Of the 34 million people with HIV infection in 2011, eight million (23%) are currently receiving antiretroviral treatment [1▪▪]. An additional seven out of 34 million people (21%) have advanced HIV infection (i.e. symptomatic or CD4 cell counts below 350 cells/μl) and need treatment according to the WHO guidelines [2▪], but are not receiving it. Most of these patients will die within the next 5 years if they cannot access antiretroviral treatment. The other 19 million out of 34 million HIV-infected people (56%) have less advanced HIV disease, but most will need to start antiretrovirals as their disease progresses. Some international treatment guidelines are recommending that treatment is started for all people with HIV infection, regardless of disease stage [3,4]. This is because earlier initiation of treatment can increase life expectancy to near-normal levels , and also reduce the chances of people transmitting HIV by up to 95% .
Although eight million people are receiving antiretroviral treatment in low- and middle-income countries, there are three main problems with their standard of medical care. First, around 42% of people in low- and middle-income countries are still receiving stavudine [1▪▪], which is no longer recommended for use [2▪,3,4]. Second, there is very limited diagnostic support – the use of viral load monitoring, which is the most accurate method for detecting treatment failure – is rare . Patients are also not routinely tested for transmitted drug resistance before starting antiretrovirals. A recent survey has shown significant rises in the prevalence of transmitted drug resistance in some low-income countries, particularly to nucleoside analogues and nonnucleosides . Third, when people fail first-line treatment, the percentage starting second-line treatment is far lower than in developed countries .
In order to achieve Universal Access, we need a simple system of treatment, using a sequence of low-cost, coformulated antiretrovirals with strong efficacy profiles, nonoverlapping resistance profiles and safety issues, which are manageable with minimal medical expertise. Only a small subset of the antiretrovirals approved may be needed. Patients who fail a first-line treatment should have access to a simple second-line treatment, and potentially third-line if required.
The costs of antiretroviral treatment in low-income countries have decreased significantly in low-income countries over the past 10 years. This is mainly because of improved manufacturing methods and economies of scale [10▪,11▪,12▪▪]. In this review, we concentrate on the key antiretrovirals, which are most likely to be included in large-scale treatment access programmes. Is there the potential to reduce costs further, by dose optimization? Are there new alternative drugs that have inherently low costs of production?
Several antiretrovirals have shown equal efficacy across a range of doses in phase 2 dose-ranging trials, but the highest tolerated dose was taken into phase 3 registration trials, examples are lopinavir/ritonavir, zidovudine and efavirenz [12▪▪,13]. The doses of three antiretrovirals – zidovudine, didanosine and stavudine – were lowered after initial regulatory approval, when lower doses were found to have equal efficacy but improved safety profiles. There are several dose optimization trials in progress. The aim of these trials is to establish noninferior efficacy for a lower dose of an antitretroviral compared with the standard dose. Sample sizes of 600–800 patients are required for these trials, with follow-up for 96 weeks . Changes to a lower dose of an antiretroviral are more acceptable if they are associated with safety benefits.
The level of evidence required to change the dose of a drug is high and involves expensive, long-term clinical trials and subsequent changes in treatment guidelines. Therefore, dose optimization should only be attempted for antiretrovirals, which are cheap to manufacture, and which are expected to be widely used in the future.
COSTS OF TREATMENT
Table 1 shows the costs of antiretrovirals per person-year in a typical high-income country (United Kingdom), and for low-income countries [10▪,11▪,15]. In low-income countries, antiretrovirals are available either from the patent-holding (originator) company or from generic companies if the patents are no longer enforced. The generic prices listed are all from generic suppliers who have passed the WHO prequalification standards for quality of product.
Competition between generic companies has led to significant reductions in costs over the past 10 years, particularly for the most widely used antiretrovirals [10▪,11▪]. The costs of generic production of protease inhibitors are similar to those of the originator companies, but second-line treatment with protease inhibitors is still not widespread in low-income countries. Some antiretrovirals are still only available from the originator companies, examples are raltegravir and etravirine.
The prices in Table 1 identify a group of antiretrovirals, which can currently be used in cheap first-line and second-line combinations in low-income countries. If we follow the consensus recommendations from the WHO meeting in 2011 , first-line treatment with tenofovir (TDF)/3TC/efavirenz would then cost US$131 per person-year. An alternative treatment for patients with adverse events on efavirenz would be TDF/3TC/nevirapine, costing US$110 per person-year. For second-line treatment, ZDV/3TC/ATV/r would cost US$407 per person-year, with the alternative of ZDV/3TC/LPV/r for US$471 per person-year. Darunavir/ritonavir is widely used in North America and Europe for first and second-line treatments, but the current costs in developing countries prevent widespread use at this stage.
Two large phase 3 trials have just been completed for the integrase inhibitor dolutegravir, showing favourable efficacy and safety in first-line treatment [17,18]. The advantage of this drug for low-income countries is the low dose, 50 mg once daily. This is 6% of the daily dose of raltegravir, which has a similar chemical structure and currently costs US$675 per year to make. If the manufacturing processes for dolutegravir can be improved to the same extent, a target price of US$40 per person-year is achievable. This would make dolutegravir a strong candidate for inclusion in either first-line treatment, or combinations with a protease inhibitor in second-line treatment. The advantage of an integrase–protease combination for second-line treatment is the lack of cross-resistance from nucleoside reverse transcriptase inhibitor (NRTI)–nonnucleoside reverse transcriptase inhibitor (NNRTI) combinations taken first-line.
The above costs can only be achieved in the least developed countries, or when drug patents have expired. Table 2 shows the dates of patent expiry for the most widely used antiretrovirals [11▪]. The original basic 20-year patents have already expired for several antiretrovirals, with key patents on efavirenz and ritonavir due to expire in 2013. However, in addition to the basic 20-year patents, the additional so-called ‘evergreen’ patents have been applied for, to extend the patent-life of antiretrovirals. For example, the original patents of zidovudine and lamivudine have expired, but there is a patent on their use as a coformulation. So, it would be legal to use generic versions of zidovudine and lamivudine as individual drugs, but not the coformulated version. There is a similar issue with the patented coformulation of tenofovir and emtricitabine. In these situations, the cost-savings from use of the drugs individually needs to be set against the higher pill counts involved.
CANDIDATE DRUGS FOR DOSE-OPTIMIZATION TRIALS
Of the antiretrovirals shown in Table 1, there are four that are cheap to manufacture, widely used and showed efficacy across a range of doses in phase 2 dose-ranging trials. These are efavirenz, atazanavir/ritonavir, ritonavir as a pharmacokinetic booster and stavudine. The ongoing trials of these antiretrovirals are described in the following sections and summarized in Table 3.
EFAVIRENZ, THE ENCORE-1 TRIAL
The rationale for evaluating lower doses of efavirenz has been described in detail elsewhere [12▪▪,13]. Briefly, the phase 2 DMP-005 trial showed similar HIV RNA reductions for three doses of efavirenz in the first-line treatment: 200, 400 and 600 mg once daily. However, only the 600-mg once daily dose was taken into phase 3. Several other studies have shown that patients could reduce dose to 200 or 400 mg efavirenz with no loss of efficacy . One of the key issues with efavirenz is adverse events of the central nervous system (CNS), such as dizziness, sleep disorders, which tend to occur within the first few weeks of starting treatment, and are associated with initially high efavirenz drug levels. In a ‘stepped-dose’ study, 114 treatment-naive patients were randomized to first-line treatment with two nucleoside analogues along with either efavirenz at 600 mg once daily or an alternative dosing of 200 mg once daily for the first 2 weeks, 400 mg once daily for weeks 2–4 and then 600 mg once daily thereafter. The full-dose group presented with a higher incidence and severity of dizziness, hangover, impaired concentration and hallucinations during the first week of treatment. The percentage of patients with HIV RNA less than 50 copies/ml at week 24 was 96% in the stepped dose group and 87% in the full-dose group .
In the ENCORE-1 trial , 572 treatment-naive patients from centres in developed and developing countries have been randomized to receive tenofovir/emtricitabine along with efavirenz at either the standard 600-mg once-daily dose or a reduced dose of 400 mg once daily. The trial has a primary endpoint of HIV RNA suppression below 200 copies/ml at week 48, and then continues until all patients have completed 96 weeks of treatment. The trial has been fully recruited and 48-week results are expected by early 2014. The trial is statistically powered to show noninferior efficacy for the lower dose efavirenz arm, compared with the standard dose arm.
There are two other potential issues with widespread first-line use of efavirenz.
Firstly, teratogenicity was seen in animal toxicology studies and led to a warning over pregnant women taking efavirenz in the first trimester. However, the WHO guidelines  have recently been changed to allow efavirenz treatment during pregnancy. This is because of recent research suggesting no increased risk of abnormalities in the infants of mothers treated with efavirenz during pregnancy, versus other antiretrovirals .
Secondly, people are not routinely genotyped before starting first-line treatment in developing countries, and there has been a rise in the prevalence of resistance to nucleoside analogues and nonnucleosides . However, it is unknown whether the prevalence of drug resistance is high enough to justify a switch to a new class of drugs in first-line, such as protease inhibitors.
ATAZANAVIR/RITONAVIR, THE LASA TRIAL
As shown in Table 1, atazanavir/ritonavir, at the dose of 300/100 mg once daily, is now the cheapest boosted protease inhibitor to produce: atazanavir has been coformulated with ritonavir to a heat-stable, one pill, once-daily formulation for use in low-income countries [10▪]. In the CASTLE study, first-line treatment with atazanavir/ritonavir 300/100 mg once daily led to similar virological efficacy compared with lopinavir/ritonavir, but with a lower rate of discontinuation . Atazanavir/ritonavir has the benefits of once-daily dosing, a lower pill count, better gastrointestinal tolerability and lower rises in lipids than with lopinavir/ritonavir. However, it may be possible to dose-optimize atazanavir to a new 200/100 mg once-daily dose, initially as a switch option for people with HIV RNA suppression on other antiretrovirals.
Atazanavir was originally evaluated as an unboosted protease inhibitor, at the 400 mg once-daily dose. Two switching studies have been conducted, evaluating unboosted atazanavir in patients with HIV RNA suppression at baseline. In the ARIES study (n = 515), the percentage of patients with HIV RNA less than 50 copies/ml at week 84 was 86% for patients switched to unboosted atazanavir 400 mg once daily versus 81% for patients taking boosted atazanavir (300/100 mg once daily) . In the SWAN study (n = 419), the percentage of patients with virological rebound was 7% for those who switched to unboosted atazanavir versus 16% for those who remained on other boosted protease inhibitors . Unboosted atazanavir, therefore, has established efficacy as a switch option for patients with HIV RNA suppression on other antiretrovirals.
Two pharmacokinetic trials have shown that atazanavir/ritonavir at the 200/100 mg once-daily dose has better pharmacokinetics than the 400 mg unboosted dose [26,27]. The LASA trial  is currently recruiting 560 patients who have HIV RNA suppression at baseline, while receiving other antiretroviral treatments. Patients are randomized to either the 200/100 mg dose or 300/100 mg once-daily doses of atazanavir/ritonavir, together with two NRTIs. The primary endpoint is noninferiority in HIV RNA suppression after 48 weeks of treatment. There are two limitations with this trial. First, the trial is being conducted mainly in Thailand, where low body weight may compensate for the lower drug doses used. Second, this is a switch study, and an additional first-line trial would be required to establish the efficacy of atazanavir/ritonavir 200/100 mg once daily in treatment-naive patients. In addition, there is more evidence for the efficacy of darunavir/ritonavir and lopinavir/ritonavir in treatment-experienced patients compared with atazanavir/ritonavir . A new clinical trial evaluating the efficacy of atazanavir/ritonavir versus other protease inhibitors should be conducted in a developing country setting, to ensure that the efficacy seen in first-line treatment is maintained.
RITONAVIR AS A PHARMACOKINETIC BOOSTER
Although ritonavir is only available at the 100 mg dose, pilot studies have shown that a 50 mg dose of ritonavir can boost atazanavir levels by the same amount . The switch to a 50 mg dose of ritonavir would require results from a bioequivalence trial using a commercial formulation, but this would be a low-cost, low-risk method to reduce treatment costs. The minimum cost of ritonavir at the 100 mg once daily dose is US$83 per person-year. This could be lowered to US$45 by a reduction in dose to 50 mg. This cost reduction could save millions of dollars per year if the use of protease inhibitors increased.
STAVUDINE – THE 20 MG TWICE-DAILY TRIAL
Stavudine was originally approved at the 40 mg twice-daily (b.i.d.) dose, but a meta-analysis showed similar efficacy but improved safety for the 30 mg b.i.d. dose . The original expanded access programme for stavudine also evaluated the 20 mg b.i.d. dose. A large 2-year randomized study  has been initiated (Witswatersland Reproductive Health Institute 001), comparing stavudine 20 mg b.i.d. with tenofovir, as part of standard first-line treatment for 1068 patients in South Africa, Uganda and India. This trial is designed to demonstrate noninferior efficacy for the lower dose stavudine arm and has a nested substudy to evaluate the risk of lipodystrophy by treatment arm. The rationale for the trial is that the toxicity profile of stavudine is dose dependent , and that the risk of serious adverse events from stavudine – in particular lactic acidosis, peripheral neuropathy and lipodystrophy – will be lower when the new 20 mg b.i.d. dose is used. Stavudine is also the cheapest nucleoside analogue to manufacture [10▪,11▪], and there would be significant cost savings if this trial showed noninferior efficacy and similar safety to tenofovir. However, the trial has attracted criticism , given that the use of stavudine is a twice-daily treatment, has no activity against hepatitis B, is no longer recommended in treatment guidelines and that the trial is too short to fully evaluate the cumulative risks of stavudine toxicity.
The combined results from the dose-optimization trials could save hundreds of millions of dollars from the overall cost of Universal Access, with the potential for safety benefits from lower doses of efavirenz, atazanavir and ritonavir. However, the field of HIV treatment is continuously evolving, and the results would need to be integrated into new treatment paradigms. Table 4 shows the currently recommended sequence of first and second-line treatments, and a potential future option. If the ENCORE-1 trial is successful, there would be a cost-saving from the lower dose of efavirenz, allowing the price of TDF/3TC/EFV to fall from US$131 to US$115. If the atazanavir/ritonavir 200/50 mg once-daily dose is successfully evaluated in randomized trials, the cost could fall by 35%, from the current level of US$304 to US$198. So, a combination of atazanavir/ritonavir with dolutegravir could cost less than US$240 per person-year, low enough to allow much wider access to second-line treatment.
The calculations in Table 4 assume that Universal Access is achieved, and of the 15 million people treated, 80% (12 million) are taking first-line treatment, whereas 20% (three million) are taking second-line treatment (in line with European and North American cohorts). The reduction in unit costs of TDF/3TC/EFV from dose optimization of efavirenz would save US$16 per person, leading to an overall saving of US$192 million per year. The switch from ZDV/3TC/ATV/r 300/100 OD to dolutegravir along with ATV/r 200/50 OD would save US$167 per person, leading to an overall saving of US$501 million. The combined saving in costs from first and second-line treatment would therefore be US$693 million per year.
Further research is needed on combinations of dolutegravir with low-dose atazanavir/ritonavir or other protease inhibitors. If successful, these could then be used as second-line combinations with no overlapping resistance to the first-line NRTI/NNRTI treatments used.
No funding was received for the writing of this article. Andrew Hill has received consultancy payments from Janssen.
There was no funding provided for this work.
Conflicts of interest
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 77–79).
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