Human immunodeficiency virus (HIV) is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDs) if left untreated. Almost 40 million people worldwide have HIV and 630,000 people died from HIV in 2023. HIV attacks the immune system by targeting white blood cells. Patients infected with HIV are more likely to contract diseases such as tuberculosis and cancer due to their decreased immune function. Currently, there is no cure for HIV, but many medications exist to treat HIV and prevent its spread. The long-term effectiveness of these medications is directly related to patient adherence and treatment resistance. Long-acting injectable medications may be a good option for patients who struggle with adherence to daily oral treatments.

What was the FLAIR trial?

The FLAIR trial was a randomized, open-label, noninferiority trial taking place in multiple treatment centers. It aimed to prove noninferiority of an injectable two-drug antiviral regimen versus an established oral three-drug antiviral regimen in patients who had never received treatment for HIV.

The experimental medication, now known as Cabenuva, is a long-acting treatment containing two medications, both of which were individually FDA-approved for the treatment of HIV prior to this trial. The first is cabotegravir, an integrase strand-transfer inhibitor (INSTI). INSTIs work by blocking the integration of viral DNA, stopping the replication of HIV. The second medication is rilpivirine, which is a nonnucleoside reverse-transcriptase inhibitor (NNRTI). NNRTIs work by inhibiting HIV-1 transcriptase which prevents HIV replication. In this trial, Cabenuva was given as an intramuscular injection once monthly.

The comparator treatment was a standard HIV treatment regimen, containing three oral antivirals: dolutegravir, abacavir, and lamivudine. This combination is taken once daily and represents a guideline-recommended treatment option for HIV.

The goal of HIV treatment is to reduce morbidity and mortality as well as decrease the spread of HIV. Antiviral medications are used to reduce a patient’s viral load to an undetectable level, which prevents HIV transmission. As defined by the CDC, antiviral treatment that results in a viral load of < 200 copies per mL is considered to be successful.

How was the study conducted?

The FLAIR trial contained two main phases, the induction phase and the maintenance phase. In the induction phase, all enrolled patients were given the three-drug oral regimen daily for 20 weeks. After 16 weeks, patients underwent additional testing to ensure that their viral load was less than 50 copies per mL. Patients who met the criteria continued to the maintenance phase where they were randomized into either the experimental or comparator treatment group. Members in the experimental group were given an oral lead-in of daily cabotegravir and rilpivirine, followed by a loading dose injection, and then continued with the monthly injectable maintenance dose thereafter. Members in the comparator group continued on the daily three-drug oral regimen. The intention-to-treat population was analyzed with a total of 566 patients split evenly between the two treatment groups.

Patients included in the FLAIR trial had to have active HIV, as determined by a plasma screening, that had never been treated with antiviral medications. This is because resistance is common in patients who have previously been treated with antiviral medications. To avoid complicating the results, the trial only included patients who had no history of antiviral use and therefore had the lowest likelihood of treatment resistance. Patients were excluded from this trial if they could not take antiviral medications due to their comorbid health conditions.

Notable inclusion criteria:

• HIV infection that has never been treated with antiviral medications
• HIV RNA level ³ 1000 copies per mL
• 18 years old or older

Notable* exclusion criteria:

• Anyone who was pregnant or breastfeeding
• Patients with active Stage 3 disease as defined by the CDC
• Hepatic impairment
• Current or previous hepatitis B infection

*This list includes highlights from the patient enrollment parameters. It does not include all exclusion criteria.

The primary endpoint measured during this trial reflects the ability of the long-acting treatment and comparator medications to provide viral suppression, which is the main goal of HIV treatment. This was defined as the percentage of participants with a plasma HIV RNA level of ³ 50 copies/mL at week 48.

The secondary endpoints provide additional data regarding treatment effectiveness, adverse events, and pharmacokinetics. The key secondary endpoint measured was the percentage of patients with a plasma HIV RNA level of < 50 copies/mL at week 48.

Some additional secondary endpoints included:

• Virologic failure
• Adverse events
• Plasma pharmacokinetics
• Adherence

The intention-to-treat population was statistically analyzed. The adjusted difference between the treatment and comparator groups was determined for the primary and secondary endpoints using a stratified Cochran-Mantel-Haenszel analysis. Based on the power of the study and the size of each study group, noninferiority for the primary outcome was proven if the difference between the two groups was less than 6 percentage points.

Outcomes of the trial

The primary endpoint occurred for 6 patients in the Cabenuva group and 7 patients in the comparator group. This was a difference of -0.4 percentage points, demonstrating noninferiority of the study drug.

The key secondary endpoint occurred in 93.6% of patients in the Cabenuva group and 93.3% of patients in the comparator group, also demonstrating noninferiority of the treatment group with an adjusted difference of 0.4 percentage points (95% CI: -3.7 to 4.5).

Adverse events were more common in the Cabenuva group (94%) versus the comparator group (80%). The most common side effect of Cabenuva was injection site reaction, occurring in 86% of patients. Injection site pain accounted for most of these and was most commonly characterized as mild in severity. After the initial injection, 71% of patients reported injection-site reactions, and at week 48, the prevalence dropped to 20% of patients who received the trial medication. Additional common adverse effects included headache, diarrhea, and upper respiratory tract infection.

The FLAIR trial showed noninferiority of Cabenuva, a long-acting injectable medication when compared to a three-drug oral regimen to treat HIV. Cabenuva achieved similar rates of viral suppression for patients who had not previously been treated with antivirals for HIV. However, it also had higher rates of adverse effects. These were most commonly injection site reactions, which can be accounted for by the difference in the route of administration.

Another clinical trial, the ATLAS trial, studied the efficacy of Cabenuva in patients who had been successfully treated for HIV with antivirals in the past. Similar outcomes were reported for both the FLAIR and ATLAS trials. These two trials provided data supporting the efficacy of Cabenuva in viral suppression for patients with HIV regardless of their previous antiviral use.

Barriers to successful HIV treatment

HIV is an extremely complex disease state to treat. Many medications can be used in a variety of combinations to treat patients. The table below outlines a few common first-line treatment recommendations.

Regimens that contain bictegravir or dolutegravir are highly effective and tolerable. They also have a lower pill burden and high barrier to resistance compared to other medications, making them good options for initial HIV treatment. Treatment is extremely patient-specific and should take into consideration a variety of factors, including viral load, previous antiviral use, resistance, concurrent infections, and patient intolerance.

Cabenuva is now part of the HIV treatment guidelines. However, Cabenuva is not currently a first-line treatment option. It should not be used if the patient has any history of treatment failure or resistance to either cabotegravir or rilpivirine. Additionally, Cabenuva is not recommended for initial viral suppression. Patients should undergo successful viral suppression with an alternative treatment regimen before switching to a long-acting injectable medication.

Adherence to antiviral medications is key to HIV treatment. These medications reduce morbidity and mortality for patients as well as prevent the spread of HIV. However, their effectiveness is directly related to patient adherence. Poor adherence increases the risk of resistance to HIV medications, limiting treatment options. Barriers to patient adherence include pill burden, complex dosing, side effects, limited access to care, stigma, poor health literacy, and more. Long-acting injectable medications could improve adherence by eliminating pill burden and reducing complex dosing schedules. However, they come with unique side effects and require monthly appointments for administration.

Treatment resistance is a major problem that occurs with HIV medications. Patients should undergo genotype testing for antiviral resistance before starting treatment. This step is of greater importance for patients who acquire HIV while using pre-exposure prophylaxis (PrEP), because some of the medications for PrEP and HIV treatment overlap. Poor adherence is a common cause of treatment resistance. However, resistance can develop even with perfect adherence. Virologic failure (HIV RNA plasma level > 200 copies/mL) due to treatment resistance often requires patients to switch treatment regimens. As patients acquire resistance to first-line treatments, they may have to switch to more complex regimens.

Pharmacists play an important role in HIV care by educating patients on treatment options and encouraging adherence.

Margaret M., APPE Student

References

1. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. The New England Journal of Medicine vol. 382,12 (2020): 1124-1135. doi:10.1056/NEJMoa1909512. Available at: https://pubmed.ncbi.nlm.nih.gov/32130806/. Accessed August 29, 2024.
2. About HIV. Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/hiv/about/index.html. Accessed August 29, 2024.
3. HIV and AIDS. World Health Organization. Available at: https://www.who.int/news-room/fact-sheets/detail/hiv-aids#:~:text=Human%20immunodeficiency%20virus%20(HIV)%20is,cells%2C%20weakening%20the%20immune%20system. Accessed August 29, 2024.
4. The Importance of Treatment Adherence in HIV. AJMC. Available at: https://www.ajmc.com/view/a472_sep13_schaecher_s231. Accessed August 29, 2024.
5. Antiretroviral Drugs for Treatment and Prevention of HIV Infections in Adults: 2022 Recommendations of the International Antiviral Society – USA Panel. International Antiviral Society. Available at: https://pubmed.ncbi.nlm.nih.gov/36454551/. Accessed August 30, 2024.

Urinary tract infection (UTI) is a broad term, encompassing simple and complex infections of the urinary tract and kidneys. In the United States, 40% of women have at least one UTI in their lifetime. Antimicrobials are the main treatment used for UTIs, but selecting the most appropriate option is complicated by increased resistance rates and patient-specific factors. Pharmacists play an important role in the healthcare team by ensuring that antimicrobial selection is optimal for each patient.

Cystitis vs. pyelonephritis

Cystitis is a UTI, consisting of a bladder or lower urinary tract infection. This is the most common type of UTI and one of the most common indications for prescribing antimicrobials in the United States.

Cystitis can be classified as complicated or uncomplicated.

• Uncomplicated cystitis is any UTI that occurs in women who are generally healthy and do not have any abnormalities in the structure or function of their urinary tract.
• Complicated cystitis is any UTI that occurs in people who have abnormalities to the structure or function of their urinary tract or have other complicating health problems.
  • UTIs that occur in men or pregnant women are always considered complicated.

Pyelonephritis is a complicated UTI that involves infection of the kidneys or upper urinary tract. This is less common than cystitis and requires more intense treatment.

Who gets UTIs?

Women are 4 times more likely to get a UTI than men. This is due to women having shorter urethras, and a shorter space between the rectum and urethra, both of which allow bacteria to travel more easily to the site of infection. Cystitis occurs most frequently in women ages 16 to 35 but can happen to anyone at any age. Pyelonephritis occurs in about 15-17 cases per 10,000 females and 3-4 cases per 10,000 males each year. In the United States, an average of 250,000 cases of pyelonephritis occur each year.

Some additional risk factors include:

• Abnormal function or anatomy of the urinary tract
• Antibiotic use
• Diabetes
• Diarrhea
• First UTI before age 15
• New or multiple sexual partners
• Menopause
• Pregnancy
• Old age or dementia
• Catheter-use

What causes UTI?

Common pathogens that cause cystitis and pyelonephritis are:

• Escherichia coli
• Proteus mirabilia
• Klebsiella pneumonias
• Staphylococcus saprophyticus
• Enterococcus

E. coli is the most common pathogen in UTIs, responsible for 75-95% of infections. One possible mechanism for the success of E. coli is the p-fimbriae appendages that adhere to epithelial cells in the urinary tract. This can prevent E. coli from being flushed out of the urinary tract, instead giving them time to colonize and spread.

UTI symptoms and diagnosis

Many cystitis symptoms overlap with other urinary tract diagnoses. Likewise, many pyelonephritis symptoms overlap with other types of infections. Therefore, it is important to collect a medical history and a full list of reported symptoms from each patient who presents with a possible UTI.

Diagnosis of UTI is made using a combination of patient-reported symptoms, a detailed medical history, and a urinalysis. No single factor alone should be used to diagnose UTIs. 

Treatment for UTIs

Antimicrobial agents are the main medications used to treat UTIs. However, the agent selected and treatment duration differ between cystitis and pyelonephritis. Medication selection should be patient-specific, taking into consideration previous antimicrobial use, history of UTIs, cost, availability, and allergies. Antimicrobial selection should also be location-specific, taking into consideration local resistance patterns.

Antimicrobial treatment is dependent on the presence of symptoms and significant bacteria in the urine sample. A notable exception is the treatment of pregnant women. All pregnant patients who have significant bacteria present in their urine should be treated with antimicrobials whether they have symptoms or not.

Cystitis treatment:

Cystitis treatment generally consists of a short course of oral antibiotics. There are multiple first-line options to choose from, all of which have similar efficacy. Second-line options are reserved for patients who cannot use any of the first-line treatments. Amoxicillin or ampicillin are NOT recommended due to poor efficacy and high resistance.

Pyelonephritis treatment

Pyelonephritis treatment generally uses longer courses of oral antimicrobials but may include IV treatment as well. Treatment may take place in the hospital or the outpatient setting depending on the severity of infection. If hospitalization is needed, patients should receive IV antimicrobials initially, then switch to oral treatment. If the patient is treated in the outpatient setting, they may use oral antimicrobials for the full treatment duration. All pregnant patients with pyelonephritis should be treated with IV therapy using ceftriaxone, cefepime, ampicillin plus gentamycin, or aztreonam.

Why is antimicrobial resistance a growing concern?

Antimicrobial resistance occurs when pathogens no longer respond to treatment with specific antimicrobial medications. In these cases, providers are required to prescribe alternative treatments that are not as specific and may come with additional side effects. A study from 2020 found that 1 in 5 UTIs caused by E. coli had reduced susceptibility to first-line treatment options such as trimethoprim/sulfamethoxazole. As more pathogens become resistant to commonly used antimicrobial medications, they will be harder to treat and treatment options will become limited.

Infections that occur due to drug-resistant pathogens have a higher rate of recurrence. It is critical to optimize treatment and limit recurrence by selecting antimicrobials using culture results and local resistance patterns and following guideline recommendations for indication and duration of therapy whenever possible.

What does this mean for pharmacists?

Almost half of the women in the United States will have at least one UTI in their lifetime. This makes UTIs one of the most common problems that require antimicrobial treatment. Pharmacists should consider the treatment guidelines, local resistance rates, and patient-specific factors when making recommendations and verifying prescriptions for UTI treatment.

Margaret M., APPE Student

References:

1. Uncomplicated Urinary Tract Infections. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470195/. Accessed August 27, 2024.
2. Acute Pyelonephritis. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK519537/. Accessed August 27, 2024.
3. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women. Infectious Disease Society of America. Available at: https://www.idsociety.org/practice-guideline/uncomplicated-cystitis-and-pyelonephritis-uti/. Accessed August 27, 2024.
4. Urinary Tract Infection in Pregnancy. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK537047/. Accessed August 28, 2024.
5. Antimicrobial resistance. World Health Organization. Available at: https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance. Accessed August 28, 2024.

Pneumonia is a lung infection caused by bacteria, fungi, or viruses. Pneumonia is the leading cause of infection-related death and the 8^th most common cause of death worldwide. In the United States, the incidence of community-acquired pneumonia (CAP) is 24.8 cases for every 10,000 adults. Hospital-acquired pneumonia (HAP) occurs in 5-10 of every 1000 hospital admissions, making it the most common infection caused by hospitalization. Antibiotics are the mainstay of pneumonia treatment, and choosing the correct antibiotic depends on various factors. Pharmacists can impact patient care by ensuring that patients receive the most appropriate therapy.

What are CAP and HAP?

Pneumonia is classified by the environment in which the infection occurred and how severe the disease is. Both classifications help to determine treatment options.

CAP is a pneumonia infection that is acquired outside of the hospital. If patients are hospitalized, it is present within the first 48 hours of hospitalization and will show up on initial cultures taken at the time of admission. CAP is the most common type of pneumonia.

CAP severity is part of the initial patient assessment to determine if a patient should be treated in an inpatient or outpatient setting. Generally, severe CAP is classified as a case with 1 or more major criteria or 3 or more minor criteria.

HAP is a pneumonia infection that is acquired during a hospital stay. It occurs after a patient has been hospitalized for more than 48 hours and is not present on initial cultures upon admission. HAP is less common than CAP but generally requires more robust treatment, which takes place in the hospital.

Pathogens that cause CAP and HAP

Pathogens causing pneumonia vary; some pathogens are more common in healthcare settings, while others are more common in everyday environments. Additionally, local infection and resistance patterns for infectious organisms can cause variation in pneumonia pathogens.

What are the signs and symptoms of pneumonia?

Many of the signs and symptoms of pneumonia are consistent with other infections. No single sign or symptom should be used to diagnose pneumonia. Similarly, the lack of a specific sign or symptom should not be used on its own to rule out pneumonia.

Common symptoms of pneumonia include:

• Fever
• Chills
• Chest pain
• Cough with sputum production
• Shortness of breath

Physical exam and lab findings:

• Increased heart rate
• Respiratory rate > 20 breaths per minute
• Elevated white blood cells (WBC)
• Lung crackles or decreased breath sounds

How is pneumonia diagnosed?

Chest X-ray is the gold-standard diagnostic test for patients with suspected pneumonia. The combination of an infiltrate on a chest x-ray and presence of clinical signs and symptoms is indicative of pneumonia and warrants empiric antibiotic treatment.

Respiratory cultures are the main laboratory evaluation used to diagnose pneumonia. However, they can be invasive and easily contaminated. They can be obtained through sputum samples, endotracheal aspiration, and bronchoscopy. Respiratory cultures are not required to diagnose pneumonia and are not commonly performed for patients with non-severe CAP. For patients with more serious infections, including severe CAP and HAP, respiratory cultures can help narrow antibiotic coverage and ensure that uncommon pathogens are appropriately covered by antibiotics.

Treatment for CAP and HAP

Antibiotics should be used to treat patients diagnosed with pneumonia. Pneumonia severity, causative pathogen, and local resistance rates should all be taken into consideration when choosing antibiotics from the treatment guidelines. Additionally, patient-specific factors such as allergies, previous infections, and previous antibiotic use should be considered before starting antibiotics.

Treatment for CAP should be continued until the patient is clinically stable and antibiotics have been given for at least 5 days. Clinical stability includes signs that the patient is recovering such as normal heart and respiratory rates, no fever, willingness to eat, stable blood pressure, and normal mental status. The duration of antibiotic treatment may be extended if the patient does not show signs of improvement or the causative pathogen is uncommon and more difficult to treat.

HAP treatment:

All patients who are diagnosed with HAP should be treated with at least 1 antibiotic. This antibiotic should cover P. aeruginosa and methicillin-susceptible staphylococcus aureus (MSSA). Additional MRSA and P. aeruginosa coverage may be indicated for specific patient populations. The table below outlines the guideline-recommended antibiotics for HAP and when additional antibiotic coverage is necessary.

Antibiotics should be narrowed to treat the causative pathogen as soon as possible. Treatment for HAP should be limited to 7 days as long as the patient is clinically improving. Clinical improvement may include a reduction in symptoms, normalized heart and respiratory rates, discontinuation of vasopressors and ventilation, and improved oxygen saturation. Antibiotics may be given for a longer duration if the patient is not clinically improving.

Viral pneumonia treatment

Viral pneumonia is rare and hard to diagnose. The main treatments for viral pneumonia are supportive care and management of precipitating infections.

Supportive care may include:

• Supplemental oxygen
• Oral or IV fluids
• Frequent meals
• Rest

Viral infections, such as influenza or respiratory syncytial virus, are the main cause of viral pneumonia. Therefore, giving antiviral medications to treat current viral infections is recommended to help speed up viral pneumonia recovery.

Fungal pneumonia treatment:

Fungal pneumonia is caused by inhaled fungal spores. It is more common in people with weakened immune systems such as organ transplant recipients, cancer patients, and the elderly.  Fungal pneumonia is often treated with antifungal medications given either by mouth or IV.

Antifungal medications used:

• Itraconazole
• Fluconazole
• Amphotericin B

How can pharmacists help?

Pneumonia is a common infection caused by a variety of pathogens. It affects a large number of people each year and is classified as community-acquired or hospital-acquired. The main treatment for pneumonia is antibiotics. Pharmacists have in-depth knowledge of antibiotics and should use that knowledge to ensure that patients with pneumonia receive optimal medications to recover promptly.

Margaret M., APPE Student

References:

1. Community-Acquired Pneumonia. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK430749/. Accessed August 26, 2024.
2. Pneumonia. National Heart, Lung, and Blood Institute. Available at: https://www.nhlbi.nih.gov/health/pneumonia. Accessed August 26, 2024.
3. Nosocomial Pneumonia. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK535441/. Accessed August 26, 2024.
4. Guidelines for Diagnosis and Treatment of Adults with Community-Acquired Pneumonia. Infectious Disease Society of America. Available at: https://www.idsociety.org/practice-guideline/community-acquired-pneumonia-cap-in-adults/. Accessed August 26, 2024.
5. 2016 Clinical Practice Guidelines for the Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia. Infectious Disease Society of America. Available at: https://www.idsociety.org/practice-guideline/hap_vap/. Accessed August 26, 2024.
6. Viral Pneumonia. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK513286/. Accessed August 27, 2024.
7. Systemic Antifungal Therapy for Invasive Pulmonary Infections. Journal of Fungi. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9966409/. Accessed August 27, 2024.