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Anti-retroviral

1. What is antiretroviral therapy ?

2. What drugs are available ?

There are three general types of antiretroviral drugs that are currently available by prescription (Table 1) or through pharmaceutical companies (expanded access programs) or clinical trials. Antiretroviral drug categories include:

Nucleoside reverse transcriptase inhibitors (NRTIs)

This group, which has been studied the most, includes zidovudine (AZT), didanosine (ddI), zalcitabine (ddC,) stavudine (d4T), lamivudine (3TC), and abacavir (ABC, Ziagen). Tenofovir (Viread) is a recently approved nucleoside agent. These drugs act by blocking a step in the reproduction of HIV called reverse transcription. This step is necessary for HIV to be prepared for incorporation into the genetic material of cells. All of these agents are available by prescription.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

This group includes nevirapine , delavirdine and efavirenz . Non-nucleoside agents also block HIV reverse transcription, but they do so in a different way than nucleoside drugs.

Protease inhibitors (PIs)

This group includes saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir/ritonavir (KALETRA), many of which are available by prescription in India. These drugs work by blocking the action of protease, a protein made by HIV, which the virus must have to reproduce and infect new cells. Protease inhibitors are the most active group of anti-HIV drugs discovered to date.

3. What is known about the effectiveness of antiretroviral therapy ?

Clinical studies show that antiretroviral drugs, when used in combination, can benefit many persons with HIV disease. This type of therapy is effective in reducing the level of circulating virus in the blood, in raising CD4 cell ("T-cell") counts, in preventing the development of complications, and in prolonging life. This beneficial effect may last several years or longer in some people and lasts as long as the virus remains susceptible to the drugs being taken. When drug resistance develops the therapy has to be changed. However, these drugs may not help everyone with HIV disease, and there remains uncertainty about how to make best use of the available agents.

Like any form of treatment, decisions about antiretroviral therapy must fit your individual needs, budgets and expectations. You should discuss with your doctor any issues that may interfere with your ability to take these medications as prescribed. Frequently missed doses diminish their effectiveness and increase the likelihood of the virus developing resistance, thus causing the therapy to be ineffective.

4. When should I start antiretroviral therapy ?

Most experts recommend starting antiretroviral therapy if you have significant symptoms related to HIV disease (AIDS or sever symptoms), if your CD4 cell ("T-cell") count is less than 350/mm3, or if your HIV viral load (level of virus in blood) is more than 30,000 (bDNA) or 55,000 (RT-PCR)copies/ml.

5. What agents should be used ?

A combination of at least three drugs is recommended. In general, a combination of two NRTIs and a PI or two NRTIs and an NNRTI is recommended. Occasionally other types of combinations, such as three NRTIs or dual PI therapy, may be suggested. Decisions about which agents to use should be based not only on their effectiveness but also on their potential side effects and your ability to take them reliably.

6. How should I be monitored when on antiretroviral therapy ?

Before starting combination antiretroviral therapy, your doctor will perform baseline laboratory studies, including a complete blood count, chemistries, CD4 count, and viral load. These laboratory studies will be repeated about four weeks later. An effective regimen should lower the viral load significantly, gradually raise the CD4 count, and not cause important side effects or laboratory abnormalities. If your antiretroviral regimen is successful, it will be continued, with laboratory studies repeated every three to four months thereafter.

7. When should my antiretroviral regimen be changed ?

Your combination of antiretroviral drugs should be changed if you are experiencing serious side effects, if your viral load is rising, if your CD4 count is dropping, or if you develop significant new complications of HIV disease.

8. What new drug combination should I receive?

There are some generally accepted recommendations for modifying antiretroviral regimens that are not working. These include:
1) changing multiple agents at the same time; and
2) choosing drugs that are unlikely to share cross-resistance with current ones.
Cross resistance refers to when a viral strain resistant to one drug is also resistant to another. Genotypic testing (profile of virus mutations) and phenotypic testing (profile of virus resistance pattern to drugs) are playing an increasingly important role in helping to select new antiretroviral regimens in developed countries.

9. How can I access experimental drugs?

Clinical trials evaluate various antiretroviral drug combinations. Some agents being tested in clinical trials are also available through pharmaceutical company expanded access programs. Your doctor or local HIV/AIDS service organization should be able to provide specific information regarding these options.

Table 1.
Antiretroviral Agents
Agent	Type	Dose	Major Toxicities
AZT	NRTI	300 mg bid	nausea, headache, low blood counts
ddI	NRTI	125-200 mg bid or 250-400 mg qd (tablet form)	diarrhea, pancreatitis, peripheral neuropathy
ddC	NRTI	0.750 mg tid	diarrhea, peripheral neuropathy
d4T	NRTI	30-40 mg bid	abnormal liver function tests, peripheral neuropathy
3TC	NRTI	150 mg bid	minor
abacavir	NRTI	300 mg bid	hypersensitivity reaction
tenofovir	NRTI (nucleotide)	300 mg qd	nausea, diarrhea, vomiting, flatulence
AZT/3TC	NRTI	one pill bid (300 mg AZT /150 mg 3TC)	see above
AZT/3TC/abacavir	NRTI	one pill bid (300 mg AZT/ 150 mg 3TC/ 300 mg abacavir)	see above
nevirapine	NNRTI	200 mg bid	rash
delavirdine	NNRTI	400 mg tid	rash
efavirenz	NNRTI	600 mg qhs	rash, dizziness, impaired concentration, insomnia, abnormal dreams
saquinavir (Fortovase)	PI	1200 mg tid	diarrhea
ritonavir	PI	600 mg bid	nausea/vomiting, drug interactions
indinavir	PI	800 mg tid	kidney stones
nelfinavir	PI	750 mg tid or 1250 mg bid	diarrhea
amprenavir	PI	1200 mg bid	nausea/vomiting, diarrhea, rash
lopinavir/ritonavir	PI	three capsules bid (133.3 mg lopinavir /33.3 mg ritonavir)	diarrhoea, nausea, weakness, headache
NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; qd = once a day; bid = twice a day; tid = three times a day; qhs = at bedtime. Symptoms of pancreatitis include nausea/vomiting and abdominal pain; symptoms of peripheral neuropathy include numbness, tingling, or burning of hands or feet. Abacavir hypersensitivity reaction consists of fever, nausea/vomiting, muscle aches, cough, shortness of breath, and/or rash.
Lactic acidosis with liver disease has been reported infrequently in patients taking nucleoside analog drugs. Abnormalities of fat and sugar metabolism, and redistribution of body fat have also been described in patients using combination antiretroviral therapy.

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