HIV and AIDS
This combination has shown similar virological efficacy as tenofovir, emtricitabine, and efavirenz for up to 96 weeks28
and
is remarkably well tolerated. No change in lipid profile has been observed. However, a number of concerns about this treatment regimen have surfaced, including its still limited experience and low genetic barrier for selection of resistance mutations. These reasons, considered together, explain why this drug has not been recommended as first-line treatment in European and French recommendations, even though it is indicated for treatment in naïve patients.
Choice of Non-nucleoside Reverse Inhibitor Transcriptase or Anti-integrase
Based on its potency and safety profile, efavirenz is typically the preferred choice, except in pregnant women for whom nevirapine must be administered due to the potential teratogenic effects of efavirenz during the first trimester of pregnancy. The only randomised study in treatment-naïve patients that compared efavirenz and nevirapine, both given with stavudine and lamivudine, have demonstrated similar virological responses for both drugs, but nevirapine did not meet criteria for non-inferiority when compared with efavirenz (70.0 % of participants in the efavirenz arm and 65.4 % in the twice-daily nevirapine arm had virological suppression).29
When combined with
tenofovir (plus lamivudine or emtricitabine), several studies with a limited number of patients have suggested a lower efficacy of nevirapine as compared to efavirenz. Interestingly, a recent, large, randomised-control trial demonstrated non-inferiority of nevirapine versus atazanavir/ritonavir with a tenofovir/emtricitabine backbone.30
Serious hepatic events, including liver-related death and skin rash have been observed when nevirapine was initiated in treatment-naïve patients, generally occurring within the first few weeks of treatment. The risk of adverse events during nevirapine-use has been linked to CD4 count at treatment-initiation and gender. Therefore, in naïve patients, nevirapine should not been given in women with CD4 count >250/mm3 and in men with CD4 count >400/mm3.31
On the other
hand, nevirapine is very well tolerated on a long-term basis and has a favourable lipid profile. Adverse effects affecting the central nervous system are the major limitation of efavirenz, yet usually are resolved after a few weeks.32
Choice of Protease Inhibitor
Each PI has its own virological potency, adverse-effect profile and pharmacokinetic properties. When selecting a boosted PI-based regimen for a treatment-naïve patient, clinicians should consider factors such as dosing frequency, food requirements, pill burden, daily ritonavir dose, potential for drug interactions, baseline hepatic function, toxicity profile of the individual PI and pregnancy status.
Preferred Protease Inhibitor Components Lopinavir/Ritonavir – Coformulated
Lopinavir/ritonavir is the only available, coformulated, boosted PI. It can be given once or twice daily, both in treatment-naïve and treatment-experienced patients.33
Several clinical trials have shown
that regimens containing twice-daily lopinavir/ritonavir with two NRTIs have high virological activity in treatment-naïve patients during long periods of follow-up. Early studies have given strong evidence that lopinavir/ritonavir was superior to nelfinavir in maintaining undetectable viral loads.34
A seven-year follow-up study of lopinavir/ritonavir and 76 Ritonavir-boosted Darunavir
The ARTEMIS study compared darunavir/ritonavir (800/100 mg once daily) with lopinavir/ritonavir (once or twice daily), both in combination with tenofovir/emtricitabine, in a randomised, open-label, non-inferiority trial. The study enrolled 689 treatment-naïve participants who had a median CD4 count of 225 cells/mm3 and a median plasma HIV-RNA level of 4.85 log10 copies/ml. At 48 weeks, darunavir/ritonavir was significantly non-inferior to lopinavir/ritonavir, as the virological response rates were significantly lower in the lopinavir/ritonavir arm for those participants whose baseline HIV-RNA levels were >100,000 copies/ml. Grades 2 to 4 adverse events, primarily diarrhoea, were seen more frequently in those receiving lopinavir/ritonavir.9
Previously,
96-week-results of the ARTEMIS trial suggested that virological response to darunavir/ritonavir was superior to response to lopinavir/ritonavir.33 However, this alleged superiority did not convince the US Federal Drug Administration (FDA) and was not mentioned in the recently revised darunavir product labelling.40
EUROPEAN INFECTIOUS DISEASE
Another option for initial therapy is the combination of tenofovir, emtricitabine and the integrase strand transfer inhibitor (INSTI) raltegravir.7
two NRTIs showed sustained virological suppression in patients who continued the originally assigned regimen.35
Previous studies have also
reported no evidence of developing resistance to PI in the event of virological failure, thus suggesting a high genetic barrier, a common feature among boosted PIs.35
However, the need for 200 mg/day of ritonavir and the higher rate of gastrointestinal side effects and hyperlipidaemia, when compared with other PIs typically prescribed with ritonavir 100 mg/day, make it more of an alternative rather than a preferred PI among PI-naïve patients, as stated in US recommendations. Mean changes from baseline in fasting total cholesterol, non-high-density lipoprotein cholesterol and triglycerides were significantly higher with lopinavir/ritonavir than with boosted-atazanavir,36
but these abnormalities have not translated into
a higher cardiovascular risk in clinical practice. European and French recommendations have generally left lopinavir/ritonavir as a first-choice PI. Lopinavir/ritonavir is currently the most frequently prescribed PI in pregnant women.
Ritonavir-boosted Atazanavir
In a clinical trial, ritonavir boosted-atazanavir, given as two pills once daily, enhances the concentration of atazanavir and improves virological activity compared with unboosted atazanavir.37
The Castle
study also compared once-daily atazanavir/ritonavir to twice-daily lopinavir/ritonavir, each in combination with tenofovir/emtricitabine, in 883 ARV-naïve participants. In this open-label, non-inferiority study, analysis at 48 weeks8
and at 96 weeks38 showed similar
virological and CD4 T-cell count responses between both regimens. Still, higher incidence of hyperbilirubinaemia and lower incidence of gastrointestinal toxicity were observed in the ritonavir-boosted atazanavir arm.
Several cases of nephrolithiasis have been reported in patients who received ritonavir-boosted or unboosted atazanavir.39
Since
atazanavir/ritonavir requires more acidic gastric pH in order to be dissolved, concomitant use of drugs that raise gastric pH levels
(i. e. antacids, H2 antagonists, proton pump inhibitors) may impair absorption of atazanavir and patients need to be aware of these problematic interactions. Atazanavir is one of the most frequently prescribed PI because it is administered once daily with low ritonavir dosage (100 mg/day) and is well tolerated. Symptomatic mild hyperbilirubinaemia does occur in less than 10 % of patients.
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