Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. A retrovirus is any Virus belonging to the viral family Retroviridae. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome When several such drugs, typically three or four, are taken in combination, the approach is known as highly active antiretroviral therapy, or HAART. The National Institutes of Health and other organizations recommend offering antiretroviral treatment to all patients with AIDS. "NIH" redirects here For other meanings of NIH see NIH (disambiguation. Because of the complexity of selecting and following a regimen, the severity of the side effects and the importance of compliance to prevent viral resistance, however, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits to patients without symptoms. Drug resistance is the reduction in effectiveness of a drug in curing a disease or improving a patient's symptoms ^[1]

There are different classes of antiretroviral drug that act at different stages of the HIV life cycle.

Contents 1 Classes of drug 1.1 Fixed dose combinations 1.2 Synergistic enhancers 2 Combination therapy 3 Current treatment guidelines 4 Concerns 5 Responses to treatment in older adults 6 Limitations of antiretroviral drug therapy 7 Adverse effects 8 See also 9 References 10 External links

Classes of drug

Antiretroviral drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits.

• Nucleoside & nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription by being incorporated into the newly synthesized viral DNA and preventing its further elongation. Reverse transcriptase inhibitors (RTIs are a class of Antiretroviral drug used to treat HIV infection Tumors, and Cancer.
• Non-nucleoside reverse transcriptase inhibitors (nNRTI) inhibit reverse transcriptase directly by binding to the enzyme and interfering with its function. Reverse transcriptase inhibitors (RTIs are a class of Antiretroviral drug used to treat HIV infection Tumors, and Cancer.
• Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for final assembly of new virons. For natural protease inhibitors please see Protease inhibitor (biology Protease inhibitors (PIs are a class of Medications used A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable
• Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. Integrase inhibitors are a class of Antiretroviral drug designed to block the action of Integrase, a viral enzyme that inserts the viral genome into the DNA Integrase is an enzyme produced by a Retrovirus (including HIV) that enables its genetic material to be integrated into the DNA of the infected cell The pre-integration complex is generally composed of the viral genetic material and associated proteins (viral and host after release into the cell There are several integrase inhibitors currently under clinical trial, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir (MK-0518 brand name Isentress) is an Antiretroviral drug produced by Merck & Co, used to treat HIV infection
• Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class. Maraviroc (brand-named Selzentry, or Celsentri outside the US Enfuvirtide ( INN) is an HIV Fusion inhibitor, the first of a novel class of Antiretroviral drugs used in Combination therapy for the
• Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Bevirimat is an anti-HIV drug derived from a Betulinic acid -like compound first isolated from Syzygium claviflorum a Chinese herb The Genome and Proteins of HIV have been the subject of extensive research since the discovery of the virus in 1983 Because these viral particles have a defective core, the virions released consist mainly of non-infectious particles. There are no drugs in this class currently available, though two are under investigation, bevirimat^[2] and Vivecon. Bevirimat is an anti-HIV drug derived from a Betulinic acid -like compound first isolated from Syzygium claviflorum a Chinese herb Vivecon is an Investigational new drug in development for the treatment of HIV infection

Fixed dose combinations

Fixed dose combinations are multiple antiretroviral drugs combined into a single pill. Fixed dose combinations of antiretrovirals are multiple antiretroviral drugs combined into a single pill which helps reduce Pill burden.

Synergistic enhancers

Synergistic enhancers either do not possess antiretroviral properties alone or are inadequate or impractical for monotherapy, but when they are taken concurrently with antiretroviral drugs they enhance the effect of one or more of those drugs (often by altering the metabolism of antiretrovirals). Synergistic enhancers of antiretrovirals usually do not possess any antiretroviral properties alone but when they are taken concurrently with antiretroviral drugs they enhance These include ritonavir which is an antiretroviral drug which belongs to the class of protease inhibitors. Ritonavir, with trade name Norvir For natural protease inhibitors please see Protease inhibitor (biology Protease inhibitors (PIs are a class of Medications used It can however be administered at a "baby" dosage to reduce the liver metabolism of other antiretroviral drugs. This principle was first exploited in the drug Kaletra (Abbott), which is a combination of ritonavir with the protease inhibitor lopinavir at a ratio (v/v) of 1:4. Lopinavir ( ABT-378) is an antiretroviral of the protease inhibitor class Lopinavir ( ABT-378) is an antiretroviral of the protease inhibitor class In Chemistry, concentration is the measure of how much of a given substance there is mixed with another substance Ritonavir is also used as an enhancer of other protease inhibitors such as saquinavir and atazanavir, and of the investigational integrase inhibitor, GS-9137. For natural protease inhibitors please see Protease inhibitor (biology Protease inhibitors (PIs are a class of Medications used Saquinavir is an Antiretroviral drug used in HIV therapy It falls in the protease inhibitor class Atazanavir, trade name Reyataz, (formerly known as BMS-232632 is an Antiretroviral drug of the protease inhibitor (PI class Integrase inhibitors are a class of Antiretroviral drug designed to block the action of Integrase, a viral enzyme that inserts the viral genome into the DNA Other synergistic enhancers are being investigated for this purpose.

Combination therapy

The life cycle of HIV can be as short as about 1. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome 5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells. ^[3] HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known Reverse transcription is the process of making a double stranded DNA (deoxyribonucleic acid molecule from a single stranded RNA (ribonucleic acid template Its short life cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable Natural selection is the process by which favorable Heritable traits become more common in successive Generations of a Population of The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made, so antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible.

Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation arises that conveys resistance to one of the drugs being taken, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs. Combinations usually comprise two nucleoside-analogue RTIs and one non-nucleoside-analogue RTI or protease inhibitor. ^[4] This three drug combination is commonly known as a triple cocktail. ^[5]

Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations. Synergy (from the Greek el-Latn syn-ergo, el συνεργός meaning working together is the term used to describe a situation where the final outcome For example, ddI and AZT inhibit each other, so taking them together is less effective than taking either one separately. Other issues further limit some people's treatment options from antiretroviral drug combinations, including their complicated dosing schedules and often severe side effects.

In recent years drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed dose combinations. Fixed dose combinations of antiretrovirals are multiple antiretroviral drugs combined into a single pill which helps reduce Pill burden. For instance, two pills containing two or three medications each can be taken twice daily. This greatly increases the ease with which they can be taken, which in turn increases adherence, and thus their effectiveness over the long-term. Lack of adherence is a primary cause of resistance development in medication-experienced patients. Patients able to adhere at this rate and higher can maintain one regimen for up to a decade without developing resistance. This greatly increases chances of long-term survival, as it leaves more drugs available to the patient for longer periods of time.

Current treatment guidelines

Antiretroviral drug treatment guidelines have changed many times. Early recommendations attempted a "hit hard, hit early" approach. A more conservative approach followed, with a starting point somewhere between 350 and 500 CD4+ T cells/mm³. The current guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and their doctor.

The current guidelines for antiretroviral therapy (ART) from the World Health Organization reflect the 2003 changes to the guidelines and recommend that in resource-limited settings (that is, developing nations), HIV-infected adults and adolescents should start ART when HIV infection has been confirmed and one of the following conditions is present ^[6]:

• Clinically advanced HIV disease;
• WHO Stage IV HIV disease, irrespective of the CD4 cell count;
• WHO Stage III disease with consideration of using CD4 cell counts less than 350/µl to assist decision making;
• WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl.

The treatment guidelines in the USA are set by the United States Department of Health and Human Services (DHHS). The United States Department of Health and Human Services ( HHS) is a Cabinet department of the United States government with the goal of protecting The current guidelines for adults and adolescents were stated on October 6, 2005 ^[7]:

• All patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count receive ART.
• Antiretroviral therapy is also recommended for asymptomatic patients with less than 200 CD4+ T cells/µl.
• Asymptomatic patients with CD4+ T cell counts of 201–350 cells/µl should be offered treatment.
• For asymptomatic patients with CD4+ T cell of greater than 350 cells/µl and plasma HIV RNA greater than 100,000 copies/ml, most experienced clinicians defer therapy but some clinicians may consider initiating treatment.
• Therapy should be deferred for patients with CD4+ T cell counts of greater than 350 cells/µl and plasma HIV RNA less than 100,000 copies/mL.

The preferred initial regimens are^[8]:

• efavirenz + zidovudine + lamivudine
• efavirenz + tenofovir + emtricitabine
• lopinavir boosted with ritonavir + zidovudine + lamivudine
• lopinavir boosted with ritonavir + tenofovir + emtricitabine. Efavirenz (brand names Sustiva and Stocrin) is a Non-nucleoside reverse transcriptase inhibitor (NNRTI and is used as part of highly active antiretroviral Zidovudine ( INN) or azidothymidine ( AZT) (also called ZDV is a nucleoside analog reverse transcriptase inhibitor (NRTI a type of Antiretroviral Lamivudine (2'3'-dideoxy-3'-thia Cytidine, commonly Tenofovir disoproxil fumarate ( TDF or PMPA) marketed by Gilead Sciences under the trade name Viread, belongs to a class of Antiretroviral Emtricitabine ( FTC) with trade name Emtriva (formerly Coviracil) is a Nucleoside Reverse transcriptase inhibitor (NRTI for the Lopinavir ( ABT-378) is an antiretroviral of the protease inhibitor class Ritonavir, with trade name Norvir

In countries with a high rate of baseline resistance, resistance testing is recommended prior to starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started which is then modified on the basis of resistance testing. In the UK, there is 11. 8% medium to high level resistance at baseline to the combination of zidovudine + lamivudine + efavirenz, and 6. Zidovudine ( INN) or azidothymidine ( AZT) (also called ZDV is a nucleoside analog reverse transcriptase inhibitor (NRTI a type of Antiretroviral Lamivudine (2'3'-dideoxy-3'-thia Cytidine, commonly Efavirenz (brand names Sustiva and Stocrin) is a Non-nucleoside reverse transcriptase inhibitor (NNRTI and is used as part of highly active antiretroviral 4% medium to high level resistance to stavudine + lamivudine + nevirapine. Stavudine (2'-3'-didehydro-2'-3'-dideoxythymidine d4T, brand name Zerit) is a nucleoside analog reverse transcriptase inhibitor (NARTI active against Lamivudine (2'3'-dideoxy-3'-thia Cytidine, commonly Nevirapine, also marketed under the trade name Viramune ( Boehringer Ingelheim) is a non-nucleoside Reverse transcriptase inhibitor (NNRTI used to treat ^[9]

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations from the DHHS have been more aggressive in children than in adults, the current guidelines were published November 3, 2005 ^[10].

In 2005, the Centers for Disease Control and Prevention in the United States recommended a 28-day HIV drug regimen for those who have been exposed to HIV (HIV Postexposure Prophylaxis [PEP])^[11]. The drugs have demonstrated effectiveness in preventing the virus nearly 100% of the time in those who received treatment within the initial 24 hours of exposure. The effectiveness falls to 52% of the time in those who are treated within 72 hours; those not treated within the first 72 hours are not recommended candidates for the regimen.

Concerns

There are several concerns about antiretroviral regimens. The drugs can have serious side effects. ^[12] Regimens can be complicated, requiring patients to take several pills at various times during the day, although treatment regimens have been greatly simplified in recent years. If patients miss doses, drug resistance can develop. ^[13] Also, providing anti-retroviral treatment is costly and resource-intensive, and the majority of the world's infected individuals cannot access treatment services.

Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance.

Responses to treatment in older adults

As people age, their bodies aren't able to repair and rebuild damaged cells, organs or tissues as rapidly as those of younger people. Diseases like HIV that attack and destroy the body's defenses can exacerbate this slowing and increase the risk of developing additional medical problems like diabetes and high blood pressure, and more physical limitations than younger adults with HIV. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc Blood pressure is also the title of a short story by Damon Runyan in Guys and Dolls and Other Stories In the early years of the HIV epidemic (before HAART), older adults' health deteriorated more rapidly than that of younger individuals - regardless of CD4 count. CD4 ( Cluster of differentiation 4 is a Glycoprotein expressed on the surface of T helper cells, Regulatory T cells, Monocytes, Several studies found that older adults had lower CD4 counts at diagnosis, faster progression to an AIDS diagnosis, more opportunistic infections, and a shorter survival rate than younger adults, regardless of when they were first diagnosed with HIV.

Recent studies have found that a person's age doesn't interfere with the ability of HAART to reduce viral load, but there may be differences between younger and older people in how well the immune system responds to treatment. Viral load is a measure of the severity of a viral infection and can be calculated by estimating the amount of virus in an involved body fluid A study published in AIDS (2000) by Roberto Manfredi and Francesco Chiodo examined the effect of HAART on older people (defined as 55 or older) compared to younger people (35 or younger). The study included 21 older people (8 women, 13 men) and 84 younger people (29 women, 55 men). The researchers found that both groups responded to HAART, especially in reducing viral load. However, CD4 counts did not increase as much in the older people relative to the younger ones. On average, CD4 counts increased from 212 to 289 for older adults after one year of HAART. During the same period, CD4 counts rose from 231 to 345 for younger people.

Some people may have a very low CD4 count even though they have an undetectable viral load. This may be related to decreased activity in the thymus (the gland where CD4 cells are made). In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum. A 2001 study in AIDS conducted by researchers in Los Angeles included 80 HIV-positive veterans (13 were over 55 and 67 were younger). Although both groups of veterans showed dramatic reductions in viral load once they were on treatment, the researchers found significant differences in CD4 levels at 3, 9, 15, and 18 months. After one year on HAART, average CD4 counts increased by 50 for the older men, compared to increases of 100 for the younger ones. This difference was not related to baseline HIV viral load, coinfection with hepatitis C, or the race/ethnicity of participants. Hepatitis C is a blood-borne infectious disease that is caused by the Hepatitis C virus ( HCV) affecting the Liver. These studies represent an important first step in understanding how their age may affect older adults' response to HIV treatment, but more studies are needed to understand the long-term effects of age on HAART in older adults.

Limitations of antiretroviral drug therapy

If an HIV infection becomes resistant to standard HAART, there are limited options. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome One option is to take larger combinations of antiretroviral drugs, an approach known as mega-HAART or salvage therapy. Salvage therapy often increases the drugs' side-effects and treatment costs. Another is to take only one or two antiretroviral drugs, specifically ones that induce HIV mutations that diminish the virulence of the infection. The most common resistance mutation to lamivudine (3TC) in particular appears to do this. Thus, 3TC can be somewhat effective even alone and when the virus is resistant to it.

If an HIV infection becomes sufficiently resistant to antiretroviral-drugs, treatment becomes more complicated and prognosis may deteriorate. Treatment options continue to improve as additional new drugs enter clinical trials. However, the limited distribution of many such drugs denies their benefits to patients in the developing world.

Drug holidays (or "structured treatment interruptions"), are intentional discontinuations of antiretroviral drug treatment. A drug holiday (sometimes also called a drug vacation, medication vacation, structured treatment interruption or strategic treatment interruption Studies of such interruptions attempt to increase the sensitivity of HIV to antiretroviral drugs. The interruptions attempt to change the selection pressure from the drug resistance back toward resistance to the human immune system, thus breeding a more drug-susceptible virus. HIV spends some of its life-cycle in a state where its DNA is entirely integrated into human DNA. Under certain conditions, drug-resistant strains of the virus can remain dormant in this state, since CD4 T-cells also are dormant when not aroused by invading organisms. The resistant strain can then reemerge when antiretroviral drugs are re-introduced.

Intermittent therapy is an experimental approach designed to reduce exposure to antiretroviral drugs in an effort to mitigate side-effects. Intermittent therapy differs from treatment interruptions in that it involves using a much shorter cycle of switching on and off the antiviral drugs. Studies of such approaches include schedules of week-on, week-off (also known as "wowo") and five-days-on, two-days-off (also known as "foto"), which skips treatment on weekends. They also seek to determine what kinds of patients are best suited for this approach. However, initial data suggest that intermittent therapy is ineffective and results in drug resistance.

It is still unclear whether suppressing or even eliminating HIV will be adequate to restore normal immune function in the long term, since HIV can damage the ability of the thymus to produce normally diverse T-cells. In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum. Also, rapid suppression of HIV and partial restoration of the immune system sometimes produces a dangerous hypersensitivity reaction, immune reconstitution inflammatory syndrome. Immune reconstitution inflammatory syndrome (IRIS or immune reconstitution syndrome (IRS is a condition seen in some cases of AIDS or Immunosuppression Research continues in these areas.

Adverse effects

Adverse effects of antiretroviral drugs vary by drug, by ethnicity, and by individual, and by interaction with other drugs, including alcohol. Hypersensitivity to some drugs may also occur in some individuals. The following list is not complete, but includes several of the common adverse effects experienced by patients taking some antiretroviral drugs: ^[14]

• Abdominal pain
• Alopecia
• Anemia
• Asthenia
• Diarrhea
• Dizziness (Vertigo)
• Fanconi syndrome
• Flatulence
• Headache
• Hepatitis
• Hyperbilirubinemia
• Hypercholesterolemia (Dyslipidemia, Hyperlipidemia, high cholesterol)
• Hyperpigmentation (of nails, palms, or soles)
• Ingrown nails
• Insomnia
• Jaundice
• Lipodystrophy
• Liver failure
• Malaise
• Mental confusion
• Mitochondrial toxicity
• Myalgia
• Myalgic Encephalomyelitis (chronic fatigue syndrome)
• Myopathy
• Nausea
• Neutropenia
• Nightmares
• Oral ulcers
• Pancreatitis
• Paresthesia (numbness)
• Peripheral neuropathy
• Rash
• Renal failure or insufficiency
• Somnolence (drowsiness)
• Stevens-Johnson syndrome
• Change in taste perception
• Vomiting
• Xeroderma (dry skin)
• Xerostomia (dry mouth)

See also

• Antiviral drug

References

External links

• Drug Chart
• Further drug information
• AIDSinfo - Comprehensive resource for HIV/AIDS treatment and clinical trial information from the U. S. Department of Health and Human Services
• Ten Texts on Saquinavir
• The Synergistic Inhibition of HIV-1 With Nucleoside Analogs Combined With A Natural Product, Resveratrol
• AZT resistance may be reversed by rheumatic drug
• Saquinavir Mesylate - Invirase (warning: commercial product web page)
• Origins of antiretroviral combination therapy
• [1] Drug Patent Expiration Info
• http://www.sciencedaily.com/releases/2007/07/070723160034.htm
• Information on D4t , stavudine, zerit - AIDS medicine
• Effects of HIV Drugs on the body
• Viral Load research papers, including effectiveness of HAART on reducing viral load

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