HIV: Now a Manageable Chronic Disease

Many advances have occurredin the treatment of humanimmunodeficiency virus (HIV)and acquired immune deficiency syndrome(AIDS) in the past decade. Currently,21 separate chemical entitieshave been approved by the FDA totreat HIV, along with 5 combinationproducts. Four classes of antiretroviralshave activity against HIV, and newclasses are under investigation. Whatwas once considered a terminal illnesshas progressed to a manageable chronicdisease through the use of theseantiretroviral medications.

While life expectancies as well asmedication exposure have increased,issues such as medication resistanceand long-term adverse effects havefactored into the decision about whento start medication treatment in individualsinfected with HIV. The currentguidelines from both the Departmentof Health and Human Services and theInternational AIDS Society-USA giverecommendations on when to startantiretrovirals (Table 1).^1,2

Commonly, antiretroviral regimensinclude at least 2 nucleoside reversetranscriptase inhibitors (NRTIs) combinedwith a non-nucleoside reversetranscriptase inhibitor (NNRTI) or a proteaseinhibitor (PI). Table 2 lists the preferredagents in each class to be usedin patients who have not previouslyreceived antiretrovirals.¹

NRTIs

NRTIs are the oldest class of antiretrovirals.A combination of medicationsfrom this class is used to createwhat is called the backbone of a patient'sregimen.

All NRTIs except abacavir must bedose-adjusted in patients with renaldysfunction. Every NRTI also carries therare but serious risk of lactic acidosis.The proposed mechanism for thisadverse event is the medication's toxicityto mitochondria. Some NRTIs arethought to carry a higher risk (didanosine,stavudine), whereas others arethought to be less likely to cause lacticacidosis (tenofovir, abacavir, lamivudine,emtracitabine).³

Tenofovir is unique because it is anucleotide reverse transcriptase inhibitor.It does not have to be intracellularlyphosphorylated before becomingactive, as the nucleosides do.

NNRTIs

Even though the FDA has approved 3NNRTIs, only 2 are typically used inpractice. These 2 NNRTIs are efavirenzand nevirapine. Etravirine (TMC-125) isan NNRTI currently in phase 3 studies.⁴

NNRTIs do not require dosing adjustmentin patients with renal dysfunction.Efavirenz is teratogenic and shouldbe avoided in pregnant women orthose who may become pregnant. It alsocan cause a false positive on tetrahydrocannabinoldrug screens and hascentral nervous system-related sideeffects. Nevirapine can cause hepatotoxicityand rash and must be dosed athalf the full dose for 2 weeks beforebeing titrated up to the full dosage.

Medication adherence is particularlyimportant with NNRTIs. Only one mutationis required to confer resistance tothe NNRTIs. Newer second-generationNNRTIs, including etravirine, will playan important role in therapy, becausethey will have a different resistanceprofile.

PIs

The most recent guidelines publishedin October 2006 stress theimportance of using boosted PI regimens.¹ Boosting involves using lowdoseritonavir to inhibit the metabolismof the PI in order to get better drugconcentrations. Nelfinavir is the only PIthat cannot be boosted by ritonavir.Regimens that contain a boosted PIshould be taken with food to decreasegastrointestinal upset. Table 3 lists thetypical boosted-PI doses and intervals.¹

PIs are metabolized hepatically bythe cytochrome P-450 system andtherefore have some significant druginteractions. Some common interactionsinvolve simvastatin, lovastatin,ergot alkaloids, St. John's wort, midazolam,triazolam, phosphodiesterase-5inhibitors (erectile dysfunction drugs),rifampin, and some enzyme-inducinganticonvulsants. Ritonavir, in particular,is a very potent CYP3A4 inhibitor. PIsrequire no dosing adjustments forrenal dysfunction.

Acid suppression can cause decreasedconcentrations of atazanavir.Therefore, proton pump inhibitors arecontraindicated with the use ofatazanavir. Also, histamine² receptorantagonists must be separated fromatazanavir dosing by 10 to 12 hours.^5,6

Newer PIs (tipranavir, approved in2005, and darunavir, approved in 2006)have been developed to treat virus thatis resistant to many of the older PIs.The RESIST and POWER trials demonstratedthat adding one of these newPIs to a patient's regimen along withenfuvirtide gave stronger results thanthe addition of the PI alone.^7,8

Metabolic syndrome has been associatedwith the long-term use of PIs. Someexperts argue that the virus itself alsocontributes to these effects that includeincreased lipids, increased blood glucose,and fat redistribution (sometimesreferred to as lipodystrophy).

Entry Inhibitors

The only FDA-approved medicationthat inhibits the entry of the virus intohost cells is enfuvirtide. It acts byinhibiting the fusion of the virus intothe CD⁴⁺ cell membrane. Enfuvirtide isadministered by subcutaneous injectiontwice daily.

This medication is reconstituted bythe patient and is stable for only 24hours once reconstituted. Because itcan take up to 45 minutes for the medicationto fully go into solution, it isusually easier for patients to reconstitute2 doses at a time and store thesecond one in the refrigerator for 12hours until the next injection.

The main side effect of enfuvirtide islocal injection site reactions. Patientsare advised to rotate injection sitesbetween the thighs, abdomen, andupper arm.^9,10

Integrase Inhibitors

Although no integrase inhibitorshave yet been approved by the FDA, 2are showing promise in clinical trials,MK-0518 and GS-9137. These medicationsinhibit the virus' ability to incorporateitself into host DNA and preventthat cell from producing new virus.^11,12

Drug Interactions

Stavudine and zidovudine are thymidineanalogues and compete for phosphorylationonce inside the cell. Therefore,these 2 medications are antagonisticand should not be used together.

Zidovudine can cause anemia andshould not be combined with othermedications that are myelosuppressive.Other medications that have overlappingtoxicities and should be avoidedtogether include stavudine anddidanosine. Both of these medicationshave a propensity to cause peripheralneuropathy, pancreatitis, and hyperlactatemia.¹

Didanosine and tenofovir were oncecommonly used together. Studies haveshown, however, that, in addition to apharmacokinetic interaction that can befixed with dose adjustments of didanosine,patients do not have the expectedincrease in CD⁴ count when these 2medications are used together.¹³

Pharmacists' Role

Because of the many drug interactions,side effects, and development ofresistance, pharmacists must pay closeattention to the dispensing of antiretrovirals.Pharmacists should instill inpatients the importance of getting alltheir medications from one pharmacyand getting timely medication refills.They also should develop a working relationshipwith patients' physicians.

Dr. Teague is a pharmacist at CooperGreen Hospital in Birmingham, Ala.

References

1. Department of Health and Human Services Guidelines. Guidelines for the use ofantiretroviral agents in HIV-1-infected adults and adolescents. October 10, 2006.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

2. Hammer S, Saag M, Schechter M, et al. Treatment for adult HIV infection. 2006recommendations of the International AIDS Society-USA panel. JAMA.2006;296(7): 827-843.

3. Moyle G. Mechanisms of HIV and nucleoside reverse transcriptase inhibitorinjury to mitochondria. Antivir Ther. 2005;10(suppl 2):M47-M52.

4. Grossman HA, Hicks C, Nadler J, et al. Efficacy and tolerability of TMC125 inHIV patients with NNRTI and PI resistance at 24 weeks: TMC125-c223. Programand abstracts of the 45th Interscience Conference on Antimicrobial Agents andChemotherapy; December 16-19, 2005; Washington, DC. Abstract H-416c.

5. Reyataz package insert. Available at: www.reyataz.com.

6. Agarwala S, Gray K, Wang Y, Grasela D. Pharmacokinetic effect ofomeprazole on atazanavir co-administered with ritonavir in healthy subjects.Abstracts of the 12th Conference on Retroviruses and OpportunisticInfections; February 22-25, 2005; Boston, Mass. Abstract 658.

7. Gazzard B, Antinori A, Cheli C, et al. Combined analysis of RESIST 96-weekdata: durability and efficacy of tipranavir/r in treatment-experienced patients; 8thInternational Congress on Drug Therapy in HIV Infection; November 12-16,2006; Glasgow, UK. Abstract #950386.

8. Wilkin T, Haubrich R, Steinhart C, et al. TMC114/r superior to standard of carein 3 class-experienced patients: 24 wks primary analysis of the Power 2 study(C202). Abstracts of the 45th Interscience Conference on Antimicrobial Agentsand Chemotherapy; December 16-19, 2005; Washington, DC. Abstract H-413.

9. Fuzeon package insert. Available at: www.fuzeon.com.

10. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor,for drug-resistant HIV infection in North and South America. N Engl J Med.2003;348(22):2175-2185.

11. Miller M, Witmer M, Stillmock K, et al. Biochemical and antiviral activity ofMK-0518, a potent HIV integrase inhibitor. Abstracts of XVI International AIDSConference; August 13-18, 2006; Toronto, Canada. Abstract THAA0302.

12. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics,and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) intreatment-naive and treatment-experienced patients. J Acquir Immune DeficSyndr. 2006;43(1):1-5.

13. Barrios A, Rend?n A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infectedpatients with complete virus suppression taking tenofovir anddidanosine. AIDS. 2005;19:569-575.