Virologic failure: When to modify therapy

Christopher J. Hoffmann, M.D., M.P.H., Richard D. Moore, M.D., M.H.S.

DEFINITION

Incomplete VL suppression or virologic rebound after complete suppression (a commonly accepted definition is an HIV RNA >200 c/mL) caused by failure of current ART regimen to maintain suppression.
Not all elevated VL is from virologic failure (e.g., clonal expansion may lead to an elevated VL without therapeutic failure or an indication to change regimens).

INDICATIONS

Indications

Virologic failure is defined as the inability to achieve or maintain VL < 200 (confirmed), which eliminates most cases of apparent viremia caused by blips or assay variability. For adherent pts who do not have resistance to prescribed drugs, VL suppression is generally achieved in 12-24 after ART initiation. Note that U=U undetectable is based on a VL< 200. In addition, the risk of developing HIV drug resistance with a VL < 200 is believed to be very low to neglible.
No consensus on optimal time to change therapy. By current guidelines, aggressive would be for 2 consecutive VL >200 after 24 wks on ARV regimen.
For extensively treated pts without suppressive options: Partial suppression (e.g. decline in VL of >0.5 log). Goal: to preserve immunologic function as long as possible. Current guidelines (DHHS, IAS-USA) state that goal of therapy for all pts is below detection of the test platform (typically < 20 or < 40).

CLINICAL RECOMMENDATION

Clinical Recommendation

Assess reason for failure:
- Adherence, tolerability (e.g. side effects)
- Absorption issues (food or fasting requirements, minerals such as calcium, magnesium, and iron reducing INSTI absorption)
- Pharmacokinetic issues (drug-drug interactions affecting pharmacokinetics or )
- HIV drug resistance
- Clonal expansion of a CD4 clone with integrated HIV
Persistent plasma HIV RNA levels ≥200 copies/mL should be considered a potential virologic failure.
Get genotype for HIV drug resistance if VL high enough (VL >500-1000). If VL < 500, consider proviral DNA genotyping (Genosure Archive). Locate all prior genotypes as well as prior resistance mutations are archived and are expected to contribute to future virologic failure.
Limited prior exposure with no resistance: Consider adherence, pharmacokinetic issues.
TDM (therapeutic drug monitoring). No clear guidelines, but consider if suspected absorption issues (e.g., GI disease, pregnancy) or unpredictable drug-drug interactions.
If VL > 1000 and no drug resistance found, almost always non-adherence. Resume regimen (if patient off > 4 wks and/or nonadherent) or start new regimen based on treatment history and repeat genotype in 2-4 wks.
Consider regimen change with repeated VL 200-1000 to minimize development of resistance, especially if on ART with low genetic barrier (e.g. NNRTI with switch to regimen with higher barrier to resistance such as a regimen containing DTG or BIC; also may consider a regimen of daily dosing rather than bid). If continuing same regimen, follow VL closely; ongoing viremia leads to accumulation of mutations.
If VL < 200, treatment change is usually not needed . If transient elevation in VL, a blip may be responsible. If persistent, consider clonal expansion. Neither cause necessitates regimen change.
New regimen should contain at least 2, and preferably 3 fully active drugs based on treatment history, resistance testing, or new class. Change ART guided by current and previous therapy and resistance testing. Consider class change (e.g. PI to NNRTI, NNRTI to PI, PI or NNRTI to CCR5, INSTI, second-generation NNRTI or PI - if not resistant), NRTI with different resistance pattern. Goal is VL suppression to < 50.
Guiding principles
- Address any identified barriers to adherence that may have contributed to failure
- Account for all HIV drug resistance mutations
- Strive to construct the most tolerable and acceptable treatment regimen to suppress reexisting drug-resistance effective
- Strive to include at least 2 active agents (e.g., INSTI plus another agent)
- Account for comorbities (CKD or chronic hepatitis B)
Extensive treatment experience: If no suppressive options (very uncommon scenario now), continuing therapy reduces risk of progression. Continuing therapy NRTI provides better control than continuing PI, though new mutations develop with both classes over time.
Treatment interruption is never indicated.

Selected Drug Comments

Selecting new regimen. Select multiple agents to minimize resistance. Select based on known resistance mutations, agents used during treatment failure, and comorbidities
Consider use of an online tool (e.g., HIV Assist: HIVASSIST hivassist.com) to help guide selection or Stanford HIV Drug Resistance Database (https://hivdb.stanford.edu/)
Substantial clinical experience with DTG + DRV + r (or DRV/c)
Potent agents with higher barrier to resistance
- ETR active against most NNRTI-resistant virus, but cross-resistance can occur. Review drug-drug interactions
- DTG, BIC active in INSTI naive and have higher barriers to resistance (oral daily)
- DRV + r or DRV/c: high barrier to resistance (oral daily)
- MVC, CCR5 antagonist, inhibits entry. Need to have CCR5 only virus (Tropism testing) (oral bid)
- FTR, attachment inhibitor (oral bid)
- IBA (ibalizumab-uiyk), post-attachment inhibitor monoclonal antibody, binds CD4 receptor (IV q2wks)
- LEN, capsid inhibitor. (SQ q6m)
ART options to support adherence
- CAB IM + RPV IM (IM q2m), can overcome adherence challenges, needs to have no CAB or RPV resistance
- LEN (potentially when paired with another long-acting agent such as CAB)

References

White JA, Wu F, Yasin S, et al. Clonally expanded HIV-1 proviruses with 5'-leader defects can give rise to nonsuppressible residual viremia. J Clin Invest. 2023;133(6). [PMID:36602866]
Comment: Primary study of clonal expansion.
Rating: Important
Jacobs JL, Halvas EK, Tosiano MA, et al. Persistent HIV-1 Viremia on Antiretroviral Therapy: Measurement and Mechanisms. Front Microbiol. 2019;10:2383. [PMID:31681237]
Comment: Review of underlying causes of persistent viremia, including clonal expansion.
Rating: Important
Nettles RE, Kieffer TL, Simmons RP, et al. Genotypic resistance in HIV-1-infected patients with persistently detectable low-level viremia while receiving highly active antiretroviral therapy. Clin Infect Dis. 2004;39(7):1030-7. [PMID:15472857]
Comment: Demonstrates potential for evolution of resistance in pts on non-suppressive HAART regimens with persistent low-level viremia.
Kantor R, Shafer RW, Follansbee S, et al. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS. 2004;18(11):1503-11. [PMID:15238768]
Comment: Retrospective study finding that after median 14 mos of continued ART with VL > 400, 75% developed new drug-resistance mutation and significantly lower genotypic susceptibility score.
Rating: Important
JJ Eron et al. Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study. J Infect Dis 2013; 207:740.
Comment: Comments: DTG effectiveness after raltegravir.
Rating: Important
DHHS Clinical Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/virologic-failure... Accessed 1/5/2025.
Comment: Has definitions for treatment failure and evaluation approaches.
Rating: Important
New York State AIDS Institute Clinical Guidelines Program: Second-Line ART after treatment failure or for regimen simplification. https://www.hivguidelines.org/guideline/hiv-2nd-line-art/?mycollection=hiv-treatment Accessed 1/5/2025.
Comment: Clear approach to managing virologic failure.

Rating: Important

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