classification of clinical stages of hiv

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Human Immune-deficiency Virus (HIV) infection is preceded by the development of Acquired Immuno-Deficiency Syndrome (AIDS). AIDS is the last outcome of HIV infections. AIDS is a fatal and terminal condition for and HIV infected patients. AIDS is a stage when HIV-seropositive patients are presented with various AIDS-related complications like opportunistic infections and cancer.

The first case of HIV infections was reported among 5 gay men from Los Angeles, USA. Although at that time neither HIV nor AIDS was a part of medical vocabulary. But these cases were reported with rare infection Pneumocystis carinii pneumonia (PCP). This is a disease not commonly noticed among general population, but has been reported with higher incidences among immune-deficient individuals. Initially these patients were diagnosed with this rare disease PCP, which could be a reason due to their immune-deficient conditions. The first case was reported by Michael Gottlieb in 1981 in New England Journal of Medicine. But there was sudden increase in demand for the drug to treat PCP was for the first time and drug-technician Ms. Sandra Ford of Center for Disease Control and Prevention, Atlanata, USA (CDC). Her observation has raised the alarm to look into this sudden increase of immune-deficiency disorders. Soon after the initial cases of PCP, world community has noticed an increase in incidences of this disease in all communities, all age group and almost all the corners of world. This kind of sudden increase in numbers of HIV infections gave a sense of feeling that this infection is spreading like a wild fire. The most unfortunate part of this saga is that there was no medicine to treat these infections, which lead to evolution of various myths. Some of these myths rather than controlling HIV infections turn out to be more spreading HIV infection rather than controlling HIV infections.

Initially, it was noticed that these infections are associated with specific community with a unique life-style, which was not approved by various religious faith. Therefore, this disease has received unexpected attention from all the quarters, and lot of money was invested to identify the causative organism as well as a treatment for the same. Later on, in 1983 Luc Montaignier from Pasteur Institute, Paris discovered the causative organism for disease and he has given it name as Lymph Adenopathy Virus (LAV). Later on this was confirmed by Robert Gallo. In 2008, Luc Montainger was awarded Nobel Prize for his contribution and discovery of HIV. In literature various names of the same virus can be found, due to variation in the names of the same organism, in 1998 the final name of this causative organism was adopted as HIV by international committee for taxonomy of viruses.

In general we know that HIV in one virus. In reality HIV is of two types, HIV-1 and HIV-2. Out of these two, HIV-1 is more prevalent and rapid progressive with fatal consequences, while HIV-2 is slow progressing and mostly confined to African continent. HIV is mostly transmitted via body fluid like as blood, semen, vaginal fluid, breast milk, vaginal fluid, etc. The major means of HIV transmission is due to unprotected sex (vaginal, oral or anal sex), blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth and breastfeeding. As per UNAIDS (2009) report more than 34 million people are living with HIV infections out of which more than 2 millions are children below the age of 16 years. Every year almost 2 million people get new infections.

HIV mainly infects T-cells (T-helper cells) because these cells are CD4 positive. HIV infects cells via CD4 receptors, that is the reason it mainly infects CD4 T-cells. For HIV infection another co-receptors also found to be important which are known as chemokine receptors. Apart from T-cells, HIV is also known to infect other cells like monocytes. HIV is a retrovirus, therefore, its genetic information is carried by RNA rather than DNA. To convert RNA into DNA HIV has a unique enzyme known as reverse transcriptase. HIV attaches to CD4 receptors and finds it entry into the cells, where RNA is converted in to cDNA, which finally integrated with the host infects cells genome. Integration of the viral DNA (proviral DNA) to the host cells initiates viral replication leading to production of new virion particle, which in turn infect new cells. In certain cells, HIV remains latently infected for a long time, and they may also become an active source of viral replication due to some activation mechanism, for which the exact mechanism is not well known.

Azidothymidine is the first medicine approved by Federal Drug Administration (FDA), USA to treat HIV infections. Later on various drugs have been developed for HIV treatment and these drugs blocks different stages of HIV replication. There is no doubt that there is unprecedented progress in anti-retroviral treatment, which has helped tremendously to improve the morbidity and mortality among HIV seropositives. Due to the availability of improved anti-retroviral drugs a HIV seropositive can live more than 20 years post HIV-infections. Out of all these treatment strategies, a new treatment regimen i.e., Highly Active Anti-retroviral Treatment (HAART) is found to be very effective to reduce viral replication significantly. Still the fact is HIV infection can be controlled only and cannot be cures.

Since, HIV infection are usually fatal and HIV infected patients are fond all across the globe, therefore, it was very difficult to manage and understand the treatment strategies for HIV infection, therefore, a need for classification of HIV infection was realised.

Need for Classification

HIV has emerged as a new disease with increasing number of its victim day-by-day. With time various tests for its diagnosis has developed along with various drugs has also evolved with time. Combination of drugs and diagnostic test has helped to generate the data both for clinical situation as well as in laboratory conditions. Every clinician or group of clinician as well laboratory scientist were interpreting data to their ability to treat patients as well as efforts to improve the conditions of HIV seropositive, where there is consistent need for the development of new drugs too. This kind of prevailing situation has been realized as a major impediment for the desired improvement in situation in HIV patient. This has become a problem to monitor HIV surveillance, epidemiology, health status of patients, designing new diagnostic tool, recommendation of different diagnostic test, recommendation of appropriate treatment strategies, maintenance of clinical data, consultation and advice from other clinician for the same patients, comparison of prevalence from one geographical location to another. It was felt that improvement of prevailing limitation for HIV infections can be achieved by developing a classification of clinical conditions into different categories on the basis of existing clinical and laboratory data.

This task for the first time was taken by Center for Disease Control and Prevention, Atlanta, USA (CDC). They have given the first ever classification of various clinical conditions of HIV seropositives in 1986, which has helped tremendously for the clinical management of HIV patients and with time CDC revise this classification based on better understanding of the clinical conditions as well as diagnostic data, as they pour in. Later on, World Health Organization (WHO) has also developed a new classification for HIV infection, which works as a reference standard through the world. Although various other classification systems does exist in the literature, but one of the most acceptable and followed one are classification of clinical conditions developed either by CDC or WHO. The classification systems developed by CDC and WHO has the same purpose and their core is the same, but cater the need of different situations.

CDC has developed a classification system initially to cater the need for a better understanding and developing strategies to control HIV infection in USA. USA being one of the most resourceful country of the world, so the criteria for classification was based on more on diagnostic data i.e., CD4 counts and viral loads, as we know these two are closely linked to each other. As matter of fact, these two clinical parameters are inversely related to each other. Undoubtedly, CDC system has certain important end points which are very useful to understand, design and develop treatment regimen for HIV seropositives. It is unfortunate, that all the people who get infection of HIV do not live in resourceful settings like USA, because neither they have all the facility to monitor the progression of disease with the help of expensive diagnostic test nor even they have access to all the expensive drugs to treat or control HIV infections. As a matter of fact, a due consideration was given by WHO to rescue the patients who live in less fortunate conditions, therefore WHO have evolved a classification system in 1990, which is based simply on the clinical signs and symptoms, although at some point of time, these cases has to go under diagnostic test too for further confirmation. Some of these situations have been improved with the development of a new institution known as UNAIDS, which works under the umbrella of UN.

Staging and Classification System by WHO

The WHO clinical staging system for HIV/AIDS was developed in 1990 and it has emphasized on clinical parameters as a guide for clinical decision-making. WHO system is very useful in resource limited settings, where patients have access to limited laboratory services. The WHO clinical staging system has been widely used in resource-limited countries, particularly in the African Region. This clinical staging can be effectively used even without the access to CD4 counts or other laboratory testing. But it is important to know that the data on CD4 levels is not a prerequisite to start antiretroviral therapy. It should only be used with the consideration of clinical stages. In 2005, WHO has revised it classification system for different clinical stages of HIV infections. WHO classification has developed a 4 stage system and those are 1) Stage I, 2) Stage II, 3) Stage III, and 4) Stage IV. Description of different stages has been given below.

Stage I: Primary HIV Infection or Seroconversion

Primary HIV infection or it is also known as acute HIV infections which occur within 2-4 weeks after initial exposure to HIV. During this phase there are large amounts of virus produced in body present in the peripheral blood of the patients and immune system respond to protect the host by antibodies against HIV antibodies as well as increase in cytotoxic T lymphocytes. This process is also known as Seroconversion. At this stage the common symptoms are mild influenza-like symptoms like fever, diarrhoea, sore throat, headaches etc. >65% cases of HIV infection are presented with these symptoms. Diagnosis of this stage is usually based detection of HIV antigens or anti-HIV antibodies in blood samples. Confirmatory tests are recommended to the patients turn out to be negative but with known history to be classified as high-risk behaviour.

Stage II: Asymptomatic Stage

Seroconversion stage is followed by asymptomatic stage lasts about ten years. During this stage viral replication slows down but does not stop. In the peripheral blood HIV level drops to very low levels. Although, antibodies against HIV can be detected in blood on regular basis. The CD4 T-cell counts are usually above 500 cells/mm3, some patient also shows CD4 T-cell count below 500 cells/mm3.

This phase can be further extended in HIV seropositives with the right choices of anti-retroviral treatments. In the present time this stage can be prolonged even up to 20 years post HIV infection with the administration of improved anti-retroviral drugs. The main objective of any treatment strategy is to keep the viral replication to minimal levels, so that immune-status deterioration can be minimized.

Stage III: Persistent Generalized Lymphoadenopathy

There are usually no signs or symptoms present in this phase, however, there may be a persistent generalized lymphadenopathy which lasts for 3 months or more at a time. It causes swollen nodes, which are usually >1cm in diameter. The patients look otherwise healthy, non-specific adenopathy may persist, but lymph node biopsy is not recommended as routine. Stage IV: Symptomatic Stage

Symptomatic HIV infection is mainly presented with higher incidences of various opportunistic infections and AIDS associated cancers. This stage of HIV infection is often characterised with multi-system disease and infections which affects all body systems. A rapid decline in immune-status is observed due to enhances HIV replication leading to rapid progression of various diseases. Some constitutional symptoms like fever, malaise, etc. appear at this stage, but they can be treated easily treated. At these stages to control HIV replication is difficult. The choices for therapeutic interventions for the improvement of health status of patients are either limited or not very useful. These symptoms are signs of terminal illness and require counselling of the patient about the final outcome of the disease rather than keeping patients in dark about the outcome.

Table 1: Clinical Stages and Common Signs and Symptoms


Stage Signs and symptoms


Stage I

Primary HIV infection Asymptomatic

(Seroconversion) Acute retroviral syndrome

CD4 >500 cells/mm3

Stage II

Asymptomatic Phase Moderate weight loss

Recurrent respiratory tract infections

Herpes zoster

Angular cheilitis

Recurrent oral ulcerations

Papular pruritic eruptions

Seborrhoeic dermatitis

Fungal nail infections of fingers

CD4 >350-499 cells/mm3

Stage III

Generalized Lympadenopathy

Severe weight loss

Unexplained chronic diarrhoea

Unexplained persistent fever

Oral candidiasis

Oral hairy leukoplakia

Pulmonary tuberculosis (TB)

Acute stomatitis, gingivitis or periodontitis

CD4 >200-349 cells/mm3

Stage IV

Symptomatic Phase HIV wasting syndrome

Pneumocystis pneumonia

Chronic herpes simplex infection

Oesophageal candidiasis

Extrapulmonary TB

Kaposi's sarcoma

Central nervous system (CNS) toxoplasmosis

HIV encephalopathy, etc.

CD4 <200 cells/mm3