Generics and HIV: cost versus care

In 2013, HIV is considered a manageable, chronic condition for which many can expect an almost normal life expectancy.(1) Deaths from AIDS-related illnesses are increasingly rare in the diagnosed population, with long-term comorbidities, such as cirrhosis secondary to viral co-infection and increased cardiovascular risk, being associated with morbidity and mortality. The majority of patients established on anti-retrovirals (ARVs) achieve and maintain a suppressed HIV viral load,(2) with toxicity and increasingly simplification of regimens the most common indication for change of therapy.(3) Improved roll-out of testing programmes, changes in international guidelines suggesting treating earlier in infection, and the offer of treatment as prevention will likely lead to a significant rise in the numbers diagnosed and commencing therapy over the coming years.

The current economic crisis has led to reductions in public services budgets across all areas, including health care. The UK National Health Service (NHS) is expected to save £20 billion by 2015, while still maintaining quality patient care.(4)

In London, the annual ARV drug expenditure is around £182 million, representing 70% of the total HIV budget, and 7% of the entire London drug budget (personal communication). An estimated £7 million funding gap in the 2013/14 London HIV budget (personal communication) can only realistically be met by cost-effective prescribing strategies. The use of zero-VAT rated medicines via home delivery, therapeutic tenders for preferred ARVs and the adoption of generic ARVs offer the best opportunities to bridge this gap, while maintaining access and quality of care. In the US, yearly cost of care for HIV patients is nearly $20,000, but some predict that in 10 years it could be treated for as little as $200 per year with the use of generic ARVs.(5)

Zidovudine, lamivudine and nevirapine are now available as generic products, including a fixed-dose combination (FDC) of lamivudine/zidovudine. Price reductions of approximately 75% have already achieved significant savings; however, the most substantial saving is likely to be seen in 2014 when the patent for efavirenz expires.

Approximately 20% of patients in London receive efavirenz, either as Sustiva® or as the single tablet regimen (STR), Atripla® (efavirenz/emtricitabine/tenofovir).

The British HIV Association (BHIVA) treatment guidelines(6) list efavirenz as a preferred drug, with approximately 75% of patients initiating first-line therapy with an efavirenz-based regimen. The current guidelines do not include cost-effectiveness analysis because of the significant variation in drug prices across the country. However, the availability of generic efavirenz may prompt a reconsideration of the choice of preferred third-line agents in combination with a nucleoside backbone in those without baseline HIV resistance or a history of depression.

The use of single generic medicines in place of originator products has not been shown to impact on outcomes across a number of therapeutic areas,(7) or within observational HIV cohorts;(8) however, many still perpetuate the myth, or misinterpret the data(9) that generic medicines are inferior, despite the only consistent practical difference between generic and patented drugs being their price.(10) What is unclear is whether splitting FDCs when part, or all, of the components are available as generic medicines will have a true impact on clinical outcomes? The current BHIVA guidelines suggest FDCs can increase adherence but their use in patients with low adherence should be balanced against other treatment characteristics, such as effectiveness, tolerability and resistance profile. European guidelines(11) acknowledge an increasing availability of generic ARVs, suggesting they can be used as long as they replace the same drug and do not break recommended FDCs.

Walensky et al(12) modelled the US financial impact of splitting Atripla® into a multi-tablet regimen (MTR) of tenofovir (Viread®), generic efavirenz, and lamivudine substituted for emtricitabine. The analysis assumed a three-pill regimen would hinder adherence and reduce viral suppression, and that lamivudine was associated with slightly inferior antiretroviral efficacy and an increased frequency of drug resistance on treatment, compared with emtricitabine. The authors estimated a first-year saving of up to US$ 920 million and lifetime average savings of US$ 42,500 per eligible patient with the three-pill regimen compared with Atripla.

They also modelled the savings if the FDC Truvada (tenofovir/emtricitabine) was combined with generic efavirenz, with first year savings of $560 million. There are a number of limitations to the model, including the suggestion that lamivudine is slightly inferior to emtricitabine, when meta-analysis does not suggest this,(13) and its application outside the US where proportionally similar savings may be different in a UK or European market where prices of originator products may be significantly lower.

Retrospective studies where patients on fixed or single tablets regimens were switched to combinations including to generic ARVs indicate a higher rate of short-term adverse events, compared with controls.(14)

This, in part, led to increased healthcare utilisation and associated costs, with only a quarter remaining on the generic regimen after their subsequent appointment. However, patients were most likely to experience side effects when emtricitabine was substituted for lamivudine, suggesting that it is the change in drug rather than the use as a generic or MTR that leads to side effects. The possibility of dissatisfaction among those asked to switch to more complex regimens was raised, potentially leading to more placebo-like side effects. A more universal policy of breaking STRs for generics was demonstrated by a Danish group that switched over 500 patients stable on Atripla® to a MTR of tenofovir, lamivudine and efavirenz.(15) Rates of HIV viral suppression did not significantly change after 48 weeks, suggesting that splitting FDCs should not impact on viral control.

Others have suggested that the use of STRs may prevent selective adherence to part of a regimen, and may be associated with reduced hospitalisations and healthcare costs.(16,17) However, these studies are typically retrospective, rely on pharmacy refill data to determine adherence patterns and cannot adjust for the reasons for selection of MTRs or STRs for individual patients, which may have significantly greater impact on outcomes than absolute pill burden.

In reality, the availability of generic drugs does not necessarily mean that an FDC needs to be split to achieve savings. The UK patent for Combivir® has expired, allowing a FDC of generic lamivudine/zidovudine to be marketed. Additionally, manufacturers of the originator STR may reduce their list price to remain competitive with generic MTR products, and may justify charging a slight premium claiming improved compliance.

The use of immediate release, twice-daily generic formulations instead of once-daily, prolonged-release originator products may have greater impact on adherence. Switching patients established on once-daily Viramune® (nevirapine) 400mg prolonged-release tablets, to generic nevirapine immediate-release tablets within the twice-daily licence may have an impact on patient acceptability. Although there are no data on the specific switch, the license for the prolonged release formulation was based on non-inferiority versus the twice-daily, immediate-release formulation,(17) so there should be little reason clinical for concern, while in practice many clinicians are prepared to advise once-daily dosing of the immediate-release form as a maintenance strategy.

One of the advantages for patients of using STRs or originator products is that they have a distinctive name or appearance. Many may remember the name Combivir®, but may not remember lamivudine/zidovudine 150/300mg tablets. Anecdotally, patients increasingly know their regimens by shape and colour, rather than by name. This could be viewed as a symptom of the success of modern therapy, that taking medicine becomes less and less part of a person’s life. However, in a generic market, there is a loss of brand identity, with the potential of regular changes in supplier leading to confusion and an increased risk of inadvertent double or missed doses.

This may pose the greatest risk to clinical outcomes with generic ARVs, particularly when combined with an increasing proportion of patients receiving their medicines by postal or van delivery rather than direct from their hospital pharmacy. Although home delivery allows significant financial savings through use of zero-rated VAT medicines, there is a risk of reduced pharmacy contact, which could lead to errors in this instance. This supports the UK position of a rigorously controlled tendering and contracting process for all ARVs purchased by hospitals, including generics, which looks to ensure a single supplier for typically two years for any drug.

Patients’ attitudes towards generic medicines are dictated by a number of factors, including information, and often misinformation, gained from the media, friends and family; their relationship with their physician and that physician’s suspicions about the quality of generics; and prior experience with generic medicines.(18) In a recent online survey conducted by the national AIDS Manual (NAM),(19) 45.5% of respondents stated they would find it annoying, confusing, inconvenient or concerning if their doctor asked them to switch to a generic drug.

Although 70.2% thought a generic would offer better value for money than a branded drug, 67.8% felt uncomfortable about how effectively a generic would be in controlling their condition, and 65.3% were uncomfortable with the possibility of increased side effects. A survey within London found no difference in patients’ experiences between those who were prescribed ARVs as a part of a therapeutic tender compared with those who started or switched to other ARVs.(20) Despite negative media coverage,(21) patients reported an overwhelming satisfaction with how their clinics managed the change but it is unclear if all clinicians engaged equally in the process.

(22) Patients’ perceptions and acceptance of the implementation of generic medicines, in particular in a switch strategy, are likely to be highly influenced by the approach of their health care team and supporting information provided by clinics and patient groups. The HIV Pharmacy Association (HIVPA) is working with the National AIDS Trust and other patient groups to provide patients with written information about generic medicines to improve their understanding and acceptability.

Although few would argue against the use of generic medicines in general, there may be exceptions to the rule. Drugs with narrow therapeutic windows may require additional monitoring to ensure efficacy, with financial savings initially being offset by increased need for monitoring or follow up, however this should only apply to those who switch from originators to generic, and ignores the longer term financial savings. There may be individual patients whose compliance may be affected by using MTRs, rather than single- or FDCs, and these may warrant individual use of originator products, but this should only be when genuine adherence issues are encountered, rather than casual patient (or prescriber) preference.

The role of the pharmacist is paramount in the successful roll-out of generic ARVs. A robust procurement processes; patient and healthcare professional education; and working in partnership with home delivery providers will ensure the use of generic medicines as both cost- and clinically effective. Systems should be put in place to ensure that patients are aware of the change to generic medicines, and what impact this will have on them. Locally, we use stickers added to prescriptions to highlight patients who are changing formulation or to a generic medicine, and document counselling and provision of written information. This is particular important for those who then receive medicines by home delivery.

The HIV Pharmacy Association (HIVPA) has worked with patient groups such as the NAM, as well as pharmaceutical companies, to provide patient information on switching to generic or new formulations of ARVs. The combination of written information and verbal counselling is designed to improve understanding and acceptability of new medicines, and generics.

The use of generic antiretrovirals offers the potential of significant financial savings at a time when the use of single-tablet regimens is both available and desired by patients and prescribers. For some, reduced convenience for the greater good may be bitter pill to swallow. However, if HIV services were able to re-invest the savings there may be an incentive for patients to not only use, but to actively switch to generic ARVs.