HIV Care is Growing in Complexity

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The proliferation of medications to aid in the suppression of viral replication for persons with HIV infection has expanded at a pace almost unparalleled in any other field of medicine.

For subspecialists who assist in the care of persons with HIV but do not prescribe the medications themselves, this proliferation of medications can certainly present challenges to keeping their education current. The nephrology literature contains numerous well-written reviews on the epidemiology of HIV-related renal disease and the pathophysiology of HIVAN.1-3 

But few resources are available to assist nephrologists in establishing the foundation for the care and treatment of a person with HIV infection. This review provides a “mini-fellowship” in the care of HIV infection irrespective of kidney disease. Its goal is to assist nephrologists in understanding the decision-making of the HIV provider. The review provides an overview of information on antiretroviral medications, their combinations, toxicities, and relevant pharmacokinetics for a nephrologist consulted to assist in the diagnosis and treatment of CKD in HIV-infected individuals or who provides dialysis to such patients.

Antiretroviral treatment goals

The goals of therapy with antiretroviral medications are to restore immune function and suppress

HIV viral load. Additional goals are to improve quality of life and preserve future therapeutic options.  This last goal is particularly relevant for those subspecialists (including nephrologists) who assist in the diagnosis and management of medication toxicities. 

 

The classes of antiretroviral medications include:

  1. Nucleoside (and nucleotide) reverse transcriptase inhibitors (NRTIs)
  2. Non-nucleoside reverse trans-criptase inhibitors (NNRTIs)
  3. Protease inhibitors (PIs)
  4. Fusion inhibitors
  5. CCR5 co-receptor antagonist

Each of the tables provides the abbreviations, generic names, and brand names for commonly used antiretrovirals. Although nephrologists are quite familiar with the three different types of names for medications frequently used (such as immunosuppressive agents), the three names for each of the ever-growing list of antiretrovirals may be daunting and confusing.

 

Highly active antiretroviral therapy (HAART) is a term reserved for specific regimens that include at least three active antiretroviral medications. The terms base and back-bone refer to specific parts of the HAART regimen. The base is either an NNRTI or a PI. The backbone frequently consists of two NRTIs.

 

Finally, given the interactions between protease inhibitors, low dose ritonavir can be used to increase the concentrations of other protease inhibitors in a manner similar to using a calcium channel blocker to increase the levels of calcineurin antagonists. This is referred to as a ritonavir-boosted PI.

 

With respect to metabolism, excretion, and potential drug interactions, most medications within each class are similar. NRTIs are largely excreted unchanged in the urine. While this suggests they all need to be dose reduced, the extent to which a reduction is required and the threshold at which medications need to be reduced vary. Abacavir, for example, does not need dose reduction at any level of kidney function, whereas zidovudine is reduced at a creatinine clearance of 15 mL/min or more.

 

Zalcitabine is reduced below a clearance of 40 mL/min. Medications reduced at clearances lower than 50 mL/min include lamivudine, stavudine, emtricitabine, and tenofovir. Didanosine is reduced at clearances below 60 mL/min. Because of the variations in their thresholds for dose reductions, combination formulations of NRTIs frequently used together (e.g. Combivir, Epzicom, Truvada, and Atripla) may be problematic to dose in persons with decreased kidney function. Given that nephrologists are frequently tasked with ensuring that medications are dosed appropriately for renal function, knowledge of a good reference for these thresholds is valuable.4 

 

NRTIs have few interactions with medications that are relevant to nephrologists, such as antihypertensives or lipid lowering agents. NNRTIs and protease inhibitors are quite different, however. NNRTIs and protease inhibitors are metabolized in the liver by the cytochrome P450 system. They do not require dose adjustment in the setting of decreasing kidney function, but they do have relevant interactions with medications that the nephrologist as a consultant or a physician providing dialysis may frequently prescribe.

 

The interactions of each specific medication in these two classes vary but can conceptually be summarized in a manner similar to the interactions with calcineurin antagonists with which nephrologists are quite familiar. Similar to calcineurin antagonists, medications that are metabolized by the cytochrome P450 system may accelerate or diminish the rates of antiretroviral metabolism lowering or raising their levels, respectively.

 

The outcome of such an unexpected and unmonitored interaction would be to lower effective levels and increase the potential for the emergence of viral resistance or raise effective levels and the potential for toxicity. Examples of relevant interactions include some Hmg CoA inhibitors (e.g. lovastatin, simvastatin, atorvastatin), calcium channel blockers (both dihydropyridine [e.g., nifedipine] and nondihydropyridine [e.g., verapamil and diltiazem]), macrolide antibiotics, and, of course, calcineurin antagonists.

 

Other medication classes such as non-sedating antihistamines and anticonvulsants also interact to a lesser extent. The package insert of each medication should be sought for more complete listings.

 

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