Complications of HIV Infection

Most complications of HIV/AIDS are as a result of suppression of T-cell mediated immunity. Anti-retroviral drugs,known as Highly Active Anti-Retroviral Therapy (HAART), are now available to inhibit the replication of the human immunodeficiency virus.1,2 This helps to prolong life, restore the patient's immune system to something approaching normal activity and reduce the chances of opportunistic infection. Combinations of three or more drugs are given to lessen the possibility of resistance.

For more information see related articles AIDS Acquired Immune Deficiency Syndrome and Chemoprophylaxis in HIV.

Pulmonary complications
Pneumocystis jirovecii pneumonia
Pneumocystis carinii is now known as Pneumocystis jirovecii. It has been one of the hallmarks of AIDS but is now less common because of antiretroviral therapy and primary prophylaxis.3 Nevertheless it remains a significant cause of pathology and is increasing in non-AIDS immunosuppressed patients (mainly transplant recipients) in whom a reservoir of infection is maintained.4,5 Most AIDS cases occur with a CD4 count < 200/mm3 and mainly at < 100/mm3.

Presentation: Typically develops over a few weeks and includes shortness of breath, dry cough and fever. There may also be malaise, fatigue, weight loss and chest pain. There may be surprisingly few signs in the chest apart from a few minor crepitations.
Investigations
Chest X-ray may show bilateral perihilar interstitial shadowing.
O2 saturation < 95% at rest or falls after exercise.
Microscopy of sputum may show P. jirovecii cysts and trophozoites with staining.
Bronchoscopy may be needed - additional findings may be TB, fungal infections and Kaposi's sarcoma.
Treatment
High dose co-trimoxazole is recommended for 3 weeks first line.
Intravenous (IV) co-trimoxazole should be given in moderate to severe cases but there is a high level of side-effects. Other options include IV pentamidine/clindamycin/primaquine or dapsone/trimethoprim. One meta-analysis suggests a low dose cotrimoxazole regime for patients with slower disease progression.6 In patients with more rapid-onset disease, higher dose co-trimoxazole may be more effective than aerosolised pentamidine but toxicity considerations need to be taken into account.7
IV steroids may be helpful in moderate to severe pneumonia, e.g. IV methylprednisolone or oral prednisolone for 5-10 days.
Oxygen may also be beneficial.
One study found that a reduction in mortality rates in recent years was most likely to be linked to improved intensive care management of severe respiratory failure.8

Bacterial pneumonia
Commonest causes are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. In advanced cases, causative organisms may include Staphylococcus aureus , Klebsiella spp. and other Gram-negative rods. The presentation may be atypical, with diffuse infiltrates appearing on the X-ray.

Fungal infections
These may include Cryptococcus spp. In disseminated infection other fungi may be involved. The first line treatment for most fungal lung infections is IV amphotericin B.9

Tuberculosis
This is very common in areas where TB is endemic. Many cases represent reactivation of previous infection. HIV-positive patients with TB are less likely to be sputum-positive with X-rays that show less cavitation and more involvement of lower lobes. They are more likely to relapse after completion of treatment and die prematurely. Treatment is the standard 3-4 drug regimen but multidrug-resistant TB strains are becoming more frequent.10 One study found that tuberculosis preventive therapy (e.g. isoniazid, co-trimoxazole) was useful in reducing the incidence of infection and death in children with HIV irrespective of whether they also received HAART.11

Mycobacterium avium complex
This is seen In advanced HIV. Patients with CD4 < 50/mm3 are at high risk. In industrialised countries, it is reported in 40% of patients with AIDS.

Presentation: Infection is disseminated and presents with fever, night sweats, weight loss, diarrhoea, abdominal pain, anaemia or hepatic dysfunction.
Diagnosis: This is by culture from blood or bone marrow or may be recognised in tissue biopsy.
Treatment: Various combinations of antituberculous therapy have been tried, including clarithromycin, ethambutol, rifampicin and streptomycin.12 The addition of IV amikacin may be beneficial. Recently, trials have shown benefit from the use of aerolised amikacin.13

Central nervous system complications
Cerebral toxoplasmosis
Toxoplasmosis is less common than it was since the advent of HAART, although is still prevalent in resource-poor countries.14 Cerebral toxoplasmosis is the most frequent central nervous system (CNS) infection when CD4 < 200/mm3. It usually occurs due to reactivation of cysts in the brain causing local lesions, typically multiple.

Presentation: Sub-acute symptoms include focal neurological disturbances, headache, confusion, fever and seizures.
Investigations
CT scan: The appearance is of a mass with a ring of contrast enhancement and associated oedema.
MRI: This may show lesions not visible on CT.
Polymerase chain reaction (PCR) test may be helpful.14
Treatment: The usual practice is to treat these symptoms as toxoplasmosis and consider biopsy if there is no improvement in 7-10 days. Treatment is sulfadiazine and pyrimethamine plus folinic acid. High level of side-effects and can use clindamycin instead of sulfadiazine. A Cochrane review suggested that trimethoprim-sulfamethoxazole may be useful in resource-poor areas.15 Steroids may be used for cerebral oedema.

Cryptococcal meningitis

Presentation: This is usually sub-acute with non-specific symptoms such as headache, vomiting and a slight fever. Neurological signs are not a major feature. Less commonly, patients present with psychiatric symptoms, convulsions, cranial nerve palsies or truncal ataxia.
Investigations: These reveal focal neurological lesions. Diagnosis is by identifying organisms in the cerebrospinal fluid (CSF).
Treatment: Amphotericin B plus 5-flucytosine are first-line therapy; however, fluconazole may be used in milder cases. The level of side-effects may be high.
Prognosis: Clinical deterioration is associated with raised intracranial pressure and the risk of blindness. Relapses occur in 50-80% of cases without prophylaxis with oral fluconazole.10

Progressive multifocal leucoencephalopathy
Progressive multifocal leucoencephalopathy (PML) is a progressive demyelinating condition of advanced disease caused by the John Cunningham virus (JCV) and presents with focal neurological signs, changes in personality and ataxia. The diagnosis is by MRI. There is no specific treatment and the patient usually dies within 6 months unless effective antiretroviral therapy is used.16 Some patients develop PML during combined antiretroviral therapy in the setting of immune reconstitution. Steroids may be useful in such cases.17

HIV encephalopathy

Presentation: The HIV virus directly infects the nervous system and most patients dying of AIDS have histological evidence of brain damage. Up to 10% develop cognitive, behavioural and mental abnormalities of dementia. In the early stages, the concentration or memory is affected, with apparent depression and a gradual diminution of intellect. There may be increasing motor problems affecting activities of daily living. Movements may be slow. Examination may reveal inco-ordination, motor weakness, hyperreflexia and extensor plantar responses.
Investigations: MRI shows reduced grey matter volume in the cortex and basal ganglia. In the late stages there is a need to differentiate from cytomegalovirus (CMV) encephalitis which usually presents with rapidly progressive convulsion and dementia.
Treatment: HAART has considerably improved the prognosis if given early enough. However, the virus may continue to remain in the body at low levels and continue to replicate, so prognosis must be guarded.18

Peripheral neuropathy and myelopathy
This can occur at any stage of HIV infection but is more common in advanced disease. At this point 10-15% of cases show distal symmetrical neuropathy affecting both sensory and motor systems. The condition may be exacerbated by antiretrovirals.19 It can cause postural hypotension, diarrhoea, impotence, impaired sweating and bladder dysfunction. HIV may directly involve the spinal cord, usually presenting with bilateral leg weakness and sensory symptoms. CMV infection presents with lumbosacral polyradiculopathy resulting in sacral paraesthesias and numbness, weakness of lower limbs and urinary retention. Treatment is mainly symptomatic with analgesics and anticonvulsants, although the use of recombinant human nerve growth factor has shown some promise.20 Another study found that capsaicin patches may be useful.21

Ocular disease
Cytomegalovirus retinitis
In the absence of antiretroviral therapy, up to 30% cases of AIDS with CD4 < 50/mm3 show reactivation of CMV with destructive blinding retinitis. It usually presents with blurred vision, partial loss of vision in one eye, floaters or flashing lights. Typical retinal changes include irregular retinal pallor with haemorrhages in a perivascular distribution. These usually start peripherally and rapidly progresses to involve the macular and whole retina causing blindness. The main treatment is IV ganciclovir which is dose-limited in approximately 10% of patients by severe neutropenia and thrombocytopenia.10

Tumours
The incidence of both Kaposi's sarcoma and non-Hodgkin's lymphoma have been markedly reduced since the introduction of HAART, although the incidence of other cancers in HIV patients has not changed.22

Kaposi's sarcoma

Presentation: This characteristically presents as multiple ecchymotic skin nodules, macules or papules. It occurs in about 15% of patients despite the advent of HAART. It often affects the face early in HIV. It is also found on mucosal surfaces, usually on the hard palate. Visceral disease commonly affects the lungs and GI tract causing dyspnoea, cough, haemoptysis, abdominal pain or bleeding.
Treatment: Radiotherapy, cryotherapy or intralesional vinblastine has been the treatment of localised disease but is being superseded by pegylated liposomal doxorubicin or liposomal daunorubicin.23 The drugs are given intravenously and have been found to produce shrinkage of the tumour in the majority of patients.24

Non-Hodgkin's lymphoma
This develops in 3-10% of HIV-positive cases with most tumours being extranodal. Around half of these are associated with Epstein-Barr virus (EBV) infection and these are more aggressive with lower survival rates. CNS sites are common, presenting with symptoms and signs of space-occupying cerebral tumour and this carries very poor prognosis with 3 months' survival without highly active antiretroviral treatment. Tumours outside the CNS can respond to standard chemotherapy regimens.25 Opportunistic infections may cause death during chemotherapy.

Oesophageal candidiasis
This presents with retrosternal pain on swallowing and is usually caused by Candida albicans. This is an AIDS-defining condition. The first line of treatment is fluconazole. Other antifungal drugs tried in refractory cases include micafungin and posaconazole.26,27