Protease inhibitor monotherapy in African setting results in viral load, but not CD4, failure in the short term

A study of protease inhibitor monotherapy in Africa has found that 25% fewer patients on monotherapy achieved an undetectable viral load than those on standard combination therapy. However, CD4 increases were the same in both groups.

The study adds to the debate about whether using cost-cutting measures such as monotherapy and dispensing with laboratory monitoring will benefit more patients in the long run than trying to use developed-country standards of care in such settings.

The  Tenth International Congress on Drug Therapy in HIV Infection (HIV10) in Glasgow featured a number of presentations on trials of boosted protease inhibitor (PI/r) monotherapy.

This concept so far has been tested in high-income countries where viral load tests are available. A study conducted in two African countries, without viral load monitoring, found that PI/r therapy was significantly less effective, in terms of achieving an undetectable viral load, than standard second-line treatment with a protease inhibitor and two nucleoside reverse transcriptase inhibitors (PI/r/NRTIs).

For every four patients who achieved a successful viral load response on PI/r/NRTI therapy, one would be likely to fail virologically if they took PI/r monotherapy, the study found.

The SARA study was a substudy of the large DART trial in Uganda and Zimbabwe, which has been conducted amongst over 3000 patients to establish if antiretroviral (ARV) therapy can be successfully used in the absence of monitoring tests, using symptoms alone to guide decisions about switching therapy. Although CD4 and viral load tests were in fact conducted in all patients during the DART study, test results were randomised either to be released immediately or to be withheld and only released after the study.

DART, as a whole, found that after five years the death rate in patients receiving standard laboratory monitoring was 10% and in those receiving clinical monitoring alone was 13.5%. Although this difference was significant, investigators pointed out that dispensing with viral load and most CD4 tests would enable them to treat up to a third more patients.

The SARA study was a substudy within DART in which patents on second-line therapy were randomised to receive boosted lopinavir (LPV/r) - either alone as monotherapy or supported by two NRTIs.  

Two hundred patients who had already been on PI/r/NRTI second-line therapy for 24 weeks were randomised either to continue PI/r/NRTI therapy or to stop taking the NRTIs. The patients had been on ARVs for a total of 4.4 years. In the DART study, second-line therapies were triggered when patients developed an AIDS-defining illness, had other serious adverse events, or when CD4 tests (withheld or otherwise) showed to the trial regulators that the count had fallen below 100 cells/mm³, at which point they alerted clinicians.         

Results already presented at the International AIDS Conference in Vienna this year (Gilks) showed that the rises in CD4 counts seen were the same in the monotherapy and combination therapy arms.  At Vienna, after 24 weeks, the average CD4 rise was 48 cells/mm³ in patients on monotherapy and 42 cells/mm³ in patients on combination therapy.  At Glasgow, presenter David Yirrell said that by week 72 the average CD4 count was 150 cells/mm³ in both arms amongst patients who had been in the trial this long.

Monotherapy was therefore equivalent to combination therapy, at least for up to 18 months, when it comes to CD4 counts. But what about viral loads? DART showed that the relatively worse outcomes for patients receiving no lab test results only started to happen after two years, and that staying on NRTIs with what turned out to have been actively replicating HIV led to high levels of NRTI drug resistance.

At randomisation, the retrospectively reviewed viral load tests showed that 87% of SARA recruits had had viral loads under 50 copies/ml at the start of the study.

After 24 weeks, 78% of those on PI/r/NRTIs  still had viral loads under  50 copies/ml, but only 59% of those on monotherapy: 24% fewer. Six per cent of patients on combination therapy had viral loads over 1000 copies/ml, but 16% of those on monotherapy.

By 96 weeks, nearly two years into the study, 50% of patients on monotherapy had a viral load below 200 compared with only 20% on combination therapy. So far, though, there is data on only a small number of patients who reached this point.

Over the course of the study there was a net viral load increase in 31% of patients, but this must be weighed against a net viral load decrease in 45% of patients.

Do these viral load failures have clinical consequences? Data from the 133 patients at the two Ugandan sites show that 7.6% of those on combination therapy, and 36% on monotherapy, had viral loads over 1000 at week 24, and resistance tests were conducted with most of these patients. Major PI resistance mutations were found in four patients out of 24 patients on monotherapy and none on combination therapy.

To summarise, over the relatively short term (follow-up in SARA was a median of 60 weeks), there was an increase in viral load but no decrease in CD4 counts in patients on monotherapy, and only one in six patients who failed monotherapy developed PI resistance. This implies the majority would be re-suppressed virologically if they resumed NRTIs, as all patients did at the end of the study. Presenter David Yirrell concluded that “longer-term trials are required before definitive conclusions can be drawn” about the wisdom of offering either monotherapy or combination therapy without lab tests.   

References

Yirrell D et al. Virological findings from the SARA trial: boosted PI monotherapy as maintenance second-line ART in Africa. Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract O115, 2010.

Gilks CF et al. Boosted protease inhibitor monotherapy as maintenance second-line anti-retroviral therapy in Africa: a randomised controlled trial (SARA). Eighteenth international AIDS Conference, Vienna, abstract LBPE16, 2010.

Pillay D et al. Emergence and evolution of drug resistance in the absence of viral load monitoring during 48 weeks of Combivir/tenofovir within the DART trial. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 642, 2007.