HIV: Now a Manageable Chronic Disease

Ami Teague, PharmD, BCPS
Published Online: Thursday, March 1, 2007
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Many advances have occurred in the treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) in the past decade. Currently, 21 separate chemical entities have been approved by the FDA to treat HIV, along with 5 combination products. Four classes of antiretrovirals have activity against HIV, and new classes are under investigation. What was once considered a terminal illness has progressed to a manageable chronic disease through the use of these antiretroviral medications.

While life expectancies as well as medication exposure have increased, issues such as medication resistance and long-term adverse effects have factored into the decision about when to start medication treatment in individuals infected with HIV. The current guidelines from both the Department of Health and Human Services and the International AIDS Society-USA give recommendations on when to start antiretrovirals (Table 1).1,2

Commonly, antiretroviral regimens include at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Table 2 lists the preferred agents in each class to be used in patients who have not previously received antiretrovirals.1

NRTIs

NRTIs are the oldest class of antiretrovirals. A combination of medications from this class is used to create what is called the backbone of a patient's regimen.

All NRTIs except abacavir must be dose-adjusted in patients with renal dysfunction. Every NRTI also carries the rare but serious risk of lactic acidosis. The proposed mechanism for this adverse event is the medication's toxicity to mitochondria. Some NRTIs are thought to carry a higher risk (didanosine, stavudine), whereas others are thought to be less likely to cause lactic acidosis (tenofovir, abacavir, lamivudine, emtracitabine).3

Tenofovir is unique because it is a nucleotide reverse transcriptase inhibitor. It does not have to be intracellularly phosphorylated before becoming active, as the nucleosides do.

NNRTIs

Even though the FDA has approved 3 NNRTIs, only 2 are typically used in practice. These 2 NNRTIs are efavirenz and nevirapine. Etravirine (TMC-125) is an NNRTI currently in phase 3 studies.4

NNRTIs do not require dosing adjustment in patients with renal dysfunction. Efavirenz is teratogenic and should be avoided in pregnant women or those who may become pregnant. It also can cause a false positive on tetrahydrocannabinol drug screens and has central nervous system-related side effects. Nevirapine can cause hepatotoxicity and rash and must be dosed at half the full dose for 2 weeks before being titrated up to the full dosage.

Medication adherence is particularly important with NNRTIs. Only one mutation is required to confer resistance to the NNRTIs. Newer second-generation NNRTIs, including etravirine, will play an important role in therapy, because they will have a different resistance profile.

PIs

The most recent guidelines published in October 2006 stress the importance of using boosted PI regimens.1 Boosting involves using lowdose ritonavir to inhibit the metabolism of the PI in order to get better drug concentrations. Nelfinavir is the only PI that cannot be boosted by ritonavir. Regimens that contain a boosted PI should be taken with food to decrease gastrointestinal upset. Table 3 lists the typical boosted-PI doses and intervals.1

PIs are metabolized hepatically by the cytochrome P-450 system and therefore have some significant drug interactions. Some common interactions involve simvastatin, lovastatin, ergot alkaloids, St. John's wort, midazolam, triazolam, phosphodiesterase-5 inhibitors (erectile dysfunction drugs), rifampin, and some enzyme-inducing anticonvulsants. Ritonavir, in particular, is a very potent CYP3A4 inhibitor. PIs require no dosing adjustments for renal dysfunction.

Acid suppression can cause decreased concentrations of atazanavir. Therefore, proton pump inhibitors are contraindicated with the use of atazanavir. Also, histamine2 receptor antagonists must be separated from atazanavir dosing by 10 to 12 hours.5,6

Newer PIs (tipranavir, approved in 2005, and darunavir, approved in 2006) have been developed to treat virus that is resistant to many of the older PIs. The RESIST and POWER trials demonstrated that adding one of these new PIs to a patient's regimen along with enfuvirtide gave stronger results than the addition of the PI alone.7,8

Metabolic syndrome has been associated with the long-term use of PIs. Some experts argue that the virus itself also contributes to these effects that include increased lipids, increased blood glucose, and fat redistribution (sometimes referred to as lipodystrophy).

Entry Inhibitors

The only FDA-approved medication that inhibits the entry of the virus into host cells is enfuvirtide. It acts by inhibiting the fusion of the virus into the CD4+ cell membrane. Enfuvirtide is administered by subcutaneous injection twice daily.

This medication is reconstituted by the patient and is stable for only 24 hours once reconstituted. Because it can take up to 45 minutes for the medication to fully go into solution, it is usually easier for patients to reconstitute 2 doses at a time and store the second one in the refrigerator for 12 hours until the next injection.

The main side effect of enfuvirtide is local injection site reactions. Patients are advised to rotate injection sites between the thighs, abdomen, and upper arm.9,10

Integrase Inhibitors

Although no integrase inhibitors have yet been approved by the FDA, 2 are showing promise in clinical trials, MK-0518 and GS-9137. These medications inhibit the virus' ability to incorporate itself into host DNA and prevent that cell from producing new virus.11,12

Drug Interactions

Stavudine and zidovudine are thymidine analogues and compete for phosphorylation once inside the cell. Therefore, these 2 medications are antagonistic and should not be used together.

Zidovudine can cause anemia and should not be combined with other medications that are myelosuppressive. Other medications that have overlapping toxicities and should be avoided together include stavudine and didanosine. Both of these medications have a propensity to cause peripheral neuropathy, pancreatitis, and hyperlactatemia.1

Didanosine and tenofovir were once commonly used together. Studies have shown, however, that, in addition to a pharmacokinetic interaction that can be fixed with dose adjustments of didanosine, patients do not have the expected increase in CD4 count when these 2 medications are used together.13

Pharmacists' Role

Because of the many drug interactions, side effects, and development of resistance, pharmacists must pay close attention to the dispensing of antiretrovirals. Pharmacists should instill in patients the importance of getting all their medications from one pharmacy and getting timely medication refills. They also should develop a working relationship with patients' physicians.

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


References

1. Department of Health and Human Services Guidelines. Guidelines for the use of antiretroviral 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. 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296(7): 827-843.

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

4. Grossman HA, Hicks C, Nadler J, et al. Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-c223. Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; 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 of omeprazole on atazanavir co-administered with ritonavir in healthy subjects. Abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 658.

7. Gazzard B, Antinori A, Cheli C, et al. Combined analysis of RESIST 96-week data: durability and efficacy of tipranavir/r in treatment-experienced patients; 8th International 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 care in 3 class-experienced patients: 24 wks primary analysis of the Power 2 study (C202). Abstracts of the 45th Interscience Conference on Antimicrobial Agents and 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 of MK-0518, a potent HIV integrase inhibitor. Abstracts of XVI International AIDS Conference; 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) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43(1):1-5.

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




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