Running out of antiretroviral treatment options may severely curtail the life expectancy of people with HIV in resource-rich countries, according to Australian research published in the online edition of AIDS. The research expands upon a study presented at the Eleventh International Congress on Drug Therapy in HIV Infection in Glasgow last year.
“Our results are clear that a substantial proportion of PLHIV [people living with HIV] will run out of effective cART [combination antiretroviral therapy] options before they have approached the life expectancy of their HIV-uninfected peers,” comment the authors. This was especially the case for people who started therapy in their early 20s.
Overall, the authors calculated that people would run out of effective treatment options after a median of 46 years. Moreover, a substantial minority of people would exhaust their therapeutic options in just 26 years.
But it can be questioned if the investigators’ calculations are reliable. By their own admission, they are partially reliant on data collected during the early years of the treatment era when combinations of drugs were used that would now be regarded as suboptimal. Modern anti-HIV drugs are significantly more potent, less toxic and easier to take than older agents, several of which are no longer manufactured.
Furthermore, new data from European cohort studies show that by 2008, resistance test data on all patients indicated that only 1% had exhausted all currently available drug options, suggesting that the assumptions used in the Australian study considerably over-estimate the risks of treatment exhaustion.
The prognosis of HIV-positive people in resource-rich countries improved dramatically after the introduction of triple-drug antiretroviral therapy in the mid 1990s. Several studies have attempted to project the life expectancy of people with HIV, with some showing that this now equals that of the general HIV-negative population.
However, investigators in Sydney were concerned that these calculations were based upon a relatively short period of follow-up and did not take into account the long-term availability of active combinations of antiretroviral drugs. The current trend to start HIV therapy at higher CD4 counts and to use antiretrovirals for prevention could, the investigators feared, mean that people would run out of treatment options, limiting their life expectancy.
The authors therefore developed their own prognostic model based upon data obtained from 3434 people (94% of whom were men) who received HIV care between 1997 and 2010. The model simulated disease progression, treatment progression and mortality to determine the time until treatment options were exhausted, and the impact of this on prognosis. They performed two simulations for scenarios when people started treatment at 20 and 40 years of age. Their calculations were based on the availability of six classes of antiretroviral drugs, and that at each treatment change, patients could replace one drug class.
According to the investigators’ projections, people would remain on their first antiretroviral combination for a median of 7.2 years. The median duration of second-line treatment was 15.2 years and third-line therapy was efficacious for 5.2 years. The durability of first-line treatment was somewhat better for people who received care between 2004 and 2010 when more potent and tolerable antiretrovirals became available. Based on data obtained from this period, the authors calculated that the median duration of first-line treatment was 8.4 years; 13.6 years would be spent taking second-line therapy; and 2.5 years were spent taking third-line combinations.
However, they also calculated that 10% of people would rapidly cycle through their treatment options, changing to second-line therapy in less than one year.
Overall, the median time until the exhaustion of all currently available treatment options was 46 years. The authors calculated that this would have a significant impact on prognosis, especially for people who started therapy at a younger age. An individual who initiated treatment at the age of 20 would be expected to live until they were 67. This compared to an average life expectancy of 82 years for HIV-negative individuals in the general population.
There was better news for people who initiated therapy at the age of 40. Their average life expectancy was 78 years.
But 10% of people were expected to run out of treatment options within 26 years, severely limiting their prognosis.
“While these results confirm the great strides made in improving the life expectancy of PLHIV, they also demonstrate the limitations,” comment the authors. “This may become even more problematic in the future if the contemporary ‘treatment as prevention’ strategy becomes mainstream practice, resulting in PLHIV being diagnosed early in the course of their infection and initiating therapy as soon as possible regardless of CD4 level.”
The researchers therefore emphasise the importance of making the most of available antiretrovirals. “By determining the most efficient combinations and order of regimen administration, we may be able to extend the viability of currently available cART over a longer period and hence increase the life expectancy of PLHIV by reducing the rate of developing multi-class resistance.”
Nevertheless, the findings of this research run counter to those of other studies which have shown ever improving life expectancies for people with HIV. The authors of the present study believe these are to some extent based on "complacency” because they are "dependent upon sequential cART regimens proving to be successful over decades".
But the authors also admit their own study has a number of limitations, including the fact that the study cohort “was primarily recruited in the early years of cART. This means that they have been more exposed to treatment that have higher toxicity and greater rates of resistance development than those that a person receiving modern standards of care would receive. The implications of this is that the model may underestimate the time spent on first and second class-stages.” Thus, the durability of HIV treatment may have been underestimated.