The development in 1996 of triple drug antiretroviral (ARV) combination therapy for patients with HIV/AIDS marked a turning point in the fight against the disease. Since that time, combination therapy has become the gold standard and all ARV regimens use at least three drugs for treatment-naive patients and at least two fully active drugs for treatment-experienced patients. The number of drugs for the treatment of HIV/AIDS has rapidly increased and currently there are more than 30 drugs available as single and combination pills belonging to five different classes. Until 2001, however, the vast majority of people living with HIV/AIDS in sub-Saharan Africa and other similar countries were unable to access the drugs due to the high cost which was about US$10 000 to US$15 000 per patient per year. In 2001, the offer by Cipla of a combination of stavudine, lamivudine and nevirapine at US$1 per day provided hope for millions of people. This was subsequently made into a single pill to improve patient adherence and this marked the beginning of the fixed-dose combination (FDC) era in ART. Currently, nearly 10 million people are receiving treatment  up from a mere few thousand in 2001, mainly from Indian generic companies and with funding from global donor agencies. Today several dual, triple and even quadruple drug FDCs (Table 1) have been developed and are becoming the norm for ARV drug therapy and pharmaceutical companies manufacturing different drugs are collaborating to produce such combinations. Although new drugs will always be needed, there are significant opportunities for improving on existing products.
OPPORTUNITIES FOR IMPROVED ANTIRETROVIRAL DRUG FORMULATIONS
ARV drugs have to be taken daily to control viral replication, and poor adherence can lead to loss of viral control, resistance to drugs and subsequent disease progression [2,3]. Poor adherence results from patient factors (substance abuse, depression, anxiety, social factors and so on), and drug-related factors such as number of pills in a day, food intake, side-effects and interactions with other drugs. Although the number of pills for treatment-naive patients is now just one pill a day; for treatment-experienced patients, the number of pills and sometimes the frequency increases. Many ARV agents have low bioavailability, poor solubility, penetrate poorly into different body compartments in which the virus resides and are associated with side-effects such as gastrointestinal distress, nausea, and general malaise leading to discontinuation of treatment. Several drugs have a high dosage requirement (Table 2) and this leads to a relatively high cost since a greater amount of the active pharmaceutical ingredient goes into it. For example, the total daily dose of Nevirapine is 400 mg, that of Efavirenz is 600 mg and Darunavir is 800–1200 mg daily. These high amounts led to a significant investment in manufacturing and reduction in dose could help reduce the pressure on capacities. Protease inhibitors (PI) are not available in combination pills and there are very few child-friendly formulations. The most widely studied PI in young children is available as an oral solution, which has a high concentration of alcohol, contains propylene glycol and has an unpleasant taste. Thus, in addition to new drugs that will always be needed, these factors provide opportunities for improving on the existing drug formulations.
STRATEGIES FOR DEVELOPING IMPROVED DRUG FORMULATIONS
The pharmaceutical industry applies a number of methods to enhance drug formulations and many of these have been applied to currently available drugs, some of which have been or are in the process of being commercialized. Many others are still in development:
1. Coformulations of two or more drugs: wherever possible, combination products are now preferred to treat HIV-infected individuals. This leads to improved adherence, ensures that all drugs have been taken, and in the recommended dosage. Most first-line treatments consist of such combination products containing two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI). Tenofovir-based combinations are the most frequently used products and are recommended as first-line treatments in the WHO 2013 released guidelines [4▪]. Recently, a combination of tenofovir, emtricitabine, cobicistat and elvitegravir was launched, the first four-drug combination product containing an integrase inhibitor. Currently, there are no coformulations of NRTIs with protease inhibitors, which are usually used in second-line treatment. In addition to lopinavir/ritonavir (LPV/r), a combination of atazanavir and ritonavir (ATV/r) is also now available in India. There are some challenges to the development of combinations with PIs particularly due to the ritonavir component, which has had to be reformulated as a heat-stable product. An option to coformulations is the development of copackaged products. This option is often used for malaria treatments and there are several such opportunities in the ART area. A copackaged product consisting of tenofovir and emtricitabine as one pill and another containing ATV/r, which can serve as an option to NNRTIs as first-line and can also be used as second-line treatment, is now available. As more and more drugs are developed, we should continue to explore various options of combination and copackaged products.
2. Sustained release preparations: Simple enhancements using a matrix delivery system leading to sustained-release or slow-release or controlled-release of the drug can reduce the frequency of administration from twice a day to once a day, reduce fluctuations between peak and trough concentrations, thereby leading to lesser toxicity and lessen chances of sub-therapeutic concentrations at the end of the dosing period. Nevirapine sustained release 400 mg has been recently approved as a once-daily preparation based on results of the VERXVE study , which showed that it was noninferior to twice daily nevirapine and the safety and adverse events were similar.
3. Nanoparticles: Nanomedicine has been in clinical application for the last several years and many drugs are already marketed which have nano size drug particles. One of the commonly employed methods to overcome the problems of inherent low bioavailability is to make smaller drug particles to overcome the problems of inherent low bioavailability. This is done using processes such as nanomilling, homogenization or precipitation [6▪]. Making smaller particle sizes of the pure drug (0.25–0.5 μm) could lead to greater absorption of the drug from the gastrointestinal tract thereby enhancing bioavailability and leading to a reduction in dose. Another way is to encapsulate the drug in carriers such as liposomes, or conjugate drugs with polymers to enhance residence time or bioavailability in the body. In some of the early experiments in which zidovudine was loaded onto hexylcyanoacrylate nanoparticles , it led to higher drug levels in animal studies and a more effective drug delivery to the reticuloendothelial system. Another recent study examined the pharmacokinetics and biodistribution of NanoART using atazanavir, ritonavir and efavirenz in human monocyte-derived macrophages as a combination product . Combination NanoART ingested by these cells lead to drug recovery lasting for 15 to more than 20 days. Thus it may be possible to have ARV drugs that last for a longer time in patients and targeting compartments such as the CNS using this approach. Another experiment used a number of protease inhibitors including atazanavir, indinavir, ritonavir, and efavirenz and demonstrated that these drugs lasted for a longer time in cells when combined with a carrier and suppressed viral replication more than 70% in the cells . Cell viability was maintained and there was no cytotoxicity. These studies raised the possibility of long acting ARVs which could be given once a fortnight or less frequently possibly through the injectable route. More recently, Martin et al. from the University of Liverpool using an emulsion template freeze drying strategy, showed that efavirenz solid drug nanoparticles had a two-fold greater accumulation in CD4 cells and the model suggested that a dose of 300 mg could be as good as the current 600 mg dose. After oral dosing in rats the Cmax, Cmin and area under the curve (AUC) were higher with the nanoparticles than the conventional solution.
4. Injectable formulations: As ARV drugs have to be taken lifelong and daily, there are possibilities of developing long acting depot formulations of the drugs. In addition this may be useful as a pre-exposure prophylaxis. A number of such depot injections have been developed for hormonal products used for contraception and antipsychotics such as haloperidol or risperidone. These use oily formulations or microfine watery suspensions or carriers, which allows slow release of the drug. A nanosuspension of rilpivirine in an aqueous carrier has been developed and initial studies in dogs using the intramuscular or subcutaneous route showed significant levels in the blood for several weeks . At the recent International AIDS society (IAS) conference, a study was presented on a combination of two ARV drugs GSK 744 and TMC 278 given as a nanosuspension intramuscularly or subcutaneously. Pharmacokinetic and safety data revealed that the drugs were generally well tolerated and clinically relevant plasma concentrations were achieved with monthly or quarterly injections .
5. Pediatric formulations: This is one of the most critical issues as one of the reasons for a significant gap in the treatment of children is the lack of availability of formulations of ARV drugs which are child-friendly. Most of them are available as solid dosage forms, liquids, which are unpalatable and inconvenient for transportation and storage. The development of a triple combination pill of stavudine, lamivudine and nevirapine in a dispersible tablet  in two strengths was a significant step and it demonstrated that a pediatric formulation for various ages and weight bands which combined three drugs is possible. Another important step was the development of abacavir/lamivudine tablets for oral dispersion as abacavir is now regarded as the NRTI of choice in combination with lamivudine [4▪]. Development of protease inhibitors has not been easy but a sprinkle formulation of lopinavir/ritonavir is in advanced development. This uses minitablets packed into a capsule and caregivers can administer the drug to children by opening the number of requisite capsules and emptying the contents onto soft food such as sweetened porridge. Cipla and Drugs for Neglected Diseases initiative (DNDi) have recently announced a program to develop two four-in-one sprinkle formulations consisting of abacavir + lamivudine + lopinavir + ritonavir and zidovudine + lamivudine + lopinavir + ritonavir, which could address the key challenge of treating children simply, in accordance with the new WHO guidelines .
6. Vaginal delivery of antimicrobials: Male to female sexual transmission accounts for the greatest percentage of HIV transmission in sub-Saharan Africa and Asia and efforts have been on for the last several years to develop microbicides which could prevent viral transmission. The efficiency of transmission depends upon a number of factors including genital shedding of the virus, viral load, and the integrity of the mucosa, frequency of sexual intercourse, hormonal status and immunocompetency [15▪▪]. There have been several notable failures in the development of microbicides, but the results of the CAPRISA study  renewed hope that vaginal use of ARVs could prevent transmission. Since then, studies have continued and newer preparations incorporating drugs such as dapavirine into rings are ongoing. Combining two or more ARV drugs in a vaginal gel form may have greater efficacy but clinical testing will be a significant challenge. Another approach has been the use of multipurpose technologies (MPT), which can prevent HIV transmission and pregnancy and/or sexually transmitted diseases simultaneously . This could take the form of a barrier contraceptive coated with an ARV agent.
There are several challenges to bringing newer formulations to the market. Although the use of nanomedicine looks very exciting, the possibility of scaling up the process to an industrial scale cost effectively will have to be worked upon. Regulatory approval will need a number of pharmacokinetic and clinical studies to demonstrate the choice of dose, route of delivery, efficacy and safety. Many of these developments are being done by generic companies who will need to collaborate with research organizations and funding agencies. The acceptance of injectable formulations is less clear and similar clinical studies examining efficacy, safety and acceptance will be needed for physicians and patients to consider injectable drugs.
There are numerous advances occurring in ARV drug formulations to achieve greater bioavailability, greater penetration into certain compartments, lesser dose and targeting specific populations such as children or healthy women to prevent acquisition of the virus. The numbers of new formulations under development however are few (Table 3) indicating challenges, limited gain in intellectual property and/or reluctance to invest in reformulation of existing drugs. Although several challengess remain whether clinical, pharmaceutical or regulatory, collaborations between stakeholders can overcome these challenges. Future work must be directed at more such opportunities so that patients, physicians and global funding agencies benefit.
Conflicts of interest
Both authors are employees of Cipla Ltd., India.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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