Other antiretroviral studies at ICAAC
Satyajit Das, HIV i-Base
Brief reviews of the main ARV studies at ICAAC.
Early HAART may improve survival
Starting treatment against deferring highly active antiretroviral therapy (HAART) at a CD4 count between 351 and 500 cells/mm3 was associated with a 70% reduction in mortality rates.
This study incorporated collaboration between 22 HIV research cohorts in North America and a standardisation of data to allow their integration and analysis. Patients were those with a CD4 count between 351 and 500 cells/mm3 who were in active follow-up between 1996 and 2006. Patients with previous antiretroviral treatment and those who already had experienced an AIDS-defining illness were excluded.
Over 2450 patients initiated HAART (8358 person-years), and just over 5900 patients (16,636 person-years) deferred treatment during the period of the study. Those who began treatment were more likely to be male sex, older, have a higher viral load at baseline, but the differences in median values between the two groups were not large.
Those who deferred starting HAART had a mortality relative hazard 1.7 times that of patients who began therapy within that CD4 range (p<0.001).
The presenting author suggested that the data strongly support the use of antiretroviral treatment for patients at a CD4 count of 500 and below, regardless of the presence of symptoms.
Previous studies have suggested similar trends, but most of the studies did not have the power to find meaningful differences in strategies. Although this was an observational study, aggregation of the cohorts together created sufficient power to reach definitive conclusions.
However, in most centres, a significant number of patients are diagnosed with HIV for the first time with low CD4 counts or with AIDS defining illnesses. The recently published joint HIV testing guidelines from BHIVA/BASHH/BIS might help to increase the uptake of HIV test and diagnose HIV cases at an earlier stage and would make them available for treatment at an earlier stage.
Ref: Kitahata MM et al. Initiating rather than deferring HAART at a CD4+ count between 351-500 cells/mm3 is associated with improved survival. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-896b.
Raltegravir in treatment-naive patients
Lennox and colleagues reported results in a late-breaker presentation from the STARTMRK Phase 3 trial comparing raltegravir to efavirenz, both in combination with Truvada, in treatment-naive HIV patients.  Raltegravir continues to impress with its safety and efficacy, this time with 48-week data from treatment-naive patients.
Patients were screened for resistance to tenofovir or emtricitabine, and the 563 patients who showed no resistance were enrolled in the randomized blinded trial to add either raltegravir (400 mg twice daily) or efavirenz (600 mg every day at bedtime) to the regimen. At baseline, a significant portion of patients had advanced HIV disease with 47% having a CD4 T cell count of 200 or less cells/mm3 and 53% having a viral load of more than 105 HIV RNA copies/mL. The primary endpoint was suppression to less than 50 HIV RNA copies/mL.
Both arms showed high rates of suppression at one year.
Using an intent-to-treat analysis, 86.1% of the raltegravir and 81.9% of the efavirenz groups achieved the primary end point of <50 copies/mL. The difference did not reach statistical significance, and the study easily achieved its goal of showing non-inferiority of raltegravir compared to efavirenz (p< 0.001).
There was faster initial suppression of viraemia in the raltegravir group, but the two groups converged over time. The increase in CD4 cells from baseline was 26 cells/mm3 higher in the raltegravir group (189 cells/mm3 vs. 163 cells/mm3), but did reach statistical significance.
Adverse effects were common in both groups (44% vs 77%), with raltegravir maintaining the more favourable profile for moderate to severe events (16% vs 32%).
One of the greatest drawbacks to efavirenz is that a portion of patients experience central nervous system (CNS) problems, some to the point of discontinuing its use. The accumulated CNS adverse events to week 8 favoured raltegravir (10.3% vs. 17.4%). Depression occurred in around 5% of patients in both groups to week 48.
There was one malignancy in the raltegravir arm and nine in the efavirenz arm, most of which were Kaposi’s sarcoma.
Total cholesterol, LDL and triglycerides increases were higher in the efavirenz arm (all p<0.001 compared to raltegravir) but efavirenz patients also experienced higher increases in HDL (p<0.001). The total-to-HDL cholesterol ratio dropped slightly in both treatment arms (NS between arms).
In summary, raltegravir showed comparable virological efficacy as efavirenz at 48 weeks in treatment-naive HIV patients, but was better tolerated.
The researchers presented some data looking at whether raltegravir could be dosed once-daily, and QQ studies are planned.
This trial possibly brings integrase inhibitors, specifically raltegravir, into the list of drugs that we could consider for first-line use.
However, unless the current price is dramatically reduced to a comparative level of other first-line combinations, it is unlikely to be broadly available in the UK.
Ref : Lennox J et al. STARTMRK, a phase III study of the safety & efficacy of raltegravir (RAL)-based vs Eeavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients. 48th ICAAC, 25-28 October 2008. Washington. Abstract : H-896a.
Darunavir is comparable to lopinavir in treatment-naive patients
In the ARTEMIS study, darunavir/ritonavir (DRV/r) appears to be statistically superior to lopinavir/ritonavir (LPV/r) in treatment-naive patients after 96 weeks of treatment. The study showed non-inferiority at 48 weeks, but at the 96-week endpoint there was statistical significance as far as superiority.
Over 680 patients were randomised to receive either DRV/r 800/100 mg once daily or a total daily dose of LPV/r 800/200 mg with backbone of Truvada (tenofovir/FTC).
At week 96, a greater percentage of patients in the DRV/r group had <50 copies/mL (79% vs. 71%, p=0.38), and the median change in absolute CD4 count was greater (+188 vs +171 cells/mm3). This continues a trend observed in week-48 data.
The authors suggest that tolerability explains much of the difference in dropouts and virologic failure between the two groups.
It is important that the LPV/R arm started with tablets and soft gel capsules as well (Table 1).
Table 1: Lopinavir dosing
|LPV dosing||LPV formulation|
Ref: Mills A et al. ARTEMIS: Efficacy and Safety of Darunavir/ritonavir (DRV/r) 800/100 mg Once-daily vs Lopinavir/ritonavir (LPV/r) in Treatment-naive, HIV-1-infected Patients at 96 Wks. 48th ICAAC, 25-28 October 2008. Washington. Abstract H 1250
Atazanavir is comparable to lopinavir/r in treatment-naive patients
A poster on the CASTLE study extended the comparison of once-daily atazanavir/ritonavir (ATV/r) and twice-daily LPV/r in treatment-naive patients. 
Earlier 48-week data demonstrated the comparability of the two therapies. By week 96, they were still comparable but had begun to show differences, but these were not statistically or clinically significant.
In an intent-to-treat (non-completer = failure) analysis at 96 weeks, 327 of 440 patients (74%) in the atazanavir/ritonavir arm achieved HIV RNA < 50 copies/mL, compared with 302 of 443 (68%) in the lopinavir/ritonavir arm (P < 0.05). Mean CD4 increases from baseline were comparable: +268 in the atazanavir/ritonavir arm and +290 in the lopinavir/ritonavir arm (p=NS).
Rates of virological failure were low in both arms, at 7%. Discontinuation of study at 96 weeks was 16% of participants in the atazanavir/ritonavir arm and 21% in the lopinavir/ritonavir arm. Both measures in this intent-to-treat analysis were affected by the higher dropout rate in the LPV/r group.
Virologic failure in both groups was around 7%. The ATV/r arm showed better gastrointestinal tolerability. It also showed an improved fasting lipid profile over baseline (total cholesterol to HDL cholesterol ratio of >5; 23% at baseline and 17% at week 96), whereas the LPV/r group showed no improvement and was more likely to initiate lipid-lowering therapy (2% vs. 9%).
There were some concern previously that ATV/r may not do well in patients with high viral load and low CD-4 count. These data show that atazanavir is just as potent a drug as other PIs in all patient populations.
Another poster from the CASTLE study suggested no adherence benefit of protease inhibitor treatment given once compared to twice a day. 
Overall, adherence rates were above 80% throughout the study and did not differ between the two groups. Interestingly, more people reported forgetting to take ATV/r (11%) than LPV/r (6%).
In the past few years, once daily antiretroviral regimens have become more common particularly since the introduction of Atripla (tenofovir + FTC + efavirenz). While people with HIV commonly express a preference for simpler regimens, there’s little comparative data to show how well they perform compared to twice daily regimens. This CASTLE analysis suggests that once daily dosing did not lead to better adherence and might actually lead to slightly higher rates of forgotten doses.
Both the ARTEMIS study and the CASTLE study suggest that PI-naive patients (in the absence of PI resistance) do not have to take more than 100 mg of ritonavir when starting with PI.
The 200mg ritonavir dose that is coformulated in lopinavir/r (Kaletra) may lead to higher triglycerides, cholesterol and GI side effects in patients who are sensitive to ritonavir.
- Molina J et al. CASTLE: atazanavir-ritonavir vs lopinavir-ritonavir in antiretroviral-naive HIV-1 infected patients: 96 week efficacy & safety. 48th ICAAC, 25-28 October 2008. Washington. Abstract; H-1250d
- Su J et al. Adherence in antiretroviral treatment-naive subjects treated with once daily atazanavir/ritonavir or twice daily lopinavir/ritonavir, both in combination with tenofovir/emtricitabine: 48 week results from the CASTLE study. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-1242.