HIV Care is Growing in Complexity

By Lynda Anne Szczech, MD, MSCE

 

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 medi-cations 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.

 

Viral tropism

 

A medication in a new drug class was approved by the FDA on August 6, 2007. Maraviroc (Selzentry, Pfizer), a CCR5 co-receptor antagonist, was approved for use in combination with other antiretorviral products for the treatment of adults infected with the CCR5-tropic HIV-1 virus who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.⁵ Viral tropism refers to the cell that the specific strain of HIV-1 infects. HIV can enter and subsequently infect a variety of immune cells such as CD4+ T cells and macrophages through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells and also with specific co-receptors.⁶ Macrophage (M-tropic) strains of HIV-1 use the β-chemokine receptor CCR5 for entry and are thus able to replicate in macrophages and CD4 + T cells.⁷ This CCR5 co-receptor is used by almost all primary HIV-1 isolates.

 

Maraviroc prevents viral entry into uninfected cells by blocking the predominant route of entry, the CCR5 co-receptor, a protein on the surface of immune cells affected by HIV. As it is metabolized in the liver by the cytochrome P450 system, medi-cations that can affect its metabolism include ketoconazole, itraconazole, clarithromycin and other macrolide antibiotics, rifampin, and anticonvulsants.

 

Treatment-related ailments

 

A functional knowledge of medication interactions with antiretro-virals is essential for additional practical reasons. The demographics of persons living with HIV and AIDS are changing with increasing age due in part to a tremendously improved survival with antiretroviral medications.8 With the aging of the population and the metabolic toxicities of the medications, increasing comorbidities such as lipid abnormalities, hypertension, diabetes mellitus, and cardiac disease have been well documented.

 

While studies suggest that HIV infection itself result in changes in lipid levels (i.e., total, HDL, LDL, and triglycerides), treatment with HAART may not return all parameters, most notably HDL, to baseline values.⁹ In addition, protease inhibitors likely play a role in triglyceride elevation.¹⁰ The increase in incidence and prevalence of diabetes mellitus among persons with HIV-infection and particularly among those receiving HAART may be similarly multifactorial. Inhibition of insulin-responsive glucose transporters¹¹ and beta cell dysfunction¹² leads to insulin resistance with likely contributions from the metabolic abnormalities that result in lipodystrophy,^13,14 suggesting roles for both the virus and its treatment in etiology. Lastly, a distinctive histologic form of accelerated atherosclerosis has been described in HIV-infected

persons.^15,16 The role of protease inhibitors remains controversial,^17-21 but the increased risk of MI among persons receiving HAART in general appears to exist.

 

Renal complications

 

One of the most common reasons nephrologists are consulted during the care of HIV-infected patients is suspicion on renal toxicity resulting from antiretroviral medication. It is in this circumstance that a thorough understanding of the totality of the care of the person with HIV must be appreciated. There are several antiretroviral medications that have the potential for renal toxicities.

 

The toxicities of tenofovir described in case reports include acute renal failure, nephrogenic diabetes insipidus, and Fanconi's syndrome.^22-26 Risk factors for these include lower kidney function, weight, and CD4 count as well as concurrent use of certain antiretrovirals (e.g. RTV-boosted PI and didanosine).^24,27,28 The frequency with which these toxicities can be expected among persons receiving tenofovir, is however, not entirely clear based on the study designs of case reports and case series. Tenofovir is used by 62% of persons with HIV who are treated in the United States²⁹ qualifying it arguably as a commonly prescribed medication.  Given that approximately half of cases of acute renal failure in an ambulatory population of persons with HIV infection can be attributed to concurrent illness or other such non-medication-related event,³⁰ the potential for falsely inferring causality in a proportion of patients with acute renal failure exists. 

 

An opposite theme may exist, however, with other medication-related toxicities such as allergic interstitial nephritis (AIN). The multiple concurrent medications that many HIV-infected persons require including trimethoprim-sulfamethoxazole likely result in an underestimation for the risk of renal failure due to this mechanism. Multiple single cases of AIN associated with a number of antiretrovirals such as atazanavir, abacavir, and efavirenz have been reported.^31-33 The degree to which these toxicities exist may be underappreciated.

 

The very nature of medication-related toxicity and our inability specifically pinpoint the etiology of an insult to the kidneys require nephrologists to quite commonly discontinue medications empirically and follow the clinical course. Where similarly effective alternative clinical regimens exist, there are no disadvantages to this strategy. However, where alternative regimens are limited (e.g., in a patient with resistant virus), the role of the nephrologist is considerably more difficult.

 

The nephrologist as a consultant

 

As with treatment of any acute or chronic infection, resistance patterns have emerged with HIV-1 in both treatment experienced pa-tients as well as treatment naïve. While frequency of resistance mutations reportedly vary based on risk behavior for acquisition, they have been reportedly as high as 15.2%.^34-36 Routine HIV resistance testing prior to initiation of ART, should be done in all patients with HIV RNA levels greater than 1,000 copies/mL. Virologic “blips” refer to intermittent periods of “detectable viremia” with loads greater than 50 copies/mL. Blips do not appear to demonstrate evolution of resistance mutations and do not require intervention unless the increase in load is sustained.37,38 Sustained increases, however, usually indicate the emergence of a resistance mutation and the potential loss in efficacy of certain antiretrovirals or classes of antiretrovirals. The analogy of the finite number of positions for potential arteriovenous access in a dialysis patient and the preservation of the limited therapeutic options is certainly valid.

 

The recognition that the “therapy” for a potential medication-related toxicity in some circumstances is more complex than simply discontinuing the potential offender is an important one. Stated another way, the need to discontinue a regimen that is currently successful in suppressing viral replication for a potential toxicity brings with it the concurrent and necessary decision to substitute a hopefully equally-as-effective regimen. Where the toxicity is major or the relationship between the toxicity is clear and indisputable, the decision on simple withdrawal of the most obvious cause (i.e., the antiretroviral) is straightforward. Where toxicity is minor and the relationship is more “possible” than “likely,” the consideration of more definitive diagnostic testing to avoid potentially un-needed changes in successful regimens should be considered. 

 

Summary

 

The arsenal of medications available to prolong survival and enhance quality of life in persons infected with HIV continues to expand. The nephrologist, as a consultant participating in the care of persons with comorbidities or toxicities, needs to find reliable, efficient, and effective resources to understand the complexities of HIV care so that he can provide the best possible advice to patients and infectious disease colleagues.

 

Dr. Szczech is associate professor of nephrology at the Duke University School of Medicine in Durham, N.C., and a member of the Renal & Urology News editorial advisory board.

 

References

 

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