Liz Hart explains HIV and AIDS, and looks at the treatment available, and the implications of this epidemic

Today, 40 million people worldwide are infected with HIV--a difficult number to understand.¹ The prevalence in the United Kingdom is 0.1%; the situation in sub-Saharan Africa is very different. The prevalence in this area is 20% or more. Imagine a place where one in five people walking along the street is infected with HIV, where there are more funerals than weddings, and the families of every person have somehow been touched by HIV.

Sub-Saharan Africa continues to bear the burden of the HIV epidemic, but epidemics are emerging in China and among intravenous drug users in Russia. The impact of HIV in the Indian subcontinent continues to emerge, and without continuous vigilance in public health, the prevalence of HIV in the developed world will rise again.

The face of HIV in Africa

Discovery of the disease

In 1981, gay men in San Francisco and other US cities began presenting with unusual infections and malignancies, most notably Pneumocystis carinii pneumonia and Kaposi's sarcoma. By the end of the year these men had immunological abnormalities for an as yet undetermined reason, they were termed as having "acquired immunodeficiency syndrome."² Human immunodeficiency virus (HIV) was discovered in Paris in 1983.³ Although it was initially called HTLV-III (human T cell lymphotrophic virus), this was soon changed to HIV (human immunodeficiency virus). Transmission routes were found to be via sexual intercourse, vertically from mother to child, and via blood transfusion.

Disease mechanisms

As a retrovirus, HIV has a core of RNA. Once HIV enters a cell, reverse transcriptase translates the RNA to DNA, which is incorporated in the cellular DNA where intracellular mechanisms go on to produce new viral particles. The most commonly infected cell is the CD4 subset of lymphocytes. The effect of infection on CD4 cells is a gradual loss of these cells with a progressive loss of the host's cellular immune response.⁴

After infection, HIV antibodies are not detectable in the body for a time. Tests for HIV are based on detecting antibodies, and during this time a person may be infectious but not have antibodies detectable by standard tests. This window period can last between six weeks and three months (varies from one month to six months). Infectivity is about 1 in 300 among discordant couples (where one partner is HIV positive and another is HIV negative) to 1 in 350 for transmission by a needlestick injury. Both these modes of transmission are affected by many factors, such as the viral load of the patient or the presence of a sexually transmitted infection for sexual transmission.⁵ Sexually transmittted infections increase the likelihood of HIV transmission probably because they weaken the mucosal barrier (although they also suggest that the person has not been having safe sex). When HIV specific antibodies begin to be produced, the seroconversion often produces an illness like glandular fever but which may be non-specifically febrile or without symptoms.⁶

Box 1: Opportunistic infections

• Pneumocystis carinii pneumonia
• Severe herpes simplex virus
• Cytomegalovirus (CMV) disease outside the liver, spleen or lymph nodes and CMV retinitis
• Cryptococcus--outside the lungs particularly cryptococcal meningitis, cryptosporidiosis with diarrhoea lasting for more than one month
• Candida--in the oesophagus, trachea, bronchi, or lungs
• Chronic intestinal isosporiasis lasting longer than one month
• Mycobacterium avium intracellulare infection
• Toxoplasmosis of the brain
• Recurrent bacterial infections can also occur such as repeated episodes of bacterial pneumonia or salmonella sepsis

Before effective treatment, the clinical course of the disease would vary greatly with an average of 8 years between initial infection and the development of AIDS and death from a variety of opportunistic infections and HIV related malignancies.⁷ Although both the opportunistic infections seen in HIV and the malignancies can occur in patients without HIV, they occur more commonly in patients with HIV.

Although a person may be HIV positive they do not necessarily have AIDS. It is now possible to monitor the absolute CD4 count of someone with AIDS and the viral load (the amount of virus present in the blood).

Infections

Definitions of AIDS have varied, but the Centers for Disease Control and Prevention's 1993 definition is used commonly. The classification is based on clinical conditions associated with HIV infection, including opportunistic infections and malignancies, and CD4 count.⁸

Box 2: Antiretroviral Drugs in current use

Nucleoside reverse transcriptase inhibitors

• Zidovudine
• Stavudine
• Lamivudine
• Abacavir
• Didanosine
• Zalcitabine
• Non-nucleoside reverse transcriptase inhibitors
• Nevirapine
• Efavirenz
• Protease inhibitors
• Indinavir
• Nelfinavir
• Saquinavir
• Ritonavir
• Lopinavir
• Amprenavir

Pneumocystosis of the lung in AIDS

Initially, a person with HIV will have infection without symptoms which can last for a number of years. This may occur after a definite documented illness at seroconversion, although many people are unsure of exactly when they became positive. Some people may have constantly enlarged lymph nodes a condition called persistant generalised lymphadenopathy.

In time, other conditions will develop because of the lack of immunity. This usually coincides with a fall in CD4 cells. Examples of these conditions include specific infections and other conditions related to HIV.

Specific infections include candidiasis (thrush) in the mouth or upper throat and candidiasis of the vagina or vulva especially if it is persistent, frequent, or responds poorly to treatment. Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome (skin area), bacillary angiomatosis, pelvic inflammatory disease and listeriosis are also included. These diseases can occur in people who are not infected with HIV but are more common and severe in people who are HIV positive.

Other problems in the progression of HIV include constitutional symptoms such as fever (38.5^oC) or diarrhoea lasting longer than one month, and cervical abnormalities of moderate or severe extent or cervical cancer--women with HIV should have regular cervical smears. Also included in this group are oral hairy leukoplakia, peripheral neuropathy, and idiopathic thrombocytopenia purpura.

As the CD4 count falls, more illnesses occur; those that are most commonly associated with HIV and AIDS are listed in box 1. Many of these diseases are also included in the World Health Organization clinical diagnosis of AIDS for use in developing countries.

Malignancies and other complications

Although many malignancies occur more often in people with HIV, the commonly associated ones include invasive cervical cancer, primary brain lymphoma, and Kaposi's sarcoma. We must also mention HIV wasting syndrome, which is a common presentation of HIV in sub-Saharan Africa giving it the nickname "slim disease." There are neurological manifestations of AIDS, including encephalopathy related to HIV, that can respond dramatically well to HIV treatment.

Treatment

HIV treatment can be divided into two areas: the treatment and prevention of opportunistic infections and drugs to specifically treat HIV itself.

The first drug to be developed for HIV was zidovudine (AZT). This inhibits reverse transcriptase enzyme and stops HIV replication. Initial trials suggested benefit from this drug and it was greeted with great excitement.⁹ However, it was soon realised that HIV rapidly became resistant to zidovudine.¹⁰ More drugs were developed over the next few years but it was the advent of protease inhibitors and the development of the concept of highly active antiretroviral therapy (HAART), that really led to a change in the prognosis for HIV.¹¹

There are now 14 drugs commonly used for HIV in three different classes (see box 2). Patients take at least three drugs usually from two different classes. The life of people infected with HIV can be prolonged by improving the immune response and their health maintained--at least for the lucky ones in the developed world. Figure 3 shows how deaths from AIDS have fallen with the introduction of antiretroviral therapy.

Fid 4 Lipodystrophy

Using drugs (zidovudine and nevirapine in particular) for the prevention of mother to child transmission is possible. These drugs can also be used for post-exposure prophylaxis after both sexual contact and after needlestick injuries.

Taking tablets every day for the rest of your life is one drawback. Yet studies have shown that without 95% adherence to the drugs the chance that the tablets work is reduced.¹² As well as sticking to a regimen of tablets, the drugs have some acute and chronic side effects. Some identify people as being on HAART, such as lipodystrophy¹³ as in figure 4; a characteristic change in body fat distribution that can occur in people treated, usually, but not exclusively, with protease inhibitors. Other side effects, such as lactic acidosis, can be life threatening.^{14 15} All drugs have the potential to cause rashes, nausea, and vomiting. Drugs for treating HIV can also cause raised cholesterol and triglycerides and other metabolic side effects.

Cysts of pneumocystis carinii in smear from bronchoalveolar lavage

Other drugs have been used, such as hydroxyurea, which is now out of fashion. Many more drugs are being developed in the hope that they can be used in regimens that are easier and have fewer side effects. The search for the ideal drug--fewer tablets, fewer side effects, minimal interactions with other drugs, and longer acting--is never ending.

looking ahead

We must look at the effects of HIV and AIDS worldwide. At the world AIDS conference (Barcelona, 9-12 July 2002) there was a lot of emphasis on the developing world. Drugs for HIV are trickling into Africa too late to help millions of people. Campaigns are gathering momentum worldwide to improve access to drugs. Research on a vaccine continues, but a commercially available effective vaccine will not be available for many years. The correct way to perform clinical trials of HIV vaccines is still the subject of ethical debates.

So, we are left with a disease that cannot be cured that affects and will kill millions worldwide, with enormous economic and humanitarian repercussions. Treatments are available for the lucky few in the developed world but they demand high compliance and can have severe irreversible side effects.