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-naïve, 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%.

Secondary endpoints included: viral suppression, death, new stage 3 or 4 events, resistance, loss to follow up, adherence, treatment changes and toxicity.

Participants were monitored clinically 3 monthly in both arms and those in the laboratory monitoring arm also had CD4 and viral load measured every 6 months.

Switching to second line was indicated by grade 3 or 4 events in the clinical monitoring arm and persistent viral load >5000 copies/mL in the laboratory monitoring arm.

Of a total of 493 patients, 256 were assigned to clinical and 237 to laboratory monitoring. Of these, 93% were followed and included in the analysis. Patients were similar at baseline with CD4 counts of 179 cells/mm3 and 182 cells/mm3 in the clinical and laboratory monitored arms respectively. Both arms had high baseline viral loads of 5.6 log₁₀ copies/mL. Overall 70% were women. About 65% started treatment with d4T + 3TC + NVP.

The trial failed to demonstrate non-inferiority of clinical monitoring:  the mean increase in the CD4 count was 175 cells/mm3 (95%CI 151-200) vs 206 cells/mm3 (95% CI 181-231) in the clinical and laboratory arms respectively. This gave a difference –31 (–63 to +2), the non-inferiority margin was –52 (–58 to –45). The analysis was last observation carried forward.

The analysis also revealed that 13 (6%) laboratory-monitored participants switched to second-line regimens because of treatment failure, compared to none of the clinically monitored participants, p<0.001. But, viral suppression (49 vs 52%), resistance (both 10%), mortality (18 vs 14%), disease progression (36 vs 29%), adherence (both 64%), loss to follow-up (9 vs 8%), and toxicity (19 vs 25%) were similar between the two groups.

Dr Kouanfack concluded that failure to demonstrate non-inferiority of immunological recovery and the need to switch to second line in this trial supports the WHO recommendation of laboratory monitoring of HAART where possible.

He also concluded that the difference between the two strategies suggest that clinical monitoring alone can be used for at least the first two years of treatment in order to expand scale up and to take into account financial and infrastructural constraints in resource limited settings.

References

1. Jourdain G et al. PHPT-3: A randomised clinical trial comparing CD4 vs viral load ART monitoring/switching strategies in Thailand. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 44.
2. Kouanfack C et al. HIV viral load, CD4 cell count, and clinical monitoring vs clinical monitoring alone for ART in rural hospitals in Cameroon: Stratall ANRS 12110/ESTHER trial, a randomised non-inferiority trial. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 45LB.

Both webcasts: Research on Delivery of Care in Developing Countries. Monday 28 February 11 am.

DART was a randomised trial comparing clinically driven monitoring (CDM) to laboratory (CD4, haematology, biochemistry) plus clinical monitoring (LCM) of 3316 HAART-naïve adults conducted in Uganda and Zimbabwe. People in both monitoring arms showed high and similar 5-year survival rate – 90% vs 87% in the LCM and CDM arms respectively – differing by a small percentage that only occurred after two years of follow up. This compared to an historical 5-year survival rate prior to HAART of only 8% in the Uganda cohort. [1]

First line HAART in this trial was AZT/3TC plus either TDF (74%), ABC (9%) or NVP (16%). Participants needing to switch to second line received LPV/r plus NRTI/s and/or NNRTI. Neither the CDM nor LCM group had real time viral load monitoring.

Ugandan patients who did not participate in one of two, nested second line RCTs had a viral load test when they left the trial and joined the national programme.

Further findings from the DART trial were presented at CROI 2011.

Cissy Kityo and colleagues showed high rates of virological suppression at 5 years after HAART initiation among the Ugandan participants alive and in follow up. [2]

Both monitoring groups switched to second line therapy following WHO stage 4 or multiple stage 3 events; the LCM group also switched at CD4 <100 cells/mm3.

A viral load measurement was available the end of the trial for the majority of eligible participants: 1207 (80%) and 187 (70%) respectively receiving first and second line at exit. The viral load sample was taken at a median of 5.2 years after initiation of HAART and 2.7 years after start of second line for those who had switched.

Of the participants who remained on first line, 81.9% (95%CI 78.5-84.9%) in LCM and 74.2% (95%CI 70.6-77.6%) in CDM had viral load <200 copies mL, p=0.001. In the LCM group 5.6% (95% CI, 3.9-7.8% had viral loads <10,000 copies, which was lower than the 10.4% (95%CI 8.1-13.1%) of participants in CDM.

Of those who switched, viral loads were similar across the two monitoring groups, p=0.6. Viral load <200 copies/mL was achieved in 88.8% (95%CI 83.3-92.9%) of participants receiving second line.

When the investigators examined the CD4 count nearest to the exit viral load measurement (taken at a maximum of 6 months apart), they found a negative association, r=0.4, as would be expected.

Of 283 (20%) participants with viral load >200 copies/mL, 29% in the LCM group and 42.2% in CDM had CD4 <200 cells/mm3.

The investigators noted that CD4 counts <100 cells/mm3 were rare in either arm; only 2 people in LCM and 7 in CDM.

A related study showed a single CD4 test with a threshold of >250 cells/mm3 could reduce inappropriate switching in clinically monitored patients. [3]

Charles Gilks and colleagues investigated the relationship between CD4 count at switch and the reason for doing so in all 675 (361 LCM and 314 CDM) DART participants switching to second line.

In the CDM arm, 206 (66%) switched due to WHO stage 4 events and 76 (24%)/32 (10%) participants single or multiple WHO stage 3 events, respectively. In LCM 265 (73%) participants switched because their CD4 count fell below 100 cells/mm3, 43 (12%) for other CD4 reasons, 37 (10%) due to WHO 4 events and 6 (23%)/10 (3%) single or multiple WHO stage 3 events.

In the LCM arm, clinical failure provoked switching in 7 (2%) of patients with CD4 >250 cells/mm3; 3 due to WHO stage 4 events, 1 single WHO stage 3 event and 3 for other CD4 reasons. This compared to 64 (20%) of participants who switched with CD4 > in the CDM arm, p=0.001. The investigators noted, however, that deaths within one year of switching were similar in CDM whether participants switched above or below 250 cells/mm3, 11/64 (17%) vs 33/250 (13%) respectively.

In the CDM group, switching due to a single WHO grade 3 event was significantly more frequent with a CD4 count of >250 cells/mm3 (27/76, 36%) compared to multiple WHO stage 3 events (4/32, 12%) or WHO stage 4 events (33/206, 16%), p=0.001.

Viral load measurements at switch were available for 108 and 113 participants in the LCM and CDM groups respectively.  Of these, 15 (14%) vs 32 (28%) respectively were <400 copies/mL, p=0.009.

In the CDM group, 25/31 (81%) with clinical failure and CD4 > 250 cells/mm3 had viral load <400 copies/mL vs 7/82 (9%) with CD4 <250 cells/mm3, p<0.001.

The investigators noted a trend to switching for single WHO stage 3 events compared to multiple WHO stage 3 or stage 4, but this was not significant, p=0.22.

They concluded that among clinically monitored patients, a single CD4 test with a threshold of 250 cells/mm3 could identify up to 80% with viral load <400 copies/mL who are unlikely to benefit from second line therapy. In DART, nearly 40% of participants who failed clinically with a single WHO stage 3 event had CD4 >250 cells/mm3. They wrote: “Targeting this group would be particularly likely to avoid premature, costly switching to second line.”

References

1. DART trial team. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. The Lancet, Volume 375, Issue 9709. 9 January 2010.
2. Kityo C et al. High rates of virologic suppression among patients not receiving routine virologic monitoring after 5 years of first-line ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 677.
3. Gilks C et al. A single CD4 Test with threshold >250 cells/mm3 can markedly reduce switching to second-line ART in African patients managed without CD4 or viral monitoring. 18th CROI, 27 February–2 March 2011, Boston.  Poster abstract 676.

WHO guidelines recommend the use of boosted protease inhibitors second line in resource limited settings. Findings from strategies looking at using lopinavir/ritonavir (LPV/r) have been uncertain to date, both in limited and richer resourced settings.

Two posters at CROI 2011 presented data from studies evaluating LPV/r monotherapy, with showed further conflicting results.

ACTG 5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy in a pilot study. It was a single arm multinational trial with sites in Malawi, Tanzania, South Africa, Thailand and India.

Participants had previously received first line NNRTI-containing regimens for at least six months and had detectable viral load 1,000–200,000 copies/mL. All participants received LPV/r monotherapy BID. The primary endpoint was remaining on monotherapy without virological failure at 24 weeks. This was defined as: failure to suppress viral load to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression.

People with virologic failure received intensification with emtricitabine (FTC) 200 mg/tenofovir (TDF) 300 mg.

There were 123 participants enrolled in this trial. About 60% were women and they were a median of 39 years of age, with a median CD4 of 164 cells/mm3 and viral load of 4.34 log₁₀ copies/mL (17% were >100,000 copies/mL).

Other baseline characteristics included: 93% with >1 year HAART, 98% with >1 NNRTI mutation and 95% with >1 NRTI mutation (87% M184V, 84% TAM, 11% K65R, 4% Q151M/L).

The majority, of participants completed 24 weeks of follow-up with the exception of one death at week 20 with a viral load of <400 copies/mL.

The investigators reported, at week 24, 107 (87%; 95% CI 80-92%) of participants remained on LPV/r monotherapy without virologic failure.

Of the remaining, 15 met the criteria for virologic failure and one added FTC/TDF before failure. Of 13 participants with data after intensification, 11 (85%) suppressed viral load to <400 copies/mL.

At virologic failure, 2/11 participants who were successfully sequenced had selected new resistance mutations (both had A71T and V82F). The overall mean CD4 count increase from baseline to week 24 was 107 cells/mm3. Overall 31 (25%) of participants experienced grade 3 or 4 toxicities. The most commonly reported grade 3 or 4 toxicities (9% of participants) were metabolic (mostly elevated lipids). Self reported adherence was high; at week 24, 83% of participants reported no missed doses.

The investigators concluded that LPV/r monotherapy showed promising preliminary activity as second-line HAART following failure of first-line NNRTI-containing regimens at 24 weeks. The lower bound of the 90% CI (81-92%) of the observed success rate (87%) was above 65%.

Torsak Bunupuradah and colleagues from the HIV STAR Study in Thailand looked at LPV/r monotherapy as second line but they also evaluated viral suppression to <50 copies/mL and included a comparison arm with triple therapy.

The STAR investigators enrolled 200 participants with viral load >1000 copies/mL on NNRTI-containing first line therapy. Participants were randomised to receive either LPV/r monotherapy ot LPV/r + TDF + 3TC.

Treatment failure was defined as viral load >400 copies/mL at >24 weeks. Participants meeting these criteria in the monotherapy arm received intensification with TDF + 3TC.

Participants in this study were about 60% men with a median age of 37 years, CD4 of 188 cells/mm3, and viral load of  4.1 log10 copies/mL.

Prior to switching, 92% of participants were receiving 3TC, 63% d4T, 23% AZT and 5% TDF. Nevirapine and efavirenz were received by 86% and 14% participants, respectively. Without significant differences between arms, 15% of participants had ≥3 TAMS, 82% had M184V/I, 6% had Q151M, and 7% had K65R.

By intent-to-treat analyses at 48 weeks, the proportion of patients with viral load <400 copies/mL the LPV/r monotherapy arm was 75% vs 86% in the TDF/3TC/LPV/r arm, p=0.53. But, only 61% of the LPV/r monotherapy arm vs 83% in TDF/3TC/LPV/r arm had a viral load <50 copies/mL, p<0.01.

Major PI mutations were detected in 1 of 2 LPV/r monotherapy and 0 of 3 TDF/3TC/LPV/r treated participants with genotype results following treatment failure. There was no significant difference in CD4 count increase between arms: 114 vs 137 cells/mm3 in the LPV/r monotherapy and TDF/3TC/LPV/r arms respectively. One death (unrelated to study drugs) was reported in each arm. Serious adverse events were reported in two patients in the LPV/r monotherapy arm and seven patients in the TDF/3TC/LPV/r arm.

The investigators concluded that LPV/r monotherapy should be used with caution as a second-line option, particularly in settings where close viral load monitoring is not available.

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The ongoing EARNEST Trial (NCT00988039) will answer the question whether or not lopinavir/r monotherapy is a sufficiently potent regimen compared to lopinavir/r combined with two NRTIs or raltegravir.

Results from this trial are expected in 2013.

References

1. Bartlett J et al. A pilot study of LPV/r monotherapy following virologic failure of first-line NNRTI-containing regimens in resource-limited settings: The Week-24 primary analysis of ACTG 5230. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 583.
2. Bunupuradah T et al. Second-line LPV/r monotherapy was inferior to TDF/3TC/LPV/r in patients who failed NNRTI regimen: HIV STAR Study. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 584.