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Human immunodeficiency virus ( HIV ) infection is the major cause of the acquired immune lack syndrome ( AIDS ) .1 HIV is most preponderantly transmitted via unprotected sexual intercourse ( around 85 % of all instances ) .1,2 Almost 60 million people have been infected with HIV and 25 million people have died due to HIV-related complications since the beginning of the epidemic in 1980’s.3

In HIV positive patients, the diminution of CD4+ lymph cells in HIV positive persons would increasingly take to AIDS, which is characterised by gradual weakening of immune map, taking to development of timeserving infections and malignancy.2 CD4+ count is a primary marker of immunosuppression and antiretroviral activity every bit good as an of import index in forecast of HIV patient.2,4 Patients with CD4+ count of & A ; lt ; 200 cell/mm3 are likely to develop timeserving tumors, blowing and neurological complication whereas invasive moniliasis, cryptococcosis, intellectual toxoplasmosis and other protozoal infections are frequently seen with CD4+ count of 50-100.2

Since the epidemic in the 80s, 5-10 % of AIDS patients in the USA, Europe and Australia were infected with cryptococcosis before the induction of extremely active anti-retroviral therapy ( HAART ) .2,5 These instances were largely presented as meningitis, and less normally pneumonia.1,2 The incidence of cryptococcosis has diminution since the extended usage of azoles as bar and treatment,6 particularly in developed countries.5 Infections are thought to be contacted through lungs via inspiration of yeast-like fungus Cryptococcus neoformans.1,7 About 75 % of HIV-related cryptococcal meningitis are shown to hold positive blood civilization consequence for C. Neoformans.8

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Testing for serum and cerebrospinal fluid ( CSF ) cryptococcal antigen is a sensitive and specific diagnostic method in cryptococcal meningitis.1 Besides being a trial to corroborate a diagnosing, it is besides really utile in finding the forecast of a patient.1 Patient is considered positive for cryptococcal infection if an antigen titre is greater than 1:8. Prognosis is regarded as hapless with CSF antigen titre of more than 1:1024 presented with alterations in mental province, a low CSF leucocyte count ( & A ; lt ; 20 cells/mm3 ) and an elevated CSF gap force per unit area of & gt ; 200mm H2O.1,2,5

In this instance, the 62 twelvemonth old male patient who is HIV positive develops cryptococcal meningitis. He should be started on intervention instantly before his status worsens.







2. Potential Short and Long Term Consequences

( Morbidity and Mortality )

About 90 % of mortality and morbidity of AIDS is caused by timeserving infections.2 Cryptococcal meningitis, one of the most common timeserving infections in HIV patients causes a high mortality of 10-30 % of all HIV deaths.5 In cardinal and southern Africa, the mortality rate among HIV-infected patient is a 44 % high.9 This rate occurs non merely in developing states, but besides in developed states, due to deficient fungicidal medicine and its combination, every bit good as the complications such as raised intracranial pressure.5 Prognosis is hapless if untreated, and leads to decease in all instances, runing from old ages in non-immunocompromised individual to hebdomads in persons with HIV infection.5,6 In a survey of AIDS patients ( n=236 ) with cryptococcal meningitis treated with amphotericin B plus flucytosine, 12 % died within 2 hebdomads and 26 % died before 10 hebdomads. In the 10-week period, merely 55 % of patient alive achieved negative CSF cultures.10Mean endurance for the disease is 5 months, and in 50 % of patients who are non under suppressive therapy, backsliding work stoppage within 6 months.2 Complete obliteration of infection in AIDS patient with intervention is improbable as patients has gradual and badly weakened immune map. Merely long term suppression and bar of backsliding seems feasible.6 Patients on care therapy with fluconazole has more than 95 % success rate in forestalling relapse.11 The backsliding rate is low ( 4 % ) with patients treated with fluconazole after induction therapy of amphotericin B.6

As the disease advancement, patients may see morbidity at different degrees, from side effects of the medicine ( Table 1 ) taken for a long period, to more serious complications arisen from cryptococcal meningitis. One of the most common complications is raised intracranial force per unit area, which is an of import subscriber towards increased mortality and morbidity in patients.12 Fifty per centum of HIV patients with cryptococcal meningitis has a markedly raised CSF gap force per unit area ( & gt ; 250 mmH2O ) . Causes of elevated intracranial force per unit area include intellectual hydrops and an uncontrolled fungous growing in the CSF, with minimum or no meningeal inflammation.12 Impairment in reabsorption of CSF in the arachnidian granulation with continuance of CSF production leads to a rise in pressure.13 Patients would see declining concern, altered mental position, ocular and hearing loss, and other neurological menifestations.5 Aggressive direction of elevated intracranial force per unit area is extreme of import in cut downing mortality every bit good as mortality to the lower limit during acute cryptococcal meningitis.12 Patients with decreased or normal CSF force per unit area show more frequent clinical response compared to those with raised force per unit area of more than 10mm ( P & A ; lt ; 0.001 ) , and a pre-treatment gap force per unit area of & A ; lt ; 250 mmH2O additions patients ‘ endurance. In a survey on increased in intracranial force per unit area in cryptococcal meningitis patients with HIV, a 14 % decease ( n=21 ) was associated with high intracranial pressure.13



Table 1:Antifungals and their common side effects.

Drugs

Side Effectss

Amphotericin B

During IV infusion- Headache, fever, asperities, sickness and emesis, hypotension

After IV infusion- Thrombophlebitis

Others: Nephrotoxicity, anemia, peripheral neuropathy, cardiac failure, immunomodulation

Flucytosine

Mild- Gastrointestinal side effects, tegument roseolas

Moderate- Myelosuppression, hepatotoxicity

Fluconazole

Mild- Nausea, emesis, tegument roseolas

Others- Elevated liver enzymes

3. Treatment Options- Advantages and Disadvantages in footings of Clinical Outcome, Adverse Effects and Cost.

The purposes of intervention for HIV patients with cryptococcal meningitis are to lessen the infection to the minimal degree, control of the intracranial force per unit area, and better the quality of patient ‘s life.1,12 Treatment utilizing fungicides entirely or in combination are the current recommendation in pull offing the disease in HIV patient.12

3.1 Antifungals for the obliteration of infection

Amphotericin B, fluconazole and flucytosine appeared to be good in handling cryptococcal meningitis in HIV patients. There are two stages of intervention: the initiation and the care therapy. The recommended intervention for cryptococcal meningitis is IV amphotericin B ( 0.7-1, up to 5mg/kg one time day-to-day ) and flucytosine ( 100mg/kg daily in 4 divided doses ) for 2 hebdomads, followed by consolidation therapy of fluconazole ( IV or unwritten 200-400mg daily ) for 8 hebdomads or more.2,12,14 Subsequently, 200mg fluconazole should be carried on as care therapy indefinitely unless immune reconstitution occurs with extremely active anti-retroviral therapy ( HAART ) .2,14

Amphotericin B is a type of polyene fungicide that works by interfering with the fungal cell membrane permeableness and with its conveyance map, organizing big pores in the membrane.15 Transmembrane ion channel created by the hydrophilic nucleus of the fungicidal molecule leads to intracellular loss of K+ , interrupting the ion balance.15 Generation of reactive O species in fungous cells and production of proinflammatory cytokine may besides lend to the fungicidal activity.16,17 Amphotericin B is selectively active towards Fungis due to its high affinity for ergosterol that present merely in fungous membrane but non in mammalian cells.16 It is given intravenously due to its hapless soaking up orally.15 Being extensively protein edge ( 99 % ) , the drug enters tissues and membranes including the blood-brain barrier with trouble, although the concentration is found to be higher in encephalon when the meninxs are inflamed.4,15

Amphotericin B shows dose dependent activity.5 Study showed that increased dosage of amphotericin B to 0.7mg/kg with or without flucytosine is significantly more effectual than 0.4mg/kg day-to-day, as 50 % rate of CSF sterilization in two hebdomads without pronounced toxicity with this higher dosage compared to 20 % rate in the lower dose group.18 Amphotericin B is excreted easy via the kidneys, with half life of up to two weeks.15 Side effects are as in Table 1. The most terrible but common inauspicious consequence is nephritic toxicity and it occurs to 80 % of patient. It is non 100 % reversible as patient still suffer from nephritic damage after the intervention has been discontinued. Frequent monitoring of nephritic map is necessary ( at least every other twenty-four hours ) , and intervention should be discontinued if plasma creatinine exceeds 250mol/L.4,5 Salt burden of 1L/day is suggested to hold protective consequence against nephritic toxicity.5,14,19 Alternatively, liposomal readying such as AmBisome can be used because it is every bit effectual as the conventional deoxycholate readying but causes fewer side effects. Hence, it is better tolerated at higher doses.5,20 Unfortunately, the liposomal readying is much more dearly-won than the conventional readying ( a 50mg phial of AmBisome cost about 20 times more than a 50mg phial of Fungizone ) .14,15

Flucytosine is an fungicidal agent given together with amphotericin B in handling terrible systemic infection.15 It should non be given entirely as opposition occurs easy. In fungous cells with presence of cytosine permease, flucytosine inhibit DNA synthesis by being converted to 5-fluorouracil which is an antimetabolite that inhibits thymidylate synthetase.15,21 Absence of cytosine permease activity in mammalian cells leads to its specificity to fungal mark cells and low toxicity to mammalian cells.5 Flucytosine can be given intravenously or orally, and is distributed throughout organic structure unstable including CSF.15 Study showed that plasma concentration is higher when it is given intravenously and CSF concentration is 84 % of that of plasma concentration. Mean peak plasma was 30mg/L for unwritten disposal compared to 63mg/L by endovenous path ( n=14 ; P & A ; lt ; 0.00001 ) twenty-two Nevertheless, bioavailability is high with unwritten disposal ( 75-90 % ) .22 Maximal antifungal consequence is achieved irrespective of the path administrated when it is given at a dosage of 75mg/kg day-to-day along with amphotericin B.22





Protein binding of flucytosine is low and the drug is able to perforate good into tissues, with approximately 80 % of serum degree achieved in CSF.4 Plasma half life of flucytosine is 3-5 hours and 90 % is eliminated through the kidneys, consequence in a drawn-out half life in patients with nephritic failure.4,15 Hence, dosage should be adjusted and plasma degree be monitored if patient has nephritic impairment.14,15 Side effects of flucytosine are presented in Table 1. The major side effects of flucytosine, myelosuppresion and GI perturbations, are dose dependent, proposing a lower dosage would hold a better clinical result with better patient tolerance.5 Myelosuppresion can be avoided by keeping the flucytosine plasma degree at 25-50mg/L and non transcending 80mg/L. Side effects are reversible upon discontinuance of the drug.4

In-vivo and in-vitro surveies demonstrated that when flucytosine was used in combination with amphotericin B in handling HIV-related cryptococcal meningitis, the consequence was at least linear if non synergistic.18 Consequences from a randomised test showed that intervention utilizing amphotericin plus flucytosine had a statistically important higher initial fungicidal activity ( measured as average rate autumn in CSF settlement organizing unit ( CFU ) count ) than utilizing amphotericin entirely, amphotericin plus fluconazole, or ternary therapy of amphotericin, flucytosince and fluconazole.23 A average autumn rate of over half a log decrease was detected in the intervention group utilizing amphotericin B plus flucytosine compared to less than a 3rd of a log obtained from intervention utilizing amphotericin alone.23 Another survey showed that the rate of CSF sterilization was higher but toxic consequence was non increased when the combination was used.18 Sixty of patients having combination therapy showed unfertile CSF civilizations at 2 hebdomads of intervention clip compared to 51 % that undergone monotherapy.2 However, in another survey, the consequence showed that more than 50 % of patient having combination therapy were discontinued from flucytosine due to cram marrow suppression and aggravation of amphotericin-induced nephritic impairment.2,18

Fluconazole, like other azoles, is a type of man-made fungistatic agent that maps by suppressing the fungous cytochrome P450 3A enzyme and lanosine 14a-demethylase which plays an of import function in synthesis of fungous membrane constituent ergosterol. As a consequence, the membrane fluidness is changed and activities of membrane-associated enzymes such as cell wall synthesis are affected.15,21 Fluconazole can be administered via unwritten or endovenous path. It is good absorbed orally ( 90 % bioavailability ) , low protein binding ( 10 % ) with high concentration is achieved in CSF ( 60 % of serum degree ) . It has half life of about 25 hours and 90 % of drug is eliminated in urine.4,15 Side effects of fluconazole are showed in table 1. In AIDS patient being treated with multiple drugs, more serious side consequence are observed and these include exfoliative skin lesions and seldom, Steven-Johnson Syndrome.15

Overall, the cost for the intervention is high as drug disposal might be life-long. The initiation therapy of Amphotericin B ( & A ; lb ; 4.12 per 50mg phial ) and flucytosine ( & A ; lb ; 30.33 for 250ml ) will be an mean adult male of 70 kilograms about & A ; lb ; 94 daily for 2 hebdomads. Cost will be higher if lipid preparation of Amphotericin B is used. For the consolidation therapy, cost of IV fluconazole ( & A ; lb ; 29.28 for 100ml bottle ) is about & amp ; lb ; 60 daily for 8 hebdomads. This monetary value is much lower if unwritten signifier is used alternatively ( 200mg 7-cap for & A ; lb ; 2.02 ) . Subsequently, care therapy of unwritten fluconazole will be about & A ; lb ; 2 weekly for a indefinite period until patient ‘s immune system is good. Besides, drugs are required to administered intravenously will be more as hospitalization and proper staff preparation is needed.12,14





3.2 Management of intracranial force per unit area.

Elevated intracranial force per unit area occurs in 50 % of HIV-associated cryptococcal meningitis patients. Treatment aims to accomplish a decrease in the force per unit area and hence a decrease in morbidity and mortality. Treatment options include intermittent drainage by agencies of consecutive lumbar puntures and usage of corticoids, acetazolaminde or mannitol.12

Prior to intercession, a CT or MRI should be carried out to govern out presence of hydrocephaly and infinite occupying lesions. In patients with normal baseline gap force per unit area ( & A ; lt ; 200 mmH2O ) , medical therapy is initiated with a lumbar puncture repeated 2 hebdomads after the beginning of therapy.12 For patients presented with opening force per unit area of & gt ; 250mm H2O, lumbar drainage should be done to accomplish a 50 % decrease in opening force per unit area. Lumber punctures should be done daily to keep the CSF gap force per unit area in the normal scope. For patients with relentless elevated force per unit area or progressive shortage in neurological map, a ventriculoperitoneal shunt is indicated.12

Assorted consequences have been shown in medical intervention utilizing steroids, acetazolamide and mannitol. Corticosteroids, as an anti-inflammatory agent, used based on the theory that it will cut down the production of monocyte, macrophage and other polymorphonuclear leucocyte, which will leads to a decrease in extra fluids in CSF space.13 However, surveies showed that usage of corticoid may non be good but is associated with increased mortality.13 Marked inflammatory response is non a characteristic in HIV-associated cryptococcal meningitis.9 In add-on, the consequence of proinflammatory cytokine in CSF that contributes to the endurance and rapid clearance of infection is suggested to be compromised when high dosage steroids is used.5

Acetazolamide ( systemic carbonic anhydrase inhibitor ) and mannitol ( hyperosmotic agent ) are effectual in cut downing intraocular force per unit area and benign intracranial high blood pressure but their usage in cut downing CSF force per unit area has non shown to be effective.4,5 In a randomised test done look intoing the usage of acetazolamide in handling cryptococcal meningitis ( n=22, get downing dosage of 250mg every 6 hr, adjusted consequently ) , it was shown that acetazolamide is associated with more serious side effects including terrible acidosis compared with intervention group with placebo. ( p=0.04 ) .24 This result, along with more serious hypokalaemia is proposed to be due to additive or interactive toxicity consequence with amphotericin B. Besides, the consequence of acetazolamide as an antisecretory may non be sufficient in cut downing the intracranial force per unit area due to severe overflow obstructor of CSF drainage.24 The benefits of Osmitrol in handling cryptococcal meningitis in HIV patient is inconclusive from clinical grounds available.9,12,13

The cost for lumbar puncture is cheap compared to other more intensive interventions that will necessitate particular attention unit scenes. Life-saving surgical intercession such as shunt arrangement possibly good but is expensive as general anesthesia is involved. Overall cost is high as hospitalization and professional accomplishments is required for monitoring and intervention.12







4. Evidence Based Treatment recommendation

Induction therapy of Amphotericin B ( 0.7-1 mg/kg/day ) with flucytosine ( 100mg/kg/day ) should be started for this patient for two hebdomads, followed by an 8-week consolidation therapy of fluconazole ( 400 mg/day ) . Subsequently, 200 mg/day of fluconazole should be continued as care therapy until immune reconstitution with antivirals is sustained.5,9,14,18 This regimen appears to be the best with mortality rate of 9.4 % at 10 hebdomads and is applied as intervention guideline in the USA and Europe.5

In a randomized controlled test, patient having unwritten fluconazole 400 mg/day for 10 hebdomads ( n=6 ) shows negative CSF civilizations after 40.6±5.4 yearss, whereas those who received 0.7 mg/kg day-to-day amphotericin B for a hebdomad and the three times daily for nine hebdomads with 150 mg/kg day-to-day flucytosine ( n=6 ) showed negative CSF civilizations after 15.6±6.6 yearss. 25 The difference between this two intervention is statistically important ( p=0.02 ) . This indicates that combination therapy of amphotericin B with flucytosine is superior and more clinically effectual compared to utilizing fluconazole entirely in intervention of cryptococcal meningitis in AIDS patients.25 Another double-blind randomised test showed that at a higher dosage of amphotericin B ( 0.7mg/kg/day ) , with or without flucytosine, is associated with a decreased mortality rate. This higher dosage resulted in a 50 % of CSF sterilization in two hebdomads without pronounced toxicity compared to a rate of 20 % when a lower dosage ( 0.4mg/kg/day ) was used ( p & A ; lt ; 0.001 ) .18

In another survey comparing the usage of amphotericin entirely and combined with flucytosine ( n=50 ) , the consequences showed that combination therapy given for 6 hebdomads cured more patient than amphotericin alone for 10 hebdomads ( 16 vs 11 ) with fewer backslidings reported ( 3 vs 11 ) , a higher CSF sterilization rate ( p & A ; lt ; 0.001 ) and less nephrotoxicity ( p & A ; lt ; 0.05 ) .26 In a randomized test conducted look intoing the consequence of combination fungicidal therapy, in intervention of cryptococcal meningitis in HIV patients ( n=64 ) , 0.7 mg/kg day-to-day amphotericin B plus 100 mg/kg day-to-day flucytosine showed the highest antifungal activity compared to amphotericin B entirely ( p=0.0006 ) ; amphotericin B with 400 milligrams day-to-day fluconazole ( p=0.02 ) ; or ternary therapy with amphotericin B, flucytosine and fluconazole ( p=0.02 ) .23

In a survey done comparing the usage of liposomal amphotericin B ( AmBisome ) and amphotericin B, sterilization of CSF were achieved in 40 % of patients treated with 4mg/kg day-to-day AmBisome four ( n=15 ) and 8 % for patients treated with amphotericin B 0.7/kg day-to-day IV ( n=12 ) in 7 yearss ( p=0.09 ) , and 66 % versus 11 % in 14 yearss ( p=0.01 ) .20 AmBisome is showed to hold significantly reduced side consequence compared to amphotericin B, with lower incidence of nephritic, hepatic or hematologic toxicity.27 Mean increased in creatinine degree were higher in patients treated with amphotericin B compared to those treated with AmBisome.28 The chief disadvantage of AmBisome being its high cost. However, cost effectivity of AmBisome can be justified as intervention period appeared to be shorter as continuance of hospitalization and extract is reduced due to faster rate of CSF sterilization. Besides, lower toxicity rate is besides good in long term as less complication is likely to occur.20

In a randomized, double-blind, controlled clinical test carried out look intoing the consequence of Sporanox and fluconazole as care therapy in handling cryptococcal meningitis, HIV patients who achieved negative CSF civilization after the acute infection were given either drugs at 200mg/d.11 In four months, 23 % of patients having Sporanox ( n= 57 ) had a backsliding with positive CSF civilization whereas merely 4 % of patient having fluconazole ( n=51 ) had the same incident ( p=0.006 ) . One of the factors proposed is that Sporanox may be less active against C. neoformans in vivo, and plasma concentration of Sporanox appeared to be lower compared to fluconazole. The usage of flucytosine during the first two hebdomads of intervention for the acute episode was associated with a lower hazard of backsliding regardless of the drug pick in care therapy, proposing a possible influence of initial intervention to subsequent disease management.11 Another double-blind randomised test done in comparing the usage of fluconazole and Sporanox in care therapy, 72 % of patients ( n=151 ) given fluconazole achieve negative sterilization of CSF in 10 hebdomads compared to 60 % in patients having Sporanox. For patients who can non digest fluconazole, Sporanox appeared to a really suited alternative.18

Monitoring of intracranial force per unit area is of import as this complication causes high mortality and morbidity in patients. In a survey of HIV associated cryptococcal meningitis patients, 14 % of decease is suspected to be due to high pre-treatment intracranial force per unit area. As inauspicious effects and characteristics of raised force per unit area may non be instantly evident before the direct measuring, serious effects and deceases occurred due to unrecognized raised pressure.13 Current pattern guideline suggests that for patients with opening force per unit area of & gt ; 250 mmH2O, encephalon scan should be carried out to govern out hydrocephaly and space-occupying lesion. Subsequently, day-to-day lumbar punctures should be done to retreat big volumes of CSF and accomplish 50 % decrease in initial gap pressure.5,12 In a survey done by AIDS Clinical Trials Group, it is concluded that opening force per unit areas of & gt ; 250mmH2O should be treated with large-volume CSF drainage.13 Lumbar puncture demonstrated superior clinical efficaciousness compared to the usage of non-invasive medical therapy utilizing steroids, acetazolamide and mannitol. The usage of this medical therapy is non supported by clinical grounds. Furthermore, the AIDS clinical tests showed that usage of high doses of corticoids in handling high CSF force per unit area are associated with significantly higher mortality compared to patients with high CSF force per unit area but receive no steroids. Sum of 41 patients were given steroids for all purpose including to stamp down reaction to Amp B and to handle raised CSF, 20 % died within two hebdomads of intervention, compared to 3 % ( n=13 ) who did non have steroids ( P & A ; lt ; 0.001 ) . Four out of 13 patients ( 31 % ) with CSF force per unit area & gt ; 350 mmH2O and given steroids died compared to 1 of 39 patient ( 3 % ) who did non have steroid and had force per unit areas & gt ; 350 mmH2O ( p=0.003 ) .13 In 18 patients given dexamethasone or methylprednisolone for raised intracranial force per unit area, 9 patients had to have excess lumbar punctures for CSF drainage.13









5. Decision

Based on groundss reviewed, I strongly recommend that this patient in the instance scenario be started on the initiation therapy ( Amphotericin B, 0.7kg/mg daily ; flucytosine, 100mg/kg daily ) for 2 hebdomads, followed by consolidation therapy ( fluconazole, 400mg/day ) 8 hebdomads and later, the care therapy ( fluconazole, 200mg/day ) until immune system recovers. At the same clip, intracranial force per unit area should be monitored at & A ; lt ; 250 mmH2O and lumbar puncture should be performed if CSF drainage is required. Besides, nephritic profile should be monitored to observe possible nephrotoxicity due to amphotericin B.

After the acute episode, patient should be farther monitored monthly to guarantee that the infection is under control.12 CD4+ count should be done to find the province of patient ‘s immune map. With patient ‘s conformity to the regimen and his advancement being monitored, he should hold a high opportunity of endurance.

Mentions:

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