.
64. The LancetH. Homosexuality law reform is just a first step for
India. The lancet. HIV. 2018;5(10):e537. https://doi.org/10.1016/
s2352-3018(18)30260-1.
65. V Singh R, Singh S, Pandey S. . Numerous giant mollusca con-
tagiosa and Kaposi’s sarcomas with HIV disease. Indian J Der-
matol Venereol Leprol. 1996;62(3):173–4.
66. Vaishnani JB, Bosamiya SS, Momin AM. Kaposi’s sarcoma: a
presenting sign of HIV. Indian J Dermatol Venereol Leprol.
2010;76(2):215. https://doi.org/10.4103/0378-6323.60542.
67. Verma SC, Robertson ES. Molecular biology and pathogenesis of
Kaposi sarcoma-associated herpesvirus. FEMS Microbiol Lett.
2003;222(2):155–63. https://doi.org/10.1016/S0378-
1097(03)00261-1.
Kaposi’s sarcoma-associated herpesvirus related malignancy in India, a rare but emerging…

68. Wakeham K, Webb EL, Sebina I, et al. Parasite infection is 71. Zhang T, Wang L. Epidemiology of Kaposi’s sarcoma-associated
associated with Kaposi’s sarcoma associated herpesvirus (KSHV) herpesvirus in Asia: challenges and opportunities. J Med Virol.
in Ugandan women. Infect Agents Cancer. 2011;6(1):15. https:// 2017;89(4):563–70. https://doi.org/10.1002/jmv.24662.
doi.org/10.1186/1750-9378-6-15. 72. Zhang T, Shao X, Chen Y, et al. Human herpesvirus 8 sero-
69. Wang X, Zou Z, Deng Z, et al. Male hormones activate EphA2 to prevalence, China. Emerg Infect Dis. 2012;18(1):150–2. https://
facilitate Kaposi’s sarcoma-associated herpesvirus infection: doi.org/10.3201/eid1801.102070.
implications for gender disparity in Kaposi’s sarcoma. PLoS
Pathog. 2017;13(9):e1006580. https://doi.org/10.1371/journal.
Publisher’s Note Springer Nature remains neutral with regard to
ppat.1006580.
jurisdictional claims in published maps and institutional affiliations.
70. Warpe BM. Kaposi sarcoma as initial presentation of HIV
infection. N Am J Med Sci. 2014;6(12):650–2. https://doi.org/10.
4103/1947-2714.147984.

123

View publication stats