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Human immunodeficiency virus infection is the major cause of the acquired immune deficiency syndrome.1 HIV is most predominantly transmitted via unprotected sexual intercourse (around 85% of all cases).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 decline of CD4+ lymphocytes in HIV positive individuals would progressively leads to AIDS, which is characterised by gradual weakening of immune function, leading to development of opportunistic infections and malignancy.2 CD4+ count is a primary marker of immunosuppression and antiretroviral activity as well as an important indicator in prognosis of HIV patient.2,4 Patients with CD4+ count of <200 cell/mm3 are likely to develop opportunistic tumours, wasting and neurological complication whereas invasive candidiasis, cryptococcosis, cerebral toxoplasmosis and other protozoal infections are often 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 initiation of highly active anti-retroviral therapy (HAART).2,5 These cases were mostly presented as meningitis, and less commonly pneumonia.1,2 The incidence of cryptococcosis has decline since the extensive use of azoles as prevention and treatment,6 especially in developed countries.5 Infections are thought to be contacted through lungs via inhalation of yeast-like fungus Cryptococcus neoformans.1,7 About 75% of HIV-related cryptococcal meningitis are shown to have positive blood culture result for C. Neoformans.8
Testing for serum and cerebrospinal fluid (CSF) cryptococcal antigen is a sensitive and specific diagnostic method in cryptococcal meningitis.1 Besides being a test to confirm a diagnosis, it is also very useful in determining the prognosis of a patient.1 Patient is considered positive for cryptococcal infection if an antigen titer is greater than 1:8. Prognosis is regarded as poor with CSF antigen titer of more than 1:1024 presented with changes in mental state, a low CSF leukocyte count (<20 cells/mm3) and an elevated CSF opening pressure of >200mm H2O.1,2,5
In this case, the 62 year old male patient who is HIV positive develops cryptococcal meningitis. He should be started on treatment immediately before his condition worsens.
Potential Short and Long Term Consequences
(Morbidity and Mortality)
Almost 90% of mortality and morbidity of AIDS is caused by opportunistic infections.2 Cryptococcal meningitis, one of the most common opportunistic infections in HIV patients causes a high mortality of 10-30% of all HIV deaths.5 In central and southern Africa, the mortality rate among HIV-infected patient is a 44% high.9 This rate occurs not only in developing countries, but also in developed countries, due to insufficient antifungal medication and its combination, as well as the complications such as raised intracranial pressure.5 Prognosis is poor if untreated, and leads to death in all cases, ranging from years in non-immunocompromised person to weeks in individuals with HIV infection.5,6 In a study of AIDS patients (n=236) with cryptococcal meningitis treated with amphotericin B plus flucytosine, 12% died within 2 weeks and 26% died before 10 weeks. In the 10-week period, only 55% of patient alive achieved negative CSF cultures.10Mean survival for the disease is 5 months, and in 50% of patients who are not under suppressive therapy, relapse strike within 6 months.2 Complete eradication of infection in AIDS patient with treatment is unlikely as patients has gradual and severely weakened immune function. Only long term suppression and prevention of relapse seems feasible.6 Patients on maintenance therapy with fluconazole has more than 95% success rate in preventing relapse.11 The relapse rate is low (4%) with patients treated with fluconazole after initiation therapy of amphotericin B.6
As the disease progress, patients may experience morbidity at different levels, from side effects of the medication (Table 1) taken for a long period, to more serious complications arisen from cryptococcal meningitis. One of the most common complications is raised intracranial pressure, which is an important contributor towards increased mortality and morbidity in patients.12 Fifty percent of HIV patients with cryptococcal meningitis has a markedly raised CSF opening pressure (>250 mmH2O). Causes of elevated intracranial pressure include cerebral oedema and an uncontrolled fungal growth in the CSF, with minimal or no meningeal inflammation.12 Impairment in resorption of CSF in the arachnoid granulation with continuation of CSF production leads to a rise in pressure.13 Patients would experience worsening headache, altered mental status, visual and hearing loss, and other neurological menifestations.5 Aggressive management of elevated intracranial pressure is utmost important in reducing mortality as well as mortality to the minimum during acute cryptococcal meningitis.12 Patients with reduced or normal CSF pressure show more frequent clinical response compared to those with raised pressure of more than 10mm (p<0.001), and a pre-treatment opening pressure of <250 mmH2O increases patients' survival. In a study on increased in intracranial pressure in cryptococcal meningitis patients with HIV, a 14% death (n=21) was associated with high intracranial pressure.13
Table 1: Antifungals and their common side effects.4
During IV infusion- Headache, pyrexia, rigors, nausea and vomiting, hypotension
After IV infusion- Thrombophlebitis
Others: Nephrotoxicity, anaemia, peripheral neuropathy, cardiac failure, immunomodulation
Mild- Gastrointestinal side effects, skin rashes
Moderate- Myelosuppression, hepatotoxicity
Mild- Nausea, vomiting, skin rashes
Others- Elevated liver enzymes
Treatment Options- Advantages and Disadvantages in terms of Clinical Outcome, Adverse Effects and Cost.
The aims of treatment for HIV patients with cryptococcal meningitis are to subside the infection to the minimum level, control of the intracranial pressure, and improve the quality of patient's life.1,12 Treatment using antifungals alone or in combination are the current recommendation in managing the disease in HIV patient.12
3.1 Antifungals for the eradication of infection
Amphotericin B, fluconazole and flucytosine appeared to be beneficial in treating cryptococcal meningitis in HIV patients. There are two phases of treatment: the induction and the maintenance therapy. The recommended treatment for cryptococcal meningitis is IV amphotericin B (0.7-1, up to 5mg/kg once daily) and flucytosine (100mg/kg daily in 4 divided doses) for 2 weeks, followed by consolidation therapy of fluconazole (IV or oral 200-400mg daily) for 8 weeks or more.2,12,14 Subsequently, 200mg fluconazole should be carried on as maintenance therapy indefinitely unless immune reconstitution occurs with highly active anti-retroviral therapy (HAART).2,14
Amphotericin B is a type of polyene antifungal that works by interfering with the fungal cell membrane permeability and with its transport function, forming large pores in the membrane.15 Transmembrane ion channel created by the hydrophilic core of the antifungal molecule leads to intracellular loss of K+, disrupting the ion balance.15 Generation of reactive oxygen species in fungal cells and production of pro-inflammatory cytokine may also contribute to the antifungal activity.16,17 Amphotericin B is selectively active towards fungi due to its high affinity for ergosterol that present only in fungal membrane but not in mammalian cells.16 It is given intravenously due to its poor absorption orally.15 Being extensively protein bound (99%), the drug enters tissues and membranes including the blood-brain barrier with difficulty, although the concentration is found to be higher in brain when the meninges are inflamed.4,15
Amphotericin B shows dose dependent activity.5 Study showed that increased dose of amphotericin B to 0.7mg/kg with or without flucytosine is significantly more effective than 0.4mg/kg daily, as 50% rate of CSF sterilisation in two weeks without marked toxicity with this higher dose compared to 20% rate in the lower dose group.18 Amphotericin B is excreted slowly via the kidneys, with half-life of up to two weeks.15 Side effects are as in Table 1. The most severe but common adverse effect is renal toxicity and it occurs to 80% of patient. It is not 100% reversible as patient still suffer from renal impairment after the treatment has been discontinued. Frequent monitoring of renal function is necessary (at least every other day), and treatment should be discontinued if plasma creatinine exceeds 250mol/L.4,5 Salt loading of 1L/day is suggested to have protective effect against renal toxicity.5,14,19 Alternatively, liposomal preparation such as AmBisome can be used because it is as effective as the conventional deoxycholate preparation but causes fewer side effects. Hence, it is better tolerated at higher doses.5,20 Unfortunately, the liposomal preparation is much more costly than the conventional preparation (a 50mg vial of AmBisome cost about 20 times more than a 50mg vial of Fungizone).14,15
Flucytosine is an antifungal agent given together with amphotericin B in treating severe systemic infection.15 It should not be given alone as resistance occurs easily. In fungal 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 target cells and low toxicity to mammalian cells.5 Flucytosine can be given intravenously or orally, and is distributed throughout body fluid 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 oral administration compared to 63mg/L by intravenous route (n=14; p<0.00001).22 Nevertheless, bioavailability is high with oral administration (75-90%).22 Maximal fungicidal effect is achieved regardless of the route administrated when it is given at a dose of 75mg/kg daily along with amphotericin B.22
Protein binding of flucytosine is low and the drug is able to penetrate well into tissues, with about 80% of serum level achieved in CSF.4 Plasma half-life of flucytosine is 3-5 hours and 90% is eliminated through the kidneys, result in a prolonged half-life in patients with renal failure.4,15 Hence, dose should be adjusted and plasma level be monitored if patient has renal impairment.14,15 Side effects of flucytosine are presented in Table 1. The major side effects of flucytosine, myelosuppresion and gastrointestinal disturbances, are dose dependent, suggesting a lower dose would have a better clinical outcome with better patient tolerance.5 Myelosuppresion can be avoided by maintaining the flucytosine plasma level at 25-50mg/L and not exceeding 80mg/L. Side effects are reversible upon discontinuation of the drug.4
In-vivo and in-vitro studies demonstrated that when flucytosine was used in combination with amphotericin B in treating HIV-related cryptococcal meningitis, the effect was at least additive if not synergistic.18 Results from a randomised trial showed that treatment using amphotericin plus flucytosine had a statistically significant higher initial fungicidal activity (measured as mean rate fall in CSF colony forming unit (CFU) count) than using amphotericin alone, amphotericin plus fluconazole, or triple therapy of amphotericin, flucytosince and fluconazole.23 A mean fall rate of over half a log reduction was detected in the treatment group using amphotericin B plus flucytosine compared to less than a third of a log obtained from treatment using amphotericin alone.23 Another study showed that the rate of CSF sterilisation was higher but toxic effect was not increased when the combination was used.18 Sixty of patients receiving combination therapy showed sterile CSF cultures at 2 weeks of treatment time compared to 51% that undergone monotherapy.2 However, in another study, the result showed that more than 50% of patient receiving combination therapy were discontinued from flucytosine due to bone marrow suppression and exacerbation of amphotericin-induced renal impairment.2,18
Fluconazole, like other azoles, is a type of synthetic fungistatic agent that functions by inhibiting the fungal cytochrome P450 3A enzyme and lanosine 14α-demethylase which plays an important role in synthesis of fungal membrane component ergosterol. As a result, the membrane fluidity is changed and activities of membrane-associated enzymes such as cell wall synthesis are affected.15,21 Fluconazole can be administered via oral or intravenous route. It is well absorbed orally (90% bioavailability), low protein binding (10%) with high concentration is achieved in CSF (60% of serum level). It has half-life of approximately 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 effect are observed and these include exfoliative skin lesions and rarely, Steven-Johnson Syndrome.15
Overall, the cost for the treatment is high as drug administration might be life-long. The induction therapy of Amphotericin B (£4.12 per 50mg vial) and flucytosine (£30.33 for 250ml) will cost an average man of 70 kg about £94 daily for 2 weeks. Cost will be higher if lipid formulation of Amphotericin B is used. For the consolidation therapy, cost of IV fluconazole (£29.28 for 100ml bottle) is approximately £60 daily for 8 weeks. This price is much lower if oral form is used instead (200mg 7-cap for £2.02). Subsequently, maintenance therapy of oral fluconazole will cost about £2 weekly for a indefinite period until patient's immune system is well. Also, drugs are required to administered intravenously will cost more as hospitalisation and proper staff training is needed.12,14
3.2 Management of intracranial pressure.
Elevated intracranial pressure occurs in 50% of HIV-associated cryptococcal meningitis patients. Treatment aims to achieve a reduction in the pressure and hence a reduction in morbidity and mortality. Treatment options include intermittent drainage by means of sequential lumbar puntures and use of corticosteroids, acetazolaminde or mannitol.12
Prior to intervention, a CT or MRI should be carried out to rule out presence of hydrocephalus and space occupying lesions. In patients with normal baseline opening pressure (<200 mmH2O), medical therapy is initiated with a lumbar puncture repeated 2 weeks after the commencement of therapy.12 For patients presented with opening pressure of >250mm H2O, lumbar drainage should be done to achieve a 50% reduction in opening pressure. Lumber punctures should be done daily to maintain the CSF opening pressure in the normal range. For patients with persistent elevated pressure or progressive deficit in neurological function, a ventriculoperitoneal shunt is indicated.12
Mixed results have been shown in medical treatment using steroids, acetazolamide and mannitol. Corticosteroids, as an anti-inflammatory agent, used based on the theory that it will reduce the production of monocyte, macrophage and other polymorphonuclear leukocyte, which will leads to a reduction in excess fluids in CSF space.13 However, studies showed that use of corticosteroid may not be beneficial but is associated with increased mortality.13 Marked inflammatory response is not a feature in HIV-associated cryptococcal meningitis.9 In addition, the effect of pro-inflammatory cytokine in CSF that contributes to the survival and rapid clearance of infection is suggested to be compromised when high dose steroids is used.5
Acetazolamide (systemic carbonic anhydrase inhibitor) and mannitol (hyperosmotic agent) are effective in reducing intraocular pressure and benign intracranial hypertension but their use in reducing CSF pressure has not shown to be effective.4,5 In a randomized trial done investigating the use of acetazolamide in treating cryptococcal meningitis(n=22, starting dose of 250mg every 6 hour, adjusted accordingly), it was shown that acetazolamide is associated with more serious side effects including severe acidosis compared with treatment group with placebo.(p=0.04).24 This outcome, along with more serious hypokalaemia is proposed to be due to additive or synergistic toxicity effect with amphotericin B. Also, the effect of acetazolamide as an antisecretory may not be sufficient in reducing the intracranial pressure due to severe overflow obstruction of CSF drainage.24 The benefits of mannitol in treating cryptococcal meningitis in HIV patient is inconclusive from clinical evidence available.9,12,13
The cost for lumbar puncture is inexpensive compared to other more intensive treatments that will require special care unit settings. Life-saving surgical intervention such as shunt placement maybe beneficial but is expensive as general anaesthesia is involved. Overall cost is high as hospitalisation and professional skills is required for monitoring and intervention.12
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 weeks, followed by an 8-week consolidation therapy of fluconazole (400 mg/day). Subsequently, 200 mg/day of fluconazole should be continued as maintenance 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 weeks and is applied as treatment guideline in the USA and Europe.5
In a randomised controlled trial, patient receiving oral fluconazole 400 mg/day for 10 weeks (n=6) shows negative CSF cultures after 40.6±5.4 days, whereas those who received 0.7 mg/kg daily amphotericin B for a week and the three times daily for nine weeks with 150 mg/kg daily flucytosine (n=6) showed negative CSF cultures after 15.6±6.6 days. 25 The difference between this two treatment is statistically significant (p=0.02). This indicates that combination therapy of amphotericin B with flucytosine is superior and more clinically effective compared to using fluconazole alone in treatment of cryptococcal meningitis in AIDS patients.25 Another double-blind randomised trial showed that at a higher dose of amphotericin B (0.7mg/kg/day), with or without flucytosine, is associated with a reduced mortality rate. This higher dose resulted in a 50% of CSF sterilisation in two weeks without marked toxicity compared to a rate of 20% when a lower dose (0.4mg/kg/day) was used (p<0.001).18
In another study comparing the use of amphotericin alone and combined with flucytosine (n=50), the results showed that combination therapy given for 6 weeks cured more patient than amphotericin alone for 10 weeks (16 vs 11) with fewer relapses reported (3 vs 11), a higher CSF sterilisation rate (p<0.001) and less nephrotoxicity (p<0.05).26 In a randomised trial conducted investigating the effect of combination antifungal therapy, in treatment of cryptococcal meningitis in HIV patients (n=64), 0.7 mg/kg daily amphotericin B plus 100 mg/kg daily flucytosine showed the highest fungicidal activity compared to amphotericin B alone (p=0.0006); amphotericin B with 400 mg daily fluconazole (p=0.02); or triple therapy with amphotericin B, flucytosine and fluconazole (p=0.02).23
In a study done comparing the use of liposomal amphotericin B (AmBisome) and amphotericin B, sterilisation of CSF were achieved in 40% of patients treated with 4mg/kg daily AmBisome iv (n=15) and 8% for patients treated with amphotericin B 0.7/kg daily IV (n=12) in 7 days (p=0.09), and 66% versus 11% in 14 days (p=0.01).20 AmBisome is showed to have significantly reduced side effect compared to amphotericin B, with lower incidence of renal, hepatic or haematological toxicity.27 Mean increased in creatinine level were higher in patients treated with amphotericin B compared to those treated with AmBisome.28 The main disadvantage of AmBisome being its high cost. However, cost effectiveness of AmBisome can be justified as treatment period appeared to be shorter as duration of hospitalisation and infusion is reduced due to faster rate of CSF sterilisation. Also, lower toxicity rate is also beneficial in long term as less complication is likely to occur.20
In a randomised, double-blind, controlled clinical trial carried out investigating the effect of itraconazole and fluconazole as maintenance therapy in treating cryptococcal meningitis, HIV patients who achieved negative CSF culture after the acute infection were given either drugs at 200mg/d.11 In four months, 23% of patients receiving itraconazole (n= 57) had a relapse with positive CSF culture whereas only 4% of patient receiving fluconazole (n=51) had the same incident (p=0.006). One of the factors proposed is that itraconazole may be less active against C. neoformans in vivo, and plasma concentration of itraconazole appeared to be lower compared to fluconazole. The use of flucytosine during the first two weeks of treatment for the acute episode was associated with a lower risk of relapse regardless of the drug choice in maintenance therapy, suggesting a possible influence of initial treatment to subsequent disease management.11 Another double-blind randomised trial done in comparing the use of fluconazole and itraconazole in maintenance therapy, 72% of patients (n=151) given fluconazole achieve negative sterilisation of CSF in 10 weeks compared to 60% in patients receiving itraconazole. For patients who cannot tolerate fluconazole, itraconazole appeared to a very suitable alternative.18
Monitoring of intracranial pressure is important as this complication causes high mortality and morbidity in patients. In a study of HIV associated cryptococcal meningitis patients, 14% of death is suspected to be due to high pre-treatment intracranial pressure. As adverse effects and features of raised pressure may not be immediately apparent before the direct measurement, serious consequences and deaths occurred due to unrecognised raised pressure.13 Current practice guideline suggests that for patients with opening pressure of >250 mmH2O, brain scan should be carried out to rule out hydrocephalus and space-occupying lesion. Subsequently, daily lumbar punctures should be done to withdraw large volumes of CSF and achieve 50% reduction in initial opening pressure.5,12 In a study done by AIDS Clinical Trials Group, it is concluded that opening pressures of >250mmH2O should be treated with large-volume CSF drainage.13 Lumbar puncture demonstrated superior clinical efficacy compared to the use of non-invasive medical therapy using steroids, acetazolamide and mannitol. The use of this medical therapy is not supported by clinical evidence. Furthermore, the AIDS clinical trials showed that use of high doses of corticosteroids in treating high CSF pressure are associated with significantly higher mortality compared to patients with high CSF pressure but receive no steroids. Total of 41 patients were given steroids for all purpose including to suppress reaction to Amp B and to treat raised CSF, 20% died within two weeks of treatment, compared to 3% (n=13) who did not receive steroids (p<0.001). Four out of 13 patients (31%) with CSF pressure >350 mmH2O and given steroids died compared to 1 of 39 patient (3%) who did not receive steroid and had pressures >350 mmH2O (p=0.003).13 In 18 patients given dexamethasone or methylprednisolone for raised intracranial pressure, 9 patients had to receive extra lumbar punctures for CSF drainage.13
Based on evidences reviewed, I strongly recommend that this patient in the case scenario be started on the induction therapy (Amphotericin B, 0.7kg/mg daily; flucytosine, 100mg/kg daily) for 2 weeks, followed by consolidation therapy (fluconazole, 400mg/day) 8 weeks and subsequently, the maintenance therapy (fluconazole, 200mg/day) until immune system recovers. At the same time, intracranial pressure should be monitored at <250 mmH2O and lumbar puncture should be performed if CSF drainage is required. Also, renal profile should be monitored to detect possible nephrotoxicity due to amphotericin B.
After the acute episode, patient should be further monitored monthly to ensure that the infection is under control.12 CD4+ count should be done to determine the state of patient's immune function. With patient's compliance to the regimen and his progress being monitored, he should have a high chance of survival.