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Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults 2016 Recommendations of the International Antiviral Society-USA Panel
 
 
  Download the PDF here
 
Special Communication | July 12, 2016
 
"With rare exception, all HIV-infected individuals with detectable viremia, regardless of their CD4 cell count, should begin antiretroviral therapy (ART) as soon as possible after diagnosis to prevent disease progression, improve clinical outcomes, and limit transmission."
 
"HIV-infected patients with hepatitis C virus (HCV) coinfection
should start an ART regimen with drugs that do not have significant drug interactions with HCV therapies (evidence rating AIIa). The recommended regimens that have the fewest drug interactions with current HCV treatments are dolutegravir/abacavir/lamivudine and dolutegravir or raltegravir plus TAF/emtricitabine. Clinicians should consult current HCV treatment guidelines prior to using any other ART regimens, particularly those that include NNRTIs, boosted HIV PIs, or elvitegravir/c.63"
 
discussed in detail below in article - "WHEN AND HOW TO SWITCH: Recommendations for when and how to switch antiretroviral regimens are summarized in Box 4. With improvements in ART, the need to switch therapy because of virologic failure and drug resistance has decreased. However, these improvements provide a rationale for switching therapy in some patients who have virologic suppression with older regimens that are less convenient or that have more adverse or toxic effects. Reasons to consider switching therapy in such patients include adverse effects, simplification (reducing doses or pills), drug-drug interactions, pregnancy or plans for pregnancy, and food restrictions."
 
discussed more below in article - "After suppression is achieved, HIV RNA should be monitored every 3 months until suppression has been sustained for 1 year and at least every 6 months thereafter for adherent patients who remain clinically stable (evidence rating AIII)."
 
".....baseline resistance testing should be performed regardless of the duration of infection because many mutations have little effect on viral fitness and may persist for years....Resistance testing is less reliable if a patient has stopped ART for longer than 1 month when the sample is collected. The absence of resistance mutations does not confirm absence of resistance in this setting."
 
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Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults 2016 Recommendations of the International Antiviral Society-USA Panel
 
JAMA. 2016
 
Huldrych F. Günthard, MD1; Michael S. Saag, MD2; Constance A. Benson, MD3; Carlos del Rio, MD4; Joseph J. Eron, MD5; Joel E. Gallant, MD, MPH6; Jennifer F. Hoy, MBBS, FRACP7; Michael J. Mugavero, MD, MHSc2; Paul E. Sax, MD8; Melanie A. Thompson, MD9; Rajesh T. Gandhi, MD10; Raphael J. Landovitz, MD11; Davey M. Smith, MD12; Donna M. Jacobsen, BS13; Paul A. Volberding, MD14
 
http://jama.jamanetwork.com/article.aspx?articleid=2533073
 
ABSTRACT
 
Importance New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults.
 
Objective To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis.
 
Evidence Review A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence.
 
Findings
 
Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count.
 
Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs.
 
Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided.
 
Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities.
 
Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence.
 
Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure.
 
Conclusions and Relevance Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.
 
INTRODUCTION
 
There have been substantial advances in the use of antiretroviral drugs (ARVs) for the treatment and prevention of HIV infection since the last version of these recommendations in 2014,1 warranting an update to the recommendations.
 
With rare exception, all HIV-infected individuals with detectable viremia, regardless of their CD4 cell count, should begin antiretroviral therapy (ART) as soon as possible after diagnosis to prevent disease progression, improve clinical outcomes, and limit transmission. This recommendation is strongly supported by recent large randomized clinical trials.2,3 New drugs that combine excellent potency with greater convenience, safety, and tolerability make lifelong viral suppression achievable and reduce the risk of viral resistance. In HIV-infected persons, ART is effective in preventing HIV transmission1,4,5 and provides individual and public health benefits. Antiretroviral therapy for individuals at risk of acquiring HIV infection (as postexposure prophylaxis [PEP] or preexposure prophylaxis [PrEP]) prevents HIV acquisition.
 
This revision of the recommendations discusses the latest developments in uses of ARVs, summarizing current knowledge on the following: when to start therapy, including optimal initial treatment regimens; ART for patients with opportunistic infections (OIs); when and how to switch ART; laboratory monitoring; engagement in care and ART adherence; and prevention of HIV infection.
 
METHODS
 
Recommendations were developed by an international panel of 14 volunteer experts in HIV research and patient care appointed by the International Antiviral Society-USA. Potential members were screened for expertise in the field, involvement in research and care, financial relationships with commercial companies, and ability to work toward consensus. The panel convened in person and by conference calls from late 2015 to mid-2016. Teams for each major section, each with a lead writer, evaluated relevant evidence and drafted recommendations for full panel review.
 
Evidence used was published in the scientific literature, presented at major scientific conferences, or released as safety reports by regulatory agencies or data and safety monitoring boards since 2014.1 Literature searches in PubMed and EMBASE were designed by an expert in systematic reviews to capture publications relevant to ART in HIV infection since the 2014 iteration of the recommendations1 through April 2016. New evidence was considered in conjunction with evidence used for prior reports.1 Approximately 320 relevant citations were identified by 1 author (P.V.) from an initial list of more than 3200. Relevant abstracts publicly presented at scientific conferences since June 2014 were identified by panel members. Manufacturers of ARVs provided lists of relevant scientific publications or abstracts presented at peer-reviewed conferences.
 
These recommendations are focused on adults (defined as aged ≥18 years) with or at risk of HIV infection in settings in which most ARVs are available (approved by regulatory bodies or in expanded access) or in late-stage development (new drug application filed).
 
Recommendations were made by consensus and rated according to the strength of the recommendation and the quality of the evidence (Table 1). Recommendations that have not changed substantially or for which few relevant data have become available since 2014 are included in the 2014 treatment recommendations1 along with detailed discussion and citations. Where appropriate, prior citations were included. Further details about the recommendations development process, panel selection, summary of evidence collection and literature search strategies, and the sponsor (International Antiviral Society-USA) and its policies are available in the Supplement.
 
WHEN TO START
 
Initiation of Therapy

 
Recommendations for when to start ART are summarized in Box 1. ART is recommended for all HIV-infected patients with detectable viremia, regardless of CD4 cell count (evidence rating AIa). Randomized clinical trial data now further confirm previous recommendations for early initiation of ART in adults1,7because of the individual-level clinical benefit (reduction in AIDS-related events, non-AIDS-related events, and all-cause mortality) (Table 2)2,3,8 and a decreased risk of HIV transmission.4
 
Patients should understand the goals of treatment and be willing to initiate therapy. Baseline resistance testing is recommended for all patients, but initiating therapy prior to availability of the results may be appropriate in some cases. Recent data suggest little transmitted drug resistance to integrase strand transfer inhibitors (InSTIs) and protease inhibitors (PIs) but not nonnucleoside reverse transcriptase inhibitors (NNRTIs).9- 11
 
Current Investigational Approaches to Starting Therapy
 
Initiation of ART is recommended as soon as possible in the setting of acute HIV infection (evidence rating BIII).1 Initiation prior to the development of HIV antibody positivity reduces the size of the latent HIV reservoir, reduces immune activation, and may protect against infection of central memory T cells. Benefits are maximal during the first few weeks after HIV infection but are apparent up to the first 6 months after infection.12- 16 However, early therapy does not prevent the establishment of the latent HIV reservoir. Planned discontinuation of early ART after a specific duration of treatment is not recommended outside research settings; the benefits do not persist and the subsequent viral rebound is associated with increased clinical events and the potential for transmission (evidence rating AIa).16- 18
 
Initiation of ART on the same day as diagnosis of HIV infection has been implemented in several cities.19,20 Evaluation of the long-term effectiveness and limitations of this strategy is needed.
 
Initiation of ART in "elite controllers" (defined as patients with confirmed HIV infection and persistent undetectable HIV RNA without ART) remains controversial. Elite controllers may still benefit from ART because they have higher levels of immune activation and an increased risk of cardiovascular disease and hospitalization compared with individuals achieving virologic suppression with ART.21 Initiation of treatment, however, is recommended for infected persons who have persistent undetectable viral load without ART but have declining CD4 cell counts (evidence rating BIII).
 
RECOMMENDED INITIAL REGIMENS
 
Recommendations for initial antiretroviral regimens are summarized in Box 2. Among adherent individuals, initial ART with 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a third active drug from a different class achieves and maintains similar virologic suppression rates in nearly all patients.22- 26 Clinicians and patients have many options and may select a regimen based on considerations other than antiviral potency. Considerations include short- and long-term adverse effects, ease of administration, drug interactions, risk of resistance if virologic failure occurs, and cost. Patients with more than 100 000 HIV RNA copies/mL or fewer than 200 CD4 cells/μL remain a subset in whom ART potency is particularly important, as certain regimens have suboptimal virologic suppression in this setting.1,7,27- 35
 
Optimal Initial Regimens
 
InSTI-based regimens are optimal for initial therapy. Recommended initial ART for most patients are (regimens are listed in alphabetic order by InSTI component; see Table 3) dolutegravir/abacavir/lamivudine (evidence rating AIa), dolutegravir plus tenofovir alafenamide (TAF)/emtricitabine (AIa), elvitegravir/cobicistat/TAF/emtricitabine (evidence rating AIa), and raltegravir plus TAF/emtricitabine (evidence rating AIII). (Components separated with a slash [/] indicate that they are available as coformulations.)
 
If TAF is not available, tenofovir disoproxil fumarate (TDF) is an effective and generally well-tolerated option. Given the limited long-term experience with TAF, some clinicians may prefer to continue using TDF pending broader experience with TAF in clinical practice.
 
InSTIs as Components of the Initial Regimen
 
In the SINGLE study, dolutegravir plus abacavir/lamivudine was superior to efavirenz/TDF/emtricitabine.36 Similar results were observed in the FLAMINGO study (comparing dolutegravir with ritonavir-boosted [/r] darunavir),37 in the WAVES study (comparing cobicistat-boosted [/c] elvitegravir with atazanavir/r in HIV-infected women),38 and in the AIDS Clinical Trials Group 5257 study (comparing raltegravir with atazanavir/r or darunavir/r).39
 
No clinical trial has directly compared all 3 currently available InSTIs. In treatment-naive patients, dolutegravir was noninferior to raltegravir, with no resistance to dolutegravir observed in that treatment group.40 In treatment-experienced patients, dolutegravir was superior to raltegravir41 and elvitegravir was noninferior to raltegravir.42 The InSTIs differ in several important features that may influence treatment choice (Table 4).
 
Abacavir as a Component of the Initial Regimen
 
Abacavir is a component of the recommended regimen of dolutegravir/abacavir/lamivudine. Approximately half of individuals who are positive for the HLA-B*5701 allele experience a hypersensitivity reaction to abacavir that may be life threatening.44 HLA-B*5701 testing should be performed prior to abacavir use (evidence rating AIa); those who test positive should not be given abacavir (evidence rating AIa). Allergy to abacavir should be listed in the medical record.
 
Although some prior comparisons of abacavir/lamivudine and TDF/emtricitabine demonstrated an efficacy advantage of TDF/emtricitabine,45,46 these differences have not been observed in studies that use dolutegravir. In the SINGLE study, all patients in the dolutegravir-containing group used abacavir/lamivudine.36 In the SPRING-2 and FLAMINGO studies, a minority of dolutegravir-treated patients used abacavir/lamivudine, and no differences in efficacy were found based on NRTI selection.
 
The association between abacavir and an increased risk of myocardial infarction remains controversial.1,7,34,35 More studies have now been published describing the association,47- 49 but the data remain inconclusive. For now, abacavir should be used with caution in patients who have or who are at high risk of cardiovascular disease.
 
TAF as a Component of the Initial Regimen
 
Compared with TDF, TAF yields a lower plasma level of tenofovir and higher intracellular concentration of the active antiviral component tenofovir diphosphate. This results in fewer tenofovir-associated toxic effects, such as proximal renal tubular toxicity and reductions in bone mineral density. One report suggested the possibility of elevated liver enzymes with TDF use, but the clinical significance is uncertain.50
 
TAF and TDF were compared in prospective clinical trials of initial therapy51,52 and in switch strategies from TDF in patients with virologic suppression and no history of resistance or treatment failure.53,54 To date, only elvitegravir/c has been used in studies of TAF as initial therapy, but a broader range of third drugs has been used in switch studies.
 
Compared with TDF, TAF has little or no effect on bone density and little or no kidney toxicity. Specifically, proximal tubulopathy has not been observed to date with TAF, which has less effect on renal tubular and overall proteinuria and estimated glomerular filtration rate (eGFR) than TDF. TAF reduces lipids less than TDF; however, this difference does not affect the ratio of total to high-density lipoprotein cholesterol. To date, no cases of clinical renal disease are directly ascribed to TAF. Tolerability of TAF and TDF is comparable, as are rates of HIV suppression, resistance with virologic failure, and increases in CD4 cell count.
 
The daily dose of TAF (25 mg or 10 mg) is lower than that of TDF (300 mg). For HIV treatment, TAF is currently available only in coformulations, consisting of emtricitabine/TAF; rilpivirine/emtricitabine/TAF; and elvitegravir/cobicistat/emtricitabine/TAF. Unlike TDF, TAF should not be used with rifamycins, and there are limited data on its safety and efficacy for pregnant women. Non-InSTI-Containing (or Non-NRTI-Containing) Initial Regimens Several non-InSTI-containing regimens suppress HIV RNA in the majority of patients who are adherent to therapy. These may be optimal for a given patient based on individual clinical characteristics, preferences, or owing to financial considerations or lack of InSTI availability. These regimens are acceptable therapeutic options. These options are listed in Table 5.
 
Initial therapy with 2 active drugs is under investigation. This strategy may offer cost or toxicity advantages over the current 3-drug regimens.56 To date, only 2 adequately powered randomized clinical trials have demonstrated noninferior outcomes of 2-drug therapy compared with 3-drug regimens. Lopinavir/r plus lamivudine was noninferior to lopinavir/r plus 2 NRTIs in one study,57 and darunavir/r plus raltegravir was noninferior to darunavir/r plus 2 NRTIs in another.58 However, these 2-drug regimens have limitations. Lopinavir/r induces relatively high rates of gastrointestinal adverse effects and hyperlipidemia. Darunavir/r plus raltegravir was associated with higher rates of treatment failure in patients with a CD4 cell count below 200/μL or an HIV RNA level above 100 000 copies/mL. A small single-group trial of dolutegravir plus lamivudine in 20 patients demonstrated promising results.59
 
Initial 2-drug regimens are recommended only in the rare situations in which a patient cannot take abacavir, TAF, or TDF (evidence rating BIa); [darunavir/c or darunavir/r] plus [raltegravir or dolutegravir] or plus [lamivudine or emtricitabine] may be considered, but the former strategy may be less effective in those with CD4 cell counts below 200/μL or HIV RNA levels above 100 000 copies/mL. Of note, there are no adequately powered studies of initial therapy of other listed 2-drug regimens besides darunavir/r plus raltegravir or lopinavir/r plus lamivudine; efficacy is assumed from other clinical trials.57,58
 
Special Considerations
 
Pregnancy

 
HIV-infected pregnant women should initiate ART for their own health and to reduce the likelihood of HIV transmission to the infant (evidence rating AIa). Nucleoside reverse transcriptase inhibitor options include abacavir/lamivudine (if the patient is HLA-B*5701 negative), TDF/emtricitabine, or zidovudine/lamivudine. Zidovudine/lamivudine is the regimen with the longest clinical experience, but it has more toxic effects. Raltegravir is the recommended InSTI for use during pregnancy. Recommended boosted PIs include atazanavir/r (once daily) or darunavir/r (twice daily). The recommended NNRTI is efavirenz when initiated after the first 8 weeks of pregnancy. If an HIV-infected woman who is taking efavirenz becomes pregnant, the regimen may be continued; changing it risks loss of virologic control.
 
Hepatitis B Virus Coinfection
 
HIV-infected patients with hepatitis B virus (HBV) coinfection should initiate a recommended ART regimen that contains TDF or TAF (evidence rating AIa), lamivudine or emtricitabine, and a third component.60- 62 Lamivudine and emtricitabine each have substantial antiviral activity against HBV. However, there is a high risk of HBV resistance and viral breakthrough if these drugs are used without TDF or TAF, and neither is recommended alone for HBV in coinfection. Entecavir may be used to treat HBV infection (evidence rating AIII). If HIV RNA is not suppressed, entecavir should be avoided because it can select for lamivudine- and emtricitabine-resistant HIV (evidence rating AIII).
 
Hepatitis C Virus Coinfection
 
HIV-infected patients with hepatitis C virus (HCV) coinfection should start an ART regimen with drugs that do not have significant drug interactions with HCV therapies (evidence rating AIIa). The recommended regimens that have the fewest drug interactions with current HCV treatments are dolutegravir/abacavir/lamivudine and dolutegravir or raltegravir plus TAF/emtricitabine. Clinicians should consult current HCV treatment guidelines prior to using any other ART regimens, particularly those that include NNRTIs, boosted HIV PIs, or elvitegravir/c.63
 
Bone Disease
 
Osteoporosis and fractures are increased with HIV infection.64 During the first 1 to 2 years after initiation of ART, patients may lose 2% to 6% of their bone mineral density at the hip and spine. Patients who receive TDF-containing regimens have a greater initial decline in bone mineral density than those who take a TAF- or abacavir-containing regimen. For this reason, TDF is not recommended for patients with osteopenia or osteoporosis (evidence rating BIII).
 
Kidney Disease
 
Monitoring for development of kidney disease with eGFR, urinalysis, and testing for glycosuria and albuminuria or proteinuria is recommended when ART is initiated or changed and every 6 months (along with HIV RNA) once HIV RNA is stable (evidence rating BIII).65 In cohort studies, TDF (especially with a boosted PI) increased the risk of chronic kidney disease.66 Tenofovir disoproxil fumarate is not recommended for patients with an eGFR below 60 mL/min.65 The options are abacavir (which does not require dose adjustment in this setting) or TAF (if creatinine clearance is above 30 mL/min) (evidence rating AIIa). Long-term data on TAF in patients with preexisting renal disease are limited.67 Tenofovir disoproxil fumarate or TAF should be discontinued if renal function worsens, particularly if there is evidence of proximal tubular dysfunction (eg, euglycemic glycosuria or urinary phosphate wasting) (evidence rating AIIa). The safety of TAF in patients with active TDF-associated proximal tubulopathy has not been determined. If possible, TAF should be initiated only after tubulopathy has resolved, with monitoring for recurrence.
 
HIV-infected patients with end-stage renal disease should be evaluated for kidney transplantation with the expectation of high rates of patient and graft survival (evidence rating AIIa).
 
Cost Considerations
 
In highly resourced countries, approximately 75% to 80% of annual HIV care expenditures are spent on medications.68 Even at full price, ART is cost-effective.69 In the United States, drug pricing discounts are common, but the amount of discount remains unknown to clinicians and patients, making it difficult to use pricing as a component of treatment decisions.
 
As more drugs become available in less-expensive generic formulations, payers may begin to use "societal benefit" as a criterion for selection of the initial regimen. One modeling study showed a savings of up to $900 million annually with routine use of a generic efavirenz-based regimen in the United States over a branded version of the same regimen.70 Although relative efficacy in viral suppression is lower with an efavirenz-based regimen than with InSTI-based regimens, the differences are modest and driven by tolerability rather than potency.71
 
Where resource constraints limit the ability of a health system to provide widespread treatment to all HIV-infected persons, a strategy of using generic formulations of recommended regimens first with use of more expensive drugs for those who demonstrate intolerance may be reasonable. Such policy decisions should be determined in consultation with HIV experts in the locale where the policy is being considered.
 
WHEN AND HOW TO SWITCH
 
Recommendations for when and how to switch antiretroviral regimens are summarized in Box 4. With improvements in ART, the need to switch therapy because of virologic failure and drug resistance has decreased. However, these improvements provide a rationale for switching therapy in some patients who have virologic suppression with older regimens that are less convenient or that have more adverse or toxic effects. Reasons to consider switching therapy in such patients include adverse effects, simplification (reducing doses or pills), drug-drug interactions, pregnancy or plans for pregnancy, and food restrictions.
 
Study data support switching from an older regimen to one of a number of single-pill regimens: dolutegravir/abacavir/lamivudine,95 elvitegravir/cobicistat/emtricitabine/TAF,53 elvitegravir/cobicistat/emtricitabine/TDF,96,97 or rilpivirine/emtricitabine/TDF.98 Data also support a switch from suppressive TDF/emtricitabine-based regimens to TAF/emtricitabine-based regimens.60 The lack of randomized clinical trial data does not preclude the possibility of a switch, provided certain caveats are considered. Induction maintenance approaches have been evaluated in which patients with virologic suppression switch from a 3-drug to a 2-drug maintenance regimen.99- 102 Although trials provide some support for this approach, it remains investigational, and induction maintenance strategies are not recommended at this time (evidence rating BIIa).
 
For patients experiencing adverse effects or drug toxicities or requesting modification or simplification of their regimen, the decision to switch is relatively easy. Situations exist in which practitioners should recommend a switch even for patients who are satisfied with their current regimen and appear to be doing well. These include when patients are taking regimens containing stavudine, didanosine, or zidovudine, largely because of long-term toxic effects, or older PIs that have higher pill burdens and greater metabolic toxicities than darunavir or atazanavir. Some drugs that are no longer recommended for initial use may often be safely continued for patients who are tolerating them. For example, although nevirapine and efavirenz have substantial early toxic effects, they are safe and tolerable in the long term. Patients taking efavirenz should be questioned carefully about the possibility of subtle neuropsychiatric adverse effects (eg, dizziness, sleep disturbances, cognitive changes, depression) that they may be unaware of or may not attribute to the drug (evidence rating BIII).
 
With the availability of TAF in its coformulations, it is possible to switch from TDF to TAF. Although the presumption of greater renal and bone safety is primarily based on surrogate markers (ie, bone density as a marker for fracture risk; eGFR and proteinuria for renal safety), these markers consistently suggest superior safety of TAF vs TDF. One exception may be modest lipid elevations due to the loss of the lipid-lowering effects of TDF. If there is no increase in the price of TAF vs that of TDF, switching from TDF to TAF is reasonable even if patients are not experiencing TDF-related toxic effects (evidence rating BIa).
 
For patients with virologic suppression, it is important to consider the possibility of drug resistance and whether the genetic barriers to resistance of the existing and proposed switch regimens are high or low. The risk of switching from a high-barrier regimen to a low-barrier regimen in patients with preexisting drug resistance has been well demonstrated.103 When possible, switches to a regimen with a lower resistance barrier should be made only after reviewing the treatment and resistance history (evidence rating AIa). When this information is not available, a proviral DNA genotype test may be helpful. The clinical utility of these assays has not yet been established, but they may be useful in detecting mutations that have been archived in resting CD4 cells but that are no longer detectable by standard commercial resistance assays.104,105 Results must be interpreted with caution because they can sometimes fail to detect existing mutations.106 Some switches in the setting of viral suppression may be safe regardless of resistance (eg, TDF to TAF, efavirenz to rilpivirine or etravirine, raltegravir or elvitegravir to dolutegravir, or lopinavir/r to boosted darunavir). Switching from a boosted PI to an NNRTI or an InSTI (with the possible exception of dolutegravir) or switching from twice-daily darunavir/r to once-daily darunavir/c is not advised without considering resistance history because of the reduced resistance barrier of the regimen (evidence rating AIII).
 
The drug-drug interactions that affect the choice of initial regimen also must be considered when switching. Whether baseline viral load should be considered before switching therapy is not clear; baseline HIV RNA levels above 100 000 copies/mL were not associated with virologic failure when patients with virologic suppression with a PI-based regimen switched to a rilpivirine-containing regimen.98
 
The approach to virologic failure of an initial NNRTI-, PI-, or InSTI-based regimen has been addressed previously.1 Failure of initial regimens that were chosen based on baseline resistance test results is generally due to poor adherence or, less commonly, to drug-drug interactions. Thus, adherence and drug interactions must be addressed before initiating the new regimen.
 
Ongoing Therapy
 
HIV RNA level should be monitored every 4 to 6 weeks after treatment is initiated or changed until it is undetectable, generally below 20 to 50 copies/mL (evidence rating AIa). Virologic suppression should occur within 24 weeks of ART initiation even when initiated during acute infection.112 Failure to achieve suppression by 24 weeks should prompt evaluation for virologic failure. After suppression is achieved, HIV RNA should be monitored every 3 months until suppression has been sustained for 1 year and at least every 6 months thereafter for adherent patients who remain clinically stable (evidence rating AIII). Therapeutic drug monitoring is not recommended except in specific circumstances, as previously described (evidence rating BIII).1
 
CD4 cell count is used to determine the need for OI prophylaxis. If pretreatment CD4 cell count is below 200/μL, reassessment is recommended every 3 to 4 months until HIV RNA is reliably suppressed and CD4 cell count is above 350/μL for 1 year. Thereafter, CD4 cell counts should be assessed at 6-month intervals until virus has been suppressed for at least 2 years and CD4 cell count is persistently stable above 500/μL (evidence rating AIII). Subsequently, repeat monitoring is not recommended unless virologic failure or intercurrent immunosuppressive conditions occur or immunosuppressive treatments are initiated (evidence rating AIII).1,113 Monitoring for safety, including measures of renal and hepatic function and fasting lipids, should be individualized based on age, comorbid conditions, and concurrent medications. Screening for sexually transmitted infections should be conducted according to guidelines, local prevalence, and patient risk.114
 
Management of Low-Level Viremia
 
Although any detectable virus has been associated with viral rebound in some studies,115,116 measurable HIV RNA between 20 and 50 copies/mL did not increase the risk of virologic failure in 1 study.117 Data are inconsistent about long-term effects of persistent HIV RNA between 50 and 200 copies/mL,116,118 and current data are insufficient to guide clinical management. Such patients should be reassessed for causes of virologic failure, evaluated again within 4 weeks, and monitored closely (evidence rating BIII). Decisions to change therapy should be individualized based on ART options, resistance history, and clinical circumstances. Treatment should be changed in patients with persistent HIV RNA above 200 copies/mL.119
 
Viral Resistance
 
Although transmitted viruses with resistance mutations can revert to wild type, baseline resistance testing should be performed regardless of the duration of infection because many mutations have little effect on viral fitness and may persist for years.120- 122 Nonnucleoside reverse transcriptase inhibitor mutations are the most common transmitted resistance mutations (4.5%-10%); NRTI (4.0%-4.5%) and PI mutations are less common (2.8%-3.4%).107,123 Virologic failure with an InSTI-containing regimen requires integrase resistance testing, as integrase resistance has been described in up to 6.8% of patients.124 Resistance testing is less reliable if a patient has stopped ART for longer than 1 month when the sample is collected. The absence of resistance mutations does not confirm absence of resistance in this setting.
 
 
 
 
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