Human
Immunodeficiency
Vi rus and L eprosy:
An Update
Diana N.J. Lockwood, MD, FRCP*, Saba M. Lambert, MBBS
KEYWORDS
 Human immunodeficiency virus  Leprosy  Coinfection
 Antiretroviral treatment
Co-infection with HIV has a major effect on the
natural history of many diseases, particularly
mycobacterial diseases. Early in the HIV epidemic
it was predicted that HIV infections would worsen
outcomes in leprosy patients with more patients
developing lepromatous disease and patients
having fewer immune reactions. Now that many
patients receive HAART tuberculoid leprosy types
predominate and reactions are an important clin-
ical feature in co-infected patients.1e4
Leprosy is a chronic infectious disease affecting
nerves and skin. It has a long incubation period of
2 to 10 years, and presents with a clinical spec-
trum depending on the relationship between the
host immune system and the bacteria. At one
end of the spectrum is tuberculoid leprosy, char-
acterized by strong cell-mediated immunity (CMI)
toward M leprae. These patients have few hypo-
pigmented, anesthetic lesions. At the other pole
is lepromatous leprosy (LL), which is characterized
by the absence of a CMI response. These patients
have numerous lesions and high bacillary loads.
Most patients have features between these two
extreme groups and fall in the categories of
borderline tuberculous (BT), borderline borderline
(BB) or borderline lepromatous (BL). The border-
line cases are immunologically unstable and at
greater risk of type 1 reaction, which affects mainly
the nerves and skin. The lepromatous types of BL
and LL are at higher risk of erythema nodosu
leprosum (ENL), a more systemic and severe
immunologic complication.
London School of Hygiene and Tropical Medicine, Keppel Street, WC1E 7HT London, UK
* Corresponding author.
E-mail address: Diana.Lockwood@lshtm.ac.uk
Dermatol Clin 29 (2011) 125128
doi:10.1016/j.det.2010.08.016
0733-8635/11/$ e see front matter 2011 Published by Elsevier Inc.
In 2008, 121 countries reported a total of 249,007
new leprosy cases to the World Health Organiza-
tion (WHO). Most endemic countries for leprosy
also have a high HIV prevalence, increasing the
possibility of HIVeleprosy coinfection.
The few published small studies provide limited
data on the course of leprosy in coinfected patients.
HIV incidence was not found to be increased
among leprosy patients compared with nonleprosy
groups.5,6 All types of leprosy can occur in coin-
fected patients. Two East African studies reporting
an increase multibacillary (MB) cases.7,8 However
since the introduction of HAART borderline tuber-
culoid leprosy is the predominant form, as reported
in Brazilian studies.9,10 Coinfected patients treated
with standard length WHO-multi-drug therapy
(MDT), have responded adequately, although there
might be a possibility of an increased relapse
rate.11 A Ugandan study demonstrated an
increased risk of developing type 1 reactions in an
MB leprosy patient with HIV,12 and increased
recurrence rates of type 1 reactions were seen in
an Ethiopian study.13 In general, however, neuritis
was not found to be more severe in HIV-positive
cases.14 A few case reports of ENL in coinfected
patients have been published. Co-infected patients
with reactions appear to need very long courses of
steroid treatment.13,14 Patients with HIV are also at
risk of developing peripheral nerve damage
including generalized peripheral neuropathy and
mono-neuritis multiplex through several mecha-
nisms, namely, treatment with antiretrovirals and
derm.theclinics.com
126 Lockwood & Lambert
HIV infection per se. In analogy to the situation for
tuberculosis in HIV coinfected individuals, it was
assumed that HIV coinfection would worsen nerve
damage in leprosy patients. There are a few early
studies reporting no increase in nerve damage in
coinfected patients.12e14 A well controlled study
of peripheral nerve function in coinfected patients
would be useful. Table 1 summarizes the expected
versus actual impact of HIV-1 on coinfected
patients.
IMMUNOLOGY OF HIV AND LEPROSY
COINFECTION
Patients with tuberculoid leprosy have good cell-
mediated immune response to M leprae, resulting
in a few skin lesions, which histologically have well
organized lymphocyte (CD681, CD31, CD81,
CD41)-rich granulomas with predominantly CD4
T cells. In contrast, patients with LL have a strong
humoral response but poor or absent cell-
medicated immunity, resulting in uncontrolled
growth of bacilli and disseminated skin lesions.
Histologic examination of biopsies from their
lesions reveals that the granulomas are comprised
of macrophages and small numbers of CD8
T cells.10
HIV affects cell-mediated immunity, and it was
initially expected that, just as in M. tuberculosis
infection, the decrease in CD4 cells would result in
decreased capacity for mycobacterial containment
and thus an increase in disseminated disease. But
studies have shown that HIV coinfected patients
with low CD4 count had borderline tuberculoid
lesions with well formed granuloma and normal
CD4 cells numbers. In contrast, coinfected patients
with LL lesions showed loose infiltrates comprised
of macrophages and a small number of almost
exclusively CD8 lymphocytes.15,16 Carvalho and
colleagues16 found that the coinfected group
exhibits lower CD4 to CD8 ratios, higher levels of
Table 1
Summary of impact of human immunodeficiency virus-1 on leprosy: expected versus actual
Epidemiologic Incidence
Clinical Tuberculoid leprosy
Treatment response
Type-1 reactional states
Neuritis
Novel findings
Histopathological Granuloma formation
Bacterial index
CD81 activation, increased Vd1 to Vd2 T cell ratios
and decreased percentages of plasmacytoid
dendritic cells as compared with HIV-1 mono-
infected patients. The exact immunopathological
mechanism underlying the possible increase in
frequency of leprosy reactions is not clear. Dysregu-
lation of the immune system and the heightened
state of immune activation in HIV infection may be
responsible. In addition, delayed clearance of
M.leprae antigen caused by impaired phagocytic
function of macrophages also has been implicated.
EFFECT OF ANTIRETROVIRAL THERAPY ON
HIV AND LEPROSY COINFECTION
Since the introduction of highly active antiretroviral
therapy (HAART) in the management of HIV, espe-
cially in regions endemic for leprosy, co-infected
patients are also developing tuberculoid leprosy
with active lesions, and ulceration of lesions is
seen in leprosy type 1 reactions. Leprosy is being
increasingly reported as part of the immune recon-
stitution inflammatory syndrome (IRIS).
IRIS is a paradoxic deterioration in clinical status
after starting HAART, a deterioration that is attribut-
able to the recovery or reactivation of someones
immune response to a latent or subclinical process.
The HAART regimes currently used increase
production and redistribution of CD41 cells and
improve pathogen-specific immunity, both to HIV
and other pathogens. While improved immunity to
HIV is the required effect from HAART, improved
immunity to other opportunistic pathogens or
development of autoimmunity can result in IRIS.
The prevalence of IRIS in cohort studies of HIV-
positive patients ranges from 3% to more than
50%, varying greatly with the acquired immunode-
ficiency syndrome (AIDS)- defining illness affecting
the patient at the start of HAART therapy.17 Risk
factors for the development of IRIS include
advanced HIV disease with a CD41 T cell count
Theory In Practice
Increase in leprosy No change
Decreased Increased
Worsened No change
Fewer Increased
Worsened ?
Presentation as immune reconstitution inflammatory
syndrome
Decreased No change
Increased No change

under 50 cells/mm, unrecognized opportunistic
infection or high microbial burden, and the number
and presence of prior opportunistic infections.
HAART triggers overt clinical manifestations of
coinfection with tuberculosis, cytomegalovirus,
herpes zoster, C and B hepatitis virus, and now
leprosy.
Since 2003, 23 reports of patients developing
leprosy as IRIS have been published.2,3,15e19
Most patients had borderline leprosy, and type 1
reactions frequently occurred. Ulceration, a highly
unusual feature in leprosy lesions, was observed in
six patients, and four patients also developed
neuritis. It may be that the high proportion of
borderline tuberculoid leprosy cases among the
HIV-infected patients on HAART could shed light
on the questions related to the kinetics of M leprae
infection and development of disease. Borderline
tuberculoid leprosy manifests 2 to 5 years after
infection, at which time specific cell-mediated
immunity is strong enough to cause tissue damage
as well as kill or at least control mycobacterial
growth. On the other hand, lepromatous (BL and
LL) forms appear in patients after longer periods
of incubation (5 to 10 years), during which time
a large number of bacilli have accumulated in the
tissue due to progressive reduction of CMI.
Although HIV patients are typically more aware of
their health status and would easily detect small
lesions, the high frequency of borderline tubercu-
loid patients and reactions among HIV-infected
individuals and the low bacillary load among the
co-infected MB patients strongly suggest an
earlier-than-usual detection of the disease in
immune-reconstituted patients.
To facilitate the recognition and classification of
leprosy-associated IRIS, the following case defini-
tion has been suggested20:
Leprosy or leprosy reaction presenting within
6 months of starting HAART
Advanced HIV infection
Low CD41 count before starting HAART
CD41 count increasing after HAART has been
started.
Subdividing leprosy-associated IRIS into groups
according to data on timing and clinical presenta-
tion may help toward defining the causes and
mechanisms of this phenomenon. Deps and Lock-
wood21 recently proposed such a subdivision, at-
tempting to separate unmasking episodes from
those of overlap of immune restoration.
There are several possible mechanisms for the
pathogenesis of leprosy IRIS. Leprosy has a long
incubation period, and HAART may provide the
immunologic trigger for normal disease. Another
HIV and Leprosy: An Update 127
explanation is that leprosy-associated IRIS is
similar to a type 1 reaction. Whatever the under-
lying mechanisms, it is likely that leprosy-
associated IRIS will be increasingly reported,
especially as access to HAART becomes more
widely available. There are also several case
reports of patients being diagnosed with leprosy
more than 6 months after the initiation of HAART.
Although these patients can present with any
kind of leprosy, including histoid leprosy,22 the
time lag of greater than 6 months since the initia-
tion of HAART excludes the diagnosis of IRIS.
SUMMARY
From the available data so far, one can conclude
that treatment of leprosy patients with concurrent
HIV infection does not differ from that of a seroneg-
ative leprosy patient: standard WHO-MDT, in
conjunction with HAART if the CD4 count is low.
Treatment of reactions can be managed with corti-
costeroids or thalidomide as appropriate.
There are currently no good prospective clinical
data on the clinical features of leprosy in HIV-
infected patients, particularly the evolution of their
skin lesions and progression of nerve damage and
response to MDT. The inclusion of HIV testing in
sentinel studies of patients relapsing after multi-
drug therapy treatment would give some indica-
tion as to whether HIV infection is an important
cofactor in relapse. Response to treatment for
neuritis and reaction in coinfected patients needs
to be studied carefully in prospective studies.
The influence of HIV infection on cell-mediated
immune responses to M leprae in the HIV-
infected patient needs exploration, especially
within the skin. The recognition of leprosy present-
ing as IRIS warrants immunologic studies, using,
for example, immunohistochemistry to delineate
cellular phenotypes within the granuloma and
mRNA and protein production to assess cytokine
expression.
Leprosy and HIV coinfection is an evolving situ-
ation with ongoing discoveries and further
research needs.
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