The treatment of HIV infection can be largely divided into specific antiviral agents that inhibit viral replication, measures that either treat or prevent (prophylaxis) its complications – namely opportunistic infections and tumours. Major advances in the treatment of HIV infection have occurred in the last few years. This has resulted in marked falls in the reported number of new AIDS cases and deaths in the developed world since 1996. Effective antiretroviral therapy regimens which substantially inhibit HIV replication and allow sustained improvements in the immune system are the main reason for this. There are currently three classes of antiretroviral agents: the nucleoside and non-nucleoside reverse transcriptase inhibitors and the protease inhibitors. Improved formulations and new drugs are continuously being evaluated and there is increasing interest in the possible role of immunotherapy combined with antiretroviral therapy to
improve specific immune responses. However, in those who are severely immunosuppressed the treatment and prophylaxis of opportunistic infections remains important. Though it cannot be overemphasised that the most effective way to prevent first episodes or recurrences of opportunistic infections is treatment with antiretroviral drugs. This chapter will cover both antiretroviral therapy and the treatments of the infections previously described in other parts of this book, in an attempt to bring all of these together in a
comprehensive manner.
Protozoal infections Pneumocystis carinii pneumonia (PCP) Although recently recognised as being more like a fungus, P. carinii is considered under protozoa here. Nowadays PCP most commonly occurs in those at risk who fail to take adequate prophylaxis or who are newly diagnosed with HIV infection in advanced disease where it is frequently the presenting illness. Clinical suspicion is aroused early in patients who are under regular medical supervision, leading to earlier diagnosis. Later diagnosis is asssociated with more severe disease and poorer treatment outcome. Techniques of diagnosis include sputum induction with nebulised saline; this obviates the need for bronchoscopy but the diagnostic sensitivity is lower. The use of lavage alone at bronchoscopy avoids transbronchial biopsy with its complications of haemorrhage and pneumothorax. Exercise oximetry and alternative imaging techniques with radiolabelled compounds are also being used in diagnosis. Monoclonal antibodies to pneumocystis proteins and sensitive DNA probes have been developed but have yet to reach the bedside. In the absence of a confirmatory test, a presumptive diagnosis may be made based on the clinical presentation and chest x ray appearances in a patient severely immunosuppressed and at risk.
High-dose intravenous co-trimoxazole for two to three weeks remains a standard first-choice regimen for severe PCP, but once fevers and symptoms have settled and blood gas values have improved the drug can be given by mouth. Side-effects are common, typically after 7–10 days. If co-trimoxazole treatment is not tolerated, alternative treatment regimens include either intravenous pentamidine or a combination of clindamycin and primaquine. Pentamidine is as effective as co-trimoxazole but has side-effects that can be life threatening and should be given by slow intravenous infusion with careful monitoring. In patients with moderate or mild PCP a combination of clindamycin and primaquine has proven clinical efficacy and is an alternative first choice for those patients who have a previous history of severe co-trimoxazole hypersensitivity. Side-effects of rash and diarrhoea are frequent. In patients presenting with severe hypoxaemia high-dose
adjunctive corticosteroid therapy is indicated and has been shown in clinical studies to reduce both mortality and morbidity Alternative second-line therapies include dapsone with trimethoprim, trimetrexate with folinic acid or Atovaquone, a hydroxy-naphthoquinone. The efficacy of atovaquone has only been established in mild to moderate P. carinii infection. Like trimetrexate it is probably less effective than co-trimoxazole but it is less toxic. New formulations have improved atovaquone’s bioavailability but it still should not be given to patients with malabsorbtion conditions, previous severe diarrhoea or those not taking oral nutrition. Due to acquired resistance, where possible atovaquone should not be given as single-agent therapy. It is commonly combined with intravenous pentamidine as an effective second-line treatment. Prophylaxis for PCP pneumonia is essential after a first attack (secondary prophylaxis) but is also recommended for all patients once their CD4 cell counts falls below 200106/l(primary prophylaxis). The risk of a first episode PCP below this CD4 count level in patients not on antiretroviral therapy is estimated to be 18% at 12 months for those who are asymptomatic, rising to 44% for those who have early symptomatic disease (for example, oral candida, fever). Cotrimoxazole 960 mg given by mouth daily or three times per
week is the most effective agent. In patients who are intolerant, alternative regimens include oral dapsone 100 mg with pyrimethamine 25 mg daily or three times per week, atovaquone 1500 mg daily or nebulised pentamidine. Dose of the latter depends on the nebuliser system: with a Respirgard II nebuliser the recommended regimen is 300 mg every four weeks. In patients with more advanced disease and CD4 counts less than 100106/l, 300 mg given every two weeks should be considered in view of the high failure rate of the monthly regimen.
Although clinical trials have shown greater efficacy for cotrimoxazole compared to other regimens, there is a high rate of discontinuation due to side-effects. Desensitisation regimens are used with the aim of reducing the rate of intolerance but there is uncertainty about their efficacy and which regimen is best. In patients responding to antiretroviral therapy, primary or secondary prophylaxis can be safely discontinued once the CD4 count has increased to levels persistently above 200106/l.
Toxoplasmosis
Cerebral toxoplasmosis is the commonest manifestation of toxoplasma infection. As toxoplasmosis is the most common cause of ring-enhancing lesions on contrast CT brain scans a presumptive diagnosis is usually made and treatment started. The condition responds well if treatment is started early, and a combination of sulphadiazine 4–6 g/day and pyrimethamine 50–100 mg a day (both by mouth in divided doses with folinic acid 15 mg daily) is the treatment of choice. Side-effects may prevent continued use of sulphadiazine, and clindamycin 600–1200 mg four times a day has been shown to be an effective alternative in controlled studies.
Corticosteroids are sometimes used in addition to first-line treatment to reduce symptomatic cerebral oedema, but a clinical and radiological response seen after two weeks of treatment may be due solely to the corticosteroid effect rather than the anti-toxoplasma treatment. A presumptive diagnosis of toxoplasma may therefore be made, although the underlying lesion may be due to something else, such as lymphoma or another infection. Relapse is common after treatment is stopped, and maintenance treatment is therefore necessary. In patients responding to antiretroviral therapy with sustained increases in CD4 count, discontinuation of prophylaxis is safe but there is limited current data to make definite recommendations.
Atovaquone 750 mg four times a day with or without pyrimethamine may be considered an alternative and the new macrolides clarithromycin 2 g daily and azithromycin, both given with pyrimethamine 75 mg/day, have also been effective in small uncontrolled studies. The most appropriate regimen for secondary prophylaxis has not been determined but treatment doses of either sulphadiazine and pyrimethamine or clindamycin and pyrimethamine are usually halved.
Of patients with positive toxoplasma serology and a CD4 count of less than 100106/l, approximately 1 in 3 will develop cerebral toxoplasmosis within 12 month without prophylaxis. Primary prophylaxis in patients with positive serology with a CD4 count of less than 100106/l is therefore recommended. Co-trimoxazole or dapsone with pyrimethamine have been shown to reduce the incidence of toxoplasmosis compared to patients taking nebulised pentamidine for
prophylaxis against PCP. Atovaquone with or without pryrimethamine may also be considered but this is based on more limited data. The macrolides clarithromycin and azithromycin might be anticipated to provide broad-spectrum prophylaxis for toxoplasmosis, atypical mycobacterial and bacterial infections, but bacterial resistance might limit their use in this situation.
Patients who are toxoplasma serology negative should be given advice to prevent exposure in primary infection with toxoplasmosis. They should be advised not to eat raw or undercooked meat and avoid directly handling cats’ faeces. Cryptosporidiosis and other protozoa In patients with less advanced HIV disease (CD4 counts >200 106/l) cryptosporridial infection usually causes a self-limiting gastrointestinal illness and symptomatic treatment with anti-diarrhoeal agents is all that maybe needed. In those with more severe immunosuppression and persistent symptoms treatment is more difficult and reported successes with a variety of agents are still anecdotal. Symptoms and excretion of cysts may be intermittent. Responses have been described after treatment with a variety of agents, including spiramycin, erythromycin, diclazuril, letrazuril, hyperimmune bovine colostrum, paromamycin, azithromycin and subcutaneous somatostatin.
Symptomatic treatment with antidiarrhoeal and antiemetic agents together with fluid, electrolyte and nutritional support should be provided. Case reports suggest that immune reconstitution is likely to result in improvement and resolution of both symptoms and infection. Thus in the absence of an effective specific treatment against cryptosporidium, infected patients should be started on antiretroviral therapy to increase the CD4 count.
Patients at risk of infection should be advised to avoid possible exposure in water supplies particularly at times of documented outbreaks. Although unproven, measures that may be considered for patients with CD4 counts less than 200106/l include using bottled water, point of use filters or boiling water for more than one minute.
For microsporidiosis there have been anecdotal reports of symptomatic improvement with albendazole 400 mg twice a day or metronidazole 500 mg three times a day. Isosporiasis is less common and appears to respond to cotrimoxazole 960 mg four times a day, but relapses occur in half of all cases.
Diarrhoea often occurs in the absence of recognised pathogens in the stool, and metronidazole has relieved symptoms in some cases.
Cerebral toxoplasmosis is the commonest manifestation of toxoplasma infection. As toxoplasmosis is the most common cause of ring-enhancing lesions on contrast CT brain scans a presumptive diagnosis is usually made and treatment started. The condition responds well if treatment is started early, and a combination of sulphadiazine 4–6 g/day and pyrimethamine 50–100 mg a day (both by mouth in divided doses with folinic acid 15 mg daily) is the treatment of choice. Side-effects may prevent continued use of sulphadiazine, and clindamycin 600–1200 mg four times a day has been shown to be an effective alternative in controlled studies.
Corticosteroids are sometimes used in addition to first-line treatment to reduce symptomatic cerebral oedema, but a clinical and radiological response seen after two weeks of treatment may be due solely to the corticosteroid effect rather than the anti-toxoplasma treatment. A presumptive diagnosis of toxoplasma may therefore be made, although the underlying lesion may be due to something else, such as lymphoma or another infection. Relapse is common after treatment is stopped, and maintenance treatment is therefore necessary. In patients responding to antiretroviral therapy with sustained increases in CD4 count, discontinuation of prophylaxis is safe but there is limited current data to make definite recommendations.
Atovaquone 750 mg four times a day with or without pyrimethamine may be considered an alternative and the new macrolides clarithromycin 2 g daily and azithromycin, both given with pyrimethamine 75 mg/day, have also been effective in small uncontrolled studies. The most appropriate regimen for secondary prophylaxis has not been determined but treatment doses of either sulphadiazine and pyrimethamine or clindamycin and pyrimethamine are usually halved.
Of patients with positive toxoplasma serology and a CD4 count of less than 100106/l, approximately 1 in 3 will develop cerebral toxoplasmosis within 12 month without prophylaxis. Primary prophylaxis in patients with positive serology with a CD4 count of less than 100106/l is therefore recommended. Co-trimoxazole or dapsone with pyrimethamine have been shown to reduce the incidence of toxoplasmosis compared to patients taking nebulised pentamidine for
prophylaxis against PCP. Atovaquone with or without pryrimethamine may also be considered but this is based on more limited data. The macrolides clarithromycin and azithromycin might be anticipated to provide broad-spectrum prophylaxis for toxoplasmosis, atypical mycobacterial and bacterial infections, but bacterial resistance might limit their use in this situation.
Patients who are toxoplasma serology negative should be given advice to prevent exposure in primary infection with toxoplasmosis. They should be advised not to eat raw or undercooked meat and avoid directly handling cats’ faeces. Cryptosporidiosis and other protozoa In patients with less advanced HIV disease (CD4 counts >200 106/l) cryptosporridial infection usually causes a self-limiting gastrointestinal illness and symptomatic treatment with anti-diarrhoeal agents is all that maybe needed. In those with more severe immunosuppression and persistent symptoms treatment is more difficult and reported successes with a variety of agents are still anecdotal. Symptoms and excretion of cysts may be intermittent. Responses have been described after treatment with a variety of agents, including spiramycin, erythromycin, diclazuril, letrazuril, hyperimmune bovine colostrum, paromamycin, azithromycin and subcutaneous somatostatin.
Symptomatic treatment with antidiarrhoeal and antiemetic agents together with fluid, electrolyte and nutritional support should be provided. Case reports suggest that immune reconstitution is likely to result in improvement and resolution of both symptoms and infection. Thus in the absence of an effective specific treatment against cryptosporidium, infected patients should be started on antiretroviral therapy to increase the CD4 count.
Patients at risk of infection should be advised to avoid possible exposure in water supplies particularly at times of documented outbreaks. Although unproven, measures that may be considered for patients with CD4 counts less than 200106/l include using bottled water, point of use filters or boiling water for more than one minute.
For microsporidiosis there have been anecdotal reports of symptomatic improvement with albendazole 400 mg twice a day or metronidazole 500 mg three times a day. Isosporiasis is less common and appears to respond to cotrimoxazole 960 mg four times a day, but relapses occur in half of all cases.
Diarrhoea often occurs in the absence of recognised pathogens in the stool, and metronidazole has relieved symptoms in some cases.
Viral infections
Severe mucocutaneous and systemic infections with herpes simplex virus are best treated with aciclovir. Prophylaxis is used after severe infection and in patients with increasing severity and frequency of recurrences. These recurrences can be a prelude to the chronic persistent mucocutaneous ulceration characteristic of AIDS.
Varicella zoster virus infections are usually treated with high-dose aciclovir given by mouth. However, dissemination of infection from dermatomal zoster is unusual even without treatment. Valaciclovir is a pro-drug of aciclovir which is used in the treatment of herpes zoster and herpes simplex infections of skin and mucous membranes. Valaciclovir is a L-valine ester of aciclovir that is rapidly converted to aciclovir after oral administration. The antiviral spectrum and mode of action is therefore the same as aciclovir. Aciclovir has, however, a low
oral bioavailability (about 15–20%). Valaciclovir has three or four times the oral bioavailability of aciclovir. Famciclovir is a diacetyl ester of 6-deoxy penciclovir which has been used in the treatment of herpes zoster and genital herpes infections. Famciclovir is metabolised to penciclovir in the intestinal wall and liver. Penciclovir and aciclovir have
similar antiviral spectrum.
Aciclovir resistant herpes simplex infections can occur, particularly in patients with advanced disease and severe immunosuppression. Alternative agents to treat resistant infections include foscarnet and cidofovir. Reactivation of cytomegalovirus with viraemia and endorgan
disease tends to occur when CD4 cell counts are persistently below 50 106/l. Ganciclovir (an acyclic analogue of deoxyguanosine), foscarnet phosphonoformate (a pyrophosphate analogue, which inhibits polymerase enzymes) and cidofovir (a nucleoside analogue with potent in vitro activity against viruses) are used for the treatment of cytomegalovirus retinopathy, gastrointestinal and neurological disease. Treatment arrests progression retinitis in most patients, and maintenance therapy is required in those patients who continue to be severely immunosuppressed to delay the time to further relapse. There is little comparative data to guide initial choice of treatment. A study comparing ganciclovir with foscarnet for treatment of CMV retinitis found no difference between the drugs in their ability to delay progression of disease, but there was a survival advantage in those patients treated with foscarnet. However, foscarnet is not as well tolerated as ganciclovir, as it produces reversible renal failure and electrolyte disturbances. Careful and frequent monitoring is required which complicates outpatient management. The major side-effect of ganciclovir is bone marrow suppression, particularly neuropenia. Support therapy with granulocyte colony simulating factor (GCSF) maybe required.
The detection of mutations in the CMV UL97 gene is associated with an increase in CMV DNA levels in blood and clinical progression of CMV retinitis during ganciclovir therapy. High-level resistance to ganciclovir results in cross-resistance to cidofovir. Resistance to foscarnet can occur but the mechanism is different.
Cidofovir has been shown to be effective however in delaying progression and time to relapse in patients who have experienced therapy failure on ganciclovir and foscarnet. The dosing schedule of cidovofir is convenient and more suitable to outpatient care than with either intravenous ganciclovir or foscarnet. It is given once weekly (5 mg/kg) for two weeks as induction therapy and then at the same dose every two weeks thereafter as maintenance therapy. The main side-effect is nephrotoxicity. The dose needs to be adjusted or treatment delayed or discontinued if there is evidence of renal tubular dysfunction, for example proteinuria, hypophosphataemia and impaired creatinine clearance. The choice of initial treatment is therefore dependent on the preferred dosing schedule, the risk of drug-associated toxicity and previous anti-CMV treatment history. Alternative treatment strategies include combination regimens of foscarnet and ganciclovir, intravitreal injections of ganciclovir or foscarnet and intraoccular implants of ganciclovir. The latter effectively prevents relapse in the treated eye for up to three months but there is an increased risk of early retinal detachment. There is a risk of CMV disease occurring in the contralateral eye or elsewhere, and thus concomitant oral ganciclovir is indicated.
Following induction therapy, secondary prophylaxis is required but can be safely discontinued without risk of relapse of retinopathy in patients who have responded to highly active antiretroviral therapy (HAART). Improved cytotoxic Tlymphocyte responses to CMV and suppression of CMV viraemia is seen in those patients with advanced disease who sustain a rise in CD4 count on HAART. Effective antiretroviral therapy has resulted in dramatic falls in the incidence of new episodes of CMV disease and of relapse. However, in patients who remain severely immunosuppressed and at risk of CMV disease and relapse, secondary prophylaxis is required. Daily intravenous foscarnet or ganciclovir regimens require an indwelling intravenous catheter which is inconvenient and complicated by the risk of bacterial infections. Either daily oral ganciclovir or two-weekly intravenous cidofovir are preferable. Although ganciclovir is poorly absorbed, the oral preparation at a daily dose of 3 g has similar efficacy to intravenous regimens in preventing progression of retinitis. Combinations of ganciclovir with greater oral bioavailability are under evaluation. Primary prophylaxis against CMV retinitis with oral ganciclovir has been investigated, but the results of two large clinical trials are conflicting, and in view of the high cost has not gained acceptance in routine clinical practice. Immune preservation or reconstitution as a result of HAART is the best prophylaxis (both primary and secondary) against CMV end-organ disease and other major opportunistic infections.
Severe mucocutaneous and systemic infections with herpes simplex virus are best treated with aciclovir. Prophylaxis is used after severe infection and in patients with increasing severity and frequency of recurrences. These recurrences can be a prelude to the chronic persistent mucocutaneous ulceration characteristic of AIDS. Varicella zoster virus infections are usually treated with high-dose aciclovir given by mouth. However, dissemination of infection from dermatomal zoster is unusual even without treatment. Valaciclovir is a pro-drug of aciclovir which is used in the treatment of herpes zoster and herpes simplex infections of skin and mucous membranes. Valaciclovir is a L-valine ester of aciclovir that is rapidly converted to aciclovir after oral administration. The antiviral spectrum and mode of action is therefore the same as aciclovir. Aciclovir has, however, a low
oral bioavailability (about 15–20%). Valaciclovir has three or four times the oral bioavailability of aciclovir. Famciclovir is a diacetyl ester of 6-deoxy penciclovir which has been used in the treatment of herpes zoster and genital herpes infections. Famciclovir is metabolised to penciclovir in the intestinal wall and liver. Penciclovir and aciclovir have
similar antiviral spectrum.
Aciclovir resistant herpes simplex infections can occur, particularly in patients with advanced disease and severe immunosuppression. Alternative agents to treat resistant infections include foscarnet and cidofovir. Reactivation of cytomegalovirus with viraemia and endorgan
disease tends to occur when CD4 cell counts are persistently below 50 106/l. Ganciclovir (an acyclic analogue of deoxyguanosine), foscarnet phosphonoformate (a pyrophosphate analogue, which inhibits polymerase enzymes) and cidofovir (a nucleoside analogue with potent in vitro activity against viruses) are used for the treatment of cytomegalovirus retinopathy, gastrointestinal and neurological disease. Treatment arrests progression retinitis in most patients, and maintenance therapy is required in those patients who continue to be severely immunosuppressed to delay the time to further relapse. There is little comparative data to guide initial choice of treatment. A study comparing ganciclovir with foscarnet for treatment of CMV retinitis found no difference between the drugs in their ability to delay progression of disease, but there was a survival advantage in those patients treated with foscarnet. However, foscarnet is not as well tolerated as ganciclovir, as it produces reversible renal failure and electrolyte disturbances. Careful and frequent monitoring is required which complicates outpatient management. The major side-effect of ganciclovir is bone marrow suppression, particularly neuropenia. Support therapy with granulocyte colony simulating factor (GCSF) maybe required.
The detection of mutations in the CMV UL97 gene is associated with an increase in CMV DNA levels in blood and clinical progression of CMV retinitis during ganciclovir therapy. High-level resistance to ganciclovir results in cross-resistance to cidofovir. Resistance to foscarnet can occur but the mechanism is different.
Cidofovir has been shown to be effective however in delaying progression and time to relapse in patients who have experienced therapy failure on ganciclovir and foscarnet. The dosing schedule of cidovofir is convenient and more suitable to outpatient care than with either intravenous ganciclovir or foscarnet. It is given once weekly (5 mg/kg) for two weeks as induction therapy and then at the same dose every two weeks thereafter as maintenance therapy. The main side-effect is nephrotoxicity. The dose needs to be adjusted or treatment delayed or discontinued if there is evidence of renal tubular dysfunction, for example proteinuria, hypophosphataemia and impaired creatinine clearance. The choice of initial treatment is therefore dependent on the preferred dosing schedule, the risk of drug-associated toxicity and previous anti-CMV treatment history. Alternative treatment strategies include combination regimens of foscarnet and ganciclovir, intravitreal injections of ganciclovir or foscarnet and intraoccular implants of ganciclovir. The latter effectively prevents relapse in the treated eye for up to three months but there is an increased risk of early retinal detachment. There is a risk of CMV disease occurring in the contralateral eye or elsewhere, and thus concomitant oral ganciclovir is indicated.
Following induction therapy, secondary prophylaxis is required but can be safely discontinued without risk of relapse of retinopathy in patients who have responded to highly active antiretroviral therapy (HAART). Improved cytotoxic Tlymphocyte responses to CMV and suppression of CMV viraemia is seen in those patients with advanced disease who sustain a rise in CD4 count on HAART. Effective antiretroviral therapy has resulted in dramatic falls in the incidence of new episodes of CMV disease and of relapse. However, in patients who remain severely immunosuppressed and at risk of CMV disease and relapse, secondary prophylaxis is required. Daily intravenous foscarnet or ganciclovir regimens require an indwelling intravenous catheter which is inconvenient and complicated by the risk of bacterial infections. Either daily oral ganciclovir or two-weekly intravenous cidofovir are preferable. Although ganciclovir is poorly absorbed, the oral preparation at a daily dose of 3 g has similar efficacy to intravenous regimens in preventing progression of retinitis. Combinations of ganciclovir with greater oral bioavailability are under evaluation. Primary prophylaxis against CMV retinitis with oral ganciclovir has been investigated, but the results of two large clinical trials are conflicting, and in view of the high cost has not gained acceptance in routine clinical practice. Immune preservation or reconstitution as a result of HAART is the best prophylaxis (both primary and secondary) against CMV end-organ disease and other major opportunistic infections.
Fungal infections
Dermatophytic fungal infections respond well to imidazole creams. Oral candida is often asymptomatic in its early stages and may not require treatment. In more severe infections local treatment with frequent nystatin suspension, or pastilles, or amphotericin lozenges can be used. Systemic treatment with oral ketoconazole or fluconazole daily is required for more severe oropharyngeal and oesophageal candidiasis. Long-term maintenance treatment may be required to prevent recurrences, and liver function tests should be monitored. Clinical resistance to treatment can occur and in the case of fluconazole may be related to emerging candida species that are less sensitive to fluconazole or to Candida albicans-resistant strains. Intermittent therapy rather than maintenance may be a more appropriate strategy to reduce this risk but has yet to be assessed in a large controlled trial. Itraconazole solution has been found to be useful in cases of clinical resistance and this may be related to its topical action, better absorption and greater spectrum of activity.
Vulvovaginal candidiasis can be a recurrent problem in women and should be treated either with topical agents (clotrimazole or miconazole pessaries and cream) or single high dose fluconazole.
Cryptococcal meningitis is treated with either fluconazole or amphotericin B with or without flucytosine. A large comparative study has shown that the overall mortality was similar in both treatment groups. However, there were more early deaths in the fluconazole group, and amphotericin sterilised the cerebrospinal fluid more rapidly but fluconazole was better tolerated. There was a 20% mortality and the factors predictive of death were an abnormal mental state, a cryptococcal antigen titre above 1 024 and a white cell count below 0.02 10 9/l in the cerebrospinal fluid. Physicians will probably therefore prefer to treat patients with these poor prognostic markers with amphotericin rather than fluconazole. With a 20% mortality irrespective of what treatment is used it is clear that improvements in treatment are required. Maintenance treatment is required in those who remain severely immunosuppressed, as replase is common. Fluconazole (200 mg/day) was more effective than amphotericin B (1 mg/kg/week) in a large randomised study. The comparative efficacy of higher doses of amphotericin maintenance treatment is unknown. Liposomal preparations of amphotericin B may be useful, particularly in patients at risk of renal toxicity. Controlled studies of high doses of fluconazole suggest greater efficacy. As with other severe opportunistic infections, immune reconstitution following HAART will allow safe discontinuation of secondary prophylaxis regimens. Amphotericin B is still the mainstay of treatment of other systemic fungal infections. Itraconazole has shown to be effective in induction and maintenance treatment of disseminated histoplasmosis.
Bacterial infections Tuberculosis in HIV infection is treated in the standard way with isoniazid and rifampicin plus either pyrazinamide or
ethambutol. Rifampicin is a potent enzyme inducer and increases the metabolism of drugs such as oral contraceptives, dapsone, fluconazole, ketoconazole and anticonvulsants. Clinicians should also be aware of drug interactions between rifamycins (rifampicin and rifabutin) and antiretroviral drugs, particularly the protease inhibitors (Pls) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Certain combinations of each are contraindicated or require dose adjustment to
Dermatophytic fungal infections respond well to imidazole creams. Oral candida is often asymptomatic in its early stages and may not require treatment. In more severe infections local treatment with frequent nystatin suspension, or pastilles, or amphotericin lozenges can be used. Systemic treatment with oral ketoconazole or fluconazole daily is required for more severe oropharyngeal and oesophageal candidiasis. Long-term maintenance treatment may be required to prevent recurrences, and liver function tests should be monitored. Clinical resistance to treatment can occur and in the case of fluconazole may be related to emerging candida species that are less sensitive to fluconazole or to Candida albicans-resistant strains. Intermittent therapy rather than maintenance may be a more appropriate strategy to reduce this risk but has yet to be assessed in a large controlled trial. Itraconazole solution has been found to be useful in cases of clinical resistance and this may be related to its topical action, better absorption and greater spectrum of activity. Vulvovaginal candidiasis can be a recurrent problem in women and should be treated either with topical agents (clotrimazole or miconazole pessaries and cream) or single high dose fluconazole.
Cryptococcal meningitis is treated with either fluconazole or amphotericin B with or without flucytosine. A large comparative study has shown that the overall mortality was similar in both treatment groups. However, there were more early deaths in the fluconazole group, and amphotericin sterilised the cerebrospinal fluid more rapidly but fluconazole was better tolerated. There was a 20% mortality and the factors predictive of death were an abnormal mental state, a cryptococcal antigen titre above 1 024 and a white cell count below 0.02 10 9/l in the cerebrospinal fluid. Physicians will probably therefore prefer to treat patients with these poor prognostic markers with amphotericin rather than fluconazole. With a 20% mortality irrespective of what treatment is used it is clear that improvements in treatment are required. Maintenance treatment is required in those who remain severely immunosuppressed, as replase is common. Fluconazole (200 mg/day) was more effective than amphotericin B (1 mg/kg/week) in a large randomised study. The comparative efficacy of higher doses of amphotericin maintenance treatment is unknown. Liposomal preparations of amphotericin B may be useful, particularly in patients at risk of renal toxicity. Controlled studies of high doses of fluconazole suggest greater efficacy. As with other severe opportunistic infections, immune reconstitution following HAART will allow safe discontinuation of secondary prophylaxis regimens. Amphotericin B is still the mainstay of treatment of other systemic fungal infections. Itraconazole has shown to be effective in induction and maintenance treatment of disseminated histoplasmosis.
Bacterial infections Tuberculosis in HIV infection is treated in the standard way with isoniazid and rifampicin plus either pyrazinamide or
ethambutol. Rifampicin is a potent enzyme inducer and increases the metabolism of drugs such as oral contraceptives, dapsone, fluconazole, ketoconazole and anticonvulsants. Clinicians should also be aware of drug interactions between rifamycins (rifampicin and rifabutin) and antiretroviral drugs, particularly the protease inhibitors (Pls) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Certain combinations of each are contraindicated or require dose adjustment to
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