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| | #REDIRECT[[HIV AIDS medical therapy#Anti Retroviral Therapy (ART)]] |
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| '''Antiretroviral drugs''' are medications for the treatment of infection by [[retrovirus]]es, primarily [[HIV]]. Different classes of antiretroviral drugs act at different stages of the HIV life cycle. Combination of several (typically three or four) antiretroviral drugs is known as '''''Highly Active Anti-Retroviral Therapy''''' ('''''HAART''''').
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| Organizations such as the [[United States]] [[National Institutes of Health]] recommend offering antiretroviral treatment to all patients with [[AIDS]]. However, because of the complexity of selecting and following a regimen, the severity of the side effects, and the importance of compliance to prevent [[Resistance to antiviral drugs|viral resistance]], such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits to patients without symptoms.<ref name="2002nihguidelines">{{cite web | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=12617573&dopt=Abstract | title=Guidelines for using antiretroviral agents among HIV-infected adults and adolescents | accessdate=2006-01-09 | year=[[2002-09-03]] | author=Panel on Clinical Practices for Treatment of HIV | publisher=PubMed and National Institutes of Health}}</ref>
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| ==Classes of antiretroviral drugs==
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| Antiretroviral drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. There are thus six broad classifications of antiretroviral drugs in development, though only the first three classes currently have licensed examples:
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| *[[Reverse transcriptase inhibitor]]s (RTIs) target construction of viral DNA by inhibiting activity of [[reverse transcriptase]]. There are two subtypes of RTIs with different mechanisms of action: nucleoside-analogue RTIs are incorporated into the viral DNA leading to chain termination, while non-nucleoside-analogue RTIs distort the binding potential of the reverse transcriptase enzyme.
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| *[[Protease inhibitor (pharmacology)|Protease inhibitors]] (PIs) target viral assembly by inhibiting the activity of [[protease]], an enzyme used by HIV to cleave nascent [[protein]]s for final assembly of new [[virons]].
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| *[[Fusion inhibitor]]s block HIV from fusing with a cell's membrane to enter and infect it. There is currently only one FDA-approved drug in this class, [[enfuvirtide]], marketed as Fuzeon.
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| *[[Integrase inhibitor]]s 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 but none are commercially available.
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| *[[Entry inhibitors]] block HIV-1 from the host cell by binding [[CCR5]], a molecule on the host membrane termed a co-receptor that HIV-1 normally uses for entry into the cell together with a primary receptor.
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| *Maturation inhibitors inhibit the last step in [[HIV_structure_and_genome#Protein_function|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. Bevirimat is the only drug that is currently under investigation.<ref>{{cite web | url = http://clinicaltrials.gov/ct/show/NCT00511368 | title = Clinical Trial: Phase 2 Safety and Efficacy Study of Bevirimat Functional Monotherapy in HIV Treatment-Experienced Patients for 2 Weeks* | accessdate = 2007-08-28 | author = Panacos Pharmaceuticals | publisher = ClinicalTrials.gov }}</ref>
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| *[[Portmanteau inhibitor]]s A new way to combat HIV through the merging of two antiviral agents into one drug, achieving the same effect as when two or more drugs are taken separately.
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| ===Recent developments===
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| IMOD (short for "Immuno-Modulator Drug") is the name of a new herbal drug developed by scientists in Iran, which has been reported to rein the AIDS virus and boost the body’s immune system. Its efficiency and safety have not yet been confirmed by the mainstream scientific community.
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| ===Fixed dose combinations===
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| [[Fixed dose combination (antiretroviral)|Fixed dose combinations]] are multiple antiretroviral drugs combined into a single pill.
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| ===Synergistic enhancers ===
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| [[Synergistic enhancer (antiretroviral)|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 that drug (often by altering the metabolism of the other antiretroviral). These include [[ritonavir]]. [[Ritonavir]], for example, is an antiretroviral drug which belongs to the class of [[protease inhibitors]]. 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 1:5. Ritonavir is also used as an enhancer of other [[protease inhibitors]] such as [[saquinavir]] and [[atazanavir]], and of the investigational [[integrase inhibitor]], GS-9137. Other synergistic enhancers are being investigated for this purpose.
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| ==Combination therapy==
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| The [[HIV#Replication cycle|life cycle of HIV]] can be as short as about 1.5 days<!-- citation needed for "1.5 days" -->: from viral entry into a cell; through replication, assembly, and release of additional viruses; to infection of other cells. HIV lacks ''proofreading'' [[enzymes]] to correct errors made when it converts its [[RNA]] into [[DNA]] via [[reverse transcription]]. 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. 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.
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| 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.<ref name="2004HAB">{{cite web| author=United States Department of Health and Human Services| year=2004| url=ftp://ftp.hrsa.gov/hab/PCGchap5.pdf| title=A Guide to Primary Care for People With HIV/AIDS, 2004 Edition| accessdate=2006-07-03 }}</ref> This three drug combination is commonly known as a triple cocktail. <ref>http://www.fda.gov/FDAC/features/1999/499_aids.html</ref>
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| Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations. 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.
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| In recent years drug companies have worked together to combine these complex regimens into simpler formulas, termed [[Fixed dose combination (antiretroviral)|fixed dose combinations]]. 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 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.
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| According to Reference 5 below, "HIV treatment should reduce your viral load to the point at which it is undetectable. An undetectable viral load does not mean that your HIV infection is gone; it simply means that the test is not sensitive enough to detect the small amount of HIV left in your blood," and "Successful HIV treatment can lower your viral load, which may reduce the risk of HIV transmission."
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| ==Current treatment guidelines==
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| 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.
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| 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 <ref name="2003who">{{cite web| author=[[World Health Organization]]| year=2003| url=http://www.who.int/hiv/pub/prev_care/en/arvrevision2003en.pdf| title=Scaling up retroviral therapy in resource limited settings| accessdate=2006-01-17 }}</ref>):
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| * Clinically advanced HIV disease;
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| * WHO Stage IV HIV disease, irrespective of the CD4 cell count;
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| * WHO Stage III disease with consideration of using CD4 cell counts less than 350/µl to assist decision making;
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| * WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl.
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| The treatment guidelines in 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 <ref name="2005dhhshivtreatment">{{cite web| author=Panel on Clinical Practices for Treatment of HIV Infection| publisher=[[Department of Health and Human Services]]| year=[[October 6]], [[2005]]| url=http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf| title=Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents| accessdate=2006-01-17}}</ref>:
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| * All patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count receive ART.
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| * Antiretroviral therapy is also recommended for asymptomatic patients with less than 200 CD4+ T cells/µl.
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| * Asymptomatic patients with CD4+ T cell counts of 201–350 cells/µl should be offered treatment.
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| * 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.
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| * 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.
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| The preferred initial regimens are<ref>{{cite web| author=[[Department of Health and Human Services]] | publisher=| year=August, 2006| url=http://aidsinfo.nih.gov/ContentFiles/HIVandItsTreatment_cbrochure_en.pdf| title=HIV and Its Treatment: What You Should Know| accessdate=2006-11-04}}</ref>:
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| * [[efavirenz]] + [[zidovudine]] + [[lamivudine]]
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| * efavirenz + [[tenofovir]] + [[emtricitabine]]
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| * [[lopinavir]] boosted with [[ritonavir]] + zidovudine + lamivudine
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| * lopinavir boosted with ritonavir + tenofovir + emtricitabine.
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| 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 6.4% medium to high level resistance to [[stavudine]] + [[lamivudine]] + [[nevirapine]].<ref>{{cite journal | title=Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study | author=UK Group of Transmitted HIV Drug Resistance | journal=Brit Med J | year=2005 | volume=331 | issue=7529 | pages=1368–71 | doi=10.1136/bmj.38665.534595.55 | id=PMID 16299012 }}</ref>
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| 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 <ref name="2005dhhshivchildren">{{cite web| author=Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children| publisher=[[Department of Health and Human Services]]| year=[[November 3]], [[2005]]| url=http://www.aidsinfo.nih.gov/ContentFiles/PediatricGuidelines_PDA.pdf| title=Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection| accessdate=2006-01-17}}</ref>.
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| 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])<ref name="2005mmwrprophylaxis">[http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5402a1.htm MMWR weekly (2005) Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States January 21, 54 (RR02), 1-20]</ref>. 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.
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| ==Concerns==
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| There are several concerns about antiretroviral regimens. The drugs can have serious side effects.<ref name="saitoh">Saitoh A, Hull AD, Franklin P, Spector SA. (2005) Myelomeningocele in an infant with intrauterine exposure to efavirenz. ''J Perinatol.'' '''25''', 555-556 PMID 16047034</ref> 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.<ref name="dybul">Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK; Panel on Clinical Practices for Treatment of HIV. (2002) Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. ''Ann Intern Med.'' '''137''', 381-433 PMID 12617573</ref> Also, providing anti-retroviral treatment is costly and resource-intensive, and the majority of the world's infected individuals cannot access treatment services.
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| 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.
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| ==Responses to treatment in older adults==
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| 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. 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. 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.
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| 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. 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.
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| 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). 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. 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.
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| == Limitations of antiretroviral drug therapy ==
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| 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.
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| 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.
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| [[Drug holiday]]s (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.
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| 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.
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| 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.
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| ==Adverse effects==
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| 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: <ref name="ucalantiviraladverseevents">{{cite web| publisher=University of California San Francisco| year=August 2004, July 2005| url=http://hivinsite.ucsf.edu/InSite?page=ar-05-01| title=Adverse Events of Antiretroviral Drugs| accessdate=2006-01-07| author=Ian McNicholl }}</ref>
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| * [[Abdominal pain]]
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| * [[Alopecia]]
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| * [[Anemia]]
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| * [[Asthenia]]
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| * [[Diarrhea]]
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| * [[Dizziness]] (Vertigo)
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| * [[Fanconi syndrome]]
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| * [[Flatulence]]
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| * [[Headache]]
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| * [[Hepatitis]]
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| * [[Hyperbilirubinemia]]
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| * [[Hypercholesterolemia]] (Dyslipidemia, Hyperlipidemia, high cholesterol)
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| * [[Hyperpigmentation]] (of nails, palms, or soles)
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| * [[Ingrown nail]]s
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| * [[Insomnia]]
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| * [[Jaundice]]
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| * [[Lipodystrophy]]
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| * [[Liver failure]]
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| * [[Malaise]]
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| * [[Mental confusion]]
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| * [[Mitochondrial toxicity]]
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| * [[Myalgia]]
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| * [[Myalgic Encephalomyelitis]] (chronic fatigue syndrome)
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| * [[Myopathy]]
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| * [[Nausea]]
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| * [[Neutropenia]]
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| * [[Nightmare]]s
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| * Oral [[ulcer]]s
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| * [[Pancreatitis]]
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| * [[Paresthesia]] (numbness)
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| * [[Peripheral neuropathy]]
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| * [[Rash]]
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| * [[Renal failure]] or insufficiency
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| * [[Somnolence]] (drowsiness)
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| * [[Stevens-Johnson syndrome]]
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| * Change in [[taste]] perception
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| * [[Vomiting]]
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| * [[Xeroderma]] (dry skin)
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| * [[Xerostomia]] (dry mouth)
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| ==See also==
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| *[[Antiviral drug]]
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| ==References==
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| {{Reflist|2}}
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| ==External links==
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| *[http://www.aidsmeds.com/lessons/DrugChart.htm Drug Chart]
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| *[http://www.aidsmeds.com/ Further drug information]
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| *[http://www.AIDSinfo.nih.gov/ NIH web site]
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| *[http://www.aidsinfonyc.org/tag/tx/saquinavirten.html Ten Texts on Saquinavir]
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| *[http://www.retroconference.org/2000/abstracts/509.htm The Synergistic Inhibition of HIV-1 With Nucleoside Analogs Combined With A Natural Product, Resveratrol]
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| *[http://www.aidsmap.com/news/newsdisplay2.asp?newsId=2161 AZT resistance may be reversed by rheumatic drug]
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| *[http://www.inviraseinfo.com Saquinavir Mesylate - Invirase (warning: commercial product web page)]
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| *[http://www.aegis.com/pubs/atn/1993/ATN17001.html Origins of antiretroviral combination therapy]
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| *[http://www.cptech.org/ip/health/aids/druginfo.html] Drug Patent Expiration Info
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| *[http://www.sciencedaily.com/releases/2007/07/070723160034.htm
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| *[http://d4t.info Information on D4t , stavudine, zerit - AIDS medicine]
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| *[http://www.acria.org/treatment/treatment_edu_summerupdate2005.html Effects of HIV Drugs on the body]
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| *[http://www.thebody.com/vltest.html Viral Load] research papers, including effectiveness of HAART on reducing viral load
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