Virological failure

The goal of ART is to suppress HIV replication to a level below which drug-resistance mutations do not emerge within the HIV genome. Although not conclusive, most evidence suggests that selection of drug-resistance mutations does not occur in patients with plasma HIV RNA levels persistently suppressed to below 200 copies/mL, although virological suppression to below the lower limit of detection (LLOD),  (<20-50 copies/ml with currently available assays) is preferable[5].

Assessing and managing PWH who are experiencing failure of ART is complex and expert advice is recommended, especially in PWH in whom in there is a history of multiple previous ART exposures. The following definitions are used to describe the different levels of virological response to ART. 

Virological Response Definitions 

(Adopted from Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. US Department of Health and Human Services6)

Virological suppression

A confirmed HIV RNA level below the LLOD of available assays.

Virological failure

The inability to achieve or maintain suppression of viral replication to an HIV RNA level <200 copies/mL

Incomplete virological response

Two consecutive plasma HIV RNA levels ≥200 copies/mL after 24 weeks on an ART regimen in a patient who has not yet had documented virological suppression on this regimen.

Virological rebound

Confirmed HIV RNA level ≥200 copies/mL after virological suppression

Virological blip

After virological suppression, an isolated detectable HIV RNA level that is followed by a return to virological suppression

Low-level viremia

Confirmed detectable HIV RNA level <200 copies/mL

Persistent HIV RNA levels ≥200 copies/mL are often associated with evidence of accumulation of antiretroviral drug-resistance mutations with the viral genome. This association is particularly common when HIV RNA levels are >500 copies/mL3. Therefore, patients who have persistent plasma HIV RNA levels ≥200 copies/mL are considered to be experiencing virological failure.

Causes of virological failure

(Adopted from Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. US Department of Health and Human Services6)

Patient/ adherence related factors 

Mental health related comorbidities (e.g. drug addiction, psychotic illness, learning disability, cognitive impairment)

Homelessness and unstable housing

Difficulty in ART access and affordability (e.g., cost, limited access to relevant health services)

ART adverse effects (e.g. GI side effects)

High pill burden and cumbersome dosing regimens

HIV-related factors

Presence of transmitted or acquired drug-resistant virus documented by current or past drug resistance test results

Prior treatment failure

Innate HIV resistance to antiretroviral drugs due to naturally-occurring mutations in HIV genes encoding enzymes targeted by the drugs

Higher pre-treatment HIV RNA level

ART regimen related factors 

Suboptimal pharmacokinetics (PKs) (e.g., variable absorption, metabolism)

Suboptimal virological potency

Low genetic barrier to resistance

Reduced efficacy due to prior exposure to suboptimal regimens (e.g., monotherapy)

Food requirements

Adverse drug-drug interactions with concomitant medications

Prescription errors