HIV-Related Opportunistic Infections: Prevention and Treatment

What are opportunistic infections?

People with advanced HIV infection are vulnerable to infections and malignancies that are called 'opportunistic infections' because they take advantage of the opportunity offered by a weakened immune system.

A partial list of the world's most common HIV-related opportunistic infections and diseases includes:

• Bacterial diseases such as tuberculosis, MAC, bacterial pneumonia and septicaemia (blood poisoning)
• Protozoal diseases such as PCP, toxoplasmosis, microsporidiosis, cryptosporidiosis, isopsoriasis and leishmaniasis
• Fungal diseases such as candidiasis, cryptococcosis and penicilliosis
  Viral diseases such as those caused by cytomegalovirus, herpes simplex and herpes zoster virus
• HIV-associated malignancies such as Kaposi's sarcoma, lymphoma and squamous cell carcinoma.

Different conditions typically occur at different stages of HIV infection. In early HIV disease people can develop tuberculosis, malaria, bacterial pneumonia, herpes zoster, staphylococcal skin infections and septicaemia. These are diseases that people with normal immune systems can also get, but with HIV they occur at a much higher rate. It also takes longer for a person with HIV to recover than it takes for someone with a healthy immune system.

When the immune system is very weak due to advanced HIV disease or AIDS, opportunistic infections such as PCP, toxoplasmosis and cryptococcosis develop. Some infections can spread to a number of different organs, which is known as 'disseminated' or 'systemic' disease. Many of the opportunistic infections that occur at this late stage can be fatal.

Why is there still a need to prevent and treat opportunistic infections?

Highly Active Antiretroviral Therapy (HAART) can reduce the amount of HIV in someone's body and restore their immune system. The introduction of HAART has dramatically reduced the incidence of opportunistic infections among HIV-positive people who have received the drugs. Yet the prevention and treatment of opportunistic infections remains essential.

Around the world, millions of people living with HIV in resource-poor communities have no access to HAART. And even where the drugs are available, they do not entirely remove the need for preventing and treating opportunistic infections. Sometimes it is advisable for people with acute opportunistic infections to begin HAART right away, especially if the infection is difficult to treat. However in certain cases it may be better to delay beginning HAART and instead only to administer treatment for the opportunistic infection, especially if there are concerns about drug interactions or overlapping drug toxicities.

Those who have already started taking antiretrovirals may require other drugs in certain circumstances. In particular, some opportunistic infections may be unmasked shortly after the beginning of HAART as the immune system starts to recover, and these may require specific treatment. Measures to prevent and treat opportunistic infections become essential if antiretrovirals stop working because of poor adherence, drug resistance or other factors.

Providing prevention and treatment of opportunistic infections not only helps HIV-positive people to live longer, healthier lives, but can also help prevent TB and other transmissible opportunistic infections from spreading to others.

Prevention of HIV-related opportunistic infections

HIV-positive people can reduce their exposure to some of the germs that threaten their health. They should be especially careful around uncooked meat, domestic animals, human excrement and lake or river water. However there is no practical way to reduce exposure to the germs that cause candidiasis, MAC, bacterial pneumonia and other diseases because they are generally common in the environment.

Several HIV-related infections (including tuberculosis, bacterial pneumonia, malaria, septicaemia and PCP) can be prevented using drugs. This is known as drug prophylaxis. One particular drug called cotrimoxazole (also known as septra, bactrim and TMP-SMX) is effective at preventing a number of opportunistic infections. This drug is both cheap and widely available. The World Health Organisation (WHO) recommends that, in resource-limited settings, the following groups of people should begin taking cotrimoxazole:

• HIV-exposed infants and children, starting at 4-6 weeks after birth, or at first contact with health care, and continued until HIV infection is excluded
• HIV-positive children less than 1 year old
• HIV-positive children aged 1-4 years who have mild, advanced or severe symptoms of HIV disease, or a CD4 count below 25%
• HIV-positive adults and adolescents who have mild, advanced or severe symptoms of HIV disease, or a CD4 count below 350 cells per ml
• HIV-positive people with a history of treated PCP.

According to WHO guidelines, treatment of HIV-positive people should continue until at least age 5, and in general should continue indefinitely, though it may sometimes be stopped following successful antiretroviral treatment.

Some of the worst affected countries may choose to treat all infants and children born to mothers confirmed or suspected of living with HIV, until HIV infection is excluded. They may also choose to treat everyone who is diagnosed with HIV, regardless of symptoms or CD4 count.

Drug prophylaxis is sometimes recommended even for those who have started HAART if they have very weak immune systems or are otherwise considered to be especially vulnerable. They may be advised to stop taking the drugs if their immune system recovers.

For people who have already contracted an opportunistic infection and undergone successful treatment, secondary prophylaxis may be advisable to prevent recurrence. This applies to diseases such as tuberculosis, salmonella, cryptococcosis and PCP.

Treatment of HIV-related opportunistic infections

Some opportunistic infections are easier to treat than others. Effective treatment depends on health services being able to procure, store, select and administer the necessary drugs and to provide related treatment, care and diagnostic services to monitor health status and treatment response.

A few opportunistic infections and symptoms such as candidiasis of the mouth, throat or vagina (thrush), herpes zoster (shingles) and herpes simplex can be managed effectively through home-based care. In a home-based care setting diagnosis is made by observing symptoms.

Some opportunistic infections may be diagnosed by observation or using a microscope, and treated where there is minimal health infrastructure. Such infections include pulmonary tuberculosis and cryptococcal meningitis.

In a medium infrastructure setting, the facilities available include X-ray equipment and culture facilities. Using these, opportunistic infections such as extra-pulmonary tuberculosis, cryptosporidiosis, isopsoriasis, PCP and Kaposi's sarcoma can be diagnosed and treated.

Opportunistic infections such as toxoplasmosis, MAC and cytomegalovirus infection can be diagnosed and treated in places with advanced infrastructure. Treating these infections is often impossible in resource poor countries. Many developing countries lack the advanced equipment and infrastructure (such as CT scanning) needed to treat these more complex infections.

Individual opportunistic infections

The following are just a few of the conditions that particularly affect people living with HIV.

Bacterial pneumonia

Pneumonia can be caused by various bacteria. Symptoms among HIV-positive people are much the same as in those without HIV infection, and include chills, rigours, chest pain and pus in the sputum. The vaccine PPV can protect people against some of the more common pneumonia-causing bacteria, and is recommended in the US.

Because other forms of respiratory infection including PCP are common among HIV-infected people, doctors must be certain of diagnosis before administering antibiotics. This may require a chest radiograph, blood cultures, a white blood cell count and tests to eliminate other infections. Treatment is usually aimed at the most commonly identified disease-causing bacteria.

Candidiasis

There are two main types of candidiasis: localised disease (of the mouth and throat or of the vagina) and systemic disease (of the oesophagus, and disseminated disease). The mouth and throat variant (commonly known as thrush or OPC) is believed to occur at least once in the lifetime of all HIV-infected patients. Occurence of the vaginal variant is common among healthy women and is unrelated to HIV status.

While OPC is not a cause of death, it can cause oral pain and make swallowing difficult. The main symptom is creamy white legions in the mouth that can be scraped away. Oesophageal (gullet) candidiasis is a more serious condition which can cause pain in the chest that increases with swallowing. Disseminated candidiasis causes fever and symptoms in the organs affected by the disease (for example, blindness when it affects the eyes), and can be life threatening.

Localised disease may be treated at first with relatively inexpensive drugs such as nystatin, miconazole or clotrimazole. Systemic candidiasis requires treatment with systemic antifungal agents such as fluconazole, ketoconazole, itraconazole or amphotericin.

Cryptococcosis

Cryptococcosis is caused by a fungus that primarily infects the brain. It most often appears as meningitis and occasionally as pulmonary or disseminated disease. Untreated cryptococcal meningitis is fatal.

Cryptococcosis is relatively easy to diagnose. However, its treatment (either amphotericin B with or without flucytosine or in mild cases with oral fluconazole) and secondary chemoprophylaxis are often impossible in developing countries because of high cost and limited availability of the drugs required.

Cryptosporidiosis and isosporiasis

Cryptosporidiosis (crypto) and isosporiasis are both caused by protozoan parasites. These diseases are easily spread by contaminated food or water, or by direct contact with an infected person or animal. Both crypto and isosporiasis cause diarrhoea, nausea, vomiting and stomach cramps. In people with healthy immune systems, these symptoms do not last more than about a week. However, if the immune system is damaged then they can continue for a long time.

Diarrhoea can interfere with the absorption of nutrients and this can lead to serious weight loss.
To confirm diagnosis of either disease, the stool is normally checked for parasites and their eggs. There is no cure for crypto, but antiretroviral therapy to restore immunity can effectively clear up the infection. For isosporiasis, TMP-SMX (trimethoprim-sulfamethoxazole) is often the preferred treatment.

Cytomegalovirus

Cytomegalovirus (CMV) is a virus that infects the whole body. It most commonly appears as retinitis, which causes blurred vision and can lead to blindness. CMV can also affect other organs, and is capable of causing fever, diarrhoea, nausea, pneumonia-like symptoms and dementia.

CMV infection may be treated with drugs such as ganciclovir, valganciclovir and forscarnet.

Herpes simplex and Herpes zoster

The usual symptoms of herpes simplex virus infection (HSV, which causes sores around the mouth and genitals) and herpes zoster virus infection ('zonal' herpes or shingles) are not life-threatening but can be extremely painful. Both viruses are also capable of causing retinitis and encephalitis (which can be life-threatening).

Both herpes simplex and herpes zoster are usually diagnosed by simple examination of the affected area, and may be treated with drugs such as acyclovir, famciclovir and valacyclovir.

Histoplasmosis

Histoplasmosis is a fungal infection that primarily affects the lungs but may also affect other organs. Symptoms can include fever, fatigue, weight loss and difficulty in breathing.

Disseminated histoplasmosis infection may be diagnosed using an antigen test, and can be fatal if left untreated. Treatment usually involves amphotericin B or itraconazole.

Kaposi's sarcoma

HIV-associated Kaposi's sarcoma causes dark blue lesions, which can occur in a variety of locations including the skin, mucous membranes, gastrointestinal tract, lungs or lymph nodes. The lesions usually appear early in the course of HIV infection.

Treatment depends on the lesions' symptoms and location. For local lesions, injection therapy with vinblastine has been used with some success. Radiotherapy can also be used, especially in hard-to reach sites such as the inner mouth, eyes, face and soles of the feet. For severe widespread disease, systemic chemotherapy is the preferred treatment.

Leishmaniasis

Leishmaniasis is transmitted by sandflies and possibly through sharing needles. The most serious of its four forms is visceral leishmaniasis (also know as kala azar) which is characterised by irregular bouts of fever, substantial weight loss, swelling of the spleen and liver and anaemia (occasionaly serious). In its more common forms, leishmaniasis can produce disfiguring lesions around the nose, mouth and throat, or skin ulcers leading to permanent scarring.

Treatment of leishmaniasis with pentavalent antimony is relatively expensive, partly because of the cost of drugs but also because hospital admission is recommended (in milder cases, trained health workers may administer the injections or infusions at a patient's home). If left untreated, visceral leishmaniasis is usually fatal.

MAC

The germs of the mycobacterium avium complex (MAC) are related to the germ that causes tuberculosis. MAC disease generally affects multiple organs, and symptoms include fever, night sweats, weight loss, fatigue, diarrhoea and abdominal pain.

MAC should be treated using at least two antimycobacterial drugs to prevent or delay the emergence of resistance. Such drugs include clarithromycin, azithromycin, ethambutol and rifabutin.

PCP

PCP is caused by a parasite that infects the lungs, which was formerly called pneumocystis carinii but has now been renamed pneumocystis jiroveci. PCP is a frequent HIV associated opportunistic infection in industrialised countries but appears to be less common in Africa. The symptoms are mainly pneumonia along with fever and respiratory symptoms such as dry cough, chest pain and dyspnoea. Definitive diagnosis requires microscopy of bodily tissues or fluids.

Severe cases of PCP are initially treated with TMP-SMX or clindamycin and oral primaquine. Mild cases can be treated with oral TMP-SMX throughout. With both of these regimens, toxicity (notably allergic-type reactions) often requires changes in therapy.

Prevention of PCP is strongly recommended for HIV-infected persons with very weak immune systems wherever PCP is a significant health problem for HIV-infected persons, and also after their first episode of PCP. The preferred drug is usually TMP-SMX.

Toxoplasmosis

Toxoplasmosis (toxo) is caused by a protozoan found in uncooked meat and cat faeces. This microbe infects the brain and can cause headache, confusion, motor weakness and fever. In the absence of treatment, disease progression results in seizures, stupour and coma. Disseminated toxo is less common, but can affect the eyes and cause pneumonia.

Definitive diagnosis of toxo requires radiographic testing (usually a CT or MRI scan). The infection is treated with drugs such as pyrimethamine, sulfadiazine and clindamycin. Leucovorin may also be used to prevent the side-effects of pyrimethamine.

Tuberculosis

Tuberculosis (TB) is a bacterial infection that primarily infects the lungs. Tuberculosis is the leading HIV-associated opportunistic disease in developing countries. For people who are dually infected with HIV and TB, the risk of developing active tuberculosis is 30-50 fold higher than for people infected with TB alone. And because mycobacterium can spread through the air, the increase in active TB cases among dually infected people means:

• more transmission of the TB germ
• more TB carriers
• more TB in the whole population.

Tuberculosis is harder to diagnose in HIV-positive people than in those who are uninfected. The diagnosis of TB is important because TB progresses faster in HIV-infected people. Also, TB in HIV-positive people is more likely to be fatal if undiagnosed or left untreated. TB occurs earlier in the course of HIV infection than many other opportunistic infections.

A proper combination of anti-TB drugs achieves both prevention and cure. Effective treatment quickly makes the individual non-contagious, which prevents further spread of the TB germ. The DOTS (directly observed short course) treatment strategy recommended by WHO treats TB in HIV-infected persons as effectively as it treats those without the virus. A complete cure takes 6 to 8 months and uses a combination of antibiotics. In addition to curing the individual, it also prevents further spread of the disease to others. This is why treating infectious cases of TB has important benefits for society as a whole.

Isoniazid preventive therapy is recommended as a health-preserving measure for HIV-infected persons at risk of TB, as well as for those with latent TB infection.

Source: by Annabel Kanabus, Jenni Fredriksson-Bass and Rob Noble.

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