Ultrastructural Liver Mitochondrial Abnormalities in HIV/HCV-Coinfected Patients Receiving Antiretroviral Therapy

Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients

“…7,8 In this 'two-hit' injury model, mitochondrial injury is multifactorial and may be explained by the cumulative effects of mitochondrial insults depending on host factors, drugs, oxidative stress, etc. [18][19][20] It is likely that decreased COX subunit I labeling and severe ultrastructural alteration correspond to profound and clinically relevant drug-induced liver toxicity, that was observed in 50% of HIV monoinfected patients and in 13% of coinfected patients. In monoinfected patients, clinical features alone were unable to diagnose severe mitochondriopathy, whereas, drug toxicity strongly impaired liver tests and lactate levels in coinfected patients.…”

Kidney failure during HIV disease treated with tenofovir, multiple concurrent diseases and drug therapies

“…the HIV-and cART related peripheral lipoatrophy (which is part of the very common lipodistrophy syndrome of many patients living with HIV, but was present in a very mild form in our patient) [49,[105][106][107]. Since according to a recent meta-analysis, the "cousin" thiazolidinedione rosiglitazon, which showed a very significant activity in recovering just tenofovir nephrotoxicity [91], but has not demonstrated significantly greater beneficial effects on the lipodistrophy syndrome over both pioglitazone and especially metformin [106], pioglitazone seems safer in patients burdened by a high cardio-cerebrovascular risk (like our patient), although the previously employed metformin proved the only insulin-sensitizer agent which has been demonstrated to partly improve visceral fat accumulation, serum lipid profile, and also endothelial function in the general population (but no data are available until now in HIV-infected patients). Anyway, we decided to favor pioglitazone (and not rosiglitazone), in our patient, who received it at the same dosage for over 16 consecutive months obtaining a full control of his diabetes mellitus, in absence of significant adverse events (including the already present mild limb edema, which remained unchanged despite pioglitazone therapy, which has lower limb edema listed among its potential side effects).…”

“…ribavirin, adefovir, ganciclovir, cidofovir, foscarnet, aminoglycosides, amphotericin B, pentamidin, vancomycin, teicoplanin, interleukin-2, and many others), but our patient never received these drugs in his proportionally "recent" history of asymptomatic HIV disease, so that he never underwent treatments with other frankly nephrotoxic compounds [7,8,10,18,19,25,59,61,62,68,69,80,81,89], and did not suffer of chronic hepatitis B or C, which are frequent events in HIV-infected individuals [28,69,[89][90][91][92]. With regard to the second of the four identified risk factor, a missed renal impairment affecting for example a person with a reduced skeletal muscle mass may result in a potential mediator of even severe nephrotoxicity.…”

“…As anticipated, the direct effects of HIV infection on the kidney sum up with a varied genetic background and an extremely broad spectrum of immune-mediated factors, physiological conditions like pregnancy [75], and especially underlying comorbidities, immune recovery due to cART itself [10,21,22,63], and especially overwhelming (also non-HIV associated) diseases, the frequent chronic co-infections (i.e. chronic hepatitis B, D, and especially C) [90][91][92], but also an increasing prevalence of sexually-transmitted diseases including syphilis [24,[99][100][101] (as in our case), and even hepatitis A [102]. As expected, the extremely different medications prescribed (or self-prescribed, or taken in a not appropriate, even "heterodox" mode by HIV-infected patients themselves) [28,83,[96][97][98]103] have their intrinsic toxicities but they also have potential, varied drug-drug interactions among an almost endless list of drugs potentially used (or useful, or needed, or taken as "recreational" ones) by individuals living with HIV, even more in the years 2010-2011, when the life expectancy of HIV-infected individuals is approaching that of the general population (Table I) [5,8,18,27,36,42,67].…”

“…raltegravir and elvitegravir), entry inhibitors (like maraviroc and vicriviroc), and fusion inhibitors (like enfuvirtide). On the other hand, some nucleos(t)ide analogues (like didanosine, whose plasmatic levels increase upon co-administation wih tenofovir) [10,38], and also the antiviral ribavirin for the treatment of chronic hepatitis C [69,[89][90][91][92], the "older", intrinsically nephrotoxic protease inhibitor indinavir [44,45,93,94], as well as the presently used first-line protease inhibitor-based cART regimens (especially those including ritonavir booster), might add subtle, but sometimes significantly kidney toxicity concerns [10,[18][19][20][37][38][39][43][44][45]60,62,71,76,85,86,88,93,94]. The "intrinsic" (pharmacologically determined), but somewhat negligible and reversible tenofovir nephrotoxicity, could be also enhanced by concomitant disorders, and even more by many concurrent medications chronically or acutely prescribed (or spontaneously taken by patients themselves), for their known, underlying chronic disorders (either associated with HIV disease and cART itself, or not), their age-related disorders, or their occasional, mild-to-moderate intercurrent or incidental illnesses, even trivial in relevance (but treated with either prescription medications or self-prescribed, over-the-counter drugs, like the non-steroideal anti-inflammatory drugs -NSAIDs) [10,18,19,43,60,76,…”