Estudio del mercado Global

The first aim of this thesis was to document progress in HIV-treatment since 1996 by reviewing changing patterns of cART use and relating those to trends in patients’ short-term clinical outcomes between 1996 and 2010. A non-selective database that collects data from all HIV-infected patients in clinical care in the Netherlands provided a unique opportunity to record the progress of cART since 1996 across a variety of clinical and non-clinical markers.

The results of this evaluation showed that the use of first-line cART in the Netherlands closely follows changes in guidelines, to the benefit of patients. Between 1996 and 2010, cART regimens changed from mainly 3TC/AZT-based or d4T/3TC-based regimens with unboosted-PIs to TDF/3TC or TDF/FTC with NNRTIs. Despite these changes, there was no significant improvement in short-term mortality, likely because the greatest impact on short-term mortality had already occurred as a consequence of the introduction of combination therapy [4,5,10,52,53,55–58]. However, newer drugs with better tolerability and simpler dosing schemes resulted in significantly improved immunological and virological outcomes and reduced incidences of switching due to toxicity and virological failure. Short-term incidence of switching has decreased significantly since 1996 on all cART lines, indicating that the duration patients spend on a cART-line before switching has improved substantially over time. The incidence of switching to simpler or newer medications in the absence of virological failure or toxicity has increased between 1996 and 2010. As far as we can tell these changes are related to new drugs becoming available rather than improvements in other aspects of clinical care. This suggests that the changing guidelines have rapidly resulted in patients shifting to newer ARV regimens and the results have been to the benefit of patients in care. However, toxicity remains the main reason for switching cART, accounting for 50% of switches of all lines in 2006-2010. The main problem is short-term toxicity, occurring within three months of starting a regimen, in particular, short-term side effects such as rashes, nausea, diarrhoea and anaemia. This

Chapter 6 – Discussion

will likely be aggravated in the future, with a growing number of ageing multi-morbid patients increasingly experiencing drug-drug interactions. Ideally, newly developed drugs will have reduced toxicity, while maintaining the high effectiveness of current ARVs and be able to be safely co- administered with other co-medications.

The second aim of this thesis was to investigate the future challenges that will arise in clinical care in the Netherlands, and to formulate strategies to address these. The documentation of progress in HIV-treatment since 1996 in this thesis and literature highlighted that a model of an ageing HIV- infected population in the Netherlands was the natural next step to achieving these goals. With the improvement in cART, HIV has become an increasingly chronic infection characterised by an ageing HIV-population. As these patients are becoming increasingly complex to manage it is important to quantify the scale of the problem facing the Netherlands in the future. An individual-based model of the ageing HIV-infected population in the Netherlands was constructed, capturing key aspects affecting clinical care of HIV-patients, including the major age-related co-morbidities, their common physiological pathways and treatment. The design of the model was carried out with the consultation of treating physicians in the Netherlands, in order to incorporate the main clinical aspects involved in the care of these patients and parameterisation was based on the Dutch national ATHENA cohort.

Model simulations showed that the age of the HIV-population in clinical care in the Netherlands is rapidly shifting to older age. Median age of patients in clinical care in the Netherlands is expected to increase from 43.9 to 56.6 years by 2030, with nearly 80% of HIV-patients aged ≥50 years. The burden of co-morbidity (age-related non-communicable conditions in addition to HIV) will increase significantly, with 86% of patients expected to suffer from at least one or more co- morbidities by 2030 and a third of patients suffering from multi-morbidity, largely driven by a steep increase in CVD. This increase in co-morbidity will result in a massive increase in polypharmacy. By 2030 half of patients in care are expected to take at least one additional co-medication and over a sixth of the patients will be taking three or more additional co-medications. The majority of patients will be on cardio-vascular medication, reflecting the increase in CVD. These changing trends in the use of co-medication are expected to lead to an increase in the number of patients with problems with HIV-medication. According to our model 40% of patients are expected to experience potential complications with recommended cART regimens by 2030.

The final chapter aimed to evaluate measures that could be integrated into HIV-care to address the growing problem posed the increasing burden of CVD. Standard care was compared to

Chapter 6 – Discussion

interactions with recommended cART regimens compared to standard care, although the analysis does not take into account potential side effects of the polypill, which will depend on the specific formulation. Together this will result in an improvement in patient health, as expressed by the number of DALYs averted, as well as a reduction in treatment costs compared to standard care. The model suggests that of the interventions considered, a smoking cessation programme will have the smallest impact on the primary prevention of CVD whilst the introduction of a polypill for all HIV- patients aged 45 and over would have the greatest impact. Changing HIV-treatment guidelines to recommend the prescription of a polypill for CVD to all HIV-patients aged 45 years and over could result in a 13% reduction in multiple morbidities and polypharmacy, a 7% reduction in potential drug- drug interactions, and a saving of 23 million Euros in treatment costs over a twenty year period compared to standard care. It should be noted that the polypill will have to be reformulated for HIV- patients due to drug-interactions between statins and some ARVs. All interventions have a long-term cost per DALY averted that is under the estimated WHO cost-effectiveness threshold of three times the GDP per capita. The smoking cessation programme has the lowest cost per DALY averted, at €70 compared to €290 for a polypill intervention for HIV-patients aged 45 and over, although it would require nearly a ten-fold higher initial investment than a polypill intervention. By 2015 all interventions considered would be cost saving compared to standard care, although the roll-out of the polypill would likely to come at a higher cost than standard care after 20 years. This may be driven by the increasing number of HIV-patients who live longer as a consequence of the polypill, and spend more time on expensive second-line and third-line cART regimens, thus outstripping the savings in CVD treatment achieved.