Case report

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

International Journal of STD & AIDS 2015, Vol. 26(6) 436–440 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414538242 std.sagepub.com

Fatuma Catherine Atieno Odongo

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 Date received: 3 March 2014; accepted: 5 May 2014

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 ¼ 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 Department of Infectious Diseases, Medical School of the University of Sa˜o Paulo, Sa˜o Paulo, Brazil Corresponding author: Fatuma Catherine Atieno Odongo, Av. Dr. Ene´as de Carvalho Aguiar, 255, Divisa˜o de Mole´stias Infecciosas - 4 andar, CEP 05403-900, Sa˜o Paulo – SP, Brazil. Email: [email protected]

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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 nonnucleoside 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 nonfunctional 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. Nanotechnology permits the development of longacting 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 antiretroviral effect by penetrating into HIV-infected monocytes and macrophages with practically no cytotoxicity.12 A subsequent study evaluated the

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International Journal of STD & AIDS 26(6) Table 1. Approved antiretroviral drugs from 1987 to 2014. Antiretroviral drug class Integrase inhibitors Fusion inhibitor Entry inhibitor Non-nucleoside reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors

Protease inhibitors

Antiretroviral drug name

Year of FDA approval

Formulation

Raltegravir Dolutegravir Enfuvirtide Maraviroc Nevirapine

2007 2013 2003 2007 1996

Tablets and oral suspension Tablets Subcutaneous injection Tablets Tablets and oral suspension

Delavirdine Efavirenz Etravirine Rilpivirine Zidovudine

1997 1998 2008 2011 1987

Didanosine Stavudine Lamivudine Abacavir Tenofovir Emtricitabine Saquinavir

1991 1994 1995 1998 2001 2003 1995 2004 1996 1996 1997 2000 2003 2003 2005 2006

Tablets Capsules and tablets Tablets Tablets Tablets, capsules, syrup and intravenous injection solution Capsules Capsules and oral solution Tablets and oral solution Tablets and oral solution Tablets and powder for oral use Capsules and oral solution Capsules Tablets Capsule Capsules Tablets and powder for oral use Tablets and oral solution Capsules Tablets and oral suspension Capsules and oral solution Tablets and oral suspension

Indinavir Ritonavir Nelfinavir Lopinavir/Ritonavir Atazanavir Fosamprenavir Tipranavir Darunavir

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

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

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Table 2. Investigational parenteral antiretroviral drugs in 2014. Antiretroviral drug class

Antiretroviral drug under study Rilpivirine (RPV)a

Non-nucleoside reverse transcriptase inhibitors Integrase inhibitors

S/GSK1265744

Entry and fusion inhibitors

PRO-140

Ibalizumab

Mechanism of action Inhibits reverse transcription of viral RNA into DNA HIV-1 integrase strand transfer inhibitor Humanized IgG4 monoclonal antibody. Binds to CCR5, inhibiting viral entry Humanized monoclonal antibody. Binds to the extracellular domain 2 of the CD4 receptor, provoking conformational changes which inhibit viral fusion

Clinical trial phase

Administration

Data not found IIB

Intramuscular/Subcutaneous

II

Subcutaneous/Intravenous

II

Intravenous

Intramuscular/subcutaneous

Source: Developed using information available at http://aidsinfo.nih.gov/drugs. a Information on parenteral RPV is not on the stated website. It has been obtained from the cited published work.

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. 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.

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International Journal of STD & AIDS 26(6)

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.

References 1. Vella S, Schwartla¨nder B, Sow SP, et al. The history of antiretroviral therapy and of its implementation in resource-limited areas of the world. AIDS 2012; 26(10): 1231–1241. 2. Montaner JS, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study. JAMA 1998; 279(12): 930–937. 3. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337(11): 725–733. 4. U.S. Department of Health and Human Services. Information on HIV/AIDS-related drugs. http://aidsinfo.nih.gov/drugs (accessed 26 April 2014). 5. Robertson D. US FDA approves new class of HIV therapeutics. Nat Biotechnol 2003; 21(5): 470–471. 6. Nunn AS, da Fonseca EM, Bastos FI, et al. AIDS treatment in Brazil: impacts and challenges. Health Aff (Millwood) 2009; 28(4): 1103–1113. 7. Boffito M, Jackson A, Owen A, et al. New Approaches to antiretroviral drug delivery: challenges and opportunities associated with the use of long-acting injectable agents. Drugs 2014; 74: 7–13. 8. Gautam N, Roy U, Balkundi S, et al. Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy. Antimicrob Agents Chemother 2013; 1(57): 3110–3120. 9. Baert L, van’t Klooster G, Dries W, et al. Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm 2009; 72(3): 502–508. 10. van ’t Klooster G, Hoeben E, Borghys H, et al. Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long-acting injectable antiretroviral formulation. Antimicrob Agents Chemother 2010; 54(5): 2042–2050.

11. Jackson A, et al. Rilpivirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV-females and rectum in males. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 35, 2012 [Original abstract not available]. Reference to abstract on article by Jared Baeten and Connie Celum. http:// www.natap.org/2014/CROI/croi_78.htm (accessed 26 April 2014). 12. Roy U, McMillan J, Alnouti Y, et al. Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1–infected human peripheral blood lymphocyte–reconstituted mice. J Infect Dis 2012; 206(10): 1577–1588. 13. Spreen W, Williams P, Margolis D, et al. First study of repeat dose co-administration of GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety, and tolerability in healthy adults [Abstract]. In: 7th IAS conference on HIV pathogenesis, treatment and prevention. Kuala Lumpur, Malaysia, 30 June–3 July 2013. http://pag.ias2013.org/ Abstracts.aspx?AID¼796 (accessed 26 April 2014). 14. Ford SL, Gould E, Chen S, et al. Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744. Antimicrob Agents Chemother 2013; 57(11): 5472–5477. 15. Andrews CD, Spreen WR, Mohri H, et al. Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science 2014; 343(6175): 1151–1154. 16. Kuritzkes DR, Jacobson J, Powderly WG, et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004; 189(2): 286–291. 17. Jacobson JM, Kuritzkes DR, Godofsky E, et al. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 2009; 53(2): 450–457. 18. Murga J, Franti M, Pevear DC, et al. Potent antiviral synergy between monoclonal antibody and small molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2006; 50(10): 3289–3296. 19. Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV infected adults. J Infect Dis 2008; 198(9): 1345–1352. 20. Jacobson JM, Thompson MA, Lalezari JP, et al. AntiHIV-1 activity of weekly or biweekly treatment with subcutaneous PRO140, a CCR5 monoclonal antibody. J Infect Dis 2010; 201(10): 1481–1487. 21. Swindells S, Flexner C, Fletcher CV, et al. The critical need for alternative antiretroviral formulations, and obstacles to their development. J Infect Dis 2011; 204(5): 669–674.

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