The PubMed database was searched under the following headings: HIV or AIDS and malaria, Malaria falciparum, leishmaniasis or Leishmania spp, Trypanosoma cruzi, American trypanosomiasis or Chagas disease, histoplasmosis, Histoplasma capsulatum, blastomycosis, Blastomyces dermatitidis, coccidioidomycosis, Coccidioides immitis, penicilliosis or Penicillium marneffei.
According to figures from the Health Protection Agency, travel abroad by United Kingdom (UK) residents followed the international trend and continued to increase with an estimated 66.4 million visits overseas in 2005. More males than females travelled from the UK and were, on average, between 35 and 44 years of age. Around two-thirds of UK residents travelled for holidays in 2005, the majority to other countries in the European Union (EU). Since 2003, visits to tropical destinations have increased by 28% compared to a decrease of 0.2% for visits within the EU. The number of visits made to see friends and relatives continued to increase at a higher rate (23% since 2003). These figures are particularly relevant to travellers with HIV either involving those with the disposable income to travel or those visiting family overseas. People living with HIV are affected by the usual coughs and travel-associated diarrhoea, however, and this may interfere with their adherence to antiretroviral medication and so pose a greater problem. Anecdotally, patients may discontinue ART while travelling, bringing risks of seroconversion-like illness to others and opportunistic infections.
10.3.1 Background and epidemiology
Malaria is a protozoal infection transmitted in endemic areas by the bite of a female anopheles mosquito. There are five main species of parasite that can infect humans but Plasmodium falciparum is the most serious and can be rapidly fatal. Every year, 1500–2000 cases are reported to the Health Protection Agency (HPA) Malaria Reference Laboratory (MRL), and there are nine to 13 deaths in the UK . Most of these are related to delay in diagnosis.
In the UK the burden of falciparum malaria falls heavily on those of African and south Asian ethnicity. According to the Health Protection Agency the commonest reason for presenting with malaria in the UK is ‘visiting family from country of origin’ and migrants now living in the UK are often poorly compliant with malaria precautions, believing themselves not to be at risk of malaria . However, immunity to malaria wanes quickly and this group of patients should be targeted for advice regarding avoiding mosquito bites and taking prophylactic antimalarials . Evidence from South Africa suggests that people with HIV who are non-immune to malaria are at higher risk of severe disease or death from malaria [3,4].
Observational and prospective studies from Africa suggest that the likelihood of severe malaria and death is increased with HIV coinfection in areas of unstable malaria transmission . The increased incidence of severe malaria is chiefly seen in individuals with CD4 T-cell counts <200/μL , but among individuals with no immunity to malaria there does not appear to be an increased incidence of parasitaemia per se . In settings of year-round malaria transmission where most adults are semi-immune to malaria, the incidence of parasitaemia and clinical malaria are increased in individuals with HIV infection .
Malaria presents non-specifically with fever, headache, arthralgia, myalgia, diarrhoea and sometimes features of bacterial infection. Patients may be severely unwell and hypotensive, requiring intensive care unit (ICU) involvement early in the hospital admission. Other than severity there is no evidence that HIV serostatus modifies presentation. Complications of malaria include hyperparasitaemia, acute renal failure, hypoglycaemia, disseminated intravascular coagulopathy, lactic acidosis, fulminant hepatic failure and cerebral malaria . Mortality is still around 20% with higher rates in HIV-seropositive individuals when treated in Africa. Controversy remains concerning the impact of malaria on mother-to-child transmission of HIV but HIV-seropositive women with malaria have an increased incidence of anaemia, infants with low birth weight, prematurity and infant mortality due to malarial parasites preferentially binding to the placenta .
- •Malaria should be diagnosed in the same way as in HIV-seronegative individuals, using a combination of thick and thin blood films with or without a rapid diagnostic (antigen) test in HIV-seropositive individuals (category IV recommendation).
In practice, this involves considering the diagnosis in anyone with fever who has returned from an endemic area. Falciparum malaria usually presents within 3 months of their return but non-falciparum malaria may recrudesce many years after their return. There is little information on how HIV may modify this but partial immunity may delay the presentation of falciparum malaria.
Malaria should be suspected in anyone returning from an endemic area, as the presentation, especially in the semi-immune person, is very variable. Diagnosis is made by a thick and thin blood film although highly sensitive and specific diagnostic dipsticks now exist [8–10]. Thick films (to diagnose malaria and estimate the percentage parasitaemia) and thin films (for speciation) should be collected on all patients (category IV recommendation) . Rapid diagnostic tests for malaria antigens may be helpful if malaria is suspected but blood films are negative. In HIV-seronegative individuals they are less sensitive but are useful for laboratories with less experience in interpreting malaria blood films . There is limited information on their performance in HIV-seropositive individuals. Current guidelines recommend that any patient considered to be at risk of viral haemorrhagic fever should have a malaria film done under category 3 conditions first .
- •Follow the World Health Organization guidelines . Antiretroviral drug interactions are hypothetical except for that between efavirenz and amodiaquine, a combination which should be avoided.
- •Non-severe falciparum malaria should be treated with oral artemether–lumefantrine or oral quinine followed by doxycycline, or with Malarone (atovaquone–proguanil) (category IV recommendation).
- •Severe falciparum malaria (>2% parasitaemia ±organ dysfunction) should be treated initially with intravenous artesunate where available or with quinine by intravenous infusion with cardiac monitoring when artesunate cannot be administered. Individuals with severe malaria should be referred promptly to a specialist unit (category IV recommendation).
The many potential antimalarial and antiretroviral drug interactions are summarized below (Table 10.1) . However, most do not seem to be clinically problematic despite many drugs being metabolized via the same hepatic cytochrome pathway. The interactions are therefore largely hypothetical except for efavirenz and amodiaquine, which should not be co-administered. The choice of antimalarials is therefore determined by the species and severity of the malaria with similar considerations as for HIV-seronegative individuals .
Table 10.1. Potential antimalarial and antiretroviral drug interactions
|Chloroquine||Ritonavir can potentially increase chloroquine levels through enzyme inhibition although no formal studies||Monitor for signs of chloroquine toxicity especially cardiotoxicity (QT interval prolongation)|
|Mefloquine||NNRTIs can potentially decrease mefloquine levels through enzyme induction||Caution|
Monitor for reduced signs of clinical effectiveness
|PIs can potentially inhibit metabolism of mefloquine through cytochrome P450 3A4. Ritonavir inhibits p-glycoprotein, which may also increase mefloquine levels.||Caution|
Monitor for signs of mefloquine toxicity such as neuropsychiatric events or changes in cardiac rhythm
|Quinine||NNRTIs can decrease levels of quinine via induction of CYP3A4||Caution|
Monitor for reduced clinical effectiveness. Check quinine levels if possible. May need to increase quinine dose
|PIs can increase quinine levels through inhibition of CYP3A4||Caution|
Monitor for signs of toxicity. Cardiac monitoring recommended for signs of prolonged QT interval. Check quinine levels if possible and dose reduce.
|Artemether/lumefantrine (Riamet)||NNRTIs can increase or decrease levels of lumefantrine and artemether||Caution|
Monitor for signs of reduced clinical effect or increased toxicity. Lumefantrine may cause cardiotoxicity
|PIs can potentially increase lumefantrine levels due to inhibition of CYP3A4|
PIs can potentially decrease artemether's conversion to its active form
Monitor for signs of cardiotoxicity. Refer to manufacturer's literature
|Atovaquone/proguanil (Malarone)||PIs may reduce levels of both components||Currently no recommendation for dose modification but clinicians advised to watch for prophylaxis failures|
|Efavirenz reduces levels of both components||Increased vigilance for prophylaxis failures.|
Uncomplicated falciparum malaria should be treated with oral artemether–lumefantrine (Co-artem, Riamet). If the weight is >35 kg the treatment schedule is four tablets at 0, 8, 24, 36, 48 and 60 h. Alternatives are oral quinine (600 mg tid po for 7 days plus doxycycline 200 mg orally once a day for 5–7 days) or Malarone (atovaquone–proguanil) (four tablets daily orally for 3 days) if there are no complications.
There is a potential interaction between ritonavir and quinine, which may result in increased quinine levels . If individuals meet criteria for parenteral quinine, they should still receive a standard loading dose of quinine (see below) but protease inhibitors should be stopped until the patient is stable and able to take oral medications. There should also be increased vigilance for signs of quinine toxicity, including evidence of prolongation of the QT interval, and quinine dose reduction may be required if any signs of toxicity are noted. Non-nucleoside reverse transcriptase inhibitors (NNRTI) may decrease quinine levels and since quinine metabolism may be enhanced with malaria this may result in significant underdosing with standard doses of quinine [15,16]. NNRTI and quinine should ideally be avoided but if the patient is already on NNRTI and quinine must be prescribed, the dose of quinine may need to be titrated against the clinical response and the patient monitored carefully for signs of toxicity, such as abnormalities on cardiac monitoring. Concerns have been raised about the safety and efficacy of artemisinin-based combination treatments when combined with antiretroviral therapy . Artesunate plus amodiaquine combinations have reduced efficacy, as compared to artemether plus lumefantrine (co-artemether), and when combined with efavirenz have been associated with hepatotoxicity and neutropenia [17–19]. Preliminary data also suggest that lumefantrine exposure is increased with nevirapine (contrary to what would be expected with an enzyme inducer). The mechanism is unknown, but it should be noted that lumefantrine exposure in controls was variable, and in many cases, low. At present there are insufficient data to recommend dose modification but increased vigilance is advised .
It was previously suggested that co-artemether (Riamet) should be avoided in patients taking protease inhibitors due to drug interactions. More recent pharmacokinetic data has suggested that when healthy volunteers received lopinavir/ritonavir with co-artemether, the area under the curve (AUC) and Cmax of artemether was only modestly reduced and that conversely lumefantrine AUC was increased, without consequences to lopinavir levels . While this may suggest co-artemether may be given with select antiretrovirals and they may be considered as preferred agents in the treatment of uncomplicated malaria further information on the efficacy and toxicity of these combinations in HIV-seropositive individuals is required and it must be emphasized that there is still limited experience of the use of these agents in HIV-seropositive individuals in Western settings.
Severe or complicated falciparum malaria is defined as cases with shock, renal impairment, acidosis, pulmonary oedema or acute respiratory distress syndrome, impaired consciousness or seizures, hypoglycaemia, very low haemoglobin (defined by WHO as <5g/dL ), haemoglobinuria or disseminated intravascular coagulopathy . It should be treated with a parenteral regimen, which should also be used in cases where the parasitaemia level is >2%, or when the individual is unable to take oral medicines. Under these circumstances falciparum malaria is treated with intravenous artesunate 2.4 mg/kg daily, given at 0, 12, 24 h then daily to complete a 7-day course combined with doxycycline 200 mg once a day. Intravenous quinine (loading dose: 20 mg/kg intravenously infused over 4 h, maximum dose 1.4 g, then 10 mg/kg intravenously by infusion over 4 h every 8 h for 48 h, then bid thereafter, until the individual is able to take oral medication) is an alternative. Rapid referral should be made to a specialist centre (category IV recommendation). The loading dose of quinine should be withheld if quinine or mefloquine has been administered in the previous 12 h. Quinine prolongs the QRS and QT intervals and can induce hypoglycaemia, so treatment must be given while connected to a cardiac monitor with regular measurement of blood glucose levels. There is a potential for increased cardiac problems due to an interaction between quinine and ritonavir.
The treatment of choice for non-falciparum malaria (P. ovale, P. vivax, P. malariae) is a 3-day course of oral chloroquine (600 mg orally, then 300 mg after 6–8 h then 300 mg daily for 2 days) followed by 14 days of primaquine (P. vivax: 30 mg orally once a day; P. ovale: 15 mg once a day) to eradicate the liver stages. Primaquine is not required for P. malariae . Patients should be tested for G6PD deficiency before starting primaquine to quantify and minimize the risk of haemolysis. Patients with G6PD deficiency can be managed with lower-dose primaquine for longer, but specialist advice should be sought.
- •All HIV-seropositive individuals who travel to malaria-endemic areas should be offered malaria prophylaxis and given general advice on how to avoid mosquito bites as part of a comprehensive pre-travel assessment (category IV recommendation).
HIV-seropositive travellers are at higher risk of severe malaria, and prevention of malaria should be strongly promoted. They should receive the same general travel advice concerning the prevention of malaria as the HIV-seronegative traveller, i.e. the ABCD of malaria prevention should be emphasized: Awareness of risk, Bite prevention, Chemoprophylaxis and prompt Diagnosis and treatment (see ).
The advice regarding chemoprophylaxis depends on the area visited, time spent and medical history and specialist advice is available from the National Travel Health Network and Centre (NaTHNaC)  funded by the Department of Health for England or ‘Fit for Travel’  in Scotland.
Although co-trimoxazole may reduce the risk of developing malaria, HIV-seropositive patients receiving co-trimoxazole should still receive standard malaria chemoprophylaxis and follow all the general advice around prevention of malaria.
The main options for chemoprophylaxis are mefloquine 250 mg orally once weekly, Malarone (atovaquone–proguanil) one tablet once daily and doxycycline 100 mg orally once daily. Chloroquine-based regimens (chloroquine 300 mg once weekly with proguanil 200 mg orally once daily) are less used now due to widespread resistance. Regimens are started 1 week prior to travel and continued for 4 weeks after return with the exception of Malarone (atovaquone–proguanil) which is started 1–2 days before travel and continued for 1 week after return and mefloquine which should be started 3–4 weeks prior to travel, if treatment naïve, to give the individual time to develop neurocognitive side effects and to change to an alternative agent, if necessary, prior to travel.
- •Mefloquine is contraindicated in patients with a history of epilepsy, neuropsychiatric disorders including depression, liver impairment and cardiac conduction disorders. Neurocognitive side effects with mefloquine are more common in women, those with low body mass index (BMI), those embarking on long-term travel and those with a history of recreational drug use [25,26]. They are particularly common in younger adults and many authorities would therefore avoid this agent in younger adults, particularly if female, with a low BMI or with a history of recreational drug use. In pregnancy, the use of mefloquine requires careful risk–benefit analysis and specialist advice should be sought. Mefloquine antagonizes the anticonvulsant effect of valproate and increases the incidence of cardiac conduction problems with moxifloxacin.
- •Malarone is safe and well tolerated. Efavirenz and protease inhibitors may reduce both atovaquone and proguanil levels and, although there are currently no recommendations to adjust the dose of Malarone, clinicians and their patients must remain vigilant for prophylaxis failures .
- •Doxycycline should be avoided in hepatic impairment, in those who cannot ensure regular administration of a sun block to prevent photosensitisation, and also in pregnant women and children under the age of 12 years.
Other areas of advice to emphasize include the use of high percentage (greater than 20%) diethyltoluamide (DEET), covering up extremities when out after dark and use of permethrin-impregnated mosquito nets to sleep under.
10.4.1 Background and epidemiology
Leishmaniasis is a group of diseases caused by protozoa of the genus Leishmania that are transmitted by sandflies, and, rarely, by injecting drug use. In the UK, most imported cases of visceral leishmaniasis come from the Mediterranean, East Africa or India, and cutaneous leishmaniasis from Central America or the Middle East . Visceral leishmaniasis in HIV-seropositive individuals usually occurs in those with CD4 counts below 200 cells/μL .
Leishmania cause three types of disease:
- ○Visceral (kala azar), which usually presents with systemic features of fever and weight loss along with hepatosplenomegaly (with splenic enlargement most prominent), with or without bone marrow involvement;
- ○Mucocutaneous, with destructive lesions of the mucous membranes of the nose or mouth;
- ○Cutaneous, causing skin ulcers, usually on the limbs or face.
Most reported cases of HIV/Leishmania co-infection in Europe are of visceral leishmaniasis . Cases may be associated with a history of intravenous drug use . Visceral leishmaniasis usually, but not always, presents in the same way as it does in HIV-seronegative people; the systemic features may be mistaken for other opportunistic infections.
Cutaneous leishmaniasis may present as it does in immunocompetent individuals with a papule that progresses to a chronic ulcer, but a wide range of atypical skin lesions may occur, and may be mistaken for Kaposi's sarcoma or bacillary angiomatosis. Isolated mucocutaneous leishmaniasis in association with HIV infection appears to be very rare in Europe, probably as L. infantum, which causes most visceral leishmaniasis in Europe, rarely causes mucosal lesions. However, any patient with a suspected leishmanial lesion on the face should be seen urgently by a specialist. Mucocutaneous leishmaniasis may be seen in cases acquired in Central or South America where the infecting species have greater tropism for mucous membranes.
- •Diagnosis of leishmaniasis requires parasitological or histological confirmation (category III recommendation).
- •Where leishmania is strongly suspected but standard tests are negative, discussion with a tropical medicine specialist is recommended to advise on the utility and interpretation of newer tests in the setting of HIV infection (category IV recommendation)
Diagnosis depends on parasitological or histological demonstration of Leishmania. Parasitological diagnosis is most useful because identification of Leishmania species may guide appropriate treatment. In the context of HIV, standard diagnostic tests may be less sensitive and expert advice should be sought (category IV).
10.4.3.1 Visceral leishmaniasis. Parasitological diagnosis may be made by microscopy, culture or PCR. Appropriate specimens include [30,32,33]:
- ○Splenic aspirate: this has the highest sensitivity, but should only be performed by a practitioner trained in the technique;
- ○Bone marrow aspirate;
- ○Biopsy specimens (such as lymph node or skin).
It is strongly recommended to liaise with the local tropical disease and parasitology service before taking specimens. Some transport media (e.g. those with antifungal agents) may inhibit leishmania culture so specimen transport should be discussed with the laboratory.
Histological diagnosis may be made on biopsy of bone marrow, lymph node, liver, skin or other tissue.
Serological tests include the direct agglutination test and ELISA to detect antibodies to recombinant K39 antigen (rK39). The sensitivity of both may be reduced in HIV/Leishmania coinfection  due to low levels of antibody in HIV-seropositive individuals .
10.4.3.2 Cutaneous leishmaniasis. Parasitological or histological diagnosis (preferably both) may be made from a skin biopsy . As above, it is important to discuss the matter with a parasitology laboratory to ensure that specimens are handled appropriately.
Serological tests are not helpful in the diagnosis of cutaneous leishmaniasis.
- •Therapy for leishmaniasis should be co-ordinated with the local tropical medicine service (category IV recommendation).
- •Liposomal amphotericin B is the treatment of choice for visceral leishmaniasis (category III recommendation).
- •Secondary prophylaxis of visceral leishmaniasis is with liposomal amphotericin B or intravenous pentamidine (category III recommendation).
10.4.4.1 Visceral leishmaniasis. The treatment of choice for visceral leishmaniasis in an HIV-seropositive person is liposomal amphotericin B 4 mg/kg for 10 doses given on days 1–5, 10, 17, 24, 31 and 38 . Although liposomal amphotericin B is the lipid formulation available in the UK in some European countries alternative lipid formulations may be used; amphotericin B lipid complex has also been used for treatment of visceral leishmaniasis . Review of clinical studies has suggested that treatment with liposomal amphotericin B is as efficacious but less toxic than treatment with pentavalent antimonials . HIV-seropositive individuals have a high relapse rate after treatment for leishmaniasis . Secondary prophylaxis of visceral leishmaniasis is the standard of care in Europe because in the pre-ART era, relapse after treatment was almost inevitable [37,39]. Pentamidine (4mg/kg every 2 weeks intravenously)  or liposomal amphotericin B (5 mg/kg every 3 weeks intravenously) may be used, while amphotericin B lipid complex has also been used for secondary prophylaxis of visceral leishmaniasis [41,42]. There is insufficient evidence to support the use of one specific regimen over another and this is best discussed with the local tropical disease service. Case series describe the use of oral miltefosine treatment when standard treatment fails [43,44]. Case reports, however, describe the failure of this approach when miltefosine is used alone . The use of pentavalent antimonials in combination with or followed by oral miltefosine, may be a better option when standard treatment fails but more data are needed before firm recommendations can be made [46,47]. Complex cases should be discussed with the local tropical medicine service.
10.4.4.2 Cutaneous leishmaniasis. Cutaneous leishmaniasis can be treated with local infiltration of sodium stibogluconate or systemic treatment, depending on the species , although there is limited experience of local therapy in individuals with HIV infection. This is best discussed with the local tropical disease service.
Primary prophylaxis of leishmaniasis is not recommended.
10.4.6 Impact of HAART
For patients not taking HAART at the time of diagnosis, there is no specific evidence to guide when HAART should be started but expert opinion suggests this should be as soon as the patient is stable on antileishmanial therapy. There are few data to guide whether and when to stop secondary prophylaxis of visceral leishmaniasis. Some authors recommend that secondary prophylaxis can be stopped if leishmaniasis has been treated successfully, the patient is stable on HAART and the CD4 T-cell count has been above 200–350 cells/μL for 3–6 months [36,49]. However, relapse is described even among patients with successful treatment and CD4 T-cell counts >200 cells/μL . Cases of leishmaniasis IRIS are described with new or worsening skin lesions including ulcers, mucocutaneous ulcers in the mouth or penis, post-kala-azar dermal leishmaniasis or uveitis [51,52]. There are also reports of visceral leishmaniasis presenting as an immune reconstitution phenomenon after the start of antiretroviral therapy .
There are multiple overlapping toxicities with HIV medication and treatment for leishmaniasis and liaison with an HIV pharmacist is recommended.
10.5 Chagas disease (Trypanosoma cruzi)
10.5.1 Background and epidemiology
Chagas disease or American trypanosomiasis is caused by a parasite, which is a member of the genus Trypanosoma; Trypanosoma cruzi. It is confined to Central and South America and its distribution extends from Mexico in the north to the northern half of Argentina and Chile in the south. T. cruzi is spread by bloodsucking triatomine insects, also known as kissing bugs, found in particular in rural areas . There is increasing recognition that reactivation of Trypanosoma cruzi infection can cause disease in patients with advanced immunosuppression, including HIV-seropositive individuals who have lived or travelled to endemic areas.
T. cruzi causes two main types of disease in people with HIV:
- ○Neurological disease; space-occupying lesions or meningoencephalitis
Clinical syndromes are most common in individuals with CD4 T-cell counts <200 cells/μL . Neurological syndromes are the commonest presentation, comprising 75% of presentations of Chagas disease in untreated HIV-seropositive patients. Patients can present with features of a space-occupying lesion, encephalitis, or meningoencephalitis . Clinical symptoms are typically of fever, headaches, seizures, vomiting and focal neurological signs and mimic toxoplasma encephalitis . Myocarditis is the second most common presentation seen in approximately a third of cases, often with concomitant neurological disease. Myocarditis is often asymptomatic and only detected at autopsy but can present with arrhythmias or heart failure [54,57]. Chagas disease may also affect the digestive tract and cause megaoesophagus or megacolon. Chagas disease should be suspected in patients from the endemic areas of Central and South America or with a history of blood transfusions or intravenous drug use with contacts from these areas.
- •Diagnosis of Chagas disease requires a combination of imaging, serology, PCR and if available histological confirmation (category III recommendation).
- •Asymptomatic individuals with HIV infection from an endemic area should be screened with serology and, if positive, be further evaluated for disease (category IV recommendation)
For neurological disease, imaging studies characteristically report space-occupying lesions similar to those described for toxoplasma encephalitis . CSF examination typically describes lymphocytic pleocytosis and elevated protein with possibly low glucose . Serological tests are generally not diagnostic for reactivation, indicating only previous exposure. PCR testing helps separate past exposure from reactivation . Parasitological studies, including thick smears or Strout's concentration method, and CSF smears (ideally after centrifugation) are usually necessary . Biopsy specimens may also aid in the diagnosis if other tests are equivocal. As there is often misdiagnosis, failure to respond to initial treatment for toxoplasmosis should raise suspicion in high-risk patients.
Currently, it is recommended that all HIV-seropositive people with epidemiological risk factors for Chagas disease be tested for antibodies to T cruzi to detect latent infection and, if positive, should be further evaluated, in discussion with a specialist tropical disease centre, for neurological, intestinal and cardiological disease.
- •Therapy for Chagas disease should be co-ordinated with the local tropical medicine service (category IV recommendation).
- •Benznidazole is the treatment of choice for acute primary infection or reactivation of Chagas disease, with nifurtimox the alternative (category III recommendation).
- •Treatment should be considered for asymptomatic individuals with HIV infection and positive serology (category III recommendation)
The recommended treatment for acute primary infection or reactivation Chagas disease in HIV-seropositive patients is benznidazole 5 mg/kg daily divided in two doses for 60–90 days. A higher dose may be needed in acute meningo-encephalitis. Nifurtimox 8–10 mg/kg daily divided in three doses for 60–120 days is considered an alternative. Following treatment, secondary prophylaxis with benznidazole 5 mg/kg three times weekly is recommended: there is no evidence to guide the optimum duration, but the duration is likely to be governed by the same factors as other opportunistic infections and be influenced by the immunological and virological response to HAART. These drugs have important side-effects and treatment should be supervised by a specialist tropical disease centre.
For asymptomatic individuals seropositive for T. cruzi, or individuals with chronic disease, a course of treatment with benznidazole or nifurtimox (regimens as above) should be considered. For individuals with virological suppression and immunological responses to HAART, the risks and benefits of treatment should be considered on a case by case basis [61,62]. Individuals not taking, and unable to or unwilling to start, HAART should be offered treatment with benznidazole or nifurtimox.
Following treatment, secondary prophylaxis is not usually required for asymptomatic individuals seropositive for T. cruzi if on HAART, but if the individual is not able to take HAART, options are either to consider secondary prophylaxis, if the benefits outweigh the risks, or alternatively to monitor the patient closely off further treatment.
There is no role for primary prophylaxis.
10.5.6 Impact of HAART
The prognosis is now generally considered to be good . Since clinical cases and reactivation are related to CD4 T-cell count, it is logical that HAART will decrease the incidence of reactivation and, anecdotally, receipt of HAART has been associated with a slower tempo of disease progression in those with disease .
10.6 Histoplasmosis, blastomycosis and coccidioidomycosis
10.6.1 Background and epidemiology
Dimorphic fungi of medical importance in HIV-seropositive individuals are Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis and Penicillium marneffei. Each of these is geographically restricted. The route of infection is via inhalation of microconidia (or arthroconidia for C. immitis) that are aerosolized and can be dispersed many miles by air. Immunocompetent hosts develop localized pulmonary disease, which is frequently asymptomatic while those with chronic lung disease develop chronic pulmonary syndromes and individuals with immunosuppression develop disseminated disease. In the post-HAART era each of these presentations can be encountered in HIV-seropositive individuals.
H. capsulatum var capsulatum is found in mid-western and south-eastern states of the United States, the Caribbean, Central America, South America, Africa, and in pockets elsewhere throughout the world . H. capsulatum var duboisii is found mainly in West and Central Africa ; it causes mainly extra-pulmonary disease. B. dermatitidis is found in the centre of the United States, along the St Lawrence Seaway and around the Great Lakes of the United States and Canada . C. immitis is found in the south-western part of the United States and in northern Mexico .
An infection should be suspected in someone who has resided in an endemic area, although for some dimorphic fungi short-term exposure during travel to an endemic area is sufficient. Infections can represent either reactivation or primary infection.
Individuals with well preserved CD4 cell counts present similarly to HIV-seronegative individuals. Infection may be asymptomatic . Clinical features, if present, involve cough and fever with focal consolidation and hilar lymphadenopathy on chest radiography . Coccidioidomycosis can present with either asymptomatic infection or as a pneumonic illness .
Pre-HAART, the most frequent manifestation of dimorphic fungal infection was as acute disseminated infections. General features of disseminated histoplasmosis include fever, weight loss and rash  and disseminated blastomycosis may be associated with neurological disease . Physical signs include focal consolidation or bilateral crackles, lymphadenopathy, hepatosplenomegaly, rash and frequently hypotension. In many cases of disseminated disease respiratory signs and symptoms are minimal.
Chest radiographs for histoplasmosis reveal interstitial, nodular or miliary infiltrates although occasionally demonstrate more focal disease. Focal pulmonary disease may be less common with coccidioidomycosis . Cavitary disease is rare but has been reported for histoplasmosis and coccidioidomycosis . A variety of extra-pulmonary manifestations are associated with disseminated disease. Histoplasmosis may be associated with oropharyngeal and gastrointestinal ulceration. Patients may present with a sepsis syndrome and hypotension . Rarer manifestations include meningitis, endocarditis or involvement of the adrenal gland . CNS disease may also occur with B. dermatitidis infection with up to 40% of individuals with AIDS having CNS disease in one pre-HAART series . Noteworthy features of coccidioidomycosis include eosinophilia, meningitis and a syndrome of weight loss and fever without focal disease. Although in the pre-HAART era coccidioidomycosis most often presented as disseminated or extensive pulmonary disease, and rarely presented as an asymptomatic infection, in the post-HAART era there has been increasing recognition of cases that are asymptomatic, which are detected with just a positive serological test or by an incidental nodule or cavity on chest radiograph . These cases are associated with an undetectable HIV-1 viral load on HAART and with a mean CD4 T-cell count of >350 cells/μL.
- •In disseminated disease cultures of bone marrow are frequently positive (category III recommendation).
- •Bone marrow trephine and culture should be performed if disseminated disease is suspected (category III recommendation).
- •Diagnosis should be sought via culture and histological methods (category III recommendation).
- •Consideration should be given to testing serum histoplasma antigen to follow the response to therapy in disseminated disease (category III recommendation).
Definitive diagnosis involves culture of the organism from sputum, broncho-alveolar lavage (BAL) or a biopsy specimen – which can take up to 4 weeks for growth – or identification of the yeast on a biopsy specimen or body fluid [66,67,70]. Each yeast has a characteristic appearance on biopsy. In disseminated disease, cultures of bone marrow are frequently positive and blood cultures may also be diagnostic . A polysaccharide antigen test for H. capsulatum var capsulatum is available and is particularly useful in patients with disseminated disease  or in BAL specimens with pulmonary disease  but its availability is largely limited to a US reference laboratory.
Serology is positive in approximately 70% of cases with coccidioidomycosis .
Patients with disseminated histoplasmosis may have very high LDH levels (>600 IU/L) . Diagnosis of CNS disease may be difficult as fungal stains, culture and even serological tests may all be negative. Real-time PCR assays seem to be very useful (up to 100% pick-up rate) , but are not yet widely available.
- •Localized disease should be treated initially as for HIV-seronegative individuals with itraconazole solution for histoplasmosis/blastomycosis and fluconazole for coccidioidomycosis (category IV recommendation).
- •Moderately severe disseminated infection should receive induction treatment with liposomal amphotericin B 3 mg/kg/day intravenously (category Ib recommendation for histoplasmosis, category IV recommendation for blastomycosis/coccidioidomycosis).
- •After induction therapy maintenance therapy should be with itraconazole or, in the case of coccidioidomycosis, fluconazole (category III recommendation).
- •Itraconazole treatment should be with the oral solution and therapeutic monitoring should be performed to ensure adequate levels (category III recommendation).
For localized histoplasmosis or blastomycosis treatment is with itraconazole 200 mg bd, administered as the oral solution due to better bioavailability, and with therapeutic monitoring to check levels due to variability between individuals . This recommendation represents an extrapolation of data and guidelines intended for HIV-seronegative individuals but seems appropriate for the less immunocompromised individuals who present with this form of disease (category IV recommendation). For C. immitis fluconazole 400–800 mg od is the preferred azole (category IV recommendation) . Itraconazole 200 mg bd po (with a loading dose of 200 mg tid/300 mg bd for 3 days) can also be used for initial treatment of mild disseminated histoplasmosis in HIV-seropositive individuals . Important interactions occur between itraconazole (and other azoles) and HAART (Table 7.1 in 7. Candidiasis). Many antiretroviral drugs, including ritonavir (and other PIs), can increase levels of itraconazole (and other azoles) while azoles modify the metabolism of antiretrovirals. If concomitant HAART is required it is advisable to select agents that have minimal drug interactions and to use therapeutic drug monitoring to check both itraconazole and potentially antiretroviral agents. Specialist advice, including that from a pharmacologist with experience of these interactions, is required to effectively manage these cases.
For moderately severe disseminated histoplasmosis , or for disseminated blastomycosis  or for disseminated coccidioidomycosis , amphotericin B is usually used for induction treatment for the first 2 weeks of therapy. Liposomal amphotericin B at 3 mg/kg iv for 2 weeks is the preferred induction agent for moderately severe disseminated histoplasmosis in HIV-seropositive individuals, on the basis of a randomized clinical trial which demonstrated less infusion-related toxicity and nephrotoxicity and greater clinical success, as compared to conventional amphotericin B (category Ib recommendation) . Although fewer data exist for other disseminated infections with dimorphic fungi, it is reasonable to consider liposomal amphotericin B at 3 mg/kg/day for 2 weeks followed by itraconazole (or fluconazole for coccidioidomycosis) for other dimorphic fungi (category IV recommendation). There is no evidence that higher doses of amphotericin offer any treatment advantage. Patients unable to tolerate amphotericin may be treated with intravenous itraconazole (fluconazole for coccidioidomycosis) although azoles have been little studied in moderately severe disseminated disease (category IV recommendation). After initial induction therapy for 2 weeks, maintenance therapy for the next 10 weeks should be with itraconazole oral solution 200 mg bd po with therapeutic drug monitoring as above. After this period the maintenance dose should be 200 mg od/bd with the goal of keeping the itraconazole level >4 mg/L (category III recommendation) . For CNS disease with histoplasmosis up to 5 mg/kg/day liposomal amphotericin B for 4–6 weeks followed by fluconazole 800 mg od (due to better CNS penetration than itraconazole) for at least 1 year is recommended .
For coccidioidomycosis there are fewer clinical data but moderately severe disease is treated with liposomal amphotericin B 3 mg/kg/day intravenously followed by maintenance with fluconazole 400–800 mg od orally (category IV recommendation). Some experts recommend using fluconazole with amphotericin B in the induction phase  and fluconazole 800 mg od orally should be used in induction therapy, with or without intrathecal amphotericin B, when there is CNS disease . Fluconazole levels do not need to be monitored.
Case reports and case series exist of the use of voriconazole and posaconazole against dimorphic fungi such as histoplasmosis and coccidioidomycosis in settings where individuals were not responding to conventional therapy, and these agents have in vitro activity against dimorphic fungi . These agents may be considered in cases intolerant to, or failing, amphotericin B and itraconazole (category III recommendation) [67,84]. CNS coccidioidomycosis requires life-long therapy . Severe pulmonary disease or granulomatous mediastinitis with histoplasmosis airway obstruction may be treated with prednisolone 60 mg histoplasmosis causing od for the first couple of weeks [69,85].
- •Routine primary prophylaxis for histoplasmosis and related dimorphic fungi is not indicated (category IV recommendation).
- •Secondary prophylaxis can be discontinued if after 1 year of antifungal therapy there has been administration of HAART for >6 months and the CD4 count is >150 cells/μL (category III recommendation).
Prophylaxis is not routinely warranted. Prophylaxis for individuals with CD4 counts <150 cells/μL who reside in an H. capsulatum var capsulatum endemic area may be considered in select cases with itraconazole 200 mg od po, which has been shown to reduce the incidence of histoplasmosis and cryptococcosis . ACTG study A5038 prospectively evaluated discontinuation of maintenance therapy for disseminated histoplasmosis when antifungal therapy had been administered for at least 12 months, HAART had been administered for at least 6 months, fungal blood cultures were negative, histoplasma urinary and serum antigen results were below the limit of detection and the CD4 count was >150 cells/μL . With 2 years of follow-up no relapses were noted. It is assumed that secondary prophylaxis can be stopped for other dimorphic fungi under similar conditions to those studied above.
10.6.6 Impact of HAART
The best time to initiate HAART is unknown; however, improved responses of histoplasmosis are seen with HAART, and histoplasmosis-associated IRIS tends not to be life threatening [87,88] so commencing treatment within 2 weeks of therapy seems appropriate (category IV recommendation).
Histoplasmosis has been associated with IRIS in individuals commencing HAART . Manifestations include lymphadenitis, hepatitis, arthritis and uveitis. There is less information with blastomycosis and coccidioidomycosis although theoretically IRIS could occur.
10.7.1 Background and epidemiology
Disseminated P. marneffei infection is a common opportunistic fungal infection in patients with advanced HIV infection who live in southeast Asia and southern China . It was originally isolated from bamboo rats and seems to be acquired by airborne contact with soil rather than the animals themselves . Cases of P. marneffei have been widely reported among visitors to Southeast Asia from countries outside the region [92–98]. There is also an increasing recognition of infection in India . In Thailand, the northern provinces are the most affected .
The most common clinical features of penicilliosis include fever, weight loss, nonproductive cough, lymphadenopathy, hepatosplenomegaly and anaemia. Many patients present with multiple papular skin lesions, which show a central necrotic umbilication and resemble molluscum contagiosum. These are often found on the face, neck, trunk and upper limbs . Untreated, disseminated P. marneffei infection is almost invariably fatal. Chest radiographs may reveal interstitial lesions, cavities, fibrotic lesions and mass lesions [101,102].
The diagnosis can be made by direct microscopic examination of smears from skin or other lesions that reveal septate yeast forms. Culture of specimens from the bone marrow, lymph nodes, skin, and other infected sites shows a characteristic red colour on plates and diamorphism, which means that the fungus changes to a hyphal form at a lower temperature. Culture of these lesions is important, because other fungal infections, such as histoplasmosis and cryptococcus, may have similar clinical manifestations [90,103]. There are no widely available serological tests for this disease although antigen can be easily detected in the urine .
- •Penicilliosis should be treated with amphotericin B induction therapy for 2 weeks, followed by itraconazole 200 mg bd orally for 10 weeks and then maintenance therapy 200 mg once a day (category IV recommendation).
Penicillium marneffei is sensitive to commonly used antifungals . In Thailand, the greatest treatment experience has been with intravenous amphotericin B 0.6 mg/kg per day for 2 weeks followed by oral itraconazole 200 mg bd po for a further 10 weeks. This regimen has a response rate of up to 95% and is well tolerated . As discussed for other dimorphic fungi induction therapy with liposomal amphotericin B, 3 mg/kg/day intravenously, for the first 2 weeks should be considered in the UK (category IV recommendation).
Itraconazole has been recommended as lifelong suppressive therapy in patients infected with HIV who have completed successful treatment of P. marneffei infection ; however, there are some recent small case series suggesting that prophylaxis may be safely discontinued when immune reconstitution occurs on ART and individuals have sustained CD4 counts >100 cells/μL [108,109].
- •Prophylaxis with itraconazole may be considered for travellers to endemic areas with CD4 counts <100 cells/μL.
It has been suggested, based on studies in other systemic mycoses  and a small trial in Thailand , that itraconazole 200 mg once a day orally be given as prophylaxis to travellers to the endemic areas who have CD4 counts <100 cells/μL .
10.7.6 Impact of HAART
There is little information on the impact of HAART on penicilliosis, but in Thailand the incidence appears low in individuals receiving HAART . Most cases of penicilliosis occur at very low CD4 cell counts where HAART is indicated by current guidance. However, HAART should be commenced in all patients diagnosed with penicilliosis as soon as a clinical response is noted to treatment of penicilliosis.
There is little information on IRIS due to penicilliosis but as with other dimorphic fungi it is a possible presentation.