• CD4 counts are performed every 3 months in asymptomatic patients (Box 3.1), but more frequently if unexpected changes are seen in either the clinical state or the viral load of the patient.

The viral load

Transitory changes in the viral load occur with intercurrent infection and vaccination. Thus treatment decisions should never be made on a one-off aberrant viral load reading without other clinical or laboratory evidence to support its validity.

A number of assays are available, the commonest being the reverse transcription polymerase chain reaction (RT-PCR). The most sensitive test is able to detect 20 copies of viral RNA/mL.

• The viral load is an independent indicator of disease progression, i.e. the higher the viral load, the more likely the patient is going to progress to severe immunosuppression and AIDS.

• It can also be used as a marker of treatment success. HIV can only develop resistance if it is allowed to replicate actively whilst in the presence of the drug. Successful treatment is dependent on the prevention of resistant strains emerging. An aim of treatment is to reduce the viral load to below the level of detection within 3 months. Persistently detectable viral loads indicate ongoing viral replication and correlate with the development of resistance and treatment failure; they would usually warrant a change in the management of the patient. Thus, the viral load is used to assess:

• the rate of immune decline in those patients ‘off’ treatment

• treatment success in those patients on treatment. Measurements should be done every 3 months in asymptomatic patients, but more frequently if unexpected changes are seen in the clinical state or CD4 count.

Genotyping

• Genotype variations within HIV exist between viral subtypes and also point mutations associated with retroviral drug usage.

• Phenotype variations give an indication of possible drug resistance, although they do not detect low levels of resistant viruses (< 20% of viral populations).

• In the absence of medication, the dominant viral species will revert back to wild type relatively quickly.

• Delay in resistance testing once medication is stopped can lead to missing resistant mutants in a patient failing a drug regimen.

• Transmission of the drug-resistant virus can occur, accounting for poor response to first-line therapy.

Thus all newly diagnosed patients should be tested for resistance, and lack of a significant fall in the viral load by 4–8 weeks requires further testing to look for minority viral species not evident at the time of initiation of therapy.

Phenotyping

This is also used to detect resistance. HIV replication in vitro in the presence of anti-retrovirals (ARVs) is tested. However, assays are complex and not widely available.

highly active anti-retroviral therapy (haart)

In order to be successful, anti-retroviral treatment has to prevent the emergence of resistant strains of virus within the patient. Because of the error-prone nature of viral reverse transcriptase, mutations arise with the ongoing viral life cycle. Reduction of this viral proliferation rate to as low as possible prevents the development of these mutations. Treatment with one or two anti-retroviral medications in the majority of patients is insufficient to reduce this rate to levels that would prevent the emergence of resistance. It is only with the use of at least three agents that the rate of viral cycling is reduced to preventative levels. Alongside viral suppression, immune reconstitution can occur, which can be monitored by rising CD4 count.

Available anti-retroviral medications, along with their side-effects, are shown in Table 3.1.

Table 3.1 Anti-retroviral drugs available in the UK

Available drugs

Nucleoside reverse transcriptase inhibitors (NRTIs)

• Zidovudine (AZT), when used as monotherapy, leads to resistant mutations appearing within the reverse transcriptase gene in months. A combined formulation with lamivudine (3TC), i.e. Combivir (AZT/3TC) has proven popular due to the decreased pill burden. Cross-resistance with other drugs in this class is a problem. Switching AZT to abacavir can reduce the rate of fat loss. The drug should not be used with D4T, as they antagonize each other’s effects. Bone marrow toxic effects can be increased by probenecid, ganciclovir, doxorubicin, co-trimoxazole, pyrimethamine and sulfadiazine.

• Stavudine (D4T) is a thymidine analogue like zidovudine. Its major problems with lipodystrophy and peripheral neuropathy have led to it becoming obsolete but it is still used in some countries. Specific mutations in the reverse transcriptase gene can confer cross-resistance between this drug and lamivudine (3TC), emtricitabine (FTC) and abacavir (ABC). Antagonistic interactions between AZT and D4T occur. Co-prescribing with other medications that are particularly neurotoxic is not advised.

• Abacavir (ABC) is a guanosine analogue that has a good side-effect profile in the majority of patients and crosses the blood–brain barrier. It is available in two combination pills: one as a triple combination with AZT and 3TC, and one as a combination with 3TC. It can be used once daily with 3TC. The triple nucleotide regime alone is now not recommended, as studies have called into doubt its effectiveness when compared with other NNRTI- or PI-based regimes. Hypersensitivity reactions are a major problem. If two differing hypersensitivity symptoms occur, stop the medication. In most cases, once stopped, the medication must never be restarted. In patients whose prescription for abacavir has been stopped for another reason, restarting the medication should be done with regular monitoring. Viral resistance to ABC occurs in a stepwise fashion, and the appearance of mutants with low-level resistance does not impede the drug’s efficacy. However, with the appearance of large numbers of AZT-associated mutations in the reverse transcriptase gene, the drug significantly loses potency.

• Lamivudine (3TC) is a popular cytosine analogue that is effective when used as part of an NNRTI- or PI-based combination regime. It can be given once daily. In general, the drug is well tolerated. Resistance to this medication develops rapidly, the commonest reverse transcriptase mutation occurring at codon 184 (M184V/I). This drug, as well as FTC, is effective in the treatment of hepatitis B.

• Didanosine (DDI) is effective as part of a combination regime in the treatment of HIV, and is available in once-daily or twice-daily formulations. Strict dietary restrictions (it must be taken 2 hours before or after food on an empty stomach) in its administration have clouded its common use (Table 3.1). The enteric-coated form is taken once daily but still has to be taken at least 2 hours before or 2 hours after any oral intake other than water. Given the number of other HIV medications that are recommended to be taken with food, this complicates the dosing regimen. The formulation contains calcium and magnesium antacids. There is evidence of cross-resistance with other NRTIs. It interacts with tenofovir, causing decreased levels of both.

• Emtricitabine (FTC) is a cytosine analogue that is active against both hepatitis B and HIV, though it is not currently recommended for the treatment of hepatitis B. It is available in a once-daily formulation and in a combination formulation with tenofovir. FTC has been compared with D4T and 3TC, and shows equivalence or improvement over the more established therapies. No studies have looked at possible interactions between FTC and other cytosine analogues (DDC and 3TC). However, with the evidence of competition between D4T and AZT, it is not recommended that they be co-prescribed. The mutation at codon 184 (M184V/I) of the reverse transcriptase gene that confers resistance to 3TC also confers resistance to FTC. The virus strains carrying this mutation are more susceptible to AZT.

Nucleotide reverse transcriptase inhibitors

• Tenofovir (TFV). Nucleoside analogues have to be intracellularly phosphorylated to become the active form of the drug — a nucleotide. Tenofovir is already in the phosphorylated form and is equivalent to other NRTIs. Tenofovir can be used as a switch medication for those patients experiencing lipid abnormalities with stavudine (D4T). It should not be used with DDI, as a fall in CD4 count can occur. Tenofovir has activity against hepatitis B and is first-line therapy in co-infected (HIV and HBV) patients, alongside 3TC. Renal dysfunction, most commonly a proximal renal tubular defect seen with the Fanconi syndrome, requires monitoring. Mutation at codon 64 of the reverse transcriptase gene (also seen with ABC) can confer resistance. The M184V/I mutation, as with AZT, can confer some increased susceptibility to this medication. Cross-resistance can occur between tenofovir and AZT or D4T. Despite this, the risk of cross-resistance with other NRTIs is relatively low. Interactions also occur between tenofovir and atazanavir or lopinavir. There is no evidence of interactions with methadone, anti-TB medication, 3TC, efavirenz and the oral contraceptive pill.

Non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs)

• Efavirenz (EFV) has proven efficacy as a first-line agent when combined with two NRTIs (not used in pregnancy). A previous psychiatric history should be taken into account in view of the dysphoria that can occur with this drug. Most side-effects will present themselves shortly after treatment is started. Liver dysfunction occurs and is more common in patients co-infected with hepatitis viruses, as efavirenz is an inducer of liver cytochrome p. 450 3A4 enzyme. Rash is common but rarely severe. Efavirenz is currently not recommended for use in women considering pregnancy. Both efavirenz and nevirapine have long half-lives.

• Nevirapine (NEV) can be as effective as PIs when combined with two NRTIs. Nevirapine, alongside AZT, has the best CNS penetration of the currently used medications. Nevirapine is taken as two tablets, which can be taken together or as a split dose. It has a low genetic barrier to resistance, and mutations at codons 103, 181, 190 and 188 of the viral reverse transcriptase gene are associated with resistance to both efavirenz and nevirapine. Like efavirenz, it has a long half-life. The common side-effects include a rash that can vary from mild and self-limiting (for 2–4 weeks) to more severe, requiring the medication to be stopped. Starting the medication at a low dose and then gradually increasing it reduces the incidence of the milder rash. Abacavir and nevirapine should not be started at the same time, as distinguishing the cause of a hypersensitivity reaction can be difficult. Liver toxicity is a serious side-effect associated with nevirapine, and has both genetic and environmental risk factors. Nevirapine is not recommended in men with CD4 counts > 400, women with CD4 counts > 250, or in patients with hepatitis virus co-infection. It is a potent inducer of the cytochrome p. 450 3A4 enzyme, and hence has many drug interactions.

• Etravirine is a drug that has recently become available; it has activity against virus resistant to other NNRTIs. It has a unique molecular flexibility, thought to account for its greater barrier to the development of resistant virus. Severe rashes have been reported as a side-effect.

Protease inhibitors (PIs)

PIs block the action of the viral protease, which cleaves large viral polypeptide chains into functioning proteins. The functioning viral protease, integrase, and reverse transcriptase enzymes are all products of protease activity. Viral protease has a fold in its quaternary structure that the inhibitors fit into, altering the protease’s catalytic activity. Mutations in the amino acids that make up the fold can impair the association of the drug with the fold and consequently lead to resistance. New virus particles can be assembled in the presence of PI medication, but these are non-infectious and hence the viral life cycle is interrupted.

• Ritonavir (RIT) is often prescribed specifically for its ability to boost the levels of another co-administered PI. It is a liver and gut enzyme inhibitor and can therefore increase the levels of other PIs and their half-life. By doing this, it can improve the side-effect profiles and dosing requirements of other PIs. It does not cross the blood–brain barrier. It can only be stored for 1 month at room temperature; thus the patient has to keep stocks refrigerated. The side-effects are one of the chief reasons why this drug is now rarely prescribed as the sole PI, but are less of a problem with the low-dose boosting regimen. As with the other PIs, there is cross-resistance of varying degrees across the whole class. In cases of ritonavir resistance the virus is almost always resistant to indinavir, and to a lesser extent nelfinavir and saquinavir. Ritonavir is a potent liver enzyme inhibitor and thus interacts with a number of other medications, potentially raising their levels dangerously.

• Lopinavir (LPV), combined with appropriate NRTIs, is the first-line PI agent of choice. Its use in naïve (previously untreated with lopinavir) patients enables individuals to have fully suppressed viral loads at 6 years after the initiation of therapy. Lopinavir is co-formulated with ritonavir, another PI. Ritonavir is a potent inhibitor of the liver enzyme that metabolizes lopinavir, and thus potentiates its action. Lopinavir can be effective in patients who have previously been given PIs, even in the presence of small numbers of PI resistance-conferring mutations. As with other members of this class, body fat changes associated with blood dyslipidaemia can occur. Mutations in the viral protease gene can confer resistance to all drugs in this class. Lopinavir has a high genetic barrier to resistance and a number of these mutations appear to be necessary before phenotypic resistance emerges.

• Fosamprenavir/amprenavir (AMP) is inferior to other PIs in treatment-naïve patients and is not recommended for use in this group of patients. This may be due to poor adherence secondary to a large and difficult pill burden (eight very large tablets a day) and side-effects. Ritonavir-boosted amprenavir is effective in patients who have resistance to nelfinavir, indinavir, ritonavir and saquinavir, and consequently it has a role in patients who have virologically failed therapy. Fosamprenavir is a prodrug of amprenavir, which in trial data has demonstrated equivalence with other PIs in treatment naïve patients. It has been put forward as an alternative to lopinavir in treatment-naïve patients because of the low incidence of PI cross-resistance in patients who fail fosamprenavir treatment; this allows other PIs to be held for effective second-line therapy. It is a sulphonamide and therefore a history of previous allergic reactions to sulphonamides makes them at risk of further reaction.

• Indinavir (IND) in combination is able to sustain a reduction in the viral load below the level of detection. Indinavir by itself requires relatively strict dietary requirements and three times a day dosing. For these reasons, together with the implications for adherence, indinavir is now usually prescribed as part of a ritonavir-boosted regimen. Resistance can occur rapidly if dosing is suboptimal. The appearance of four or more mutations in the susceptible codons of the protease gene can confer high-level resistance. Indinavir is metabolized by the liver and thus interacts with other liver enzyme inhibitors and inducers.

• Atazanavir (ATZ) is only recommended for use in treatment-experienced patients. It is as effective in first-line therapy as efavirenz and nelfinavir in some studies. It is the only PI currently available that is suitable for once-daily dosing. Haematuria has been reported in patients taking this drug. It appears that atazanavir-treated patients have less harmful lipid changes than those treated with other PIs such as efavirenz. There is also evidence of an improvement in lipodystrophy upon switching from another regimen. Like other PIs, atazanavir is a p. 450 3A4 inhibitor and consequently has a wide range of interactions. Atazanavir resistance emerges with increasing numbers of mutations in the viral protease gene. An interesting mutation at codon 150 of the viral protease gene confers resistance to atazanavir but increases sensitivity to other PIs. Hyperbilirubinaemia is a frequent side-effect but is not associated with liver enzyme changes and rarely causes cessation of treatment.

• Saquinavir (SAQ) has a long record of effectiveness in the treatment of HIV. Hard gel saquinavir is nearly always prescribed as a combination with ritonavir. To prevent problems with adherence, medicines that symptomatically treat these side-effects can be given prior to the prescription. As with other drugs of this class, treatment is associated with lipodystrophy. Resistance is associated with mutations at codons 48 and 90 of the protease gene. Saquinavir inhibits not only cytochrome p. 450 3A4, but also P-glycoprotein, and consequently interacts with a number of other drugs.

• Tipranavir (TPR) is a non-peptidic PI, which inhibits the protease enzyme. Due to its different chemical structure, viral strains resistant to other PIs are sensitive to tipranavir. It is used in treatment-experienced patients, with favourable results. In combination with the fusion inhibitor, T20, results are even more promising. No data are available yet on this drug’s use in treatment-naïve patients. Rash is potentially worse with the oral contraceptive pill. Tipranavir was developed with a view to treating patients with cross-class resistance to PIs. For resistance to develop, a number of mutations must occur in the protease gene. The codons at which these occur differ from the ones that confer cross-class resistance.

• Darunavir is a boosted PI that received approval for use in treatment-experienced patients in 2008 and approval for use in treatment-naïve patients in 2009. Studies have shown favourable results compared to lopinavir. Mild to moderate rash is seen in some patients; other side-effects reported include diarrhoea, headache, vomiting, abdominal pain and constipation. Reported drug interactions include atorvastatin, pravastatin, rifabutin, saquinavir, lopinavir and maraviroc.

Integrase inhibitors

• Raltegravir is a selective inhibitor of HIV integrase, which blocks viral replication by preventing the insertion of HIV DNA into the human DNA genome. It is only used in patients who are resistant to many anti-retrovirals.

Fusion inhibitors

Two glycoproteins on the surface of HIV (gp120 and gp41) are used to engage and bind to the host T-cells. Engagement of gp120 with CD4 exposes the hydrophobic tip of gp41, which dives straight to the nearest hydrophobic environment, the host T-cell’s bilipid membrane.

• Enfuvirtide works by binding to gp41 and preventing the fusion of HIV’s viral envelope with the host T-cell. Its use is in patients who have failed a number of other regimens. It is the only HIV drug that has to be taken subcutaneously and injections have to be prepared daily. A needle-free method of delivery has been developed using a carbon dioxide-powered jet, with fewer incidences of injection site reactions. Injection site reactions are currently the most common side-effects (95%). These vary between an itchy rash, red, swollen or puffy skin, hardened skin or injection site cysts or nodules. Other reported effects include bacterial pneumonia, headache, insomnia, neuropathy and eosinophilia. No interactions between T-20 and other drugs have been noted so far. Resistance mutations to T-20 can occur rapidly, in the gene encoding viral gp41. However, there is good evidence that resistance to other classes of drugs does not leave patients resistant to T-20.

Co-receptor blockers

• Maraviroc, a chemokine receptor antagonist, blocks the cellular CCR5 receptor entry by CCR5 trophic strains of HIV. It is used with other anti-retrovirals in patients previously treated. Its use is hampered by the need for a phenotypic test of viral tropism prior to use.

Indications for anti-retroviral therapy

Symptomatic HIV infection

• In individuals with evidence of a disease related to immunosuppression, treatment should be initiated irrespective of the CD4 count and viral load.

• TB, though being an AIDS-defining illness, is not strictly an opportunistic infection, as immunocompetent patients can have the disease. Hence there is debate as to whether pulmonary TB infection in the context of HIV is an absolute indication for the initiation of therapy in the absence of evidence of other immunosuppression.

Asymptomatic HIV infection

• CD4 count < 200 at diagnosis. Start treatment immediately. This is the level often used in countries with poor resources and inadequate HAART supplies.

• CD4 counts < 350. Start treatment when the patient is ready, and certainly no later than CD4 < 200.

• Asymptomatic patients with CD4 counts > 500 with a low CD4 percentage, hepatitis B/C or cardiovascular risk. Special consideration is necessary and treatment may be indicated.

Currently, there is little evidence that treatment during primary infection of HIV alters the natural course of the disease. However, there is evidence that treatment during primary infection can preserve anti-HIV-specific CD4 responses, which are usually lost early in the disease. It is therefore recommended that patients be offered entry into a clinical trial of treatment.

Starting therapy

There is a wide range of drugs available for the treatment of HIV. Standard therapy is two NRTIs, e.g. tenofovir and emtricitabine, combined with either a ritonavir-boosted PI, e.g. lopinavir, or an NNRTI, e.g. efavirenz, except in women wishing to become pregnant. The choice between the two is debatable. The lower resistance of NNRTIs to mutation is used as an argument for their use as first-line therapy, in that they are less likely to be successful when used as a second-line agent.

Other options include boosted saquinavir– and boosted fosamprenavir-based regimes. Evidence is not sufficient for the use of boosted atazanavir in naïve patients.

• Changing therapy because of virologic failure. Patients should be considered for a change in therapy if their viral load rises to > 400 copies/mL on two separate occasions at least 1 month apart. A resistance test should be carried out, and assessment made of potential causes such as poor adherence, drug interactions and side-effects. The new regimen should contain at least three drugs that resistance testing and past history suggest would have antiviral activity in vivo. In patients with evidence of multiple multi-class drug resistance, the aim of treatment shifts from maintaining an undetectable viral load to one of preserving immunological function. In patients with stable CD4 counts (50–100), delaying new combinations containing just one new drug to a time when more drugs may become available is also advised.

• Structured treatment interruptions. These were tried but recent data suggest that patients do less well than on conventional therapy.

Adherence

For treatment to be effective the patient must adhere to the required dosing schedules and dietary requirements for anti-retroviral medication. Levels of adherence below 95% have been associated with poor responses and the emergence of resistant virus. Greater understanding of factors that can improve adherence is required.

• Patient factors include

• An understanding of living with HIV, and optimizing motivation and commitment to maintain this.

• Social and behavioural factors that may impact upon an individual’s adherence to difficult medication regimes.

• Mental health illness, which needs to be treated effectively.

• Regime factors include

• Noting individual patient preferences for regimen characteristics, such as pill burden, pill size, dosing frequency and dietary requirements.

• Informing patients of likely toxicities and encouraging them to report these to the clinician.

• Noting potential drug interactions and making necessary dose adjustments.

The clinician should be aware of the full range of support services that can help with these factors.

Adherence should be monitored regularly in the clinic and recorded in the notes. The management of any failing therapy must include a comprehensive review to assess whether poor adherence has led to the problem, and ways in which this can be avoided in the future.

Choice of drugs (Table 3.1)

The drug regimen used for starting therapy must be individualized to suit each patient’s needs.

• Nucleoside reverse transcription inhibitor (NRTI). The combination of two NRTIs to form a backbone to the treatment is increasingly influenced by both efficacy and ease of administration. The availability of the once-daily, one-tablet, fixed-dose combinations, Truvada (TFV/FTC) and Kivexa (ABC/3TC), has led to the majority of patients who are naïve to medication being prescribed one of these as their 2NRTI backbone. Combivir (AZT/3TC), with a twice-daily dosing schedule and poorer toxicity profile, is less frequently prescribed.

• Non-nucleoside reverse transcriptase inhibitor (NNRTI). The decision about use of an NNRTI or a boosted PI will depend on the particular circumstances of each patient but, following clinical trial data, an NNRTI-based regimen is most commonly prescribed to treatment-naïve patients.

• Efavirenz is frequently used, having demonstrated good durability over time, and potency at low CD4 counts and in high viral loads. It has the advantage of once-daily dosing but is associated with CNS side-effects (Table 3.1) and is contraindicated in pregnancy. A fixed-dose preparation of efavirenz co-formulated with Truvada (Atripla) allows for a ‘one pill once a day’ regimen.

• Nevirapine is of equivalent potency to efavirenz but has a higher incidence of hepatotoxicity and rash and is taken twice daily. Toxicity is greater in women and in those with higher CD4 counts. It is contraindicated in women with CD4 counts > 250 cells and in men with counts > 400. However, it a useful alternative to efavirenz if CNS side-effects are troublesome and in women with lower CD4 counts who wish to conceive.

• Etravirine is a second-generation NNRTI, active against drug-resistant strains and useful in treatment-experienced patients.

• Protease inhibitor (PI). This class of drugs has demonstrated excellent efficacy in clinical practice. A PI combined with a low dose of ritonavir (a boosting PI) provides a pharmacokinetic advantage and is now most commonly used in naïve patients. When this approach is used, the half-life of the active drug is increased, allowing greater drug exposure, fewer pills with enhanced potency and minimized risk of resistance. The disadvantage is a possible risk of greater lipid abnormalities, particularly raised fasting triglycerides. Darunavir/ritonavir, lopinavir/ritonavir and fosamprenavir/ritonavir (all taken twice daily) are recommended for first-line therapy, with saquinavir/ritonavir as an alternative. All three regimens commonly cause gastrointestinal disturbance and lipid abnormalities. Atazanavir/ritonavir is a once-daily regimen.

Currently, treatment-naïve patients should be treated with two NRTIs, with either an NNRTI or a PI. Despite interest in the use of PI monotherapy in some situations, the current data do not support its use in treatment-naïve patients.

Opportunistic infection in the haart era

Fungal infection

Candidiasis

Candidiasis is caused by infection with various Candida species, the commonest being C. albicans. Genital infection is frequently seen in the immunocompetent population, but in immunosuppressed individuals, oral candidiasis appears, with removable white plaques or even erythematous patches. Oesophageal disease produces pain and difficulty with swallowing, and indicates severe immunosuppression. Cerebral and pulmonary disease also occurs.

• Diagnosis is confirmed by tissue samples, but often is retrospective following a good response to a trial of treatment.

Treatment

• Skin infection can be treated with creams such as clotrimazole.

• Oral disease can be treated with nystatin pastilles or fluconazole oral solution. In more severe oral and oesophageal disease, systemic treatment is warranted with fluconazole 50–200 mg daily for 7 days or itraconazole 200–400 mg for 7–14 days.

• Systemic infections can be treated with liposomal amphotericin B when very severe.

Cryptococcosis

Cryptococcosis is caused by infection with the yeast-like fungus, Cryptococcus neoformans. Patients are at risk when their CD4 counts fall < 100. Cryptococcosis presents with meningism, neurological dysfunction and sometimes pulmonary symptoms.

• Diagnosis is confirmed by the presence of organisms seen with India ink stain or the detection of the cryptococcal antigen within blood or CSF. Patients can develop extremely high CSF pressures, and may need repeated lumbar puncture or even insertion of a ventro-peritoneal shunt.

• Treatment is divided into ‘induction’ and ‘maintenance’ phases.

• Induction is usually with liposomal amphotericin B 3 mg/kg IV daily. There is some evidence that the addition of flucytosine 100 mg/kg/day in 4 divided doses can be helpful in resistant cases.

• Maintenance is with oral fluconazole 400 mg daily, which can be stopped if a sustained immune recovery is seen following the initiation of HAART.

Aspergillosis

Infection occurs with a neutropenia, CD4 count < 50 mm³, use of steroids and previous Pneumocystis infection. It presents with fever, dry cough and breathlessness. Extrapulmonary disease can occur in skin, brain, spleen, liver, heart and pancreas. Aspergillus species can often be found asymptomatically in the lung, and diagnosis is by demonstration of invasive infiltration within the lung or by detection of the organism in an atypical site.

• Treatment is with voriconazole 400 mg twice daily for 2 doses, followed by 200 mg twice daily. Amphotericin is an alternative.

Histoplasmosis

Histoplasmosis is usually caused by Histoplasma capsulatum, and leads to fever, weight loss, shortness of breath and skin lesions. Hepatosplenomegaly, neurological dysfunction, lymphadenopathy and bone marrow suppression occur.

• Diagnosis can be confirmed by growing samples from affected sites. A urine antigen test is available.

• Treatment is initially with an induction phase of amphotericin B 1–3 mg/kg daily IV or itraconazole 200 mg twice daily for 2 days, then 200 mg daily for a maximum of 12 days, followed by a maintenance phase also using itraconazole 200 mg daily.

Pneumocystis infection

Infection is caused by P. jiroveci, an atypical fungus. It is found in patients with CD4 counts < 200. Patients complain of shortness of breath on exertion, fever, dry cough, weight loss, malaise and chest pain or tightness. Oxygen desaturation can be demonstrated on exercise. All patients need ABG measurement. Treatment can be started presumptively in patients with risk factors.

• Diagnosis should then be confirmed by demonstration of the organism, obtained from either induced sputum or bronchoalveolar lavage. A CT scan shows a bilateral ground-glass appearance in the lung fields, indicating an alveolitis.

• Primary prophylaxis has a proven role for the prevention of this condition in patients with CD4 counts < 200. Oral co-trimoxazole 960 mg daily oral or 960 mg oral 3 times weekly is usually used. If this is not tolerated, aerosoled pentamidine 300 mg nebulized every 3–4 weeks, dapsone 50–100 mg daily oral or atovaquone 750 mg oral twice daily may be used. Primary or secondary prophylaxis can be stopped if a CD4 count > 250 is achieved with HAART and then maintained.

• Treatment for primary infection is with co-trimoxazole 120 mg/kg IV or oral in 2–4 divided doses for 14–21 days. Other options include pentamidine 4 mg/kg IV infusion for 14 days or (for mild disease) 600 mg inhaled for 3 weeks, atovaquone 750 mg twice daily oral, and dapsone and trimethoprim (dapsone 100 mg once daily oral; trimethoprim 20 mg/kg oral) in divided doses, both for 14–21 days. Atovaquone should not be used for severe cases.

Patients with severe disease (defined by a PaO₂ < 8 kPa) should also be treated with a steroid (e.g. methyl prednisolone 40 mg for the first 5 days) to prevent ARDS.

Protozoal infection

Toxoplasmosis

Toxoplasmosis is caused by Toxoplasma gondii infection and is transmitted by ingesting undercooked meat. Disease is usually caused by reactivation of dormant tissue cysts within the brain, when a previously infected patient becomes immunocompromised. Reactivation presents with symptoms such as fever, confusion and headache with focal signs due to multiple mass lesions within the cranium. A brain imaging study often reveals typical multiple ring-enhancing lesions.

• Diagnosis is usually confirmed retrospectively by response to treatment. A brain biopsy is occasionally indicated.

• Treatment with oral sulfadiazine 2 g 4 times daily for up to 6 weeks and oral pyrimethamine 75 mg once daily has proven efficacy. Less common treatments include oral clindamycin 600 mg 4 times daily with pyrimethamine in patients with sulphonamide allergy. Atovaquone and fansidar have also been used successfully. Repeat brain scan 2 weeks after initiation of therapy should show radiological improvement, the absence of which may indicate another diagnosis. Treatment is continued for 6 weeks, followed by maintenance therapy with lower doses of sulfadiazine 500 mg 4 times daily and pyrimethamine 25 mg daily, clindamycin and pyrimethamine or atovaquone. Maintenance treatment can be stopped if a sustained immune recovery is seen with HAART.

• Prophylaxis. All newly diagnosed HIV-positive patients should have Toxoplasma serology carried out. Patients who are negative for Toxoplasma should be advised to avoid handling and eating undercooked meat. Serology-negative patients should also avoid handling cats. Prophylaxis is given in patients with CD4 counts < 200 until immunity is restored with HAART. Co-trimoxazole, prescribed for prevention of Pneumocystis, is an effective option for prophylaxis, as is the combination of dapsone and pyrimethamine. Nebulized pentamidine does not provide effective prophylaxis for this protozoal infection.

Cryptosporidiosis

Cryptosporidiosis is caused by infection with Cryptosporidium parvum and leads to chronic diarrhoea and/or sclerosing cholangitis. Diarrhoea can be large-volume and intermittent, or small-volume and frequent, depending on the site of infection. Sclerosing cholangitis presents with deranged liver biochemistry with or without jaundice. Diagnosis is with stool samples (up to six samples may be required) or bowel biopsy. No specific treatments have been proven to be effective in the treatment of cryptosporidiosis; however, patients who successfully immune-reconstitute with HAART will eventually eradicate the organism.

Viral infection

Cytomegalovirus (CMV)

Cytomegalovirus is a member of the herpes virus family. In immunocompetent individuals primary infection leads to a mild, self-limiting, flu-like illness. Fifty percent of the general population have been exposed. Previous CMV exposure can be detected by CMV serology. Reactivation occurs with severe immunosuppression (usually CD4 counts < 50), and can lead to retinitis, encephalitis, adrenalitis, oesophagitis, colitis and pneumonitis. Regular screening for CMV retinitis should be carried out in all patients with CD4 counts < 50, as symptoms are often non-specific. Fundoscopy in active disease reveals white exudates with haemorrhages. Other presentations depend on the organ system involved. The histological hallmark of CMV disease is the presence of owl’s eye inclusion bodies on biopsy specimens.

• Diagnosis of retinitis is clinical. The presence of blood or CSF PCR positivity is an indication to commence treatment, as this is a marker of current or imminent disease.

• Treatment is with ganciclovir 5 mg/kg IV twice daily for 14–21 days, foscarnet 90 mg/kg twice daily IV for 14–21 days or cidofovir. The drugs are usually prescribed to be given by the IV route. However, intravitreal injections of ganciclovir and foscarnet can be used for active retinitis. Oral valganciclovir 900 mg daily is also an effective treatment for acute CMV retinitis. Systemic treatment with these agents is associated with side-effects that can be limiting. The patient needs to remain on lifelong treatment, unless significant immune reconstitution is seen.

Herpes simplex virus (HSV)

Exposure to the herpes simplex viruses is common and causes cold sores, genital disease and even encephalitis in immunocompetent individuals. In HIV infection, all these presentations are possible and, in addition, oesophagus, colon, liver, eye and lung can all be affected. Skin and genital disease is often more common, greater in severity and longer in duration.

• Diagnosis is usually by PCR-based assays of lesional samples.

• Treatment is with aciclovir (mild: 200–400 mg oral five times daily for 5 days, severe: 5 mg/kg IV 8 hourly, encephalitis 10 mg/kg IV 3 times daily for 7-14 days), valaciclovir, famciclovir, foscarnet and cidofovir all having activity against this virus.

JC virus

The JC virus is a papova virus that can lead to progressive multifocal leucoencephalopathy (PML). It is seen in patients with CD4 counts < 100. Presentation is with cognitive impairment and confusion, but focal neurological signs are detectable in most patients on presentation. White matter disease, with non-enhancing high-signal lesions seen on T₂-weighted MRI, is the classical radiological finding. JC virus can be detected in CSF by PCR techniques. Brain biopsy is the only definitive diagnostic procedure. The only specific treatment available is cidofovir, but data are inconclusive on its efficacy. Immune reconstitution is associated with improved survival but, despite this, PML remains a life-threatening condition with a poor prognosis.

Hepatitis B virus (HBV)

HBV shares common routes of transmission with HIV. At diagnosis all patients with HIV should be screened for co-infection. Hepatitis B infection does not hasten HIV disease progression in co-infected individuals. However, HIV infection accelerates the liver disease, and increasing risks of cirrhosis and hepatocellular carcinoma occur with co-infection. Hepatitis B vaccination should be given to all HIV patients who are HBsAg negative.

• Diagnosis is by hepatitis serology, with measurement of HBV DNA (p. 181).

• Treatment of patients with co-infection of HIV and HBV is with a combination of tenofovir with emtricitabine or lamivudine, along with other anti-retrovirals. If patients only require HBV treatment, they should receive antivirals not active against HIV, e.g. PEG interferon.

• Other management consists of informing patients of the dangers of alcohol, offering vaccination to contacts (Box 3.2), and giving specific anti-HBV treatments (p. 183).

Box 3.2 Use of vaccines in HIV-infected adults

Vaccines that are contraindicated in all HIV-infected adults

• Cholera — CVD103-HgR (live)

• Influenza — intranasal (live)

• Poliomyelitis — oral (OPV) (live)

• Typhoid — Ty21a (live)

• Tuberculosis (BCG) (live)

• Smallpox (vaccinia) (live)

Vaccines that can be used only in asymptomatic HIV-infected adults with a current CD4 count > 200 cells/mm³

• Measles, mumps, rubella (MMR)

• Varicella

• Yellow fever

Hepatitis C virus (HCV)

HCV and HIV share some common routes of infection, e.g., via blood products, although sexual and vertical transmission of HCV is rare. All patients should be screened for co-infection at presentation. HIV infection appears to hasten the process of liver damage to which chronic HCV infection can lead. There are conflicting data on whether hepatitis C infection hastens HIV disease progression.

• Diagnosis is usually via serology. PCR tests of HCV RNA are useful to quantify viral load.

• Treatment should include advice on alcohol avoidance, prevention of further transmission, vaccination against HBV if negative, and consideration for specific HCV antiviral therapy (p. 186).

Bacterial infection

Respiratory infection

Patients with HIV have impaired B-cell function due to the lack of appropriate T-cell ‘help’. Consequently, HIV-infected patients are at increased risk of infection from a wide range of bacteria, including Streptococcus, Haemophilus, Pseudomonas and Klebsiella species. Patients should be vaccinated with both pneumococcal and Haemophilus vaccines.

Mycobacterium TB

Patients who are infected with HIV are likely to reactivate latent TB disease and have higher rates of extrapulmonary disease. There is also evidence that recent exposure to the tubercle bacillus causes a significant number of new presentations and that active TB can increase the rate of progression of HIV.

• Clinical features of TB comprise night sweats, weight loss, hepatosplenomegaly and lymphadenopathy. Pulmonary TB presents with symptoms of chest pain, chronic productive cough and haemoptysis. Virtually any extrapulmonary site can be involved, including CNS, gastrointestinal tract, genitourinary tract and joints.

• Treatment is increasingly problematic due to the emergence of drug-resistant TB. Multiple drug resistance (MDR) occurs worldwide in about 20% of cases, with 2% having extensive drug resistance (XDR, p. 514). Nosocomial transmission of XDR is an increasing problem. To establish the presence of resistance rapidly, samples must be sent to the reference laboratory for molecular detection of species and resistance. Early morning sputum samples, pleural aspiration and biopsy if effusion is present, along with bronchial washings, may all be necessary to diagnose pulmonary disease. For extrapulmonary disease, tissue samples should not all be placed in formalin and sent to histopathology; some should be sent in a dry sterile container for microbiological culture. As large a volume of CSF should be sent to be tested for suspected CNS disease. Bone marrow and liver biopsy may be necessary for suspected miliary disease. It is essential that treatment be carried out with at least four separate drugs to which the organism is sensitive (p. 86).