Antiretroviral Therapy for HIV-Infected Adults Management

Evaluation

The goals of initial evaluation include the confirmation of the presence of HIV infection, gathering of appropriate baseline historical and laboratory information, ensuring patient understanding of HIV infection and its transmission, and the initiation of care as recommended by established guidelines. Initial evaluation consists of complete medical history including immunization history, physical examination and lab evaluation. Evaluation must also include assessment of social support, comorbidities, substance abuse, high-risk behaviors, mental illness, and economic factors. Patients should also be counseled regarding the implications of HIV infection.

Indications and Recommendations for Starting ART  

Regardless of CD4 cell count or WHO clinical stage, initiation of ART is strongly recommended for individuals with the following conditions:

• All HIV-infected individuals, including all HIV-infected women
• Pregnancy
  • All pregnant and breastfeeding women with acute or recent HIV infection should start a combination of ART as soon as possible to prevent mother-to-child transmission of HIV
  • Early treatment during and after pregnancy
• History of an AIDS-defining illness
• HIV-associated nephropathy (HIVAN)
• HIV/HBC, and HIV/HCV coinfections
• HIV with active TB disease coinfection
  • TB treatment should be started not later than 8 weeks after its initiation
  • Alcohol dependence, active drug use, and mental health disorders should not withhold TB treatment
• Advanced HIV disease (clinical stage 3 or 4)
• HIV-positive partners in serodiscordant couples
• Treat all patients including asymptomatic individuals with CD4 T-cell count of 350-500 cells/mm³ regardless of the clinical stage but prioritize patients with CD4 T-cell count of ≥350 cells/mm³ and those with advanced HIV disease
• ART should be offered to patients who are at risk of transmitting HIV to sexual partners
  • Effective ART has been shown to prevent transmission of HIC from an infected individual to a sexual partner
• ART is recommended in patients >50 years of age, regardless of CD4 cell count
  • Immunologic response to ART may be reduced and risk of non-AIDS complications may be increased in older HIV-infected patients 
• ART is recommended for all HIV-infected individuals to reduce the risk of disease progression and prevent its transmission
• Patients starting ART should be willing, able to commit, understand the risks and benefits of therapy and the importance of adherence
• All patients who are HIV-positive should be counseled on how the infection is being transmitted, how can it be prevented, and the responsibility of notifying their partners about the infection

Assessment of Treatment Failure  

Treatment failure can be defined as a suboptimal response to ART. It is often associated with virologic failure, immunologic failure, and/or clinical progression. The main cause of treatment failure is suboptimal adherence to treatment regimens and to care.  

Virologic Failure  

Incomplete virologic response occurs when 2 consecutive plasma HIV RNA levels remain ≥200 copies/mL after 24 weeks on ART regimen in a patient without documented virologic suppression on that regimen. Virologic rebound is confirmed HIV RNA levels become detectable (≥200 copies/mL) after virologic suppression. This usually occurs within days to weeks after stopping ART. Low-level viremia is confirmed when HIV RNA levels are detectable but are <200 copies/mL. A virologic blip is an isolated detectable HIV RNA level (<200 copies/mL; after virologic suppression) that is then followed by a return to virologic suppression. Virologic failure is the inability to achieve or maintain suppression of virologic replication to an HIV RNA level of <200 copies/mL or persistently detectable HIV RNA level that is >1,000 copies/mL. Virologic suppression is confirmed when HIV RNA levels reach below the limit of detection (<50 copies/mL). Virologic failure can be caused by various factors (eg suboptimal adherence and drug intolerance or toxicity which account for 28-40% of virologic failure).  

Other causes of virologic failure include:

• Patient factors: Comorbidities, psychosocial factors (eg unstable housing, missed clinic appointments, affordability and cost of ARV drugs, 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 a viral load of >200 copies/mL. Drug resistance tests tend to be cumulative for a given patient, thus, all prior resistance tests and treatment history should be considered. Viral resistance testing may be done when viral load is >1,000 copies/mL during ART treatment or within 4 weeks after treatment discontinuation.  

Non-nucleoside reverse transcriptase inhibitor (NNRTI) plus 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Regimen Failure  

The presence of viral resistance to NNRTI with or without M184V/I mutation confers high-level of resistance to Emtricitabine (FTC) and Lamivudine (3TC).  

Boosted Protease Inhibitor (PI) plus 2 NRTIs Regimen Failure  

Most patients who have failed this regimen will have no resistance or with resistance only to 3TC or FTC. Regimen failure is due to poor adherence, drug-drug interactions, or drug-food interactions.  

Integrase Strand Transfer Inhibitor (INST) plus 2 NRTIs Regimen Failure  

INSTI plus 2 NRTIs regimen failure is associated with emergent resistance to 3TC or FTC with or without additional NRTI mutations, and possibly to INSTI as well.  

INSTI plus NNRTI Regimen Failure  

INSTI plus NNRTI regimen failure is associated with resistance to 1 or both medications in the regimen.  

Immunologic Failure  

In the case of immunologic failure, despite virologic suppression on ART, CD4 cell count fails to show adequate response or persistently declines. Although there is no specific definition for immunologic failure, some studies have defined it as a failure to increase CD4 counts above a specific threshold (eg >350 or 500 cells/mm³ over a period of 4-7 years). The CD4 counts in ART-naïve patients with initial regimen increase to approximately 150 cells/mm³ within the first 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  

In assessing immunologic failure, repeat testing to confirm CD4 count is done. It is also important to assess comorbidities and untreated coinfections. Lastly, medication history, especially focusing on those which are known to decrease white blood cell (WBC) count, specifically CD4 should be reviewed (eg interferon, Prednisone, cancer chemotherapy agents, Zidovudine, combination of Tenofovir disoproxil fumarate [TDF] and Didanosine [ddI]).  

Clinical Progression  

Clinical progression occurs when there is persistence or recurrence of HIV-related events after at least 3 months on ARV regimen, excluding immune reconstitution syndromes or symptoms attributable to persistence of opportunistic infections that require longer treatment. 

Principles of Therapy

The following are the goals of ART:

• Sustained suppression of viral load for a maximum possible duration
• Restore and preserve immunologic function
• Reduce HIV-related morbidity and mortality
• Improve quality of life
• Increase lifespan
• Prevent HIV transmission
• Prevent emergence of HIV drug resistance

Low baseline viremia, with high ARV regimen potency, tolerability and convenience of the regimen, and excellent adherence are predictors of virologic success.

Antiretroviral Therapy for HIV-Infected Adults_Management 2

• Patients age ≥50 years
• Pregnant women with early HIV-infection as soon as possible to prevent perinatal transmission of HIV-1
• HIV with coinfection (HBV, HCV, active TB)
• AIDS-defining illness, including HIV-associated dementia (HAD) and AIDS-associated malignancies
• HIVAN
• Acute or early infections
• Low CD4 counts (eg <350 cells/ mm³)
• Acute opportunistic infections (eg cryptosporidiosis, microsporidiosis, PML)
• HIV/HBV with evidence of chronic liver disease
• Those patients with severe or has prolonged symptoms

ART is also recommended for serodiscordant couples. When starting ART, it is important to educate patients about its benefits and considerations to optimize compliance to therapy. Before starting ART, women in the reproductive age must undergo pregnancy test and the person’s intentions regarding pregnancy should be discussed. The patient should attain the maximum viral suppression before attempting contraception to minimize risk of perinatal HIV transmission to the infant. Lastly, information regarding the maintenance of plasma HIV RNA to <200 copies/mL including any measurable value below this threshold should be given to people with HIV with ART to prevent sexual transmission of HIV to their partners.  

ART in Special Populations  

All pregnant and breastfeeding women with acute or recent HIV infection should start ART regimen as soon as possible to prevent mother-to-child transmission and to protect their own health. Elite HIV controllers (patients with HIV with plasma HIV-1 RNA levels below level of quantification for years without ART) are recommended to start ART in the presence of HIV disease progression defined as decreasing CD4 counts or development of HIV-related complications.  

The principles of active TB treatment in HIV-infected patients are the same as those for HIV-uninfected patients. All HIV patients coinfected with active TB should be immediately started on TB treatment. In patients with CD4 counts <50 cells/mm³, ART is started within 2 weeks of TB treatment. On the other hand, those with CD4 counts ≥50 cells/mm³, ART is started within 8 weeks of TB treatment. In patients with drug-resistant TB, ART is started within the first 8 weeks following TB treatment regardless of CD4 count. In patients with HBV coinfection, ART drugs that are active against HBV are continued even in the setting of HIV virologic failure. The drug active against HBV is continued and combined with other suitable ART agents to achieve HIV suppression.  

Concurrent treatment of HIV and HCV infection may be complicated by other overlapping drug toxicities and high pill burden. The decision to start HCV treatment should be consider the medical need for such treatment based on the HCV stage. ART is recommended in patients >50 years of age regardless of CD4 count because of immunologic response to ART may be reduced in older HIV-infected patients and the risk of non-AIDS complications may increase. ART is also recommended for all individuals with HIV-1 infection, the goal being to suppress plasma HIV-1 RNA to undetectable levels. In patients with early HIV-1 infection in whom therapy is initiated, testing for plasma HIV-1 RNA levels, CD4 T lymphocyte counts, and toxicity monitoring should be performed as described for patients with chronic HIV-1 infection. Genotypic drug resistance testing should be performed before the initiation of ART to guide selection of the regimen. In patients without transmitted drug-resistant virus, therapy should be initiated with one of the combination regimens for patients with chronic HIV-1 infection. Patients starting ART should be willing and able to commit to treatment and should understand the possible benefits and risks of therapy and the importance of adherence.  

Pharmacological therapy

Regimen Selection  

The selection of treatment regimen should be individualized based on virologic efficacy, toxicity, potential drug-drug interaction, dosing frequency, pill burden, resistance testing results, comorbidities, patient characteristics (eg pregnancy potential, adherence potential), the needs to enhance adherence, and support long-term treatment success. The initial treatment regimen for treatment-naïve patients consists of 2 NRTIs plus either an INSTI, NNRTI, or pharmacokinetic (PK)-enhanced PI. The 2-drug regimen consisting of Dolutegravir (DTG) and 3TC may also be used for initial therapy. Viral suppression using another ART regimen is recommended for patients without previous ART and would wish to start intramuscular (IM) CAB-LA and Rilpivirine (RPV) before switching to oral then injectable CAB and RPV.  

Characteristics to consider in all patients with HIV:

• Pretreatment HIV RNA (viral load)
• Pretreatment CD4 count
• History of use of CAB-LA as pre-exposure prophylaxis
• HIV genotypic drug resistance test results
• HLA-B*5701 status
• Individual preferences
• Anticipated adherence to the regimen
• Initiation of ART before availability of baseline lab results

Recommended Antiretroviral Drug Regimens for Most Patients with HIV  

The following regimens are recommended based on their durable virologic efficacy, favorable tolerability and toxic profiles, and their ease of use. 

Antiretroviral Therapy for HIV-Infected Adults_Management

• ABC/3TC
• TAD/FTC
• TDF/3TC
• TDF/FTC

Currently, 3 of the approved NRTIs have activity against hepatitis virus (HBV) which are 3TC, FTC, and TDF. Single- and dual-NRTI therapy are not recommended as these have not demonstrated sustained and potent virologic activity. D4T should not be used as a first-line agent due to its metabolic toxicities. Dual NRTIs are commonly used in combination with an NNRTI, a PI, an INSTI, or a CCR5 antagonist. In clinical practice, most dual NRTI combinations consist of a primary NRTI plus 3TC or FTC.  

Abacavir (ABC)/Lamivudine (3TC) (Coformulated)  

ABC/3TC remains a good dual-NRTI option for some ART-naïve patients. This should only be given to patients who tested negative for HLA-B*5701 as ABC has the potential for serious hypersensitivity reactions. ABC/3TC with EFC or ATV/r is recommended in patients with pretreatment viral loads or <100, copies/mL. While DTG/ABC/3TC is recommended as the initial regimen for most people with HIV. This fixed dose combination has the advantage of once-daily dosing. However, this should be used with caution in patients at higher risk for cardiovascular disease.  

Emtricitabine (FTC) and Lamivudine (3TC)  

FTC and 3TC are used interchangeably in combination with other ARV. Both drugs have activity against HBV but are not sufficient for HBV treatment when used as a monotherapy due to emergence of resistance. Their doses must be adjusted in patients with CrCl <50 mL/min. They are well tolerated without significant treatment-limiting adverse effects. However, coadministration of sorbitol-containing drugs with 3TC should be avoided, and that suboptimal viral suppression will lead to selection of M184V mutation.  

Tenofovir alafenamide (TAF)/Emtricitabine (FTC) (Coformulated)  

TAF is a prodrug of TFV which is hydrolyzed to TFV in plasma and converted to TFV-diphosphate intracellularly where it acts as a NRTI. TAF/FTC is the recommended NRTI combination for initial ART in most people with HIV when given with BIC, DTG, and RAL, and as part of the recommended regimens in certain clinical conditions. This is also coformulated with BIC, DRV/c, EVG/r or RPV and safe for patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min. It may be used in patients with eGFR of <30 mL/min and on chronic hemodialysis. TAF/FTC is active against HBV and may be used as a NRTI pair in an ARV regimen in patients with HIV-HBV coinfection. TAF has clinically significant greater virologic efficacy when used with PK boosters as compared to TDF. It is also associated with lesser bone and renal toxicities compared to TDF.  

TAF is recommended as first choice NRTI over TDF for the patients with known chronic kidney disease (CKD) or at high risk for CKD, patients with previous TDF toxicity, patients with osteoporosis or progressive osteopenia or have high risk factors for osteoporosis, patients with a history of fragility fracture, and when nephrotoxic drugs are coadministered. However, TAF should be avoided or used with caution with any Rifampicin-containing regimen.  

Tenofovir disoproxil fumarate (TDF)/Emtricitabine (FTC) (Coformulated) and TDF/Lamivudine (3TC) (Coformulated)  

Tenofovir is a nucleotide analog with potent activity against both HIV and HBV. It has a long intracellular half-life which allows for once-daily dosing. TDF demonstrated potent virologic activity when used with either 3TC or FTC as part of an EFV-based regimen in ART-naïve patients. TDF is associated with lower lipid levels compared to TAF, however, renal impairment has been reported, with greater risk of renal dysfunction when used in PI-based regimens. TDF causes renal toxicity, including proximal tubulopathy and acute or chronic renal insufficiency especially when in combination with PK boosters. Hence, use of TDF is not recommended in patients with pre-existing renal insufficiency (CrCl <60 mL/min). Dose adjustments are recommended when TDF is used and patient’s CrCl falls <50 mL/min. Additionally, TDF decreases bone mineral (BMD) more than other NRTI combinations, thus, TDF should be avoided or used with caution in patients with renal disease or osteoporosis. TDF/FTC or TDF/3TC are recommended NRTI combinations for initial ART in most people with HIV when combined with DTG or RAL. TDF plus either 3TC or FTC may be used as NRTI combination for patients coinfected with both HIV and HBV. TDF/FTC is the recommended dual-NRTI in patients coinfected with HIV-HBV. Use of a single HBV-active NRTI (either 3TC or FTC) is not recommended as it can lead to HBV resistance. TDF/FTC is coformulated with EFV, EVG/c and RPV as STRs as more favorable lipid effects than ABC or TAF. TDF/FTC gives a better virologic response than ABC/3TC in patients with a baseline viral load of ≥100,000 copies/mL when combined with ATV/r or EFV. TDF/3TC is coformulated with DOR and EFV as well. Lastly, boosters should be avoided in patients taking TDF when possible. 

PI-based Regimens  

PI-based regimens have demonstrated durability and virologic potency in ART-naïve patients, and higher barrier to resistance compared to NNRTIs, EVG, and RAL. Resistance mutations are seldom detected in PI-based regimens at virologic failure, unlike NNRTI- and INSTI-based regimens. These regimens are also useful for patients at risk for intermittent treatment because of poor adherence.  

Boosted PI Regimens  

PK enhancement of PI-based regimens with either Cobicistat or RTV increases concentration and prolongs the half-lives of PIs. Boosted ATV or DRV-based regimen are recommended for rapid ART initiation or in the setting of acute HIV infection before the availability of resistance test results. RTV-boosted PI-based regimens have demonstrated good immunologic and virologic responses.  

The advantage of PI-based regimens is that drug resistance to most PIs requires multiple mutations in the HIV protease gene and seldom develops after early virologic failure, especially when RTV boosting is used. As such, PI resistance is not common at the time of treatment failure with PK-boosted PIs. However, the disadvantage is that PIs are often associated with gastrointestinal (GI) symptoms than EFV-based regimens and EFV-like regimens and are also associated with hepatic transaminase elevations. Other disadvantages include higher pill burden and more clinically significant drug interactions seen with RTV-boosted PI regimens than with NNRTI-based regimens.  

Atazanavir plus Ritonavir (ATV/r) or Atazanavir plus Cobicistat (ATV/c)   

ATV/r and ATV/c combined with TDF/FTC are recommended as initial ART regimens for ART-naïve patients in certain clinical conditions regardless of pretreatment HIV RNA. However, ATV/c plus TDF/FTC is not recommended for patients with CrCl of <70 mL/min, and ATV/c plus TAF/FTC is not recommended for patients with CrCl of <30 mL/min. ATV/r or ATV/c plus ABC/3TC is recommended as other regimens. However, its use is limited to patients with pre-ART HIV RNA <100,000 copies/mL. The advantages of these regimens (ATV/r and ATV/c) are that a clinical trial has shown RTV-boosting of ATV enhances ATV concentration, improving virologic activity as compared to ATV alone. Another advantage is the presence of fewer metabolic adverse events compared to older boosted-PI agents. The disadvantages however are the higher rate of adverse effect-associated drug discontinuation, main adverse effect is indirect hyperbilirubinemia that is not associated with hepatic transaminase elevation, and the requirement for gastric acid pH for dissolution, thus antacids, H2 antagonists, and PPIs may impair its absorption.  

Darunavir plus Cobicistat (DRV/c)  

Regimens consisting of DRV/c plus either TAF or TDF plus either FTC or 3TC is recommended for most patients with HIV with history of CAB-LA use as pre-exposure prophylaxis before genotypic test results are available. However, DRV/c plus TDF/FTC and DRV/c plus TAF/FTS are not recommended in patients with CrCl of <70 mL/min and <30 mL/min respectively.  

Darunavir plus Ritonavir (DRV/r)  

Regimens consisting of DRV/r plus TAF or TDF/FTC or 3TC are recommended as the initial ART in certain clinical conditions. The ARTEMIS study has shown that DRV/r, compared with Lopinavir plus Ritonavir (LPV/r) (both in combination with TDF/FTC), have a superior virologic response. However, they must be used in caution in patients with sulfonamide allergies. The advantages of DRV/r are the higher barrier to resistance, and the lower rate of treatment-emergent resistance.  

Fosamprenavir plus Ritonavir (FPV/r)  

FPV/r is recommended as an alternative PI-based regimen with once- or twice-daily dosing. Studies on FPV/r have shown similar CD4 and virologic benefits compared to ATV/r, both in combination with TDF/FTC.  

Indinavir plus Ritonavir (IDV/r)   

IDV/r is associated with high incidence of nephrolithiasis, hence, when taking IDV, high fluid intake is recommended.  

Lopinavir plus Ritonavir (LPV/r)  

LPV/r is the only available coformulated boosted PI with RTV. Compared with other PIs boosted with 100 mg/daily of RTV, LPR/r should be boosted 200 mg/daily of RTV. However, it is associated with higher rated of GI side effects and hyperlipidemia. Additionally, once-daily LPV/r should not be given to patients who have HIV mutations associated with PI resistance. Twice-daily dosing is preferred for pregnant women, especially during the third trimester, when LPV levels are expected to decline.  

Saquinavir plus Ritonavir (SQV/r)  

SQV/r has a high pill burden, requires twice-daily dosing and 200 milligrams of RTV. At the recommended dose, this regimen is associated with increases in both PR and QT prolongation, with the degree of QT prolongation greater than those seen in other boosted PI. Hence, electrocardiogram (ECG) is recommended prior to its initiation. This may be an acceptable regimen but should be used with caution against certain ART-naïve patients, but is contraindicated in patients with QT prolongation, complete AV block, refractory hypokalemia or hypomagnesemia).  

Tipranavir plus Ritonavir (TPV/r)  

TPV requires a higher dose of RTV for boosting compared to other PIs, and has higher adverse events rates compared to other RTV-boosted PIs.  

Unboosted PI-based Component  

Atazanavir (ATV)  

ATV is given once daily and has fewer effects on lipid profiles compared with other PIs. It may be an acceptable initial therapy when once-daily regimen is desired and when there is concern for hyperlipidemia. Studies have shown it to have similar virologic efficacy to ATV-based combination regimens with either EFV- or NVP-based regimens. RTV boosting is needed when given with TDF or EFV since the latter can lower ATV concentrations.  

Fosamprenavir (FPV)  

Indinavir (IDV)  

Nelfinavir (NFV)  

Ritonavir (RTV)

2-Drug ARV Regimens when ABC, TAF, and TDF Cannot be Used or Are Not Optimal  

These regimens are not recommended in patients with HBV coinfection, unless separate HBV therapy is administered, or with known pre-existing resistance to any of the ARVs in the combination.  

DTG/3TC  

DTG/3TC is the preferred regimen for most people with HIV when ABC, TAF, or TDF is not optimal. However, it is not recommended in patients with a viral load of >500,000 copies/mL, patients with HBV coinfection, or when ART is to be started before the availability of results of HIV genotypic resistance testing for reverse transcriptase.  

DRV/r Plus 3TC  

DRV/r plus 3TC may be an option for people with HIV who cannot take ABC, TAF, or TDF. The ANDES trial results showed that dual therapy with DRV/r plus 3TC was noninferior to triple therapy with DV/r plus TDF/3TC and showed similar virologic suppression rates in patients with viral loads of >100,000 copies/mL in both dual- and triple-therapy groups.  

DRV/r (Once Daily) Plus RAL (Twice Daily)  

DRV/r once-daily plus RAL twice-daily is an alternative regimen for patients who cannot take ABC, TAF, or TDF. It is recommended only for patients with baseline CD4 counts of >200 cells/mm³ and viral loads <100,000 copies/mL.  

CCR5 Antagonist-based Regimens  

CCR5 Antagonist (eg Maraviroc [MVC]) Plus 2 NRTIs (Zidovudine/Lamivudine)  

MVC is recommended only as an acceptable regimen for ART-naïve patients due to its limited experience with regimens other than ZDV/3TC, its cost as it requires tropism assay prior to use, and requirement for twice-daily dosing.  

Fusion Inhibitor-based Regimen

Enfuvirtide (T20)  

T20 is an HIV-1 fusion inhibitor that is a treatment option for inclusion in a regimen when drug resistance to a previously given ART regimen is confirmed.  

ART Optimization  

ART optimization is a treatment strategy wherein the patient is switched from an effective ARV regimen to an alternative ARV regimen due to adverse effects, drug-drug or drug-food interactions, pill burden, pregnancy, cost, or the wish to simplify a regimen. The goal is to maintain viral suppression without compromising future treatment options.  

The following are reasons to consider regimen optimization in the setting of viral suppression:

• Simplification of regimen by reducing pill burden and/or dosing frequency
• Enhancement of tolerability and/or reduction of short- and long-term toxicity
• Prevention or mitigation of drug-drug interactions
• Elimination of fluid or food requirements
• Switching to a long-acting injectable regimen for pill fatigue relief or reduction of potential stigma associated with daily oral medication intake
• Coverage for HBV coinfection
• For optimal use of ART during pregnancy or when pregnancy is desired
• Cost reduction

The patient’s treatment history including virologic responses, previous ART-associated toxicities and intolerances, and cumulative resistance test results should all be considered before selecting a new ARV regimen. It must be noted that proviral DNA genotyping may be performed for individuals with multiple virologic failures, unavailability of resistance history or low-level viremia at the time of the switch. Additionally, potential drug-drug interactions with ARV regimens and concomitant medications should be considered in selecting a new regimen. ART optimization for patients with existing NRTI resistance should include 2 NRTIs, TAF or TDF, plus FTC or 3TC in the regimen together with a fully active, high resistance barrier agent such as DTG, boosted DRV, or BIC. Also, administration of CAB-LA and RPV every 1 or 2 months is an optimization option for patients engaged with their health care, virologically suppressed on oral therapy for 3-6 months, and agree to make frequent follow-ups needed to receive injectable agents. In patients with HIV-HBV coinfection, ARV agents active against HBV should be continued during the switch or initiation of specific anti-HBV agents should be done. Referral to an HIV specialist is also recommended when planning ART optimization for patients with history of resistance to ≥1 drug classes. Monitoring of tolerability, viral suppression, adherence, and safety is recommended during the first 3 months after the regimen switch.

Within-Class Switches in 3-Drug Regimens  

Such strategy is prompted by adverse events or availability of ARVs in the same class which offer a better safety profile, decreased dosing frequency, high resistance barrier, lower pill burden, or not requiring PK enhancement. This includes switches from TDF or ABC to TAF, from RAL to DTG, from DTG, EVG/c or RAL to BIC, and from EFV to RPV or DOR.  

Between-Class Switches in 3-Drug Regimens  

Examples of between-class switches in 3-Drug Regimens include switching from a boosted PI to an INSTI, from a boosted PI to RPV or DOR, and from an NNRTI to an INSTI.  

2-Drug Regimen Switches  

2-drug regimen switches should be considered for individuals with viral suppression if there is no historical resistance without HBV coinfection. This includes DTG plus RPV and DTG plus 3TC or FTC. Boosted PI plus 3TC is recommended only in the absence of alternative treatment options and may be an option for patients with resistance and or intolerance to 3TC or FTC, ABC, and TAF or TDF. The long-acting ART including Ibalizumab (IBA), an anti-CD4 monoclonal antibody given intravenously (IV) every 2 weeks in combination with optimized background therapy in heavily treatment-experienced patients, and long-acting injectable CAB in combination with RPV have been approved for use. These regimens have improved the quality of life in patients suffering from pill fatigue and have the advantage of reducing the frequency of dosing. They are recommended for patients with consistent engagement in their health care. CAB-LA plus RPV is recommended as replacement of an existing oral therapy in patients with sustained, 3-6 months, virologic suppression (viral load of <50 copies/mL) on a stable ARV regimen, without history of treatment failure and without known or suspected resistance to either CAB or RPV. It is administered IM once a month or every 2 months. It is recommended that viral load be monitored 4-8 weeks after a switch to CAB-LA plus RPV and drug resistance testing be done when viremia develops.  

Optimization Strategies for Patients with Viral Suppression and History of Limited Drug Resistance  

Such strategies include within class switching from DTG to BIC and switching to BIV-based therapy.  

Optimization Strategies for Patients with Viral Suppression and History of Complex Underlying Drug Resistance  
 
It is important that the patient’s ARV history and cumulative drug resistance profile should be considered and referral to an HIV specialist is recommended. It must be noted that switching to EVG/c/TAF/FTC plus DRV has been shown to be a potential optimization strategy for patients on complicated salvage regimens.  

Optimization Strategies for Patients with Viral Suppression and History of Limited Drug Resistance  

Options for patients with viral suppression and history of limited drug resistance include within class switching from DTG to BIC and switching to BIC-based regimens.  

Optimization Strategies for Patients with Viral Suppression and History of Complex Underlying Drug Resistance  

The patient’s ARV history and cumulative drug resistance profile should be considered and referral to an HIV specialist is recommended. Switching to EVG/c/TAF/FTC plus DRV has been shown to be a potential optimization strategy for patients on complicated salvage regimens.

Management of Patients with Treatment Failure  

Referral to an expert is recommended in all patients who experience treatment failure.  

General Approach to Patients with Virologic Failure  

In patients who experience virologic failure, evaluation should include assessment of adherence, drug-drug or food interactions, drug tolerability, 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. Possible clinical scenarios involved in treatment failure should be identified (eg patient adherence, timing of drug resistance test, presence of a highly drug-resistant HIV). The 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. It is recommended that the ART regimen be changed as soon as virologic failure is confirmed. However, it must be noted that there is no consensus for the optimal time to change therapy. Patients who failed second-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. 

In establishing a new ART regimen, the patient’s treatment history, including the results of both past and current resistance tests, are reviewed. At least 2, preferably 3, fully active agents with high barrier to resistance are identified to be combined 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. The new regimen may include an INSTI, preferably the second generation DTG plus a PK-enhanced PI, preferably DRV, without NRTIs if both are fully active. Three 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. 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), and drugs with novel mechanism of action which the patient has not previously received should be included. 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. The ARV drugs such as NRTIs, PIs, and second-generation INSTI with partial activity may be retained as part of the salvage regimen. ARV agents where resistance 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 in changing regimens in patients with HIV-HBV coinfection. But, in patients with a high chance of clinical progression and with limited drug options, adding a single drug regimen may reduce the risk of immediate clinical progression.  

Interrupting or discontinuing the treatment is not recommended since this may lead to a rapid decline in the CD4 count and a rise in HIV RNA and may increase the risk of 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 of <100 cells/mm³, adding a single ART agent may reduce risk of immediate clinical progression. Such a strategy may produce transient increases in CD4 cell counts and/or decrease HIV RNA levels 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 is performed if inadequate virologic response is detected.  

Management of Patients with Low-Level Viremia

It must be noted that patients usually do not need to change ARV regimens and must continue their current regimen with reinforcement of treatment adherence. Monitoring of viral load is recommended every 3 months to evaluate the need for ARV change.  

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

Patients with persistent viral loads range of 200-1,000 copies/mL are considered to have virologic failure. In such cases, drug resistance testing is recommended especially if the viral load is >500 copies/mL. Proviral DNA genotypic testing may be done if the genotypic resistance testing is not possible because of low viral load levels. The management is also the same for patients with viral load of >1,000 copies/mL.  

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

In these cases, there has been noted suboptimal adherence. Comprehensive evaluation must be performed to determine the level of adherence, identify underlying causes of incomplete adherence, and to simplify regimen (eg simplify dose frequency, reduce pill count, simplify food requirement). Access to ART and patient’s tolerance to the current regimen must be evaluated and intolerance must be addressed by treating symptoms. The 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 also be reviewed. Continuation of the current regimen is recommended if the regimen is well tolerated, without significant drug-drug or drug-food interactions, and with focus on improving patient adherence. Changing the regimen is recommended 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 the viral load is recommended every 4-8 weeks after treatment modification of reinforcement of treatment adherence. Lastly, genotypic resistance testing is recommended if the viral load remains >200 copies/mL.  

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

It is recommended to modify the regimen if new or previously detected resistance mutations will compromise the regimen. It is best done before worsening of viremia or before reduction of CD4 counts.  

Management of Virologic Failure on the First ART 

NNRTI plus 2 NRTI Regimen Failure  

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

Boosted PI plus 2 NRTIs Regimen Failure  

Switching to an INSTI-based regimen (eg DTG, BIC) plus 2 NRTIs, with ≥1 being 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 plus 2 partially active NRTIs (TAF or TDF plus 3TC or FTC) may be an option if fully active NRTI cannot be assured. Continuing the 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 being fully active is an option. Different fully active boosted PI plus 2 partially active NRTIs (TAF or TDF plus 3TC or FTC) is an option if the full activity of ≥1 NRTI cannot be assured.

INSTI plus 2 NRTIs Regimen Failure  

In INSTI plus 2 NRTIs regimen failure, the treatment strategies will depend on drug resistance test results and the potential potency of the new regimen. Modified regimens for patients with virologic failure without INSTI resistance include a boosted PI plus 2 NNRTIs with ≥1 being fully active, or DTG or BIC plus 2 NRTIs with ≥1 being fully active, or a boosted PI plus DTG. Modified regimens for patients with virologic failure with RAL and/or EVG resistance but with DTG susceptibility include a boosted PI plus 2 NRTIs with ≥1 being fully active, or DTG (twice daily) plus 2 NRTIs with ≥1 being fully active, or DTG (twice daily) plus a boosted PI.  

INSTI plus NNRTI Regimen Failure  

In INSTI plus NNRTI regimen failure, the treatment strategies will depend on the previous treatment history, results of drug resistance test, and the potential potency of the next regimen.  

Management of Second-Line Failure and Beyond

Drug Resistance with Fully Active ART Options  

In the case of drug resistance with fully active ART options in a possible second-line failure, the treatment options will depend on the previous treatment history, drug resistance test results, and tropism testing if a CCR5 antagonist will be used. A boosted PI plus 2 NRTIS with ≥1 being fully active is a treatment option for patients with fully active boosted PI but without a second generation INSTI in their regimen. DTG or BIC plus 2 NRTIs with ≥1 being fully active can be considered an option for patients with a fully active second generation INSTI with an unboosted PI as regimen. A boosted PI plus INSTI, or a boosted PI plus 2 NRTIs with ≥1 being fully active, or DTG or BIC plus 2 NRTIs with ≥1 being fully active are treatment options for patients with a regimen of fully active PI and INSTI.  

Multidrug Resistance without Fully Active ART Options  

The goal in patients with multidrug resistance is to achieve maximal virologic suppression. However, if this is not possible, ART should be geared towards preserving immunological function, preventing clinical progression, and minimizing further resistance development which can compromise future regimens. The new regimen must consist of at least 2, and preferably 3, fully active drugs including those with novel mechanisms of action, if a fully boosted PI or a second generation INSTI is not available. Enrollment in clinical trials may also be considered. IBA, a CD4 post-attachment inhibitor, and Fostemavir (FTR), a gp120-directed inhibitor, are alternatives for patients with detectable viremia without other treatment options. Finally, discontinuation of all ARV agents is not recommended.  

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

The treatment options for ART-experienced patients who present with an incomplete or without any 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 and starting 2-3 agents that are predicted to be fully active based on patient’s treatment history. If there is no 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. Lastly, virologic response monitoring through viral load must be performed within 4-8 weeks after reinitiation of the ART and immediate drug resistance testing be performed if there is inadequate virologic response.  

Management of Immunologic Failure  

Immunologic failure focuses on patients with CD4 counts of <200 cells/mm³. In such cases, ART intensification wherein 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 also not recommended because it does not consistently reduce all relevant markers of immune activation and improve CD4 cell recovery. The use of interleukin-2 is not recommended as well because clinical trials have shown no benefit with its use. It must be remembered that immune-based therapies should not be used except for clinical trials.  

Management of Acute HIV Infection in People Taking Pre-exposure Prophylaxis  

People who acquire HIV while taking pre-exposure prophylaxis such as oral FTC plus either TAF or TDF, and CAB-LA may have ambiguous test results. Immediate confirmation of HIV diagnosis is recommended for individuals with positive HIV Ag/Ab test results or positive HIV RNA test results and a negative HIV antibody test result. People with viral load of ≥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. The pre-exposure prophylaxis will be changed to a triple-drug ART regimen which includes a high resistance barrier agent usually DTG, BIC, or DRV/c plus 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 a negative HIV antibody test result and very low positive quantitative HIV RNA test result (<200 copies/mL). 

Prevention

Prevention of HIV Transmission  

The 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 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 first 6 months of treatment 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 who are on ART but are 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.