Pmlive.com

Over the last 30 years, the face of human immunodeficiency virus (HIV) has changed from one largely associated with homosexuality, drug addicts, prejudice, fear and rejection without much hope of a future, to one involving innocent children born of mothers living with HIV for whom it is hoped the disease will be curable and even eradicated. 

According to the World Health Organization (WHO) and UNAIDS, 34 million people were living with HIV worldwide in 2011. Sub-Saharan Africa was, and still is, the most severely affected area. Approximately 5 per cent of adults in this region live with HIV, representing almost 70 per cent of the global HIV-infected population. On a positive note, the number of newly infected people has declined by approximately 25 per cent over the past ten years and, importantly, over the past two years, half of the reductions in HIV infections has been in children.

Treatment and prevention
The approach to, and success of, HIV treatment and prevention has improved such that the disease may now be considered a manageable, life-long condition.

Currently available therapeutics do not provide a cure, but may prevent infection or attenuate viral load after the fact; for this, the currently available agents are required to be taken daily, and for life. This poses problems relating to compliance and potential for the development of drug resistance. To prevent the latter, it is recommended that therapy includes a combination of drugs from at least two different classes. However, the increased pill burden results in non-adherence to medication. Consequently, suppression of viraemia is compromised and risk of disease transmission increased in non-compliant patients.

The development of future HIV therapies is governed by the need to provide complex drug combinations in the simplest, patient-friendly formulation. The majority of the currently marketed HIV therapeutics are single agents spanning a variety of drug classes; not all are available as once-daily formulations.

There are two main approaches evident in the development of HIV therapeutics that aim to prevent drug resistance and to increase patient compliance: addition of pharmacokinetic enhancers (‘boosting’ agents) to already established drugs, and drug ‘cocktails’ in a single tablet; in some cases these approaches have been combined.

Fixed-dose combinations
There are currently three fixed-dose combination (FDC) products that are available for treatment of HIV – elvitegravir/emtricitabine/tenofovir disoproxil fumarate/cobicistat (Stribild; Gilead Sciences), emtricitabine/rilpivirine/tenofovir disoproxil fumarate (Eviplera, Complera; Gilead, Tibotec) and lopinavir/ritonavir (Kaletra; Abbott Laboratories).

Gilead and Johnson & Johnson (J&J) are developing an oral FDC tablet comprising cobicistat (pharmacoenhancer) and darunavir (HIV protease inhibitor). Phase III trials are underway in the European Union (EU) and US in both treatment-naive and treatment-experienced HIV patients. Darunavir (Prezista; Tibotec) is a protease inhibitor that is already launched as a single agent. Cobicistat does not have antiviral activity against HIV in its own right, but acts as a booster by inhibiting cytochrome P450 3A (CYP3A) and increasing blood drug concentrations of certain therapeutic agents, thus facilitating convenient once-daily dosing.

ViiV Healthcare, in a joint venture with GlaxoSmithKline and Pfizer, is developing a triple-drug cocktail – abacavir/dolutegravir/lamivudine – that combines three distinct mechanisms of action: inhibition of HIV replication, inhibition of HIV integrase and a nucleoside reverse transcriptase inhibitor (NRTI), respectively.

Combining the ‘boosting’ and ‘cocktail’ approaches, Gilead Sciences is developing a quadruple-drug FDC product, cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide (C/E/F/TAF), which entered phase III trials in the US and Puerto Rico in late 2012/early 2013. Two similarly designed studies (Study 104 and Study 111) are being conducted in treatment-naive HIV-1 patients; recruitment will also extend to several countries including the EU, Asia and Latin America. Tenofovir alafenamide (GS 7340) and tenofovir disproxil fumarate (TDF, Viread) are two prodrugs developed by Gilead and designed to have better oral availability and adverse events profiles than tenofovir. TDF is a component of the only quadruple-drug FDC (Stribild) currently launched (US only).

Promising results from a phase II head-to-head study were presented at 20th Conference on Retroviruses and Opportunistic Infections Conference (CROI) in March 2013, which demonstrated that both C/E/F/TAF and Stribild had similar efficacies and overall tolerability profiles, but that C/E/F/TAF had less negative impact on renal function and bone mineral density.

Non-oral prophylactic agents
Despite the downward trend in HIV prevalence over the past few years, according to UNAIDS, the majority of all the people living with AIDS are women, and most of the newly infected patients are children resulting from maternally-transmitted virus. It would therefore seem appropriate to target these particular patient populations with regard to the design of the drug formulation. Appropriately, two vaginally-administered, prophylactic formulations are in phase III development in African regions.

Tenofovir (Gilead, CONRAD) is a NRTI compound in development as a topical vaginal gel in phase III trials in South Africa. Nucleotides are characterised by their ability to form reservoirs of active drug within infected and non-infected (resting) cells; this allows sustained inhibition of viral replication after a single dose, and offers the potential for infrequent dosing and development of resistance, as well as prophylactic use. However, this product requires repeated application, prior to and after sexual intercourse, and is perhaps less user friendly than the slow-release dapivirine intravaginal ring preparation (Janssen, International Partnership for Microbicides) currently in phase III trials in South Africa, Malawi, Uganda, Zambia and Zimbabwe.

Dapivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that entered phase III development in late 2012. The ASPIRE trial is assessing the efficacy of monthly-renewed dapivirine intravaginal rings in approximately 3540 women from Central- East- and South Africa. The preparation is stable and easy to distribute, which is beneficial for use in these developing countries.

A different therapeutic approach to this global epidemic has been adopted by Sanofi Pasteur. Currently, the company has one vaccine in phase III development for both treatment and prevention of HIV. The HIV vaccine vCP1521 comprises a live, attenuated, canarypox viral vector (ALVAC), into which selected HIV-1 genes are inserted. ALVAC-HIV vCP1521 is one of four recombinant vectors in clinical development. This product expresses gp120 of sub-type E (the clade predominant in Thailand).

Most of the newly infected patients are children resulting from maternally-transmitted virus

Results from a proof-of-concept phase III trial (RV144) showed that ALVAC-HIV vCP1521 significantly reduced the rate of HIV infection by 31 per cent, compared with placebo. RV144 was the world’s largest AIDS vaccine study and the first government-sponsored, phase III prime-boost trial involving 16·402 healthy volunteers in Thailand. Participants received ALVAC-HIV vCP1521 as the prime and HIV gp120 vaccine (VaxGen; AIDSVAX B/E) as the boost, over a 6-month period with a 3-year follow-up. The trial data also provided important information regarding the future design of vaccines with respect to a potential target within the HIV genome. Completion of the RV144 trial is expected during the first half of 2013.

Preregistration – the race is on
There are three products currently in preregistration in the EU and/or North America for the management of HIV: two are single-agent oral HIV integrase inhibitors and one is a single-tablet cocktail.

Elvitegravir (Gilead) is awaiting both EU and US approval for treatment-experienced HIV-1 infections. Data from the pivotal 96-week Study 145 were used to support these applications, which showed that elvitegravir was non-inferior to raltegravir (HIV integrase inhibitor; Merck & Co) in treatment-experienced HIV-1 patients who also received a ritonavir-boosted protease inhibitor and another antiviral agent. A decision regarding the US application is imminent.

Following rapidly on the heels of elvitegravir is the other orally administered HIV integrase inhibitor, dolutegravir (ViiV Healthcare), which is awaiting approval in the US, Canada and EU for use in patients aged at least 12 years. Priority review has been granted in the US and a decision is expected in August 2013. This product is a non-boosted, once-daily therapy for use in both treatment-naive and treatment-experienced HIV-1 patients.

Dolutegravir has performed well against its potential market competitors, according to data from the four phase III trials used to support the registrational application. It has been compared with two already marketed therapeutics, raltegravir and Stribild. Dolutegravir demonstrated non-inferiority to raltegravir in treatment-experienced and treatment-naive HIV-1 patients, and showed limited potential for developing integrase resistance. Dolutegravir (combined with abacavir/lamivudine) has also shown a similar 48-week virological suppression rate and a somewhat better tolerability profile than Stribild.

Efavirenz/lamivudine/TDF (Mylan Laboratories) is indicated for use alone, or in combination with other antiretrovirals, as first- or second-line treatment of HIV-1-infected adults. Tentative approval of the NDA has been granted in the US, under the President’s Emergency Plan for AIDS Relief (PEPFAR) initiative that includes an expedited review process and encourages worldwide sponsors to submit US marketing applications for single entity, FDC and co-packaged versions of previously approved antiretrovirals. ‘Tentative’ rather than ‘full’ approval is given to those products that contain agents that still have patent or marketing exclusivity protection in the US.

Striding forward
The global community has made significant strides forward in its mission to eradicate the HIV (and ultimately the deadly AIDS) epidemic. Back in 1996, the advent of potent combination antiretroviral therapy (ART or cART or HAART) served as the impetus for changing the course of the HIV epidemic – resulting in HAART becoming the standard of care for HIV. These ‘cocktails’ of three or more ARTs gave patients and scientists new hope and have significantly improved life expectancy from months, to decades. Development of agents for successful treatment and prevention of HIV is complex, particularly given that combined mechanisms of action are recommended and that exceptional patient compliance is required. Pill burden is often the barrier to therapeutic efficacy in patients with HIV. However, the ‘boosted’ and ‘cocktail’ products in late-stage development appear to be catering for these requirements. Additional hope is offered with the 20+ pipeline compounds in phase II clinical trials, with the majority of these being vaccines, CCR5 receptor antagonists and NNRTIs.