One noteworthy interaction that the clinician caring for HIV-infected patients should be aware of is the interaction of ribavirin with zidovudine. Ribavirin decreases the phosphorylation of zidovudine and stavudine in vitro, resulting in decreased concentrations of the active compound. HIV-infected patients who are coinfected with hepatitis C may be treated with regimens that include ribavirin, which may reduce the efficacy of zidovudine (15). Another important interaction is the effect of nevirapine or efavirenz on plasma methadone concentrations. Both drugs can decrease methadone plasma levels by 50%, and patients receiving chronic therapy may need increased methadone doses to prevent withdrawal symptoms (16).
Protease inhibitors are associated with numerous interactions including certain antiarrhythmics, sedatives, hypnotics, ergot derivatives, and several lipid-lowering agents (statins). Not only do protease inhibitors affect the metabolism of certain drugs, but also their own metabolism is altered by other inducers or inhibitors of cytochrome activity that can cause clinically important decreases in serum levels of protease inhibitors. One widely recognized interaction is that of rifampin, which may decrease levels of some protease inhibitors by 80%. The resulting low plasma concentrations may promote viral resistance and result in treatment failure. Patients being treated for tuberculosis, who are also receiving protease inhibitors should be treated with a four-drug regimen that includes rifabutin (at half dose) instead of rifampin. Updated guidelines for the use of rifabutin or rifampin in HIV-infected patients receiving antiretroviral agents have been reviewed recently (17).
Other potent inducers such as phenytoin, phenobarbital, and carbamazepine can cause similar reductions in serum levels of protease inhibitors. Azole antifungal drugs and macrolides also have important interactions that complicate both the treatment and prophylaxis of opportunistic infections.
Interactions that interfere with absorption can also affect plasma drug concentrations. For example, the absorption of fluconazole is unaffected by variations in gastric pH, while itraconazole and ketoconazole require an acidic environment for optimal absorption. The protease inhibitor, atazanavir, also requires a low pH for absorption and thus is contraindicated with the use of proton pump inhibitors; taking atazanavir with acidic beverages is not sufficient to overcome this (18).
New information about drug interactions becomes known on almost a daily basis in patients with HIV infection. The number of documented and theoretical interactions can become overwhelming to the clinician. Clinicians should suspect potential drug interactions in a patient who is failing therapy but who is adherent to HAART. Fortunately, there are extensive tables on Web sites (www.hivatis.org) and product information to aid in the recognition and management of drug interactions.
Complications of HAART
Diabetes mellitus, hyperlipidemias, lipodystrophy, and insulin resistance are among the many complex metabolic abnormalities attributable to the use of HAART. For the most part, these complications are managed conservatively and usually do not mandate the discontinuation of HAART. Pancreatitis, hepatic steatosis, and lactic acidosis are wellrecognized complications of NRTIs. These are usually more acute and may result in hospitalization and necessitate the discontinuation of medications. Cessation of the offending agent (didanosine [ddI], stavudine [d4T], and zalcitabine [ddC) usually results in resolution of pancreatitis, but the episode may limit use of these agents in the future. Hepatic steatosis and lactic acidosis are rare but life-threatening adverse effects associated with the mitochondrial toxicity seen with the NRTIs. Symptoms usually develop insidiously with nausea, vomiting, abdominal pain, weight loss, or dyspnea and can progress rapidly to fatal lactic acidosis. Hepatomegaly, ascites, elevated liver associated enzymes, and an increased anion gap with lactic acidemia are usually present (19,20). Discontinuation of antiretroivirals is imperative.
There is an accumulating body of evidence that suggests that HIV-infected patients receiving HAART may be at risk for accelerated coronary disease (21). In addition, some cohort studies have reported an increased incidence of myocardial infarction (MI) following the introduction of HAART and the risk for MI rose progressively with the number of years on antiretroviral therapy (22,23). However, it is important to note that many traditional risk factors for coronary artery disease contribute more substantially to the risk for a cardiovascular event than does HAART. Therefore, aggressive modification of primary cardiac risk factors is warranted.