Monitoring Treatment in Resource-Limited Settings: Results From PHPT-3 and Stratall ANRS12110/ESTER Trials
In resource-limited settings, optimal monitoring and switching criteria from first-line to second-line therapy is unclear. Results from two trials were shown as oral presentations that suggest that monitoring viral load is not essential for switch to second line.1,2
Marc Lallemant showed data from PHPT-3, which was conducted in Thailand. This was a randomised double-blind (until first switch) non-inferiority trial. Participants were randomised to CD4 or viral load monitoring, which was conducted every three months.
Dr Lallemant explained that the trial was designed for a setting with only two lines of treatment and where second line is far more expensive than first line. The investigators wanted to test whether monitoring and switching people without viral load compromised their health or their future options.
PHPT-3 enrolled HIV-positive adults (CD4 count 50 to 250 cells/mm3, not hepatitis B or C co-infected), starting NNRTI-based HAART.
In the CD4 monitoring arm, patients switched to second-line protease inhibitor (PI) -based therapy when they had confirmed CD4 decline of 30% or more from peak, and in viral load monitoring they switched when they had confirmed viral load >400 copies/mL.
The primary endpoint was death, new AIDS-defining event or clinical failure -- defined as CD4 <50 cells/mm3 -- at 3 years. Secondary endpoints included proportions switching to second line, time to switch, resistance mutations at failure and future treatment options.
The trial enrolled 716 patients of which 60% were women. Their median CD4 count at baseline was 144 cells/mm3 (range 90 to 200 cells/mm3).
Regimens were 65% efavirenz-based regimen and 66% of participants received tenofovir/FTC. Other study drugs were nevirapine and AZT/3TC. At 3 years of follow up 93.3% of patients were evaluable. Ten percent stopped treatment for toxicity across both groups.
There were 58 clinical failures overall, 28 and 30 in the CD4 and viral load groups respectively. The respective rates of clinical failure per patient years were 2.3 vs. 2.5 and of death 1.1 vs. 1.4.
In multivariate analysis, anaemia, adjusted HR 2.7 (95% CI 1.5-4.8), p=0.001; CD4 <150 cells/mm3, AHR 2.3 (95% CI 1.2-4.2), p=0.009 and viral load >5 log, AHR 1.8 (95% CI 1.0-3.0), p=0.04, were predictive of clinical failure at 3 years.
The probability of switch to second-line (excluding toxicity/intolerance) was 5.2% (95% CI 3.2-8.4%) vs 7.5% (95% CI 5.0 -11.1%) in the CD4 and viral load groups respectively, p= 0.10.
The respective median times to switch were 11.7 months (95% CI 7.7-19.4) vs. 24.7 (15.9-35.0), p=0.001. And the median duration of viraemia >400 copies/mL was 7.2 months (IQR 5.8 to 8.0) vs. 15.8 months (8.5 to 20.4), p= 0.002. But the median CD4 counts were 426 cells/mm3 vs. 420 cells/mm3, respectively.
Dr Lallemant noted that 15/31 patients in the CD4 monitoring arm who switched to second-line had viral load <50 copies/mL at the time of switching.
Viral load was <50 copies/mL in 99% of patients at 3 years follow-up and patients with CD4 monitoring did not have fewer future treatment options, with the exception of one patient with multiple thymidine analogue mutations (D67N/M41L/L210W/T215Y).
Dr Lallemant concluded that, after 3 years, the rate of clinical failure was very low and did not differ between the two strategies. Most mutations had been selected at the time of virological failure. The additional time spent on failing treatment in the CD4 arm did not result in reduced future treatment options.
He noted that the conclusions from PHPT-3 are similar to those from DART and HBAC in adults and PENPACT-1 in children. He added that the need for viral load monitoring may be less important than close and regular safety, tolerability, adherence, and immunological monitoring. He remarked that the nurse/patient team with expert assistance from doctors, biologists and patient networks "maximizes efficacy and durability."
This was followed by a related presentation of data from the Stratall ANRS12110/ESTER trial.
Charles Kouanfack showed findings from a trial designed to compare clinical monitoring alone with laboratory and clinical monitoring. This trial was conducted in 9 rural district hospitals in Yaounde, Cameroon.
Dr Kouanfack explained, in Cameroon, the national programme followed WHO guidance for a public health approach based on decentralised, integrated HIV care delivery in facilities where laboratory monitoring is generally unavailable. He noted that the 2010 guidelines also state that using viral load monitoring to detect treatment failure and switch is recommended but has "low quality evidence".
Stratall ANRS12110/ESTER was a randomised non-inferiority trial enrolling HAART-naive, HIV-positive adults with a WHO stage 3-4 disease or stage 2 and total lymphocyte count <1200 cells/mm3, who were followed for 2 years. Management was by the health workers in charge of routine activities.
The primary endpoint was mean increase in CD4. The increase in the clinical monitoring arm was judged to be non-inferior to that in the laboratory monitoring arm if the difference was less than or equal to 25%.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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