Antiretroviral Options for Naïve and Virologically Controlled Patients
Darunavir is the most recent PI. Once-daily administration, low dosage of ritonavir boost (100 mg/day), efficacy and good overall tolerance has made it increasingly popular. Rash, usually mild, occurs in less than ten percent of patients who take darunavir.
Ritonavir-boosted Fosamprenavir
Twice-daily ritonavir-boosted fosamprenavir was non-inferior to twice-daily lopinavir/ritonavir and metabolic adverse effects occurred at similar frequencies for both regimens. Despite these data, boosted-fosamprenavir has not been recommended as a first-choice PI, mainly because it requires BID administration and concomitant 200 mg/day dosage of ritonavir as well as the relatively high incidence of rash during treatment.
Ritonavir-boosted Saquinavir
Saquinavir was one of the first PIs, whose very poor bioavailability is only partially improved by ritonavir. In the GEMINI study, saquinavir/ritonavir (1,000/100 mg twice daily) was compared with lopinavir/ritonavir, both given twice daily, in combination with tenofovir/emtricitabine given once daily. Both arms demonstrated similar levels of viral suppression (64.7 versus 63.5 %) and had substantial increases in CD4 count at 48 weeks.43
However, triglyceride levels were
significantly higher in the lopinavir/ritonavir arm. The need for twice-daily dosing and concomitant 200 mg per day ritonavir make ritonavir-boosted saquinavir an appropriate alternative PI for treatment-naïve patients.
Integrase Strand Transfer Inhibitor-based Regimen plus Two Nucleoside Reverse Transcriptase Inhibitors
Raltegravir is an INSTI that has been approved by the FDA for use in treatment-naïve patients. This indication was based on results from the STARTMRK trial, a Phase III study that compared raltegravir (400 mg twice daily) to efavirenz (600 mg once daily), each in combination with tenofovir/emtricitabine. This multinational, double-blind, placebo-controlled study enrolled 563 subjects with plasma HIV-1 RNA levels >5,000 copies/ml. At week 48, similar numbers of subjects achieved HIV-1 RNA levels <50 copies/ml in both groups (86.1 and 81.9 % for raltegravir and efavirenz, respectively, p<0.001 for non-inferiority). CD4 cell counts rose by 189/mm3 in the raltegravir group versus 163/mm3 in the efavirenz group. Serious adverse events were rare and occurred at similar frequencies in both groups.7
At 96 weeks, virological and immunological
responses remained similar in both groups and no additional safety concerns were identified.28
Comparisons of raltegravir-based regimens with other regimens in treatment-naïve subjects have not yet been reported and there is no extensive follow-up in patients treated with raltegravir than with efavirenz or boosted PIs when initial therapy is concerned. Similar to efavirenz, raltegravir has a lower genetic barrier to resistance than ritonavir-boosted PIs and resistance mutations were observed at approximately the same frequency in the comparative trial. Cross-resistance has been recently observed between raltegravir and the new antiintegrase, elvitegravir.44
Current European and
French recommendations, as opposed to American guidelines, consider raltegravir-based regimen as a suitable alternative
EUROPEAN INFECTIOUS DISEASE
The three studies above give us important insights into how HIV can be treated without nucleoside analogues. However, none of them show any
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Ritonavir-boosted fosamprenavir is recommended as an alternative PI. The KLEAN trial compared twice-daily ritonavir-boosted fosamprenavir with lopinavir/ritonavir, each in combination with abacavir and lamivudine, in treatment-naïve patients. At weeks 48 and 144, similar percentages of subjects achieved HIV-RNA viral loads of <400 copies/ml.41,42
regimen. However, further studies are needed in order to validate current recommendations.
New strategies Maraviroc-based Regimen
The MERIT study compared the C-C chemokine receptor type 5 (CCR5)-antagonist maraviroc with efavirenz, both in combination with zidovudine/lamivudine, in a randomised, double-blind trial among treatment-naïve participants.45
Only participants with CCR5 virus and
no prior evidence of resistance to any drugs used in the study were enrolled (n=633). At 48 weeks, virological suppression (defined as HIV RNA <50 copies/ml) was observed in 65.2 % of maraviroc-treated patients and in 69.2 % efavirenz-treated patients, which did not meet the a. priori criteria established by the investigators to demonstrate non-inferiority for maraviroc. CD4 count did increase by an average of 170 cells/mm3 in the maraviroc arm and 143 cells/mm3 in the efavirenz arm. At 48 weeks, more participants discontinued maraviroc due to lack of efficacy (11.9 versus 4.2 %), whereas fewer participants discontinued maraviroc for toxicity reasons (4.2 versus 13.6 %). Follow-up results at 96 weeks demonstrated durable responses.46
Taking these results
into consideration, the use of maraviroc is still hampered by requiring a tropism test and the relatively high frequency of drug interactions. However, genotypic tests are continuously improving and even as safety data are reassuring, there remains some uncertainty on the long-term impact of CCR5 blockade. This drug still needs to find its place in the armentarium, as illustrated by its approval among treatment-naïve patients in the US but not in Europe.
Nucleoside-sparing Approaches
Results of several studies assessing the combination of raltegravir and PI are available. The Progress study compared raltegravir versus tenofovir-emtricitabine (FTC), both in combination with lopinavir/ritonavir regimen, among treatment-naïve patients. At 48 weeks, virological suppression was observed in 83.2 % of the patients with raltegravir and in 84.8 % of patients in the other arm, demonstrating non-inferiority of the nucleosidic-sparing regimen at 48 weeks. These results should be confirmed at week 96, along with further investigation on resistance mutations. In addition, lopinavir/ritonavir/raltegravir requires three pills, twice daily, which is a relatively high pill burden in dosing frequency with respect to other currently approved regimens.47
The SPARTAN study also looked at raltegravir twice daily plus unboosted atazanavir twice daily compared with a standard regimen of tenofovir/FTC plus boosted atazanavir. Although, comparable virological outcomes were observed between the two strategies, failures in raltegravir plus unboosted atazanavir arm were associated with high rate of raltegravir resistance. In addition, the rate of hyperbilirubinaemia, especially at grade IV, was significantly higher. Currently in Europe, a larger, more strongly powered study is in progress, examining the effect of darunavir/ritonavir plus raltegravir on virological outcomes.48
Another
Despite the small sample-size of this particular study, virological outcomes were comparable. Unfortunately, only patients with R5 virus could be enrolled, thus pre-treatment tropism assays would be necessary for this regimen.
strategy has also been suggested in which maraviroc once-daily 150 mg is added to atazanavir/raltegravir, which has also been compared in a clinical trial with a standard regimen of tenofovir, FTC and boosted atazanavir.49
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