Update on Long-Acting Regimens for the Treatment of HIV-1

Viral suppression is one of the major goals of the Centers for Disease Control and Prevention (CDC) Ending the HIV Epidemic in the US (EHE) initiative.1 Viral suppression is defined in this context as fewer than 200 copies of HIV per mL of blood by 2025 in at least 95% of the individuals infected with HIV in the US, with the further goal of remaining at or above 95% suppression in 2030 (Figure 1).2 This is important because viral suppression not only minimizes an individual’s HIV disease activity but also reduces transmission of HIV from infected individuals to their uninfected sexual partners. Large studies have demonstrated that if viral load is further suppressed to the point that HIV becomes undetectable, risk of transmission via sexual activity is largely eliminated.



In turn, adherence to antiretroviral (ART) medication is generally considered to be the strongest predictor of HIV treatment success. However, even assuming that the patient is promptly linked to suitable care and interventions upon diagnosis (Figure 2),2 poor long-term adherence remains a notable challenge and is associated with virologic failure, disease progression, and adverse effects including increased mortality.2,3 Patients who take a daily oral ART regimen may have problems with adherence due to “pill fatigue,” dosing complexity and its demands on attention, and subsequent lost motivation. Other barriers to patient adherence include the stigma related to HIV status and concern about inadvertent disclosure, disruptive life events or long-term instability in living conditions, and mental or emotional comorbid conditions.



Long-acting (LA) ART regimens may offer advantages in ensuring medication adherence. A drug combination administered at longer intervals, as opposed to one self-administered daily, may reduce stigma and patients’ cognitive and emotional loads. Physician-patient contact may increase, providing further potential to ensure full adherence. An injectable form of LA ART therapy may also improve absorption, reduce gastrointestinal side effects, and circumvent difficulty in swallowing pills.4

A Long-Acting Injectable Regimen

To date, combination therapy with cabotegravir plus rilpivirine,5 administered by intramuscular injection, is the only US Food and Drug Administration (FDA)-approved complete LA regimen for HIV-1 viral suppression. Cabotegravir is an HIV-1 integrase strand transfer inhibitor (INSTI); rilpivirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Cabotegravir and rilpivirine are most commonly used in combination, although cabotegravir is also approved as a single agent as oral preexposure prophylaxis.
 
Phase 3 trials demonstrated cabotegravir plus rilpivirine to be noninferior to standard-of-care oral ART. In the phase 3 FLAIR study (ClinicalTrials.gov Identifier: NCT02938520), ART-naive patients received oral induction therapy comprising dolutegravir, abacavir, and lamivudine for 20 weeks.6 Participants who had a plasma HIV-1 level of fewer than 50 copies per mL were randomly assigned 1:1 to continue the current oral therapy or switch to LA therapy, which required a 4-week period of oral lead-in therapy with cabotegravir and rilpivirine, for a 48-week study period. At the initial 48-week endpoint, LA cabotegravir plus rilpivirine was found to be noninferior to the standard-of-care regimen.
 
In a subsequent extension phase of FLAIR, patients initially assigned to remain on oral therapy were given the option to extend their participation by switching to LA cabotegravir plus rilpivirine, either on a direct-to-injection basis or following oral lead-in therapy. Efficacy, safety, and tolerability were comparable across the 2 extension switch groups. In reporting 124-week results for the LA therapy group from the initial phase of FLAIR, the investigators concluded that LA cabotegravir plus rilpivirine offered durability as maintenance therapy.
 
The randomized phase 3 ATLAS study (ClinicalTrials.gov Identifier: NCT02951052)  tested LA cabotegravir plus rilpivirine in treatment-experienced patients who were assigned to continue their current therapy or switch to the LA cabotegravir plus rilpivirine after the oral lead-in period of 4 weeks.7 This investigation, which stratified patients into subgroups based on the drug classes represented in their baseline ART regimen, showed LA therapy to be noninferior to the baseline regimens at 48 weeks in terms of efficacy, safety, and tolerability.
 
Subsequent phase 2 and phase 3 studies, including ATLAS-2M (ClinicalTrials.gov Identifier: NCT03299049), have demonstrated highly comparable clinical results whether participants received LA cabotegravir plus rilpivirine every 8 weeks or every 4 weeks.8 Through week 96, participants more strongly preferred administration every 8 weeks compared with 4-week (injection) or daily (oral) dosing intervals. More recent reporting at 152 weeks9 has demonstrated durable viral suppression with administration at both 4-week and 8-week intervals. The most common drug-related adverse event in these studies has been injection-site reaction, followed by pyrexia and fatigue.
 
In 2021 the FDA approved the LA cabotegravir plus rilpivirine regimen for administration every 4 weeks; in early 2022, the FDA expanded its approval to administration every 8 weeks.10 The European Medicines Agency (EMA) has also approved this regimen at both the 4-week and 8-week intervals.11


Cabotegravir plus rilpivirine regimen adverse effects
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Adverse effects commonly reported with cabotegravir plus rilpivirine include injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

Who Is Eligible for Long-Acting Therapy?

Currently, LA cabotegravir plus rilpivirine is recommended for patients with HIV-1 twelve years of age or older weighing at least 35 kg and without a history of treatment failures/viral resistance to either cabotegravir or rilpivirine.10 Notably, a pooled analysis of data from the ATLAS and FLAIR trials12 showed that mutations conferring drug resistance were widespread among the small proportion of patients receiving LA cabotegravir plus rilpivirine with confirmed virologic failure. Candidates for this treatment regimen also should be willing and able to commit to injection visits every 4 or 8 weeks.
 
The LA cabotegravir plus rilpivirine regimen is contraindicated in patients with a history of hypersensitivity reaction to either agent, and in patients who concurrently receive carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone, or St John’s wort. There is a risk of torsade de pointes when given in combination with some antibiotics.10
 
Patients with hepatitis B virus (HBV) were excluded from both the FLAIR and ATLAS trials. Cabotegravir and rilpivirine have not demonstrated efficacy against HBV13; this limits the clinical utility of these drugs in patients who are coinfected with HIV-1 and HBV. Given the exclusion criteria of the ATLAS and FLAIR trials, there is also limited information regarding whether the LA cabotegravir plus rilpivirine regimen is suitable for patients who are pregnant, those with serious hepatic or renal pathology, patients with poorly-controlled HIV infection, and young children. These trials excluded patients with viral mutations associated with resistance to INSTIs or NNRTIs, except for the HIV-1 RT K103N mutation in isolation; clinicians have been advised to test patient who are candidates for this regimen for resistance-associated mutations, given that these mutations appear to be associated with virologic failure of this regimen.14
 
Finally, it is important for patients to understand that treatment adherence remains essential to maintaining HIV-1 suppression, even though they will not self-administer their medications daily. Patients who find it challenging to attend 4-week (or 8-week) visits for maintenance injections, and clinics facing challenges (eg, with staffing, other resources) offering routine visits, must bear in mind the risk of viral rebound and evolution of drug resistance if patient adherence is incomplete. Clinics offering LA cabotegravir plus rilpivirine must maintain cold-chain storage for these medications and should designate staff resources, time, and clinic space for injection visits and dose preparation.
 
Although improved adherence is commonly considered a key motivator behind implementing a long-acting regimen such as cabotegravir plus rilpivirine, there is a lack of real-world data regarding whether this LA regimen indeed lowers barriers to adherence. These data will likely emerge from future long-term, prospective studies.

LA Cabotegravir Plus Rilpivirine Combination Injection: Administration and Dosage

During the optional oral lead-in period, which allows the clinician to assess drug tolerability, the recommended daily dosage is 30 mg cabotegravir plus 25 mg rilpivirine, administered for at least 28 days5 or until the first injection dose is given (Table). The loading dose for the complete LA injection regimen, if administered every 4 weeks, consists of 3 mL injections each of cabotegravir (600 mg) and rilpivirine (900 mg), generally in opposite gluteal muscles. Maintenance administration begins 1 month after these initiation injections; the monthly dose is 2 mL injections each of cabotegravir (400 mg) and rilpivirine (600 mg).
 
If this therapy is administered every 8 weeks, the loading dose includes 3-mL injections each of cabotegravir (600 mg) and rilpivirine (900 mg) after the oral lead-in period and 1 month after. Maintenance administration begins 2 months after the second loading dose at the same dose (Table).5



Results of the aforementioned phase 3 trials indicated that receipt of injection approximately 7 days from the monthly (or bimonthly) scheduled date was acceptable. If the patient misses, or plans to miss, a scheduled LA injection, bridging with oral medication is recommended to maintain virological drug activity. This relies on the availability of the cabotegravir and rilpivirine oral formulations, such as those used during the lead-in to the LA injection study regimens. Ideally clinics and patients should plan to secure those equivalents in advance,15 because their availability through community pharmacies cannot be assured. Cabotegravir, in particular, is not available at pharmacies.16

Additional Existing and Emerging Options for Use of LA HIV Treatment Regimens

Ibalizumab is a humanized immunoglobulin G4 (IgG4) antibody approved for treatment of multidrug-resistant HIV infections. It is not a complete regimen, but is used in combination with the patient’s existing or optimized background ART regimen.17 The loading dose is 2000 mg administered intravenously followed by maintenance intravenous infusions of 800 mg, saline-diluted, every 2 weeks. It has the disadvantage of more frequent administration than other LA drugs and requires patients to adhere to their previous ART regimens. Nevertheless, the advent of this drug may represent a step toward less-than-daily dosing for patients with multidrug-resistant HIV-1.
 
Numerous other ART drugs and novel formulations of existing ART are in development. Advances in LA ART will likely address and overcome the disadvantages and limitations of currently available LA regimens.15 For example, subcutaneous implant formulations, currently in preclinical and early phase studies, may permit longer release time with improved cellular uptake. Other future LA ART may be self-administered at home by subcutaneous injection. Reduced volume of injectable doses may limit the frequent injection site reactions secondary to relatively large (2 mL and 3 mL) intramuscular injections. Such advances should help to address challenging medication adherence problems and possibly reduce the need for oral lead-in therapy.

References

1. Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV epidemic: a plan for the United States. JAMA. 2019;321(9):844-845. doi:10.1001/jama.2019.1343

2. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2019. HIV Surveillance Supplemental Report 2021;26(No. 2). Published May 2021. Accessed September 24, 2022. https://www.cdc.gov/hiv/library/reports/hiv-surveillance/vol-26-no-2/index.html

3. Nachega JB, Marconi VC, van Zyl GU, et al. HIV treatment adherence, drug resistance, virologic failure: evolving concepts. Infect Disord Drug Targets. 2011;11(2):167-174. doi:10.2174/187152611795589663

4. Akinwunmi B, Buchenberger D, Scherzer J, et al. Factors associated with interest in a long-acting HIV regimen: perspectives of people living with HIV and healthcare providers in four European countries. Sex Transm Infect. 2021;97(8):566. doi:10.1136/sextrans-2020-054648

5. Cabenuva. Prescribing information. ViiV Healthcare; 2022. Accessed September 24, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Cabenuva/pdf/CABENUVA-PI-PIL-IFU2-IFU3.PDF

6. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/NEJMoa1909512

7. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. doi:10.1056/NEJMoa1904398

8. Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV. 2021;8(11):E679-E689. doi:10.1016/S2352-3018(21)00185-5

9. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir + rilpivirine every 2 months: ATLAS-2M week 152 results. Poster presented at: Conference on Retroviruses and Opportunistic Infections 2022; February 12-16, 2022; Seattle, Washington; Poster 479.  

10. ViiV Healthcare announces US FDA approval of Cabenuva (cabotegravir, rilpivirine) for use every two months, expanding the label of the first and only complete long-acting HIV treatment. ViiV Healthcare. Published February 1, 2022. Accessed September 24, 2022. https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2022/january/viiv-healthcare-announces-fda-approval-of-cabenuva-for-use-every-two-months/

11. First long-acting injectable antiretroviral therapy for HIV recommended approval. European Medicines Agency. Published October 16, 2020. Accessed September 24, 2022. https://www.ema.europa.eu/en/news/first-long-acting-injectable-antiretroviral-therapy-hiv-recommended-approval

12. Rizzardini G, Overton ET, Orkin C, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498-506. doi:10.1097/QAI.0000000000002466

13. Bollinger RC, Thio CL, Sulkowski MS, McKenzie-White J, Thomas DL, Flexner C. Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV. Lancet HIV. 2020;7(6):E443-E448. doi:10.1016/S2352-3018(19)30342-X

14. McGowan JP, Fine SM, Vail RM, et al; on behalf of Medical Care Criteria Committee of the New York State Department of Health AIDS Institute (NYSDOH AI). Use of injectable CAB/RPV LA as replacement ART in virally suppressed adults. Johns Hopkins University; 2022. Accessed September 24, 2022.

15. Scarsi KK, Swindells S. The promise of improved adherence with long-acting antiretroviral therapy: what are the data? J Int Assoc Provid AIDS Care. Published online April 27, 2021. doi:10.1177/23259582211009011

16. Preparing for long-acting antiretroviral treatment. American Academy of HIV Medicine. February 25, 2021. Accessed September 24, 2022. https://aahivm.org/wp-content/uploads/2021/03/Long-Acting-ARVs-_Final-2-25-21_PDF.pdf

17. Emu B, Fessel WJ, Schrader S, et al. Forty-eight-week safety and efficacy on-treatment analysis of ibalizumab in patients with multi-drug resistant HIV-1. Open Forum Infect Dis. 2017;4(suppl 1):S38-S39. doi:10.1093/ofid/ofx162.093 

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Clinical Advisor had no role in this content’s preparation.

Reviewed October 2022

Global Warming Could Heat Up Kidney Stone Rate

City residents walking in sunlight
People living in urban areas, which are typically are warmer than other places, could be especially prone to increases in kidney stone risk. Source: Getty Images

Climate change is thought to be responsible for much of the extreme weather affecting people around the world, such as stronger hurricanes and other storms that dump increasing amounts of rain and cause catastrophic flooding, unprecedented heat waves, and prolonged droughts that imperil agriculture and health. Extreme weather events generate headlines and dramatic images, so some of the subtle effects of rising global temperatures on health may get little attention.

One plausible effect could be an increase in kidney stone risk. Higher temperatures can increase water loss through perspiration and cause dehydration. This lowers urine volume and concentrates substances in urine that can form kidney stones, such as calcium, oxalate, phosphate, and uric acid.

“So it’s not hard to conclude that greater exposure to heat, even for relatively short periods of time, is likely to increase kidney stone prevalence,” said nephrologist David S. Goldfarb, MD, Professor of Medicine at the NYU Grossman School of Medicine and Director of the Kidney Stone Prevention Program at NYU Langone Health in New York.

Studies have clearly demonstrated a link between higher temperatures and elevated kidney stone risk. Pediatric urologist Gregory E. Tasian, MD, MSc, associate professor of surgery at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia, led one of those studies. He and his colleagues looked at the effect of temperature on kidney stone presentation in 5 major US cities with diverse climates. They discovered that a daily mean temperature of 30 vs 10 °C (86 vs 50 °F) was significantly associated with a 38%, 37%, 36%, and 47% increased risk for kidney stone presentations in Atlanta, Chicago, Dallas, and Philadelphia, respectively, according to their 2014 report in Environmental Health Perspectives.1 The investigators found a nonsignificant 11% increased risk in Los Angeles. The study also revealed a short lag between daily temperatures and medical visits for kidney stones, with the maximum risk occurring within 3 days of temperature exposure.


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Other studies in the United States, the Middle East, and elsewhere have documented that emergency department visits for kidney stones occur more frequently in summer than winter.

Kidney stone prevalence already has been on the rise. In the United States, the overall prevalence of kidney stones increased from 3.2% in 1980 to 10.1% in 2016, Api Chewcharat, MD, and Gary Curhan, MD, ScD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, reported in a 2020 paper in Urolithiasis.2 At the American Urological Association’s 2022 annual meeting, Shirley Y. Zhang, a medical student at the University of Alabama School of Medicine in Birmingham, reported on a study by her and her collaborators showing that the prevalence of symptomatic kidney stones among children in the southeastern United States increased 84.4% from 2006 to 2020.

The precise reasons for the upward trend are unclear, but researchers have cited dietary changes and an increasing prevalence of diabetes and obesity among the underlying causes. Now, global warming is considered to be in the mix of risk factors for kidney stones.

The effect of higher temperatures on kidney stone risk would be especially pronounced in urban areas because they tend to be warmer than rural environments, said Dr Goldfarb, who has advanced a hypothesis that urban heat islands contribute to a growing prevalence of kidney stones.3 As he explained in an interview, the asphalt, concrete, and other building materials that make up the urban milieu absorb more heat during the day and give up that heat to the atmosphere at night compared with rural settings, he said. This results in areas characterized not only by higher daytime temperatures but less dipping of temperatures at night compared with rural areas. Consequently, urbanites may have prolonged exposure to higher temperatures compared with their rural counterparts, Dr Goldfarb said.

“Our urban heat island hypothesis suggests that the temperatures in cities are really much more of an issue than the average temperature of the Earth,” Dr Goldfarb said. “There’s no question that global warming and climate change contribute to increasing temperatures in urban environments.”

And cities are where most of the world’s people live. According to the United Nations Department of Economic and Social Affairs, 55% of the world’s population live in urban areas, and this proportion is expected to rise to 68% by 2050. The proportion of city dwellers is much higher in the United States, where 80.7% of the nation’s population lived in urban areas in 2010, according to US Census data.

Dr Goldfarb acknowledged that it is difficult to disentangle the effect of heat from other factors that influence development of kidney stones. He noted, for example, that city residents may have different diets, activities, and occupations that increase their risk for kidney stones compared with people who live in rural communities. In addition, access to medical and imaging modalities and intensity of medical surveillance for kidney stones may be greater in cities, suggesting that evidence for increased kidney stone prevalence in urban settings could be related to greater detection rather than a true increase in prevalence.

Dr Tasian, who also is surgical director of the Pediatric Kidney Stone Center at the Children’s Hospital of Philadelphia, pointed out that established associations between temperature and kidney stone presentations could be complicated by changes in human behavior in response to higher temperature. For example, he and his collaborators observed a ceiling effect in Dallas, where temperatures above 30 °C did not result in an increased risk for kidney stone presentations. It could be that the city’s population adapted to the local climate such that residents spend more time indoors in air conditioned rooms and increase their fluid intake at higher temperatures, Dr Tasian postulated.

What would happen, then, in places where air conditioning is not widely used, such as in Europe? According to Inaba-Denko, a company that manufactures air conditioning products, air conditioning is present in only 20% of households in Europe, with much lower proportions in some countries, such as the United Kingdom (approximately 3% of residential homes), France (approximately 5%), and Germany (approximately 3%). Much of Europe has experienced record-breaking heat waves with temperatures above 100 °F this summer, and climate change is widely blamed for the phenomenon. Dr Goldfarb and Dr Tasian say it is plausible that the effect of global warming on kidney stones’ prevalence could be more pronounced in these and other places where air conditioning is uncommon.

Although stronger storms, massive floods and wildfires, and property destruction are among the attention-grabbing events attributed to global warming, an increase in the prevalence of kidney stones brought on by rising temperatures could be among the underappreciated threats to health.

References

  1. Tasian GE, Pulido JE, Gasparrini A, et al. Daily mean temperature and clinical kidney stone presentation in five U.S. metropolitan areas: A time-series analysis. Environ Health Perspect. 2014;122(10):1081-1087. doi:10.1289/ehp.1307703
  2. Chewcharat A, Curhan G. Trends in the prevalence of kidney stones in the United States from 2007 to 2016. Urolithiasis. 2021;49(1):27-39. doi:10.1007/s00240-020-01210-w
  3. Goldfarb DS, Hirsch J. Hypothesis: Urbanization and exposure to urban heat islands contribute to increasing prevalence of kidney stones. Med Hypotheses. 2015;85(6):953-957. doi:10.1016/j.mehy.2015.09.003

This article originally appeared on Renal and Urology News

Newly Minted PAs Ready to Tackle Health Disparities

health care disparities
“PAs are a major part of the solution to improve access to care, meet the increasing demand for high-quality providers, and address issues pertaining to health care disparities in patients with chronic conditions,” said Dr Orozco. Credit: Getty Images

New data shows that the PA profession is growing by leaps and bounds with the number of newly certified PAs reaching a record high of 10,950 in 2021. With nearly 160,000 PAs in practice and numbers projected to increase by 31% between 2020 and 2030, it is hard to understand how the gaps in health care access remain. We spoke with American Academy of Physician Associates (AAPA) President and Chair of the Board Jennifer M. Orozco, DMSc, PA-C, DFAAPA, to better understand the PA professional landscape and what can be done to help PAs better tackle health care disparities.

Dr Orozco is also director of Advanced Practice Providers at Rush University Medical Center in Chicago and assistant professor in the Department of PA Studies at Rush University College of Health Sciences.

Q: What is underlying the marked gaps in health care access and health disparities in the US?

Jennifer Orozco AAPA 2022
Jennifer M. Orozco, DMSc, PA-C, DFAAPA

Dr Orozco: The reality is that patient needs are outpacing provider supply. We know that 96 million Americans lack adequate access to primary care and less than half of those with access are actually having their needs met. We have 155 million Americans without access to mental health care. We have an aging population projected to reach almost 95 million by 2060. And approximately 42% of adults over the age of 20 years are obese and many have obesity-related conditions such as heart disease, stroke, type 2 diabetes, and certain types of cancer.

We have had a mass exodus in the health care workforce across the country and now face a projected workforce shortage of 3.2 million health care workers by 2026. In rural areas, the gaps in access may be even wider. However, findings from a JAMA study showed a 49.3% increase in the density of PAs in rural counties between 2009 and 2017 compared with a 14% increase among physicians in these areas. PAs can help improve access to care, especially given that the profession is projected to grow 31% between 2020 and 2030. However, we are not utilizing PAs as best as we should due to outdated legislation that prevents PAs from practicing to the full extent of their education and training.


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Credit: Health Resources & Services Administration

Q: Can you give an example of how PAs are not used to the fullest extent of their training?

Dr Orozco: A colleague of mine practices in a rural part of Southeast Colorado, which recently experienced a large turnover among all health care providers. She’s worked as a PA there for nearly 20 years providing preventative HIV treatment, hepatitis treatment, and long-acting contraceptives among other services. Her supervising physician left and the new physician who was hired does not specialize in infectious disease or gynecologic care. Because these areas are not in the physician’s scope of practice, the PA is now no longer allowed to perform these services. She has to send her patients — whom she has been caring for for years — hours away to access care.

This is one example of how deep-seated in tradition we are in medicine; we can’t let go of things that don’t make sense anymore. At Rush, we discuss how we need to push the status quo and bring everyone along with us. I have this same philosophy at AAPA. Many people can deliver health care, whether they are a PA, a nurse, nurse practitioner (NP),  or physical therapist; we have to start being innovative in health care delivery in order to meet the needs of our patients.

Q: What can clinicians do to help lobby for legislative change?

Dr Orozco: I think it is about building relationships — not just with legislators and policy makers, but with all stakeholders in a modern health care delivery system — and chipping away [at the status quo] to make a difference. Talk to people who will listen and keep pushing where you can. Always keep the discussion patient-focused because they are the ones who suffer if we can’t enact change.

Q: The recently released NCCPA survey showed a record number of PAs entering the field in 2021. What is attracting people to become PAs?

Dr Orozco: The pandemic heightened the need for more health care providers, but even prior to that, the PA profession was highly sought after. For the fifth year in a row, PA was named one of the top 2 health care jobs in the country by US News & World Report in its annual Best Jobs List. In this day and age, especially across generations, people really want to get into health care to serve patients. All of the evidence that we have gathered over the years on how PAs practice, are trained, and the high quality of care that they deliver is attracting people to become PAs.

Q: Did any data on practice patterns from the NCCPA survey surprise you?

Dr Orozco: I wasn’t surprised by many of the statistics as they align with the shifts we are seeing in health care, which is a good sign. The survey showed this continuing shift from inpatient management to ambulatory care. From a health care system perspective, we started to focus on ambulatory footprint expansion, particularly with the rise of telemedicine during the pandemic.

Q: What else would you like to tell Clinical Advisor readers?

Dr Orozco: The biggest take-home message is that PAs are a major part of the solution to improve access to care, meet the increasing demand for high-quality providers, and address issues pertaining to health care disparities in patients with chronic conditions. We will never have enough PAs, physicians, NPs, or nurses to meet patient demand. Yet, we have this untapped supply of 160,000 highly-trained PAs who have completed one of the most rigorous medical education models yet are not being optimally utilized. The continued growth in the PA profession is tremendous. At AAPA, I continue to focus on elevating awareness about how PAs go beyond for their patients every day, and why it is so important that we remove archaic and outdated barriers so that we can continue to provide all patients the care they deserve.

We have to modernize health care delivery. The old way hasn’t worked for a long time and the pandemic has heightened the need for change. PAs are highly educated and trained and able to take care of complex patients. The PA profession is continuing to grow and is here to help improve access in this country and provide high-quality care for patients.

Hepatits C Screening Recommended for Adults, Pregnant Women

The researchers found that 3621 cases of acute hepatitis C were reported during 2018, representing an estimated 50,300 cases.

HealthDay News — Hepatitis C screening is recommended for all adults and for all pregnant women, except where the prevalence is below 0.1%; meanwhile, the annual rate of reported acute hepatitis C cases increased to 1.2 per 100,000 population in 2018, according to recommendations and a report published in the April 10 issue of the US Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report.

Sarah Schillie, MD, from the CDC in Atlanta, and colleagues updated and summarized previously published recommendations regarding testing for hepatitis C infection in the United States. The researchers issued 2 new recommendations for hepatitis C screening, which are applicable in all settings except where the prevalence is less than 0.1%; screening at least once in a lifetime for all adults aged ≥18 years and hepatitis C screening for all pregnant women in each pregnancy.

A. Blythe Ryerson, PhD, also from the CDC, and colleagues determined the rate of acute hepatitis C cases reported to the CDC by age group and year during 2009 to 2018. The researchers found that 3621 cases of acute hepatitis C were reported during 2018, representing an estimated 50,300 cases. There was an increase in the annual rate of reported acute hepatitis C cases per 100,000 population from 0.3 in 2009 to 1.2 in 2018. In 2018, there was a bimodal distribution of newly reported chronic hepatitis C cases, with the highest proportions seen among those aged 20 to 39 and 50 to 69 years.

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“These findings highlight the need for immediate implementation of the new CDC universal hepatitis C screening recommendations for all adults and pregnant women,” Ryerson and colleagues write.


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Direct-Acting Agents Help to Eliminate Hepatitis C in Liver Transplant Recipients

liver
HCV is one of the most common reasons for liver transplantation in the United States and recurrent infection can lead to both patient and graft loss.

The introduction of direct-acting agents (DAAs) has caused a significant reduction in the percentage of liver transplant recipients for hepatitis C virus (HCV) who are viremic after surgery, according to study results published in the Journal of Clinical and Translational Hepatology.1

HCV is one of the most common reasons for liver transplantation in the United States,2,3  and recurrent infection can lead to both patient and graft loss.4,5 DAAs have increased cure rates and have been found to be safe, effective, and tolerable after liver transplantation.6-8 Use of DAAs began at the University of California Los Angeles Medical Center in 2013, and therefore researchers at that institution studied the effect of DAAs on the elimination of HCV in 634 patients with HCV who underwent liver transplantation between January 2005 and June 2017.1 

After analyzing data on the date of transplant and the type and timing of antiviral therapy, they found that the percentage of patients who were treated within 12 months of transplant increased from 6% in 2005 to 2013 to 33% in 2014 to 2016 (P <.001). Within 2 years of liver transplant, more patients were cured of HCV in the study period from 2014 to 2016 compared with 2005 to 2013 (78% vs 18%, P <.001). The percentage of patients undergoing an additional liver transplant at 1 year after the original transplant decreased from 5.5% in 2005 to 2013 to 1.5% in 2014 to 2016 (P =.011). In addition, there was a significantly higher rate of pre-transplant HCV treatment in liver transplant recipients after 2013; prior to 2014, 5% of transplant recipients were treated before transplantation compared with 25% of recipients of transplantation after 2014 (P <.001).

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Investigators concluded that “HCV can be eliminated from the liver transplant cohort in this country with treatment commencing either before or after liver transplantation.”1 In addition, “preliminary results suggest the decreased need for transplant in the direct-acting agents era.”


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References

  1. Saab S, Challita Y, Chen PH, et al. Elimination of hepatitis C in liver transplant recipients. J Clin Transl Hepatol. 2018;6(3):247-250.
  2. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2013 Annual Data Report: liver. Am J Transplant. 2015;15 Suppl 2:1-28.
  3. Goldberg D, Ditah IC, Saeian K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterol. 2017;152:1090–1099.e1.
  4. Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology. 2002;122:889-896.
  5. Firpi RJ, Clark V, Soldevila-Pico C, et al. The natural history of hepatitis C cirrhosis after liver transplantation. Liver Transpl. 2009;15:1063-1071.
  6. Saab S, Manne V, Bau S, et al. Boceprevir in liver transplant recipients. Liver Int. 2015;35:192-197.
  7. Suraweera D, Sundaram V, Saab S. Treatment of hepatitis C virus infection in liver transplant recipients. Gastroenterol Hepatol. 2016;12:23-30.
  8. Brown RS Jr, O’Leary JG, Reddy KR, et al. Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: real-world experience from the hepatitis C therapeutic registry and research network. Liver Transpl. 2016;22:24-33.

This article originally appeared on Infectious Disease Advisor

Hepatitis C and eczema


Hepatitis C and eczema?
Several dermatologic manifestations of hepatitis C infection have been described.

What is the etiology of neuropathic flexion deformities of the fingers and dry, scaling palms related to hepatitis C infection?—MARY CARTER, CANP, Penrose, Calif.

Several dermatologic manifestations of hepatitis C infection have been described. These manifestations include pruritus, porphyria cutanea tarda, cryoglobulinemia and vasculitis, salivary gland lesions (lymphocytic capillaritis and lymphocytic sialadenitis), lichen planus, polyarteritis nodosa, urticaria, erythema nodosum, and erythema multiforme (Int J Dermatol. 1997;36:251-254).

Combination therapy with interferon alpha-2b plus ribavirin for 24 to 48 hours has been used as initial treatment for chronic hepatitis C infection. Either agent, when used individually, can cause dermatologic side effects. Several reports of eczema have been described in patients with hepatitis C infection who were treated with interferon alpha-2b and ribavirin (Arch Dermatol. 2004;140:215-217; available at archderm.jamanetwork.com/article.aspx?articleid=480239, accessed December 15, 2013). A literature search does not reveal any citations for the symptoms described by Ms. Carter.—Philip R. Cohen, MD (183-4)


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These are letters from practitioners around the country who want to share their clinical problems and successes, observations and pearls with their colleagues. We invite you to participate. If you have a clinical pearl, submit it here. 

Once-daily daclatasvir plus sofosbuvir yields high SVR in HCV

Daclatasvir plus sofosbuvir combo promising hepatitis C treatment
Daclatasvir plus sofosbuvir combo promising hepatitis C treatment

For patients with hepatitis C infection, an experimental oral antiviral drug combination of daclatasvir and sofosbuvir may be an effective and safe treatment option, research published in the New England Journal of Medicine suggests.

To evaluate the safety and efficacy of combination daclatasvir plus sofosbuvir, the investigators conducted an open-label study. Study participants (n=211) were randomly assigned to receive sofosbuvir for 1 week, then daclatasvir and sofosbuvir for 23 weeks; daclatasvir and sofobuvir for 24 weeks; or daclatasvir, sofosbuvir, and ribavirin for 24 weeks.

Overall, most patients had a sustained virologic response, including 98% of patients with genotype 1 infection — the most common hepatitis infection strain in the United States — and 91% of patients infected with genotype 2 or 3.

Daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with characteristics that were previously associated with a poor response to treatment — HCV genotypes 1a and 3, the non-CC IL28B genotype, and black race.


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Chronic infection with hepatitis C virus (HCV) affects more than 170 million patients globally, and since 2007, HCV-related deaths have surpassed deaths attributed to HIV, noted the researchers.

“This research paves the way for safe, tolerable and effective treatment options for the vast majority of those infected with hepatitis C,” said Mark S. Sulkowski, MD, of Johns Hopkins University in Baltimore, Maryland, in a university press release.

“Standard treatments for the disease are going to improve dramatically within the next year, leading to unprecedented advances for the treatment of patients infected with the hepatitis C virus.”

References

  1. Sulkowski MS et al. NEJM. 2015; doi: 10.1056/NEJMoa1306218

Disclosures

The study was funded by Gilead Sciences and Bristol-Myers Squibb. Sulkowski is a paid consultant to both Gilead Sciences and Bristol-Myers Squibb.

Does extensive hepatitis C screening help or harm?

Does more extensive hepatitis C screening help or hurt patients?
Does more extensive hepatitis C screening help or hurt patients?

Though many global health-care organizations support more extensive hepatitis C screening, some researchers are calling for more research into the risks and benefits of more widespread screening for the disease.

In 2012, the CDC recommended that all patients born between 1945 and 1965 be screened for hepatitis C, with the U.S. Preventive Services Task Force (USPSTF), and World Health Organization (WHO) calling for an expansion of screening in 2013 and 2014, respectively.

The USPSTF, however, noted the absence of studies on “long-term harms associated with antiviral regimens” and “the outcomes of treatment in screen-detected patients.”’

Prior to the 2012 recommendation, screening was focused only on patients at high risk for developing the disease, such as intravenous drug users and those who received a transfusion prior to 1992.


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“We have a limited window of opportunity to collect appropriate evidence on whether this [widespread screening] is a good idea,” wrote Kenneth W. Lin, MD, of Georgetown University School of Medicine, and colleagues in the BMJ.

Current drug trials have relied on surrogate markers such as sustained virological response (SVR), which does not indicate cure, the researchers pointed out, and newer treatment regimens carry a risk for serious adverse events including persistent disability, hospital admission, and death.

“We know current medications can result in the virus becoming undetectable in a high number of people after three to six months, but 80% of people with hepatitis C do fine with or without treatment,” Lin said in a press release. “We need to know if the treatments have any long-term impact on the remaining 20% who are destined to develop liver failure, liver cancer or die from the disease.”

A shift in clinical trial design away from categorizing patients with hepatitis C by SVR towards categorizing them by risk for who will, or will not, develop end-stage renal disease is needed, the researchers argued.

“Since most individuals with hepatitis C never develop symptoms and die with it not of it, exposing these individuals to the harms of treatment with no possible benefit might outweigh benefits for the minority destined to develop end-stage disease,” they wrote.

In the United States, more than 2.7 million patients have hepatitis C. Many patients with the disease do not have symptoms and are not aware they have it. An estimated 16,000 patients require a liver transplant or die from hepatitis C each year. 

References

  1. Kortez RL et al. BMJ. 2015; doi: http://dx.doi.org/10.1136/bmj.g7809

HCV treatment with direct antiviral agents improves carotid atherosclerosis

cirrhosis of liver with chronic hepatitis
Researchers found a significant reduction in the prevalence of HCV patients with carotid thickening from baseline to follow-up.

Hepatitis C virus (HCV) eradication by direct antiviral agents (DAAs) improves carotid atherosclerosis in patients with advanced fibrosis and compensated cirrhosis, according to a study published in the Journal of Hepatology.

Salvatore Petta, Assistant Professor at the Center for Gastroenterology and Hepatology, University of Palermo, Italy, and colleagues, evaluated 182 consecutive HCV patients with advanced fibrosis or compensated cirrhosis by virologic, anthropometric, and metabolic measurements. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT≥1 mm), and carotid plaques were evaluated by ultrasonography at baseline and 9 to 12 months after the end of therapy.

A total of 56% of patients were men, mean age was 63.1 years, and 65.9% had compensated cirrhosis. One patient in 5 had diabetes, 14.3% were obese, 41.8% had arterial hypertension, and 35.2% were smokers. Mean IMT was 0.94 mm, 42.9% had IMT≥1 mm, and 42.9% had carotid plaques.

All patients achieved a 12-week sustained virologic response. IMT significantly decreased from baseline to follow-up (0.94±0.29 mm vs 0.81±0.27). A consistent, significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs 17%), while no changes were reported for carotid plaques (42.8% vs 47.8%). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity.


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“HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis without or with additional metabolic risk factors,” the authors concluded. “The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term.”

Reference

Petta S, Adinolfi LE, Fracanzani AL, et al. Hepatitis C virus eradication by direct antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. J Hepatol. 2018 Mar 2. doi: 10.1016/j.jhep.2018.02.015 [Epub ahead of print].

Managing hepatitis C

What is the best way to manage a patient with documented hepatitis C whose liver function tests fluctuate between 100 and 150 units/L and whose hepatitis B virus DNA polymerase chain reaction is undetectable?
—Nilesh N. Patel, MD, West Covina, Calif.

Your patient probably has chronic active hepatitis C. Hepatitis B infection should be diagnosed with the appropriate serologic assays and not by molecular diagnostics (www.cdc.gov/ncidod/diseases/hepatitis/b/hbv_silent_killer.pdf. Accessed June 11, 2008). The clinical approach to this patient should be based on prevention and therapy. Prevention efforts should focus on vaccinations for other hepatitis viruses, if applicable, and also on the complete abstinence from alcohol. Therapeutic options must be considered once the patient’s liver biopsy, HCV genotype, psychosocial profile, and HIV status have been determined (www.aasld.org/eweb/docs/hepatitisc.pdf. Accessed June 11, 2008). If pegylated interferon is appropriate, consultation with an experienced specialist should be obtained prior to the initiation of therapy.
—Cedric W. Spak, MD, MPH (117-7)

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