6 HIV-associated infections
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- Common HIV-associated infections
- Pneumocystis pneumonia
- Infections of the central nervous system
- Tuberculosis co-infection
- Case studies
When you have completed this chapter you should be able to:
- Define HIV-associated infections.
- List the common HIV-associated infections.
- Diagnose and manage most HIV-associated infections.
- Explain why tuberculosis is a common and important HIV-associated infection.
- Describe how tuberculosis presents in patients with HIV infection.
- Describe the management of patients with tuberculosis and HIV co-infection.
Common HIV-associated infections
6-1 What are HIV-associated infections?
HIV-associated infections (or opportunistic infections) are infections which are common in patients with HIV infection. They ‘take the opportunity’ of infecting and causing illness in patients with a weakened immune system.
HIV-associated infections are common in patients with a weakened immune system.
6-2 Which are the common HIV-associated infections?
The following infections are uncommon in HIV-negative people, but common in HIV-positive people:
- Oral candidiasis (thrush)
- Tuberculosis (TB)
- Recurrent bacterial pneumonia
- Shingles (herpes zoster)
- Severe, recurrent genital herpes
- Severe, recurrent mouth ulcers
The following infections are rare in HIV-negative people and are AIDS-defining. This means that people who have these infections usually have advanced HIV infection.
- Oesophageal candidiasis
- Pneumocystis pneumonia
- Cryptococcal meningitis
- Cerebral toxoplasmosis
- Cytomegalovirus (CMV) retinitis
- Less common HIV-associated infections include chronic diarrhoea due to isosporiasis or cryptosporidiosis, non-tuberculosis mycobacteria and disseminated fungal infections.
6-3 Do HIV-associated infections always indicate that the patient has AIDS?
No, as many of the milder HIV-associated infections such as pulmonary TB or shingles may also be found in HIV-negative patients and patients with stage 1 to 3 HIV infections (i.e. not AIDS). These infections, however, should always alert one to the fact that the patient may have HIV infection. HIV-associated infections are therefore an important indicator for HIV counselling and screening.
6-4 What are AIDS-defining illnesses?
Clinical conditions that are so rare in people with a healthy immune system that they usually indicate that the person has AIDS (stage 4 HIV infection). AIDS-defining illnesses include:
- Infections such as oesophageal candidiasis, extrapulmonary TB, cryptococcal meningitis and pneumocystis pneumonia.
- Illnesses other than infections, such as HIV wasting syndrome, Kaposi’s sarcoma and non-Hodgkin’s lymphoma.
Both infections and malignancies can be AIDS-defining illnesses.
- A number of malignancies associated with AIDS have a viral cause.
6-5 Which patients are at high risk of contracting HIV-associated infections?
- HIV-infected patients with moderately low CD4 counts (50 to 200 cells/µl) commonly get infections which are uncommon in people with a normal immune system, e.g. tuberculosis and pneumococcal pneumonia. However, some of the milder HIV-associated infections may occur in HIV patients with CD4 counts above 200 cells/µl.
- HIV-infected patients with very low CD4 counts (below 50 cells/µl) commonly become infected with rare organisms such as Pneumocystis and Toxoplasmosis.
The lower the CD4 count, the higher the risk of getting an HIV-associated infection.
6-6 Can HIV-associated infections be prevented?
The best way of preventing most severe HIV-associated infections and TB is to start antiretroviral treatment (ART) in HIV patients while the CD4 count is still high. The risk of HIV-associated infections can also be reduced by:
- Primary prophylaxis that prevents the HIV-associated infection from occurring. This is done for Pneumocystis.
- Secondary prophylaxis that prevents recurrences of HIV-associated infections which have already occurred. This is done for cryptococcal meningitis.
- TB prophylaxis in HIV infected patients is the prevention of active TB disease in patients who already have latent TB infection that is being controlled by their own immune system. Therefore preventing progression to active disease when the immune system gets compromised is another example of secondary prevention.
6-7 How does oral candidiasis present?
Oral candidiasis (also called thrush or moniliasis) occurs mostly in HIV patients with a CD4 count below 200 cells/µl. It is a stage 3 disease and may indicate advanced immunodeficiency. The patient complains of a painful mouth and white patches are seen on the tongue, palate and inside the cheeks. White patches may also be seen in the pharynx (oropharyngeal candidiasis). Women living with HIV often have severe or recurrent vulvovaginal candidiasis.
- The diagnosis of oral Candida infection can be confirmed on microscopy when the fungal spores and hyphae (threads) can be seen.
Oral candidiasis in adults is often an early sign that the patient has HIV infection.
6-8 How is oral candidiasis treated?
Candidiasis of the mouth and pharynx can be treated with topical nystatin drops 1 ml every 6 hours. A patient may also suck amphotericin B lozenges and patients who do not respond may be treated with fluconazole 100 mg daily for 7 days. Recurrences are common in patients who are not on ART.
6-9 What bacterial infections are common in HIV patients?
Most HIV patients are at an increased risk of serious or recurrent bacterial infections such as:
A wide range of bacteria may cause either pneumonia or meningitis such as Pneumococcus, Haemophilus and Staphylococcus. These infections should be treated as for patients who are not HIV positive.
Prophylaxis with co-trimoxazole reduces the risk of many bacterial infections.
Common bacterial infections are often serious or recurrent in HIV patients.
6-10 What organisms may cause diarrhoea in HIV patients?
A number of organisms that do not cause problems in healthy people may cause chronic diarrhoea in HIV-infected patients. Examples are non-typhoid Salmonella, Cryptosporidium and Isospora. Patients with severe or chronic diarrhoea should be referred to hospital if dehydrated.
- Isosporiasis responds to co-trimoxazole. Cryptosporidium infection often only resolves when the patient is given ART.
6-11 What is shingles?
Shingles (Herpes zoster) is a very painful vesicular rash which usually only affects 1 part of the body. It is commonly seen in older people and is uncommon in young healthy adults. It is caused by reactivation of the chickenpox virus (Varicella zoster) which has been silent in nerve cells, usually after a childhood infection. Shingles is infectious and can cause chickenpox in children. Pain typically occurs for a few days before the rash appears.
Shingles is common in young adults living with HIV as their damaged immune system no longer keeps the virus under control. Patients with shingles should be treated early with high doses of oral acyclovir (800 mg 4-hourly for 5 days). The eye may become involved, which can cause blindness. Patients with face or eye involvement should be urgently referred to hospital for treatment.
Shingles in a young adult suggests HIV infection.
- Early treatment with steroids and acyclovir may prevent the development of painful post-shingles neuralgia. Only use steroids after consultation with an infectious-disease specialist.
6-12 Why is recurrent herpes infection common in people living with HIV?
A painful, recurrent rash with many small vesicles in the genital or anal area is usually due to a Herpes simplex infection. This sexually transmitted disease is often severe and recurrent in patients living with HIV due to their damaged immune systems. The mouth and lips may also be involved. Patients with severe infection should be treated with oral acyclovir (400 mg 8-hourly for 5 days).
Recurrent, severe herpes is common in people living with HIV.
- Genital and anal herpes are usually sexually transmitted and caused by Herpes simplex virus II (HSV-II) while oral herpes is usually due to recurrence of a childhood infection caused by HSV-I.
6-13 What are common causes of a sore mouth in people living with HIV?
- Oral candidiasis. This is the most common mouth condition associated with HIV infection.
- Severe, recurrent aphthous ulcers. These are very painful ulcers that can occur anywhere in the mouth. They may be single or multiple, small or large. Manage with paracetamol (Panado) for pain, and chlorhexidine mouthwashes to prevent secondary bacterial infection. Local (topical) steroids (e.g. Kenalog in Orabase) or spraying a beclomethasone inhaler directly onto the ulcer is helpful in severe cases.
- Herpes infections. These multiple, shallow ulcers are often recurrent and can become chronic. Topical gentian violet or 0.1% povidone-iodine (Betadine mouth wash) may be used while oral acyclovir is indicated for large ulcers.
- Necrotising ulcerative gingivitis. This causes bleeding and ulceration along the gum margins of the teeth. Mouth washes with 0.2% chlorhexidine gluconate helps while oral metronidazole (Flagyl) is indicated in severe cases. Severe cases should be referred to a dental hygienist.
In contrast, oral hairy leucoplakia is not painful and does not require any treatment.
6-14 How does oesophageal candidiasis present?
Oesophageal candidiasis is very common in patients with a CD4 count below 100 cells/µl. Patients present with pain and difficulty on swallowing. Patients with oesophageal candidiasis usually have oral candidiasis as well, which helps make the diagnosis. Oesophageal candidiasis may result in dehydration due to poor fluid intake.
Oesophageal candidiasis presents with painful swallowing and almost always indicates advanced HIV infection.
6-15 How is oesophageal candidiasis treated?
Oesophageal candidiasis is treated with oral fluconazole (200 mg daily for 14 days). Local treatment with topical drugs is not adequate. Patients with oesophageal candidiasis must be referred to hospital if they need intravenous rehydration. It is useful to give patients a glass of water to drink so that you can assess how easily they are able to swallow.
6-16 What is pneumocystis pneumonia?
Pneumocystis pneumonia is a severe lung infection caused by a fungus called Pneumocystis jirovecii. HIV patients, especially children, are particularly likely to develop pneumocystis pneumonia if their CD4 count is below 100 cells/µl.
- Contrary to earlier teaching, Pneumocystis jirovecii (and not Pneumocystis carinii) infects humans. Pneumocystis is a yeast-like fungus causing Pneumocycstis jirovecii pneumonia (PJP).
6-17 How is pneumocystis pneumonia diagnosed?
The patient presents with:
- A dry cough
- Progressive shortness of breath, especially with exercise
- Weight loss, fatigue and a feeling of being unwell
- Cyanosis in severe cases
Early in the infection the chest X-ray may appear normal. Later the appearance is that of ‘ground glass’, often involving both lungs.
- A definitive diagnosis is made by staining sputum, which can be obtained after saline nebulisation in a patient with a dry cough. Treatment may be initiated in patients with clinical symptoms after tuberculosis and bacterial pneumonia have been excluded.
6-18 How is a patient with pneumocystis pneumonia managed?
Oral co-trimoxazole, 4 tablets every 6 hours in patients of 60 kg or more and 3 tablets every 6 hours in patients under 60 kg, is the treatment of choice. Severe cases (with an oxygen saturation below 70% on room air) also require steroids. Patients with severe pneumonia need to be hospitalised, and will need oxygen alone or oxygen with continuous positive airways pressure.
- The full blood count and differential white cell count (neutropaenia), as well as serum potassium concentration should be monitored in patients on such high doses of co-trimoxazole.
6-19 Can pneumocystis pneumonia be prevented?
Yes. Prophylactic oral co-trimoxazole, 2 tablets daily should be given to people living with HIV with a CD4 count below 200 cells/µl or stage 2, 3 or 4 disease. Prophylaxis can be stopped when the CD4 count is above 200 cells/µl after starting treatment.
- Dapsone 100 mg daily can be used by patients who do not tolerate co-trimoxazole.
6-20 Can prophylactic co-trimoxazole prevent other HIV-associated infections?
Prophylactic co-trimoxazole can lower the risk of the following HIV-associated infections:
- Pneumocystis pneumonia
- Bacterial infections
- Diarrhoea caused by Isospora
- Dapsone only prevents Pneumocystis infections.
6-21 Does co-trimoxazole have side effects?
Yes. Especially in patients who are receiving ART. The commonest side effect is a rash. This can be severe and even life threatening. The rash can occur for the first time even if the patient has been on co-trimoxazole treatment for many months or years.
- Co-trimoxazole may cause hypersensitivity reactions with bone marrow suppression as well as hepatitis.
Infections of the central nervous system
6-22 Which HIV-associated infections can affect the brain?
- Cryptococcal meningitis
- Cytomegalovirus (CMV)
- Tuberculous meningitis
6-23 What is cryptococcal meningitis?
This is a serious infection of the meninges caused by a fungus called Cryptococcus neoformans. Cryptococcal meningitis is rare in healthy people and is not infectious to others. It is usually seen in patients with advanced HIV infection and a CD4 count below 100 cell/µl.
Cryptococcus is an important cause of meningitis in patients with advanced HIV infection.
- Cryptococcus may also cause a disseminated infection which involves other organs such as the lungs and skin.
6-24 How is cryptococcal meningitis diagnosed?
It presents with the clinical signs of meningitis that may range from mild to severe, i.e. fever, headache, nausea and vomiting, neck stiffness, confusion and drowsiness.
The diagnosis is confirmed by examining the cerebrospinal fluid (CSF) obtained by lumbar puncture. The diagnostic tests on the CSF are:
- Indian ink stain
- Cryptococcal antigen
- CSF chemistry may be normal or only mildly abnormal early in the infection. The Indian ink stain is not very sensitive while culture takes weeks. The antigen test in both CSF and serum is very sensitive for cryptococcal meningitis.
6-25 How is cryptococcal meningitis treated?
All patients with a clinical suspicion of meningitis must be urgently referred to hospital. Amphotericin B is given intravenously for 2 weeks followed by high oral doses of fluconazole for a further 8 weeks.
6-26 Can cryptococcal meningitis be prevented?
Yes. Patients with CD4 counts below 100 cells/µl should have blood taken for a cryptococcal latex agglutination test (CLAT) and if positive and asymptomatic, should receive primary prophylaxis with fluconazole. The dose for primary prophylaxis is 800 mg fluconazole by mouth daily for 2 weeks, then 400 mg daily by mouth for 8 weeks, then 200 mg per day until the CD4 count is above 200 cells/µl for at least 6 months.
Patients who have been treated and have recovered from cryptococcal meningitis should be placed on secondary fluconazole prophylaxis to reduce the risk of a repeat infection. The dose of daily oral fluconazole for secondary prophylaxis is 200 mg daily. Prophylaxis can be stopped when the CD4 count rises above 200 cells/µl.
- Fluconazole is used both as primary prophylaxis for the prevention of cryptococcal meningitis and as secondary prophylaxis to prevent a recurrence after treatment of cryptococcal meningitis.
6-27 What is cerebral toxoplasmosis?
Toxoplasma gondii is a single-cell organism (parasite) that can cause serious illness with brain infection (encephalitis) in patients with advanced HIV infection and a CD4 count below 100 cells/µl. Toxoplasmosis is not infectious to others. Patients with cerebral toxoplasmosis present with fits, abnormal behaviour and/or drowsiness. The diagnosis is confirmed on CT scan. Patients with suspected cerebral toxoplasmosis must be urgently referred to hospital for investigation and treatment with a prolonged course of co-trimoxazole.
Cerebral toxoplasmosis is a serious complication of AIDS. It may also infect the lungs.
6-28 What problems may be caused by cytomegalovirus (CMV)?
This virus commonly causes mild illness in healthy children and adults. Most people are infected as children. In patients living with HIV with a very low CD4 count, CMV may cause retinitis (infection of the eye), encephalitis (brain infection), hepatitis, pneumonitis and bowel infection. This may be a primary infection or recurrence of a childhood infection.
CMV retinitis presents with sudden impaired vision and is the commonest cause of blindness in people living with HIV with low CD4 counts. Suspected cases must be urgently referred to hospital for diagnosis and treatment with ganciclovir. Visual impairment caused by CMV may be permanent.
CMV retinitis may cause blindness in people living with HIV.
6-29 What is tuberculosis co-infection?
Tuberculosis co-infection occurs when a person living with HIV also has tuberculosis.
6-30 What is tuberculosis?
Tuberculosis (TB) is a chronic infectious disease which is caused by TB bacteria. Tuberculosis usually affects the lungs (pulmonary tuberculosis), but may involve other organs (extrapulmonary tuberculosis).
- Mycobacterium tuberculosis, the common cause of tuberculosis, was first described by Robert Koch in 1882. Non-tuberculous Mycobacterial infections such as Mycobacterium avium complex (or MAC) may occur in patients with advanced HIV infection.
6-31 How are TB bacteria spread from person to person?
TB bacteria are usually spread when a person with untreated pulmonary tuberculosis talks, coughs, spits, laughs, shouts, sings or sneezes. This sends a spray of very small droplets into the air. These small drops contain live TB bacteria (TB bacilli) from the person’s lungs. They float in the air for up to 1 hour and can be breathed in by other people. This may result in TB infection of the lung. Patients with many TB bacteria in their sputum (‘open TB’) are very infectious to others.
- Less commonly, TB bacteria in unpasteurised cows’ milk can be drunk and cause TB infection of the intestines.
TB bacteria are spread by people with untreated pulmonary tuberculosis.
6-32 Do all people who are infected with TB bacteria develop tuberculosis?
No. Most people infected with TB bacteria do not develop tuberculosis because their healthy immune system is able to control the infection and stop the TB bacteria from multiplying and spreading. However, the TB bacteria are often not all killed but only kept under control. This is called latent TB infection.
Most HIV-negative people infected with TB bacteria do not develop tuberculosis.
- People can have latent TB infection and not develop the disease, tuberculosis.
6-33 How soon after TB infection does tuberculosis develop?
This will depend on the ability of the person’s immune system to control the spread of the TB bacteria. If the immune system is strong the TB infection will be well controlled and not spread to other parts of the lung or to other organs (primary infection only, without progressing to tuberculosis). However, if the immune system is weak, the TB infection may rapidly spread within the lung or to other organs (tuberculosis or TB disease). Some patients are able to control the primary infection for months or many years (latent phase) but the infection may then spread to cause tuberculosis if the immune system becomes weakened (reactivation).
6-34 Is TB infection common in the general population in South Africa?
Infection with TB bacteria is very common, and it is estimated that almost 50% of all South Africans are infected, especially during childhood, and then continue to have latent TB. However, only about 10% of healthy, HIV-negative people with latent TB infection develop tuberculosis during their lifetime. Therefore, latent TB infection is far more common than tuberculosis in the general population.
TB infection is very common in South Africa.
6-35 Are patients with HIV infection at increased risk of developing tuberculosis?
Yes. Tuberculosis is very common in people living with HIV, and is often the first indication of illness in a person who is living with HIV. All people living with HIV are at an increased risk of developing tuberculosis because of their suppressed immune system. In people living with HIV, new primary TB infection progresses to tuberculosis in 30% of cases, while an additional 10% per year will develop tuberculosis due to reactivation of latent TB infection. This contrasts with HIV-negative people who only have a small risk of developing tuberculosis in their lifetime. HIV has therefore changed the natural history of tuberculosis, making it the most common HIV-associated disease in South Africa.
Tuberculosis is very common in people living with HIV and is the most common HIV-associated disease in South Africa.
6-36 How many adults with tuberculosis are also living with HIV ?
In South Africa over 50% of adults with tuberculosis are also living with HIV. It is therefore essential to screen for HIV in all patients presenting with tuberculosis.
All patients with tuberculosis must be screened for HIV infection. In 2016, TB was still the main cause of death in men in South Africa.
6-37 Why is tuberculosis so common in people living with HIV?
People living with HIV have damaged immune systems which are not able to control the TB infection. Tuberculosis in people living with HIV may be due to either:
- Reactivation of a latent TB infection, which has been under control for many years. Often the original TB infection occurred during childhood. With weakening of the immune system by HIV infection the old TB infection starts to spread, resulting in tuberculosis.
- A new primary TB infection which progresses to tuberculosis. The weakened immune system is unable to kill the TB bacteria and keep the TB infection under control.
HIV infection probably does not increase the risk of TB infection but greatly increases the risk of old or new TB infections progressing rapidly to tuberculosis.
6-38 What is the effect of HIV infection on the progress of tuberculosis?
The course of tuberculosis is often very rapid in people living with HIV. Both new and old TB infections spread quickly. Therefore, people co-infected with TB and HIV may need hospitalisation.
The course of tuberculosis is very rapid in patients with HIV infection.
- HIV infection with a damaged immune system prevents the normal cellular response to TB.
6-39 Is tuberculosis a common cause of death in people living with HIV?
Tuberculosis is the most common cause of death in adults with HIV infection in South Africa.
Tuberculosis is the commonest cause of death in adults with HIV infection in South Africa.
6-40 What is the effect of tuberculosis on the progress of HIV infection?
People living with untreated HIV infection become worse much more rapidly if they also have TB co-infection, which further damages the immune system.
Therefore, HIV infection speeds up the progress of tuberculosis, while tuberculosis speeds up the progress of HIV infection. This is the great danger of HIV and TB co-infection.
The progress of HIV infection is made worse with TB co-infection.
6-41 Which organs, other than the lungs, can be affected by tuberculosis?
Tuberculosis may affect most organs of the body, such as the lymph nodes, bowel, meninges, brain, kidneys and spine, especially in people living with HIV. This is called extrapulmonary tuberculosis. The commonest form of extrapulmonary tuberculosis in people living with HIV is enlarged lymph nodes (tuberculous lymphadenopathy). Tuberculous meningitis and disseminated tuberculosis are also common in people living with HIV. Disseminated tuberculosis presents with 2 or more organs involved.
The risk of extrapulmonary tuberculosis increases when the CD4 count is low. Therefore, extrapulmonary tuberculosis is more common in people with advanced HIV disease.
6-42 What are the symptoms and signs of pulmonary tuberculosis?
Patients with pulmonary TB may present with any of the following:
- Chronic cough for more than 2 weeks. Some patients may cough up blood (haemoptysis).
- Fever for more than 2 weeks.
- Severe night sweats for more than 2 weeks.
- Loss of appetite and weight loss.
- Tiredness and weakness.
A careful history is the best way to screen for tuberculosis. Any 2 of the above symptoms or signs strongly suggests tuberculosis. Always suspect tuberculosis in any person living with HIV who has a cough lasting more than 2 weeks. Advanced HIV infection can also result in fever, night sweats, weight loss, tiredness and weakness.
Pulmonary tuberculosis usually presents with chronic cough, fever, severe night sweats and weight loss.
6-43 How is the clinical diagnosis of pulmonary tuberculosis confirmed?
Two sputum samples should be sent for testing for acid-fast bacilli (i.e. TB bacteria). If available, a GeneXpert test should be done on 1 sample. GeneXpert is a rapid (result available within hours) and sensitive method of detecting TB bacilli in sputum. It can also determine if the TB bacilli are resistant to rifampicin and isoniazid. If the GeneXpert or smear results are positive the patient should be started on TB treatment. Where GeneXpert is available, if it is positive, the second sample will be used for smear microscopy. Smear-positive patients have pulmonary tuberculosis and are infectious.
- A positive GeneXpert takes 2 years to return to negative after successful treatment of tuberculosis, and so should not be used as a diagnostic test if a patient has had tuberculosis in the past 2 years.
- If the GeneXpert or smear is negative, the second specimen should be used for TB culture.
- Patients who have clinical findings that are very suggestive of pulmonary TB but a negative GeneXpert or smear should have a chest X-ray if possible. This is particularly important for sick patients with low CD4 counts as the delay in making the TB diagnosis while waiting for a TB culture result could be fatal. Typical adult tuberculosis with cavities (holes) in the upper lobes may be seen in patients with only mild depression of their CD4 count. However, patients with advanced HIV infection may have widespread TB pneumonia, pleural effusions or enlarged TB lymph nodes (non-cavity tuberculosis).
- A sputum culture should be done in all people living with HIV who have symptoms of tuberculosis and a negative smear or GeneXpert result. The culture may be positive even if the smear examination is negative.
- In people living with HIV co-infected with tuberculosis, the chest X-ray may appear normal and the GeneXpert or sputum stain and culture may also be normal, making the clinical diagnosis difficult to confirm. A good clinical response to TB (anti-tuberculous) treatment may be the only way to confirm the diagnosis in these patients.
Sometimes the clinical diagnosis of tuberculosis is difficult to confirm and treatment may be started based on signs and symptoms alone.
- Lymph node biopsy is often helpful. Ideally all positive sputum samples should be cultured for drug resistance.
TB cultures may take up to 42 days to yield results.
6-44 Are people with pulmonary tuberculosis a danger to the general public?
Any patient with pulmonary tuberculosis may be infectious to the general public. As the number of people living with HIV who are co-infected with tuberculosis increases, the risk of tuberculosis in HIV-negative people will also increase as they are being exposed to more TB bacteria. As a result of the HIV epidemic, tuberculosis has become a common disease in South Africa. It is therefore in the public’s best interest to prevent and manage tuberculosis well.
The HIV epidemic is increasing the risk of tuberculosis to the general public.
- In South Africa the steady fall in numbers of tuberculosis cases suddenly reversed in the 1990s when the incidence of tuberculosis dramatically climbed as the HIV epidemic spread.
6-45 How can tuberculosis be prevented in people living with HIV?
- The risk of tuberculosis can be reduced in people living with HIV by controlling tuberculosis in the general public and thereby reducing their exposure to TB bacteria. A high cure rate of tuberculosis by a well-functioning DOT programme is very important.
- Some protection can be obtained by giving all children BCG immunisation at birth.
- INH prophylaxis can be given to patients at high risk of tuberculosis.
6-46 What does DOT stand for?
Directly observed treatment (DOT) is a course of TB treatment where taking the medication is observed each day by a supporter. The supporter is a responsible friend or family member or a healthcare worker who makes sure that each dose of TB treatment is correctly taken.
- In contrast, DOTS (directly observed treatment, short-course) is a management programme which uses a short, intensive course of TB treatment that is supervised by a supporter.
6-47 What is TB prophylaxis?
People living with HIV who are at high risk of tuberculosis can be protected by isoniazid (INH) at a dose of 300 mg daily. Prophylaxis prevents the reactivation of an old TB infection as well as the spread of new TB infections.
It is suggested that TB prophylaxis should be given to people living with HIV who have a positive Mantoux skin test result of 5 mm or more. A positive Mantoux skin test indicates that the person has latent TB infection. INH prophylaxis should be given for at least 36 months. It is very important to exclude active tuberculosis before starting INH prophylaxis as monotherapy with INH may lead to TB drug resistance.
If a Mantoux test is not available, INH should be given for 12 months if the patient is on ART, and 6 months if they are not yet on ART.
TB prophylaxis is important in people living with HIV who are at high risk of tuberculosis.
- TB prophylaxis may also be given to children who are HIV negative and under the age of 5 years who are living with a person that has tuberculosis. TB prophylaxis is also given to HIV positive children at any age to prevent TB transmission.
Pyridoxine 25 mg per day is often given with INH to reduce the risk of INH-induced peripheral neuropathy.
6-48 Should HIV infection and tuberculosis be treated at the same time?
Yes. However, the TB treatment should be started before beginning antiretroviral treatment because:
- The immune reconstitution inflammatory syndrome (IRIS) may occur. This is particularly common if TB treatment is given for less than 2 months before antiretroviral treatment is started, especially if the CD4 count is less than 50 cells/µl.
- Adverse effects due to interactions between the various anti-tuberculosis and antiretroviral drugs (ARVs) are common.
- TB and ARVs often have similar side effects, which can be more frequent and severe if the drugs are taken together.
- A large number of different tablets have to be taken when both infections are treated at the same time. This may affect adherence.
Therefore treatment of HIV and tuberculosis at the same time has many problems. However, if antiretroviral treatment is delayed too long, the patient may become seriously ill or die.
Tuberculosis treatment should be started before starting antiretroviral treatment.
- Steroids should be given when antiretroviral treatment is started if the CD4 count is below 100 cells/µl to prevent IRIS and death. Studies have shown that steroids reduce the occurrence of TB IRIS by up to 30% in these patients.
6-49 How is drug-sensitive pulmonary tuberculosis treated?
An intensive phase of treatment for 2 months is followed by a continuation phase of 4 months. Therefore, treatment for tuberculosis usually lasts 6 months.
Usually rifampicin, isoniazid (INH), pyrazinamide and ethambutol are given in a combination tablet (Rifafour) for the intensive phase of treatment. Daily dosage with combination tablets is given according to a patient’s body weight:
- 2 tablets if 30 to 37 kg
- 3 tablets if 38 to 54 kg
- 4 tablets if 55 to 70 kg
- 5 tablets if over 70 kg
For the continuation phase, a patient’s weigh is used to determine a combination tablet of rifampicin and INH only (Rifinah):
- 2 tablets if 30 to 37 kg
- 3 tablets if 38 to 54 kg
- 4 tablets if 55 kg or more.
Tuberculosis in people living with HIV infection usually responds well to treatment.
The commonly used combination tablet for the intensive phase contains rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg, while the combination tablet for the continuation phase contains rifampicin 150 mg and isoniazid 75 mg. Double-strength tablets are available for patients weighing 55 kg or more.
Tuberculosis is treated with a multiple drug regimen using combination tablets.
6-50 What is the importance of excellent adherence to treatment?
As with ART, it is extremely important that TB treatment is given correctly every day for the full course. Poor adherence is the main reason for treatment failure and the most important cause of multi-drug-resistant tuberculosis (MDR-TB).
6-51 Do people living with HIV who are on antiretroviral treatment have a lower risk of tuberculosis?
The risk of tuberculosis is greatly reduced in the short term in patients on ART (in the first 3 years) as their CD4 counts are increasing. However, as patients on ART now live longer, the lifetime risk of TB is still high. As a result, the incidence of tuberculosis in the community may not fall with the roll-out of ART.
6-52 Is it important to screen all patients for tuberculosis before starting antiretroviral treatment?
Yes. Tuberculosis should be excluded by taking a careful history before starting ART. Any person living with HIV who has a chronic cough should be fully investigated for tuberculosis.
6-53 When should antiretroviral treatment be started in people living with HIV who have tuberculosis?
- Start ART 2 to 8 weeks after starting TB treatment, as soon as patient is stable and tolerating TB treatment, if:
- The CD4 count is above 50 cells/µl and the patient is well
- The patient, does not have stage 4 disease, the patient does not have markers of severity (low BMI or low haemoglobin level). Generally, in this group, ART should be started as soon as the patient is tolerating their TB treatment. This is usually within 2-4 weeks.
- Start ART within 2 weeks of starting TB treatment if:
- The CD4 count is below 50 cells/µl
- Clinical stage is 4
- The patient is severely ill
- The patient may die if the treatment is delayed any longer.
- Patients with TB meningitis (or cryptococcal meningitis) should have TB treatment for 4 to 6 weeks before starting ART.
6-54 What should be done if patients on antiretroviral treatment develop tuberculosis?
The ART must be continued and TB treatment started. There is no need to delay starting the TB treatment.
- The patient would also need their CD4 count and viral load checked to exclude a non-suppressed HIV being the cause of a weakened immune system.
6-55 How do drugs used to treat tuberculosis and HIV interact with each other?
In patients who are already on antiretroviral treatment when tuberculosis is diagnosed, some of the drugs being used in antiretroviral treatment may have to be changed:
- Rifampicin is very important in the treatment of tuberculosis but it affects the serum drug levels of many of the drugs used in antiretroviral treatment. As a result, the choice of ARVs and their doses may need to be changed.
- If first-line combination antiretroviral treatment used, efavirenz is preferred to nevirapine, as rifampicin may lower the blood level of nevirapine. There is also an increased risk of liver toxicity if nevirapine and TB medication are used together.
- If second-line antiretroviral combination is used, the dose of lopinavir/ritonavir should be doubled (from 2 Aluvia tablets twice daily to 4 Aluvia tablets twice daily), as TB treatment lowers the blood level of lopinavir.
- If dolutegravir is used, whether for first; second or third line treatment, the dose also needs to be doubled to 100 mg daily. This will require an extra dolutegravir tablet (50mg) if the patient is on TLD (the combination of tenofovir, lamivudine and dolutegravir i.e. TDF/FTC/DTG).
As there are complex interactions between the drugs used to treat TB and the drugs used for antiretroviral treatment, the management of these patients, especially those on Aluvia or dolutegravir, may need to be reviewed by a doctor experienced in managing patients with TB and HIV co-infection.
- Tenofovir should not be used with aminoglycosides as both are potentially nephrotoxic. Patients with drug resistant TB who require an aminoglycoside should preferably not be treated with tenofovir. Abacavir may be used instead.
Drugs used in TB therapy and antiretroviral treatment may interact with each other.
- Rifampicin induces liver enzymes which break down some drugs used in antiretroviral treatment.
6-56 What are the shared side effects of the drugs used to treat tuberculosis and HIV?
Nausea, rash, hepatitis and peripheral neuropathy may be caused by both the drugs used to treat tuberculosis and those to treat HIV. As a result these side effects (adverse effects) are commoner and may be more serious if the 2 drug regimens are used together. This may result in a change in the choice of antiretroviral drugs.
Drug side effects are more frequent and may be more severe if anti-tuberculous and antiretroviral treatments are given together.
6-57 Can taking many tablets at a time cause problems?
Adherence may be poor when so many tablets need to be taken together. There may also be confusion between the many different types of tablets. Patients should be told they will have to take a large number of tablets, and should be counselled about these possible problems. A clearly written plan for both TB and ART is helpful.
A pillbox that may be prefilled weekly by the patients can also be helpful.
6-58 Is resistant tuberculosis a problem in HIV patients?
Tuberculosis resistant to many of the TB drugs is a growing problem in both people living with HIV and those who are HIV negative. A combination of HIV infection and drug-resistant tuberculosis is often fatal. Therefore, good adherence is essential in the treatment of both tuberculosis and HIV to prevent drug resistance.
Multi-drug-resistant (MDR) TB is resistant to both INH and rifampicin. This is becoming a more common in South Africa.
- Extensively drug-resistant (XDR) TB is resistant to more than INH and rifampicin and often resistant to all the standard TB drugs.
6-59 Are the public health strategies to treat tuberculosis and HIV similar?
There are important differences in the way that treatment is managed:
- In TB programmes that use the DOTS approach, responsibility for ensuring adherence is largely placed on a supporter rather than on the patient. In contrast, with ART, the responsibility is on patients themselves.
- A course of TB treatment is usually for 6 to 8 months only, while ART is for life.
6-60 Who should be responsible for the TB treatment?
Previously people living with HIV who have tuberculosis co-infection were referred to a local TB clinic for treatment of their tuberculosis. HIV and TB infections should preferably be managed at a single clinic.
Patients with TB and HIV co-infection should be managed at a single clinic.
6-61 What are the advantages of managing both tuberculosis and HIV at the same clinic?
- It avoids the need for referring patients to a separate clinic for their TB treatment. Previously the need to attend 2 clinics, often far apart from each other, was inconvenient for patients, with the result that many did not attend clinic regularly. This resulted in poor adherence and more drug resistance. It also added to the cost of transport and resulted in more days away from work.
- Doctors and nurses managing people living with HIV in one clinic also found it difficult to know what other treatment the patient was receiving at another clinic and how the patient was responding to treatment. With a combined clinic, the patients only need to get to know one set of staff which improves communication.
- As the adverse effects of ARVs and TB drugs are often similar and more severe, and there may be drug interactions, it is far better if the management of both conditions is managed by a single team of health workers.
- With a combined HIV and TB clinic fewer HIV-positive patients should die of undetected tuberculosis.
There are many advantages to the combined management of tuberculosis and HIV infection.
6-62 How can adherence to TB treatment be improved?
- Use directly observed treatment (DOT) or Community Care Worker support for home treatment.
- Treatment counselling should be given to teach the importance of excellent adherence and prepare for home treatment. Usually 3 counselling sessions are given by a treatment counsellor at the health facility.
- Treatment should be started and supervised at the health facility for 2 weeks while the patient is being counselled. This also allows for any adverse effects to be detected.
- Arrange a home visit by community care worker to identify any factors which may increase the risk of poor adherence or stopping treatment.
- The patient should identify a suitable treatment supporter (treatment ‘buddy’) who can assist with DOT and report any treatment problems. The treatment supporter should attend at least 1, and preferably all 3 counselling sessions at the health facility.
- Further treatment sessions are given at the start of the continuation phase.
If all these steps are taken treatment adherence should be excellent and most patients should complete their full course of treatment. This will improve survival and reduce the risk of drug resistance.
Case study 1
A 20-year-old man presents with a very painful mouth for the past few days. On examination he has white patches on his tongue and palate. When questioned, he admits to difficulty swallowing.
1. What is the likely diagnosis?
Oral candidiasis. He probably also has oesophageal candidiasis as he has difficulty swallowing.
2. What is the likely underlying cause?
HIV infection with suppression of his immune function. Oral candidiasis is uncommon in healthy adults with a normal immune system.
3. What is the management of oral candidiasis?
Topical nystatin drops 1 ml every 6 hours. He could also suck amphotericin B lozenges or nystatin vaginal pessaries. Prescribe oral fluconazole or refer if the candidiasis is not cleared after 5 days of treatment.
4. What is the management of oesophageal candidiasis?
Oral fluconazole. Make sure the patient is not dehydrated. If so, intravenous fluid may be needed. Dehydrated patients should be referred to hospital.
5. What are the other causes of a sore mouth in a patient with HIV infection?
Aphthous ulcers, herpes ulcers and gingivitis.
6. Is oral candidiasis an HIV-associated infection?
Yes. An HIV-associated infection occurs far more commonly in HIV-positive people than people who are HIV negative. These infections are more common because HIV damages the immune system by reducing the CD4 count. Oral candidiasis indicates stage 3 disease.
Case study 2
A young woman complains of weight loss and chronic diarrhoea. For the past few days she has had severe pain on 1 side of her chest. She has noticed a rash with small vesicles (blisters) in the same area as the pain.
1. What is the cause of the pain and rash?
Herpes Zoster (Shingles). This typically presents as localised pain followed by a vesicular rash.
2. Is this the same as chickenpox?
No, but both rashes are due to the Varicella zoster virus. For many years the virus remains in nerve cells following chickenpox as a child. When the immune system is weakened, the virus is reactivated, causing shingles. Shingles is infectious and can cause chickenpox in others.
3. What is the concern when a young person gets shingles?
It suggests that the person has HIV infection. Shingles is uncommon in healthy HIV-negative young people and is usually seen in an older person.
4. What is the management of shingles?
Early treatment with oral acyclovir. If the pain or rash involves the face or eye, the patient must be referred urgently to hospital.
5. What is the likely cause of her chronic diarrhoea?
This is almost certainly caused by an infection associated with HIV. A number of organisms cause chronic diarrhoea in HIV patients, such as non-typhoid Salmonella, Cryptosporidium and Isospora. She should be treated symptomatically and a stool sample should be sent for microscopy and culture. If the diarrhoea does not resolve despite treatment and ART, she should be referred to hospital for further diagnosis and treatment.
6. What prophylaxis will help prevent chronic diarrhoea?
Prophylaxis with co-trimoxazole will help prevent diarrhoea due to bacterial infections as well as infections with Isospora.
Case study 3
A known HIV patient develops a dry cough and fever. After a few days he feels worse and becomes short of breath.
1. What is the probable diagnosis?
Pneumonia. Cough, fever and shortness of breath suggest a lung infection.
2. What are the likely causes?
Bacterial pneumonia, pneumocystis pneumonia or tuberculosis. The most likely cause in this case is pneumocystis pneumonia.
3. How can the diagnosis be confirmed?
A chest X-ray will be helpful in most cases. Exclude tuberculosis and bacterial pneumonia. Where laboratory support and saline nebulisation are available, request an examination for Pneumocystis in a sputum specimen.
4. What is the treatment of pneumocystis pneumonia?
Oral co-trimoxazole, 4 tablets every 6 hours in patients weighing 60 kg or more and 3 tablets every 6 hours in patients under 60 kg. Patients who are severely ill or cyanosed need oxygen and admission to hospital. Severe cases may need steroids.
5. What is an AIDS-defining illness?
These are conditions which are very rare in people who do not have AIDS (stage 4 HIV infection). Pneumocystis is an AIDS-defining illness, therefore anyone presenting with pneumocystis pneumonia almost certainly has AIDS. Certain malignancies such as Kaposi’s sarcoma and non-lymphoid lymphoma are also AIDS-defining illnesses.
6. What other infections are AIDS-defining illnesses?
Oesophageal candidiasis, cryptococcal meningitis, cerebral toxoplasmosis and CMV retinitis all indicate stage 4 HIV infection.
Case study 4
An HIV-positive patient presents with a chronic cough, night sweats and fever. A chest X-ray suggests pulmonary tuberculosis.
1. How common is tuberculosis in HIV-positive patients?
Very common. It is the commonest HIV-associated infection in adults in South Africa.
2. Is tuberculosis dangerous in patients with HIV?
Yes, it is the commonest cause of death in adults with HIV in South Africa, especially in men.
3. How can tuberculosis be prevented in HIV-positive people?
By controlling tuberculosis in the general population and the routine use of BCG immunisation in infants. TB prophylaxis (primary prevention) with isoniazid in people living with HIV who have a positive Mantoux skin test is effective in reducing the incidence of tuberculosis in these high-risk patients.
4. How is tuberculosis treated?
With a course of multi-drug therapy. Usually rifampicin, isoniazid, pyrazinamide and ethambutol are used together. HIV-positive patients with tuberculosis usually respond well to TB treatment.
5. Should tuberculosis and HIV both be treated at the same time?
If possible, TB treatment should be started first before starting ART. Therefore all patients should be screened for tuberculosis before ART is started. If the patient is already on ART when the diagnosis of tuberculosis is made, the anti-tuberculosis treatment should be added to the ART without delay.
6. What are the problems if tuberculosis and HIV are treated together?
Drugs used to treat tuberculosis and HIV often interact with each other. The risk of side effects is increased and adherence is often poor due to the large number of tablets that have to be taken each day.