Parenteral antiretroviral formulations are still urgently needed: a case report and commentary

Abstract

This case report highlights a challenging clinical dilemma to administer antiretroviral therapy in a critically-ill human immunodeficiency virus-infected patient who presented with multiple opportunistic infections and a non-functional gastrointestinal tract. The need for parenteral antiretroviral drug options is discussed and investigational drugs are briefly reviewed.

Keywords

Parenteral antiretroviral drugs human immunodeficiency virus acquired immunodeficiency syndrome HIV AIDS opportunistic infections non-functional gastrointestinal tract highly active antiretroviral therapy

Introduction

Highly active antiretroviral therapy (HAART) revolutionized human immunodeficiency virus (HIV) treatment since its introduction for HIV patient care. HAART significantly reduced the incidence of opportunistic diseases and mortality rates due to opportunistic infections. Currently, six antiretroviral drug (ARD) classes comprising over 20 ARDs have been approved for the treatment of HIV infection. However, only two parenteral ARD options are available for patients who present non-functional gastrointestinal tracts.

Case report

A 39-year-old man was hospitalized with complaints of abdominal pain, weight loss, shortness of breath and fever for 2 months. Patient examination revealed emaciation, fever, mild tachypnoea and diffuse lymphadenopathy. His abdomen was distended, tender, with normal bowel sounds. Neurological examination performed due to nystagmus revealed cerebellar ataxia. Brain magnetic resonance imaging (MRI) showed altered signal intensity of the right cerebellar white matter and peduncle, suggestive of progressive multifocal leukoencephalopathy. Investigation revealed HIV infection with CD4 count of 42 cells/mm³ (5%) and viral load of 237,354 copies/ml (5.38 log). Arterial blood gas result showed severe hypoxaemia (PO₂ = 53 mmHg). Thoracic computed tomography (CT) revealed diffuse ground-glass pulmonary opacity and necrotic cervical, mediastinal and paratracheal lymphadenopathy. Abdominal CT showed mesenteric, iliac and inguinal lymphadenopathy. Empirical therapy was administered for both community-acquired and pneumocystis pneumonia with intravenous (IV) ceftriaxone 1 g q12 h and sulfamethoxazole-trimethoprim 400/80 mg three ampoules q 6 h, respectively.

On day 4, he presented with acute respiratory failure requiring mechanical ventilation. Pneumocystis jirovecii polymerase chain reaction (PCR) was positive in tracheal secretion. On day 5, cerebrospinal fluid PCR for JC virus was positive. On day 7, digestive endoscopy showed gastric lesions confirmed as Kaposi’s sarcoma (KS) by biopsy and oesophageal candidiasis. Candidiasis was treated with fluconazole 100 mg IV q24 h. Lung KS was also confirmed by transbronchial biopsy. Lymph node biopsy showed caseating granulomas and Ziehl-Neelsen stain was positive for acid-fast bacilli. Treatment for disseminated tuberculosis was initiated with rectal administration of rifampin 1200 mg, pyrazinamide 2000 mg and ethambutol 1200 mg once daily. Since hospital admission, the patient presented constant abdominal distension and vomiting which worsened with enteral tube feeding. For this reason, he had been placed on total parenteral nutrition. The general surgery team attributed the patient’s non-functional gastrointestinal tract to Ogilvie syndrome. Colonoscopy was not performed.

On day 23, the patient presented with respiratory distress. Laboratory findings of pancytopaenia, increased lactate dehydrogenase, liver and pancreatic enzymes suggested cytomegalovirus infection. Empirical treatment was started with ganciclovir 5 mg/kg IV q24 h, adjusted for renal impairment. Considering his critical condition and multiple opportunistic infections, HAART was initiated. Nevertheless, HAART administration via enteral tube was unsuccessful due to the non-functional gastrointestinal tract.

Antituberculous therapy was switched to amikacin 750 mg IV q24 h, levofloxacin 750 mg IV q24 h and rifampin 600 mg once daily via nasoenteral tube. HAART initiation remained challenging due to lack of parenteral options. Therapy with IV zidovudine and subcutaneous (SC) enfuvirtide was discouraged considering the risk of promoting HIV resistance since the bioavailability of a third ARD administered via nasoenteral tube could not be guaranteed. This patient suffered from recurrent nosocomial pneumonia and expired on day 34.

Discussion

HIV infection was inevitably fatal before the discovery of ARDs. In 1987, the nucleoside reverse transcriptase inhibitor (NRTI), zidovudine was the first attempt to treat HIV.¹ From 1996, new ARD classes, such as non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease enzyme inhibitors emerged. Clinical trials evaluating triple therapy showed that combining zidovudine, didanosine and nevirapine, or zidovudine, lamivudine and indinavir was superior to dual NRTI therapy.^2,3

Although over 20 ARDs have been approved (Table 1), the only parenteral option available in HIV treatment in special cases, such as patients with non-functional gastrointestinal tracts, are IV zidovudine and SC enfuvirtide.⁴ Enfuvirtide is an expensive drug that requires twice daily SC injection, thus making it impractical for long-term HIV treatment.⁵ Lack of parenteral ARD options in settings where patients still present to health centres with advanced HIV infection is a concern. Brazil is a middle-income country with an outstanding national HIV/AIDS treatment programme that provides free universal access to HAART,⁶ but as shown, lack of parenteral ARD options can restrict the standard of care for critical AIDS patients.

Table 1.

Approved antiretroviral drugs from 1987 to 2014.

Antiretroviral drug class	Antiretroviral drug name	Year of FDA approval	Formulation
Integrase inhibitors	Raltegravir	2007	Tablets and oral suspension
	Dolutegravir	2013	Tablets
Fusion inhibitor	Enfuvirtide	2003	Subcutaneous injection
Entry inhibitor	Maraviroc	2007	Tablets
Non-nucleoside reverse transcriptase inhibitors	Nevirapine	1996	Tablets and oral suspension
	Delavirdine	1997	Tablets
	Efavirenz	1998	Capsules and tablets
	Etravirine	2008	Tablets
	Rilpivirine	2011	Tablets
Nucleoside reverse transcriptase inhibitors	Zidovudine	1987	Tablets, capsules, syrup and intravenous injection solution
	Didanosine	1991	Capsules
	Stavudine	1994	Capsules and oral solution
	Lamivudine	1995	Tablets and oral solution
	Abacavir	1998	Tablets and oral solution
	Tenofovir	2001	Tablets and powder for oral use
	Emtricitabine	2003	Capsules and oral solution
Protease inhibitors	Saquinavir	1995 2004	Capsules Tablets
	Indinavir	1996	Capsule
	Ritonavir	1996	Capsules
	Nelfinavir	1997	Tablets and powder for oral use
	Lopinavir/Ritonavir	2000	Tablets and oral solution
	Atazanavir	2003	Capsules
	Fosamprenavir	2003	Tablets and oral suspension
	Tipranavir	2005	Capsules and oral solution
	Darunavir	2006	Tablets and oral suspension

Source: Developed using information available at http://aidsinfo.nih.gov/drugs.

Nanotechnology permits the development of long-acting parenteral nanoformulated ARD formulations (nanosuspensions) with sustained drug release and delivery to sites of action.^7,8 The oral formulation of rilpivirine (RPV), a new NNRTI, was approved for treatment-naive HIV infected patients, but injectable nanosuspension of RPV, formerly known as TMC278, is under investigation. RPV nanosuspension promises long-lasting blood concentrations and potential use in a single monthly dose in humans.^9,10

An experimental study evaluating the pharmacokinetics of intramuscular (IM) and SC RPV nanosuspension showed that more stable plasma concentrations were achieved after SC injection. RPV nanosuspension maintained satisfactory plasma concentration and sustained drug release ranging from 3 weeks to 3 months in mice and dogs, respectively.⁹ In a subsequent study evaluating IM and SC injections of 200-nm RPV nanosuspension in rats and dogs, both routes of administration were well tolerated and safe. Stable plasma concentrations were seen with SC administration. Initial RPV bioavailability was almost 100%, with plasma concentrations decreasing progressively over months after SC administration.¹⁰ Research presented at the 19th Conference on Opportunistic Infections (CROI) in 2012 showed the results of a phase I study of injectable RPV for HIV pre-exposure prophylaxis. Twenty HIV-negative women received 300 mg, 600 mg and 1200 mg of RPV injections and six HIV-negative men received a 600 mg dose. Blood, tissue biopsies and genital fluids were sampled to evaluate drug concentrations. Prolonged plasma and genital tract exposures were achieved in both groups. In the women, genital fluid drug concentrations were higher than the plasma concentration.¹¹

The effects of combining long-acting nanoformulated antiretroviral therapy (nanoART) have also been evaluated in severe combined immune-deficient mice reconstituted with human peripheral blood lymphocytes and infected with type 1 HIV. This pilot efficacy study evaluated antiretroviral activity of nanoformulated injectable atazanavir, ritonavir and efavirenz at doses ranging from 80 mg/kg to 250 mg/kg compared to oral administration of the native drugs. Injectable atazanavir, ritonavir and efavirenz attenuated viral replication and preserved the CD4 cell count when compared to the effects seen with oral administration of the original drugs. These nanoformulations were also shown to enhance intracellular anti-retroviral effect by penetrating into HIV-infected monocytes and macrophages with practically no cytotoxicity.¹² A subsequent study evaluated the pharmacokinetics and tissue distribution of SC or IM nanoformulated atazanavir and ritonavir compared to the native drugs in mice and monkeys. Atazanavir and ritonavir concentrations in plasma, tissues and injection site after parenteral administration were, respectively, 13-, 41-, and 4,500-fold higher than those resulting from native-drug administration 14 days after being administered. NanoART was found to create intracellular depot sites in tissue macrophages due to its enhanced intracellular penetration.⁸

GSK1265744 is an investigational HIV integrase inhibitor and analogue of dolutegravir undergoing studies for oral and long-acting parenteral nanoformulations.^4,13 One study evaluated the pharmacokinetics and safety of the co-administration of GSK1265744 and RPV nanosuspensions in healthy adults. All subjects received a 14-day lead-in of oral GSK7126544 (30 mg/day) before parenteral administration of SC/IM GSK7126544 alone or IM GSK7126544 plus IM RPV. The highest GSK1265744 plasma concentrations were achieved after an IM loading dose of 800 mg, followed by a lower dosage of 400 mg administered once monthly for three months. The mean plasma concentrations achieved after IM RPV injections were comparable to those achieved after oral RPV (25 mg/day). Monthly parenteral administrations of GSK1265744 and RPV maintained adequate plasma levels. Both parenteral formulations of GSK1265744 and RPV were safe and well tolerated. Mild to moderate injection site reactions were common; involving mostly pain after IM injection.¹³ Another study evaluated the oral co-administration of RPV and GSK1265744, or RPV and dolutegravir in a cohort of 16 healthy subjects. The combinations of RPV with GSK1265744 or dolutegravir were well tolerated. No drug interactions were observed. The most common adverse event in the RPV and GSK1265744 cohort was decreased appetite. From this study, lack of interactions between oral formulations of RPV and GSK1265744 supports the possibility of co-administration of RPV and GSK1265744 long-acting depot injections.¹⁴

In a recent publication, the efficacy of GSK1265744 for pre-exposure prophylaxis was evaluated in rhesus macaques challenged by non-traumatic intrarectal inoculation of simian immunodeficiency virus (SIV). The macaques were challenged weekly for up to 8 weeks or until infection was confirmed by real-time PCR. GSK1265744 injections were administered at 50 mg/kg doses to 8 macaques 1 week before the first viral exposure and then after 4 weeks, while 8 macaques remained untreated. All untreated macaques became infected during the challenge period. The macaques that received GSK1265744 injections maintained high plasma drug concentrations for up to 12 weeks, except for one. Proviral DNA was not identified in the mononuclear cells or rectum tissues of drug-treated macaques, except for the macaque that did not achieve satisfactory drug plasma concentrations. In this one, rectal mucosal mononuclear cells were infected. The half-life of GSK1265744 was extremely shorter in macaques (3–12 days). The half-life in humans has been shown to range from 21 to 50 days; hence a more durable protective effect can be expected. An efficacy study in men who have sex with men, as well as macaque experiments to protect against intravaginal and intravenous SIV challenges are necessary.¹⁵

Also under investigation is ibalizumab, a humanized murine monoclonal antibody that targets HIV cell entry by inducing CD4 conformational changes and coating cell receptors, thereby preventing attachment and viral entry into host cell.^4,16 Ibalizumab has been shown to be safe and well tolerated in a phase II trial. Intravenous administration generates prolonged plasma exposures for up to 4 weeks post-administration.¹⁷ PRO 140, a SC or IV monoclonal antibody, that acts by blocking HIV cell entry by binding to the CCR5 co-receptor with possible synergistic effects with maraviroc is also under investigation. ^4,18–20 Investigational parenteral ARDs are listed in Table 2.

Table 2.

Investigational parenteral antiretroviral drugs in 2014.

Antiretroviral drug class	Antiretroviral drug under study	Mechanism of action	Clinical trial phase	Administration
Non-nucleoside reverse transcriptase inhibitors	Rilpivirine (RPV)^a	Inhibits reverse transcription of viral RNA into DNA	Data not found	Intramuscular/Subcutaneous
Integrase inhibitors	S/GSK1265744	HIV-1 integrase strand transfer inhibitor	IIB	Intramuscular/subcutaneous
Entry and fusion inhibitors	PRO-140	Humanized IgG4 monoclonal antibody. Binds to CCR5, inhibiting viral entry	II	Subcutaneous/Intravenous
	Ibalizumab	Humanized monoclonal antibody. Binds to the extracellular domain 2 of the CD4 receptor, provoking conformational changes which inhibit viral fusion	II	Intravenous

Source: Developed using information available at http://aidsinfo.nih.gov/drugs.

^aInformation on parenteral RPV is not on the stated website. It has been obtained from the cited published work.

Advantages of injectable ARD options include guaranteed tissue penetration after administration, as well as stable and effective plasma concentrations by avoiding first-pass metabolism and the impact of food on drug bioavailability.⁹ Long-acting parenteral ARDs are also expected to play a role in HIV pre-exposure prophylaxis both for prevention of sexual and mother-to-child transmission of HIV.^7,9–11 Injectable nanosuspensions will largely benefit patients with altered drug availability such as those who present with limited drug adherence or who cannot ingest drug formulations.¹²

A previous perspective paper also conveyed the need for alternative ARD formulations and indicated that one obstacle to parenteral ARD development would be the cost. Considering the need for a full parenteral HAART regimen, the authors suggested developing parenteral formulations of one NNRTI, one protease inhibitor and a combination of zidovudine with either emtricitabine or lamivudine.²¹ While parenteral ARD development costs could be an obstacle in developing countries, it is highly important that such options are also accessible to these countries. In conclusion, drug researchers are encouraged to thoroughly consider further development of parenteral ARD options.

Footnotes

Acknowledgements

I would like to sincerely thank Janeita Tashieann Reid for her time and effort in reviewing this work.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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