This Week in HIV Research: Life in the Integrase Era
In the U.S., HIV had long since transitioned from death sentence to chronic illness by the time integrase inhibitors became a commonly prescribed antiretroviral drug class in the mid-2010s. So it can be easy to overlook the massive impact they’ve had on HIV treatment and care, relative to the revolutionary effect that combining NNRTIs, NRTIs, and protease inhibitors had starting in the late 1990s.
But the word “massive” doesn’t overstate the degree to which integrase inhibitors have altered the clinical landscape of HIV, on issues large and small—efficacy, tolerability, resistance, interactions, pregnancy, the list goes on. We touch on a couple of them in our latest tour of recently published HIV research, along with a couple of other stories that caught our eye.
On tap this week:
- Drug interactions decline in the integrase era—but less than expected, thanks to increased comedication use.
- Despite the association of integrase inhibitors with weight gain, the class nonetheless may be associated with fewer overall cardiac events.
- A deep dive into HIV drug resistance in Florida finds that mutations are common—but with wide variations in prevalence by demographic group.
- Frailty symptoms may signal neurocognitive disorder risks among people with HIV, even among people with a CD4 count typically deemed quite healthy.
Let’s get into some of the details, shall we? To beat HIV, you have to follow the science!
Drug-Drug Interactions Become Less Common Among Swiss PLWH—But With a “But”
While potential drug-drug interactions have declined over the past decade in the Swiss HIV Cohort Study, they did not drop as much as anticipated, thanks to an increase in the use of other medications as people living with HIV (PLWH) age, researchers reported in Clinical Infectious Diseases.
A 2008 survey of the cohort found that 59% of people had prescriptions that could interact with their antiretrovirals, and that such interactions were of clinical relevance or had at least a weak clinical significance. That percentage dropped to 43% in the 2018 survey. The downward trend was mostly attributed to the increasingly widespread usage of unboosted integrase inhibitors.
Demographically, older participants and those who had lived with HIV for a long time were more likely to have prescriptions with potential drug interactions, likely because of one of three trends: increased medication burden from comorbidities as a result of aging; adverse effects from the use of older antiretrovirals; or a long period of time spent with an unsuppressed HIV viral load.
Of note, both the 2008 and 2018 surveys found that 2% of participants had a potentially harmful drug interaction. Usually, the danger involved the coadministration of corticosteroids and boosted antiretrovirals, which can cause Cushing syndrome. Corticosteroids are often prescribed by non-HIV physicians who may be unaware of the potential interaction, study authors noted. They developed an informational leaflet that participants can give to their non-HIV doctors to increase awareness of this problem.
In addition, to more generally curb drug interaction risks, researchers recommended using unboosted antiretroivrals, regularly reconciling all medications used by a patient, and systematically using existing tools to flag potential interactions before prescribing a new medication.
Integrase Inhibitors May Be Associated With Fewer Cardiac Events
In adjusted analyses, integrase strand transfer inhibitor-based antiretroviral treatment was associated with significantly lower odds of major adverse cardiac events compared to other HIV regimens, researchers reported in Journal of Acquired Immune Deficiency Syndromes.
Data came from 20,242 new antiretroviral initiations between 2008 and 2015 among PLWH with commercial insurance or Medicaid in the U.S. Twenty-five percent of these regimens were INSTI-based, and 203 major adverse cardiac events occurred during the study period.
After weighting for underlying conditions, as well as changes in prescribing patterns due to guideline updates, the adjusted odds ratio for a major heart problem was 0.79 for those on INSTIs compared to other antiretrovirals. The unadjusted model did not show any difference between regimens, likely because more participants prescribed INSTIs had underlying conditions that put them at risk of cardiovascular problems compared to those on other regimens, the authors theorized. (Other studies of specific INSTIs have found no association between those medications and greater cardiovascular risk factors, but did find a link to weight gain, which could in itself increase CVD risk—thus leading providers to avoid prescribing integrase inhibitors to people who already had CVD risk factors.)
The current study is based on administrative billing data, does not consider viral suppression, and lacks data on smoking, body mass index, family history, and other risk factors. The authors called for verifying results in other cohorts and with specific antiretrovirals.
This study had been presented in a poster at the 2019 Conference on Retroviruses and Opportunistic Infections.
In Florida, HIV Drug Resistance Rates Vary Widely by Demographic
Virus mutations that confer resistance against certain antiretrovirals are more common in Florida counties with lower socioeconomic status, higher unemployment rates, and poor mental health compared to other counties in the state, a retrospective analysis of 34,447 HIV sequences published in The Journal of Infectious Diseases found.
The samples were obtained between 2012 and 2017 and sequenced for mutations known to be associated with resistance to HIV drugs. Overall, resistance was more prevalent in Florida—the state with the highest HIV incidence in the U.S.—than in North America in general. The prevalence of any drug class mutation was highest for NNRTIs (30%), followed by 19% for NRTIs, 8% for integrase inhibitors, and 7% for protease inhibitors. (The researchers did not explore the effect of drug resistance on treatment efficacy or virologic failure.)
The authors found significant heterogeneity among demographic subgroups. For instance, multi-drug resistance and NRTI resistance were slightly higher among men than women; Black people had higher rates of resistance to integrase inhibitors, NRTIs, and NNRTIs than white people, but a lower rate of resistance to protease inhibitors than white or Latinx people; and NNRTI resistance rates in particular appeared to vary widely by county.
People who acquired HIV perinatally had the highest odds of drug resistance, likely due to transmitted mutations from the mother. Surprisingly, people who inject drugs had lower odds; study authors credited this result to the state’s test-and-treat initiative, but called for additional analysis of the finding.
While overall resistance against protease and integrase inhibitors was lower than other drug classes, it was more common in samples from later years, indicating an increase in such mutations—although the study authors acknowledged that shifting prescribing practices could be a confounding factor that was not accounted for in the study.
Despite the study findings, the authors warned against using county-level socioeconomic data to form assumptions regarding a specific individual’s level of drug resistance. They called for more genotype testing of individuals’ virus as well as molecular surveillance to support public health in the state.
Frailty Linked to Neurocognitive Problems Even at Normal CD4 Counts
People living with HIV who experience symptoms of frailty are more likely to develop HIV-associated neurocognitive disorders (HAND) than those without such symptoms, even at CD4 thresholds normally considered to be healthy, according to a small study reported in Journal of Acquired Immune Deficiency Syndromes.
Researchers evaluated 178 PWLH, 12% of whom were women, at the University of California-San Diego between 2014 and 2019. They found that an association between frailty symptoms and HAND risk appeared for people whose CD4 count was below 642 cells/mm3, which lies within the normal CD4 count range. The association became clinically significant for those with at least two defined symptoms of frailty.
While no association between HAND and viral load was observed, few participants had viral loads < 50 copies/mL in the first place, making data on this point unreliable. Previously, nadir CD4 count had been associated with HAND. The current study shows that current CD4 count—which, unlike the nadir, can often be modified—is also important, the authors explained.
Since older people are more likely to be frail, the association between frailty symptoms and HAND becomes particularly important as PLWH age. “A CD4 count below 642 cells/mm3 should prompt clinicians to assess for frailty, and identification of 2 frailty symptoms in [PLWH] should prompt for closer monitoring of CD4 to identify or possib[ly] mitigate neurocognitive impairment,” study authors recommended.