HIV infection
After primary infection, there is a long asymptomatic phase, which may last for several years. Thus, the patient who is infected with HIV, but is asymptomatic or mildly symptomatic, is referred to as "HIV positive". During this phase, the virus is actively multiplying and destroying the CD4 cells.

AIDS
When the CD4 cells decrease to 200 cells/ l, or the patient starts suffering from a characteristic range of severe opportunistic infections(AIDS-defining illnesses), he is said to be suffering from AIDS. It may take 8-10 years to reach this stage, although this may vary between patients.

Thus, AIDS represents an advanced stage of HIV infection, when the patient suffers from a characteristic range of opportunistic infections.

HIV infection and AIDS in South-East Asia (WHO)
Recognition of Symptomatic HIV infection - Suggestive clinical findings
1. Fever of more than one month's duration
2. Weight loss of more than 10%
3. Diarrhoea of more than one month's duration
4. Mucocutaneous manifestations
5. Generalised lymphadenopathy (extra-inguinal)
6. Infections, severe or recurrent

• Past or present multidermatomal herpes zoster
• Hairy leukoplakia
• Warts
• Molluscum contagiosum
• Oral thrush
• Papulonecrotic lesion
• Folliculitis
• Vulvovaginitis

7. Others

• Severe recurrent seborrheic dermatitis
• Chronic prurigo
• Reiter's syndrome
• Kaposi's sarcoma

8. Unexplained neurological manifestations e.g. seizures, motor or sensory deficits, dementia and progressive headache

9. Chronic cough of more than one month's duration or unexplained respiratory distress

10. Cytomegalovirus retinitis

11. Extrapulmonary or disseminated and extensive pulmonary tuberculosis

12. Recurrent pneumonia

13. Invasive cervical carcinoma

WHO clinical case definition for AIDS in South-East Asia
Clinical AIDS in an adult is defined as an individual who has been identified as meeting the two criteria A and B below:

A. Positive test for HIV infection by two tests based on preferably two different antigens.

B. Any one of the following criteria:

1. - Weight loss of 10% body weight or cachexia, not known to be due to a condition unrelated to HIV infection
   - Chronic diarrhoea of one month's duration, intermittent or constant
2. Disseminated, miliary or extrapulmonary tuberculosis
3. Candidiasis of the oesophagus; diagnosable as dysphagia, odynophagia and oral candidiasis
4. Neurological impairment restricting daily activities, not known to be due to a condition unrelated to HIV (e.g. trauma)
5. Kaposi's sarcoma.

What is the treatment approach for an HIV-positive patient?
Basically, the treatment of an HIV-infected patient involves:
A) Inhibiting the replication of the virus using antiretroviral drugs
B) Treatment and prophylaxis of opportunistic infections
C) Psychosocial support

What does antiretroviral therapy do?
Antiretroviral therapy helps in:
1. Inhibiting viral replication
2. Preserving immune function
3. Preventing disease progression
4. Reducing the incidence of opportunistic infections
5. Prolonging survival

What is the goal of antiretroviral therapy?
Currently, the goal of antiretroviral therapy is to bring down viral load to undetectable levels, usually below 50 copies/ml. The time taken to achieve this goal depends on the baseline viral load. In most patients, adherence to a triple drug antiretroviral regimen results in a large decrease (about 1 log10 or ten fold) in viral load by 2-8 weeks. The viral load should continue to decline over the following weeks and in most individuals becomes undetectable (<50 RNA copies/ml) by 16-20 weeks.

The durability of the plasma viral load response is critical for the long term clinical outcome of the patient. Data suggest that the initial decline of viral load is predictive of the durability of viral load suppression.

Benefits of antiretroviral therapy
Antiretroviral therapy has been proven to be effective in:
1. Decreasing viral load
2. Increasing CD4 counts
3. Decreasing the incidence of opportunistic infections
4. Preventing disease progression
5. Prolonging survival
6. Enabling the patient to lead a productive life e.g. resuming his job
7. Improving quality of life
8. Possibly reducing the risk of transmission

Classes of antiretrovirals
Antiretrovirals generally target two key enzymes that the virus requires in order to replicate: protease and reverse transcriptase.

Thus, protease inhibitors (PIs) target the protease enzyme, whereas reverse transcriptase inhibitors target the reverse transcriptase enzyme. Reverse transcriptase inhibitors are further divided into two types - nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) - based on slight differences in their chemical structure and mode of action.

Classification of antiretrovirals

How do these drugs act?
An essential step for HIV replication is the conversion of its RNA to DNA. This step is mediated by reverse transcriptase. Both NRTIs and NNRTIs inhibit reverse transcriptase.

After multiplication of the virus is complete, the enzyme protease is required for maturation of these newly produced viruses. Protease inhibitors inhibit this enzyme.

Thus, HIV replication can be inhibited by inhibiting these crucial enzymes.

When should antiretroviral therapy be initiated?
In an asymptomatic patient, current international guidelines recommend that antiretroviral therapy should be initiated when CD4 count goes below 350 cells/ l or HIV RNA is above 30-55,000 copies/ml. All symptomatic patients should be offered antiretroviral therapy irrespective of CD4 counts or plasma viral load.

The best indication to start antiretroviral therapy is when a well-informed patient is ready.

Why is combination therapy recommended?
HIV has the ability to rapidly develop resistance if any one drug is used alone. Hence, a minimum of three drugs have to be used in combination. This triple drug regimen is commonly referred to as HAART, which is an acronymn for Highly Active Antiretroviral Therapy.

What are the strategies for using antiretroviral therapy?
Even if triple therapy is used, over a period of time, there is a possibility of the virus developing resistance and the patient failing his initial treatment regimen (manifested by an increase in viral load occurring after viral suppression has been demonstrated). Hence, the initiation of antiretroviral therapy should be viewed as the beginning of a longer term strategy. When choosing an initial regimen, possible future combinations have to be borne in mind.

In other words, clinicians should design a long-term plan for the patient, as discussed below.

How is antiretroviral therapy initiated?
It is recommended to initiate antiretroviral therapy in naïve patients (i.e. patients who have not yet been treated with antiretrovirals) using a combination of two NRTIs with either one PI or one NNRTI. For example, zidovudine + lamivudine + indinavir or stavudine + lamivudine + nevirapine or efavirenz.

An alternative initial regimen consists of 2 PIs with 2 NRTIs. The simultaneous initiation of all the drugs is recommended and sequential addition should be avoided.

While choosing the 2 NRTI component of triple drug therapy, the following two-drug combinations should not be used, as they are either antagonistic, or have overlapping toxicities.

1. Zidovudine + Stavudine
2. Zalcitabine + Stavudine
3. Zalcitabine + Didanosine

What are the recommendations for treating a patient who has failed the initial antiretroviral regimen?
If, for example, a patient has started therapy on a PI-based regimen and is no longer responding to this regimen, his second-line regimen may include an NNRTI-based regimen, and vice versa. It is recommended that the second-line regimen should ideally contain three drugs to which the patient has never been exposed. Moreover, these second-line drugs should not be cross-resistant with the first-line drugs - most PIs and all NNRTIs show cross-resistance.

What are the possible advantages and disadvantages of initiating therapy with PI-based versus NNRTI-based regimens?
Table: Advantages and disadvantages of PI-based and NNRTI-based initial regimens

In treatment-experienced patients, there are more data to support the use of PI-based regimens. Some metabolic complications, such as lactic acidosis, have been ascribed to the NRTI component of combination antiretroviral regimens.

Which antiretrovirals are available in India?

* Manufactured in India by Cipla

Which fixed-dose combinations are available in India?*

* Manufactured in India by Cipla

How long should the HIV-infected patient continue taking antiretrovirals?
It is important to appreciate that antiretroviral therapy should be continued indefinitely. This is because therapy is suppressive and not curative. The patient should be started on antiretrovirals only if he is committed to lifelong therapy.

Why can't HIV infection be eradicated?
HIV infects various cells and body compartments including the CNS, testes, etc. The virus remains latent in certain cells such as the long-lived resting memory CD4 cells. Antiretroviral therapy is not effective against these cells as they are not actively multiplying. Hence eradication of HIV is presently not considered to be a realistic goal.

What are the triple drug antiretroviral combinations offered by Cipla?

• Lamivudine + Stavudine + Nevirapine (TRIOMUNE-30/40)
• Zidovudine + Lamivudine + Nevirapine (DUOVIR-N)
• Lamivudine + Stavudine (LAMIVIR-S 30/40) + Efavirenz (EFAVIR)
• Zidovudine + Lamivudine (DUOVIR) + Efavirenz (EFAVIR)
• Lamivudine + Stavudine (LAMIVIR-S 30/40) + Indinavir (INDIVAN)
• Zidovudine + Lamivudine (DUOVIR) + Indinavir (INDIVAN)
• Didanosine (DINEX) + Stavudine (STAVIR-40) + Nevirapine (NEVIMUNE)
• Didanosine (DINEX) + Stavudine (STAVIR-40) + Efavirenz (EFAVIR)
• Didanosine (DINEX) + Stavudine (STAVIR-40) + Indinavir (INDIVAN)

There are many issues associated with the use of antiretroviral therapy, such as:

1. Adherence

Adherence is a crucial determinant of therapeutic success with antiretrovirals. The issue of compliance with multidrug antiretroviral regimens has been addressed with the introduction of fixed-dose combinations of antiretrovirals, which combine 2 or all 3 drugs into a single pill. This drastically reduces the overall pill burden and improves compliance with therapy.

In this regard, NNRTI-based regimens have lower pill burdens as compared to PI-based regimens. Moreover, NNRTI-based regimens are not associated with complex restrictions regarding food intake and storage.

2. Drug interactions

The NNRTI class of drugs exhibits a few drug interactions, whereas the NRTI class is not associated with clinically significant drug interactions.

The protease inhibitors most frequently exhibit drug interactions with each other, and also with other drugs e.g. anti-TB drugs, antifungals. This poses a problem for treating the HIV-positive patient, because these are common opportunistic infections, especially in our country.

3. Side effects
The non-nucleoside reverse transcriptase inhibitors are generally associated with short-term hypersensitivity reactions, such as rash. In contrast, the protease inhibitors are associated with some of the most severe long-term side effects. These include:

• Lipodystrophy (the arms, legs and face appear to lose weight, whereas the central portion of the body accumulates fat and becomes obese)
• Diabetes
• Increased cholesterol and triglyceride levels
• Hypertension
• Osteoporosis
• Gynaecomastia
• Kidney stones (indinavir)

The non-nucleoside reverse transcriptase inhibitor class of drugs is not associated with significant long term toxicities, but certain patients may develop a rash or elevated liver enzymes during the first few weeks of therapy.

The nucleoside reverse transcriptase inhibitor class of drugs may be associated with anemia (zidovudine), lactic acidosis, peripheral neuropathy or pancreatitis.

4. Access
The patient should be able to afford antiretroviral therapy for an indefinite period of time. Towards this end, Cipla has endeavoured to make antiretroviral therapy more affordable by drastically reducing the price of its antiretroviral range.

All the above issues need to be discussed with the patient prior to starting treatment.

Before initiating antiretroviral therapy, it is essential to discuss the following points with the patient:

• Therapy available today is suppressive, and not curative. But treatment helps the patient to lead a more productive and healthy life.
• The duration of therapy is lifelong. HIV may be regarded as a chronic illness, just like diabetes or hypertension.
• Although treatment is expensive, the prices of antiretrovirals have now been reduced.
• Long term adverse events may occur, but there are drugs to manage these side effects.
• There is a potential for drug interactions with other concomitant medications.
• There may be a number of pills to be swallowed per day, depending on the antiretroviral regimen chosen. However, some of the newer regimens entail taking a total of only 2-5 tablets per day.
• Adherence is critical, else the virus quickly develops resistance. This is especially important with respect to antiretroviral drugs.
• It is important to inform patients that even if they are receiving therapy they should not donate blood and should practice protected sex, since the patient is still capable of infecting others.

Cipla has also taken the initiative in bringing out a patient education booklet titled 'Living with Hope'.* This is available in the following languages: English, Hindi, Marathi, Gujarati, Tamil, Telugu, Malayalam, Kannada and Bengali. This booklet answers practical questions on HIV infection and its treatment that are commonly asked by patients.