Antiretroviral Options for Naïve and Virologically Controlled Patients
atazanavir/ritonavir. Study arms were unblinded early due to a lower virological response in participants randomised to abacavir/lamivudine with a pre-treatment HIV-RNA >100,000 copies/ml. In the ACTG 5202 study, the HLA-B*5701 gene, which is associated with higher risk of abacavir hypersensitivity, was not tested at baseline and the efficacy criteria at week 16 was earlier than in previous trials. In contrast, the HEAT study demonstrated non-inferiority of these NRTI fixed-dose combinations with lopinavir/ritonavir, regardless of baseline viral load. However, a warning has been issued by all expert groups on abacavir-use in patients with a viral load higher than 100,000 copies/ml.
Renal impairment, manifested by increases in serum creatininaemia, glycosuria, hypophosphataemia and acute tubular necrosis, has been reported with tenofovir use and should be closely monitored.13,14 Risk factors include advanced HIV disease, longer durations of ARV treatment, and pre-existing renal impairment.15,16
The once-daily administration and lack of impact on fat tissue make tenofovir/emtricitabine an attractive choice, compared to thymidine analogues, such as zidovudine and stavudine.
The strong anti-HBV activity and the fact that no HBV resistance mutation has been clearly described thus far makes tenofovir-based regimens the unanimous first choice for HIV-HBV co-infected patients.
Abacavir/Lamivudine – Coformulated Abacavir/Lamivudine is the other fixed-dose combination of nucleoside analogues that can be given once daily and is only associated with a low risk of fat toxicity. Hypersensitivity reactions (HSR) have been observed in 5–8 % of patients starting abacavir. Severe and fatal HSR have been almost exclusively observed in cases of reintroducing abacavir after previous HSR. The risk of HSR is highly associated with the presence of the HLA-B*5701 allele.17,18
Pretreatment screening should be done in
all patients considered for abacavir treatment. Even if HLA-B*5701 allele is not found, patients should be aware of the risk of HSR, albeit low, during the first weeks of treatment. The potential cardiovascular risks of abacavir-containing regimens are still being debated.
The D:A:D collaboration released a large, multinational, observational cohort, in which recent (within six months) or current use of abacavir predicted an increased risk of myocardial infarction (MI) (relative risk 1.9; 95 % CI, 1.5–2.6).19
Data from the French hospital database also
showed that short-term or recent exposure to abacavir was associated with an increased risk of MI. However, when analysing a subset of matched cases and controls who did not use cocaine or intravenous drugs, no additional risk in MI with abacavir was observed.20
which confers a high barrier towards genetic resistance. In patients who experience virological failure during their first PI-based regimen, very few to none have detectable PI-mutations at failure. Resistance to efavirenz or nevirapine, however, is conferred by a single mutation in the reverse transcriptase gene, and develops rapidly after virological failure.27
Drug resistance to most PIs requires multiple mutations in the HIV protease gene,27
The low genetic barrier of currently
available NNRTIs remains a major concern as high level cross resistance among first generation NNRTIs is common.
Although
data on cardiovascular risk are conflicting and no hypothetical mechanism has been demonstrated, European recommendations specify that abacavir/lamivudine should be used with caution in patients with high cardiovascular risk.
Zidovudine/Lamivudine
Zidovudine/lamivudine remains the preferred option only in pregnant women. This dual NRTI regimen has the most favourable pharmacokinetic, safety, and demonstrated efficacy data for both mother and newborn. Primarily because of its greater toxicity (haematological and mitochondrial toxicity) compared with tenofovir/emtricitabine, zidovudine/lamivudine and twice-daily (BID) administration is now an alternative rather than a preferred dual-NRTI option.
EUROPEAN INFECTIOUS DISEASE
In terms of convenience, the coformulated tablet of tenofovir, emtricitabine and efavirenz allows for once-daily dosing with a single tablet. Most PI-based regimens include ritonavir, may be dosed once or twice daily and generally require a higher number of pills included in the regimen, nevertheless the pill burden associated with PI-based regimens has greatly decreased over the past few decades. However, when patients who take once-daily treatment have poor observance, the risk of resuming HIV replication is higher than in those who have poor adherence with twice-daily regimens.
Drug–drug interactions are equally important when considering both kinds of regimens, nonetheless more clinically significant interactions are typically seen with ritonavir-boosted regimens due to the potent inhibitory effect of ritonavir on the cytochrome P450-3A4 isoenzyme. All these points should be considered while choosing the third agent.
75
The Third Agent in Tri-therapy – Protease Inhibitor or Non-nucleoside Reverse Inhibitor Transcriptase or Anti-integrase?
Studies comparing efavirenz-based regimens with other regimens have demonstrated its superiority when administered with two NRTIs versus first-generation, PI-based regimens, such as indinavir,21 triple-NRTI–based regimens.22
or Moreover, the effectiveness of efavirenz
was more recently compared to PI, as results from the ACTG A5142 randomised-control study showed a higher percentage of patients attaining a virological response at 96 weeks with an efavirenz-based regimen compared to a lopinavir/ritonavir-based regimen together with dual-NRTI. As expected, the risk of resistance in failing patients was higher with efavirenz than with lopinavir/ritonavir.23
In this
study, lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine.24
The A1424-034 study
demonstrated comparable virological and immunological responses with boosted atazanavir- and efavirenz-based regimens.25
The adverse events of PI-based regimens generally and more frequently, include gastrointestinal symptoms, whereas efavirenz-based regimens are more associated with rash and are more likely to affect the central nervous system. A number of metabolic abnormalities, including dyslipidaemia, insulin resistance and lipohypertrophy, have been associated with PI-use.24
These complications may result in adverse,
long-term consequences, such as increased cardiovascular events, as suggested by a D:A:D collaboration in which the cumulative use of lopinavir/ritonavir or indinavir was associated with an increased risk of MI, coronary heart disease, and stroke.26
In another observational
analysis from a French cohort, the use of amprenavir or fosamprenavir (with or without ritonavir), or the use of lopinavir/ritonavir, was associated with a higher rate of MI.20
However, both studies are
observational cohort studies and the results must be interpreted with caution (given the potential for confounding).
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