http://www.info.gov.hk/aids/pdf/g190htm/22.

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V. MAJOR OPPORTUNISTIC INFECTIONS

22. CANDIDIASIS AND HIV

Kenny CW CHAN The first report of AIDS described 5 patients with Pneumocystis carinii pneumonia. All of them had laboratory-confirmed mucosal infection with Candida albicans. This led the authors to suggest the 'possibility of a cellular-immune dysfunction related to a common exposure that predisposes indi iduals to opportunistic infections such as ! pneumocystosis and candidiasis'. Indeed candidiasis is now "nown to be the most common opportunistic fungal infection in #I$ disease. In #I$-positi e patients% both colonisation and disease in oral ca ity and other mucosal surfaces is common% especially with C. albicans% at rates that increase with progression of disease. & Such #I$-induced alterations as decreased sali ary IgA le els% impairment of mucosal 'D( cells% altered cyto"ine secretion and a shift to Th& cyto"ine expression in sali a li"ely contribute to Candida colonisation and disease.)'andidiasis is also associated with use of oral contracepti es% smo"ing% dentures% and immune suppression related to chemotherapeutic agents% corticosteroids% pregnancy and diabetes. In #I$ infection% these conditions may aggra ate or precipitate candidiasis.

Epidemiolo y o! "#ndidi#$i$ in HIV%AIDS

There are two main forms of candidiasis - mucosal and disseminated. As with other opportunistic infections% the introduction of highly acti e antiretro iral therapy *#AA+T, has led to a decreased incidence of oral and oesophageal candidiasis.( -ucosal candidiasis% in the form of oral% oesophageal or aginal infections% is common in #I$.AIDS. The incidence of oral candidiasis in #I$ infection aries from /0 to 1)0% depending on patient mix% diagnostic criteria and study methods. A re iew of local #I$-infected

women showed that the pre alence of oral candidiasis was 10 and that of aginal candidiasis &20.5 In an early study of #I$-infected women% Candida aginitis was the commonest #I$-associated clinical condition in women.3 Infections tend to persist and are associated with a lower 'D( count and higher #I$ iral load./ In the re ised !11) 'D' case definition%2 aginal candidiasis that was persistent% fre4uent or poorly responsi e to therapy% as well as oral candidiasis% became a designated #I$-associated category 5 condition. In recent years% howe er% the status of recurrent aginal candidiasis as a sentinel of #I$ infection has been called into 4uestion% as it has ne er been supported by prospecti e controlled studies. In the current classification% oesophageal candidiasis is an AIDS-defining condition% occurring with a 'D(6&77.89 and usually in con:unction with oral candidiasis. +arely% oral candidiasis may occur in the setting of primary #I$ infection when the 'D( count is significantly reduced. ;nli"e mucosal candidiasis% disseminated candidiasis is remar"ably uncommon in AIDS. This is li"ely due to relati ely ade4uate neutrophil function in most #I$-infected indi iduals. Although candidaemia has been reported in AIDS% it usually occurred in the presence of other ris" factors such as neutropaenia% parenteral nutrition% abdominal surgery% broad spectrum antibiotics% cancer and corticosteroid use.1%!7

O&#l "#ndidi#$i$
<ral candidiasis is an independent prognostic factor of #I$ disease progression%!! and it therefore could predict the occurrence of Pneumocystis jiroveci pneumonia *='=,. Its presence is an indication for ='= prophylaxis and consideration of treatment with #AA+T.

Clinical features and diagnosis

The symptoms of oral thrush are burning pain% altered taste sensation% and difficulty with swallowing. These contribute to poor oral inta"e and weight loss. #owe er% most patients are asymptomatic. There are ( forms of disease on examination>

P$e'domem(&#no'$ "#ndidi#$i$ )*+&'$+, is characterised by the presence of white or creamy pla4ues on the dorsal surface of the tongue% the hard or soft palate and buccal mucosa. Such lesions can be scraped off with a tongue depressor% lea ing a raw or bleeding surface. E&y*+em#*o'$ "#ndidi#$i$ appears on the dorsal surface of the tongue as a patchy depilated area% sometimes with corresponding *"issing, smooth red patches on the palate. The patient is more li"ely to be symptomatic with complaints of burning pain while eating spicy foods. An 'l#& "+eili*i$ appears as crac"ing% fissuring% or erythema at the corner of the mouth. <ccasionally% C#ndid# causes hyper"eratosis *candidal leukoplakia,% causing diagnostic difficulty with oral hairy leu"opla"ia. Diagnosis can be confirmed by biopsy. C. albicans is a common commensal of the s"in and mucosal surface. Its isolation therefore does not e4uate disease. Diagnosis of candidiasis is usually made on the grounds of clinical symptoms and physical examination. It may be possible to scrape off thrush. In atypical cases% microscopic examination of a ?<# smear helps support the diagnosis by showing pseudohyphae and blastospores. 'ulture is not routinely indicated% but if performed% it identifies the Candida species and helps predict resistance. In vitro resistance test may be considered in recurrent and refractory infections. The ma:or differential diagnosis of oral candidiasis is oral hairy leu"opla"ia% which is usually located at the sides of the tongue and cannot be scraped off. 'andidal leu"opla"ia cannot be wiped off either but will regress with prolonged antifungal therapy. 5iopsy will also show yeasts.

Initial treatment
@luconaAole *!77 mg 4d for /-!( d or till thrush resol esB some authorities recommend a loading dose of &77 mg on Day !,% with its superior effecti eness in #I$ infected patients is the standard of care and

is particularly indicated in the e ent of low 'D( or recurrent disease. The other aAoles> ItraconaAole oral solution at &77 mg 4d is as effecti e as fluconaAole but is less well tolerated. ?etoconaAole and itraconaAole capsules are less effecti e and not recommended. 'lotrimaAole tablet *4id to 5x.d for /-!( d, and nystatin oral suspension *5 m9 swish and swallow 4id to 5x.day for /-!( d, are cheaper but lesser alternati es. They are :ustified in patients with relati ely high 'D( count and less se ere disease.

Recurrences and refractory disease

<ral candidiasis typically responds well to fluconaAole% but recurs unless there is significant immune reco ery with #AA+T. +ecurrences after treatment may be due to C. albicans% a new strain of C. albicans with resistance% or with a non-albicans species of Candida such as C. glabrata% C. parapsilosis% C. krusei and C. dublinensis. The latter may be confused with C. albicans as both are associated with germ tube formation in the laboratory. It is not uncommon that multiple species or more than one genotype of C. albicans is isolated. Species other than C. albicans are generally less susceptible to therapy% and arise mainly with low 'D( count and after repeated or prolonged antifungal treatment. +ecurrent disease is usually managed in the same way as initial disease. The disease may become refractory to treatment% in which case treatment failure has occurred and diagnosis should be confirmed with microscopy or culture. Treatment options are>

Increasing fluconaAole dosage% up to 277 mg.d ItraconaAole solution &77 mg bid I$ amphotericin 5 7.) mg."g.d has identified non-albicans species or if in vitro sensiti ity a ailable% they should be ta"en into account in the selection of Cith immune reco ery after the use of #AA+T% pre iously oral candidiasis generally becomes more responsi e to

If culture results are treatment. refractory treatment.

Oe$op+# e#l "#ndidi#$i$

Clinical features and diagnosis
In a similar fashion to oral thrush% oesophageal candidiasis may be presumpti ely diagnosed when typical symptoms occur% especially in the presence of oral candidiasis. Typical symptoms are retrosternal pain% odynophagia and dysphagia. 'onstitutional symptoms% including fe er% occur only occasionally. ;pper endoscopy is warranted in case of treatment failure to identify adherent% whitish mucosal pla4ues and superficial mucosal ulcerations% and to differentiate from such lesions as herpetic oesophagitis% '-$ oesophagitis% aphthous ulceration% ADT-induced ulceration% and idiopathic or #I$ oesophagitis. 5iopsy of the lesions typically shows characteristic Candida yeast forms in tissue% accompanied by a neutrophilic response. The species can be identified by culture. <ccasionally% oesophageal candidiasis is asymptomatic and diagnosed when upper endoscopy is performed for an unrelated cause. <esophageal candidiasis may uncommonly be complicated by beAoar formation% perforation and fistula formation. If there is se ere neutropaenia% oesophagitis may also lead to candidaemia or bacteraemia.

Therapy
Systemic therapy is necessary for oesophageal candidiasis in the form of fluconaAole &77-(77 mg 4d for &-) wee"s. An acceptable alternati e is itraconaAole oral solution !77-&77 mg bid. ItraconaAole capsules and "etoconaAole are less effecti e. @ailure of symptoms to respond to fluconaAole in /-!7 days should preferably be followed by upper endoscopy to confirm the diagnosis and rule out coexisting diseases% after which the following options may be used>

Increasing fluconaAole dosage up to 277 mg.d <ral itraconaAole solution &77 mg bid

I$ caspofungin 57 mg 4d */7 mg on day !, <ral oriconaAole &77 mg bid I$ amphotericin 5 7.)-7.5 mg."g.d E.- flucytosine

The Candida species in ol ed may pro ide aluable guidance to the choice of therapy. +esistance testing is not routinely performed and may be difficult to interpret. The natural history of oesophageal candidiasis is recurrence within two to three months after treatment. 9ong term suppressi e therapy *secondary prophylaxis, with fluconaAole *!77-&77 mg 4d, or itraconaAole solution *&77 mg 4d, may be considered in fre4uently recurrent disease. It is important that #AA+T be initiated upon the diagnosis of oesophageal candidiasis.

V# in#l "#ndidi#$i$
Clinical features and diagnosis
=atients may be asymptomatic or may complain of peri aginal pruritus or dysuria. A gynaecologic examination typically shows erythematous labia% shallow% linear ulcerations on the introitus and.or satellite papules beyond the main area of erythema. Candida discharge is classically thic"% white and adherent. Diagnosis of aginal candidiasis is often made clinically and treatment begun empirically. <ther symptoms include external dysuria% aginal soreness and ul ar burning. Cith atypical presentation or treatment failure% a !70 ?<# smear should be performed% for demonstrating budding yeast and pseudohyphae. Fram stain and culture are also useful. $aginal p# is normal% i.e. 6G(.5. The whiff test should also be negati e in aginal candidiasis. Hote that isolation of Candida in an asymptomatic woman does not indicate treatment% as Candida may also exist as commensal in the agina. The following table summarises the distinguishing features of aginal candidiasis from trichomoniasis and bacterial aginosis% the ma:or differential diagnoses *5ox &&.!,.

Treatment
Topical therapy generally suffices. The following regimens% as used in #I$-negati e women% are appropriate as first line therapy. They are also safe in pregnancy.

Single dose therapy

Two isoconaAole *Fyno-Tra ogen, aginal )77 mg tablets =$ x ! TioconaAole *Fyno-Trosyd, 3.50 ointment (.3 g =$ x !

3-day therapy

Two clotrimaAole !77 mg *Fyne-9otremin, =$ x ) days TioconaAole *Fyno-Trosyd, &0 cream 5g =$ x ) days

7-day azole therapy

'lotrimaAole !77 mg *Fyne-9otremin, =$ x / days

!-day therapy

<ne nystatin aginal tablet *!75u, at bedtime% for !( days

Although /-day therapy is more effecti e than the more abbre iated regimens and nystatin% the difference is probably not clinically significant. Aggra ating factors should be ruled out and controlled if possible. These include diabetes% douching% pregnancy% corticosteroid use% concurrent antibiotic% hormonal contracepti es% tight-fitting synthetic underwear and possibly spermicides. "ecurrent in#ection can be a ma:or problem in both #I$ positi e and negati e women. It is important that the presence of aggra ating factors be re iewed and controlled if there is any. <n ruling out other causes of chronic aginitis% one may re-treat with the abo e regimens but with a longer duration. Alternati ely one may consider the following oral regimens>

Single-dose fluconaAole !57 mg *as effecti e as / days of intra aginal clotrimaAole, ItraconaAole &77 mg bid for ! day *limited clinical data, ItraconaAole &77 mg 4d for ) days *limited clinical data,

'ulture is useful in identifying non-albicans Candida spp. Cith oral aAoles% one must be assured that the patient is recei ing ade4uate contraception. Suppressive therapy with intermittent fluconaAole is generally not ad ised but may be considered in the case of recurrent aginal candidiasis% defined as IG( episodes of symptomatic aginal candidiasis annually. The diagnosis should be confirmed by culture before such treatment. The sexual partner may also be examined for balanitis and treated% though its alue in decreasing the occurrence of aginal candidiasis is contro ersial. The options of suppressi e therapy are>

@luconaAole !57 mg 4w" ItraconaAole 57-!77 mg 4w"

Cith these regimens% cost is a ma:or concern. 9ong term use of the cheaper "etoconaAole is not ad isable because of li"elihood of interaction with protease inhibitors and unreliable absorption in AIDS patients. The need for such maintenance treatment is ree aluated after 3 months. Although suppressi e therapy is usually effecti e% )7-(70 of women ha e recurrent disease once therapy is discontinued. 'laims for certain probiotics% such as 9actobacilli% to pre ent aginal candidiasis and bacterial aginosis are unsubstantiated. They are not recommended for use% especially in ad anced immunosuppression.

P&e-en*ion o! "#ndidi#$i$
As a strategy to pre ent candidiasis% the pre ention of exposure is impractical as Candida is common in the en ironment and as a commensal. The use of fluconaAole is effecti e in prospecti e controlled trials to pre ent cryptococcosis as well as mucosal candidiasis in ad anced #I$ disease. #owe er% mortality is not reduced. =rolonged primary prophylaxis is therefore not ad ised% Jbecause of the effecti eness of therapy for acute disease% the low mortality associated with mucosal candidiasis% the potential for resistant Candidaorganisms to de elop% the possibility of drug interactions% and the cost of prophylaxisJ.!&

As secondary prophylaxis% chronic treatment with fluconaAole !77-&77 mg daily may be considered in fre4uently recurrent esophageal candidiasis. #owe er% recurrent oesophagitis is becoming uncommon in the era of #AA+T.

An*i!'n #l *+e&#py
The mainstay of treatment of candidiasis is the use of antifungals. Since oral and aginal candidiasis can occur in the presence of a relati ely high 'D( count% the impact of #AA+T on their occurrence may be less than that on oesophageal candidiasis. He ertheless% a higher 'D( count and a more competent 'D( repertoire should theoretically contribute to a more rapid cure with antifungals and possibly less resistance. It is not uncommon to obser e that #AA+T therapy results in resolution of refractory% drug-resistant mucosal candidiasis% e en with limited immune reco ery.!) It is hypothesised that #I$ protease inhibitors ha e specific anti-Candida efficacy by inhibiting the secreted aspartic proteinases of Candida albicans% a "ey irulence factor.!(%!5

Anti-Candida agents
In #ong ?ong% the readily a ailable antifungals appropriate for mucosal candidiasis include> The aAoles> isoconaAole *Fyno-Tra ogen, aginal tablet% clotrimaAole *Fyne-9otremin, aginal tablet% tioconaAole *Fyno-Trosyd, aginal tablet% cream and ointment% and oral "etoconaAole% itraconaAole% and fluconaAole The polyenes> nystatin *suspension !75u.m9 and pessary,% amphotericin 5 *I$ and loAenge,% and talsutin *coformulated tetracycline and amphotericin 5, aginal tablet ;se of topical agents is limited to oral and aginal candidiasis. Systemic agents e.g. fluconaAole% are indicated for second line therapy% ad anced AIDS and oesophageal candidiasis. Among the systemic aAoles% efficacy is generally highest with fluconaAole and itraconaAole solution. ?etoconaAole is inferior% probably because of impaired absorption in ad anced AIDS. The relati e inefficacy of clotrimaAole troches and nystatin suspension%

howe er% is partially offset by their low cost. It is emphasised that for oesophageal candidiasis% only systemic agents are useful. @lucytosine may be used only in combination with an aAole or amphotericin 5 for se ere disease% since resistance rapidly emerges if flucytosine is used alone. The newer antifungals of oriconaAole% caspofungin and micafungin ha e been found to be effecti e in treatment of oesophageal candidiasis. Although they are not readily a ailable% they should be considered in refractory disease. In mucosal candidiasis refractory to aAoles and amphotericin 5% anecdotal success has been reported of treatment with interferon-K and recombinant granulocyte-macrophage colony stimulating factor. #owe er% with the extensi e antifungal armamentarium now a ailable% there is limited role for their use.

Antifungal susceptibility
Despite years of use% resistance to amphotericin 5 is still relati ely rare. <n the other hand% widespread use of systemic aAoles in recent years has led to the emergence of primary and secondary resistance% especially in ad anced AIDS.!3 Although a standard for antifungal sensiti ity testing against Candida has been defined and continues to be refined by the Hational 'ommittee for 'linical 9aboratory Standards *H''9S,% its use in the clinical setting is still ery limited. @urthermore% not all aAole-resistant candidiasis can be explained by in vitro resistance. This implies that in the e ent of failure% treatment is usually changed without clear ob:ecti e criteria. In general the options are increasing the dosage% changing to a new drug% or using combinations of drugs. 'ommonly% resistance is caused by infection with non-albicans Candida which are intrinsically less susceptible to treatment.

Drug interaction
Systemic aAoles are metabolised by the cytochrome =(57 *'L=, enAymes and hence may ha e significant drug interactions. Their metabolism is increased by rifamycins% long-acting barbiturates and phenytoin.

@luconaAole has the least propensity to cause drug interactions. $oriconaAole% "etoconaAole and itraconAole are all contraindicated with cisapride% terfenadine and astemiAole for fear of entricular arrhythmia. They may also increase the le els of sulfonyureas% #-F 'o-A reductase inhibitors *statins, omepraAoles and ergot al"aloids. There is also interaction with protease inhibitors which are also metabolised by the same enAymes. In particular% full-dose ritona ir *(77 mg bid or more, is contraindicated with oriconaAole. 5aby dose of ritona ir *&77 mg bid or less, as pharmaco"inetic enhancer may be used with caution. Mfa irenA is also contraindicated as it decreases le els of oriconaAole by /70. @luconaAole may increase the le el of rifabutin leading to u eitis. 'aspofungin is much less prone to serious drug interactions. He ertheless% with concurrent efa irenA% ne irapine% rifampin and phenytoin% caspofungin should be increased to /7 mg.d.

Teratogenicity
'raniofacial and s"eletal abnormalities ha e been reported following prolonged in utero exposure to fluconaAole. ItraconaAole is embryotoxic in animal systems. 'onse4uently systemic aAoles are contraindicated in pregnancy. Teratogenic effects on rats ha e also been obser ed with flucytosine which is therefore also contraindicated in pregnancy.

Re!e&en"e$
!. 'enters for Disease 'ontrol *'D',. =neumocystis pneumonia--9os Angeles. --C+ -orb -ortal C"ly +ep !12!B)7>&57-&.

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