Antiretroviral%20therapy%20for%20hiv-infected%20adults Management

• Treatment failure can be defined as a suboptimal response to antiretroviral therapy
  • Often associated with virologic failure, immunologic failure, and/or clinical progression
  • Main cause is suboptimal adherence to treatment regimens and to care

Virologic Failure

• Incomplete virologic response is when 2 consecutive plasma HIV RNA levels remain at ≥200 copies/mL after 24 weeks on ART regimen in a patient without documented virologic suppression on that regimen
• Virologic rebound is confirmed detectable HIV RNA (>200 copies/mL) after virologic suppression
  • Occurs within days to weeks after stopping ART
• Low-level viremia is confirmed when detectable HIV RNA levels are <200 copies/mL
• Virologic blip is an isolated detectable HIV RNA level (after virologic suppression) that is followed by a return to virologic suppression
• Virologic failure is the inability to achieve or maintain suppression of viral replication (to an HIV RNA level of <200 copies/mL)
  • Virologic suppression is a confirmed HIV RNA level below the limit of assay detection (eg <50 copies/mL)
  • Caused by various factors (suboptimal adherence and drug intolerance/toxicity account for 28-40% of virologic failure)
    • Patient/adherence-related factors: Comorbidities, psychosocial factors including unstable housing, missed clinic appointments, affordability and cost of ARV drugs, adverse drug effects, high pill burden and/or dosing frequency
    • HIV-related factors: Higher baseline HIV RNA level, prior treatment failure, presence of transmitted or acquired drug-resistant virus which may or may not be documented by current or past drug resistance test results, innate drug resistance to administered ARV drugs
    • ART regimen-related characteristics: Low resistance barrier, drug-drug interactions, reduced efficacy due to prior exposure to suboptimal regimens, suboptimal virologic potency and pharmacokinetics, food requirements, prescription errors
    • Healthcare provider characteristics (experience or expertise in HIV treatment)

Assessment of Virologic Failure

• If virologic failure is suspected or confirmed, the following concerns should be addressed:
  • Occurrence of HIV-related clinical events
  • ARV treatment history
  • HIV RNA and CD4 T-cell count changes over time
  • Results of prior resistance testing
  • Medication-taking history (includes patient adherence, tolerability of medications, dosing frequency and pharmacokinetic issues)
  • Concomitant medications and comorbidities
• Suspected drug resistance should be addressed by performing resistance testing while patient is on the failing ART regimen or within 4 weeks after discontinuation of a non-long-acting ARV regimen 
• Drug resistance testing is recommended in patients with virologic failure and viral load >200 copies/mL
  • Drug resistance tests tend to be cumulative for a given patient; thus, all prior resistance test results and treatment history should be considered

NNRTI + 2 NRTIs Regimen Failure

• Presence of viral resistance to NNRTI with or without M184V/I mutation conferring high-level resistance to FTC and 3TC

Boosted PI + 2 NRTIs Regimen Failure

• Most patients will have no resistance or with resistance only to 3TC or FTC
• Due to poor adherence, drug-drug interactions, or drug-food interactions

INSTI + 2 NRTIs Regimen Failure

• Associated with emergent resistance to 3TC or FTC with or without additional NRTI mutations and possibly INSTI

INSTI + NNRTI Regimen Failure

• Associated with resistance to 1 or both of the medications in the regimen

Immunologic Failure

• Despite virologic suppression on ART, CD4 cell count fails to show adequate response or persistently declines
• Although no specific definition for immunologic failure exists, some studies have defined it as failure to increase CD4 counts above a specific threshold (eg >350 or 500 cells/mm³ over a period of 4-7 years)
  • CD4 counts in ART-naive patients with initial regimen increase to approximately 150 cells/mm³ within the 1st year and a plateau may occur after 4-6 years of treatment with viral suppression
  • A persistently low CD4 count while on ART is associated with a small but appreciable risk of AIDS- and non-AIDS-related (eg cardiovascular, renal, hepatic diseases) morbidity and mortality

Assessment of Immunologic Failure

• Confirm CD4 count by repeat testing
• Assess comorbidities and untreated coinfections
• Review medication history, focusing on those which are known to decrease white blood cell (WBC) count, especially CD4 (eg interferon, Prednisone, cancer chemotherapy agents, Zidovudine, combination of TDF and Didanosine)

Clinical Progression

• Persistence or recurrence of HIV-related events (after at least 3 months on an antiretroviral regimen), excluding immune reconstitution syndromes or symptoms attributable to persistence of opportunistic infections that may require longer treatment

Patients on ART

• Symptom-directed lab monitoring for safety and toxicity is recommended for those on ART
• CD4 T-cell count and plasma HIV RNA (viral load) are the 2 markers used routinely to evaluate immune function and level of viremia
  • Viral load is used to monitor therapy effectiveness after ART initiation
    • If resources are available, use viral load to confirm suspected treatment failure based on clinical and/or immunological criteria

Recommended Laboratory Parameters and Monitoring Schedule for Patients After Initiation of ART

• CD4 count monitoring is recommended:
  • Every 3 months if CD4 count is <300 cells/mm³ during the 1st 2 years of ART then every 6 months after 2 years of consistently suppressed HIV RNA
    • A repeat CD4 count after 3 months from ART initiation will help determine the magnitude of immune reconstitution and is most important for patients who initiate ART with more advanced disease and require prophylaxis or treatment for opportunistic infections
  • Every 6 months during the 1st 2 years of ART if CD4 count is ≥300 cells/mm³
  • Every 12 months in clinically stable patients with consistently suppressed viral load after 2 years on ART if CD4 count is 300-500 cells/mm³ and optional for those with CD4 count >500 cells/mm³
  • Every 3-6 months in patients who fail to maintain viral suppression while on ART
• HIV viral load monitoring is recommended:
  
  • 4-8 weeks post-ART initiation or modification to confirm an adequate virologic response to ART, indicating appropriate regimen selection and adherence to therapy
  • Repeat viral load measurement at 4- to 8-week intervals until the level falls below the assay’s limit of detection
    • If HIV RNA is detectable at 4-8 weeks, repeat every 4-8 weeks until suppression to <50 copies/mL, then every 3-6 months thereafter
  • Every 3-6 months for patients on a stable ART regimen or as clinically indicated; may extend to every 6 months for adherent patients with suppressed viral load and stable clinical and immunologic status for >1 year
  • In virologically suppressed patients in whom ART was modified because of drug toxicity or for regimens implification, measurement should be performed within 4-8 weeks after changing the therapy to confirm effectiveness of the new regimen
  • In patients with virologic failure and require ARV regimen modification, viral load is measured before ART change and within 4-8 weeks after regimen modification to confirm adequate virologic response to the new regimen; repeat viral load measurement is recommended every 4-8 weeks until level falls below the assay's limit of detection
  • Frequency of monitoring in patients with suboptimal response to ART will depend on the adherence and availability of other treatment options
• Fasting lipid profile monitoring
  • Consider after 1-3 months after ART initiation or modification then every 12 months if normal at baseline and with cardiovascular (CV) risk and every 5 years if normal at baseline or if clinically indicated
• CBC with count
  • Every 3-6 months when monitoring CD4 count then every 12 months when CD4 count is no longer monitored
    • More frequent monitoring is recommended in patients receiving drugs which can cause cytopenias
• Basic chemistry
  • Eg serum Na, K, bicarbonate, chloride, BUN, creatinine, glucose (preferably fasting), liver transaminases, creatinine-based glomerular filtration rate (GFR) and total bilirubin
  • 4-8 weeks post-ART then every 6 months thereafter or if clinically indicated
    • Include phosphorus if on Tenofovir disoproxil fumarate (TDF) and Tenofovir alafenamide (TAF)
• Urinalysis
  • Monitor urine glucose and protein during treatment with TDF- or TAF-containing regimens
    • More frequent monitoring may be indicated for patients with evidence of kidney disease (eg decreased GFR, proteinuria) or increased risk of renal insufficiency [eg diabetes mellitus (DM), hypertensive patients]
• In addition to viral load monitoring, other factors should be assessed such as adherence to prescribed ART regimen, altered pharmacology, drug interactions
• Drug resistance testing for patients who fail to achieve viral suppression and aid in the choice of an alternative regimen
  • Recommended when modifying regimen to assist in the selection of active drugs in patients with virologic failure and HIV RNA levels >200 copies/mL or patients with suboptimal viral load reduction
    • May be considered in patients with confirmed HIV RNA levels >200 copies/mL but <500 copies/mL
  • Reverse transcriptase and protease genotypic resistance testing is recommended in all patients with virologic failure while integrase resistance testing is recommended in patients with virologic failure while on INSTI-based therapy
  • Drug resistance testing in the setting of virologic failure is performed while still on ARV regimen for patients receiving non-long-acting ARV therapy or within 4 weeks after discontinuing ARV regimen
  • Recommended in all patients who experienced virologic failure with injectable CAB-LA and Rilpivirine regimen or acquired HIV after receiving CAB-LA as pre-exposure prophylaxis regardless of the amount of time since drug discontinuation
  • Genotypic drug resistance testing is preferred to guide therapy in patients with suboptimal virologic response or virologic failure while on 1st- or 2nd-line therapy and in patients with known or without suspected complex resistance mutation patterns
  • Phenotypic drug resistance testing is recommended in addition to genotypic drug resistance testing in patients with known or suspected complex drug resistance mutation patterns
  • Previous and current drug resistance test results should be reviewed and taken into consideration when constructing a new regimen

Patients Not Started on ART

• Patients not yet eligible for ART should have CD4 count measurement every 3-6 months to assess urgency of ART initiation and the need for prophylaxis for opportunistic infections
• HBsAg should be performed to help identify people with HIV/HBV coinfection so appropriate ART can be given (eg TDF-containing ART)
• Patients should continue their regular visits for monitoring, prophylaxis and other medical treatment
• ART should be discussed and offered again to patients who initially declined treatment
  • Discuss the benefits of ART and the risks of delaying the treatment
  • Provide support or counselling if lack of readiness, coping mechanisms or probable compliance difficulties are at issue

• Consider expert referral for all patients who experience treatment failure

General Approach to Patients with Virologic Failure

• Evaluation should include assessment of adherence, drug-drug or drug-food interaction, drug tolerability and severity of the patient’s HIV disease, history of ART, concomitant medications, results of prior drug resistance testing, and CD4 and HIV RNA counts over time
  • Identify possible clinical scenario involved in treatment failure (eg patient adherence, timing of the drug resistance test, presence of a highly drug resistant HIV)
• Goal of treatment in ART-experienced patients with drug resistance who are experiencing failure is to re-establish virologic suppression (HIV RNA levels below the lower limits of detection of currently used assays)
• Change the ART regimen as soon as virologic failure is confirmed
  • There is no consensus for the optimal time to change therapy
  • Patients who failed 2nd-line agents without new antiretroviral options should continue with a tolerated regimen
  • The goal is to suppress HIV replication to a level where drug resistance mutations do not emerge
• To establish a new ART regimen, review patient’s treatment history, including results of both past and current resistance tests, and identify at least 2 (preferably 3) fully active agents with high barrier to resistance to combine with an optimized background ART regimen
  • ARV drugs with high barrier to resistance are those where emergent resistance is not common in patients with virologic failure which include BIC, DRV, and DTG
    • New regimen may include an INSTI preferably the 2nd-generation DTG plus PK-enhanced PI preferably DRV, without NRTIs, if both are fully active
    • 3 fully active drugs should be included in the new ARV regimen if a fully active drug with high resistance barrier is not available
  • Fully active agents are those that are likely to have virologic activity based on the patient’s drug resistance test results, treatment history and the drug’s mechanism of action
    • Include drugs from classes where the patient has no history of drug resistance, newer members of existing drug classes expected to be fully active against HIV isolates (eg BIC, DOR, DRV, DTG), drugs with novel mechanism of action which the patient has not previously received
  • Adding a single fully active agent is not recommended since this increases the risk of rapid development of resistance
  • Partially active agents are those predicted to have antiviral activity but to a lesser extent than when there is no underlying drug resistance
    • ARV drugs such as NRTIs, PIs and 2nd-generation INSTIs with partial activity may be retained as part of the salvage regimen
  • ARV agents where resistance is expected should be discontinued
  • ARV agents active against HBV must be continued as part of the new regimen or initiation of Entecavir is recommended when not possible when changing regimens in patients with HIV/HBV coinfection is needed
  • But in patients with a high chance of clinical progression and limited drug options, adding a single drug regimen may reduce risk of immediate clinical progression
• Interrupting or discontinuing treatment is not recommended since this may lead to rapid decline in the CD4 count and rise in HIV RNA and may increase the risk for clinical progression
• In cases of patients that are highly ART-experienced, where maximal virologic response is not possible, ART should be continued with regimens that are designed to preserve CD4 cell counts, avoid clinical progression, and minimize toxicity
• In patients with limited drug choices and a high likelihood of clinical progression (eg CD4 count <100 cells/mm³), adding a single ART agent may reduce the risk of immediate clinical progression
  • May produce transient increases in CD4 cell counts and/or decreases in HIV RNA which have been associated with clinical benefits
• Monitoring for virologic responses after regimen switch is recommended within 4-8 weeks and immediate drug resistance testing performed if with inadequate virologic response is detected

Management of Patients with Low-Level Viremia

• Patients usually do not need to change ARV regimen and must continue the current regimen
• Monitoring of viral load is recommended every 3 months to evaluate the need for ARV change

Management of Patients with Viral Load ≥200 copies/mL and <1,000 copies/mL

• Patients with persistent viral load range from 200-1,000 copies/mL are considered to have virologic failure
• Drug resistance testing is recommended especially in patients with viral load >500 copies/mL
  • Proviral DNA genotypic testing may be done if genotypic resistance testing is not possible because of low viral load levels
• Management is the same for patients with viral load >1,000 copies/mL

Management of Patients with Viral Load ≥1,000 copies/mL Without Identified Drug Resistance Mutations Using Current or Previous Genotypic Resistance Test Results

• Associated with suboptimal adherence
• Comprehensive evaluation must be performed to determine the level of adherence, identify underlying causes of incomplete adherence and to simplify the regimen (eg simplify dose frequency, reduce pill count, simplify food requirement)
  • Access to ART must be evaluated
  • Patient's tolerance to current regimen must be evaluated and intolerance must be addressed by treating symptoms
  • Concomitant medications and dietary supplements must be reviewed
  • Therapeutic drug monitoring may be done if PK drug-drug interactions or drug absorption impairment is suspected
  • Food requirements for each drug must be reviewed
• Continuation of current regimen is recommended if regimen is well tolerated and without significant drug-drug or drug-food interactions with focus on improving patient adherence
• Changing the regimen to an equally effective but more tolerable regimen is recommended if current ARV agents are poorly tolerated or in the presence of drug-drug or drug-food interactions
• Monitoring of viral load is recommended every 4-8 weeks after treatment modification or reinforcement of treatment adherence
  • Genotypic resistance testing is recommended if viral load remains >200 copies/mL

Management of Patients with Viral Load >1,000 copies/mL and Identified Drug Resistance

• Modification of the regimen is recommended if new or previously detected resistance mutations will compromise the regimen
  • Best done before worsening of viremia or before reduction of CD4 counts

Management of Virologic Failure on the 1st ART
NNRTI + 2 NRTIs Regimen Failure

• Fully active DTG + 2 NRTIs, with ≥1 of which is fully active, is a recommended treatment option after a 1st-line NNRTI-based therapy failure
  • Fully active DTG + 2 partially active NRTIs may be an option if ≥1 fully active NRTI cannot be assured
• Boosted PIs preferably DRV + 2 NRTIs, with ≥1 of which is fully active, is recommended as a treatment option after a 1st-line NNRTI-based therapy failure
  • Fully active boosted DRV + 2 partially active NRTIs may be an option if ≥1 fully active NRTI cannot be assured
• Boosted PIs (LPV/r) + INSTI (RAL) may be a treatment option for patients with virologic failure on an NNRTI based regimen
  • Boosted PI (DRV) + DTG may also be an option

Boosted PI + 2 NRTIs Regimen Failure

• Switching to an INSTI-based regimen (eg DTG, BIC) + 2 NRTIs, with ≥1 of which is fully active, is the preferred option due to better tolerability, high resistance barrier and lack of drug-drug interactions
  • DTG is preferred over BIC if only 1 of the NRTI is fully active or if adherence is a concern
  • DTG + 2 partially active NRTIs (TAF or TDF + 3TC or FTC) may be an option if ≥1 fully active NRTI cannot be assured
• Continuing current regimen is an option if the regimen is well tolerated and without drug-drug or drug-food interactions, with support for enhancing adherence and viral load monitoring
• Switching to another boosted PI-based regimen without proof of cross resistance plus INSTI or 2 NRTIs, with ≥1 of which is fully active may be an option
  • Different fully active boosted PI + at 2 partially active NRTIs (TAF or TDF + 3TC or FTC), if full activity of ≥1 NRTI cannot be assured

INSTI + 2 NRTIs Regimen Failure

• Treatment strategies will depend on drug resistance test results and potential potency of the new regimen
• Modified regimens for patients with virologic failure without INSTI resistance include:
  • Boosted PI + 2 NRTIs, with ≥1 of which is fully active, or
  • DTG or BIC + 2 NRTIs, with ≥1 of which is fully active, or
  • Boosted PI + DTG
• Modified regimens for patients with virologic failure with RAL and/or EVG resistance but with DTG susceptibility include:
  • Boosted PI + 2 NRTIs, with ≥1 of which is fully active, or
  • DTG (twice daily) + 2 NRTIs, with ≥1 of which is fully active, or
  • DTG (twice daily) + boosted PI

INSTI + NNRTI Regimen Failure

• Treatment strategies will depend on previous treatment history, results of drug resistance tests, and potential potency of the next regimen

Management of 2nd-Line Failure and Beyond
Drug Resistance with Fully Active ART Options

• Treatment options will depend on previous treatment history, drug resistance test results and tropism testing if a CCR5 antagonist will be used
• Treatment option for patients with fully active boosted PI but not 2nd-generation INSTI regimen: Boosted PI+ 2 NRTIs, with ≥1 of which is fully active
• Treatment option for patients with fully active 2nd-generation INSTI, with unboosted PI regimen: DTG or BIC+ 2 NRTIs, with ≥1 of which is fully active
• Treatment options for patients with fully active PI and INSTI regimen:
  • Boosted PI + INSTI, or
  • Boosted PI + 2 NRTIs, with ≥1 of which is fully active, or
  • DTG or BIC + 2 NRTIs, with ≥1 of which is fully active

Multidrug Resistance Without Fully Active ART Options

• Goal is to achieve maximal virologic suppression but if not possible, ART should preserve immunologic function, prevent clinical progression and minimize further resistance development which can compromise future regimens
• New regimen must consist of at least 2 and preferably 3 fully active drugs including those with novel mechanisms of action, if a fully active boosted PI or a 2nd-generation INSTI is not available
• Enrollment in clinical trials may be considered
• Ibalizumab (IBA): CD4 post-attachment inhibitor which may be an option for patients with detectable viremia without other treatment options
• Fostemsavir (FTR): gp120-directed inhibitor which may be an option for patients with detectable viremia without other treatment options
• Discontinuation of all ARV agents is not recommended

Management of ART-Experienced Patients with Suspected Drug Resistance and with Limited/Incomplete Information

• Treatment options for ART-experienced patients who present with incomplete or without self-reported history, medical records, or results of drug resistance tests include:
  • Restarting the most recent ART regimen and evaluation of drug resistance after 2-4 weeks to guide the selection of the next regimen
  • Starting 2-3 agents that are predicted to be fully active based on patient's treatment history; if without treatment history, agents with high resistance barrier including twice-daily DTG, BIC/TAF/FTC, and/or boosted DRV may be used as part of the regimen
• Virologic response monitoring by determining viral load must be performed within 4-8 weeks after re-initiation of the ART and immediate drug resistance test performed if with inadequate virologic response

Management of Immunologic Failure

• Focus on patients with CD4 counts <200 cells/mm³
• ART intensification wherein an ARV agent is added to a suppressive ART regimen is not recommended because it does not reduce immune activation and improve CD4 cell recovery
• Switching ARV drug classes is not recommended because it does not consistently reduce all relevant markers of immune activation and improve CD4 cell recovery
• Use of interleukin-2 is not recommended because clinical trials have shown no benefit with its use
  • Immune-based therapies should not be used except for clinical trials

• People who acquire HIV while taking pre-exposure prophylaxis such as oral FTC + either TAF or TDF, and CAB-LA may have ambiguous HIV test results
• Immediate confirmation of HIV diagnosis is recommended for individuals with positive HIV Ag/Ab test result or positive HIV RNA test result and a negative HIV antibody test result
• People with viral load ≥200 copies/mL and taking pre-exposure prophylaxis is recommended to be initiated immediately with an effective HIV treatment regimen while waiting for confirmation of HIV diagnosis
  • Pre-exposure prophylaxis will be changed to triple-drug ART regimen which includes a high resistance barrier agent usually DTG, BIC or DRV/c + 2 NRTIs
• A confirmatory HIV antibody test and repeat quantitative plasma HIV RNA test is recommended to be performed and test results known before ART initiation in individuals taking pre-exposure prophylaxis with negative HIV antibody test result and very low positive quantitative HIV RNA test result (<200 copies/mL)

• All individuals undergoing human immunodeficiency virus (HIV) testing should be counseled when their results are given, regardless of the test result

HIV-positive Patients

• Clearly inform the patient of the test result and allow him/her the time to consider it
• Ensure that the patient understands the result and allow questions to be asked
• Provide emotional support and crisis management
• Discuss any immediate concerns and determine available and acceptable social network to offer support
• Discuss treatment and follow-up services available, including care and support services, prevention of mother-to-child transmission
• Provide information on prevention of HIV transmission (including provision of male and female condoms and guidance on their use) and relevant health preventive measures (eg good nutrition)
• Notification, counselling and referral for HIV testing of partners and children

HIV-negative Patients

• Explanation of the test result, including information on the window period for the appearance of HIV antibodies and a recommendation to re-test in case of a recent exposure
• Educate on methods of prevention of HIV transmission
• Provision of male and female condoms and guidance on their use
• Start ART to uninfected partner for prevention

• Use of ART and achieving sustained viral suppression prevents sexual transmission of HIV
• Viral load suppression to <200 copies/mL with ART prevents sexual transmission of HIV
• Patients starting on ART are recommended to use another form of prevention with sexual partners (eg condoms, pre-exposure prophylaxis for the HIV-negative sexual partner or sexual abstinence) for at least the 1st 6 months of treatment and until a viral load of <200 copies/mL is confirmed
• Additional methods of prevention are recommended to prevent transmission of HIV to sexual partners when viral load is ≥200 copies/mL until suppression to <200 copies/mL is confirmed
• Patients on ART and not using other methods of prevention of HIV transmission with sexual partners are recommended to maintain high levels of ART adherence because transmission is possible during periods of treatment interruption or poor adherence
  • Assessment of adherence and counseling is recommended at each visit to stress the importance of adherence for the patient's health as well as its role in HIV transmission prevention
• Immediate ART initiation is also recommended for all pregnant individuals with HIV to prevent HIV transmission to the newborn