#24-312: HIV Prevention and Management

Elliot is a new patient in the pharmacy today. He is a 35-year-old male with no known chronic medical conditions. His social history is significant for occasional alcohol consumption. He denies smoking or illicit drug use. He reports having unprotected sex with multiple male partners over the last six months.

What behaviors, if any, increase his risk for transmitting or acquiring HIV?

In the U.S., the most common way that HIV is transmitted is through unprotected anal or vaginal sex with someone who has HIV [4]. Receptive anal sex poses a higher risk of acquiring HIV, followed by insertive anal sex, followed by receptive penile-vaginal sex, and finally followed by insertive penile-vaginal sex [5]. Protection options include use of a condom or taking medications to prevent transmission of HIV, known as pre-exposure prophylaxis (PrEP), discussed later in the course.

There are nonsexual ways for HIV to be transmitted from person to person. For example, HIV can be transmitted by sharing injection drug use equipment with someone who has HIV. Equipment could include needles, syringes, etc. [6]. And sharing doesn't have to mean using the equipment right after it has been used by someone else. HIV can survive in a used needle for up to 42 days, depending on storage conditions [7]. It is also possible for a mother to pass HIV on to her child during pregnancy, birth, or while breastfeeding [6].

There are other less common ways that HIV can be passed from one person to another. It is extremely rare, but HIV has been transmitted [6]:

Transmission of HIV from a healthcare worker to a patient is rare. There are only a few reported cases. One example was in 1990 when a Florida dentist was associated with infecting several patients with HIV [8]. A second case of probable HIV transmission involved an orthopedic surgeon during a prolonged surgical procedure [9].

Three conditions are necessary for healthcare personnel to pose a risk for bloodborne virus transmission to patients. The healthcare worker:

The vast majority of healthcare workers with HIV pose no risk to patients because they do not perform activities in which both the second and third conditions are met. Healthcare workers with HIV, or other bloodborne pathogens, such as hepatitis B or hepatitis C, should follow preventive measures outlined in infection control policies to minimize provider-to-patient transmission [10].

The risk of healthcare workers being exposed to HIV while on the job (known as occupational exposure) is also very low. The risk is low because of protective practices and personal protective equipment used on the job to prevent HIV and other bloodborne infections. If a healthcare worker is exposed to HIV while on the job, the most common way this happens is being stuck with an HIV-contaminated needle or other sharp object. It is estimated that the risk of HIV acquired from being stuck with a needle used on a person who has HIV is less than 1% [11].

A mutually monogamous relationship with an individual who has tested negative for HIV is the safest contact for people who are sexually active. Safer sex practices should be encouraged for all patients, even if both partners in the relationship are living with HIV, in order to prevent transmission of a different HIV strain to the other partner. It's very important that patients living with HIV are adherent to their antiretroviral therapy (ART), since ART can keep levels of the virus very low, to the point where it may be less likely to be transmitted to their partners. It's also important for patients to be encouraged to report symptoms of sexually transmitted infections (STIs) so that they can be treated. The risk of acquiring HIV through sexual intercourse is increased if an STI (chlamydia, gonorrhea, etc.) is also present, so patients should not have sex (even protected sex) until the STI is successfully treated [17].

Condoms

One very important component of safer sex practices includes the use of condoms. But be aware that not all condoms are effective at preventing the transmission of HIV. And condoms may not work if they are improperly stored and used.

There are several types of condoms: latex (synthetic), lambskin (of animal origin), polyisoprene (synthetic), and polyurethane (synthetic). Latex condoms should be recommended to protect against HIV and STIs. Lambskin condoms should not be used as they have small holes in them and don't protect against HIV and STIs. Polyurethane or polyisoprene condoms are a good substitute for latex condoms for patients with a latex allergy, but they break more easily than latex condoms. Female condoms are made of nitrile. When used properly in the vagina, female condoms seem to prevent HIV and STIs as well as latex condoms. It is not known how effective female condoms are if used by men or women for anal sex [17].

Condoms are considered highly effective if used correctly and consistently [17]. It's recommended to use lubricants with condoms, to prevent them from breaking. Male latex condoms should only be lubricated with water- or silicone-based lubricants; they should not be lubricated with oil-based products. For instance, patients should not use Vaseline, mineral oil, shortening, or other vegetable oils as lubricants when using latex condoms. Oil-based lubricants can weaken the latex membrane and cause it to break. On the other hand, any type of lubricant can be used with nitrile female condoms [17].

Patients should use a lubricated condom that is within the expiration date, and they should store condoms in a cool, dry place, not in their wallet or in the glove compartment of their car. Patients need to understand the correct way to use a condom. You can refer patients to the CDC's website for more information on correct use of condoms. You can also print out patient fact sheets that cover the correct use of male (sometimes called external) or female (sometimes called internal) condoms from the CDC to provide to patients [18,19].

Nonoxynol-9, a commonly used spermicidal agent, does NOT protect against HIV virus or other STIs. In fact, nonoxynol-9 can increase the risk of HIV transmission [20].

Sharing needles, syringes, or other drug injection equipment, such as cookers, increases the risk of getting or transmitting HIV and other bloodborne infections. In addition, substance use disorder can alter a person's judgment and possibly increase the chance that a person engages in unsafe sex practices [21]. When under the influence of drugs or alcohol, people may be more likely to engage in risky sexual behaviors, such as unprotected sex, sex with multiple partners, or trading sex for drugs [21].

The most effective way to reduce the risk of getting or transmitting HIV through injection drug use is to stop injecting drugs. However, this may not be possible for some patients. Patients engaging in injection drug use should be educated on the availability of drug treatment programs and referred to a provider who can help get the process started. More information on drug treatment programs and other resources that can help these individuals can be found on the Substance Abuse and Mental Health Services Administration (SAMHSA) website [22].

For people who are not willing or able to stop injecting drugs, there are some "safer" practices [23]:

HIV is a bloodborne pathogen. Occupational Safety and Health Administration's (OSHA) Bloodborne Pathogens Standard was primarily developed for workers in hospitals, funeral homes, nursing homes, clinics, law enforcement agencies, emergency response organizations, and HIV/hepatitis B virus (HBV) research laboratories, but it does not provide a comprehensive list of jobs that it covers. Instead, it states that it covers all employees who could be "reasonably anticipated," as a result of performing their job duties, to have contact with blood and other potentially infectious materials [24]. Some examples of workers at risk include pharmacy staff, physicians, nurses, laboratory workers, ambulance workers, and dental workers.

Per OSHA, employers must provide a safe work environment. OSHA requires that employees who could come into contact with materials that may have HIV wear personal protective equipment, such as gloves, gowns, masks, and goggles; wash their hands with soap before and after putting on gloves; and dispose of needles and other sharps properly in a sharps container. To prevent needle sticks, avoid bending or recapping needles or use needleless devices [25]. These strategies are known as "universal precautions." Be sure to always follow your company's policies and training requirements around bloodborne pathogens and infection control.

What is pre-exposure prophylaxis? How often do you interact with patients who are receiving pre-exposure prophylaxis? Which patients should receive pre-exposure prophylaxis? What regimens are used for pre-exposure prophylaxis?

Taking antiretrovirals daily BEFORE someone has HIV is called PRE-exposure prophylaxis (PrEP). The goal of PrEP is to reduce the risk of acquiring HIV. The CDC and United States Preventative Services Task Force (USPSTF) recommend offering PrEP to high-risk patients to reduce the development of new cases of HIV [26,27]. Oral once-daily emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (Truvada) or emtricitabine 200 mg/tenofovir alafenamide 25 mg (Descovy) are available options for PrEP for high-risk adults and adolescents weighing at least 77 pounds (35 kilograms) [27,28]. Emtricitabine/tenofovir alafenamide PrEP is only approved for men or transgender women who have sex with men. More data are needed before it can be used in other high-risk populations (e.g., individuals at risk of HIV from receptive vaginal sex) [27]. Injectable cabotegravir (Apretude) is another option for adults and adolescents weighing at least 77 pounds (35 kilograms) who report sexual behaviors that place them at substantial ongoing risk for HIV exposure. This gluteal intramuscular injection is given as two initial injections administered one month apart, and then one injection is given every two months thereafter. Injections must be given by a healthcare provider [27,29].

People at high risk of HIV infection may include persons [26,27]:

Be aware that some patients may request PrEP because of specific concerns about acquiring HIV; however, they may not feel comfortable reporting their sexual or injection behaviors to their healthcare provider. For this reason, it's recommended to provide PrEP to patients who request it after an attempt is made to assess their sexual or injection behaviors [27].

Some states allow pharmacists to provide PrEP through a protocol or collaborative practice agreement. If your pharmacy is involved in furnishing PrEP to patients, work together as a team to help streamline this process. For example, pharmacy technicians can help support pharmacists by developing a system for efficient documentation, billing, patient follow-up, etc.. If your pharmacy isn't able to provide PrEP to patients without a prescription from a prescriber, pharmacy teams can still play an active role in screening and referring patients who are likely to benefit.

Patients taking PrEP may experience side effects, including diarrhea, nausea, abdominal pain, flatulence, headache, and weight loss. These side effects usually go away within a few days to weeks [27,30,31,32].

There are some data to support a different dosing strategy (not taking PrEP once every day) with emtricitabine/tenofovir disoproxil fumarate for PrEP, but only in men who have sex with men infrequently. This other dosing strategy is called on-demand dosing, or "2-1-1" dosing. With on-demand dosing, two emtricitabine/tenofovir disoproxil fumarate tablets are taken from two to 24 hours BEFORE sexual exposure, followed by one emtricitabine/tenofovir disoproxil fumarate tablet taken 24 hours after the first two tablets were taken, and then one more tablet taken 48 hours after the first two tablets were taken [33,34]. This dosing strategy may be more complex to adhere to for some compared to daily dosing. More data are needed before it can be routinely recommended.

PrEP is not appropriate for everyone. For example, patients who already have HIV are not appropriate candidates. Since meds used for PrEP are the same meds used in HIV treatment regimens, patients who have HIV may develop drug resistance (the virus could start to resist the effects of the meds) if they take PrEP. This could negatively impact the efficacy of preferred HIV regimens and limit the options available for the patient. Because of this, screening for HIV is recommended prior to starting PrEP and every three months during therapy (or every two months for patients getting injectable cabotegravir) [27,30]. Expect patients to be limited to a 90-day supply, in order to ensure appropriate monitoring is completed prior to continuing with PrEP therapy.

Let's go back to Elliot. He is a 35-year-old male patient who has no known chronic medical conditions. His social history is significant for occasional alcohol consumption. He denies smoking or illicit drug use. He reports having unprotected sex with multiple male partners over the last six months.

Is PrEP appropriate for Elliot? If so, what regimen would you expect to be started? What test(s) should be done prior to starting PrEP?

What is postexposure prophylaxis? When is postexposure prophylaxis used? How long should patients take postexposure prophylaxis? What regimens have you seen used for postexposure prophylaxis?

After someone is potentially exposed to HIV, postexposure prophylaxis (also called PEP, nPEP [nonoccupational PEP], oPEP [occupational PEP]) can be used to reduce the risk of developing HIV. PEP is different than PrEP. PEP is only used in emergency situations. It is to be taken for a short period of time (28 days) after a possible exposure to HIV, and unlike PrEP, is not to be taken long-term. PEP is not 100% effective. However, to maximize the benefit, quick access to PEP is very important. PEP needs to be started as soon as possible, usually no later than 72 hours after a possible exposure [35; 36; 37].

Follow your facility policies and procedures to handle any occupational exposures, such as if a healthcare worker has a needlestick. Listen and watch for patients who may need nPEP after a nonoccupational exposure. Patients should be promptly referred for evaluation and possible treatment, or if your facility allows, follow your company policies and procedures to evaluate risk and provide nPEP by protocol.

PEP is recommended if the source patient has HIV and there was exposure to blood or body fluids that poses substantial risk, such as sharing a needle. It gets more complicated if the HIV status of the source patient is not known. During these situations, the risk of HIV transmission needs to be assessed to determine if PEP is appropriate. For example, risk is high with receptive anal sex, much lower with vaginal sex, and negligible from oral sex with no visible blood [35,36]. PEP should not be delayed while waiting for HIV test results and can be discontinued if test results come back saying the source patient does not have HIV.

For most patients weighing at least 88 pounds (40 kg) who need PEP and have normal kidney function (creatinine clearance [CrCl] 60 mL/min or greater), recommended options include [35; 36; 37; 38]:

PLUS

Be aware that for now, there are not enough data to recommend tenofovir alafenamide-containing products for PEP.

If assistance is needed in selecting or assessing a PEP regimen, such as for a pregnant patient, children, or patients with reduced kidney function, an infectious disease expert should be consulted. For example, infectious disease experts can be reached at the University of California San Francisco's National Clinical Consultation Center [35,39,40]. And, as with any medication used for HIV, be sure to screen for drug-drug interactions [41]. For example, patients taking dolutegravir should avoid or separate their dose from cations (magnesium, etc.) and avoid CYP3A4 inducers (phenytoin, etc.) as these may decrease dolutegravir levels [41].

Patients receiving PEP should be advised to engage in safer practices to reduce HIV risk (condoms, clean syringes, etc.). Develop a system to follow up with patients who pick up a prescription for PEP to ensure adherence. Watch for patients getting multiple courses of PEP. If patients have ongoing risks after completing PEP, it may be appropriate for them to receive PrEP for long-term HIV prevention, rather than repeat courses of PEP.

The first stage is the acute infection. Acute HIV infection usually develops within about two to four weeks after being exposed to HIV. During the acute infection stage, some people have flu-like symptoms (fever, headache, rash, etc.). During this time, the HIV virus rapidly multiplies and spreads throughout the body. The virus attacks and destroys the infection-fighting CD4 cells of the immune system. During the acute HIV infection stage, HIV virus levels in the blood are very high, increasing the risk of transmission [42].

The second stage of HIV infection is chronic HIV infection. This stage can also be referred to as asymptomatic HIV infection or clinical latency. During the chronic HIV stage, the HIV virus continues to multiply in the body but at very low levels. People with chronic HIV infection may appear asymptomatic, without any HIV-related symptoms. Without ART, chronic HIV infection usually advances to AIDS in ten years or longer. However, it is possible that in some people it may advance faster. People taking ART may be in the chronic HIV infection stage for several decades. It is still possible to transmit HIV to others during this stage. However, people who maintain an undetectable viral load with ART essentially have no risk of transmitting HIV to a partner through sex [42].

The third and most severe stage of HIV is AIDS. Because over time HIV has caused severe damage to the immune system, the body is no longer able to fight off opportunistic infections. Opportunistic infections are infections and infection-related cancers that are more common or are more severe in people with a weakened immune system than in people with a healthy immune system. People with HIV are diagnosed with AIDS if they have a CD4 count of less than 200 cells/mm³ or if they develop certain opportunistic infections (i.e., "AIDS-defining conditions"). Individuals diagnosed with AIDS usually have a high viral load and are easily able to transmit HIV to others. Without treatment, people with AIDS typically are only able to survive about three years [42].

Opportunistic Infections

Opportunistic infections can be caused by viruses, bacteria, fungi, and parasites. Many opportunistic infections (certain forms of pneumonia, tuberculosis [TB], etc.) are considered AIDS-defining conditions and are included in the CDC's list of diagnostic criteria for AIDS [43]. AIDS-defining conditions are infections and cancers that are life-threatening in people with HIV [44].

CDC considers the following illnesses to be AIDS-defining conditions [45]:

• Candidiasis of the esophagus, bronchi, trachea, or lungs (but NOT the mouth [thrush])

• Cervical cancer, invasive

• Coccidioidomycosis, disseminated or extrapulmonary

• Cryptococcosis, extrapulmonary

• Cryptosporidiosis, chronic intestinal (greater than one month’s duration)

• Cytomegalovirus disease or CMV (other than liver, spleen, or nodes)

• Cytomegalovirus retinitis (with loss of vision)

• Encephalopathy, HIV related

• Herpes simplex: chronic ulcer(s) (lasting more than one month); or bronchitis, pneumonitis, or esophagitis

• Histoplasmosis, disseminated or extrapulmonary

• Isosporiasis, chronic intestinal (lasting more than one month)

• Kaposi sarcoma

• Lymphoma, Burkitt’s (or equivalent term)

• Lymphoma, immunoblastic (or equivalent term)

• Lymphoma, primary, of brain

• Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary

• Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)

• Mycobacterium, other species, or unidentified species, disseminated or extrapulmonary

• Pneumocystis pneumonia (PCP)

• Pneumonia, recurrent

• Progressive multifocal leukoencephalopathy

• Salmonella septicemia, recurrent

• Toxoplasmosis of brain

• Wasting syndrome due to HIV

The best protection against opportunistic infections is prevention. Patients who have HIV should do the following to reduce their risk of opportunistic infections [44]:

• Avoid eating raw or undercooked foods

• Safely handle and care for pets or animals. Pets can carry diseases that don't usually affect people with a healthy immune system but may pose a risk to a patient with HIV. Patients should avoid direct contact with pet feces (i.e., wear gloves), wash their hands after handling the pet (especially before eating), control fleas, avoid getting scratched or bitten, and keep cats indoors and clean their litter boxes daily (using gloves) [46].

• Stay current on vaccinations. The following are examples of inactivated vaccines that are routinely recommended for patients with HIV who meet age requirements per the Advisory Committee on Immunization Practices (ACIP) recommendations: influenza, COVID-19, hepatitis A, hepatitis B, human papillomavirus (HPV), meningococcal, pneumococcal, zoster, and tetanus, diphtheria, and pertussis (Tdap). Additional vaccines may be recommended for patients with HIV based on previous vaccination, risk factors for other diseases, or certain HIV-related factors. Refer to the most current CDC immunization schedules [47,48,49].

• Travel safely. For instance, patients need to make sure they have enough of their medications, have the appropriate vaccines for international travel, continue to eat and drink safely and avoid direct contact with animal waste, etc. Share the CDC's "Traveling with HIV" fact sheet for safe travel abroad for people living with HIV [50].

Sometimes medications are used in patients at high risk for opportunistic infections, such as if their CD4 count falls below a certain number. The U.S. National Institutes of Health (NIH) Office of AIDS Research maintains a regularly updated guideline for the prevention and treatment of opportunistic infections in patients with HIV [51]. Below are some examples of "chemoprophylaxis" (i.e., the use of medications to prevent disease) regimens that you may see used [51]:

• Azithromycin 600 mg PO twice weekly or 1,200 mg PO once weekly to prevent Mycobacterium avium complex

• Fluconazole 400 mg PO once daily to prevent coccidioidomycosis

• Itraconazole 200 mg PO once daily to prevent histoplasmosis

• Isoniazid 300 mg PO daily plus rifampin 600 mg PO daily plus pyridoxine 25 to 50 mg PO daily for three months for the treatment of latent TB infection (to prevent the development of TB disease)

• TMP/SMX 160/800 mg PO once daily to preventPneumocystispneumonia andToxoplasma gondiiencephalitis

Antiretroviral drugs are the cornerstone of HIV treatment. They work on different parts of the HIV lifecycle. There are more than 30 FDA-approved antiretroviral drugs in several different classes available to treat HIV infections. ART should be initiated in all persons with HIV, immediately after diagnosis (or as soon as possible). ART helps to reduce morbidity and mortality and to prevent the transmission of HIV to others. Patients should be educated on the benefits of ART and the importance of adherence. They should also be encouraged to take an active role in their treatment [53].

The classes of FDA-approved antiretrovirals include [53]:

• NucleoSIDE/nucleoTIDE reverse transcriptase inhibitors (NRTIs)

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

• Protease inhibitors (PIs)

• Integrase strand transfer inhibitors (INSTIs)

• Fusion inhibitor

• CCR5 antagonist

• CD4 T lymphocyte (CD4) post-attachment inhibitor

• gp120 attachment inhibitor

• Capsid inhibitor

In addition, two drugs (ritonavir and cobicistat) are used as pharmacokinetic enhancers, or more commonly referred to as "boosters," to help improve the effects of protease inhibitors and the INSTI elvitegravir [53].

Providing details about dosing and all of the potential adverse effects of every single antiretroviral is beyond the scope of this course. Therefore, while reviewing each class of medications, significant adverse effects and important clinical pearls will be reviewed. If interested, you can refer to preferred drug information sources or product labeling for dosing and a complete review of potential adverse effects associated with individual products.

NucleoSIDE/NucleoTIDE and Non-Nucleoside Reverse Transcriptase Inhibitors (NRTIs and NNRTIs)

Examples of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) include:

NRTIs

• abacavir* (ABC, Ziagen)

• emtricitabine* (FTC, Emtriva)

• lamivudine* (3TC, Epivir; do NOT confuse with Epivir HBV as it is a different, lower dose of lamivudine and indicted for hepatitis B, not HIV)

• tenofovir alafenamide* (TAF, Vemlidy)

• tenofovir disoproxil fumarate* (TDF, Viread)

• zidovudine* (AZT, ZDV, Retrovir)

NNRTIs

• doravirine* (DOR, Pifeltro)

• efavirenz* (EFV, Sustiva)

• etravirine (ETR, Intelence)

• nevirapine (NVP, Viramune)

• rilpivirine* (RPV, Edurant)

*Also available in one or more combination products. See list below.

NRTIs and NNRTIs inhibit HIV reverse transcriptase, an enzyme responsible for viral replication early in the viral life cycle.

Adverse effects for the nucleoSIDE reverse transcriptase inhibitors vary but include pancreatitis (inflammation of the pancreas), bone marrow toxicity, peripheral neuropathy (nerve pain), and liver toxicity. Although rare, all of the nucleoside analogues carry warnings about potentially fatal lactic acidosis (a buildup of lactic acid in the blood, which can cause the blood to get too acidic) and severe hepatomegaly (liver enlargement) with steatosis (buildup of excess fat in liver cells). Abacavir also carries a boxed warning about a potentially fatal hypersensitivity reaction (nausea, vomiting, diarrhea, headache, fever, rash, gastrointestinal distress, malaise, fatigue, respiratory symptoms) that can occur in approximately 5% to 8% of patients during the initial six weeks of therapy. Genetic testing is used to predict the likelihood of the abacavir hypersensitivity reaction. Patients who test positive for the HLA-B*5701 gene are likely to be allergic to abacavir, so abacavir should be avoided in these patients [28].

NucleoTIDE reverse transcriptase inhibitors tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) carry similar black box warnings about lactic acidosis and hepatomegaly. Both forms of tenofovir seem to be equally efficacious, but there are some side effect differences. One difference is that TAF is less likely to impair renal function or decrease bone mineral density. However, it's too soon to say if patients taking a regimen containing TAF instead of TDF have fewer kidney issues or fractures since these adverse effects are rare with either tenofovir formulation [54]. Another difference is that TAF has been associated with higher rates of triglyceride (a type of fat) elevation and weight gain compared to TDF [53].

Kidney function tests should be assessed before starting TAF- or TDF-containing regimens and monitored every six months or sooner if there are renal abnormalities. Biannual, or more frequent (every three to six months), monitoring of kidney function is recommended, as Fanconi syndrome (a rare kidney disorder where essential minerals and nutrients are eliminated rather than reabsorbed) is a potential rare side effect with these therapies [27,28,55].

Be especially vigilant when coming across drug-drug interaction alerts with NNRTIs. They have the potential for drug interactions due to their effects on cytochrome P450 enzymes (the enzymes involved in the metabolism, or breakdown, of drugs). Enzyme inducers increase the breakdown of drugs metabolized by the same enzyme system, causing reductions in their blood levels and efficacy. Conversely, enzyme inhibitors reduce the breakdown of drugs so that levels can increase, sometimes to toxic levels. Nevirapine is an enzyme inducer and is also able to induce its own metabolism since it's also a substrate (a substance which an enzyme acts on) of the CYP3A4 enzyme. Etravirine and efavirenz are both inhibitors and inducers, but efavirenz appears to act more as an inducer than an inhibitor. Doravirine and rilpivirine are neither a P450 inducer nor an inhibitor, but are a P450 substrate and have several drug interactions [56].

Protease Inhibitors (PIs)

Examples of PIs include:

• atazanavir (ATV, Reyataz; ATV/c, Evotaz^α)

• darunavir* (DRV, Prezista; DRV/c, Prezcobix^α)

• lopinavir/ritonavirα (LPV/r, Kaletra)

• ritonavir† (RTV, Norvir)

*Also available in one or more combination products. See list below.

^αFormulated in combination with cobicistat or ritonavir to boost concentration of the PI.

†Although ritonavir is a PI, it's generally used as a booster in HIV treatment regimens.

PIs block protease activity that is essential for viral replication late in the virus life cycle.

Boosters such as ritonavir or cobicistat are often used to inhibit the metabolism of the concomitant PI and maximize or "boost" the blood levels of the co-administered PI. Major advantages of "boosted" PI combination therapy include higher PI levels with the potential to overcome viral resistance; lower drug dosages, which require fewer pills; and less frequent dosing. Be sure to include a "Take with food" auxiliary label on prescriptions for ritonavir, since it must be taken with food for optimal absorption [53]. The exception to this is for lopinavir/ritonavir (Kaletra) tablets, which can be taken with or without food; however, the oral solution should be taken with food [28].

All of the PIs have precautions about causing liver impairment or worsening existing liver impairment [28]. There are other adverse effects with PIs that may negatively impact adherence. A big cosmetic concern for patients is abnormal fat redistribution syndrome (lipodystrophy). It consists of two distinct syndromes: lipohypertrophy, or central body fat accumulation characterized by a "dorsal fat pad," increased abdominal girth, and increased breast size in women; and lipoatrophy, or peripheral wasting (loss of fat) of the face, buttocks, and extremities (arms, legs, etc.). The lipohypertrophy is likely due to the protease component while the lipoatrophy is more likely caused by an NRTI used in combination. Fat redistribution is seen less frequently with darunavir. PIs may also increase the risk for diabetes (and can worsen diabetes in people who already have it), high cholesterol, and possibly heart disease.

Like NNRTIs, PIs are also inhibitors and inducers of the cytochrome P450 system. Ritonavir is the most potent inhibitor. Although interactions with drugs metabolized by the cytochrome P450 system are a problem, the interaction can be useful (like when using ritonavir for boosting). Drug interactions are complicated with HIV regimens, and a thorough review with a pharmacist is recommended prior to adding any new medications to a patient's profile.

Integrase Strand Transfer Inhibitors (INSTIs)

Examples of INSTIs include:

• bictegravir (BIC, only available as a combination product with emtricitabine and tenofovir alafenamide; Biktarvy)

• cabotegravir* (CAB, Vocabria, Apretude^ꞵ)

• dolutegravir* (DTG, Tivicay)

• elvitegravir (EVG, only available as part of combination meds which also contain the booster cobicistat [e.g., Genvoya, Stribild])

• raltegravir (RAL, Isentress, Isentress HD)

*Also available in one or more combination products. See list below.

^ꞵIndicated for PrEP only.

INSTIs block the integrase enzyme needed for viral DNA to enter into the host cell's nucleus, where it can start to replicate. Expect many patients to start HIV regimens with INSTIs. They have fewer drug-drug interactions and are often better tolerated than PIs or NNRTIs. However, they have been associated with weight gain.

But be aware, oral absorption of all INSTIs can be reduced by many commonly used minerals. And dosing to avoid this interaction can be complicated and confusing. For example, patients taking antacids or other products containing aluminium or magnesium should take these at least two hours after or six hours before bictegravir-containing regimens [53]. Bictegravir-containing regimens can be administered simultaneously with products containing calcium or iron if being taken with food. However, administration of bictegravir-containing regimens under fasting conditions simultaneously with, or two hours after, products containing calcium or iron is not recommended [53]. Since antacids, calcium supplements, and iron products are often obtained without a prescription, be sure to gather information on all over-the-counter products (medications, supplements, herbals, etc.) a patient is taking, and add this to their patient profile so the pharmacist can review.

Since elvitegravir must be combined with the booster cobicistat, it is subject to more drug interactions than the other INSTIs [53]. Also, raltegravir is generally less preferred than bictegravir and dolutegravir because it's less convenient for patients to take [53]. It is not available in a combination pill and raltegravir-containing regimens have a higher pill burden than regimens containing bictegravir or dolutegravir [53].

Although cabotegravir is available as an oral dosage form (Vocabria), its intended use is as "lead-in" therapy along with rilpivirine (Edurant) [28]. These oral meds should be taken together for one month before startingCabenuvawhich is an injectable combination of cabotegravir and rilpivirine [28]. This lead-in therapy is recommended in order to assess the tolerability of cabotegravir prior to administration of the injection.Cabenuvais an intramuscular (IM) injection that must be given as two IM gluteal injections (one vial of cabotegravir and one vial of rilpivirine) by a healthcare provider [28]. It is either given once a month or once every two months, depending on how it's dosed. But keep in mind that cabotegravir is not for initial therapy as it hasn't been studied in this population [28,53]. Expect it to be reserved for patients who want less frequent med dosing and who have achieved viral suppression on an ART regimen for at least three months, are stable (e.g., don't have active hepatitis B infection), are not pregnant or planning to become pregnant, and have no prior virologic failures and no known or anticipated risk of resistance to cabotegravir or rilpivirine [28,53].

Other Classes of Antiretrovirals

At the time of publication, the other available classes of antiretrovirals include:

• Fusion inhibitor, which blocks the fusion of HIV with CD4 cells to prevent cell entry.

  • enfuvirtide (T-20, Fuzeon)

• CCR5 antagonist, which blocks a CCR5 co-receptor required for HIV cell entry.

  • maraviroc (MVC, Selzentry)

• CD4 post-attachment inhibitor, which binds to CD4 cells to interfere with post-attachment steps required for HIV to enter into host cells.

  • ibalizumab-uiyk (IBA, Trogarzo)

• gp120 attachment inhibitor, which binds to the gp120 protein on the outer surface of HIV, preventing HIV from entering CD4 cells.

  • fostemsavir (FTR, Rukobia)

• Capsid inhibitor, which interferes with the HIV capsid, a protein shell that protects HIV’s genetic material and enzymes needed for viral replication.

  • lenacapavir (LEN, Sunlenca)

There are a few other classes of antiretrovirals available for use in the treatment of HIV infection. The classes include a fusion inhibitor, CCR5 antagonist, a CD4 post-attachment inhibitor, a gp120 attachment inhibitor, and a capsid inhibitor. These are currently NOT recommended as initial therapy and are much less commonly used than the other available classes. Two of these meds are not currently available in an oral dosage form. Enfuvirtide is given as a subcutaneous injection. Ibalizumab is given as an intravenous infusion. Both of these options have only been studied in patients failing other treatments. Maraviroc is available as an oral formulation, but has not shown benefit compared to other recommended regimens and requires a blood test before prescribing to make sure it will be effective [53]. Fostemsavir is also available as an oral tablet. It may be effective in achieving viral suppression in patients with multidrug resistant HIV, but it was only studied in a very small number of patients with virologic failure [53]. Lenacapavir is available in both an oral tablet and subcutaneous injection, but initiation dosing options must always include at least one dose of the subcutaneous injection, and ongoing maintenance dosing is every six months with the injection only. It's also only approved for "heavily treatment-experienced" adults with multidrug-resistant infection.

Combination Products

There are several fixed-dose, multi-class, combination products available for the treatment of HIV. These combinations are a great advancement in the treatment of HIV, offering simplified dosing strategies. Often, these combinations help simplify dosing to just one tablet once a day.

Examples of combination products used in the treatment of HIV include:

• abacavir/dolutegravir/lamivudine (Triumeq)

• abacavir/lamivudine (Epzicom)

• bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy)

• cabotegravir/rilpivirine (Cabenuva)*

• darunavir/cobicistat (Prezcobix)

• darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza)

• dolutegravir/lamivudine (Dovato)

• dolutegravir/rilpivirine (Juluca)

• doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo)

• efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla)

• efavirenz/lamivudine/tenofovir disoproxil fumarate (Symfi, Symfi Lo)

• elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya)

• elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild)

• emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey)

• emtricitabine/rilpivirine/tenofovir disoproxil fumarate (Complera)

• emtricitabine/tenofovir alafenamide (Descovy)

• emtricitabine/tenofovir disoproxil fumarate (Truvada)

• lamivudine/tenofovir disoproxil fumarate (Cimduo)

*Unlike all of the other products on this list which are oral medications, this is an IM injection.

Let's go back to Elliot who is a 35-year-old male patient at risk for HIV due to having unprotected sex with multiple male partners over the last six months.

An HIV point-of-care test was performed and was reactive for HIV. Elliott was referred to a provider who ordered an HIV confirmatory test which was positive. Therefore, he was not offered PrEP. He is agreeable to starting ART. He is HLA-B*5701 positive and he does not have hepatitis B infection. Which regimen(s) would you expect to see prescribed for his initial therapy?

Most initial regimens for someone who has never been treated with ART (i.e., "treatment naive") will contain two NRTIs combined with a third medication from one of three drug classes: INSTI, NNRTI, or PI with a booster (cobicistat or ritonavir). There is also one two-drug regimen (dolutegravir plus lamivudine) that may be recommended as a first-line option for initial therapy in some patients with HIV.

In general, INSTI-based regimens are preferred because they are highly effective, well tolerated, and have fewer drug interactions compared to PI-based regimens. However, patients with a history of having received the cabotegravir long-acting injectable for PrEP will require INSTI genotypic resistance testing before initiating INSTI therapy. This is because drug levels of long-acting cabotegravir may be present in some individuals for up to four years, and this persistent suboptimal drug exposure may select for INSTI-resistant virus [53].

Expect to see one of the following recommended combinations as initial therapy for treatment-naive patients [53]:

There are additional regimens that may be used as initial therapy in certain clinical situations. But these regimens have some disadvantages compared to the preferred regimens listed above or have less supporting data. The full list can be found within the guidelines, but some examples of these regimens include [53]:

Some antiretroviral components or regimens are NOT recommended as initial therapy for different reasons, such as inferior efficacy, more side effects, or higher pill burden when compared to preferred therapies. Examples of components or regimens that are NOT recommended include [53]:

Be aware of special considerations when caring for patients with HIV.

Drug-Drug Interactions

Many ART regimens have the potential for drug-drug interactions. Pharmacists should always review drug-drug interaction alerts that appear when filling prescriptions for HIV meds. In addition, patients will need to be counseled by the pharmacist on the importance of asking about drug-drug interactions prior to starting any new medications.

There are some HIV medication-specific drug-drug interaction resources that you may find useful [41,57,58]:

• University of Liverpool, HIV drug interactions

• Johns Hopkins University, HIV Clinical Guidelines Program, Drug-drug interactions section

• U.S. Federal HIV/AIDS guidelines, Drug-drug interactions section

HIV Treatment in Patients of Childbearing Age or Pregnancy

Patients of childbearing potential will need to take a pregnancy test before starting antiretrovirals and use contraception during therapy. But some antiretrovirals have significant interactions with hormonal contraceptives. For example, many of the protease inhibitors, efavirenz, and elvitegravir/cobicistat-based regimens have drug-drug interactions with combined oral contraceptives. On the other hand, several studies have shown that etravirine, rilpivirine, and nevirapine did not significantly affect hormone levels in individuals with HIV who were using combined oral contraceptives. There are a few ways these drug-drug interactions between antiretrovirals and contraceptives can be addressed. Patients can be switched to an alternative or additional effective contraceptive method to help prevent unplanned pregnancy. Or they can be switched to an antiretroviral regimen that does not interact with hormonal contraceptives [53].

HIV can be passed to the fetus in utero during pregnancy, during childbirth, or through breastfeeding. All pregnant patients, particularly those with any risk factors for HIV, should be routinely tested for HIV because effective ART can reduce the risk of transmission to the newborn to less than 1%. If an HIV rapid test or HIV viral load is positive at the time of delivery, antiretroviral therapy should be started as soon as possible, even before confirmation testing. This is because the benefits of preventing mother-to-child transmission during childbirth outweigh the risks of antiretroviral toxicity [59].

Expert advice regarding ART and HIV care for the pregnant mother and the child can be obtained 24 hours, seven days a week, by calling the National Clinician Consultation Center's Perinatal HIV Hotline at 888-448-8765 [60]. Healthcare providers caring for pregnant women exposed to antiretrovirals are advised to report prenatal exposures to the Antiretroviral Pregnancy Registry by calling 800-258-4263 or making a submission online [61].

Florida's Special Provisions for Pregnant Patients [62]

In Florida, physicians and midwives who care for pregnant patients are required to provide HIV testing (and other STI testing) to the patient and counsel the patient on the availability of treatment if they test positive. The provider must tell the patient that they will be tested and of their right to refuse. If the patient objects, a reasonable attempt must be made to obtain a written statement of objection, signed by the patient, and placed in the medical record.

Hospitalized Patients with HIV

Be prepared to tackle formulary issues with HIV meds. Familiarize yourself with the non-formulary process, policies on interchanging HIV meds, and polices on patients using home supplies of medications. When taking medication histories, make sure to document all meds the patient is taking including the dosage form, how they take it, and when they took their last dose. Be sure to double-check brand and full generic names of HIV med combos, to help prevent mix-ups. For example, dolutegravir/lamivudine (Dovato) could be mistaken for abacavir/dolutegravir/lamivudine (Triumeq), since they have similar ingredients.

Complete HIV regimens should be started within 24 hours of admission. Don't be surprised if the patient has to be switched from their combo antiretroviral pill to individual components while in-house. If the full regimen cannot be started or continued for any reason, it's best to hold the entire regimen. Using partial regimens can lead to resistance. For example, it's better to wait for a supply of Biktarvy than to start emtricitabine and tenofovir without bictegravir. In scenarios where a non-formulary med is used, you'll want to monitor the stock closely since they may not get reordered the same way as formulary meds.

Pay extra attention to HIV meds during medication reconciliation. Up to 86% of hospitalized patients with HIV experience at least one medication error. These errors most commonly involve antiretroviral regimens, dosing, scheduling, and drug-drug or drug-food interactions [65].

Use the toolbox, Medication Adherence Strategies (link provided in the Additional Resources section) to help patients stick to their regimen.

A patient's willingness and readiness to adhere to drug therapy is critical for antiretroviral success and to prevent the development of drug resistance and regimen failure. Help patients identify tools to assist them with being adherent to their meds, such as a pillbox, calendar reminders, or medication adherence apps. Be on the lookout for nonadherence, such as if a patient is refilling a med late or hasn't picked up a filled medication. If cost is an issue, help patients explore patient assistance programs from drug manufacturers or work with your local department of health to identify additional financial resources, such as through the Ryan White HIV/AIDS Program [66,67].

Pharmacists should look for ways to simplify regimens, such as with fixed-dose combinations, once-daily regimens, and "boosted" protease therapy (fewer daily doses, fewer pills per dose, etc.), and minimize drug interactions and side effects to help improve adherence.

The obligation of healthcare workers to provide services for all patients who seek care is an issue that has come up in the past for patients with HIV. Studies have shown that some healthcare workers may be reluctant to care for patients with HIV or AIDS because of the following reasons:

When helping to care for patients with HIV/AIDS, identify your own prejudices. By identifying your personal prejudices, you can more easily work on resolving these prejudices to provide care to patients with HIV.

Be aware that refusing to provide care or services to a patient living with HIV is discrimination and likely a violation of your company's policy, in addition to federal and local laws [68].

The Golden Rule approach is an excellent model to use in caring for patients with HIV. The Golden Rule is, "Do unto others as you would have them do unto you."