Part III: Heavily TreatmentExperienced PWH

How does the presence of drug-resistant mutations affect the management of HTE individuals?

As mentioned briefly with regard to LAI LEN, HTE patients with HIV are typically defined as those having ≤2 ARV classes available for use, with limited fully-active agents within each class.55 Along the same lines, MDR HIV refers to strains with reduced susceptibility to multiple ARV classes.17 Fortunately, the prevalence of HTE patients with HIV has declined dramatically, from 7.5% in 2006 to <1% in 2017, related to the introduction of high barrier to resistance drugs, including boosted PIs and second-generation INSTIs such as DTG and BIC.55 Despite their low prevalence, HTE patients are complex to manage even for the most experienced providers. The ultimate goal of ART is to create a regimen that will suppress viral replication to below the limit of detection.55 Effective HIV management maximally suppresses plasma HIV RNA, preventing disease progression and the emergence of drug-resistant virus. Maintaining an undetectable VL improves patient outcomes (eg, morbidity and mortality) and reduces the risk of HIV transmission,55 therefore benefitting both the patient and the community. In order to design an active ART regimen, providers must have a detailed understanding of the underlying processes that caused previous treatment failures, diagnostics to define the amount and mechanisms of resistance present, and available ARVs to achieve viral suppression in the face of multiple resistance mutations. The complexity involved in understanding previous and current individual drug-resistance mutations cannot be overstated, and designing an active ART regimen can be time consuming and challenging, especially in patients with numerous comorbidities and medications that may increase the risk of DDIs. Additionally, the dosage of certain ARVs may be different for these patients.

Drug-resistant mutations can predate the initiation of a specific ART regimen or can develop when viral replication continues in the face of ongoing drug pressure.17 The cause of MDR HIV is multifactorial and can vary greatly between patients. Many factors can contribute to an MDR virus, including the intrinsic biology of HIV, genetic barriers to resistance, ART regimen potency, pharmacokinetics of ARVs, and drug-taking behavior.17 HIV inherently has high rates of replication and an error-prone reverse transcriptase. This combination leads to the spontaneous occurrence of mutations, most of which decrease the fitness of the virus. Suboptimal drug levels that are unable to suppress viral replication allow the virus to continue to replicate and accumulate mutations. There are many potential causes of low serum trough concentrations. Specific pharmacokinetics of older ARVs, such as the unboosted PIs (eg, saquinavir) that had low bioavailability and very rapid clearance resulted in rapid mutation accumulation and treatment failure. But low serum drug concentration can also can occur due to DDIs (eg, poor absorption, competing CYP or transporter metabolism), varying half-lives between agents in combination ART, and poor drug-taking behavior (such as missed doses) that allows viral replication in the face of suboptimal drug exposure.66 Mutations can persist in proviral HIV DNA in resting CD4+ memory T cells even if HIV RNA suppression is achieved with a subsequent, more-potent regimen. If in the future drugs to which viable proviral mutations exist are used, mutants can reemerge in the plasma viral RNA and either cause overt virologic failure or become more drug resistant through the gradual accumulation of additional resistance mutations.

The genetic barrier to resistance is a complex concept, and finding an exact definition can be elusive. In general, it describes how hard it is for the virus to become resistant to a specific drug. HIV can more easily (and quickly) become resistant to a drug with a lower barrier to resistance than to one with a higher barrier. Resistance should be seen as a continuum, not an absolute high or low barrier.67 Additionally, drug exposure is a key component of the barrier to resistance; therefore, the same drug given at a higher dosage will result in a higher barrier to resistance (eg, DRV/r dosed once or twice a day). Individual ARVs have higher or lower genetic barriers to resistance. In general, when ARVs have a higher barrier to resistance, they lose clinical utility only after the accumulation of multiple mutations. On the contrary, when an agent has a low barrier to resistance, one mutation is usually enough to cause virologic failure. High barrier to resistance drugs require longer periods of viral replication to become resistant and fail than low barrier drugs; therefore, they are more tolerant and forgiving of poor drug-taking behavior. They also require fewer additional active agents than low-barrier drugs.67

How do I approach decision-making when a patient with HIV presents with virologic failure?

There are many potential causes of virological failure, and HCPs must make every effort to determine which of these are contributing to the loss of viral suppression. The first step is to examine drug-taking behavior, such as missed doses. Once proper adherence has been established or associated barriers to adherence (eg, intolerance to side effects or pill burden, issues with medication procurement, difficulty swallowing pills) are resolved, treatment issues related to pharmacokinetics (eg, DDIs leading to poor absorption or rapid clearance) should be explored and ruled out.55 It is important to investigate the use of OTC medications and food supplements with patients taking ARVs, as well as reconciling their known prescription medications. Examples of common DDIs include acid-suppressant OTC medications that can prevent the absorption of oral acid-dependent absorption ARVs (eg, RPV, atazanavir) and medications with polyvalent cations

Where to Check for ARV Drug-Drug Interactions

Liverpool HIV Drug Interactions: https://www.hiv-druginteractions.org/checker

New York State Department of Health AIDS Institute: https://www.hivguidelines.org/antiretroviral-therapy/ddis/ Department of Health and Human Services: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelinesadult-and-adolescent-arv/drug-interactions-overview

(such as magnesium, calcium, iron, or aluminum), including multivitamins, that may cause chelation of INSTIs and reduced absorption when coadministered.55 Moreover, medications that significantly induce the CYP3A4 pathway (eg, carbamazepine, rifamycin) can drastically reduce levels of many ARVs and are often contraindicated.55 For more specific information about individual drug interactions with ARVs, the University of Liverpool has an online database of HIV drug interactions that is useful to check (either on their website or smartphone app) before new medications are added to a PWH’s regimen, or to confirm that there are no current DDIs that may be contributing to virologic failure.50

What resistance testing should be performed?

For all patients whose ART regimen is not successful, genotypic resistance testing should be performed while the patient is still on the regimen or immediately after stopping. It is also very helpful to have complete historical genotype results, if possible, because results often change when new drugs are used. Circulating genotypes generally require an HIV VL of >200 c/mL (frequently even >500 c/mL is necessary) to be completed but this is lab dependent.55 Proviral DNA testing is a potential option, although currently not validated as a useful clinical tool, when the VL is between 200 and 500 c/mL. Genotype testing typically screens for mutations on the 3 major HIV enzymes: reverse transcriptase, protease, and integrase (which in some labs needs to be ordered separately). Because combinations of mutations can be synergistic or mitigating, interpreting test results and applying them to develop a new active ART regimen can be extremely challenging. There are a number of interpretation systems available to assist. Examples include the Stanford HIV Drug Resistance Database (online and free) and assistance from the “HIV warmline,” a national clinical consultation center operated by the University of California, San Francisco, that can be utilized for assistance.68,69 Using the Stanford database, an individual’s resistance can be assessed by entering known resistance mutations, which generates the level of resistance to each drug and ARV class. This information can then be used to develop an active ART regimen.

Rarely, phenotypic and tropism testing may be considered. Phenotypic resistance testing reports the concentration of drug needed to inhibit 50% of viral growth. This may be useful when many RAMs are present, but it is more expensive and takes longer to receive results compared with genotype testing.55 Phenotypic tests have also not been clinically validated for many of the currently used drugs and, in general, should be ordered only in consultation with experts. Tropism screening is used to determine which coreceptor an individual’s specific HIV variant uses during the viral entry process. This is required when evaluating whether or not to include maraviroc (MVC) in an ART regimen because MVC requires C-C chemokine receptor type 5 (CCR5) as the only coreceptor in order to be effective.55 Although not commonly used in treatmentnaive patients, MVC may be useful in HTE individuals if tropism testing confirms activity.

How do I select an active ART regimen for an HTE individual with HIV?

When choosing a new ART regimen for an HTE individual, both resistance results and ARV history should be considered.55 Regimens for HTE individuals are often complex and may require twice-daily dosing and multiple pills. Therefore, counseling the patient and motivating them are the keys to success. If possible, it is also beneficial to simplify the regimen to promote adherence, but only if antiviral potency is not sacrificed. Ideally, resistance testing should be performed when a patient is either on the failing regimen or within 3 to 4 weeks of regimen discontinuation, to maximize the detection of all resistance mutations present. Because previous resistance mutations may not result from current circulating HIV, archived resistance testing may be useful, but caution is necessary because false-positives or -negatives are possible.17 Proviral DNA testing for archived resistance and its interpretation should only be done with expert advice. Other important considerations when selecting an ART regimen include the presence or likelihood of DDIs, either between ARVs or between medications for comorbid conditions, and the presence of coinfection with HBV, that will require treatment with tenofovir, FTC, and/or 3TC.55 Discontinuing agents aimed at HBV treatment can result in an acute hepatitis flare even if these ARVs are not currently active against the individual’s HIV. Also, use of 3TC or FTC as the sole HBV drug is contraindicated. If HBV infection has not been ruled out, regimens containing TDF/TAF with 3TC/ FTC cannot be discontinued.70 Medication history may also help guide treatment decisions, as patterns of ARV use may suggest common resistance to those agents. This is especially important in the absence of previous resistance testing as a guide.

In extremely HTE individuals or some resourcelimited settings, a fully-suppressive ART regimen may not be possible. It is important to note that it is not recommended to add one fully-active ARV agent to the failing regimen nor to place the patient on treatment interruption. An active ART regimen should be created with a combination of ARVs with ≥2 known fully-active agents (overall activity score of 2, with each agent getting a score between 0 and 1, with 0 being no activity, 0.5 being partial activity, and 1 being full activity). Drugs with a high barrier to resistance should be preferred, if at all possible, and should be used at the highest dose approved (eg, DTG 50 mg × 2). If only one of these classes is fully active, other partially-active agents may be used to complete the regimen.17 Selecting a salvage regimen is individualized to the patient, based on their unique pattern of resistance; however, there are certain ARVs that are more likely to remain active in this population (Table 10A-D).55 Drugs utilizing new mechanisms of action such as fostemsavir (FTR) and LEN remain fully active in these patients and should be included in the regimen if there is doubt about there being sufficient activity.

Based on our knowledge of resistance mechanisms in HIV, certain clinical considerations are particularly important: FTC and 3TC are both commonly used in HIV regimens, and the most prevalent NRTI-associated mutation, M184V, results in high-level resistance to these drugs. But the presence of M184V reduces viral fitness and actually increases sensitivity to some NRTIs (eg, tenofovir).71,72 Furthermore, concurrent K65R and M184V mutations may return partial activity to tenofovir. Studies

A: Major NRTI Resistance Mutations

have shown 3TC continues to have a suppressive impact on HIV RNA levels (about 0.5 log), even when M184V is present. Thus, continuing 3TC or FTC may have clinical value even when M184V is detected. Furthermore, a K65R + M184V mutational profile does not negate a contribution to viral suppression if tenofovir with either 3TC or FTC is prescribed in combination with a boosted PI or DTG.73,74 Some of the pivotal clinical trials evaluating ARVs in HTE patients can help guide the individualized selection of an active ART regimen (Table 11); however, given the breadth and intricacy involved in interpreting results of resistance testing and then designing an active ART regimen in HTE patients, it is imperative that only experienced HIV providers undertake this task in clinical practice. Input from a pharmacist with expertise in HIV drugs can be extremely helpful.

Overall, some of the basic principles in the management of HTE PWH include using DTG and/or a boosted PI (preferably boosted DRV) as the new regimen if sufficiently active and especially if resistance to multiple agents is present. Both boosted DRV and DTG have a higher barrier to resistance when dosed twice daily and are needed for many advanced HTE PWH. In general, the new regimen is designed by combining drugs with remaining activity to build a regimen with a sufficiently high barrier to resistance to avoid future failure while minimizing DDIs, toxicity, and complex dosing schedules. Although this process must be individualized, there are some basic principles that can be considered55:

3TC, lamivudine; ABC, abacavir; AZT, zidovudine; d4T, stavudine; DRM, drug-resistance mutation; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; Ins, insertion; INSTI, integrase strand transfer inhibitor; MDR, multidrug resistance; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; r, ritonavir; TAM, thymidine analog mutation; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; VF, virologic failure.

Bold underline: High-level reduced susceptibility or virologic response. Bold: Reduced susceptibility or virologic response. Plain text: Reduced susceptibility in combination with other NRTI-resistance mutations. Asterisk: Increased susceptibility.

M184VI: Although they cause high-level in vitro resistance to 3FTC, they are not contraindications to 3FTC because they increase TFV and AZT susceptibility and decrease viral replication fitness. K65R: The most common DRM in patients with VF on a TFV-regimen. It causes a clinically relevant 2-fold reduction in TFV susceptibility. However, K65R + M184VI reduces TFV susceptibility <1.5-fold. INSTI-/PI-naive patients with K65R + M184VI who receive TFV/3FTC and a highly potent third drug (eg, DTG or DRV/r) respond as well or better than those receiving AZT/3TC, even though K65R increases AZT susceptibility. TFV, TDF, and TAF: TDF and TAF are TFV triphosphate prodrugs. Although TDF and TAF have similar resistance profiles, TAF attains higher intracellular levels.

Additional TFV-selected mutations of uncertain phenotypic and clinical significance include A62V, K65N, K70GQNTdel, and L74I. TAMs: Selected by AZT and d4T; facilitate primer unblocking. Non-TAMs prevent NRTI incorporation. T215SCDEIVALN (T215 revertants) emerge from T215YF in the absence of NRTIs. MDR: T69 insertions occur with TAMs. Q151M occurs with non-TAMs and the accessory mutations A62V, V75I, F77L, and F116Y.

TABLE 10 A-D. Major HIV-1 Drug Resistance Mutations68

B: Major NNRTI Resistance Mutations

DOR, doravirine; EFV, efavirenz; ETR, etravirine; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; RPV, rilpivirine.

Bold underline: High-level reduced susceptibility or virologic response. Bold: Reduced susceptibility or virologic response. Plain text: Reduced susceptibility in combination with other NNRTI-resistance mutations.

Additional Mutations: A98G (DOR, EFV, ETR, NVP, RPV); E138GQKR are nonpolymorphic mutations associated with intermediate/high-level RPV resistance. E138A is a polymorphic mutation associated with low-level RPV resistance. Y188CH are associated with intermediate/high-level resistance to EFV; G190Q is a rare mutation that may have an effect similar to G190E; P225H (DOR, EFV); L234I (DOR); Y318F (DOR, NVP).

Synergistic combinations: V179D + K103R reduce NVP and EFV susceptibility >10-fold. Y181C + V179F cause high-level ETR and RPV resistance.

DOR and ETR often require multiple mutations: DOR—high level with Y188L, V106A, F227L/C, M230L, or any combination of V106 and F227 mutations.

ETR: L100I, K101P, Y181C/I/V, M230L. But multiple non-DOR mutations at common positions such as Y181 and G190 can produce intermediate levels of reduced DOR susceptibility.

C: Major INSTI Resistance Mutations

BIC, bictegravir; CAB, cabotegravir; DRM, drug-resistance mutation; DTG, dolutegravir; EVG, elvitegravir; INSTI, integrase strand transfer inhibitor; RAL, raltegravir.

Bold underline: High-level reduced susceptibility or virologic response. Bold: Low-level reduced susceptibility or virologic response.

Plain text: Reduced susceptibility in combination with other INSTI-resistance mutations.

Additional mutations: T97A is a polymorphic mutation (1%-4%) in INSTI-naive patients. In combination with Q148 + G140/E138 DRMs, it causes high-level BIC/DTG resistance. H51Y, F121Y, S147G, S153YF, and S230R are additional nonpolymorphic INSTI DRMs. E92GV, Y143HKSGA, P145S, Q146LP, Q148N, G149A, V151AL, and N155ST are rare nonpolymorphic mutations that reduce RAL and/or EVG susceptibility. L74M, V151I, E157Q, G163KR, and D232N are common polymorphic accessory DRMs. Mutations outside of IN in the polypurine tract have also rarely been reported to reduce INSTI susceptibility.

D: Major PI Resistance Mutations

ATV, atazanavir; DRV, darunavir; LPV, lopinavir; NFV, nelfinavir; PI, protease inhibitor; r, ritonavir.

Bold underline: High-level reduced susceptibility or virological response. Bold: Reduced susceptibility or virological response. Plain text: Reduced susceptibility in combination with other PI-resistance mutations.

Additional mutations: L10F, V11I, K20TV, L23I, L33F, K43T, F53L, Q58E, A71IL, G73STCA, T74P, N83D, and L89V/T are common nonpolymorphic accessory resistance mutations. L10F, V11IL, L33F, T74P, and L89V are accessory resistance mutations associated with reduced DRV/r susceptibility. D30N and N88D are nonpolymorphic resistance mutations selected by NFV. L10RY, V11L, L24F, M46V, G48ASTLQ, F53Y, I54S, V82CM, I84AC, N88TG are rare nonpolymorphic variants.