Antiretroviral Treatment Failure

Despite major advances in treatment of progressive HIV disease, approximately 40% of patients will not achieve sustained viremia below the limits of detection, which is the accepted definition of treatment success (Lucas et al., 1999). 

Poor adherence is the most important cause of failure of ART, and cognitive impairment is clearly a risk factor for this, such as in patients with HAD. Other reasons include drug intolerance, development of adverse effects, impaired drug absorption and/or metabolism, pharmacokinetic interactions, and pre-existing viral resistance. 

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In summary, M3 shows potent viral load reduction, a strong safety profile (with no evidence of organ toxicity or clinical intolerance), no evidence of clinically significant drug interactions, and, quite importantly, no evidence of rapid resistance development, which is a primary cause for antiretroviral treatment failure (125-127). 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

Treatment considerations for antiretroviral-experienced patients are much more complex than for patients who are naive to therapy. Prior to changing therapy, the reasons for treatment failure should be identified. A comprehensive review of the patient s severity of disease, antiretroviral treatment history, adherence to therapy, intolerance or toxicity, concomitant drug therapies, co-morbidities, and results of current and past HIV resistance testing should be performed. If patients fail therapy due to poor adherence, the underlying reasons must be determined and addressed prior to initiation of new therapy. Reasons for poor adherence include problems with medication access, active substance abuse, depression and/or denial of the disease, and a lack of education on the importance of 100%... 

Indinavir is a protease inhibitor used in the management of HIV infection. CYP3A4 mediates the biotransformation of indinavir in vitro (85,86), and in vivo, indinavir has been shown to be a potent competitive and mechanism-based inhibitor of CYP3A4 (85,87). Piscitelli and coworkers (80) examined the effect of St. John s wort (300 mg t.i.d. x 14 days) administration on indinavir (800 mg q.i.d. x 8 hr x four doses) exposure in eight healthy volunteers (two females). The administration of St. John s wort for 14 days resulted in a significant 54 /o reduction in the indinavir eight-hour area under the concentration-time curve, from 35.8 13.0 to 15.6 5.8 pg X hr/mL. The authors conclude that the magnitude in the reduction in indinavir concentrations may result in the development of antiretroviral resistance and subsequent treatment failure. 

Meynard J-L, Vray M, Morand-Joubert L, Race E> Descamps D, Peytavin G, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure a randomized trial. AIDS 2002 16 727-36. 

Such adulteration is perilous owing to the unanticipated drag-herb interactions that may arise 43). Recently, two African medicinal plants, Hypoxis hemerocallidea (African potato) and Sutherlandia frutescens (L.) R.Br. (Fabaceae) often recommended for treatment of HIV/AIDS, showed a negative interaction with antiretroviral medication, thus patients may be at risk from treatment failure, viral resistance or drag toxicity (53). Consequently, even when these interferences do not actively cause morbidity and mortality, they can weaken the therapeutic value of concomitantly administered conventional drags... 

Turkova A, Ball C, Gilmour-White S, Rela M, Mieli-Vergani G. A paediatric case of acute liver failure associated with efavirenz-based highly active antiretroviral therapy and effective use of raltegravir in combination antiretroviral treatment after liver transplantation. J Antimicrob Che-mother 2009 63(3) 623-5. 

Lalezari JP, Bellos NC, Sathasivam K, Richmond GJ, Cohen CJ, Myers RA Jr, Henry DH, Rask-ino C, Melby T, Murchison H, Zhang Y, Spence R, Greenberg ML, Demasi RA, Miralles GD (2005b) T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen. J Infect Dis 191 1155-1163... 

The first approval of a therapeutic use for recombinant EPO was in 1989 for the treatment of anemia related to chronic renal failure. The treatment with EPO stimulates production of erythrocytes and improves the patient s quality of life, as well as reducing or eliminating the need for blood transfusion. There are other non-renal applications, such as the minimization of blood transfusion after surgery, the prevention of anemia after bone marrow transplantation, and the treatment of anemia caused by the use of antiretroviral drugs, by chemotherapy, and by prematurity. 

Nevirapine (NVP), a nonnucleoside reverse transcriptase inhibitor, is widely used for the treatment of human immunodeficiency virus (HIV) infections. It is the main option for the first-line treatment of HIV-1, together with two nucleoside reverse transcriptase inhibitors, in countries with limited resources. NVP is associated with two serious clinically restrictive side effects skin reactions and hepatotoxicity. Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in HIV-infected patients taking NVP (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents 2008). For this reason, NVP is given a black box warning for hepatotoxicity, and concern has been raised over NVP-based treatment. 

Hodder SL. Re Important new clinical data. Potential early virolc ic failure associated with the combination antiretroviral regimen of tenofovir disc roxil fumarate, didanosine, and either efavirenz or nevirapine in BTV treatment-naive patients with high baseline viral loads. Bristol-Myers Squibb Company, November 2004. Available at http //www.fda.gov/oashi/aids/l]kserv/bms.jx]f (accessed 21/08/07). 

Preliminary results from a study in healthy subjects suggest that the concurrent use of atovaquone 750 mg twice daily and indinavir 800 mg three times daily results in a minor 5% decrease in the AUC of indinavir, and a 13% increase in the AUC of atovaquone. The UK manufacturer of atovaquone notes that concurrent use decreased the minimum level and AUC of indinavir by 23% and 9%, respectively. They recommend that caution should be exercised on concurrent use because of the potential risk of failure of indinavir treatment. However, note that the effect was small and that indinavir is often used with other antiretrovirals, which might modify the interaction by affecting indinavir levels. 

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