Transmitted drug resistance now less likely to harm HIV treatment options, US study finds

The rising prevalence of transmitted antiretroviral drug resistance in the United States is unlikely to affect the success of first-line treatment in the future and is largely unconnected with recent treatment failure in people already on antiretroviral therapy, a large analysis published in Clinical Infectious Diseases shows.

As a result of the rising prevalence of transmitted drug resistance, drug resistance testing at the time of diagnosis or prior to starting treatment has been standard practice since the early-2000s in most clinical settings in the United States. Although studies have reported an increased prevalence of drug resistance, information is lacking regarding the likely impact of transmitted drug resistance on newer treatment regimens, based on integrase inhibitors.

Kaiser Permanente Northern California provides care to approximately 25% of insured people with HIV in the northern part of the state. Between 2003 and 2015, 4253 antiretroviral-naïve patients receiving care in Kaiser Permanente Northern California clinics underwent genotypic drug resistance testing.

Glossary

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

integrase

HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected.

resistance testing

Laboratory testing to determine if an individual’s HIV strain is resistant to anti-HIV drugs. 

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

first-line therapy

The regimen used when starting treatment for the first time.

Just under 14% of people had transmitted drug resistance. The predominant route of acquisition was sex between men (60%). The most common form of resistance was to non-nucleoside reverse transcriptase inhibitors (NNRTIs) (7.2% of all people) and to nucleoside reverse transcriptase inhibitors (NRTIs) (5.8%). Protease inhibitor resistance was less frequent (3.2%) as was resistance to multiple drug classes (1.9%).

A median of 305 people were tested each year and a trend analysis showed that over time, the prevalence of transmitted drug resistance increased by 5% per year (odds ratio 1.05, 95% CI 1.03-108, p < .0001). Resistance to an NNRTI increased by 11% year (OR 1.11, 95% CI 1.08-1.15, p < .001) but the prevalence of NRTI resistance did not increase significantly during the study period. Increases in protease inhibitor and multi-class resistance were modest and of borderline statistical significance.

The most common drug resistance mutations were associated with high-level resistance to efavirenz or nevirapine (348 cases). Of the entire population who underwent resistance testing, just under 8% had some degree of resistance to efavirenz and 5% to rilpivirine.

Resistance mutations associated with NRTI treatment were predominantly thymidine analogue mutations that cause reduced susceptibility to zidovudine. Just under 5% of the entire cohort had mutations associated with reduced susceptibility, 2.8% to abacavir and 2.2% to tenofovir. The M184V mutation associated with reduced susceptibility to lamivudine or emtricitabine was extremely rare.

Protease inhibitor resistance mutations were less frequent and overwhelmingly associated with protease inhibitors no longer in clinical use. Approximately 2% of the entire cohort had some degree of resistance to boosted atazanavir and 0.3% to boosted darunavir.

No resistance to integrase inhibitors was reported.

The lack of evidence of widespread resistance to newer drugs in people with transmitted resistance suggests that most drug-resistant strains of HIV are being transmitted by people who have themselves acquired a drug-resistant form of HIV, say the study authors. Only 14% of the viruses with transmitted drug resistance could be matched to viral sequences in the Kaiser Permanente Northern California population already taking antiretroviral treatment. The researchers found numerous clusters of untreated people with identical drug resistance patterns, including one cluster in which phylogenetic sequencing suggested that at least seven separate individuals had passed on HIV containing the L90M protease inhibitor resistance mutation and the Y181C NNRTI resistance mutation.

A study in the United Kingdom found a similar pattern while a recent Swiss study found that drug resistance was not affecting treatment options.

“The evolution of US treatment guidelines towards first-line regimens that include an integrase […] inhibitor or [boosted] darunavir means that the preferred first-line regimens are highly active in patients with transmitted drug resistance,” the authors conclude.

References

Rhee SY et al. Trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance in a large US clinic population. Clin Infect Dis, advance online publication, 2018.

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