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| __NOTOC__
| | #REDIRECT [[AIDS medical therapy]] |
| {{AIDS}}
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| {{CMG}}; '''Associate Editors-in-Chief:''' [[User:Ujjwal Rastogi|Ujjwal Rastogi, MBBS]]
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| ==Overview==
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| The primary goal of [[antiretroviral]] therapy (ART) is to reduce HIV-associated [[morbidity]] and [[mortality]]. This goal is best accomplished by using effective ART to maximally inhibit HIV replication, as defined by achieving and maintaining [[plasma]] HIV [[RNA]] ([[viral load]]) below levels detectable by commercially available [[assay]]s. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated [[inflammation]] and possibly its associated complications.
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| The results of a [[randomized controlled trial]] and several observational [[cohort]] studies demonstrated that ART can reduce [[transmission]] of HIV. Therefore, a secondary goal of ART is to reduce an HIV-infected individual’s risk of transmitting the virus to others.
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| Results from multiple observational cohort studies demonstrate benefits of ART in reducing AIDS- and non-AIDS associated morbidity and mortality in patients with CD4 counts ranging from 350 to 500 cells/mm3.
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| ==Chapter Outline==
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| This chapter is outlined as follows:
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| *'''[[AIDS medical therapy treatment naive patients#Benefits|I) Benefits of Antiretroviral Therapy]]'''
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| **[[AIDS medical therapy treatment naive patients#1. Reduction in Mortality and/or AIDS-Related Morbidity According to Pretreatment CD4 Cell Count|1. Reduction in Mortality and/or AIDS-Related Morbidity According to Pretreatment CD4 Cell Count]]
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| ***[[AIDS medical therapy treatment naive patients#Patients with a history of an AIDS-defining illness or CD4 count <350 cells/mm3'|Patients with a history of an AIDS-defining illness or CD4 count <350 cells/mm3]]
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| ***[[AIDS medical therapy treatment naive patients#Patients with a CD4 count between 350 and 500 cells/mm3|Patients with a CD4 count between 350 and 500 cells/mm3]]
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| ***[[AIDS medical therapy treatment naive patients#Patients with CD4 counts >500 cells/mm3|Patients with CD4 counts >500 cells/mm3]]
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| **[[AIDS medical therapy treatment naive patients#2. Effects of Viral Replication on HIV-Related Morbidity|2. Effects of Viral Replication on HIV-Related Morbidity]]
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| **[[AIDS medical therapy treatment naive patients#3. Effects of ART on HIV-Related Morbidity|3. Effects of ART on HIV-Related Morbidity]]
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| ***[[AIDS medical therapy treatment naive patients#A) HIV-associated nephropathy|A) HIV-associated nephropathy]]
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| ***[[AIDS medical therapy treatment naive patients#B) Coinfection with hepatitis B virus and/or hepatitis C virus|B) Coinfection with hepatitis B virus and/or hepatitis C virus]]
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| ***[[AIDS medical therapy treatment naive patients#C) Cardiovascular disease|C) Cardiovascular disease]]
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| ***[[AIDS medical therapy treatment naive patients#D) Malignancies|D) Malignancies]]
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| ***[[AIDS medical therapy treatment naive patients#E) Neurological diseases|E) Neurological diseases]]
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| ***[[AIDS medical therapy treatment naive patients#F) Age and treatment-related immune reconstitution|F) Age and treatment-related immune reconstitution]]
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| ***[[AIDS medical therapy treatment naive patients#G) T-cell activation and inflammation|G) T-cell activation and inflammation]]
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| **[[AIDS medical therapy treatment naive patients#4. Antiretroviral Therapy for Prevention of HIV Transmission| 4. Antiretroviral Therapy for Prevention of HIV Transmission]]
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| ***[[AIDS medical therapy treatment naive patients#A) Prevention of perinatal transmission|A) Prevention of perinatal transmission]]
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| ***[[AIDS medical therapy treatment naive patients#B) Prevention of sexual transmission|B) Prevention of sexual transmission]]
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| *'''[[AIDS medical therapy treatment naive patients#Potential limitations of earlier initiation of therapy|II) Potential limitations of earlier initiation of therapy]]'''
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| **[[AIDS medical therapy treatment naive patients#1) Antiretroviral drug toxicities and quality of life|1) Antiretroviral drug toxicities and quality of life]]
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| **[[AIDS medical therapy treatment naive patients#2) Nonadherence to Antiretroviral Therapy|2) Nonadherence to Antiretroviral Therapy]]
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| **[[AIDS medical therapy treatment naive patients#3) Cost of therapy|3) Cost of therapy]]
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| *'''[[AIDS medical therapy treatment naive patients#Conditions favoring more rapid initiation of therapy|III) Conditions favoring more rapid initiation of therapy]]'''
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| *'''[[AIDS medical therapy treatment naive patients#Conditions where deferral of therapy may be considered|IV) Conditions where deferral of therapy may be considered]]'''
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| ==Antiretroviral Therapy==
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| ===Benefits===
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| ====1. Reduction in Mortality and/or AIDS-Related Morbidity According to Pretreatment CD4 Cell Count====
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| ====='''Patients with a history of an AIDS-defining illness or CD4 count <350 cells/mm<sup>3</sup>''''=====
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| *HIV-infected patients with CD4 counts <200 cells/mm<sup>3</sup> are at higher risk of opportunistic diseases, non-AIDS morbidity, and death than HIV-infected patients with higher CD4 counts. Randomized controlled trials in patients with CD4 counts <200 cells/mm<sup>3</sup> and/or a history of an AIDS-defining condition provide strong evidence that ART improves survival and delays disease progression in these patients.<ref name="pmid19440326">{{cite journal |author=Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L |title=Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial |journal=PLoS ONE |volume=4 |issue=5 |pages=e5575 |year=2009 |pmid=19440326 |pmc=2680972 |doi=10.1371/journal.pone.0005575 |url=http://dx.plos.org/10.1371/journal.pone.0005575 |accessdate=2012-05-10}}</ref><ref name="pmid10376616">{{cite journal |author= |title=Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trialists' Collaborative Group |journal=Lancet |volume=353 |issue=9169 |pages=2014–25 |year=1999 |month=June |pmid=10376616 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673698122638 |accessdate=2012-05-10}}</ref><ref name="pmid9287227">{{cite journal |author=Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ, Feinberg JE, Balfour HH, Deyton LR, Chodakewitz JA, Fischl MA |title=A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team |journal=N. Engl. J. Med. |volume=337 |issue=11 |pages=725–33 |year=1997 |month=September |pmid=9287227 |doi=10.1056/NEJM199709113371101 |url=http://dx.doi.org/10.1056/NEJM199709113371101 |accessdate=2012-05-10}}</ref> Long-term data from multiple observational cohort studies comparing earlier ART (initiated at CD4 count >200 cells/mm<sup>3</sup>) with later treatment (initiated at CD4 count <200 cells/mm<sup>3</sup>) also have provided strong support for these findings.<ref name="pmid9848347">{{cite journal |author=Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, d'Arminio Monforte A, Yust I, Bruun JN, Phillips AN, Lundgren JD |title=Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group |journal=Lancet |volume=352 |issue=9142 |pages=1725–30 |year=1998 |month=November |pmid=9848347 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673698032012 |accessdate=2012-05-10}}</ref><ref name="pmid11722271">{{cite journal |author=Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, Montaner JS |title=Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy |journal=JAMA |volume=286 |issue=20 |pages=2568–77 |year=2001 |month=November |pmid=11722271 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11722271 |accessdate=2012-05-10}}</ref>
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| *Few large, randomized controlled trials address when to start therapy in patients with CD4 counts >200 cells/mm<sup>3</sup>. CIPRA HT-001, a randomized clinical trial conducted in Haiti, enrolled 816 participants without AIDS. Participants were randomized to start ART at CD4 counts of 200 to 350 cells/mm<sup>3</sup> or to defer treatment until their CD4 counts dropped to <200 cells/mm<sup>3</sup> or they developed an AIDS-defining condition. An interim analysis of the study showed that, compared with participants who began ART with CD4 counts of 200 to 350 cells/mm<sup>3</sup>, patients who deferred therapy had a higher mortality rate (23 vs. 6 deaths, hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 1.6–9.8) and greater incident tuberculosis (TB) (HR = 2.0,95% CI: 1.2–3.6).
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| *The SMART study was a multinational trial enrolling more than 5,400 participants with CD4 counts >350 cells/mm<sup>3</sup>. Participants were randomised to continuous ART or to treatment interruption until CD4 count dropped to <250 cells/mm<sup>3</sup>. In a subgroup analysis involving the 249 study participants who were ART naïve at enrollment, a trend of lower risk of serious AIDS- and non-AIDS-related events was seen in those who initiated therapy immediately compared with those who deferred therapy until CD4 count dropped to <250 cells/mm<sup>3</sup> (p = 0.06)
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| *Collectively, these studies support the Panel’s recommendation that ART should be initiated in patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm<sup>3</sup> ('''AI''')
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| ====='''Patients with a CD4 count between 350 and 500 cells/mm<sup>3</sup>'''=====
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| *There are no randomized trials using current combination regimens in patients with CD4 counts >350 cells/mm<sup>3</sup> to provide data that directly address the question of when to start therapy in patients with CD4 counts of 350–500 cells/mm<sup>3</sup>. Data from the ART Cohort Collaboration (ART-CC), which included 61,798 patient-years of follow-up, showed a declining risk of AIDS or death for up to 5 years in subjects starting therapy with a CD4 count ≥350 cells/mm<sup>3</sup> compared with subjects starting between 200 and 349 cells/mm<sup>3</sup>. A more recent rigorous analysis of this cohort found that deferring therapy until the 251 to 350 cells/mm<sup>3</sup> range was associated with a higher rate of progression to AIDS and death compared with initiating therapy in the 351 to 450 cells/mm<sup>3</sup> range (risk ratio: 1.28, 95% confidence interval [CI]: 1.04 to 1.57).
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| *In a collaboration of North American cohort studies (NA-ACCORD) that evaluated patients regardless of whether they had started therapy, the 6,278 patients who deferred therapy until CD4 counts were <350 cells/mm<sup>3</sup> had an increased risk of death compared with 2,084 patients who initiated therapy with CD4 counts between 351 and 500 cells/mm<sup>3</sup> (risk ratio: 1.69, 95% CI: 1.26 to 2.26) after adjustment for other factors that differed between these two groups.
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| *Another collaboration of cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) included 8,392 ART-naive patients with initial CD4 counts >500 cells/mm<sup>3</sup> who experienced declines in CD4 count to <500 cells/mm<sup>3</sup>. The study estimated that delaying initiation of ART until a patient had a CD4 count <350 cells/mm<sup>3</sup> was associated with a greater risk of AIDS-defining illness or death than initating ART with a CD4 count between 350 and 500 cells/mm<sup>3</sup> (HR: 1.38, 95% CI: 1.23–1.56). There was, however, no evidence of a difference in mortality (HR: 1.01, 95% CI: 0.84–1.22).
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| *A collaboration of cohort studies from Europe, Australia, and Canada (the CASCADE Collaboration) included 5,527 ART-naive patients with CD4 counts in the 350 to 499 cells/mm<sup>3</sup> range. Compared with patients who deferred therapy until their CD4 counts fell to <350 cells/mm<sup>3</sup>, patients who started ART immediately had a marginally lower risk of AIDS-defining illness or death (HR: 0.75, 95% CI: 0.49–1.14) and a lower risk of death (HR: 0.51, 95% CI: 0.33–0.80).
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| *Randomized data showing clinical evidence favoring ART in patients with higher CD4 cell counts comes from a small subgroup analysis of the SMART trial, undertaken primarily in North and South America, Europe, and Australia, which randomized participants with CD4 counts >350 cells/mm<sup>3</sup> to continuous ART or to treatment interruption until CD4 count dropped to <250 cells/mm<sup>3</sup>. In the subgroup of 249 participants who were ART naive at enrollment (median CD4 count: 437 cells/mm<sup>3</sup>), participants who deferred therapy until CD4 count dropped to <250 cells/mm<sup>3</sup> had a greater risk of serious AIDS- and non-AIDS-related events than those who initiated therapy immediately (7 vs. 2 events, HR: 4.6, 95% CI: 1.0–22.2).
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| *HPTN 052 was a large multinational, multicontinental (Africa, Asia, South America, and North America) randomized trial that examined whether treatment of HIV-infected individuals reduces transmission to their uninfected sexual partners. An additional objective of the study was to determine whether ART reduces clinical events in the HIV-infected participants. This trial enrolled 1,763 HIV-infected participants with CD4 counts between 350 and 550 cells/mm<sup>3</sup> and their HIV-uninfected partners. The infected participants were randomized to initiate ART immediately or to delay initiation until they had 2 consecutive CD4 counts less than 250 cells/mm<sup>3</sup>. At a median follow-up of 1.7 years, there were 40 events/deaths in the immediate therapy arm versus 65 events/deaths in the delayed arm (HR: 0.59, 95% CI: 0.40–0.88). The observed difference was driven mainly by the incidence of extrapulmonary TB (3 events in the immediate therapy arm vs. 17 events in the delayed therapy arm). The difference in mortality rates observed between the immediate and deferred therapy arms (10 vs. 13 deaths, respectively; HR: 0.77, 95% CI: 0.34–1.76) was not significant.
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| *Collectively, these studies suggest that initiating ART in patients with CD4 counts between 350 and 500 cells/mm<sup>3</sup> reduces HIV-related disease progression; whether there is a corresponding reduction in mortality is unclear. This benefit supports the Panel’s recommendation that ART should be initiated in patients with CD4 counts of 350 to 500 cells/mm<sup>3</sup> (AII). Recent evidence demonstrating the public health benefit of earlier intervention further supports the strength of this recommendation (see Prevention of Sexual Transmission).
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| ====='''Patients with CD4 counts >500 cells/mm<sup>3</sup>'''=====
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| *The NA-ACCORD study also observed patients who started ART at CD4 counts >500 cells/mm<sup>3</sup> or after CD4 counts dropped below this threshold. The adjusted mortality rates were significantly higher in the 6,935 patients who deferred therapy until their CD4 counts fell to <500 cells/mm<sup>3</sup> than in the 2,200 patients who started therapy at CD4 count >500 cells/mm <sup>3</sup> (risk ratio: 1.94, 95% CI: 1.37–2.79).<ref name="pmid19339714">{{cite journal |author=Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, Hogg RS, Deeks SG, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Martin JN, Klein MB, Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara LM, Horberg MA, Silverberg MJ, Gebo KA, Goedert JJ, Benson CA, Collier AC, Van Rompaey SE, Crane HM, McKaig RG, Lau B, Freeman AM, Moore RD |title=Effect of early versus deferred antiretroviral therapy for HIV on survival |journal=N. Engl. J. Med. |volume=360 |issue=18 |pages=1815–26 |year=2009 |month=April |pmid=19339714 |pmc=2854555 |doi=10.1056/NEJMoa0807252 |url=http://dx.doi.org/10.1056/NEJMoa0807252 |accessdate=2012-05-20}}</ref> Although large and generally representative of the HIV-infected patients in care in the United States, the study has several limitations, including the small number of deaths and the potential for unmeasured confounders that might have influenced outcomes independent of ART.
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| *In contrast, results from 2 cohort studies did not identify a benefit of earlier initiation of therapy in reducing AIDS progression or death. In an analysis of the ART-CC cohort,<ref name="pmid19361855">{{cite journal |author=Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, Funk MJ, Geskus RB, Gill J, Dabis F, Miró JM, Justice AC, Ledergerber B, Fätkenheuer G, Hogg RS, Monforte AD, Saag M, Smith C, Staszewski S, Egger M, Cole SR |title=Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies |journal=Lancet |volume=373 |issue=9672 |pages=1352–63 |year=2009 |month=April |pmid=19361855 |pmc=2670965 |doi=10.1016/S0140-6736(09)60612-7 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(09)60612-7 |accessdate=2012-05-20}}</ref> the rate of progression to AIDS/death associated with deferral of therapy until CD4 count in the the 351 to 450 cells/mm3 range was similar to the rate with initiation of therapy with CD4 count in the 451 to 550 cells/mm3 range (HR: 0.99, 95% CI: 0.76–1.29). There was no significant difference in rate of death identified (HR: 0.93, 95% CI: 0.60–1.44). This study also found that the proportion of patients with CD4 counts between 451 and 550 cells/mm<sup>3</sup> who would progress to AIDS or death before having a CD4 count <450 cells/mm<sup>3</sup> was low (1.6%; 95% CI: 1.1%–2.1%). In the CASCADE Collaboration,<ref name="pmid21949165">{{cite journal |author= |title=Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters |journal=Arch. Intern. Med. |volume=171 |issue=17 |pages=1560–9 |year=2011 |month=September |pmid=21949165 |doi=10.1001/archinternmed.2011.401 |url=http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinternmed.2011.401 |accessdate=2012-05-20}}</ref> among the 5,162 patients with CD4 counts in the 500 to 799 cells/mm3 range, compared with patients who deferred therapy, those who started ART immediately did not experience a significant reduction in the composite outcome of progression to AIDS/death (HR: 1.10, 95% CI: 0.67–1.79) or death (HR: 1.02, 95% CI: 0.49–2.12).
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| *With a better understanding of the pathogenesis of HIV infection, the growing awareness that untreated HIV infection increases the risk of many non-AIDS-defining diseases (as discussed below), and the benefit of ART in reducing transmission of HIV, the Panel also recommends initiation of ART in patients with CD4 counts >500 cells/mm3 ('''BIII'''). However, in making this recommendation the Panel notes that the amount of data supporting earlier initiation of therapy decreases as the CD4 count increases to >500 cells/mm<sup>3</sup> and that concerns remain over the unknown overall benefit, long-term risks, and cumulative additional costs associated with earlier treatment.
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| *When discussing starting ART at high CD4 cell counts (>500 cells/mm<sup>3</sup>), clinicians should inform patients that data on the clinical benefit of starting treatment at such levels are not conclusive, especially for patients with very high CD4 counts. The same is true for individuals with low viral load set points at presentation and for “elite controllers”. Further ongoing research (both randomized clinical trials and cohort studies) to assess the short- and long-term clinical and public health benefits and cost effectiveness of starting therapy at higher CD4 counts is needed. Findings from such research will provide the Panel with guidance to make future recommendations.
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| ====2. Effects of Viral Replication on HIV-Related Morbidity====
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| *Since the mid-1990s, measures of viral replication have been known to predict HIV disease progression. Among untreated HIV-infected individuals, time to clinical progression and mortality is fastest in those with greater viral loads.<ref name="pmid8638160">{{cite journal |author=Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA |title=Prognosis in HIV-1 infection predicted by the quantity of virus in plasma |journal=Science |volume=272 |issue=5265 |pages=1167–70 |year=1996 |month=May |pmid=8638160 |doi= |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8638160 |accessdate=2012-05-21}}</ref> This finding is confirmed across the wide spectrum of HIV-infected patient populations such as injection drug users (IDUs),<ref name="pmid9424041">{{cite journal |author=Vlahov D, Graham N, Hoover D, Flynn C, Bartlett JG, Margolick JB, Lyles CM, Nelson KE, Smith D, Holmberg S, Farzadegan H |title=Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count |journal=JAMA |volume=279 |issue=1 |pages=35–40 |year=1998 |month=January |pmid=9424041 |doi= |url= |accessdate=2012-05-21}}</ref> women,<ref name="pmid10509574">{{cite journal |author=Anastos K, Kalish LA, Hessol N, Weiser B, Melnick S, Burns D, Delapenha R, DeHovitz J, Cohen M, Meyer W, Bremer J, Kovacs A |title=The relative value of CD4 cell count and quantitative HIV-1 RNA in predicting survival in HIV-1-infected women: results of the women's interagency HIV study |journal=AIDS |volume=13 |issue=13 |pages=1717–26 |year=1999 |month=September |pmid=10509574 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=13&issue=13&spage=1717 |accessdate=2012-05-21}}</ref> and individuals with hemophilia.<ref name="pmid8656501">{{cite journal |author=O'Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen AR, Luban N, Hatzakis A, Aledort LM, Rosenberg PS, Miley WJ, Kroner BL, Goedert JJ |title=Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study |journal=JAMA |volume=276 |issue=2 |pages=105–10 |year=1996 |month=July |pmid=8656501 |doi= |url= |accessdate=2012-05-21}}</ref> Several studies have shown the prognostic value of pretherapy viral load for predicting post-therapy response.<ref name="pmid12126821">{{cite journal |author=Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA |title=Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies |journal=Lancet |volume=360 |issue=9327 |pages=119–29 |year=2002 |month=July |pmid=12126821 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673602094114 |accessdate=2012-05-21}}</ref><ref name="pmid14970148">{{cite journal |author=Anastos K, Barrón Y, Cohen MH, Greenblatt RM, Minkoff H, Levine A, Young M, Gange SJ |title=The prognostic importance of changes in CD4+ cell count and HIV-1 RNA level in women after initiating highly active antiretroviral therapy |journal=Ann. Intern. Med. |volume=140 |issue=4 |pages=256–64 |year=2004 |month=February |pmid=14970148 |doi= |url= |accessdate=2012-05-21}}</ref> Once therapy has been initiated, failure to achieve viral suppression <ref name="pmid8552144">{{cite journal |author=O'Brien WA, Hartigan PM, Martin D, Esinhart J, Hill A, Benoit S, Rubin M, Simberkoff MS, Hamilton JD |title=Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS |journal=N. Engl. J. Med. |volume=334 |issue=7 |pages=426–31 |year=1996 |month=February |pmid=8552144 |doi=10.1056/NEJM199602153340703 |url=http://dx.doi.org/10.1056/NEJM199602153340703 |accessdate=2012-05-21}}</ref><ref name="pmid9182469">{{cite journal |author=Hughes MD, Johnson VA, Hirsch MS, Bremer JW, Elbeik T, Erice A, Kuritzkes DR, Scott WA, Spector SA, Basgoz N, Fischl MA, D'Aquila RT |title=Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team |journal=Ann. Intern. Med. |volume=126 |issue=12 |pages=929–38 |year=1997 |month=June |pmid=9182469 |doi= |url= |accessdate=2012-05-21}}</ref><ref name="pmid12957089">{{cite journal |author=Chêne G, Sterne JA, May M, Costagliola D, Ledergerber B, Phillips AN, Dabis F, Lundgren J, D'Arminio Monforte A, de Wolf F, Hogg R, Reiss P, Justice A, Leport C, Staszewski S, Gill J, Fatkenheuer G, Egger ME |title=Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies |journal=Lancet |volume=362 |issue=9385 |pages=679–86 |year=2003 |month=August |pmid=12957089 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673603142298 |accessdate=2012-05-21}}</ref> and viral load at the time of treatment failure <ref name="pmid19845473">{{cite journal |author=Deeks SG, Gange SJ, Kitahata MM, Saag MS, Justice AC, Hogg RS, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Benson CA, Collier AC, Martin JN, Klein MB, Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara LM, Horberg MA, Silverberg MJ, Gebo KA, Kushel MB, Goedert JJ, McKaig RG, Moore RD |title=Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America |journal=Clin. Infect. Dis. |volume=49 |issue=10 |pages=1582–90 |year=2009 |month=November |pmid=19845473 |pmc=2871149 |doi=10.1086/644768 |url=http://www.cid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=19845473 |accessdate=2012-05-21}}</ref> are predictive of clinical disease progression.
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| *More recent studies have examined the impact of ongoing viral replication for both longer durations and at higher CD4 cell counts. Using viremia copy-years, a novel metric for summarizing viral load over time, the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort found that total cumulative exposure to replicating virus over time is independently associated with mortality. Using viremia copy-years, the HR for mortality was 1.81 per log10 copy-year/mL (95% CI: 1.51–2.18), which was the only viral load-related variable that retained statistical significance in the multivariable model (HR 1.44 per log10 copy-year/mL; 95% CI: 1.07–1.94). These findings support the concept that unchecked viral replication, which occurs in the absence of effective ART, is a factor in disease progression and death, but the precise mechanism remains ill defined.<ref name="pmid21890751">{{cite journal |author=Mugavero MJ, Napravnik S, Cole SR, Eron JJ, Lau B, Crane HM, Kitahata MM, Willig JH, Moore RD, Deeks SG, Saag MS |title=Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy |journal=Clin. Infect. Dis. |volume=53 |issue=9 |pages=927–35 |year=2011 |month=November |pmid=21890751 |doi=10.1093/cid/cir526 |url=http://www.cid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=21890751 |accessdate=2012-05-21}}</ref>
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| *The EuroSIDA collaboration evaluated HIV-infected individuals with CD4 counts >350 cells/ mm<sup>3</sup> segregated by three viral load strata (<500 copies/mL, 500–9,999 copies/mL, and ≥10,000 copies/mL) to determine the impact of viral load on fatal and nonfatal AIDS-related and non-AIDS-related events. The lower viral load stratum included more subjects on ART (92%) than the middle (62%) and high (31%) viral load strata. After adjustment for age, region, and ART, the rates of non-AIDS events were 61% (P = 0.001) and 66% (P = 0.004) higher in participants with viral loads 500 to 9,999 copies/mL and ≥10,000 copies/mL, respectively, than in individuals with viral loads <500 copies/mL. These data further confirm that unchecked viral replication is associated with adverse clinical outcomes in individuals with CD4 counts >350 cells/mm<sup>3</sup>.<ref name="pmid21918422">{{cite journal |author=Reekie J, Gatell JM, Yust I, Bakowska E, Rakhmanova A, Losso M, Krasnov M, Francioli P, Kowalska JD, Mocroft A |title=Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata |journal=AIDS |volume=25 |issue=18 |pages=2259–68 |year=2011 |month=November |pmid=21918422 |doi=10.1097/QAD.0b013e32834cdb4b |url= |accessdate=2012-05-21}}</ref>
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| *Collectively, these data show that the harm of ongoing viral replication affects both untreated patients and those who are on ART but continue to be viremic. The harm of ongoing viral replication in patients on ART is compounded by the risk of emergence of drug-resistant virus. Therefore, all patients on ART should be carefully monitored and counseled on the importance of adherence to therapy.
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| ====3. Effects of ART on HIV-Related Morbidity====
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| HIV-associated immune deficiency, the direct effects of HIV on end organs, and the indirect effects of HIV-associated inflammation on these organs all contribute to HIV-related morbidity and mortality. In general, the available data demonstrate that:
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| | |
| * Untreated HIV infection may have detrimental effects at all stages of infection.
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| * Earlier treatment may prevent the damage associated with HIV replication during early stages of infection.
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| * ART is beneficial even when initiated later in infection; however, later therapy may not repair damage associated with viral replication during early stages of infection.
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| * Sustaining viral suppression and maintaining higher CD4 count, mostly as a result of effective combination ART, may delay, prevent, or reverse some non-AIDS-defining complications, such as HIV-associated kidney disease, liver disease, CVD, neurologic complications, and malignancies, as discussed below.
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| =====A) [[HIV associated nephropathy|HIV-associated nephropathy]] =====
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| HIV-associated nephropathy (HIVAN) is the most common cause of chronic kidney disease in HIV-infected individuals that may lead to end-stage kidney disease.<ref name="pmid15327410">{{cite journal |author=Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, Fields TA, Svetkey LP, Flanagan KH, Klotman PE, Winston JA |title=The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection |journal=Kidney Int. |volume=66 |issue=3 |pages=1145–52 |year=2004 |month=September |pmid=15327410 |doi=10.1111/j.1523-1755.2004.00865.x |url=http://dx.doi.org/10.1111/j.1523-1755.2004.00865.x |accessdate=2012-05-21}}</ref> HIVAN is almost exclusively seen in black patients and can occur at any CD4 count. Ongoing viral replication appears to be directly involved in renal injury <ref name="pmid11984599">{{cite journal |author=Marras D, Bruggeman LA, Gao F, Tanji N, Mansukhani MM, Cara A, Ross MD, Gusella GL, Benson G, D'Agati VD, Hahn BH, Klotman ME, Klotman PE |title=Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy |journal=Nat. Med. |volume=8 |issue=5 |pages=522–6 |year=2002 |month=May |pmid=11984599 |doi=10.1038/nm0502-522 |url=http://dx.doi.org/10.1038/nm0502-522 |accessdate=2012-05-21}}</ref> and HIVAN is extremely uncommon in virologically suppressed patients.<ref name="pmid16804855">{{cite journal |author=Estrella M, Fine DM, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, Scheel PJ, Atta MG |title=HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients |journal=Clin. Infect. Dis. |volume=43 |issue=3 |pages=377–80 |year=2006 |month=August |pmid=16804855 |doi=10.1086/505497 |url=http://www.cid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16804855 |accessdate=2012-05-21}}</ref> ART in patients with HIVAN has been associated with both preserved renal function and prolonged survival.<ref name="pmid16864598">{{cite journal |author=Atta MG, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, Scheel PJ, Fine DM |title=Antiretroviral therapy in the treatment of HIV-associated nephropathy |journal=Nephrol. Dial. Transplant. |volume=21 |issue=10 |pages=2809–13 |year=2006 |month=October |pmid=16864598 |doi=10.1093/ndt/gfl337 |url=http://ndt.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16864598 |accessdate=2012-05-21}}</ref><ref name="pmid15987747">{{cite journal |author=Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE |title=Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease |journal=J. Am. Soc. Nephrol. |volume=16 |issue=8 |pages=2412–20 |year=2005 |month=August |pmid=15987747 |doi=10.1681/ASN.2005040340 |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=15987747 |accessdate=2012-05-21}}</ref><ref name="pmid18301060">{{cite journal |author=Kalayjian RC, Franceschini N, Gupta SK, Szczech LA, Mupere E, Bosch RJ, Smurzynski M, Albert JM |title=Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease |journal=AIDS |volume=22 |issue=4 |pages=481–7 |year=2008 |month=February |pmid=18301060 |doi=10.1097/QAD.0b013e3282f4706d |url= |accessdate=2012-05-21}}</ref> Therefore, ART should be started in patients with HIVAN, regardless of CD4 count, at the earliest sign of renal dysfunction ('''AII''').
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| =====B) Coinfection with hepatitis B virus and/or hepatitis C virus=====
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| *HIV infection is associated with more rapid progression of viral [[hepatitis]]-related liver disease, including [[cirrhosis]], [[End stage liver failure|end-stage liver disease]], [[hepatocellular carcinoma]], and fatal hepatic failure. <ref name="pmid18784461">{{cite journal |author=Thein HH, Yi Q, Dore GJ, Krahn MD |title=Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis |journal=AIDS |volume=22 |issue=15 |pages=1979–91 |year=2008 |month=October |pmid=18784461 |doi=10.1097/QAD.0b013e32830e6d51 |url= |accessdate=2012-05-21}}</ref><ref name="pmid12493258">{{cite journal |author=Thio CL, Seaberg EC, Skolasky R, Phair J, Visscher B, Muñoz A, Thomas DL |title=HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS) |journal=Lancet |volume=360 |issue=9349 |pages=1921–6 |year=2002 |month=December |pmid=12493258 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673602119131 |accessdate=2012-05-21}}</ref> The pathogenesis of accelerated liver disease in HIV-infected patients has not been fully elucidated but HIV-related immunodeficiency and a direct interaction between HIV and hepatic stellate and Kupffer cells have been implicated.<ref name="pmid16908797">{{cite journal |author=Weber R, Sabin CA, Friis-Møller N, Reiss P, El-Sadr WM, Kirk O, Dabis F, Law MG, Pradier C, De Wit S, Akerlund B, Calvo G, Monforte A, Rickenbach M, Ledergerber B, Phillips AN, Lundgren JD |title=Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study |journal=Arch. Intern. Med. |volume=166 |issue=15 |pages=1632–41 |year=2006 |pmid=16908797 |doi=10.1001/archinte.166.15.1632 |url=http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinte.166.15.1632 |accessdate=2012-05-21}}</ref><ref name="pmid18457674">{{cite journal |author=Balagopal A, Philp FH, Astemborski J, Block TM, Mehta A, Long R, Kirk GD, Mehta SH, Cox AL, Thomas DL, Ray SC |title=Human immunodeficiency virus-related microbial translocation and progression of hepatitis C |journal=Gastroenterology |volume=135 |issue=1 |pages=226–33 |year=2008 |month=July |pmid=18457674 |pmc=2644903 |doi=10.1053/j.gastro.2008.03.022 |url=http://linkinghub.elsevier.com/retrieve/pii/S0016-5085(08)00458-7 |accessdate=2012-05-21}}</ref><ref name="pmid17477814">{{cite journal |author=Blackard JT, Kang M, St Clair JB, Lin W, Kamegaya Y, Sherman KE, Koziel MJ, Peters MG, Andersen J, Chung RT |title=Viral factors associated with cytokine expression during HCV/HIV co-infection |journal=J. Interferon Cytokine Res. |volume=27 |issue=4 |pages=263–9 |year=2007 |month=April |pmid=17477814 |doi=10.1089/jir.2006.0147 |url=http://dx.doi.org/10.1089/jir.2006.0147 |accessdate=2012-05-21}}</ref>
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| *In individuals coinfected with HBV and/or hepatitis C virus (HCV), ART may attenuate liver disease progression by preserving or restoring immune function and reducing HIV-related immune activation and inflammation.<ref name="pmid19670415">{{cite journal |author=Macías J, Berenguer J, Japón MA, Girón JA, Rivero A, López-Cortés LF, Moreno A, González-Serrano M, Iribarren JA, Ortega E, Miralles P, Mira JA, Pineda JA |title=Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus |journal=Hepatology |volume=50 |issue=4 |pages=1056–63 |year=2009 |month=October |pmid=19670415 |doi=10.1002/hep.23136 |url=http://dx.doi.org/10.1002/hep.23136 |accessdate=2012-05-21}}</ref><ref name="pmid18710499">{{cite journal |author=Verma S, Goldin RD, Main J |title=Hepatic steatosis in patients with HIV-Hepatitis C Virus coinfection: is it associated with antiretroviral therapy and more advanced hepatic fibrosis? |journal=BMC Res Notes |volume=1 |issue= |pages=46 |year=2008 |pmid=18710499 |pmc=2527001 |doi=10.1186/1756-0500-1-46 |url=http://www.biomedcentral.com/1756-0500/1/46 |accessdate=2012-05-21}}</ref><ref name="pmid19347994">{{cite journal |author=Ragni MV, Nalesnik MA, Schillo R, Dang Q |title=Highly active antiretroviral therapy improves ESLD-free survival in HIV-HCV co-infection |journal=Haemophilia |volume=15 |issue=2 |pages=552–8 |year=2009 |month=March |pmid=19347994 |pmc=2722242 |doi= |url= |accessdate=2012-05-21}}</ref>
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| *Antiretroviral (ARV) drugs active against both HIV and HBV (such as [[tenofovir]] disoproxil fumarate [TDF], [[lamivudine]] [3TC], and [[emtricitabine]] [FTC]) also may prevent development of significant liver disease by directly suppressing HBV replication.<ref name="pmid18697216">{{cite journal |author=Matthews GV, Avihingsanon A, Lewin SR, Amin J, Rerknimitr R, Petcharapirat P, Marks P, Sasadeusz J, Cooper DA, Bowden S, Locarnini S, Ruxrungtham K, Dore GJ |title=A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naïve individuals in Thailand |journal=Hepatology |volume=48 |issue=4 |pages=1062–9 |year=2008 |month=October |pmid=18697216 |doi=10.1002/hep.22462 |url=http://dx.doi.org/10.1002/hep.22462 |accessdate=2012-05-21}}</ref><ref name="pmid17058225">{{cite journal |author=Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B |title=Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127 |journal=Hepatology |volume=44 |issue=5 |pages=1110–6 |year=2006 |month=November |pmid=17058225 |doi=10.1002/hep.21388 |url=http://dx.doi.org/10.1002/hep.21388 |accessdate=2012-05-21}}</ref> Although ARV drugs do not inhibit HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or CD4 counts are increased.<ref name="pmid19797971">{{cite journal |author=Avidan NU, Goldstein D, Rozenberg L, McLaughlin M, Ferenci P, Masur H, Buti M, Fauci AS, Polis MA, Kottilil S |title=Hepatitis C viral kinetics during treatment with peg IFN-alpha-2b in HIV/HCV coinfected patients as a function of baseline CD4+ T-cell counts |journal=J. Acquir. Immune Defic. Syndr. |volume=52 |issue=4 |pages=452–8 |year=2009 |month=December |pmid=19797971 |pmc=2783427 |doi=10.1097/QAI.0b013e3181be7249 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=52&issue=4&spage=452 |accessdate=2012-05-22}}</ref>
| |
| *Chronic viral hepatitis increases the risk of ARV-induced liver injury; however, the majority of coinfected persons do not develop clinically significant liver injury.<ref name="pmid20032785">{{cite journal |author=Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Wirtz V, Lataillade M, Absalon J, McGrath D |title=Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study |journal=J. Acquir. Immune Defic. Syndr. |volume=53 |issue=3 |pages=323–32 |year=2010 |month=March |pmid=20032785 |doi=10.1097/QAI.0b013e3181c990bf |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=53&issue=3&spage=323 |accessdate=2012-05-22}}</ref><ref name="pmid18650512">{{cite journal |author=Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Nguyen BY, Teppler H |title=Raltegravir with optimized background therapy for resistant HIV-1 infection |journal=N. Engl. J. Med. |volume=359 |issue=4 |pages=339–54 |year=2008 |month=July |pmid=18650512 |doi=10.1056/NEJMoa0708975 |url=http://dx.doi.org/10.1056/NEJMoa0708975 |accessdate=2012-05-22}}</ref><ref name="pmid17416261">{{cite journal |author=Clotet B, Bellos N, Molina JM, Cooper D, Goffard JC, Lazzarin A, Wöhrmann A, Katlama C, Wilkin T, Haubrich R, Cohen C, Farthing C, Jayaweera D, Markowitz M, Ruane P, Spinosa-Guzman S, Lefebvre E |title=Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials |journal=Lancet |volume=369 |issue=9568 |pages=1169–78 |year=2007 |month=April |pmid=17416261 |doi=10.1016/S0140-6736(07)60497-8 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60497-8 |accessdate=2012-05-22}}</ref> Some studies suggest that the rate of hepatotoxicity is greater in persons with more advanced HIV disease.
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| *Nevirapine (NVP) toxicity is a notable exception: the hypersensitivity reaction (HSR) and associated hepatotoxicity to this drug are more frequent in patients with higher pretreatment CD4 cell counts.<ref name="pmid15764851">{{cite journal |author=van Leth F, Andrews S, Grinsztejn B, Wilkins E, Lazanas MK, Lange JM, Montaner J |title=The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART |journal=AIDS |volume=19 |issue=5 |pages=463–71 |year=2005 |month=March |pmid=15764851 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=19&issue=5&spage=463 |accessdate=2012-05-22}}</ref> Collectively, these data suggest earlier treatment of HIV infection in persons coinfected with HBV, and likely HCV, may reduce the risk of liver disease progression. Thus, ART is recommended for patients coinfected with HBV ('''AII'''). ART for patients coinfected with HBV should include drugs with activity against both HIV and HBV ('''AII''').
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| *ART also is recommended for most patients coinfected with HCV ('''BII'''), including those with high CD4 counts and those with cirrhosis. Combined HIV/HCV treatment can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be considered for HIV/HCV-coinfected patients regardless of CD4 cell count, for patients infected with HCV genotype 1, some clinicians may choose to defer ART in HIV treatment-naive patients with CD4 counts >500 cells/mm<sup>3</sup> until HCV treatment that includes the HCV NS3/4A protease inhibitors (PIs) is completed.
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| | |
| =====C) Cardiovascular disease=====
| |
| *Among HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for a third of serious non-AIDS conditions and at least 10% of deaths.<ref name="pmid20453631">{{cite journal |author=Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law M, Monforte A, Kirk O, Friis-Moller N, Phillips A, Reiss P, El Sadr W, Pradier C, Worm SW |title=Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study |journal=AIDS |volume=24 |issue=10 |pages=1537–48 |year=2010 |month=June |pmid=20453631 |doi=10.1097/QAD.0b013e32833a0918 |url= |accessdate=2012-05-21}}</ref><ref name="pmid20700060">{{cite journal |author=Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, Gatell J, Rakhmanova A, Johnson M, Kirk O, Lundgren J |title=Serious fatal and nonfatal non-AIDS-defining illnesses in Europe |journal=J. Acquir. Immune Defic. Syndr. |volume=55 |issue=2 |pages=262–70 |year=2010 |month=October |pmid=20700060 |doi=10.1097/QAI.0b013e3181e9be6b |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=55&issue=2&spage=262 |accessdate=2012-05-21}}</ref> Studies link exposure to specific ARV drugs to a higher risk of CVD.<ref name="pmid17460226">{{cite journal |author=Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD |title=Class of antiretroviral drugs and the risk of myocardial infarction |journal=N. Engl. J. Med. |volume=356 |issue=17 |pages=1723–35 |year=2007 |month=April |pmid=17460226 |doi=10.1056/NEJMoa062744 |url=http://dx.doi.org/10.1056/NEJMoa062744 |accessdate=2012-05-22}}</ref><ref name="pmid18387667">{{cite journal |author=Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, D'Arminio Monforte A, Friis-Møller N, Kirk O, Pradier C, Weller I, Phillips AN, Lundgren JD |title=Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration |journal=Lancet |volume=371 |issue=9622 |pages=1417–26 |year=2008 |month=April |pmid=18387667 |pmc=2688660 |doi=10.1016/S0140-6736(08)60423-7 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)60423-7 |accessdate=2012-05-22}}</ref> In one study, compared with HIV-uninfected controls, HIV-infected men on ART had a more atherogenic lipid profile as assessed by lipoprotein particle size analysis.<ref name="pmid18545156">{{cite journal |author=Riddler SA, Li X, Otvos J, Post W, Palella F, Kingsley L, Visscher B, Jacobson LP, Sharrett AR |title=Antiretroviral therapy is associated with an atherogenic lipoprotein phenotype among HIV-1-infected men in the Multicenter AIDS Cohort Study |journal=J. Acquir. Immune Defic. Syndr. |volume=48 |issue=3 |pages=281–8 |year=2008 |month=July |pmid=18545156 |doi=10.1097/QAI.0b013e31817bbbf0 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=48&issue=3&spage=281 |accessdate=2012-05-22}}</ref> Untreated HIV infection also may be associated with an increased risk of CVD. In several cross-sectional studies, levels of markers of inflammation and endothelial dysfunction were higher in HIV-infected patients than in HIV-uninfected controls.<ref name="pmid18989230">{{cite journal |author=Ross AC, Armentrout R, O'Riordan MA, Storer N, Rizk N, Harrill D, El Bejjani D, McComsey GA |title=Endothelial activation markers are linked to HIV status and are independent of antiretroviral therapy and lipoatrophy |journal=J. Acquir. Immune Defic. Syndr. |volume=49 |issue=5 |pages=499–506 |year=2008 |month=December |pmid=18989230 |pmc=2778267 |doi=10.1097/QAI.0b013e318189a794 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=49&issue=5&spage=499 |accessdate=2012-05-22}}</ref><ref name="pmid19731451">{{cite journal |author=Baker JV, Duprez D, Rapkin J, Hullsiek KH, Quick H, Grimm R, Neaton JD, Henry K |title=Untreated HIV infection and large and small artery elasticity |journal=J. Acquir. Immune Defic. Syndr. |volume=52 |issue=1 |pages=25–31 |year=2009 |month=September |pmid=19731451 |pmc=2764552 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=52&issue=1&spage=25 |accessdate=2012-05-22}}</ref> In two randomized trials, markers of inflammation and coagulation increased following treatment interruption.<ref name="pmid19425222">{{cite journal |author=Calmy A, Gayet-Ageron A, Montecucco F, Nguyen A, Mach F, Burger F, Ubolyam S, Carr A, Ruxungtham K, Hirschel B, Ananworanich J |title=HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial |journal=AIDS |volume=23 |issue=8 |pages=929–39 |year=2009 |month=May |pmid=19425222 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=23&issue=8&spage=929 |accessdate=2012-05-22}}</ref><ref name="pmid18942885">{{cite journal |author=Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD |title=Inflammatory and coagulation biomarkers and mortality in patients with HIV infection |journal=PLoS Med. |volume=5 |issue=10 |pages=e203 |year=2008 |month=October |pmid=18942885 |pmc=2570418 |doi=10.1371/journal.pmed.0050203 |url=http://dx.plos.org/10.1371/journal.pmed.0050203 |accessdate=2012-05-22}}</ref> One study suggests that ART may improve endothelial function.<ref name="pmid18687253">{{cite journal |author=Torriani FJ, Komarow L, Parker RA, Cotter BR, Currier JS, Dubé MP, Fichtenbaum CJ, Gerschenson M, Mitchell CK, Murphy RL, Squires K, Stein JH |title=Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s |journal=J. Am. Coll. Cardiol. |volume=52 |issue=7 |pages=569–76 |year=2008 |month=August |pmid=18687253 |pmc=2603599 |doi=10.1016/j.jacc.2008.04.049 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(08)01870-6 |accessdate=2012-05-22}}</ref>
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| *In the SMART study, the risk of cardiovascular events was greater in participants randomized to CD4-guided treatment interruption than in participants who received continuous ART.<ref name="pmid19152399">{{cite journal |author=Sarmati L, Andreoni C, Nicastri E, Tommasi C, Buonomini A, D'Ettorre G, Corpolongo A, Dori L, Montano M, Volpi A, Narciso P, Vullo V, Andreoni M |title=Prognostic factors of long-term CD4+count-guided interruption of antiretroviral treatment |journal=J. Med. Virol. |volume=81 |issue=3 |pages=481–7 |year=2009 |month=March |pmid=19152399 |doi=10.1002/jmv.21424 |url=http://dx.doi.org/10.1002/jmv.21424 |accessdate=2012-05-22}}</ref> In other studies, ART resulted in marked improvement in parameters associated with CVD, including markers of inflammation (such as interleukin 6 [IL-6] and high-sensitivity C-reactive protein [hsCRP]) and endothelial dysfunction. A modest association between lower CD4 count while on therapy and short-term risk of CVD also exists.<ref name="pmid19571723">{{cite journal |author=Marin B, Thiébaut R, Bucher HC, Rondeau V, Costagliola D, Dorrucci M, Hamouda O, Prins M, Walker S, Porter K, Sabin C, Chêne G |title=Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy |journal=AIDS |volume=23 |issue=13 |pages=1743–53 |year=2009 |month=August |pmid=19571723 |pmc=3305466 |doi=10.1097/QAD.0b013e32832e9b78 |url= |accessdate=2012-05-22}}</ref><ref name="pmid19005264">{{cite journal |author=Phillips AN, Neaton J, Lundgren JD |title=The role of HIV in serious diseases other than AIDS |journal=AIDS |volume=22 |issue=18 |pages=2409–18 |year=2008 |month=November |pmid=19005264 |pmc=2679976 |doi=10.1097/QAD.0b013e3283174636 |url= |accessdate=2012-05-22}}</ref> However, in at least one of these cohorts (the CASCADE study), the link between CD4 count and fatal cardiovascular events was no longer statistically significant when adjusted for plasma HIV RNA level. Collectively, the data linking viremia and endothelial dysfunction and inflammation, the increased risk of cardiovascular events with treatment interruption, and the association between CVD and CD4 cell depletion suggest that early control of HIV replication with ART can be used as a strategy to reduce risk of CVD. Therefore, ART should be considered for HIV-infected individuals with a significant risk of CVD, as assessed by medical history and established estimated risk calculations ('''BII''').
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| | |
| =====D) Malignancies=====
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| Several population-based analyses suggest that the incidence of non-AIDS-associated malignancies is increased in chronic HIV infection. The incidence of non-AIDS-defining malignancies is higher in HIV-infected subjects than in matched HIV-uninfected controls.<ref name="pmid19617846">{{cite journal |author=Bedimo RJ, McGinnis KA, Dunlap M, Rodriguez-Barradas MC, Justice AC |title=Incidence of non-AIDS-defining malignancies in HIV-infected versus noninfected patients in the HAART era: impact of immunosuppression |journal=J. Acquir. Immune Defic. Syndr. |volume=52 |issue=2 |pages=203–8 |year=2009 |month=October |pmid=19617846 |pmc=2814969 |doi=10.1097/QAI.0b013e3181b033ab |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=52&issue=2&spage=203 |accessdate=2012-05-22}}</ref> Large cohort studies enrolling mainly patients receiving ART have reported a consistent link between low CD4 counts (<350–500 cells/mm<sup>3</sup>) and the risk of AIDS- and/or non-AIDS-defining malignancies. The ANRS C04 Study demonstrated a statistically significant relative risk of all cancers evaluated (except for anal carcinoma) in patients with CD4 counts <500 cells/mm<sup>3</sup> compared with patients with current CD4 counts >500 cells/mm<sup>3</sup>, and, regardless of CD4 count, a protective effect of ART for HIV-associated malignancies.<ref name="pmid19818686">{{cite journal |author=Guiguet M, Boué F, Cadranel J, Lang JM, Rosenthal E, Costagliola D |title=Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study |journal=Lancet Oncol. |volume=10 |issue=12 |pages=1152–9 |year=2009 |month=December |pmid=19818686 |doi=10.1016/S1470-2045(09)70282-7 |url=http://linkinghub.elsevier.com/retrieve/pii/S1470-2045(09)70282-7 |accessdate=2012-05-22}}</ref> This potential effect of HIV-associated immunodeficiency is striking particularly with regard to cancers associated with chronic viral infections such as [[HBV]], [[HCV]], [[human papilloma virus]] (HPV), [[Epstein-Barr virus]] (EBV), and [[human herpesvirus 8]] (HHV-8).<ref name="pmid17617273">{{cite journal |author=Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM |title=Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis |journal=Lancet |volume=370 |issue=9581 |pages=59–67 |year=2007 |month=July |pmid=17617273 |doi=10.1016/S0140-6736(07)61050-2 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)61050-2 |accessdate=2012-05-22}}</ref><ref name="pmid19741479">{{cite journal |author=Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, Klein D, Quesenberry CP, Towner WJ, Abrams DI |title=HIV infection and the risk of cancers with and without a known infectious cause |journal=AIDS |volume=23 |issue=17 |pages=2337–45 |year=2009 |month=November |pmid=19741479 |pmc=2863991 |doi=10.1097/QAD.0b013e3283319184 |url= |accessdate=2012-05-22}}</ref> Cumulative HIV viremia, independent of other factors, may also be associated with the risk of [[non-Hodgkin lymphoma]] and other [[AIDS-defining malignancies]]. Since the early 1990s, incidence rates for many cancers, including Kaposi sarcoma, diffuse large B-cell lymphoma, and primary central nervous system (CNS) lymphoma, have declined markedly in HIV-infected individuals in the United States. However, for other cancers, such as [[Burkitt lymphoma]], [[Hodgkin lymphoma]], [[cervical cancer]], and [[anal cancer]], similar reductions in incidence have not been observed. Declines in overall mortality and aging of HIV-infected cohorts increase overall cancer incidence, which may confound a clear assessment of the impact of ART on preventing the development of malignancies. Taken together this evidence suggests that initiating ART to suppress HIV replication and maintain CD4 counts at levels >350 to 500 cells/mm<sup>3</sup> may reduce the overall incidence of both AIDS-defining and non-AIDS-defining malignancies ('''CIII'''), although the effect on incidence is most likely to be heterogeneous across various cancer types.
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| | |
| ===== E) Neurological diseases=====
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| *Although HIV RNA can be detected in the cerebrospinal fluid (CSF) of most untreated patients, these patients usually do not present with overt symptoms of HIV-associated neurological disease. In some patients CNS infection progresses to HIV encephalitis and can present as HIV-associated dementia (HAD). This progression is usually in the context of more advanced untreated systemic HIV infection when severe CNS opportunistic infections (OIs) also cause high morbidity and mortality.
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| *ART has had a profound impact on the nervous system complications of HIV infection. Effective viral suppression resulting from ART has dramatically reduced the incidence of HAD and severe CNS OIs. Suppressive ART usually reduces CSF HIV RNA to undetectable levels. Exceptional cases of symptomatic and asymptomatic CNS viral escape, in which HIV RNA is detectable in CSF despite viral suppression in plasma, have been documented. This suggests that in some settings monitoring CSF HIV RNA may be useful.
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| *Recent attention has turned to milder forms of CNS dysfunction, defined by impairment on formal neuropsychological testing. It is unclear whether this impairment is a consequence of injury sustained before treatment initiation or whether neurologic damage can continue or develop despite systemically effective ART. The association of cognitive impairment with low nadir CD4 counts supports pretreatment injury and bolsters the argument that earlier initiation of ART may prevent subsequent brain dysfunction.
| |
| *The peripheral nervous system (PNS) also is a target in HIV infection, and several types of neuropathies have been identified. Most common is HIV-associated polyneuropathy, a chronic, predominantly sensory and sometimes painful neuropathy. The impact of early treatment on this and other forms of neuropathy is not as clearly defined as on HAD.
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| =====F) Age and treatment-related immune reconstitution =====
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| The CD4 cell response to ART is an important predictor of short- and long-term morbidity and mortality. Treatment initiation at an older age is consistently associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical outcomes.
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| | |
| =====G) T-cell activation and inflammation=====
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| Early untreated HIV infection is associated with sustained high-level inflammation and T-cell activation. The degree of T-cell activation during untreated HIV disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and peripheral CD4 T-cell count. ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation. Persistent T-cell activation and/or T-cell dysfunction is particularly evident in patients who delay therapy until later stage disease (CD4 count <350 cells/mm<sup>3</sup>. The degree of persistent inflammation during treatment, as represented by the levels of IL-6, may be independently associated with risk of death. Collectively, these observations support earlier use of ART for at least two reasons. First, treatment decreases the level of inflammation and T-cell activation, which may be associated with reduced short-term risk of AIDS- and non-AIDS-related morbidity and mortality. Second, because the degree of residual inflammation and/or T-cell dysfunction during ART appears to be higher in patients with lower CD4 cell nadirs, earlier treatment may result in less residual immunological perturbations on therapy and, hence, less risk for AIDS- and non-AIDS-related complications ('''CIII''').
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| ====4. Antiretroviral Therapy for Prevention of HIV Transmission====
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| ===== A) Prevention of perinatal transmission=====
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| Effective ART reduces transmission of HIV. The most dramatic and well-established example of this effect is the use of ART in pregnant women to prevent perinatal transmission of HIV. Effective suppression of HIV replication, as reflected in plasma HIV RNA, is a key determinant in reducing perinatal transmission. In the setting of ART initiation prior to 28 weeks’ gestation and an HIV RNA level <50 copies/mL near delivery, use of combination ART during pregnancy has reduced the rate of perinatal transmission of HIV from approximately 20% to 30% to <0.5%. Thus, use of combination ART drug regimens is recommended for all HIV-infected pregnant women ('''AI'''). Following delivery, in the absence of breastfeeding, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as those regarding ART for other non-pregnant individuals.
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| ===== B) Prevention of sexual transmission=====
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| *Recent study results provide strong support for the premise that treatment of the HIV-infected individual can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the concentration of the virus in genital secretions.<ref name="pmid10708281">{{cite journal |author=Vernazza PL, Troiani L, Flepp MJ, Cone RW, Schock J, Roth F, Boggian K, Cohen MS, Fiscus SA, Eron JJ |title=Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study |journal=AIDS |volume=14 |issue=2 |pages=117–21 |year=2000 |month=January |pmid=10708281 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=14&issue=2&spage=117 |accessdate=2012-05-22}}</ref><ref name="pmid12598766">{{cite journal |author=Coombs RW, Reichelderfer PS, Landay AL |title=Recent observations on HIV type-1 infection in the genital tract of men and women |journal=AIDS |volume=17 |issue=4 |pages=455–80 |year=2003 |month=March |pmid=12598766 |doi=10.1097/01.aids.0000042970.95433.f9 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0269-9370&volume=17&issue=4&spage=455 |accessdate=2012-05-22}}</ref>
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| | |
| *HPTN 052 was a multicontinental trial that enrolled 1,763 HIV-serodiscordant couples, in which the HIV-infected partner was ART naive and had a CD4 count of 350 to 550 cells/mm3 at enrollment. The study compared immediate ART with delayed therapy (not started until CD4 count <250 cells/mm3) for the HIV-infected partner. At study entry, 98% of the participants were in heterosexual monogamous relationships. All study participants were counseled on behavioral modification and condom use. Twenty-eight linked HIV transmission events were identified during the study period but only 1 event occurred in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04, 95% CI: 0.01–0.27, P <0.001). These results show that early ART is more effective at preventing transmission of HIV than all other behavioral and biomedical prevention interventions studied to date, including condom use, male circumcision, vaginal microbicides, HIV vaccination, and pre-exposure prophylaxis. This study, as well as other observational studies, and modeling analyses showing a decreased rate of HIV transmission among serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viremia in ART-adherent patients with no concomitant sexually transmitted diseases (STDs) substantially reduces the risk of transmission of HIV. HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing. However, the prevention benefits of effective ART probably will apply to these populations as well. Therefore, the Panel recommends that ART be offered to patients who are at risk of transmitting HIV to sexual partners. (The strength of this recommendation varies according to mode of sexual transmission: '''AI''' for heterosexual transmission and '''AIII''' for male-to-male and other modes of sexual transmission.) Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen and counsel patients that ART is not a substitute for condom use and behavioral modification and that ART does not protect against other STDs
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| | |
| ==Potential limitations of earlier initiation of therapy==
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| *Although there are benefits associated with earlier initiation of ART, there also are some limitations to using this approach in all patients. Concerns about long-term toxicity and development of resistance to ARV drugs have served as a rationale for deferral of HIV therapy. However, evidence thus far indicates that resistance occurs more frequently in individuals who initiate therapy later in the course of infection than in those who initiate ART earlier. Earlier initiation of ART at higher CD4 counts (e.g., >500 cells/mm3) results in greater cumulative time on therapy. Nevertheless, assuming treatment will continue for several decades regardless of when therapy is initiated, the incremental increase in drug exposure associated with starting therapy at higher CD4 counts will represent a small percentage of the total time on ART for most patients.
| |
| *Newer ARV drugs are generally better tolerated, more convenient, and more effective than drugs used in older regimens but there are fewer longer term safety data for the newer agents. Analyses supporting initiation of ART at CD4 counts >350 cells/mm3 (e.g., NA-ACCORD and ART-CC) were based on observational cohort data where patients were largely treated with regimens less commonly used in current clinical practice. In addition, these studies reported on clinical endpoints of death and/or AIDS disease progression but lacked information on drug toxicities, emergent drug resistance, or adherence. Therefore, in considering earlier initiation of therapy, concerns for some adverse consequences of ART remain.
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| ===1) Antiretroviral drug toxicities and quality of life===
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| | |
| *Earlier initiation of ART extends exposure to ARV agents by several years. The D:A:D study found an increased incidence of CVD associated with cumulative exposure to some drugs in the nucleoside reverse transcriptase inhibitor (NRTI) and PI drug classes.<ref name="pmid17460226">{{cite journal |author=Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD |title=Class of antiretroviral drugs and the risk of myocardial infarction |journal=N. Engl. J. Med. |volume=356 |issue=17 |pages=1723–35 |year=2007 |month=April |pmid=17460226 |doi=10.1056/NEJMoa062744 |url=http://dx.doi.org/10.1056/NEJMoa062744 |accessdate=2012-05-23}}</ref><ref name="pmid20039804">{{cite journal |author=Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, Monforte AD, Friis-Møller N, Kirk O, Fontas E, Weller I, Phillips A, Lundgren J |title=Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study |journal=J. Infect. Dis. |volume=201 |issue=3 |pages=318–30 |year=2010 |month=February |pmid=20039804 |doi=10.1086/649897 |url=http://www.jid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=20039804 |accessdate=2012-05-23}}</ref>
| |
| *In the SMART study, compared with interruption or deferral of therapy, continuous exposure to ART was associated with significantly greater loss of bone density. There may be unknown complications related to cumulative use of ARV drugs for many decades.<ref name="pmid17135583">{{cite journal |author=El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fätkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C |title=CD4+ count-guided interruption of antiretroviral treatment |journal=N. Engl. J. Med. |volume=355 |issue=22 |pages=2283–96 |year=2006 |month=November |pmid=17135583 |doi=10.1056/NEJMoa062360 |url=http://dx.doi.org/10.1056/NEJMoa062360 |accessdate=2012-05-23}}</ref>
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| *ART frequently improves quality of life for symptomatic patients. However, some side effects of ART may impair the quality of life for some patients, especially those who are asymptomatic at initiation of therapy. For example, efavirenz (EFV) can cause neurocognitive or psychiatric side effects and all the PIs have been associated with gastrointestinal (GI) side effects. Furthermore, some patients may find that the inconvenience of taking medication every day outweighs the overall benefit of early ART and may choose to delay therapy.
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| ===2) Nonadherence to Antiretroviral Therapy===
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| | |
| At any CD4 count, adherence to therapy is essential to achieve viral suppression and prevent emergence of drug-resistance mutations. Several behavioral and social factors associated with poor adherence, such as untreated major psychiatric disorders, active substance abuse, unfavorable social circumstances, patient concerns about side effects, and poor adherence to clinic visits, have been identified. Clinicians should identify areas where additional intervention is needed to improve adherence both before and after initiation of therapy.
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| | |
| ===3) Cost of therapy===
| |
| *In resource-rich countries, the cost of ART exceeds $10,000 per year. Several modeling studies support the cost effectiveness of HIV therapy initiated soon after diagnosis.<ref name="pmid11248160">{{cite journal |author=Freedberg KA, Losina E, Weinstein MC, Paltiel AD, Cohen CJ, Seage GR, Craven DE, Zhang H, Kimmel AD, Goldie SJ |title=The cost effectiveness of combination antiretroviral therapy for HIV disease |journal=N. Engl. J. Med. |volume=344 |issue=11 |pages=824–31 |year=2001 |month=March |pmid=11248160 |doi=10.1056/NEJM200103153441108 |url=http://dx.doi.org/10.1056/NEJM200103153441108 |accessdate=2012-05-23}}</ref><ref name="pmid11527782">{{cite journal |author=Schackman BR, Goldie SJ, Weinstein MC, Losina E, Zhang H, Freedberg KA |title=Cost-effectiveness of earlier initiation of antiretroviral therapy for uninsured HIV-infected adults |journal=Am J Public Health |volume=91 |issue=9 |pages=1456–63 |year=2001 |month=September |pmid=11527782 |pmc=1446805 |doi= |url= |accessdate=2012-05-23}}</ref><ref name="pmid16044008">{{cite journal |author=Mauskopf J, Kitahata M, Kauf T, Richter A, Tolson J |title=HIV antiretroviral treatment: early versus later |journal=J. Acquir. Immune Defic. Syndr. |volume=39 |issue=5 |pages=562–9 |year=2005 |month=August |pmid=16044008 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=39&issue=5&spage=562 |accessdate=2012-05-23}}</ref> One study reported that the annual cost of care is 2.5 times higher for patients with CD4 counts <50 cells/mm3 than for patients with CD4 counts >350 cells/mm3. A large proportion of the health care expenditure in patients with advanced infection is from non-ARV drugs and hospitalization. However, no comparisons of costs for patients starting ART with CD4 count 350 to 500 cells/mm3 and those for patients starting ART at >500 cells/mm3 have been reported.
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| *Historically, concerns about long-term toxicity, reduced quality of life, and the potential for emerging drug resistance served as key reasons to defer HIV therapy in asymptomatic patients for as long as possible. Inherent in this reasoning was the assumption that in asymptomatic patients the harm associated with viral replication was less than the harm associated with the toxicities of ART. There is now more evidence that untreated HIV infection has negative consequences on health at all stages of disease. Also, the currently preferred ART regimens are better tolerated than previous regimens, leading to greater effectiveness, improved adherence,<ref name="pmid18784459">{{cite journal |author=Willig JH, Abroms S, Westfall AO, Routman J, Adusumilli S, Varshney M, Allison J, Chatham A, Raper JL, Kaslow RA, Saag MS, Mugavero MJ |title=Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy |journal=AIDS |volume=22 |issue=15 |pages=1951–60 |year=2008 |month=October |pmid=18784459 |pmc=2828871 |doi=10.1097/QAD.0b013e32830efd79 |url= |accessdate=2012-05-23}}</ref> and lower frequency of emerging drug resistance. Therefore, the current guidelines emphasize avoiding adverse consequences of untreated HIV infection while managing potential drug toxicity associated with ART.
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| ==Conditions favoring more rapid initiation of therapy==
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| * Several conditions increase the urgency for therapy, including:
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| ** [[Pregnancy]] ('''AI''')
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| ** [[AIDS defining illnesses|AIDS-defining conditions]] ('''AI''')
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| ** Acute [[HIV opportunistic infections|OI]]s
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| ** Lower [[CD4 counts]] (e.g., <200 cells/mm3) ('''AI''')
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| ** [[HIVAN]] ('''AII''')
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| ** HIV/HBV [[coinfection]] ('''AII''')
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| ** Rapidly declining CD4 counts (e.g., >100 cells/mm3 decrease per year) ('''AIII''')
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| ** Higher [[viral loads]] (e.g., >100,000 copies/mL) ('''BII''')
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| | |
| * In patients with opportunistic conditions for which no effective therapy exists (e.g., [[cryptosporidiosis]], [[microsporidiosis]], [[progressive multifocal leukoencephalopathy]]) but in whom ART may improve outcomes by improving immune responses, the benefits of ART outweigh any increased risk; therefore, treatment should be started as soon as possible ('''AIII''').
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| * In patients who have active TB, initiating ART during treatment for TB confers a significant survival advantage; therefore, ART should be initiated as recommended.
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| ==Conditions where deferral of therapy may be considered==
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| *Some patients and their clinicians may decide to defer therapy for a period of time on the basis of clinical or personal circumstances. Deferring therapy for the reasons discussed below may be reasonable in patients with high CD4 counts (e.g., >500 cells/mm3) but deferring therapy in patients with much lower CD4 counts (e.g., <200 cells/mm3) should be considered only in rare situations and should be undertaken with close clinical follow-up. A brief delay in initiating therapy to allow a patient more time to prepare for lifelong treatment may be considered.
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| *In the setting of some OIs, such as [[Cryptococcus|cryptococcal meningitis]] or [[Nontuberculous mycobacteria|nontuberculous mycobacterial infections]], for which immediate therapy may increase the risk of immune reconstitution inflammatory syndrome ([[IRIS]]), a short delay before initiating ART may be warranted ('''CIII''').<ref name="pmid19365271">{{cite journal |author=Bicanic T, Meintjes G, Rebe K, Williams A, Loyse A, Wood R, Hayes M, Jaffar S, Harrison T |title=Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study |journal=J. Acquir. Immune Defic. Syndr. |volume=51 |issue=2 |pages=130–4 |year=2009 |month=June |pmid=19365271 |doi=10.1097/QAI.0b013e3181a56f2e |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=51&issue=2&spage=130 |accessdate=2012-05-23}}</ref><ref name="pmid16231262">{{cite journal |author=Phillips P, Bonner S, Gataric N, Bai T, Wilcox P, Hogg R, O'Shaughnessy M, Montaner J |title=Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up |journal=Clin. Infect. Dis. |volume=41 |issue=10 |pages=1483–97 |year=2005 |month=November |pmid=16231262 |doi=10.1086/497269 |url=http://www.cid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16231262 |accessdate=2012-05-23}}</ref> In the setting of other OIs, such as [[Pneumocystis jiroveci pneumonia]] (PCP), early initiation of ART is associated with increased survival<ref name="pmid19440326">{{cite journal |author=Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L |title=Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial |journal=PLoS ONE |volume=4 |issue=5 |pages=e5575 |year=2009 |pmid=19440326 |pmc=2680972 |doi=10.1371/journal.pone.0005575 |url=http://dx.plos.org/10.1371/journal.pone.0005575 |accessdate=2012-05-23}}</ref>; therefore, therapy should not be delayed ('''AI''').
| |
| *'''When there are significant barriers to adherence''': In patients with higher CD4 counts who are at risk of poor adherence, it may be prudent to defer treatment while addressing the barriers to adherence. However, in patients with conditions that require urgent initiation of ART (see above), therapy should be started while simultaneously addressing the barriers to adherence.
| |
| ** Several methodologies exist to help providers assess adherence. When the most feasible measure of adherence is self-report, this assessment should be completed at each clinic visit using one of the available reliable and valid instruments. If other objective measures (e.g., pharmacy refill data, pill count) are available, these methods should be used to assess adherence at each follow-up visit.<ref name="pmid18494555">{{cite journal |author=Bisson GP, Gross R, Bellamy S, Chittams J, Hislop M, Regensberg L, Frank I, Maartens G, Nachega JB |title=Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy |journal=PLoS Med. |volume=5 |issue=5 |pages=e109 |year=2008 |month=May |pmid=18494555 |pmc=2386831 |doi=10.1371/journal.pmed.0050109 |url=http://dx.plos.org/10.1371/journal.pmed.0050109 |accessdate=2012-05-23}}</ref><ref name="pmid18977718">{{cite journal |author=Kalichman SC, Amaral CM, Cherry C, Flanagan J, Pope H, Eaton L, Kalichman MO, Cain D, Detorio M, Caliendo A, Schinazi RF |title=Monitoring medication adherence by unannounced pill counts conducted by telephone: reliability and criterion-related validity |journal=HIV Clin Trials |volume=9 |issue=5 |pages=298–308 |year=2008 |pmid=18977718 |pmc=2937191 |doi=10.1310/hct0905-298 |url=http://thomasland.metapress.com/openurl.asp?genre=article&id=doi:10.1310/hct0905-298 |accessdate=2012-05-23}}</ref> Continuous assessment and counseling make it possible for the clinician to intervene early to address barriers to adherence occurring at any point during treatment.
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| *'''Presence of comorbidities that complicate or prohibit antiretroviral therapy:''' Deferral of ART may be considered when either the treatment or manifestations of other medical conditions could complicate the treatment of HIV infection or vice versa. Examples include
| |
| ** Surgery that may result in an extended interruption of ART.
| |
| ** Treatment with medications that have clinically significant drug interactions with ART and for which alternative medications are not available.
| |
| ** In each of these circumstances, the assumption is that the situation is temporary and that ART will be initiated after the conflicting condition has resolved.
| |
| *Some less common situations exist in which ART may not be indicated at any time while CD4 counts remain high. In particular, such situations include that of patients with a poor prognosis due to a concomitant medical condition who would not be expected to gain survival or quality-of-life benefits from ART. Examples include patients with incurable non-HIV-related malignancies or end-stage liver disease who are not being considered for liver transplantation. The decision to forego ART in such patients may be easier to make in those with higher CD4 counts; they are likely asymptomatic for HIV, and their survival is unlikely to be prolonged by ART. However, it should be noted that ART may improve outcomes, including survival, in patients with some HIV-associated malignancies (e.g., lymphoma or Kaposi sarcoma) and in patients with liver disease due to chronic HBV or HCV.
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| *'''Long-term nonprogressors and elite HIV controllers :''' A small subset of ARV-untreated HIV-infected individuals (~3%-5%) can maintain normal CD4 cell counts for many years (long-term nonprogressors), and an even smaller subset (~1%) can maintain suppressed viral loads for years (elite controllers). Although therapy theoretically may be beneficial for patients in either group, clinical data supporting therapy for nonprogressors and elite controllers are lacking.
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| ==NIH Recommendations==
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| ===Initiating Antiretroviral Therapy in Treatment-Naive Patients===
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| *Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:
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| ** CD4 count <350 cells/mm3 ('''AI''')
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| ** CD4 count 350 to 500 cells/mm3 ('''AII''')
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| ** CD4 count >500 cells/mm3 ('''BIII''')
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| *Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions:
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| ** Pregnancy ('''AI''')
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| ** History of an AIDS-defining illness ('''AI''')
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| ** HIV-associated nephropathy (HIVAN) ('''AII''')
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| ** HIV/hepatitis B virus (HBV) coinfection ('''AII''')
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| *Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner; therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners ('''AI'''[heterosexuals] or '''AIII''' [other transmission risk groups].
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| * Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence ('''AIII'''). Patients may choose to postpone therapy, and providers, on a case-bycase basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.
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| ====What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient====
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| The Panel recommends the following as preferred regimens for antiretroviral (ARV)-naive patients:
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| * efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) ('''AI''')
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| * ritonavir-boosted atazanavir + tenofovir/emtricitabine (ATV/r + TDF/FTC) ('''AI''')
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| * ritonavir-boosted darunavir + tenofovir/emtricitabine (DRV/r + TDF/FTC) ('''AI''')
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| * raltegravir + tenofovir/emtricitabine (RAL + TDF/FTC) ('''AI''').
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| * Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions.
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| * Based on individual patient characteristics and needs, in some instances, an alternative regimen may actually be a preferred regimen for a patient.
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| [[AIDS medical therapy treatment naive patients#top|back to top]]
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| ==Reference==
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| {{reflist|2}}
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| [[Category:HIV/AIDS]]
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| {{WH}}
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| {{WS}}
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