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 In 2008, 121 countries reported a total of 249,007
natural history of many diseases, particularly new leprosy cases to the World Health Organiza-
mycobacterial diseases. Early in the HIV epidemic tion (WHO). Most endemic countries for leprosy
it was predicted that HIV infections would worsen also have a high HIV prevalence, increasing the
outcomes in leprosy patients with more patients possibility of HIVeleprosy coinfection.
developing lepromatous disease and patients The few published small studies provide limited
having fewer immune reactions. Now that many data on the course of leprosy in coinfected patients.
patients receive HAART tuberculoid leprosy types HIV incidence was not found to be increased
predominate and reactions are an important clin- among leprosy patients compared with nonleprosy
ical feature in co-infected patients.1e4 groups.5,6 All types of leprosy can occur in coin-
Leprosy is a chronic infectious disease affecting fected patients. Two East African studies reporting
nerves and skin. It has a long incubation period of an increase multibacillary (MB) cases.7,8 However
2 to 10 years, and presents with a clinical spec- since the introduction of HAART borderline tuber-
trum depending on the relationship between the culoid leprosy is the predominant form, as reported
host immune system and the bacteria. At one in Brazilian studies.9,10 Coinfected patients treated
end of the spectrum is tuberculoid leprosy, char- with standard length WHO-multi-drug therapy
acterized by strong cell-mediated immunity (CMI) (MDT), have responded adequately, although there
toward M leprae. These patients have few hypo- might be a possibility of an increased relapse
pigmented, anesthetic lesions. At the other pole rate.11 A Ugandan study demonstrated an
is lepromatous leprosy (LL), which is characterized increased risk of developing type 1 reactions in an
by the absence of a CMI response. These patients MB leprosy patient with HIV,12 and increased
have numerous lesions and high bacillary loads. recurrence rates of type 1 reactions were seen in
Most patients have features between these two an Ethiopian study.13 In general, however, neuritis
extreme groups and fall in the categories of was not found to be more severe in HIV-positive
borderline tuberculous (BT), borderline borderline cases.14 A few case reports of ENL in coinfected
(BB) or borderline lepromatous (BL). The border- patients have been published. Co-infected patients
line cases are immunologically unstable and at with reactions appear to need very long courses of
greater risk of type 1 reaction, which affects mainly steroid treatment.13,14 Patients with HIV are also at
the nerves and skin. The lepromatous types of BL risk of developing peripheral nerve damage
and LL are at higher risk of erythema nodosu including generalized peripheral neuropathy and
leprosum (ENL), a more systemic and severe mono-neuritis multiplex through several mecha-
immunologic complication. nisms, namely, treatment with antiretrovirals and
derm.theclinics.com

London School of Hygiene and Tropical Medicine, Keppel Street, WC1E 7HT London, UK
* Corresponding author.
E-mail address: [email protected]

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.
126 Lockwood & Lambert

HIV infection per se. In analogy to the situation for CD81 activation, increased Vd1 to Vd2 T cell ratios
tuberculosis in HIV coinfected individuals, it was and decreased percentages of plasmacytoid
assumed that HIV coinfection would worsen nerve dendritic cells as compared with HIV-1 mono-
damage in leprosy patients. There are a few early infected patients. The exact immunopathological
studies reporting no increase in nerve damage in mechanism underlying the possible increase in
coinfected patients.12e14 A well controlled study frequency of leprosy reactions is not clear. Dysregu-
of peripheral nerve function in coinfected patients lation of the immune system and the heightened
would be useful. Table 1 summarizes the expected state of immune activation in HIV infection may be
versus actual impact of HIV-1 on coinfected responsible. In addition, delayed clearance of
patients. M.leprae antigen caused by impaired phagocytic
function of macrophages also has been implicated.

IMMUNOLOGY OF HIV AND LEPROSY

COINFECTION EFFECT OF ANTIRETROVIRAL THERAPY ON
HIV AND LEPROSY COINFECTION
Patients with tuberculoid leprosy have good cell-
mediated immune response to M leprae, resulting Since the introduction of highly active antiretroviral
in a few skin lesions, which histologically have well therapy (HAART) in the management of HIV, espe-
organized lymphocyte (CD681, CD31, CD81, cially in regions endemic for leprosy, co-infected
CD41)-rich granulomas with predominantly CD4 patients are also developing tuberculoid leprosy
T cells. In contrast, patients with LL have a strong with active lesions, and ulceration of lesions is
humoral response but poor or absent cell- seen in leprosy type 1 reactions. Leprosy is being
medicated immunity, resulting in uncontrolled increasingly reported as part of the immune recon-
growth of bacilli and disseminated skin lesions. stitution inflammatory syndrome (IRIS).
Histologic examination of biopsies from their IRIS is a paradoxic deterioration in clinical status
lesions reveals that the granulomas are comprised after starting HAART, a deterioration that is attribut-
of macrophages and small numbers of CD8 able to the recovery or reactivation of someones
T cells.10 immune response to a latent or subclinical process.
HIV affects cell-mediated immunity, and it was The HAART regimes currently used increase
initially expected that, just as in M. tuberculosis production and redistribution of CD41 cells and
infection, the decrease in CD4 cells would result in improve pathogen-specific immunity, both to HIV
decreased capacity for mycobacterial containment and other pathogens. While improved immunity to
and thus an increase in disseminated disease. But HIV is the required effect from HAART, improved
studies have shown that HIV coinfected patients immunity to other opportunistic pathogens or
with low CD4 count had borderline tuberculoid development of autoimmunity can result in IRIS.
lesions with well formed granuloma and normal The prevalence of IRIS in cohort studies of HIV-
CD4 cells numbers. In contrast, coinfected patients positive patients ranges from 3% to more than
with LL lesions showed loose infiltrates comprised 50%, varying greatly with the acquired immunode-
of macrophages and a small number of almost ficiency syndrome (AIDS)- defining illness affecting
exclusively CD8 lymphocytes.15,16 Carvalho and the patient at the start of HAART therapy.17 Risk
colleagues16 found that the coinfected group factors for the development of IRIS include
exhibits lower CD4 to CD8 ratios, higher levels of advanced HIV disease with a CD41 T cell count

Table 1
Summary of impact of human immunodeficiency virus-1 on leprosy: expected versus actual

Theory In Practice
Epidemiologic Incidence Increase in leprosy No change
Clinical Tuberculoid leprosy Decreased Increased
Treatment response Worsened No change
Type-1 reactional states Fewer Increased
Neuritis Worsened ?
Novel findings Presentation as immune reconstitution inflammatory
syndrome
Histopathological Granuloma formation Decreased No change
Bacterial index Increased No change
 HIV and Leprosy: An Update 127

under 50 cells/mm, unrecognized opportunistic explanation is that leprosy-associated IRIS is

infection or high microbial burden, and the number similar to a type 1 reaction. Whatever the under-
and presence of prior opportunistic infections. lying mechanisms, it is likely that leprosy-
HAART triggers overt clinical manifestations of associated IRIS will be increasingly reported,
coinfection with tuberculosis, cytomegalovirus, especially as access to HAART becomes more
herpes zoster, C and B hepatitis virus, and now widely available. There are also several case
leprosy. reports of patients being diagnosed with leprosy
Since 2003, 23 reports of patients developing more than 6 months after the initiation of HAART.
leprosy as IRIS have been published.2,3,15e19 Although these patients can present with any
Most patients had borderline leprosy, and type 1 kind of leprosy, including histoid leprosy,22 the
reactions frequently occurred. Ulceration, a highly time lag of greater than 6 months since the initia-
unusual feature in leprosy lesions, was observed in tion of HAART excludes the diagnosis of IRIS.
six patients, and four patients also developed
neuritis. It may be that the high proportion of
borderline tuberculoid leprosy cases among the SUMMARY
HIV-infected patients on HAART could shed light
on the questions related to the kinetics of M leprae From the available data so far, one can conclude
infection and development of disease. Borderline that treatment of leprosy patients with concurrent
tuberculoid leprosy manifests 2 to 5 years after HIV infection does not differ from that of a seroneg-
infection, at which time specific cell-mediated ative leprosy patient: standard WHO-MDT, in
immunity is strong enough to cause tissue damage conjunction with HAART if the CD4 count is low.
as well as kill or at least control mycobacterial Treatment of reactions can be managed with corti-
growth. On the other hand, lepromatous (BL and costeroids or thalidomide as appropriate.
LL) forms appear in patients after longer periods There are currently no good prospective clinical
of incubation (5 to 10 years), during which time data on the clinical features of leprosy in HIV-
a large number of bacilli have accumulated in the infected patients, particularly the evolution of their
tissue due to progressive reduction of CMI. skin lesions and progression of nerve damage and
Although HIV patients are typically more aware of response to MDT. The inclusion of HIV testing in
their health status and would easily detect small sentinel studies of patients relapsing after multi-
lesions, the high frequency of borderline tubercu- drug therapy treatment would give some indica-
loid patients and reactions among HIV-infected tion as to whether HIV infection is an important
individuals and the low bacillary load among the cofactor in relapse. Response to treatment for
co-infected MB patients strongly suggest an neuritis and reaction in coinfected patients needs
earlier-than-usual detection of the disease in to be studied carefully in prospective studies.
immune-reconstituted patients. The influence of HIV infection on cell-mediated
To facilitate the recognition and classification of immune responses to M leprae in the HIV-
leprosy-associated IRIS, the following case defini- infected patient needs exploration, especially
tion has been suggested20: within the skin. The recognition of leprosy present-
ing as IRIS warrants immunologic studies, using,
Leprosy or leprosy reaction presenting within for example, immunohistochemistry to delineate
6 months of starting HAART cellular phenotypes within the granuloma and
Advanced HIV infection mRNA and protein production to assess cytokine
Low CD41 count before starting HAART expression.
CD41 count increasing after HAART has been Leprosy and HIV coinfection is an evolving situ-
started. ation with ongoing discoveries and further
research needs.
Subdividing leprosy-associated IRIS into groups
according to data on timing and clinical presenta-
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