Abacavir treatment with

There was significant improvement in signs of mitochondrial toxicity in 49 patients who switched from stavudine to abacavir compared with 63 patients who continued to take stavudine in a non-randomized study for 12 months (152). Only patients who remained on their assigned treatment were included in the analysis. Lactate concentrations were assessed at baseline, week 24, and week 48, and electrical bioimpedance was performed in 22 cases and 12 controls at baseline and week 48. There were significant falls in serum lactate concentrations at weeks 24 and 48 in cases compared with controls. Patients who switched had a trend towards fat gain, while controls had significant reductions in total body fat and percentage of body fat. 

The effects of abacavir have been evaluated in a study in over 13 000 adults who no longer responded to commercially available treatment regimens (2). By month 2 of treatment with abacavir, plasma HIV-1 RNA concentrations fell by at least half a log unit in 31% of patients, and in 5.6% of the patients HIV-1 RNA concentrations fell to under 400 copies/ml. Serious drug-related adverse events were reported by 7.7% of patients. The most common were nausea, skin rash, diarrhea, malaise or fatigue, and fever. About 4.6% of patients had a hypersensitivity reaction that was possibly drug-related. 

Henry K, Wallace RJ, Belhnan PC, Norris D, Fisher RL, Ross LL, Liao Q, Shaefer MS TARGET Study Team. Twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1 results of the TARGET Study. J Infect Dis 2001 183(4) 571-8. 

Acute kidney injury with eosinophihc interstitial nephritis was attributed to abacavir in one patient with HIV infection who also had what appeared to be "classic" FSGS on renal biopsy [83]. The serum creatinine returned to baseline levels after treatment with prednisone and discontinuation of abacavir. 

Before Initiating treatment with abacavir, screening for carriage of the HLA-B 5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Abacavir should not be used in patients known to cany the HLA-B 5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing... 

A single 300-mg dose of zidovudine was given with abacavir 600 mg to 13 mV-positive subjects. The pharmaeokinetics of abacavir were not significantly affected. The zidovudine maximum plasma level deereased by 20%, but the AUC was unchanged. This ehange is not thought to be elin-ically significant and so no dose alteration would seem neeessaty on eon-current use. These results were eonfirmed in a steady-state study in which 79 mV-positive subjects received 8 weeks of treatment with abacavir 600 mg to 1.8 g daily, in divided doses, and zidovudine 600 mg daily, in divided doses. The triple NRTI eombination of abacavir, lamivudine and zidovudine may also be considered if protease inhibitors or NNRTIs cannot be used. ... 

The present NRTIs available for the treatment of HIV are zidovudine (azidothymidine, AZT), stavu-dine (d4T), didanosine (ddl), lamivudine (3TC), dideoxycytidine (ddC, zalcitabine) and abacavir, emtricitabine and tenofovir disoproxil. Combination formulations are abcavir combined with zidovudine and lamivudine and the abacavir-lamivudine combination. 

Lamivudine (3TC, Epivir) is a cytosine nucleoside analogue with activity against HIV-1, HIV-2, and hepatitis B virus. It is approved as part of a multidrug regimen for the therapy of HIV infection in adults and children and has been used for HIV postexposure prophylaxis. Combination products contain lamivudine with either zidovudine (Combivir) or zidovudine and abacavir (Trizivir). The use of low-dose lamivudine in the treatment of chronic hepatitis B is described in Chapter 50. 

Lamivudine is the best-tolerated NRTI. Its most common adverse effects include headache, malaise, fatigue, and insomnia. Pancreatitis is rare. Gastrointestinal complaints are common with lamivudine-zidovudine therapy but are probably mainly due to the zidovudine component. Lamivudine resistance sometimes occurs early in treatment. Cross-resistance to zal-citabine, didanosine, and abacavir can occur simultaneously. Withdrawal of lamivudine in patients infected with both hepatitis B virus and HIV can cause a flare-up of hepatitis symptoms. 

Abacavir is associated with side effects such as anorexia, nausea, vomiting, malaise, headache, and insomnia. A potentially fatal hypersensitivity reaction develops in approximately 5% of patients, usually early in the course of treatment. Fever and rash are the most common symptoms of this reaction malaise, respiratory symptoms, and gastrointestinal complaints may also occur. Resistance to abacavir may be associated with resistance to zidovudine, didanosine, and lamivudine. 

After oral administration, abacavir is rapidly absorbed, and its bioavailability is about 83%. Food does not interfere with its absorption, and it is metabolized by alcohol dehydrogenase to 5 -carboxylic acid derivative and to S -glucuronidc by glucuronidation. Abacavir does not affect the cytochrome P-450 system. In combination with other antiretroviral drugs, abacavir is indicated for the treatment of HIV-1 infection. It is more potent than other nucleoside reverse transcriptase inhibitors in reducing HIV plasma concentration and increasing CD4+ count. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Zidovudine monotherapy was the only available treatment for HIV disease before the 1990s, and was used until 1992. Zidovudine monotherapy has been proven to be efficacious for both the treatment of HAD as well as for HIV-associated minor cognitive/motor disorder (MCMD) (Arendt et al., 1992 Sidtis et al., 1993 Tozzi et al., 1993). Unfortunately, the beneficial effect of zidovudine was transient and an addition of a second NRTI such as dideoxyinosine (ddl), lamivudine (3TC), or dideoxycytidine (ddC), may not further improve psychomotor performance. Stavudine was shown to improve motor performance even after pretreatment with zidovndine (Arendt et al., 2001). A study in 1998, using abacavir versns placebo showed no nenrologic deterioration in the abacavir group as compared with the placebo group (Lanier et al., 2001). However, there was no benefit when abacavir was added to a stable ART, despite good proven CNS penetration. 

The efficacy and safety of abacavir (NRTI) and efavirenz (NNRTI) plus background therapy have been retrospectively evaluated in 50 patients, who had previously been treated with HAART (3). There was some immunological benefit, albeit limited, in most of the patients. Adverse effects were not mentioned in detail, but the dropout rate during the first 4 weeks of treatment was high, owing to skin rashes and hypersensitivity reactions. 

Abacavir is an antiretroviral/nucleoside reverse transcriptase inhibitor. It is used in the treatment of HIV-1 in combination with other antiretroviral agents. Abacavir is converted inside cells to an active metabolite, carbovir 5 -triphosphate, which is a potent inhibitor of the HIV-1 reverse transcriptase. 

The Corey-Winter reaction has also been used in a formal synthesis of the AIDS drug (-)-abacavir (35).16 Thionocarbonate 33 was prepared from diol 32 in 78% yield. Then, treatment of 33 with phospholidine 21 afforded olefin 34 in 65% yield. The preparation of 34 constitutes a formal synthesis of (-)-abacavir (35). 

---