Interactions between HIV infection and leprosy: a paradox

Review

Interactions between HIV infection and leprosy: a paradox Andrew P Ustianowski, Stephen D Lawn, Diana N J Lockwood Lancet Infect Dis 2006; 6: 350–60 The Hospital for Tropical Diseases, London, UK (A P Ustianowski MRCP, S D Lawn MD, D N J Lockwood FRCP); Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK (A P Ustianowski, S D Lawn, D N J Lockwood); Monsall Unit, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Manchester, UK (A P Ustianowski); and Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa (S D Lawn) Correspondence to: Dr Diana Lockwood, Hospital for Tropical Diseases, Mortimer Market Centre, Capper Street, London WC1E 6AU, UK. Tel +44 (0)20 7387 9300 ext 5970; fax +44 (0)20 7380 9761; [email protected]

Early in the HIV epidemic it was feared that the disease would undermine leprosy control, as has occurred with tuberculosis. It was predicted that patients with leprosy and HIV coinfection would have an increased risk of lepromatous disease and a faster clinical evolution, and that the leprosy would be more difficult to treat. None of these concerns have materialised and the interaction between HIV and Mycobacterium leprae seems to be far more subtle than that between HIV and tuberculosis. We review the epidemiological, clinical, and pathological data relating to leprosy/HIV coinfection. The published epidemiological data are limited in quality but show neither an increased HIV prevalence among leprosy cases nor an alteration in clinical spectrum of leprosy among coinfected patients. Some data suggest that immune-mediated reactions that complicate leprosy occur at a higher frequency in coinfected patients. Leprosy has now been reported presenting as immune reconstitution disease among patients commencing highly active antiretroviral treatment. Histopathological observations reveal a normal spectrum of appearances in biopsies of leprosy lesions from coinfected patients, even among those with advanced immunodeficiency. These observations suggest that cell-mediated immune responses to M leprae are preserved at the site of disease despite evidence that these responses are abrogated systemically, by contrast with tuberculosis, in which the host granulomatous response is impaired by HIV coinfection. We speculate that this paradox may relate to differences between the activation state and rates of cell turnover within leprosy and tuberculosis granulomas that differentially affect the susceptibility of the granulomas to HIV. The interactions between leprosy and HIV have been little studied and further research on the clinical, pathological, and management aspects of this coinfection is warranted.

Introduction Leprosy—an infection of the skin and peripheral nerves by Mycobacterium leprae (panel)—continues to be a publichealth problem, with 407 791 new cases registered in 2004.1 India, Brazil, Congo, Nepal, Tanzania, and Mozambique have the highest numbers of new cases. HIV prevalence rates are also increasing in many countries where leprosy

Panel: Leprosy—relevant key clinical facts Aetiology Leprosy results from infection with Mycobacterium leprae which affects principally the skin, peripheral nerves, and eyes. Spectrum Clinical disease occurs on a spectrum determined by the host immune response. At either end of the spectrum are polar tuberculoid and polar lepromatous disease with borderline forms (borderline tuberculoid, borderline, borderline lepromatous) in between. Incubation Varies widely from months to 30 years, with means of 4 years for tuberculoid and 10 years for lepromatous disease. Clinical presentation Patients with tuberculoid disease have few, well demarcated, anaesthetic skin lesions, whereas lepromatous patients have widespread and diffuse disease. Acid-fast bacilli are usually absent on direct microscopy in tuberculoid disease but abundant in lepromatous leprosy. Reactions Borderline disease is often immunologically unstable and fluctuations in immune response may lead to inflammatory reactions. Reversal reactions, typified by new inflammatory skin lesions and neuritis, usually result from increased T-cell responses. Erythema nodosum leprosum, an immune complex-mediated inflammatory reaction, develops in some lepromatous patients and presents with fever, pain, skin nodules, neuritis, and inflammation of the eyes, lymph nodes, testes, and joints.

350

is endemic. Although the number of coinfected patients has not been estimated, the increasing geographic overlap of these two diseases will very likely result in increasing numbers of individuals being dually infected (figure 1). Since HIV infection has a profound effect on the incidence and clinicopathological features of tuberculosis, there was concern early in the HIV epidemic that a similar interaction might exist between HIV infection and leprosy. However, a literature review in 1993 concluded that the prevalence of HIV among leprosy cases was not higher than among control groups and that HIV coinfection did not affect the tuberculoid-lepromatous clinical spectrum of leprosy.4 Other inconclusive data suggested that coinfected patients might have more severe leprosy neuritis and an increased frequency of immune-mediated type 1 (reversal) reactions. Over the past 10 years, the HIV epidemics in many countries with endemic leprosy have evolved and matured. We examine the cumulative evidence regarding the interaction of these diseases and consider mechanisms that may underlie the apparent paradox between the markedly differing effects of HIV-1 infection on tuberculosis and leprosy.

Epidemiological data Does HIV infection increase the risk of developing leprosy? The long incubation period and low incidence of leprosy make it impossible to do either prospective cohort studies of the incidence of leprosy in HIV-positive patients and HIV-negative controls or case control studies of the prevalence of leprosy among HIV-positive and HIV-negative groups. All published studies have instead examined HIV seroprevalence among previously established leprosy cohorts or in series of newly diagnosed leprosy patients compared with control groups (table 1). http://infection.thelancet.com Vol 6 June 2006

Review

Eastern Europe and central Asia 0·7 million

Western Europe 0·54 million North America 0·92 million

Nepal 8020 new leprosy cases North Africa and Middle East 0·40 million

Caribbean 0·39 million

Sub-Saharan Africa 25·3 million

South America 1·4 million

Brazil 41 070 new leprosy cases

Eastern Asia and Pacific 0·64 million

South and southeast Asia 5·8 million

India 559 938 new leprosy cases

Burma 10 286 new leprosy cases

Oceania 0·015 million

Mozambique 6617 new leprosy cases

Madagascar 8445 new leprosy cases

Figure 1: World map showing the numbers of adults and children living with HIV/AIDS at the end of 2002 and the six countries with the greatest number of new cases of leprosy in the same year The six countries account for 88·2% of the world’s new cases of leprosy. Data derived from WHO/UNAIDS.2,3

Most of these studies found no significant difference in HIV-1 seroprevalence between case and control groups. However, four studies,6,12,14,18 including the largest,14 demonstrated a modestly increased HIV seroprevalence and another study9 showed a borderline trend. Overall, these studies indicate that any increase in HIV prevalence among leprosy patients is likely to be small and substantially lower than HIV rates among patients with tuberculosis or disease due to Mycobacterium avium complex (MAC). The varying conclusions from these studies (table 1) reflect the considerable difficulties in studying the interaction of these diseases. Most included small numbers of dually infected patients, none considered levels of immunosuppression (eg, blood CD4 cell count), and little consideration was given to potential confounding factors— eg, age, sex, sexual experience and behaviour, socioeconomic status, and urban/rural residence. HIV coinfection is likely to affect health-seeking behaviour and thus may alter the chance of leprosy being diagnosed. The use of blood donors as controls produces additional confounding, since individuals who know they are infected with HIV are unlikely to volunteer as donors. Many studies were done in leprosy referral centres where only a subset of leprosy cases are seen and these cases are more likely to have more severe leprosy with widespread skin and nerve involvement. Many studies were done in the early to mid-1990s and the HIV epidemic has since matured in most of these countries, with both increasing numbers of infected http://infection.thelancet.com Vol 6 June 2006

individuals and increasing proportions of patients with advanced immunodeficiency. Previous data may not be representative of present demographics or numbers and, at the time, the small numbers of coinfected patients were not necessarily representative of the situation in the field or in wider or neighbouring areas. For example, it was estimated that India had 1·75 million HIV cases in 1994 but 5·1 million cases at the start of 2004,19,20 and two studies8,10 were done in Ethiopia, which has a lower HIV prevalence than surrounding countries. The data in table 1 is not suitable for a meta-analysis because of insufficient descriptions of methods and analyses in many of the reports, differing inclusion criteria and designs, and methodological limitations. However, some of the larger studies deserve closer scrutiny. The largest, by van den Broek and colleagues14 in Tanzania in the early 1990s, is unique in being country wide. However, only 69% of the nationally notified leprosy patients (probably an underestimate of total cases) were enrolled. 52 cases had insufficient data and the analysis was based on 679 patients, of whom 83 were HIV seropositive. The HIV diagnosis was not robust, since it relied upon a single ELISA test. The patients self-reported to leprosy and hospital centres and blood donors served as controls matched for sex, age, and residence (urban vs rural), which is suboptimal, since individuals known to have either infection are unlikely to serve as blood donors and selfreporting of leprosy probably biases towards urban and peri-urban areas. Matching for rural residence alone 351

Review

misses this divide and does not account for roadside residence (with proportionately higher HIV rates). An odds ratio of 2·5 (95% CI 2·0–3·2) was observed for the risk of HIV seropositivity among leprosy patients. Frommel and colleagues10 did a study in an Ethiopian urban specialist referral centre during the late 1980s and early 1990s. 644 leprosy patients were enrolled, of whom 31 were HIV seropositive. Although HIV infection and leprosy were not significantly associated, the controls were suboptimal (age-matched and sex-matched patients from the same hospital but with very different residence). Other studies21,22 have been published but report only anecdotal cases or small uncontrolled series and have not been included in table 1. There are concerns about the reliability of the HIV diagnoses in some studies. Table 2 illustrates the proportion of patients found to be HIV-1 seropositive by single and confirmatory assays, and demonstrates a high rate of probable false-positive results. The HIV diagnoses in some studies are therefore potentially suspect, including the study by van den Broek and colleagues,14 because of the use of a single ELISA for HIV diagnosis. Leprosy might affect the specificity or sensitivity of some early assays for HIV

diagnosis25,26 because patients with lepromatous leprosy have a polyclonal hypergammaglobulinaemia that can, for example, cause false-positive results in syphilis serology and rheumatoid factor assays.27,28 Lepromatous patients also produce antibodies to mycobacterial cell wall antigens and these may cross-react with the HIV-1 pol and gag proteins in certain assays,17,24 although other workers have failed to detect such effects.29,30 Newer serological assays are more reliable, and indeterminate or non-confirmed results may be assessed by PCR. The converse problem—ie, HIV infection causing falsepositive serological assays for leprosy—has also been reported. Antibody levels to phenolic glycolipid 1, a M leprae-specific antigen that can be used for leprosy serodiagnosis, were significantly raised in 65 (14·9%) of 437 Cuban HIV-infected patients (p=0·05), none of whom had evidence of leprosy.31 These important interactions deserve contemporary and definitive studies.

Clinical spectrum of disease The clinical spectrum of leprosy depends on specific host immunity. Patients with tuberculoid leprosy have vigorous cell-mediated immune responses to M leprae,

Country

Years of study

Reported HIV-1 seropositivity rate: coinfected/leprosy cases (%)

Odds ratio (95% CI) of an increase in HIV seropositivity

Comments on study

Republic of Congo, Cote d’Ivoire, Senegal, and Yemen5

1986–88

43/1245 (3·5)

No significant increase

Unclear patient and control ascertainment Poor design

Zambia6

1987

p<0·05 but odds ratio not stated

Small cohort Suboptimal controls Hospital-based

Malawi7

1988–89

2/112 (1·8)

No significant increase

Small numbers of HIV seropositive patients

Ethiopia8

1988–89

8/250 (3·2)

No significant increase

Low numbers of HIV seropositive patients Suboptimal controls Referral centre-based

6/18 (33·3)

Kenya9

1989–90

20/129 (15·5)

1·8 (0·9–3·2)

Unclear design and controls

Ethiopia10

1989–92

31/644 (4·8)

No significant increase

Suboptimal controls Urban referral centre-based

Brazil11

1990–92

3/1016 (0·3)

No significant increase

Small numbers of HIV seropositive patients Suboptimal controls Hospital-based

Tanzania12

1991

9/93 (9·7)

2·2 (1·0–4·7)

Suboptimal design and controls Small cohort Hospital-based Passive case-finding

Uganda13

1991–92

23/189 (12·2)

No significant increase

Suboptimal controls Passive case-finding

Tanzania14

1991–93

83/697 (11·9)

2·5 (2·0–3·2)

Suboptimal controls Suboptimal HIV diagnosis Passive case-finding

India15

1992–93

4/1019 (0·4)

No significant increase

Small numbers of HIV seropositive patients Hospital-based

Mali16

1992–94

11/740 (1·5)

No significant increase

Suboptimal controls Hospital referral centre-based

Democratic Republic of Congo17

?1997–98

2/57 (3·5)

No significant increase

Small cohort Suboptimal controls

Nigeria18

1997–98

11/105 (10·5)

2·53 (1·04–6·15)

Suboptimal controls Referral centre-based

Table 1: Major studies examining the rate of HIV seropositivity among leprosy patients

352

http://infection.thelancet.com Vol 6 June 2006

Review

whereas those with lepromatous disease do not have cellmediated immune responses but rather produce high titres of M leprae-specific antibodies.32 Since HIV principally affects host cell-mediated immune responses, it was predicted that coinfected patients would present with lepromatous disease,33 analogous to coinfection with other mycobacteria (eg, MAC) where granuloma formation is poor and there are abundant acid-fast bacilli. Conversely it has been postulated that the differential long incubation periods for leprosy (2–5 years for tuberculoid and 5–15 years for lepromatous disease) might bias towards tuberculoid disease, since patients might die of AIDS-related infections before manifesting their lepromatous leprosy. Five major studies report that the ratio of lepromatous to tuberculoid disease is not significantly affected by HIV coi nfection.9,10,14,22,34 A significantly greater proportion of tuberculoid leprosy (p=0·012) was demonstrated in one study,16 while another reported a significant increase in lepromatous disease (OR 4·6, 95% CI 1·3–13·2).12 In the latter study, two patients may have been misclassified, potentially accounting for this apparent difference.12 Kawuma and co-workers13 comment that there were substantially more lepromatous patients among the HIV/ M leprae coinfected, but provide no numerical data. Collectively, neither these studies nor other small series and case reports suggest that coinfection with HIV alters the clinical spectrum of leprosy (table 3). The histological features of leprosy also appear to be preserved in HIVinfected patients.35,36,39,42–45,47–54,56–59 This observation is important because it indicates preservation of the T-cellmediated immune response to M leprae at the tuberculoid end of the spectrum.

Clinical features of leprosy Patients with leprosy present with skin lesions and nerve damage. The published data suggest that the range of skin lesions from hypopigmented tuberculoid lesions to nodular lepromatous lesions is present in HIV-infected patients (table 3). Prospective studies are needed to establish the degree of inflammation in the lesions of patients with HIV coinfection. Peripheral nerve damage, the main feature of leprosy, affects over one-third of patients with multibacillary leprosy at the time of diagnosis.60 No data indicate whether HIV infection worsens nerve damage in leprosy, although it may alter the immune response in nerves to M leprae and is itself neuropathic, and so could act synergistically. Determining whether these interactions occur requires a well controlled study of peripheral nerve function.

Treatment It has been postulated that HIV infection might affect the efficacy of multidrug therapy for leprosy, with HIV-positive patients potentially taking longer to clear mycobacteria from lesions or experiencing a higher relapse rate. The limited published data (table 3) suggest that HIV/leprosyhttp://infection.thelancet.com Vol 6 June 2006

Country

Number screened

Numbers HIV seropositive by: First ELISA

Second ELISA

Third ELISA

Western blot/immunoblot

Brazil23

234

14

0

..

..

Mali16

740

27

..

..

11 ..

India15

1019

30

14

3

Brazil11

1016

11

3

-

..

Zaire24

57

41

39

..

2

..=not done/reported.*Substantial rates of false positives seen.

Table 2: Proportion/number of leprosy patients HIV seropositive by initial and confirmatory assays*

coinfected patients respond equally well to multidrug therapy without the need for prolonged treatment courses and experience similar side-effect profiles. However, relapses are rare after multidrug therapy, being about 1 per 1000 person-years for tuberculoid patients and 0–20·4 per 1000 person-years for multibacillary disease.61 Thus, even a small increase in the relapse rate would be difficult to detect. The inclusion of HIV testing in sentinel studies of patients relapsing after multidrug therapy treatment would give some indication as to whether HIV infection is an important cofactor in relapse. Larger formal studies of the clinical response of skin lesions and nerve impairment to multidrug treatment in HIV-infected patients are also required.

Leprosy reactions Borderline disease comprises the spectrum of clinical forms of leprosy that lie between the tuberculoid and lepromatous poles and are designated as borderline tuberculoid, borderline, and borderline lepromatous (panel). These forms are often immunologically unstable, potentially leading to reactional states. Type 1 (reversal) reactions manifest as painful, inflamed skin lesions and a painful neuritis that may result in loss of peripheral nerve function. The precise molecular trigger for reversal reactions remains unknown, but there is evidence of spontaneous increases in T-cell reactivity to M leprae antigens and macrophage activation. CD4+ cells migrate into lesions and raised levels of both cytokine mRNA and protein for Th1 cytokines (interferon γ, interleukin 1β, interleukin 2, and interleukin 12) and the macrophage-derived cytokine tumour necrosis factor α (TNFα) have been demonstrated in skin lesions.62–64 Cytokine production in the lesions decreases with resolution of the reaction. However, in some borderline lepromatous patients lesions remain active with ongoing cytokine production even after 6 months of corticosteroid treatment.65 Reactions may occur spontaneously after starting multidrug therapy or in the post-partum period when maternal cell-mediated immune responses return to pre-pregnancy levels. Patients with borderline lepromatous and lepromatous leprosy are at risk of developing erythema nodosum leprosum (type 2 reaction), a systemic inflammatory response with deposition of extravascular immune 353

Review

complexes leading to neutrophil infiltration and complement activation. This reaction is frequently accompanied by high circulating concentrations of TNFα. Some evidence suggests that the frequency and type of reactions are altered by HIV coinfection. Studies from Country

Number of Clinical leprosy patients classification

CD4 cell counts (cells per µL)

Abnormal clinical presentation/ progress/ response?

Brazil and USA35

One

BT

..

..

South America and Caribbean36

One

BL (with RR)

300

..

Zambia37

Ten

Five BT Two BB Two BL One LL

..

Poor outcome of treatment of active neuritis in one BT patient

Paraguay38

One

BL

..

..

39

Senegal

One

BL (with RR)

10

..

Uganda40

Two

One BT, one BL

..

..

Uganda41

One

BL (with recurrent RR)

..

..

Argentina42

One

LL with ENL

1563

..

Brazil43

One

LL with ENL

..

Became HIV seropositive after leprosy diagnosis

USA44

One

BT (subsequent RR)

96

..

India45

One

LL*

..

..

India46

Two

One LL, one BL

..

..

Zaire and Brazil47

Five

Two LL, two BT, one BL

.. .. ..

One LL relapsed

Brazil48

11

Three BL Eight BT

BL: 648, 564, .. BT: 185, 74, 0, 64, 19, 379, .., ..

..

India49

One

BT

..

Poor clinical response to treatment

India50

Four

One pure neural LL Three BL

460 330, 510, ..

..

India51

Three

One BL, two indeterminate

BL: 858 Indeterminate: .., 337

Relapsing reversal reaction in BL patient

India52

Three

One BL (with RR) One BT/BB (with RR) One BT/BB (with mild RR)

..

..

Spain53

One

LL

800

..

India54

One

BL

..

..

India55

Two

Two BT

..

..

India56

One

BT (with RR)

350

Complete facial nerve palsy

India57

One

LL (with ENL)

300

..

India58

Three

Two BT One BB

BT: 482, 540 BB: 240

..

Brazil59

22

Five TT Nine BT One LL Three indeterminate Two tuberculoid† Two lepromatous†

TT: 201, 430, 164, 104, 427 BT: 79, 17, 55, 73, 60, 489, 177, 152, 35 LL: 80 Indeterminate: 748, 27, 245 Tuberculoid: 207, 154 Lepromatous: 67, 8

..

..= not reported; BB = borderline; BT=borderline tuberculoid; BL=borderline lepromatous; ENL=erythema nodosum leprosum; LL=polar lepromatous; RR=reversal reaction. *Determined by authors. †Not further sub-classified.

Table 3: Clinical features reported in leprosy/HIV-1 coinfection case reports and small series

354

Ethiopia have demonstrated a higher risk of erythema nodosum leprosum (RR 5·2, 95% CI 1·7–15·9), and an increase in recurrent reversal reactions (RR 2·7, 95% CI 1·4–5·1), but no effect on neuritis or reversal reactions overall.34,66,67 However, these data are based on very small numbers (only two coinfected patients had erythema nodosum leprosum and three had recurrent reversal reactions). A study in Uganda showed that patients with lepromatous disease and HIV coinfection are at higher risk of reversal reactions and neuritis (both p<0·0005), but responded as expected to steroid therapy;68 others have reported poorer responses to treatment for active neuritis.37 This area requires prospective investigation.

Impact of leprosy on HIV disease and progression Epidemiological data support the hypothesis that tuberculosis accelerates the decline in immune function in HIV-infected individuals,69,70 the proposed biological mechanism principally being an augmented rate of HIV replication. The question has also been raised as to whether leprosy may similarly affect the natural history of HIV infection.4 Although no epidemiological data address this question, this seems very unlikely from a mechanistic viewpoint. Potential acceleration of HIV pathogenesis by tuberculosis and other coinfections is most likely to be related to a marked proinflammatory cytokine drive that augments HIV replication systemically;71 this is not present among patients with leprosy except during severe erythema nodosum leprosum. It would be very difficult to design studies to address this question.

Immune reconstitution disease Use of highly active antiretroviral treatment (HAART) since the mid-1990s has led to a dramatic decline in HIV-associated morbidity and mortality among patient populations with access to these drugs.72–74 The beneficial effects of HAART result from the gradual restoration of pathogen-specific immune responses that follows suppression of viral replication. However, following the initiation of HAART, the early rapid phase of immune reconstitution may be complicated by clinical phenomena in which either previously subclinical infections are “unmasked” or pre-existing opportunistic infections clinically deteriorate.75–77 These clinical phenomena result from immunopathological host inflammatory responses being “switched on” during HAART. Various terms have been used to refer to such phenomena, including the immune reconstitution inflammatory syndrome and immune reconstitution disease (IRD). IRD is associated with a wide range of infections,75 but is most commonly associated with Mycobacterium tuberculosis and MAC.77 IRD develops during the first 3 months of HAART in individuals with advanced pre-treatment immunodeficiency; blood CD4 lymphocyte counts are typically less than 100 cells per μL.75–77 Immunopathology is usually triggered via cell-mediated type 1 cytokine secreting immune http://infection.thelancet.com Vol 6 June 2006

Review

Reference

Country

Manifestation

Leprosy classification

HAART regimen

Number of weeks on HAART

CD4 cell count (cells per µL) IRD

Baseline

IRD

Lawn et al86

Ugandan immigrant to UK

Single skin lesion with reversal reaction

BT

2 NRTI + NNRTI

4

10

70

120 000

1000

Pignataro et al87

Brazil

Ulcerating skin lesion with reversal reaction

BT

2 NRTI + PI

8

147

499

..

..

..

Couppie et al88

Brazil

Multiple ulcerating skin lesions with reversal reaction

BL

2 NRTI + NNRTI

4

37

200

..

..

..

French Guiana

Two ulcerating skin lesions with reversal reaction

BB

3 NRTI

6

87

257

19 000

<650

French Guiana

Multiple skin lesions with reversal reaction plus neuritis

BT

3 NRTI

8

130

278

40 701

68

Steroids

Martinique

Multiple skin lesions with reversal reaction plus neuritis

BT

2 NRTI + PI

12

31

171

62 700

50

Steroids

Brazil

Skin lesion with reversal reaction

BT

NS

8–24

73

270

..

..

Brazil

Skin lesion with reversal reaction

BT

NS

8–24

35

100

..

..

..

Brazilian immigrant to Italy

Single skin lesion and/or neuritis

BT

2 NRTI + PI

8

7

90

..

..

None

Baseline

Pereira et al59

Visco-Comandini et al89

Viral load (copies per mL)

Adjunctive interventions

Steroids + azathioprine

None

..

..=not reported; BB=borderline; BL=borderline lepromatous; BT=borderline tuberculoid; HAART=highly active antiretroviral treatment; IRD=immune reconstitution disease; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.

Table 4: Features of nine cases of leprosy-associated immune reconstitution disease

responses.77 An unusually vigorous granulomatous response with or without caseation is described in tuberculosis-associated or MAC-associated IRD; lymph nodes may suppurate and biopsy specimens of affected tissues may reveal a degree of necrotising inflammation that is unusual in the context of profoundly immunocompromised patients.78–85 Over the past 2 years, nine cases of leprosy presenting as IRD have been published (table 4). Among eight of the patients leprosy presented for the first time and in one a pre-existing skin lesion clinically deteriorated. All were borderline forms of disease with cutaneous lesions in reversal reaction. Ulceration, a highly unusual feature in leprosy lesions, was observed in three patients; four patients also developed neuritis. Nearly all these manifestations presented within 3 months of starting HAART (median 8 weeks, range 4–24 weeks). The pre-HAART median CD4 cell count was 37 cells per μL (range 10–147 cells per μL). Development of IRD was associated with marked increases in blood CD4 cell count and major reductions in plasma viral load, indicating a good response to HAART. Three patients received oral corticosteroids in addition to antileprosy treatment for IRD and HAART was not interrupted in any. One patient developed a severe and protracted reversal reaction in a facial skin lesion (figure 2) that required high-dose corticosteroids for 8 months. Azathioprine was eventually prescribed as a steroidsparing agent.86 Several possible explanations may underline the phenomenon of leprosy IRD. Leprosy has a long incubation period and tuberculoid and borderline forms of leprosy require a M leprae-specific cellular immune response for lesions to manifest. It is therefore possible http://infection.thelancet.com Vol 6 June 2006

that HAART may simply provide the immunological “trigger” leading to the “normal” presentation of disease. However, this hypothesis would not explain the unusual and florid manifestations described in some of the cases—eg, ulceration of cutaneous lesions. A second explanation is that leprosy-associated IRD is similar to a leprosy type 1 reaction in which there is a sudden unexplained switching on of Th1 type responses to M leprae antigens. Indeed, most of the patients presented with type 1 reactions, some requiring adjunctive immunosuppressive treatment. It is therefore possible that, even though HIV may not impair immune responses to M leprae, HAART may serve as a trigger for unusually florid reactional states. A third hypothesis would have to assume that HIV coinfection results in a degree of suppression of host responses to M leprae infection that is reversed after commencing HAART. Indeed, suppression of immune responses to a copathogen is implicit in most definitions of IRD. In this context, it is intriguing that these cases of leprosy-associated IRD may therefore provide indirect evidence that, in at least a proportion of patients, the clinical presentation of leprosy is suppressed by HIVassociated immunodeficiency. Whatever the underlying mechanisms, it is likely that leprosy-associated IRD will be increasingly reported. It is noteworthy that half of the cases of IRD were reported from Brazil. This country has the unique combination of high and increasing case numbers for leprosy, a well established HIV epidemic, and a government funded programme of antiretroviral therapy. A similar situation is likely to develop in India, which has 70% of the world leprosy cases, an expanding HIV epidemic, and the possibility of widely available antiretroviral therapy. It is 355

Review

not yet clear whether IRD triggers the “normal” presentation of leprosy or whether the natural history of leprosy is actually accelerated by IRD leading to the premature presentation of leprosy.

The paradox Whereas the evidence reviewed above suggests that HIV infection has little impact on leprosy, the interaction of HIV with tuberculosis—a closely related mycobacterial disease—is profound. First, HIV infection has had a major impact on the epidemiology of tuberculosis globally, and has emerged as the single strongest risk factor for development of active tuberculous disease.90 Among HIV-infected individuals with latent M tuberculosis infection, the lifetime risk of developing active tuberculosis is estimated to be approximately 10% per year91 and HIV infection is also associated with a heightened susceptibility to exogenous tuberculosis infection and a higher rate of progressive primary disease.92 Second, although there are no data to indicate that HIV substantially alters the clinical manifestations of leprosy (with the exception of leprosy IRD), advancing HIV-associated immunodeficiency has profound effects on the clinical presentation of tuberculosis.93,94 Reduced immunological capacity for mycobacterial containment and reduced tissue immunopathology result in an increased frequency of radiographically atypical pulmonary tuberculosis and an increased risk of extrapulmonary and disseminated disease.93–96

Figure 2: Borderline tuberculoid leprosy with a reversal reaction presenting as immune reconstitution disease shortly after commencement of highly active antiretroviral treatment The arrow indicates thickened tender great auricular nerve. The skin lesions show erythema and oedema, typical changes in a leprosy reaction. Reproduced from reference 86 with permission from the University of Chicago Press.

356

Data from histological studies are consistent with these marked effects of HIV on tuberculosis. Histological studies of tuberculosis and HIV-1 coinfection reveal a spectrum of appearances that reflects the degree of immunosuppression.97 Low blood CD4 lymphocyte counts are associated with reduced numbers of CD4 lymphocytes in tuberculous lesions, failure of epithelioid differentiation and activation of macrophages, and failure of Langhans giant cell formation. As a result, granulomas may either be poorly formed or completely fail to develop, and acid-fast bacilli are numerous.97,98 These histological observations can be understood in the context of the diverse effects of HIV on the host granulomatous response to M tuberculosis.98 By contrast, evidence suggests that the host granulomatous response to M leprae is preserved among individuals with HIV.48 This key observation may prove critical to our understanding the paradox of the differential impact of HIV on tuberculosis and leprosy. Sampaio and colleagues48 described eight patients with borderline tuberculoid leprosy who had HIV-1 coinfection and found that despite the patients having very low blood CD4 cell counts, biopsies of their skin lesions nevertheless showed well-formed granulomas that contained normal numbers of CD4 lymphocytes.48 This observation is key since the predominant cell observed in leprosy skin lesions at the tuberculoid end of the clinical spectrum is the CD4 T lymphocyte,99 which is also the principal cellular target of HIV. Sampaio and colleagues further demonstrated expression of human leucocyte antigen (HLA)-DR by dermal cells adjacent to the granulomas, providing evidence of local interferon-γ production. Absence of bacteria provided additional evidence of an effective functional immune response.48 These key observations define the principal question that needs to be addressed concerning this paradox: why does HIV have little discernable impact on leprosy granulomas but an extremely marked effect on tuberculous granulomas? In addressing this question, it is first important to note that the effects of HIV on immune cells may be compartmentalised to some extent and that peripheral blood CD4 cell counts do not necessarily reflect either the number or function of CD4 cells at actual sites of coinfections. The histological findings of Sampaio and colleagues48 indicated that the patients with leprosy and AIDS in their study had retained functional M lepraespecific CD4 lymphocyte clones at the site of infection. However, depressed cutaneous hypersensitivity and invitro lymphoproliferative responses to M leprae antigens indicated that systemic immune responses were impaired.48 This differential impact on the local versus systemic immune response to M leprae is in contrast with the marked abrogation of both systemic and local T-cell responses in patients with AIDS and M tuberculosis infection.98 A possible reason for this disparity might be the relative susceptibility of leprosy and tuberculous granulomas to http://infection.thelancet.com Vol 6 June 2006

Review

HIV. Differences in the immunological activation state of the two types of granuloma may affect the likelihood with which they recruit HIV-infected cells and their susceptibility to the establishment of a productive viral infection. High cell turnover within highly activated tuberculous granulomas is likely to be associated with a high rate of mononuclear cell recruitment from systemic cell pools, increasing the potential for entry of HIV-infected cells. By comparison, leprosy granulomas are typically less activated and rates of cell apoptosis and cell turnover are much lower, resulting in a lower risk of HIV-infected cells being recruited. The likelihood of an HIV-infected cell establishing a productive, spreading infection after recruitment to a granuloma is also likely to be determined by the type of granuloma involved. Establishment of infection is strongly related to the immunological activation state of target mononuclear cells.71 Activated cells are more readily infected with HIV due to upregulation of chemokine coreceptors,100 and acceleration of the viral life cycle profoundly increases the rate of viral replication.71 Compared with M leprae, M tuberculosis has a much greater capacity to induce secretion of TNFα,101,102 which is critical to the immunopathogenesis of HIV-1 infection.71,103 As a result, compared with leprosy granulomas, the inflammatory microenvironment at sites of M tuberculosis infection are likely to be much more conducive to the establishment and propagation of HIV infection. Furthermore, as a secondary effect, viral load and associated immunological effects of HIV are maximal at sites of M tuberculosis infection,98,104,105 leading to abrogation of the local granulomatous host response. We suggest that these differences between the M tuberculosis and M leprae granulomas provide a biologically plausible explanation for the observed differences between their interactions with HIV-1. The pathophysiological mechanisms that may underlie the possible increase in frequency of leprosy reactions in HIV-infected patients is unclear. However, the dysregulation of the immune system and heightened state of immune activation that characterises HIV infection may increase the propensity for such reactions. Furthermore, since phagocytic function of macrophages may be impaired by HIV infection,106 it is possible that the rate of clearance of M leprae antigens from the tissues is impaired, thereby increasing the likelihood of reactional states.

Future research Nearly every aspect of the interaction between leprosy and HIV infection warrants further study. Large epidemiological studies in areas where HIV and leprosy are prevalent are needed to definitively document the epidemiological and clinical associations of these diseases. Serological assays for HIV among leprosy patients need to be rigorously evaluated, especially among patients with lepromatous leprosy in whom hypergammaglobulinaemia may interfere with the http://infection.thelancet.com Vol 6 June 2006

assays. The impact of HIV on neurological disease among leprosy patients needs to be carefully documented and optimum strategies for the treatment of type 1 and type 2 reactions in coinfected patients should be studied. Azathioprine and ciclosporin are currently being evaluated as adjunctive treatments for leprosy reactions107 and these studies could usefully be extended to include coinfected patients. However, the role of immunosuppressive agents, including steroids, needs to be carefully monitored since coinfected patients are likely to reside in areas where there is a high incidence of tuberculosis; thus, any treatment needs to be carefully weighed against an increased risk of tuberculosis and other opportunist infections. Setting up these studies will require the formation of regional collaborations and networks because eligible patients will present in low numbers and mainly to specialised centres. Dissemination of information about leprosy presenting as IRD is also needed so that clinicians in leprosy and HIV endemic countries recognise this novel manifestation. 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 presenting as IRD warrants immunological studies, using, for example, immunohistochemistry to delineate cellular phenotypes within the granuloma and mRNA and protein production to assess cytokine expression. The impact of HIV could be explored in different mycobacterial diseases, including leprosy, tuberculosis, and non-tuberculous mycobacteria using insitu hybridisation techniques.

Conclusions Although some studies have demonstrated a modest increase in HIV-1 seroprevalence among leprosy patients compared with non-leprosy controls, most have shown no such association. All the studies are, however, limited in their statistical power, design, and execution. The clinicopathological spectrum of leprosy appears to be unaltered; however, HIV coinfection seems to be associated with an increased rate of leprosy reactions. There is no evidence that adverse reactions to leprosy multidrug therapy are increased or that treatment outcomes are altered by coinfection with HIV, although this has not been adequately studied. Why there is such a differential effect of HIV coinfection on leprosy compared with tuberculosis is not clear. Although systemic host responses to M leprae are impaired in HIV-infected individuals with borderline tuberculoid leprosy, paradoxically the host granulomatous response at the site of disease appears to be preserved. We speculate that this difference may relate to the effects of the intense inflammatory microenvironment at the site of tuberculosis accelerating HIV pathogenesis and impairing granuloma formation and function. The relatively low grade inflammatory process in leprosy lesions may be less permissive to both recruitment of 357

Review

Search strategy and selection criteria Papers for this review were identified by searches of PubMed with the search terms “leprosy” and “HIV” to April 2005, and from references contained within these and other relevant papers. All clinical and epidemiological papers were reviewed independently by two of the authors (AU and DNL), assessing quality and outcomes reported. Only papers published in English were considered.

13

14

15

16

17

HIV-infected mononuclear cells and to propagation of the virus, thereby permitting a more normal immune response. However, data that either confirm or refute this hypothesis are lacking. So far the global community has failed to eradicate leprosy as a public-health problem, although initial plans were to achieve this goal by 2000, and then by 2005. Fortunately, it seems that the HIV pandemic has not served to further undermine leprosy control efforts. By contrast, fuelled by the HIV pandemic, tuberculosis continues to increase as a threat with present estimates of 8 million new cases and approximately 2 million deaths occurring annually. Studies of molecular pathogenesis, particularly those that investigate and exploit apparent differences between these microbes, could reveal much that may be of importance to our understanding of the pathogenesis of these three diseases. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments SDL is funded by the Wellcome Trust, London. References 1 WHO. Global leprosy situation 2005. Wkly Epidemiol Rec 2005; 80: 289–95. 2 UNAIDS/WHO. AIDS epidemic update December 2002. http://data. unaids.org/Publications/IRC-pub03/epiupdate2002_en.pdf (accessed Apr 10, 2006). 3 WHO. Leprosy elimination project: status report 2002–2003. Geneva: WHO, 2004. 4 Lucas S. Human immunodeficiency virus and leprosy. Lepr Rev 1993; 64: 97–103. 5 Leonard G, Sangare A, Verdier M, et al. Prevalence of HIV infection among patients with leprosy in African countries and Yemen. J Acquir Immune Defic Syndr 1990; 3: 1109–13. 6 Meeran K. Prevalence of HIV infection among patients with leprosy and tuberculosis in rural Zambia. BMJ 1989; 298: 364–65. 7 Ponnighaus JM, Mwanjasi LJ, Fine PE, et al. Is HIV infection a risk factor for leprosy? Int J Lepr Other Mycobact Dis 1991; 59: 221–28. 8 Tekle-Haimanot R, Frommel D, Tadesse T, et al. A survey of HTLV-1 and HIVs in Ethiopian leprosy patients. AIDS 1991; 5: 108–10. 9 Orege PA, Fine PE, Lucas SB, et al. A case control study on human immunodeficiency virus-1 (HIV-1) infection as a risk factor for tuberculosis and leprosy in western Kenya. Tuber Lung Dis 1993; 74: 377–81. 10 Frommel D, Tekle-Haimanot R, Verdier M, et al. HIV infection and leprosy: a four-year survey in Ethiopia. Lancet 1994; 344: 165–66. 11 Andrade VL, Moreira AT, Regazzi Avelleira JC, et al. Prevalence of HIV1 in leprosy patients in Rio de Janeiro, Brazil. Acta Leprol 1997; 10: 159–63. 12 Borgdorff MW, van den BJ, Chum HJ, et al. HIV-1 infection as a risk factor for leprosy; a case-control study in Tanzania. Int J Lepr Other Mycobact Dis 1993; 61: 556–62.

358

18

19

20

21 22

23 24

25

26

27 28 29

30

31 32 33 34

35

36

37 38 39

Kawuma HJ, Bwire R, Adatu-Engwau F. Leprosy and infection with the human immunodeficiency virus in Uganda; a case-control study. Int J Lepr Other Mycobact Dis 1994; 62: 521–26. van den Broek J, Chum HJ, Swai R, et al. Association between leprosy and HIV infection in Tanzania. Int J Lepr Other Mycobact Dis 1997; 65: 203–10. Sekar B, Jayasheela M, Chattopadhya D, et al. Prevalence of HIV infection and high-risk characteristics among leprosy patients of south India; a case-control study. Int J Lepr Other Mycobact Dis 1994; 62: 527–31. Lienhardt C, Kamate B, Jamet P, et al. Effect of HIV infection on leprosy: a three-year survey in Bamako, Mali. Int J Lepr Other Mycobact Dis 1996; 64: 383–91. Milanga M, Kashala LO, Mbayo I, et al. Brief survey of leprosy situation in Congo: sero-epidemiologic profile in correlation with some emerging viral infections. Nihon Hansenbyo Gakkai Zasshi 1999; 68: 109–16. Moses AE, Adelowo KA, Ajayi BB. Prevalence of HIV-1 infection among patients with leprosy and pulmonary tuberculosis in a semiarid region, Nigeria. J R Soc Health 2003; 123: 117–19. UNAIDS/WHO. 2004 report on the global HIV/AIDS epidemic. http://www.unaids.org/bangkok2004/GAR2004_pdf/GAR2004_ Execsumm_en.pdf (accessed Apr 28, 2006). Anthony B, Mertens TE, Lal S. Estimation of adult HIV prevalence as of the end of 1994 in India. Indian J Public Health 1995; 39: 79–85. Hussain T, Kulshreshtha K, Ghei SK, et al. HIV seroprevalence in leprosy patients. Int J Lepr Other Mycobact Dis 2000; 68: 67–69. Munyao TM, Bwayo JJ, Owili DM, et al. Human immunodeficiency virus- 1 in leprosy patients attending Kenyatta National Hospital, Nairobi. East Afr Med J 1994; 71: 490–92. Machado P, David Y, Pedroso C, et al. Leprosy and HIV infection in Bahia, Brazil. Int J Lepr Other Mycobact Dis 1998; 66: 227–29. Kashala O, Marlink R, Ilunga M, et al. Infection with human immunodeficiency virus type 1 (HIV-1) and human T cell lymphotropic viruses among leprosy patients and contacts: correlation between HIV-1 cross-reactivity and antibodies to lipoarabinomannan. J Infect Dis 1994; 169: 296–304. Andrade VL, Avelleira JC, Marques A, et al. Leprosy as cause of falsepositive results in serological assays for the detection of antibodies to HIV-1. Int J Lepr Other Mycobact Dis 1991; 59: 125–26. ShivRaj L, Patil SA, Girdhar A, et al. Antibodies to HIV-1 in sera from patients with mycobacterial infections. Int J Lepr Other Mycobact Dis 1988; 56: 546–51. Harboe M. Rheumatoid factors in leprosy and parasitic diseases. Scand J Rheumatol Suppl 1988; 75: 309–13. Murray KA. Syphilis in patients with Hansen’s disease. Int J Lepr Other Mycobact Dis 1982; 50: 152–58. Lucas SB, Fine PE, Sterne JA, et al. Infection with human immunodeficiency virus type 1 among leprosy patients in Zaire. J Infect Dis 1995; 171: 502–04. Sterne JA, Turner AC, Fine PE, et al. Testing for antibody to human immunodeficiency virus type 1 in a population in which mycobacterial diseases are endemic. J Infect Dis 1995; 172: 543–46. Gonzalez-Abreu E, Rodriquez ME, Perez J, et al. PGL-I antibody in HIV infected patients. Lepr Rev 1993; 64: 275–76. Britton WJ, Lockwood DN. Leprosy. Lancet 2004; 363: 1209–19. Turk JL, Rees RJ. AIDS and leprosy. Lepr Rev 1988; 59: 193–94. Gebre S, Saunderson P, Messele T, et al. The effect of HIV status on the clinical picture of leprosy: a prospective study in Ethiopia. Lepr Rev 2000; 71: 338–43. Lamfers EJ, Bastiaans AH, Mravunac M, et al. Leprosy in the acquired immunodeficiency syndrome. Ann Intern Med 1987; 107: 111–12. Kennedy C, Lien RA, Stolz E, et al. Leprosy and human immunodeficiency virus infection. A closer look at the lesions. Int J Dermatol 1990; 29: 139–40. Vreeburg AE. Clinical observations on leprosy patients with HIV1infection in Zambia. Lepr Rev 1992; 63: 134–40. Graf vB, Alvarenga A, Namiki M. Leprosy in HIV-positive and syphilitic young Paraguayan man. Acta Leprol 1992; 8: 103–04. Blum L, Flageul B, Sow S, et al. Leprosy reversal reaction in HIVpositive patients. Int J Lepr Other Mycobact Dis 1993; 61: 214–17.

http://infection.thelancet.com Vol 6 June 2006

Review

40

41

42

43 44 45 46 47

48

49 50

51 52

53

54

55

56

57

58 59

60

61 62

63

64

Bwire R, Kawuma HJ. Leprosy, Kaposi’s sarcoma and the acquired immunodeficiency syndrome in two African patients. Trans R Soc Trop Med Hyg 1993; 87: 559. Bwire R, Kawuma HJ. Human immunodeficiency virus and leprosy—type 1 reactions, nerve damage and steroid therapy: ‘a case report’. Lepr Rev 1993; 64: 267-269. Olivares LM, Pizzariello GE, Benetucci J, et al. Lepromatous leprosy and HIV infection. Int J Lepr Other Mycobact Dis 1994; 62: 295–96. de Almeida AM, Roselino AM, Foss NT. Leprosy and HIV infection. Int J Lepr Other Mycobact Dis 1994; 62: 133–35. Goodless DR, Viciana AL, Pardo RJ, et al. Borderline tuberculoid Hansen’s disease in AIDS. J Am Acad Dermatol 1994; 30: 866–69. Arora VK, Johri A. Reactivation of tuberculosis and leprosy in an HIVpositive case. Tuber Lung Dis 1994; 75: 237–38. Jayasheela M, Sharma RN, Sekar B, et al. HIV infection amongst leprosy patients in south India. Indian J Lepr 1994; 66: 429–33. Moran CA, Nelson AM, Tuur SM, et al. Leprosy in five human immunodeficiency virus-infected patients. Mod Pathol 1995; 8: 662–64. Sampaio EP, Caneshi JR, Nery JA, et al. Cellular immune response to Mycobacterium leprae infection in human immunodeficiency virusinfected individuals. Infect Immun 1995; 63: 1848–54. Thappa DM, Garg BR, Rao MV, et al. Impact of HIV infection on leprosy. Indian J Lepr 1996; 68: 255–56. Jacob M, George S, Pulimood S, et al. Short-term follow up of patients with multibacillary leprosy and HIV infection. Int J Lepr Other Mycobact Dis 1996; 64: 392–95. Sayal SK, Das AL, Gupta CM. Concurrent leprosy and HIV infection: a report of three cases. Indian J Lepr 1997; 69: 261–65. Arunthathi S, Ebenezer L, Kumuda C. Reversal reaction, nerve damage and steroid therapy in three multibacillary HIV positive patients. Lepr Rev 1998; 69: 173–77. Moreno-Gimenez IC, Valverde F, Rios JI, et al. Lepromatous leprosy in an HIV-positive patient in Spain. J Eur Acad Dermatol Venereol 2000; 14: 290–92. Mendiratta VR, Sharma RC, Sardana K, et al. Smear positive leprosy with HIV infection, silent neuritis and extensive tinea corporis and tinea unguium in an Indian male. Indian J Lepr 2001; 73: 349–52. Lanjewar DN, Bhosale A, Iyer A. Spectrum of dermatopathologic lesions associated with HIV/AIDS in India. Indian J Pathol Microbiol 2002; 45: 293–98. Belliappa AD, Bhat RM, Martis J. Leprosy in type I reaction and diabetes mellitus in a patient with HIV infection. Int J Dermatol 2002; 41: 694–95. Inamadar AC, Palit A, Athanikar SB, et al. Generalized anetoderma in a patient with HIV and dual mycobacterial infection. Lepr Rev 2003; 74: 275–78. Rath N, Kar HK. Leprosy in HIV infection: a study of three cases. Indian J Lepr 2003; 75: 355–59. Pereira GA, Stefani MM, Araujo Filho JA, et al. Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium leprae coinfection: HIV-1 subtypes and clinical, immunologic, and histopathologic profiles in a Brazilian cohort. Am J Trop Med Hyg 2004; 71: 679–84. van Brakel WH, Nicholls PG, Das L, et al. The INFIR Cohort Study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in north India. Lepr Rev 2005; 76: 14–34. Lockwood DN. Leprosy. Clin Evid 2004; 12: 1103-1114. Cooper CL, Mueller C, Sinchaisri TA, et al. Analysis of naturally occurring delayed-type hypersensitivity reactions in leprosy by in situ hybridization. J Exp Med 1989; 169: 1565–81. Khanolkar-Young S, Rayment N, Brickell PM, et al. Tumour necrosis factor-alpha (TNF-alpha) synthesis is associated with the skin and peripheral nerve pathology of leprosy reversal reactions. Clin Exp Immunol 1995; 99: 196–202. Sreenivasan P, Misra RS, Wilfred D, et al. Lepromatous leprosy patients show T helper 1-like cytokine profile with differential expression of interleukin-10 during type 1 and 2 reactions. Immunology 1998; 95: 529–36.

http://infection.thelancet.com Vol 6 June 2006

65

66

67

68

69

70

71

72

73

74

75 76 77

78

79

80

81

82

83

84

85 86

87

88

Little D, Khanolkar-Young S, Coulthart A, et al. Immunohistochemical analysis of cellular infiltrate and gamma interferon, interleukin-12, and inducible nitric oxide synthase expression in leprosy type 1 (reversal) reactions before and during prednisolone treatment. Infect Immun 2001; 69: 3413–17. Saunderson P, Gebre S, Byass P. ENL reactions in the multibacillary cases of the AMFES cohort in central Ethiopia: incidence and risk factors. Lepr Rev 2000; 71: 318–24. Saunderson P, Gebre S, Byass P. Reversal reactions in the skin lesions of AMFES patients: incidence and risk factors. Lepr Rev 2000; 71: 309–17. Bwire R, Kawuma HJ. Type 1 reactions in leprosy, neuritis and steroid therapy: the impact of the human immunodeficiency virus. Trans R Soc Trop Med Hyg 1994; 88: 315–16. Whalen C, Horsburgh CR, Hom D, et al. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med 1995; 151: 129–35. Whalen CC, Nsubuga P, Okwera A, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 2000; 14: 1219–28. Lawn SD, Butera ST, Folks TM. Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection. Clin Microbiol Rev 2001; 14: 753–77. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360: 119–29. Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003; 362: 22–29. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60. Shelburne SA III, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003; 5: 67–79. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18: 1615–27. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5: 361–73. del Giudice P, Durant J, Counillon E, et al. Mycobacterial cutaneous manifestations: a new sign of immune restoration syndrome in patients with acquired immunodeficiency syndrome. Arch Dermatol 1999; 135: 1129–30. Lawn SD, Bicanic TA, Macallan DC. Pyomyositis and cutaneous abscesses due to Mycobacterium avium: an immune reconstitution manifestation in a patient with AIDS. Clin Infect Dis 2004; 38: 461–63. Zamir E, Hudson H, Ober RR, et al. Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis? Ophthalmology 2002; 109: 2144–48. Bartley PB, Allworth AM, Eisen DP. Mycobacterium avium complex causing endobronchial disease in AIDS patients after partial immune restoration. Int J Tuberc Lung Dis 1999; 3: 1132–36. French MA, Mallal SA, Dawkins RL. Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIVinfected patients. AIDS 1992; 6: 1293–97. Cabie A, Abel S, Brebion A, et al. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 1998; 17: 812–13. Dworkin MS, Fratkin MD. Mycobacterium avium complex lymph node abscess after use of highly active antiretroviral therapy in a patient with AIDS. Arch Intern Med 1998; 158: 1828. Price LM, O’Mahony C. Focal adenitis developing after immune reconstitution with HAART. Int J STD AIDS 2000; 11: 685–86. Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person. Clin Infect Dis 2003; 36: e5–e6. Pignataro P, Rocha AS, Nery JA, et al. Leprosy and AIDS: two cases of increasing inflammatory reactions at the start of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2004; 23: 408–11. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol 2004; 140: 997–1000.

359

Review

89

90

91

92

93

94 95

96 97

98

360

Visco-Comandini U, Longo B, Cuzzi T, et al. Tuberculoid leprosy in a patient with AIDS: a manifestation of immune restoration syndrome. Scand J Infect Dis 2004; 36: 881–83. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009–21. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989; 320: 545–50. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragmentlength polymorphisms. N Engl J Med 1992; 326: 231–35. Elliott AM, Halwiindi B, Hayes RJ, et al. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. J Trop Med Hyg 1993; 96: 1–11. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999; 340: 367–73. Lawn SD, Evans AJ, Sedgwick PM, et al. Pulmonary tuberculosis: radiological features in west Africans coinfected with HIV. Br J Radiol 1999; 72: 339–44. Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7: 1569–79. Lucas SB, Nelson AM. Pathogenesis of tuberculosis in human immunodeficiency virus-infected people. In: Bloom BR, ed. Tuberculosis: pathogenesis, protection and control. Washington, DC: ASM Press, 1994: 503–13. Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002; 4: 635–46.

99

100

101

102

103

104

105

106

107

Van Voorhis WC, Kaplan G, Sarno EN, et al. The cutaneous infiltrates of leprosy: cellular characteristics and the predominant T-cell phenotypes. N Engl J Med 1982; 307: 1593–97. Juffermans NP, Speelman P, Verbon A, et al. Patients with active tuberculosis have increased expression of HIV coreceptors CXCR4 and CCR5 on CD4(+) T cells. Clin Infect Dis 2001; 32: 650–52. Sampaio EP, Oliveira RB, Warwick-Davies J, et al. T cell-monocyte contact enhances tumor necrosis factor-alpha production in response to Mycobacterium leprae. J Infect Dis 2000; 182: 1463–72. Flad HD, Gercken J, Hubner L, et al. Cytokines in mycobacterial infections: in vitro and ex vivo studies. Arch Immunol Ther Exp (Warsz) 1995; 43: 153–58. Matsuyama T, Kobayashi N, Yamamoto N. Cytokines and HIV infection: is AIDS a tumor necrosis factor disease? AIDS 1991; 5: 1405–17. Lawn SD, Pisell TL, Hirsch CS, et al. Anatomically compartmentalized human immunodeficiency virus replication in HLA-DR+ cells and CD14+ macrophages at the site of pleural tuberculosis coinfection. J Infect Dis 2001; 184: 1127–33. Nakata K, Rom WN, Honda Y, et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung. Am J Respir Crit Care Med 1997; 155: 996–1003. Kedzierska K, Mak J, Mijch A, et al. Granulocyte-macrophage colonystimulating factor augments phagocytosis of Mycobacterium avium complex by human immunodeficiency virus type 1-infected monocytes/macrophages in vitro and in vivo. J Infect Dis 2000; 181: 390–94. Marlowe SN, Hawksworth RA, Butlin CR, et al. Clinical outcomes in a randomized controlled study comparing azathioprine and prednisolone versus prednisolone alone in the treatment of severe leprosy type 1 reactions in Nepal. Trans R Soc Trop Med Hyg 2004; 98: 602–09.

http://infection.thelancet.com Vol 6 June 2006