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Antiretroviral therapy (ART) resistance is only one of the reasons for virologic failure among people living with HIV. But no matter the reason, the goal should always be to find the proper ART regimen that will help a patient reduce the viral load.

The NIH's (developed by a working group of the Office of AIDS Research Advisory Council) notes that treatment resistance and drug-resistant mutations are less likely to develop in patients who are virally suppressed or below the lower limit of detection.

"Although not conclusive, the evidence suggests that selection of drug-resistance mutations does not occur in patients with HIV-RNA levels that are persistently suppressed below the [lower limit of detection] of current assays," the panel wrote.

Virologic failure is defined as after 24 weeks of ART, or a "recurrence in viremia," defined as a viral load greater than 200 copies/mL "on two consecutive measurements taken approximately one month apart" for patients who were previously virally suppressed.

Data from the World Health Organization (WHO) estimate that the worldwide prevalence of pre-treatment HIV drug resistance to older non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (NVP, Viramune) or efavirenz (EFV, Sustiva) . In fact, resistance to NNRTIs is over three times higher in treatment-experienced patients, and over half of infants born to mothers with HIV also have resistance to NNRTIs, the WHO noted. "Global prevalence of resistance to the NNRTI drug class emphasizes the need to fast-track the transition to the newer dolutegravir-based regimens."

As such, guideline recommendations for initial ART regimens focus on integrase-inhibitor based medications with nucleoside reverse transcriptase (NRTI) .

Determining Treatment Resistance

According to HIV.gov, treatment-naive patients should undergo genotypic drug-resistance testing prior to initiation of ART, specifically for mutations in the reverse transcriptase and protease genes. In addition, if a patient has previously used long-acting cabotegravir (Apretude) as pre-exposure prophylaxis (PrEP), or if "transmitted integrase strand inhibitor (INSTI) resistance is suspected," testing should also include the integrase gene.

Previously treated patients with virologic failure should also undergo reverse transcriptase and protease gene testing, but integrase gene testing should be performed only if the patient was previously on an INSTI-based ART regimen, the panel added.

For both previously treated and untreated patients with virologic failure, therapy should not be delayed while waiting for the results of genotypic resistance tests.

Interestingly, the panel noted that testing may be "unsuccessful" for patients whose HIV RNA is 200-500 copies/mL, but should "still be considered."

Genotypic resistance testing is preferred, however, and in some cases phenotypic resistance testing may be added for patients with "known or suspected complex drug-resistance mutation patterns," according to HIV.gov.

Therapy for Previously Treated Patients

For patients who exhibit NRTI resistance, that "two NRTIs -- tenofovir alafenamide or tenofovir disoproxil fumarate plus emtricitabine (FTC) or lamivudine (3TC) -- should be included in the regimen with a fully active, high resistance barrier drug, such as dolutegravir, boosted-darunavir, or bictegravir."

The International Association of Providers of AIDS Care (IAPAC) , noting that a new regimen should include two or even three "fully active" antiretroviral drugs. "Fully active" was defined as a drug expected to have "uncompromised activity" based on a patient's drug resistance test results and ART history. The new drug may also have a different mechanism of action.

HIV.gov noted that if no fully active drug with a high resistance barrier (such as dolutegravir or boosted-darunavir) is available, three drugs should be added to the new ART regimen.

But adding a single antiretroviral therapy, especially a boosted protease inhibitor or an INSTI, has been linked with "unacceptable rates of virologic failure and development of drug resistance," and is not recommended, HIV.gov stated. Consulting with an HIV specialist may be the best option for patients for whom one or more drug classes have failed.

HIV.gov recommended closely monitoring patients for at least 3 months for "tolerability, viral suppression, adherence, and safety" after an ART regimen switch, and ongoing counseling regarding ART adherence is very important.

Other Reasons for Virologic Failure

Reasons for treatment failure fall into three categories, according to IAPAC:

• Adherence-related factors

• HIV-related factors

• ART-related factors

The organization delved into certain social and psychological factors that might explain reasons for non-adherence, such as patients with mental health disorders, neurocognitive impairment, active substance use, unstable housing, and "high pill burden or dosing frequency."

In addition to resistance testing, IAPAC urged a full evaluation of patients with virologic failure, including "assessment of adherence, drug-drug and drug-food interactions, and drug tolerability," as well as viral RNA and CD4 cell count and ART history.

"Medical management of people experiencing ART failure is complex," IAPAC emphasized. "Often the causes of virologic failure can be identified, but in some cases, they are not obvious."

Part 1: The Evolution of HIV: From Death Sentence to Chronic Condition

Part 2: Antiretroviral Therapy for HIV: When Less May Be More

Part 3: Viral Load: HIV's Most Important Disease Marker

Part 4: Case Study: Managing Upper Urinary Tract Kidney Stones in HIV+ Patients

Part 5: All About PrEP: Pills, Shots, and Stigma