Triple-class failure emerges slowly in UK patients

Evidence from a large cohort of HIV-positive patients in the UK suggests that extensive virological failure of the three main classes of antiretroviral drugs emerges slowly, with a little over 10% of patients having extensive triple-class failure ten years after starting potent antiretroviral therapy, according to a study published in the December 8^th edition of The Lancet.

The study also showed that 60% of patients with extensive triple-class failure had at least one viral load measurement below 50 copies/ml after failure had occurred, suggesting that failed treatment continued to have some antiretroviral effect. Furthermore, there was good survival five years after the emergence of extensive virological failure, the cumulative risk of death being 10.6%.

The investigators think that their findings are "good news" for treatment programmes in resource-limited countries which are reliant upon drugs from the NRTI, NNRTI and boosted-protease inhibitor classes.

Results from the study also showed the importance of cutting the rate of late diagnosis in the UK, as patients who commenced potent anti-HIV treatment when their CD4 cell count was above 200 cells/mm³ were significantly less likely to develop extensive triple-class resistance than those who started therapy with a CD4 cell count below this level.

But an accompanying editorial draws less optimistic conclusions and states that the study is a “wake-up call" for global access to salvage therapy.

Background to the study

Investigators from the UK Collaborative HIV Cohort (UK CHIC) wished to estimate the proportion of patients with extensive triple-class failure ten years after the initiation of potent anti-HIV therapy and to describe the characteristics associated with early failure. Such data will assist in predicting the need for new drugs and healthcare resources in both industrialised and resource-limited settings.

Three new classes of antiretroviral drugs, fusion inhibitors, integrase inhibitors and CCR5 antagonists, have recently become available to patients with extensive treatment failure in the UK and similar countries, extending their treatment options and offering the possibility of long-term viral suppression. Nevertheless, triple-class failure is still considered an important “mile stone” and a warning that treatment options could soon be exhausted.

In resource-limited settings, NRTIs, NNRTIs and ritonavir-boosted protease inhibitors are likely to be the only antiretroviral drugs available for some time, so an appreciation of the durability of these drugs is essential for long-term planning.

Study design and population

Extensive failure of a drug class was defined as the virological failure of any drug within it. Extensive triple-class failure was defined as the virological failure of at least one drug from each of the NRTI, NNRTI and ritonavir-boosted protease inhibitor classes.

A total of 7,916 patients from ten HIV treatment centres were included in the investigators’ analysis. A quarter were women, the median age was 36 years, 61% initiated antiretroviral therapy with a regimen that included two NRTIs and an NNRTI, the median CD4 cell count when anti-HIV therapy was started was 187 cells/mm³, viral load at this time was 100,000 copies/ml and 20% of patients had an AIDS diagnosis when therapy was initiated.

Results

A total of 167 patients (2.1% of the cohort) developed extensive triple-class failure during 27,441 person years of follow-up. Of these 167 patients, 129 (77%) had previously had a viral load below 50 copies/ml. Patients were heavily treatment-experienced at the time that extensive triple-class failure occurred with 90% having received therapy with seven antiretroviral drugs or more, and 19% nine of more drugs.

The investigators estimated that the cumulative five-year risk of extensive triple-class failure was 3.5%, with the risk increasing to 10.2% ten years after the initiation of potent anti-HIV treatment.

Factors significantly associated with extensive triple-class failure were a low CD4 cell count at the start of antiretroviral therapy (p

Further analysis showed that patients who started antiretroviral therapy with a CD4 cell count above 200 cells/mm³ had a cumulative risk of triple-class failure over ten years of 5.5% compared to a risk of 12.1% for patients who started therapy with a CD4 cell count below 200 cells/mm³.

Viral load results after extensive triple-class failure were examined by the investigators. They found that 60% of patients had at least one viral load measurement below 50 copies/ml after experiencing such failure, with 44% having at least two consecutive measurements below 50 copies/ml.

A total of 239 patients from the entire cohort of 7,916 patients died within ten years of starting anti-HIV therapy. The cumulative risk of death five years after extensive triple-class failure was 10.6%.

“Our study has shown that the rate at which patients starting antiretroviral therapy have extensive virological failure of the three main antiretroviral drug classes seems to be low”, write the investigators. They add, “even in patients who have such extensive virological failure, the death rate remains fairly low…this finding suggests that drugs in these classes can sustain virological efficacy for a sustained length of time, which is especially encouraging for developing countries where drug availability will probably be restricted to the three original classes for some time.”

An accompanying editorial notes that patients in resource-limited setting have access to fewer diagnostic tests and antiretroviral drugs than patients in the UK. The authors believe that the data from the UK CHIC “underscore the need for access to alternative, less toxic, and more affordable first-line, second-line and now third-line antiretroviral drugs in developing countries…we can think of no reasonable explanation to patients about why they access few and relatively poorer drug formulations.” The authors of the editorial conclude, “we need a visionary response that treats poor patients as optimally as wealthier patients. In years to come, we will look back and wonder if we can really say we did the best we could.”