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STIs Reached Record Highs, Then COVID-19 Hit. Test Makers Now Ponder What's Next

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NEW YORK – As the COVID-19 pandemic pushes into a third year, public health experts and PCR-based assay makers are eager to know whether an increase in sexually transmitted infections is on the horizon.

Rates of STIs in the US had been rising for a decade until lockdowns in the early days of the pandemic led to a sharp reduction in STI testing and screening. Although levels have since recovered, experts are uncertain whether missed cases will lead to increased STI rates, or whether the impact will be offset by pandemic-related changes in sexual behavior.

For developers of STI tests, that uncertainty could present challenges as they try to prepare and prioritize for the future.

STIs aren't usually fatal, but they can still create a myriad of personal and public health issues. Chronic, untreated infections in women cause pelvic inflammatory disease in about 12 percent of cases according to one estimate, and approximately 1 in 5 PID cases will result in infertility. Even an asymptomatic STI can increase a person's risk of picking up other infections, like HIV, and STIs can lead to complications for pregnant people and their babies, including infant death in cases of congenital infection.

The majority of people infected with two of the most prevalent STIs — chlamydia and gonorrhea — have no symptoms whatsoever. For chlamydia, an estimated 90 percent of cases in males are asymptomatic, as are between 70 and 95 percent of cases in females. Gonorrhea infections are also asymptomatic in a little more than half of all cases.

To tamp down rising rates of these infections, the US Centers for Disease Control and Prevention recommends annual screening using nucleic acid amplification tests, and screening up to four times per year for some high-risk groups. Symptomatic cases are also frequently tested using molecular diagnostics, with gonorrhea in particular also isolated and cultured for national reporting and surveillance.

But not only did the pandemic lead to shortages in sample collection and preparation devices, testing reagents, and healthcare and lab staff, it also saw fewer people willing to step into a clinician's office for routine screening.

Overall, STI rates in the US had already risen to an all-time high in 2019, continuing a trend that had been going on for six consecutive years, according to the CDC.

The agency's 2019 STD Surveillance Report, published in April 2021, noted that there were 1,808,703 cases of Chlamydia trachomatis and 616,392 cases of gonorrhea reported to the CDC in 2019. In total, there were 2.5 million reported cases of chlamydia, gonorrhea, and syphilis — the three most commonly reported STDs that year — which represented a nearly 30 percent increase between 2015 and 2019, CDC said.

Then, COVID happened, resulting in a dramatic reduction in the number of detected STI cases, according to local as well as national data.

Barbara Van Der Pol runs a clinical microbiology lab at the University of Alabama, Birmingham, and specializes in STIs. The precarious state of plastic consumables and sample prep supplies for molecular testing led her lab, and many others, to restrict STI testing to symptomatic cases and pivot their resources to COVID testing.

"There were three months where nobody in the country could get collection devices, because the same swab used for STI specimens was being used to collect nasal swabs," Van Der Pol said in a recent interview. Just as her lab had restarted its full-capacity STI clinical lab testing a few months ago, the Delta variant came roaring in, and now some of the supplies the lab needs for STI testing are in short supply again, she said.

In a study published online in the American Journal of Preventive Medicine in May, Van Der Pol and colleagues from Quest Diagnostics and Pennsylvania State University reported CT/NG screening hit a low point in April 2020.

The team saw a 59 percent decrease in screening for female patients and a 63 percent decrease for male patients. Further, the results correlated with increases in positivity rates for both chlamydia and gonorrhea.

Overall, the team estimated that in their sample, there were 27,659 cases of chlamydia and 5,577 chases of gonorrhea missed between March and June of 2020.

Philip Chan, a physician and researcher at Brown University who treats STIs in Rhode Island, noted that staff in health departments and publicly funded clinics shifted from STIs to COVID-19 response. Data recently published by him and his team also showed that the pandemic significantly reduced the average number of STI clinic visits per week.

Nationally, reported STI diagnoses dropped significantly, then resurged in 2020 due to COVID-19 lockdowns, according to the CDC. Specifically, a CDC study in Sexually Transmitted Diseases showed that during the most restrictive period of pandemic lockdowns in early April 2020, chlamydia cases dropped nearly 50 percent compared to the same time in 2019. Reported gonorrhea infections fell more than 71 percent, and syphilis infection diagnoses dropped nearly 64 percent. In April 2020 alone, the CDC estimated that roughly 30,000 gonorrhea cases went undetected.

Through a spokesperson, the CDC said three factors likely contributed to the initial decrease in reported cases: reduced screening, limited resources, and stay-at-home orders which may have influenced sexual behaviors and reduced STD transmission.

Yet, by the end of 2020 infection detection resurged, according to CDC data, and the missed cases were mostly recouped. The cumulative total number of cases in the US was just 1 percent lower for syphilis and 14 percent lower for chlamydia for the year than expected, and cumulative numbers of gonorrhea infections were more than 7 percent higher compared to 2019, implying a resurgence of cases.

Commercial perspectives

In September 2020, the CDC issued guidance to healthcare providers on ways to prioritize testing during a national shortage of chlamydia and gonorrhea molecular diagnostic test kits and laboratory supplies.

"The shortages affect multiple diagnostic companies, public health and commercial laboratories, and impact several components of the specimen collection and testing process," the agency wrote in the Dear Colleague Letter.

The agency provided an update in June 2021, noting that "one of the main manufacturers of chlamydia/gonorrhea diagnostic test kits is reporting to CDC that their STI diagnostic test supplies are readily available at normal levels," while other manufacturers reported "continued improvement" in product availability and anticipated "near normal levels" of supplies in the coming months.

Major suppliers of molecular diagnostic tests for STIs — including Roche, Hologic, and Becton Dickinson — report that STI assay ordering dropped off significantly last year, but that ordering and availability have mostly returned to pre-pandemic rates.

Cindy Perettie, head of Molecular Labs at Roche, said that early in the pandemic the firm invested to scale up production capacity across its core diagnostics business, but that "Roche observed a core business decline, including STIs, at the start of the pandemic," with declines corresponding to peaks in COVID-19 across the world.

But now, Roche has seen an increase in STI testing demand across several of its lab customers, and the firm plans to support higher testing volumes, Perettie said. "We work closely with our country affiliates and customers to plan, as accurately as possible, future demands, in order to secure and safeguard our manufacturing and distribution capabilities," she added.

Kevin Thornal, Hologic's division president of diagnostic solutions, said that Hologic also experienced a significant drop in demand for its STI assays in the spring and summer of 2020 due to the COVID-19 pandemic. "This allowed us to divert some of our manufacturing capacity to production of our Aptima SARS-CoV-2 assay to help meet the rapidly escalating public health need for COVID testing," he said.

Simultaneously, Hologic also initiated aggressive efforts to increase its molecular diagnostics capacities at its San Diego and Manchester, UK, manufacturing sites.

"As of today, demand for STI assays has reverted to nearly pre-pandemic levels, while the need for COVID testing remains high," Thornal noted. But, because of the increased production capacities, the firm is "currently meeting demand on all fronts."

Hologic is also continuing its manufacturing expansion. "We are on track to have the capacity to make at least 75 million tests a quarter across our portfolio by early 2022, which is more than triple our pre-pandemic capacity," Thornal also said.

At Becton Dickinson, Chris Beddard, business line leader of core MDx and women's health and cancer at BD Integrated Diagnostic Solutions, said the firm focused on COVID-19 assay manufacturing in the early months of the pandemic.

However, BD manufactures STI tests on multiple platforms, including the BD Viper XTR and BD Viper LT Systems, and the firm has been able to maintain a steady supply consistent with customer demands, and "unimpacted by COVID-19 test manufacturing," Beddard said.

Nevertheless, BD also experienced declines in demand for STI assays early in the pandemic "as laboratories were, of course, focusing resources to support the urgent need for COVID-19 testing," Beddard said, while people were perhaps reluctant to visit physicians for routine and non-COVID-related health concerns.

BD has since seen demand return to pre-COVID levels.

"It is difficult to predict the immediate- and long-term impact on STI rates that the pandemic may have, but BD continues to have the capacity to expand, to innovate, and to address customer demands and changes in the healthcare landscape," Beddard said.

Resistance, risk, and innovation

What the ultimate consequence of missed cases will be on future STI rates is unknown, and may not be known for years to come.

Charles Cartwright, senior VP of clinical affairs at SpeeDx, suggested in an interview that an explosion in cases may not happen, but even so, "it will take three or four years before that is actually able to be analyzed," he said, in part because surveillance data takes a long time to be published.

Rates of antimicrobial resistance, particularly for gonorrhea, may also potentially be impacted.

SpeeDx offers a gonorrhea diagnostic test that supports "resistance-guided therapy," essentially detecting whether an infection is susceptible to a second-tier antibiotic. The firm partnered with Roche last year to offer its resistance assays, and Perettie said Roche saw this as a unique opportunity to extend an important test to its customers, as AMR STIs are "now listed by the Centers for Disease Control and Prevention as key threats due to the rising resistance and the limited available treatment options." In the long term, Roche sees the partnership as "a key strategic goal" to extend solutions to customers as quickly as possible, Perettie also said.

The increase in reported gonorrhea cases in the CDC's preliminary 2020 data is "definitely concerning," the agency spokesperson said, and it is something the CDC is continuing to study.

Past data suggest that about half of all gonorrhea cases are resistant to at least one antibiotic. CDC has not completed analysis for its 2020 resistance monitoring data, but indications are that there could be an upswing in antibiotic resistance.

For example, without treatment, people may have been carrying gonorrhea infections for a longer time, which increases the chance of the bacteria developing resistance. Asymptomatic oral and rectal infections, in particular, may have gone undetected due to decreased screening, and these sites are more prone to encourage resistance development through horizontal gene transfer with other commensal bacteria.

The newest CDC STI guidelines recommend gonorrhea be treated with an injectable antibiotic, and it is possible there were more cases treated with a less effective oral treatment at times when access to clinical settings was limited or difficult, a CDC spokesperson also said. This is particularly relevant for oral gonorrhea because almost all of these infections are asymptomatic and so, detection depends on screening.

The CDC confirmed that its Gonococcal Isolate Surveillance Project, or GISP, was able to continue surveillance throughout the pandemic.

However, some participating clinics were closed, STI patients were not always the highest priority, health department staff were moved to COVID-19 duties, and testing facilities were short on test kits and lab equipment. The ways all these factors ultimately impacted the GISP program are still being evaluated.

Different groups may also be differently impacted by STIs — due to a historic lack of care, aversion to seeking treatment, or prevalence of practices that better enable certain transmission events.

The CDC noted in its report on 2019's rates that certain populations had already been disproportionately impacted by STIs. Many nonwhite populations, for example, have significantly higher rates of STIs, including African Americans, whose STI rates were as much as eight times higher than for non-Hispanic white people. Meanwhile, American Indian, Alaska Native, Native Hawaiian and other Pacific Islander populations were as much as five times higher, and Hispanics had STI rates twice as high.

Also, gay and bisexual men who have sex with men made up nearly half of the total number of primary and secondary syphilis cases in 2019, and in some areas of the US, rates of gonorrhea among this group were 42 times that of heterosexual men.

And young people — specifically ages 15 to 24 — are also disproportionately impacted, making up 61 percent of the nation's chlamydia cases in 2019 and 42 percent of all gonorrhea cases.

The CDC noted in its assessment that pre-existing disparities in STI services may now also be impacted by staff returning to STI testing labs burnt out by stints of COVID testing. On the other hand, the CDC identified "several new and innovative ways STD services can meet more people where they are" during the COVID-19 pandemic and in the future.

These include walk-in STD express clinics, partnerships with pharmacies and retail health clinics, telehealth, and new support for self-testing and patient-collected specimens.

Prognostication

At least one epidemiological model of chlamydia screening suggests that there would have been twice as many infections if there had been no screening programs and notification of partners between 2000 and 2015. Nevertheless, it is possible that missed cases and limited testing resources during the pandemic will be offset by the stay-at-home orders, which may have affected sexual behaviors.

Given that STIs have been increasing for the past decade, Brown's Chan said they will likely continue to increase. But, although clinics saw fewer patients, "on the flip side, I think people were socializing less ... and less socializing means, in many cases, less sex." Anecdotally, Chan said some of the higher-risk patients he sees, who typically have many sexual partners, seem to have picked a single partner with whom to get through the pandemic.

Point-of-care STI tests are also on the cusp of making an impact, and Chan noted that the research that went into COVID diagnostics could hopefully translate to other public health concerns, like STIs.

SpeeDx's Cartwright also highlighted that COVID-19 led many firms, including SpeeDx, to dramatically scale up manufacturing capacity across the spectrum of molecular diagnostics. "Big instrument companies have placed a lot of instruments, and companies like ours have greatly increased our ability to manufacture large amounts of product to meet demand," he said.

Given the number of COVID tests being run daily, "there will be a huge amount of excess capacity in laboratory testing" when the pandemic ends. Combined with an influx in cash, Cartwright said diagnostics companies may become less nervous about menu expansion into STIs, which would in turn help to grow the market.

Still, whether diseases that tend to more strongly impact marginalized groups can ever be given enough attention and funding to be fully controlled is an open question. Van Der Pol noted that STI funding is "orders of magnitude less" than funding for HIV research, for example.

Similarly, antibiotic resistance in gonorrhea is a growing problem, and STIs continue to be especially problematic for women who are of reproductive age. Van Der Pol suggested that this demographic is most likely to be impacted by missed cases during the pandemic. "I think we are going to see a lot of infertility coming out of this, since people will have had untreated infections that have gone on for a year or more," she said.

The solution, ultimately, is to declare that "these are important infections that we should always be paying attention to," and for society to get over the stigma and learn to talk about STIs, Van Der Pol said.

"Hiding them is part of why we are not getting rid of them," she said.

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