An Update on the Current Treatment of HIV

Release Date: August 1, 2009

Expiration Date: August 31, 2011

FACULTY:

Ami Teague, PharmD, BCPS, AAHIVE
Assistant Professor of Pharmacy Practice,
McWhorter School of Pharmacy,
Samford University, Birmingham, Alabama

GOAL:

To familiarize pharmacists with the current treatment options for human immunodeficiency virus, the adverse effects and main drug interactions with antiretrovirals, and the appropriate monitoring parameters of therapy.

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Among the more than 20 chemical entities available to treat human immunodeficiency virus (HIV), there are six different classes of medication with different mechanisms of action. Through the use of combinations of drugs from these different classes, patients living with HIV can have very promising futures.

The Department of Health and Human Services (DHHS) provides guidelines on when and how to treat HIV.¹ Though the idea of when to start antiretroviral therapy has changed over the years, recent data show that patients benefit when medication is initiated before the CD4 (antigenic marker on helper T cells) count falls below 350 cells/mm³.² Originally the thought was to treat as soon as possible, but as long-term adverse effects and resistance to antiretrovirals were identified, researchers began to look further into the benefits and risks of starting treatment at different clinical points. These clinical points include CD4 count and viral load, though less emphasis has been put on the viral load in recent guidelines. HIV-associated nephropathy (HIVAN) and pregnancy are also compelling indications to initiate antiretroviral treatment regardless of CD4 count. Other factors important in deciding when to treat include personal preference and the patient’s social history. Because adherence is critical, the patient must personally be ready to initiate therapy. Social aspects such as homelessness, addictions, unsupportive and/or unaware family and friends, and psychiatric illness should play a role in this decision.

Nucleoside Reverse Transcriptase Inhibitors

The first drug approved to treat HIV was zidovudine, a member of the nucleoside reverse transcriptase inhibitors (NRTIs). These medications are active once they are phosphorylated within the cell and inhibit the reverse transcriptase enzyme by mimicking naturally occurring nucleotides. Reverse transcriptase would normally allow for the conversion of viral RNA to DNA after the virus enters the host cell. This class of antiretrovirals is often referred to as the backbone of a regimen. The typical first-line regimens given to patients who have not been previously treated for HIV (treatment naïve) include two medications from this class. The DHHS guidelines recommend tenofovir and emtricitabine as the preferred NRTI backbone in treatment-naïve individuals.¹

Tenofovir is considered a part of the nucleoside reverse transcriptase class, but it differs from the others because it is a nucleotide (rather than nucleoside) and does not require phosphorylation to be active. Tenofovir is dosed once daily and is usually well tolerated by patients. It is coformulated with emtricitabine in a single tablet, which can be taken once daily. Tenofovir should be used cautiously in patients with renal dysfunction. There have been cases of acute increases in serum creatinine with administration of tenofovir as a result of acute tubular necrosis.³

Zidovudine, mentioned above, is known for its role in pregnancy. Because it has been studied in pregnancy with good outcomes, all women who are pregnant and are taking antiretrovirals should receive zidovudine as a part of their treatment regimen. In addition to its use during pregnancy, zidovudine is given intravenously to HIV-positive women during labor to decrease the risk of transmission of HIV to the baby during the delivery process. Neonates born to HIV-positive mothers are also given zidovudine liquid for the first 6 weeks of life.⁴ Following the above recommendations can decrease the risk of vertical transmission of HIV from mother to baby from almost one-third to close to 1%.

Abacavir is the only NRTI that does not require dosage adjustment in the presence of renal dysfunction. It also carries the risk of a hypersensitivity reaction (HSR). When a product that contains abacavir is dispensed, a warning card is provided to the patient. This card lists the signs and symptoms of this HSR, including fever, rash, and shortness of breath. Now, a test is available that can screen for patients at highest risk for experiencing abacavir hypersensitivity. HLA-B*5701 is a gene that was found to be associated with this HSR.⁵ Being HLA-B*5701 positive, however, does not guarantee a reaction. In patients who are found to be HLA-B*5701 positive, abacavir should be avoided and added to their allergy profiles. There has been some controversy surrounding the association with abacavir use and cardiovascular risk. The D:A:D Study Group showed a correlation between the use of abacavir within the previous 6 months and an increased risk of myocardial infarction in its observational cohort; however, a pooled analysis of clinical trials by the manufacturer of abacavir did not demonstrate an increased risk compared with controls.^6,7 Because the data are inconclusive, patients and providers must weigh the benefits and possible risks when initiating abacavir.

All medications in the NRTI class carry a black box warning for lactic acidosis. This is a rare but serious, and sometimes fatal, complication that has been found more likely with certain drugs in this class compared to others. The thymidine analogues stavudine and zidovudine, along with didanosine, are thought to carry a higher risk due to their increased mitochondrial toxicity. All antiretrovirals can cause the initial feeling of fatigue and headache, and many carry a degree of nausea potential. Lamivudine and emtricitabine, which are both cytosine analogues, should not be used together because they are essentially identical in action and resistance profile, and stavudine and zidovudine should not be used together because they compete for phosphorylation and are therefore antagonistic to each other. As with other disease states, medications with similar side-effect profiles should be used with caution. An example in the NRTI class would be the use of didanosine and stavudine, which in combination can cause an increase in risk of peripheral neuropathy and pancreatitis. Didanosine should be taken on an empty stomach as opposed to the other NRTIs, which can be taken without regard to food. It is wise to avoid using two NRTIs that are analogues of the same endogenous nucleotides in the same antiretroviral regimen. Besides the interaction between the two thymidine analogues, the adenosine analogues didanosine and tenofovir are involved in a drug interaction requiring dose adjustment, and also produce results that are suboptimal in relation to treatment response. TABLE 1 lists all marketed antiretrovirals, including those from the NRTI class, brand name, normal dosing, and the most common adverse effects associated with each.

Table 1
Antiretrovirals by Class
NAME	DOSAGE	COMMON ADVERSE EFFECTS
Nucleoside Reverse Transcriptase Inhibitors
Abacavir (Ziagen)	300 mg bid or 600 mg daily	Hypersensitivity reaction, headache, nausea
Didanosine (Videx EC)	400 mg daily	Pancreatitis, peripheral neuropathy
Emtricitabine (Emtriva)	200 mg daily	Hyperpigmentation of palms and soles of feet
Lamivudine (Epivir)	150 mg bid or 300 mg daily	Headache, nausea
Stavudine (Zerit)	40 mg bid	Peripheral neuropathy, lipoatrophy
Tenofovir (Viread)	300 mg daily	Nausea, flatulence, nephrotoxicity
Zidovudine (Retrovir)	300 mg bid	Nausea, anemia, myopathy
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz (Sustiva)	600 mg QHS	Vivid dreams, drowsiness
Etravirine (Intelence)	200 mg bid	Nausea, rash
Nevirapine (Viramune)	200 mg daily x 14 days, then 200 mg bid	Hepatotoxicity, rash
Protease Inhibitors
Atazanavir (Reyataz)	400 mg dailya 300 mg with 100 mg RTV daily	Hyperbilirubinemia, nephrolithiasis
Darunavir (Prezista)	800 mg with 100 mg RTV dailya 600 mg with 100 mg RTV bid	Rash, headache, nausea, diarrhea
Fosamprenavir (Lexiva)	1,400 mg bida 1,400 mg with 100-200 mg RTV dailya 700 mg with 100 mg RTV bid	Rash, nausea, diarrhea
Indinavir (Crixivan)	800 mg with RTV 100 mg bid	Nephrolithiasis, hyperbilirubinemia
Lopinavir/ritonavir (Kaletra)	800/200 mg dailya 400/100 mg bid	Nausea, diarrhea
Nelfinavir (Viracept)	1,250 mg bid	Diarrhea
Ritonavir (Norvir)	See other PIs	Nausea, diarrhea, paresthesias
Saquinavir (Invirase)	1,000 mg with RTV 100 mg bid	Nausea, diarrhea
Tipranavir (Aptivus)	500 mg with RTV 200 mg bid	Rash, nausea, diarrhea, headache, hepatotoxicity
CCR5 Inhibitor
Maraviroc (Selzentry)	150-600 mg bid	Rash, cough, fever, hepatotoxicity
Fusion Inhibitor
Enfuvirtide (Fuzeon)	90 mg (1 mL) SC bid	Injection-site reactions
Integrase Inhibitor
Raltegravir (Isentress)	400 mg bid	Nausea, headache, CPK elevation
Combination Products
Zidovudine and lamivudine (Combivir)		300/150 mg bid
Zidovudine, lamivudine, and abacavir (Trizivir)		300/150/300 bid
Lamivudine and abacavir (Epzicom)		300/600 mg daily
Tenofovir and emtricitabine (Truvada)		300/200 mg daily
Tenofovir, emtricitabine, and efavirenz (Atripla)		300/200/600 mg QHS
a Only for use in treatment-naïve patients. CPK: creatine phosphokinase; PI: protease inhibitor; QHS: every night; RTV: ritonavir; SC: subcutaneously.

Nonnucleoside Reverse Transcriptase Inhibitors

In a treatment-naïve patient, many times the NRTI backbone described above is paired with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI). The NNRTI class includes efavirenz, nevirapine, etravirine, and the rarely used delavirdine. These drugs work to inhibit reverse transcriptase but by a different mechanism than the above NRTIs. NNRTIs inhibit reverse transcriptase by binding directly to the enzyme adjacent to the active site. Efavirenz paired with tenofovir and emtricitabine has been manufactured into one pill that patients can take once daily, typically at bedtime. This particular combination provides for a very convenient regimen but is not optimal for all patients. The NNRTI class has a low resistance barrier, and around 5% of treatment-naïve patients may initially present with resistance to this class of medications because only a single mutation is required to confer resistance to three of the four drugs in this class, and these three medications exhibit cross resistance.⁸ The percentage of resistant antiretroviral-naïve virus may vary from one geographic region to another. NNRTIs are metabolized through the cytochrome P450 system and have many drug interactions.

The current guidelines recommend efavirenz as the preferred NNRTI for treatment-naïve patients.¹ Efavirenz is a mixed inducer/inhibitor of cytochrome P450 enzymes. It has a unique set of central nervous system side effects that includes drowsiness and vivid dreams. Because it typically causes sedation, it is dosed at bedtime. Increased fat intake around the time of administration increases the absorption of efavirenz and results in more intense side effects. For this reason, it is recommended that it be taken on an empty stomach or with a light, low-fat snack. It is the only antiretroviral that is a known teratogen and should be avoided in pregnant women or women of childbearing age who are not on adequate birth control. Another unique fact about efavirenz is that it may cause a false-positive cannabinoid drug test. This may be important in those patients with jobs that require drug screening/testing because a letter from the physician or pharmacy noting this possible lab interaction would disclose the patient’s HIV status. Like many other antiretrovirals, especially PIs, efavirenz may have a negative effect on a patient’s lipid profile.

Nevirapine is the only antiretroviral that is initiated at a lower dose and then later titrated up to the maintenance dose. Patients are instructed to take nevirapine once daily for the first 2 weeks of treatment before increasing the dosage to twice daily. Because nevirapine carries a risk of hepatotoxicity, laboratory tests are conducted to assess liver function before the dose is increased. These first 2 weeks of therapy are also used to monitor for rash since nevirapine has been known to cause Stevens-Johnson syndrome, a serious, life-threatening skin rash. Individuals with higher CD4 counts are at increased risk for hepatotoxicity with nevirapine. It is recommended that women with CD4 counts greater than 250 and men with CD4 counts greater than 400 not be initiated on nevirapine.¹

Only etravirine, the newest NNRTI, has a more extensive resistance profile; this means that it takes more than one mutation to cause resistance. However, the etravirine studies for FDA approval were not done in treatment-naïve patients, and as a result this medication is reserved for therapy in treatment-experienced patients and in combination with more than just the above-mentioned NRTI backbone. However, etravirine is contraindicated with the PIs atazanavir, tipranavir, and fosamprenavir or with any unboosted PI. Etravirine is a substrate of the CYP enzymes 3A4, 2C9, and 2C19. It acts as an inducer of 3A4 and an inhibitor of 2C9 and 2C19. Etravirine should be taken with food to improve concentrations.¹

Protease Inhibitors

The use of PIs, the first of which was FDA approved in 1995, had a positive influence on mortality rates in HIV-infected patients. PIs inhibit the protease enzyme that is used to cut proteins into the usable portions needed to make new functional virions. If these proteins are left uncut, they leave the virion without the proteins necessary to infect other cells. A PI can be paired with NRTIs to make a PI-based regimen. The newest guidelines highly recommend that all PIs be combined with ritonavir. Ritonavir is a PI exhibiting strong inhibition of CYP3A4. When first manufactured, it was used as a PI at full dose, but its gastrointestinal and lipid effects make it a less desirable PI compared to other medications available in this class. Today, it is used in small doses (usually 100 mg per dose of the main PI) to “boost” other PIs by inhibiting their metabolism, resulting in higher concentrations for longer periods of time. According to the DHHS guidelines, the preferred PI-based regimens are all ritonavir-boosted. These preferred regimens include boosted atazanavir, darunavir, fosamprenavir, and lopinavir.¹ Nelfinavir is the only PI that cannot be boosted by ritonavir and should be taken with food to increase absorption. According to the FDA, saquinavir, darunavir, lopinavir, and tipranavir must be given with low-dose ritonavir. Lopinavir is not available as a single entity and is the only PI that is coformulated with ritonavir. Ritonavir-boosted regimens should be taken with food to improve tolerability. As a class, PIs may increase the risk of bleeding in patients with hemophilia and may have altered kinetics in pregnancy. PIs have been associated with long-term metabolic effects including increased triglycerides, increased blood glucose, and fat redistribution, sometimes called lipodystrophy. To treat these subsequent conditions, lifestyle modifications including diet and exercise and, many times, drug therapy are required.

In general, PIs are inhibitors of CYP3A4. The only exception is the PI tipranavir, which is an inducer. Because of this unique characteristic, tipranavir must be given with a higher dose of ritonavir for boosting. Tipranavir also carries a black box warning for intracranial hemorrhage. TABLE 2 includes a list of drugs whose use is contraindicated with PIs as a class, though there are individual PIs that have additional severe drug interactions. There are also interactions that are not contraindications but require dose modifications. A common example is the use of phosphodiesterase (PDE₅) inhibitors or erectile dysfunction drugs with PIs. When used together, the dose of the PDE₅ inhibitor must be decreased and the interval between doses extended (i.e., sildenafil 25 mg no more than every 48 hours). Several PIs, including fosamprenavir, darunavir, and tipranavir, contain a sulfa moiety and could potentially cause a reaction in an individual with a sulfonamide allergy. The cross-sensitivity is rarely seen clinically but should be kept in mind, especially for patients with a previous severe reaction to sulfa-containing drugs.

Table 2

Drugs That Are Contraindicated With PIs

Ergot alkaloids Simvastatin, lovastatin Midazolam, triazolam Inducing anticonvulsants Rifampin St. John’s wort Fluticasonea

aFor patients on ritonavir-boosted regimens and includes nasal and inhaled formulations. PIs: protease inhibitors.

Atazanavir is thought to have the least effect on lipids and may be a better choice in a patient with baseline dyslipidemia. The hyperbilirubinemia associated with atazanavir is usually subclinical and only notable as an increase in a laboratory value. However, scleral icterus may sometimes be present, and a patient may desire a medication change because of cosmetic concerns. While not originally thought to be an adverse effect of atazanavir, case reports of nephrolithiasis have been associated with atazanavir, and its package insert was updated in 2007 to include this as a precaution. Atazanavir, in addition to fosamprenavir, can be given without ritonavir, unboosted, although this dosing is not preferred by the current HIV treatment guidelines and is only an option in treatment-naïve individuals.¹ Atazanavir does interact with most acid-reducing agents including antacids, H₂-blockers, and proton pump inhibitors (PPIs). Antacids should be administered 2 hours before or 1 hour after atazanavir administration. H₂-blockers may be administered simultaneously or at least 10 hours after boosted atazanavir administration. PPI use is not recommended with atazanavir in treatment-experienced patients. However, in treatment-naïve patients a maximum dose equivalent to omeprazole 20 mg daily may be used but must be separated from atazanavir administration by 12 hours.⁹ Indinavir can also cause hyperbilirubinemia in addition to nephrolithiasis. Patients taking atazanavir and indinavir should be counseled to increase fluid intake to decrease the risk of nephrolithiasis.

Other Therapies

One of the two newest antiretrovirals, maraviroc, is the only CCR5 inhibitor on the market. When HIV infects a cell, the viral protein gp120 must first bind to a CD4 receptor on the lymphocyte cell surface. Next, it binds to a coreceptor, CCR5 or CXCR4. Some HIV viruses can use one or the other coreceptor and some can use either. There is a tropism assay available to assess a particular patient’s virus tropism. Testing is required before initiation of maraviroc because it is only effective against pure CCR5 tropic virus. If a patient has CXCR4, dual, or mixed tropic virus, maraviroc should not be used. CCR5 tropic virus is common in treatment-naïve patients, but the incidence of pure CCR5 virus decreases with time. Pure CXCR4 virus is rare, but many patients will have dual or mixed tropic virus. Maraviroc has many drug interactions. When used along with strong CYP3A inhibitors, maraviroc is dosed at 150 mg bid. In conjunction with strong CYP3A inducers, the maraviroc dose is 600 mg bid. When neither a strong inducer nor a strong inhibitor is present in the patient’s medication regimen, the normal dose is 300 mg bid.¹⁰

Enfuvirtide is a fusion inhibitor and is supplied as a powder for injection. It binds to gp41, which would normally initiate fusion of the virus into the lymphocyte cell surface. Once enfuvirtide is reconstituted with sterile water, it is given as a subcutaneous injection twice daily. Two doses can be reconstituted at the same time and the unused dose placed in the refrigerator. Refrigerated doses must be used within 24 hours of reconstitution. Enfuvirtide is usually reserved for patients who have already tried initial and subsequent sets of antiretrovirals that were discontinued for various adverse effects or resistance. The most common side effect is injection-site reactions that produce knots under the skin that disappear with time. Patients should be encouraged to rotate injection sites and never inject into one of these preexisting knots. Sites used for this subcutaneous injection are the same as used for insulin—the abdomen, thighs, and upper arms.¹¹

Raltegravir, another new medication used to treat HIV, inhibits the enzyme integrase. Integrase’s role would normally include creating available ends on newly created viral DNA, aiding entry of this DNA into the cell’s nucleus, and then splicing viral DNA into the host DNA inside the nucleus. Because raltegravir is not metabolized by the cytochrome P450 system, it has minimal drug interactions. Raltegravir undergoes UGT1A1-mediated glucuronidation. There is a documented interaction with rifampin due to rifampin’s induction of UGT, resulting in the need to increase the raltegravir dose to 800 mg twice daily from the normal 400-mg twice daily dose.¹² Raltegravir is usually well tolerated.

One goal of antiretroviral therapy includes achieving an undetectable viral load, many times reported as less than 50 copies/mL depending on how low the assay can measure. Another goal includes increasing the patient’s CD4 count to a level that is near that of an uninfected individual, which decreases the patient’s risk of acquiring opportunistic infections. It is recommended that a patient’s antiretroviral regimen include at least three drug entities that are active against the patient’s HIV. In some treatment-experienced patients who have exhausted many previous antiretroviral options, it may be necessary to have only two active antiretrovirals in their regimen. It is more common to see regimens that include two NRTIs and one NNRTI or two NRTIs and one ritonavir-boosted PI; however, it is not uncommon to see drugs from all three of these classes used in one regimen or two PIs (in addition to ritonavir) in the same regimen. Of course, there is also incorporation of medications from some of the more unique classes such as an integrase inhibitor, CCR5 inhibitor, or fusion inhibitor. Careful attention to drug interactions is required when combining many of these medications due to their involvement with CYP450.

There are certain antiretroviral combinations that are never recommended to treat HIV infection. Monotherapy with a single antiretroviral, for example, is not recommended. Out of necessity, monotherapy with zidovudine was used after its marketing because it was the only available antiretroviral. Monotherapy sets the stage for resistance to occur and is virologically inferior to combination regimens. Therapy with dual or triple NRTIs alone is also discouraged. The 2NN Study demonstrated that regimens that included two NNRTIs had more adverse events when compared to regimens that included just one of the NNRTIs.¹³ It is also important to remember antiretroviral combinations that should not be used due to overlapping toxicities or drug interactions.

Resistance testing is recommended in treatment-naïve patients, during pregnancy, and in instances of treatment failure not attributable to lack of adherence or adverse effects. Genotype results can be obtained faster than phenotype results and include a list of all mutations found in the patient’s HIV virus. Phenotyping compares response of the patient’s virus to each antiretroviral with the response of a wild-type virus. These results are reported in fold changes of IC₅₀.

Guarding Against Opportunistic Infections

Once patients with HIV experience immunosuppression based on decreases in CD4 count, they are at risk for many opportunistic infections. Medications can be given to prevent several of these infections. Pneumocystis jiroveci pneumonia (PCP) is seen more than 90% of the time in patients with a CD4 count less than 200 cells/mm³. Therefore, it is recommended that patients with CD4 counts under 200 cells/mm³ receive prophylaxis to decrease their risk.¹ First-line prophylaxis would be sulfamethoxazole/trimethoprim (TMP) 800/160 mg daily. If a patient has a sulfa allergy, dapsone 100 mg should be used as an alternative. There is a small percentage of sulfa-allergic patients who will also have a reaction to dapsone. In these circumstances, atovaquone or inhaled pentamidine may be used. For patients with a CD4 count less than 50 cells/mm³, prophylaxis for Mycobacterium avium complex (MAC) is recommended. Azithromycin 1,200 mg once weekly is typically used, but clarithromycin 500 mg twice daily is also acceptable. Patients with CD4 counts less than 100 cells/mm³ and positive toxo immunoglobulin (Ig)G are at increased risk for Toxoplasmosis gondii. The first-line regimen to protect against PCP, sulfamethoxazole/TMP 800/160 mg daily, also provides prophylaxis for toxoplasmosis. If a patient is on an alternative PCP prophylaxis regimen and meets toxoplasmosis prophylaxis criteria, care should be taken to ensure that adequate toxoplasmosis coverage is added.¹⁴

Role of the Pharmacist

Important patient counseling points for antiretroviral regimens include confirming that the patient understands the goals of treatment and stressing adherence. Just as it is useful for patients with hypertension to know their current blood pressure or those with diabetes to know their most recent glycosylated hemoglobin level and the goals associated with each, it is important for a patient with HIV to know his or her CD4 count and viral load and what the goals of therapy are for these numbers. With the newer formulations of many of the antiretrovirals, storage is not a concern. However, there are a few formulations that must be refrigerated prior to dispensing, and the patient must be advised to keep the product at room temperature or cooler. These products include ritonavir capsules (Norvir), lopinavir/ritonavir liquid (Kaletra), and tipranavir capsules (Aptivus) and are stable outside of the refrigerator for 30, 60, and 60 days, respectively.^15-17

Pharmacists have the unique opportunity to be able to educate HIV-infected patients about their antiretroviral medications; monitor all of a patient’s medications, including OTC drugs and herbals, for drug interactions; and provide patients with advice and services to increase medication adherence. As persons infected with HIV continue to live longer lives and take many complex medication regimens, pharmacists will continue to become a more vital component of their health care team. Pharmacists will need to be diligent in medication history review with each patient before dispensing medications. Services to help patients become more adherent include simple ideas such as refill reminders and daily pill boxes. All of these important tasks are vital to the care of HIV-infected patients.