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Classes of drug

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

•  Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription by being incorporated into the newly synthesized viral DNA and preventing its further elongation.
• Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase directly by binding to the enzyme and interfering with its function.
• 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.
• Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir became the first to receive FDA approval in October 2007.
• 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.
• 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). 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 and Vivecon.
• AV-HALTs (AntiViral HyperActivation Limiting Therapeutics or 'virostatics') combine immunomodulating and antiviral properties to inhibit a specific antiviral target while also limiting the hyper-elevated state of immune system activation driving disease progression.
• Broad spectrum inhibitors. Some natural antivirals, such as extracts from certain species of mushrooms like Shiitake and Oyster mushrooms, may contain multiple pharmacologically active compounds, which inhibit the virus at various different stages in its life cycle. Researchers have also isolated a protease inhibitor from the Shiitake mushroom.

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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:

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 for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests) have been set by the International AIDS Society-USA(IAS-USA) since 1996. The IAS-USA is a 501(c)(3) not-for-profit organization in the USA (and is not related to the worldwide International AIDS Society or IAS). The IAS-USA guidelines for antiretroviral therapy are developed by a volunteer panel of experts. Its last update was published in August 2008 in the Journal of the American Medical Association  In this update, the panel recommends that therapy be initiated before the CD4+ cell count declines to below 350/uL and be individualized for the particular patient's situation and comorbidities. For initial therapy, it recommends 2 NRTIs with either an NNRTI or a ritonavir-boosted PI. In antiretroviral therapy failure, the goal of subsequent treatment is suppression of HIV-1 RNA to below detection; the treatment should ideally have 3 new drugs to which the patient's virus is susceptible. Therapy in selected clinical situations is also described. The IAS-USA also sponsors the development of guidelines for the use of drug resistance testing in patients with HIV-1 infection

The treatment guidelines specifically for the USA are set by the United States Department of Health and Human Services (DHHS). The current guidelines for adults and adolescents were stated on October 6, 2005:

• 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:

• efavirenz + zidovudine + lamivudine
• efavirenz + tenofovir + emtricitabine
• lopinavir boosted with ritonavir + zidovudine + lamivudine
• lopinavir boosted with ritonavir + tenofovir + emtricitabine.

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 efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine.

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, in particular 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.

In 2005, the Centers for Disease Control and Prevention in the United States recommended a 28-day HIV drug regimen for those that have been exposed to HIV (HIV Postexposure Prophylaxis [PEP]). The WHO recommendations on treatment are that the minimum that should be used is dual NRTIs for 28 days, with triple therapy (dual NRTIs plus a boosted PI) being offered where there is a risk of resistance [23]. The effectiveness of this intervention has never been precisely ascertained, but it is believed to be most effective the sooner the drugs are administered, and useless if treatment is delayed too long; hence it is not usually recommended that it be started on the basis of an exposure more than 76 hours prior to starting therapy.

The use of antiretrovirals is also recommended for the prevention of mother-to-child transmission of HIV-1. The current WHO recommended regimen is as follows: where the pregnant woman does not yet need to start ART for therapeutic reasons, she should start Zidovudine (AZT) from 28 weeks or as soon as possible thereafter, be provided with single-dose Nevirapine (NVP) when entering labour, and be given AZT+3TC for one week following delivery. Meanwhile, whether the mother was on the above or standard ART, the child should be given single dose Nevirapine immediately after delivery and daily Zidovudine until one week old. Complementary measures that may also be used include caesarian section and formula feeding; in some settings, the combination of providing all these measures has succeeded in reducing the risk of infection from 25% to about 1%

Concerns

There are several concerns about antiretroviral regimens. The drugs can have serious side-effects. 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. 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.

Limitations of antiretroviral drug therapy
If an HIV infection becomes resistant to standard HAART, there are limited options. 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. 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. Also, rapid suppression of HIV and partial restoration of the immune system sometimes produces a dangerous hypersensitivity reaction, immune reconstitution inflammatory syndrome. Research continues in these areas.

Adverse effects
Adverse effects of antiretroviral drugs vary by drug, by ethnicity, 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: [27]

• 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
• Lipoatrophy / Lipodystrophy
• Liiver failure
• Malaise
• Mental confusion
• Migraines
• Mitochondrial toxicity
•  Mood swings
• Myalgia
• Myalgic Encephalomyelitis (chronic fatigue syndrome)
• Myopathy
• Nausea
• Neutropenia (low number of white blood cells)
• 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)