Difference between revisions of "AIDS antiretroviral drugs"

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#REDIRECT[[HIV AIDS medical therapy#Anti Retroviral Therapy (ART)]]
'''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''''').
Since viral load is the single greatest risk factor for all modes of HIV transmission, use of ART decreases the risk of HIV transmission from one person to another.
==Classes of antiretroviral drugs==
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:
*'''[[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.
**[[Reverse transcriptase inhibitor#Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)|Nucleoside reverse transcriptase inhibitors (NRTI)]] and [[Non-nucleoside reverse transcriptase inhibitors#Nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs)|nucleotide reverse transciptase inhibitors (NtRTI)]] are [[nucleoside]] and [[nucleotide]] [[Structural analog|analogues]] which inhibit reverse transcription by being incorporated into the newly synthesized viral DNA strand as faulty [[nucleotide|nucleotides]]; they both act as [[competitive inhibitor|competitive substrate inhibitors]].
**[[Reverse transcriptase inhibitor#Non-nucleoside reverse transcriptase inhibitors (NNRTIs)|Non-Nucleoside reverse transcriptase inhibitors (NNRTI)]] inhibit reverse transcriptase by binding to an [[Allosteric regulation|allosteric site]] of the enzyme; NNRTIs act as [[Non-competitive inhibition|non-competitive inhibitors]] of reverse transcriptase.
*'''[[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]].
*'''[[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, and [[raltegravir]] became the first to receive FDA approval in October 2007.
*'''[[Entry inhibitors]]''' include fusion inhibitors and CCR5-inhibitors. [[CCR5-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. [[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.
*'''[[Maturation inhibitor|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. [[interferon|Alpha interferon]] is a currently available agent in this class.<ref name="pmid18389079">{{cite journal | author = Barr SD, Smiley JR, Bushman FD | editor1-last = Hope | editor1-first = Thomas J. | title = The interferon response inhibits HIV particle production by induction of TRIM22 | journal = [[PLoS Pathog.]] | volume = 4 | issue = 2 | pages = e1000007 | year = 2008 | month = February | pmid = 18389079 | pmc = 2279259 | doi = 10.1371/journal.ppat.1000007 | url = http://dx.plos.org/10.1371/journal.ppat.1000007 | issn = }}</ref> Two additional inhibitors under investigation are [[bevirimat]] <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> and [[Vivecon]].
==Current Scenario: Presently known drugs==
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>
{| class="wikitable"
! [[Reverse transcriptase inhibitor#Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)|Nucleoside reverse transcriptase inhibitors (NRTI)]] || [[Protease inhibitor (pharmacology)|Protease Inhibitors]] || [[ Reverse transcriptase inhibitor#Non-nucleoside reverse transcriptase inhibitors (NNRTIs)|Non-Nucleoside reverse transcriptase inhibitors (NNRTI) ]] || [[Integrase inhibitor]] || [[Entry inhibitors]]
| [[Abacavir]] (ABC) || [[Atazanavir]] || [[Delavirdine]] || [[Raltegravir]] (2007)<ref name="pmid17434380">{{cite journal |author=Cahn P, Sued O |title=Raltegravir: a new antiretroviral class for salvage therapy |journal=Lancet |volume=369 |issue=9569 |pages=1235–6 |year=2007 |month=April |pmid=17434380 |doi=10.1016/S0140-6736(07)60571-6 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60571-6 |accessdate=2012-03-19}}</ref> || [[CCR5|Chemokine Receptor]] Antagonists ([[Maraviroc]] - 2007)
| [[Didanosine]] (ddI) (1991) || [[Darunavir]] || [[Efavirenz]] || [[Elvitegravir]] (Phase III trial terminated) [[http://clinicaltrials.gov/ct2/show/NCT00707733]] || [[Fusion inhibitor|Fusion Inhibitors]] ([[Enfuvirtide]] - 2003)
| [[Emtricitabine]] (FTC) || [[Fosamprenavir]] || [[Nevirapine]] (1996)  ||    || 
| [[Lamivudine]] (3TC) || [[Indinavir]] || [[Etravirine]]  ||    || 
| [[Stavudine]] (d4T) || [[Lopinavir]]/[[ritonavir]] || [[Rilpivirine]] ('''2011''') [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm256087.htm]  ||    || 
| [[Tenofovir]] (TDF) || [[Nelfinavir]]  ||  ||      || 
| [[Zalcitabine]] (ddC;no longer available in the United States) || [[Saquinavir]]  ||    ||      || 
| [[Zidovudine]] (ZDV, [[Retrovir]]; formerly [[azidothymidine]] [AZT] ('''1987''') || [[Tipranavir]]  ||  ||      || 
== Investigational approaches==
=== Anti-viral hyperactivation limiting therapeutics ===
[[AV-HALT]]s (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.<ref name="pmid15990570">{{cite journal |author=Lori F, Foli A, Groff A, Lova L, Whitman L, Bakare N, Pollard RB, Lisziewicz J |title=Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms |journal=AIDS |volume=19 |issue=11 |pages=1173–81 |year=2005 |month=July |pmid=15990570 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=19&issue=11&spage=1173 |accessdate=2012-03-10}}</ref>
===Recent developments===
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.
===Synergistic enhancers ===
[[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). This group include [[ritonavir]].
'''Example:''' [[Ritonavir]] 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.
==Combination therapy==
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  →  release of additional viruses  →  infection of other cells.'''
===Rationale for combination therapy: Advantages===
*Human Immunodeficiency Virus lacks [[DNA polymerase|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 [[Mutation|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.
*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>
*When antiretroviral drugs are used improperly, these multi-drug resistant strains can become the dominant genotypes very rapidly. Improper serial use of the reverse transcriptase inhibitors [[zidovudine]], [[didanosine]], [[zalcitabine]], [[stavudine]], and [[lamivudine]] can lead to the development of multi-drug resistant mutations.
**The mutations can include the V75I, F77L, K103N, F116Y, Q151M, and the M184V mutation. These mutations were observed before protease inhibitors had come into widespread use.
**  The mutants retained sensitivity to the early [[protease inhibitor]] [[saquinavir]]. These mutants were also sensitive to the rarely used reverse transcriptase inhibitor [[foscarnet]].<ref name="pmid8896496">{{cite journal |author=Schmit JC, Cogniaux J, Hermans P, Van Vaeck C, Sprecher S, Van Remoortel B, Witvrouw M, Balzarini J, Desmyter J, De Clercq E, Vandamme AM |title=Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain |journal=J. Infect. Dis. |volume=174 |issue=5 |pages=962–8 |year=1996 |month=November |pmid=8896496 |doi= |url=http://www.jid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8896496 |accessdate=2012-03-19}}</ref>
* Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.
: '''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.
===Current Scenario===
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.
===Fixed dose combinations===
[[Fixed dose combination (antiretroviral)|Fixed dose combinations]] are multiple antiretroviral drugs combined into a single pill.
{| class="wikitable"
! Brand Name !! Drug Names ([[International Nonproprietary Name|INN]]) !! Date of FDA Approval
| [[Combivir]] || [[zidovudine]] + [[lamivudine]] || September 26, 1997
| [[Trizivir]] || [[abacavir]] + [[zidovudine]] + [[lamivudine]] || November 15, 2000 
| [[Lopinavir|Kaletra]] || [[lopinavir]] + [[ritonavir]] || September 15, 2000
| [[Epzicom]] (in USA)<br />[[Kivexa]] (in Europe) ||  [[abacavir]] + [[lamivudine]] || August 2, 2004 
| [[Truvada]] || [[tenofovir]]/[[emtricitabine]] || August 2, 2004
| [[Atripla]] || [[efavirenz]] + [[tenofovir]]/[[emtricitabine]] || July 12, 2006
===Portmanteau Inhibitor===
A portmanteau inhibitor is a combination of two drug molecules, each of which itself is a type of [[enzyme inhibitor|inhibitor]].  The term was coined in 2007 by University of Minnesota researchers who designed and synthesized a combination [[HIV]] [[reverse transcriptase inhibitor]] and an [[integrase inhibitor]],<ref name="KARE11_story">{{cite web|url=http://www.kare11.com/news/news_article.aspx?storyid=260376|title= U of M researchers announce advance in treatment of HIV|date=25 July 2007|accessdate=25 July 2007}}</ref><ref name="scidaily_story">{{cite web|url=http://www.sciencedaily.com/releases/2007/07/070723160034.htm|title=Researchers Discover New Method To Combat HIV|date=25 July 2007|accessdate=25 July 2007}}</ref><ref name="PMID_17608468">{{cite journal|pmid=17608468|title=Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase|author=Zhengqiang Wang, Eric M. Bennett, Daniel J. Wilson, Christine Salomon, and Robert Vince|journal=Journal of Medicinal Chemistry|year=2007|volume=50|issue=15|url=http://pubs.acs.org/doi/abs/10.1021/jm070512p|pages=3416–3419|doi=10.1021/jm070512p}}</ref> and in 2011 by a team of researchers combining an integrase inhibitor with a CCR5 [[entry inhibitor]].<ref name="pmid21227704">{{cite journal |author=Bodiwala HS, Sabde S, Gupta P, Mukherjee R, Kumar R, Garg P, Bhutani KK, Mitra D, Singh IP |title=Design and synthesis of caffeoyl-anilides as portmanteau inhibitors of HIV-1 integrase and CCR5 |journal=Bioorg. Med. Chem. |volume=19 |issue=3 |pages=1256–63 |year=2011 |month=February |pmid=21227704 |doi=10.1016/j.bmc.2010.12.031 |url=http://linkinghub.elsevier.com/retrieve/pii/S0968-0896(10)01122-3 |accessdate=2012-03-12}}</ref>
==Treatment Guidelines==
===Initiation of antiretroviral therapy===
Antiretroviral drug treatment guidelines have changed over time. Prior to 1987, no antiretroviral drugs were available and treatment consisted of treating complications from the immunodeficiency. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.<ref name="pmid7614897">{{cite journal |author=Darbyshire J |title=Perspectives in drug therapy of HIV infection |journal=Drugs |volume=49 Suppl 1 |issue= |pages=1–3; discussion 38–40 |year=1995 |pmid=7614897 |doi= |url=http://content.wkhealth.com/linkback/openurl?issn=0012-6667&volume=49&issue=&spage=1 |accessdate=2012-03-20}}</ref>
In 1995, [[David Ho (scientist)|David Ho]] promoted a "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.<ref name="pmid7616996">{{cite journal |author=Ho DD |title=Time to hit HIV, early and hard |journal=N. Engl. J. Med. |volume=333 |issue=7 |pages=450–1 |year=1995 |month=August |pmid=7616996 |doi=10.1056/NEJM199508173330710 |url=http://www.nejm.org/doi/abs/10.1056/NEJM199508173330710?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |accessdate=2012-03-20}}</ref> Later reviews noted that this approach significantly increased the risks, side effects and development of multidrug resistance, and this approach was largely abandoned.<ref name="pmid10902643">{{cite journal |author=Harrington M, Carpenter CC |title=Hit HIV-1 hard, but only when necessary |journal=Lancet |volume=355 |issue=9221 |pages=2147–52 |year=2000 |month=June |pmid=10902643 |doi=10.1016/S0140-6736(00)02388-6 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(00)02388-6 |accessdate=2012-03-20}}</ref> 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.
There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped.  This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited.  This allows the drug resistant strains to become dominant.  This in turn makes it harder to treat the infected individual as well as anyone else they infect.
=== World Health Organization ===
In 2010, WHO has made the following recommendations[http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf]:
:'''When to start?'''
*All adolescents and adults including pregnant women with HIV infection and CD4 counts of ≤350 cells/mm3, should start ART, regardless of the presence or absence of clinical symptoms.
*Those with severe or advanced clinical disease (WHO clinical [[WHO Disease Staging System for HIV Infection and Disease in Children#Clinical Stage 3|stage 3]] or [[WHO Disease Staging System for HIV Infection and Disease in Children#Clinical Stage 4|4]]) should start ART irrespective of their CD4 cell count.
:'''What to use in first line therapy?'''
*First-line therapy should consist of '''an NNRTI + two NRTIs''', one of which should be zidovudine (AZT) or tenofovir (TDF).
*Countries should take steps to progressively reduce the use of stavudine (d4T) in first-line regimens because of its well-recognized toxicities.
:'''What to use in second-line therapy?'''
*Second-line ART should consist of a ritonavir-boosted protease inhibitor (PI) plus two NRTIs, one of which should be AZT or TDF, based on what was used in first-line therapy.
*Ritonavir-boosted atazanavir (ATV/r) or lopinavir/ritonavir (LPV/r) are the preferred PI's.
:'''Laboratory monitoring'''
*All patients should have access to CD4 cell–count testing to optimize pre-ART care and ART management.
*Viral-load testing is recommended to confirm suspected treatment failure.
*Drug toxicity monitoring should be symptom-directed.
:'''HIV/TB coinfection'''
*Irrespective of CD4 cell counts, patients coinfected with HIV and TB should be started on ART as soon as possible after starting [[Tuberculosis medical therapy|TB treatment]].
:'''HIV/HBV coinfection'''
*Irrespective of CD4 cell counts or WHO clinical stage, patients who require treatment for HBV infection should start ART.
*First-line and second-line regimens for these individuals should contain TDF and either emtricitabine (FTC) or lamivudine (3TC).
=== Department of Health and Human Services ===
The treatment guidelines in the USA are set by the [[United States Department of Health and Human Services]] (DHHS).
Following recommendations were made in '''2005''' guidelines for adults and adolescents <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>:
* 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.
In '''2011''', following changes were made to the existing guideline: [[http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf]]
:'''Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens'''
*Rilpivirine added as an alternative NNRTI option for initial therapy in treatment-naive patients.
*All nevirapine-based regimens reclassified as acceptable options for treatment-naive patients (females with pretreatment CD4 count <250 cells/mm3 or males with pretreatment CD4 count <400 cells/mm3).
:'''Protease Inhibitor (PI)-Based Regimens'''
*“Ritonavir-boosted darunavir + abacavir/lamivudine” reclassified as an alternative regimen (BIII); previously the regimen was recommended as a regimen that may be acceptable but more definitive data are needed (CIII).
:'''Raltegravir-Based Regimens'''
*“Raltegravir + abacavir/lamivudine” reclassified as an alternative regimen (BIII); previously, the regimen was classified as a regimen that may be acceptable but more definitive data are needed (CIII)
:'''Dual-Nucleoside Reverse Transcriptase Inhibitor (NRTI) Options'''
*“Zidovudine + lamivudine” reclassified from an alternative dual-NRTI option to an acceptable option because the combination has greater toxicities compared with tenofovir/emtricitabine and abacavir/lamivudine and requires twice daily dosing. However, zidovudine + lamivudine remains as the preferred dual-NRTI for pregnant women receiving antiretroviral therapy (ART) for prevention of perinatal transmission of HIV.
'''Rating of Recommendations''': A = Strong; B = Moderate; C = Optional Rating of Evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion.
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>:
* [[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 [[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&ndash;71 | doi=10.1136/bmj.38665.534595.55 | id=PMID 16299012 }}</ref>
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>.
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.
===Guidelines for initiation of ART===
{| border="1"
| Year
| AIDS/Symptoms
| CD4 <200
| CD4 200-350
| CD4 350-500
| CD4 >500
| DHHS [http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf]
| 2011
| Yes
| Yes
| Yes
| Yes
| Yes (optional)
| IAS-USA<ref name="pmid20639566">{{cite journal |author=Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A, Gatell JM, Günthard HF, Hammer SM, Hirsch MS, Jacobsen DM, Reiss P, Richman DD, Volberding PA, Yeni P, Schooley RT |title=Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel |journal=JAMA |volume=304|issue=3 |pages=321–33 |year=2010 |month=July |pmid=20639566 |doi=10.1001/jama.2010.1004|url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=20639566 |accessdate=2012-03-08}}</ref>
| 2010
| Yes
| Yes
| Yes
| Yes
| consider
| UK
| 2008
| Yes
| Yes
| Yes
| clinical trial
| clinical trial
| EACS<ref name="pmid18257769">{{cite journal |author=Clumeck N, Pozniak A, Raffi F |title=European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults |journal=HIV Med. |volume=9 |issue=2 |pages=65–71|year=2008 |month=February |pmid=18257769 |doi=10.1111/j.1468-1293.2007.00533.x |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1464-2662&date=2008&volume=9&issue=2&spage=65 |accessdate=2012-03-08}}</ref>
| 2011
| Yes
| Yes
| Yes
| consider
| defer
| WHO [[http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf]]
| 2010
| Yes
| Yes
| Yes
| No
| No
There are several concerns about antiretroviral regimens:
*'''Intolerance''': The drugs can have serious side-effects,<ref name="saitoh">{{cite journal |author=Saitoh A, Hull AD, Franklin P, Spector SA |title=Myelomeningocele in an infant with intrauterine exposure to efavirenz |journal=J Perinatol |volume=25 |issue=8 |pages=555–6 |year=2005 |month=August |pmid=16047034 |doi=10.1038/sj.jp.7211343 |url=}}</ref> particularly in advanced disease.<ref name= pmid2201071 >{{cite journal| last1 = Groopman| first1 = JE| title = Zidovudine intolerance.| journal = Reviews of infectious diseases| volume = 12 Suppl 5| pages = S500–6| year = 1990| pmid = 2201071}}</ref>
*'''Resistance''': If patients miss doses, drug resistance can develop.
*'''Cost''': Providing anti-retroviral treatment is costly and resource-intensive,{{Quantify|date=September 2011}} and the majority of the world's infected individuals cannot access treatment services.
*'''Public health''': Individuals who fail to use antiretrovirals properly can develop multi-drug resistant strains which can be passed onto others.<ref name="pmid9648307">{{cite journal | author = Beardsley T | title = Coping with HIV's ethical dilemmas | journal = [[Scientific American]] | volume = 279 | issue = 1 | pages = 106–7 | year = 1998 | month = July | pmid = 9648307 | doi = 10.1038/scientificamerican0798-106| url = | issn = }}</ref>
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. 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.
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.
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.
== 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.
===Intermittent therapy===
[[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.
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.
With the exception of [[post-exposure prophylaxis]], current treatment guidelines do not call for the interruption of drug therapy once it has been initiated.[[http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf]]
==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: <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>
{| class="wikitable" cellpadding=5
|  '''Causative Drug'''  ||  '''Side-effect'''
|'''Nucleoside reverse transcriptase inhibitors'''
| [[Abacavir]] || [[Hypersensitivity reaction]], [[Diarrhea]]
| [[Didanosine]] || [[Peripheral neuropathy]], [[pancreatitis]], [[nausea]], [[lactic acidosis]]
| [[Emtricitabine]] || [[Hyperpigmentation]], [[Insomnia]]
| [[Lamivudine]] || Severe acute exacerbation of [[hepatitis]] may occur with [[HBV]]
-coinfection upon discontinuation, [[Headache]]
| [[Stavudine]] || [[Peripheral neuropathy]], [[pancreatitis]], [[nausea]], [[lactic acidosis]]
[[Lipoatrophy]], [[hyperlipidemia]]
| [[Tenofovir]] || [[Diarrhea]], [[nausea]], [[flatulence]], [[vomiting]], [[renal failure]] <ref name="pmid20673002">{{cite journal |author=Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M |title=Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients |journal=Clin. Infect. Dis. |volume=51 |issue=5 |pages=496–505 |year=2010 |month=September |pmid=20673002 |doi=10.1086/655681 |url=http://www.cid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=20673002 |accessdate=2012-03-19}}</ref>
| [[Zalcitabine]] ||  [[Peripheral neuropathy]], [[pancreatitis]], [[nausea]], [[lactic acidosis]],
| [[Zidovudine]] ||  [[Nausea]], [[vomiting]], [[headache]], [[asthenia]], [[anemia]], [[neutropenia]]
|'''Non-Nucleoside Reverse Transcriptase inhibitors (NNRTI's)
| [[Delavirdine]] || [[Rash]], [[headache]]
| [[Efavirenz]] || [[Rash]], [[ hyperlipidemia ]], CNS ([[somnolence]], confusion, visual [[hallucination]]), [[teratogenic]]
| [[Etravirine]] || [[Rash]], [[nausea]]
| [[Nevirapine]] || [[Rash]], [[hepatitis]]
| [[Rilpivirine]] || [[Rash]], [[ headache ]], [[Depressive disorder]], [[insomnia]]
| '''Protease Inhibitors (PI's)
| [[Atazanavir]] || [[Hyperbilirubinemia]], prolonged [[PR interval]], [[hyperglycemia]], skin [[rash]] (20%)
| [[Darunavir ]] || [[Rash]], [[nausea]], [[ hyperlipidemia ]], [[diarrhea]]
| [[Fosamprenavir]] || [[Rash]], [[nausea]], [[ hyperlipidemia ]], [[diarrhea]], [[hyperlipidemia]]
| [[Indinavir]] || [[Nephrolithiasis]], [[ Hyperbilirubinemia]], [[hyperlipidemia]]], [[hyperglycemia]]
| [[Lopinavir]]/[[ritonavir]] || [[Nausea]], [[vomiting]], [[diarrhea]], [[asthenia]], [[hyperglycemia]], [[hyperlipidemia]]
| [[Saquinavir]] ||  [[Diarrhea]], [[nausea]], [[ hyperlipidemia ]], [[hyperglycemia]],prolonged [[PR interval]] & [[QT interval]]
| [[Tipranavir]] || [[Hepatotoxicity]], [[Intracranial hemorrhage]] (rare cases), [[hyperlipidemia]]], [[hyperglycemia]]
| '''Integrase Inhibitor'''
| [[Raltegravir]] || [[Diarrhea]], [[nausea]], [[ headache ]], [[CK]] elevation, [[myopathy]]/[[rhabdomyolysis]] (rare)
| '''Chemokine Receptor Antagonists (CCR5 Antagonist)'''
| [[Maraviroc]] || [[Dizziness]], [[Constipation]], [[ rash ]]
| '''Fusion inhibitor (FI)'''
| [[Enfuvirtide]] || Injection-site reactions ([[pain]], [[erythema]], [[induration]], [[nodules]])
==Latest Updates==
According to World Health Organization (WHO)[http://www.who.int/hiv/topics/treatment/en/index.html]:
{| class="wikitable" cellpadding=5
|  13 July 2011  ||  UNAIDS and WHO hail new results showing that a once-daily pill for HIV-negative people can prevent them from acquiring HIV
|  3 June 2011  ||  HIV treatment reaching 6.6 million people, but majority still in need
|  April 2011  ||  Short-term priorities for antiretroviral drug optimization
==Post-exposure prophylaxis==
To read more about post-exposure prophylaxis, click [[HIV prophylaxis#Post-exposure prophylaxis|here]]
==Pre-exposure prophylaxis==
To read more about pre-exposure prophylaxis, click [[HIV prophylaxis#Pre-exposure prophylaxis|here]]
==External links==
*[http://www.AIDSinfo.nih.gov/ NIH web site]
*[http://www.retroconference.org/2000/abstracts/509.htm The Synergistic Inhibition of HIV-1 With Nucleoside Analogs Combined With A Natural Product, Resveratrol]
*[http://www.aidsmap.com/news/newsdisplay2.asp?newsId=2161 AZT resistance may be reversed by rheumatic drug]
*[http://www.aegis.com/pubs/atn/1993/ATN17001.html Origins of antiretroviral combination therapy]
*Drug Patent Expiration Info[http://www.cptech.org/ip/health/aids/druginfo.html]
*[http://www.thebody.com/vltest.html Viral Load] research papers, including effectiveness of HAART on reducing viral load
==Related Chapters==
*[[Antiretroviral therapy in pregnancy]]
*[[Antiviral drug]]
*[[HIV prophylaxis#Post-exposure prophylaxis|Post-exposure prophylaxis]]
*[[HIV prophylaxis#Pre-exposure prophylaxis|Pre-exposure prophylaxis]]
[[Category:Antiretroviral drugs]]
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Latest revision as of 18:22, 21 October 2014