Efficacy and Safety of Tenofovir Disoproxil Fumarate Versus Low-Dose Stavudine Over 96 Weeks: A Multicountry Randomized, Noninferiority Trial

Willem Daniel Francois Venter, Andrew Kambugu, Matthew F Chersich, Stephen Becker, Andrew Hill, Natasha Arulappan, Michelle Moorhouse, Mohammed Majam, Godspower Akpomiemie, Simiso Sokhela, Selvamuthu Poongulali, Charles Feldman, Chris Duncombe, David H Brown Ripin, Alinda Vos, Nagalingeswaran Kumarasamy, Willem Daniel Francois Venter, Andrew Kambugu, Matthew F Chersich, Stephen Becker, Andrew Hill, Natasha Arulappan, Michelle Moorhouse, Mohammed Majam, Godspower Akpomiemie, Simiso Sokhela, Selvamuthu Poongulali, Charles Feldman, Chris Duncombe, David H Brown Ripin, Alinda Vos, Nagalingeswaran Kumarasamy

Abstract

Background: Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF).

Setting: HIV-1-infected treatment-naive adults in India, South Africa, and Uganda.

Methods: A phase-4, 96-week, randomized, double-blind, noninferiority trial compared d4T 20 mg twice daily and TDF, taken in combination with lamivudine (3TC) and efavirenz (EFV). The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies per milliliter at 48 weeks. Adverse events assessments included measures of bone density and body fat. The trial is registered on Clinicaltrials.gov (NCT02670772).

Results: Between 2012 and 2014, 536 participants were recruited per arm. At week 96, trial completion rates were 75.7% with d4T/3TC/EFV (n = 406) and 82.1% with TDF/3TC/EFV (n = 440, P = 0.011). Noncompletion was largely due to virological failure [6.2% (33) with d4T/3TC/EFV versus 5.4% (29) with TDF/3TC/EFV; P = 0.60]. For the primary endpoint, d4T/3TC/EFV was noninferior to TDF/3TC/EFV (79.3%, 425/536 versus 80.8% 433/536; difference = -1.49%, 95% CI: -6.3 to 3.3; P < 0.001). Drug-related adverse event discontinuations were higher with d4T (6.7%, 36), than TDF (1.1%, 6; P < 0.001). Lipodystrophy was more common with d4T (5.6%, 30) than TDF (0.2%, 1; P < 0.001). Creatinine clearance increased in both arms, by 18.1 mL/min in the d4T arm and 14.2 mL/min with TDF (P = 0.03). Hip bone density measures, however, showed greater loss with TDF.

Conclusions: Low-dose d4T combined with 3TC/EFV demonstrated noninferior virological efficacy compared with TDF/3TC/EFV, but mitochondrial toxicity remained high. Little renal toxicity occurred in either arm. Implications of bone mineral density changes with TDF warrant investigation.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

FIGURE 1.
FIGURE 1.
Trial profile.
FIGURE 2.
FIGURE 2.
DEXA scan—hips bone mineral density percentage change from baseline.
FIGURE 3.
FIGURE 3.
Lumbar spine bone mineral density and percentage change from baseline.

References

    1. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection, Recommendations for a Public Health Approach. 2nd ed; 2016.
    1. Grayson ML, Cosgrove SE, Crowe S, et al. Kucers' the Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic, and Antiviral Drugs. 7th ed Boca Raton, FL: CRC Press; 2017.
    1. McComsey G, Lonergan JT. Mitochondrial dysfunction: patient monitoring and toxicity management. J Acquir Immune Defic Syndr. 2004;37(suppl 1):S30–S35.
    1. Subbaraman R, Chaguturu SK, Mayer KH, et al. Adverse effects of highly active antiretroviral therapy in developing countries. Clin Infect Dis. 2007;45:1093–1101.
    1. WHO. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach. 2010 Revision; 2010.
    1. Clinton Health Access Initiative. ARV Market Report: The State of the Antiretroviral Drug Market in Low-and Middle-Income Countries, 2014–2019. Issue 6; 2015.
    1. Vento S, Lanzafame M, Lattuada E, et al. Dose reduction of antiretrovirals: a feasible and testable approach to expand HIV treatment in developing countries. Trop Med Int Health. 2013;18:40–44.
    1. Hill A, Ananworanich J, Calmy A. Dose optimisation: a strategy to improve tolerability and lower antiretroviral drug prices in low and middle income countries. Open Infect Dis J. 2010;4:85–91.
    1. Hill A, Ruxrungtham K, Hanvanich M, et al. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother. 2007;8:679–688.
    1. Sanchez-Conde M, de Mendoza C, Jimenez-Nacher I, et al. Reductions in stavudine dose might ameliorate mitochondrial-associated complications without compromising antiviral activity. HIV Clin Trials. 2005;6:197–202.
    1. Milinkovic A, Martinez E, Lopez S, et al. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Antivir Ther. 2007;12:407–415.
    1. Magula N, Dedicoat M. Low dose versus high dose stavudine for treating people with HIV infection. Cochrane Database Syst Rev. 2015;1:CD007497.
    1. WHO. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach—2006 Revision; 2006.
    1. Koegl C, Wolf E, Postel N, et al. Low dose stavudine: as effective as standard dose but less side effects. Paper presented at: 9th European AIDS Conference, Abstract no. 9.8; October 25–29, 2003; Warsaw, Poland.
    1. Hanvanich M, Prasanthai V, Riengchan P, et al. Reduction of d4T improves lipoatrophy without virologic failure. Paper presented at: 2nd International AIDS Society Conference, Abstract no. 749; July 13–16, 2003; Paris, France.
    1. Delpierre C, Cuzin L, Alvarez M, et al. Lowering stavudine dosages does not compromise anti-viral efficacy in HIV-1-infected patients. Paper presented at: 9th European AIDS Conference, Abstract no. 9.4/2; October 25–29, 2003; Warsaw, Poland.
    1. Hill A. d4T: keep it or abandon it? Asian Biomed. 2010;4:541–546.
    1. McComsey GA, Lo Re V, III, O'Riordan M, et al. Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study. Clin Infect Dis. 2008;46:1290–1296.
    1. Menezes CN, Crowther NJ, Duarte R, et al. A randomized clinical trial comparing metabolic parameters after 48 weeks of standard- and low-dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV-infected South African patients. HIV Med. 2014;15:3–12.
    1. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191–201.
    1. Grant PM, Cotter AG. Tenofovir and bone health. Curr Opin HIV AIDS. 2016;11:326–332.
    1. Bedimo R, Rosenblatt L, Myers J. Systematic review of renal and bone safety of the antiretroviral regimen efavirenz, emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection. HIV Clin Trials. 2016;17:246–266.
    1. MSF Geneva. Untangling the Web of ARV Price Reductions. 14th ed; 2011.
    1. Bendavid E, Grant P, Talbot A, et al. Cost-effectiveness of antiretroviral regimens in the World Health Organization's treatment guidelines: a South African analysis. AIDS. 2011;25:211–220.
    1. Bender MA, Kumarasamy N, Mayer KH, et al. Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India. Clin Infect Dis. 2010;50:416–425.
    1. Rosen S, Long L, Fox M, et al. Cost and cost-effectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa. J Acquir Immune Defic Syndr. 2008;48:334–344.
    1. Division of AIDS (DAIDS). Table for Grading the Severity of Adult and Pediatric Adverse Events. Version 2.0; 2014.
    1. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment Guidance for Industry; 2015.
    1. Department of Health and Human Services (DHHS), Food and Drug Administration, Center for Drug Evaluation and Research (US) Clinical Medical. Guidance for Industry: Antiretroviral Drugs Using Plasma HIV RNA Measurements—Clinical Considerations for Accelerated and Traditional Approval; 2002.
    1. Rossouw T, Botes M, Conradie F. Overview of HIV-related lipodystrophy. South Afr J HIV Med. 2013;14:29–33.
    1. Giralt M, Domingo P, Guallar JP, et al. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther. 2006;11:729–740.
    1. Fabian J, Venter WD, Mkhabela L, et al. Symptomatic hyperlactataemia in adults on antiretroviral therapy: a single-centre experience. S Afr Med J. 2008;98:795–800.
    1. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.
    1. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385:2606–2615.
    1. Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. 2016;3:e158–e165.
    1. Aloy B, Tazi I, Bagnis CI, et al. Is tenofovir alafenamide safer than tenofovir disoproxil fumarate for the kidneys? AIDS Rev. 2016;18:184–192.
    1. De Waal R, Cohen K, Fox MP, et al. Changes in estimated glomerular filtration rate over time in South African HIV-1-infected patients receiving tenofovir: a retrospective cohort study. J Int AIDS Soc. 2017;20:1–8.
    1. Nkhoma ET, Rosenblatt L, Myers J, et al. Real-world assessment of renal and bone safety among patients with HIV infection exposed to tenofovir disoproxil fumarate-containing single-tablet regimens. PLoS One. 2016;11:e0166982.
    1. Duvivier C, Kolta S, Assoumou L, et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS. 2009;23:817–824.
    1. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203:1791–1801.
    1. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010;51:963–972.
    1. Hemkens LG, Ewald H, Santini-Oliveira M, et al. Comparative effectiveness of tenofovir in treatment-naive HIV-infected patients: systematic review and meta-analysis. HIV Clin Trials. 2015;16:178–189.
    1. Njuguna C, Swart A, Blockman M, et al. Cases of antiretroviral-associated gynaecomastia reported to the National HIV and Tuberculosis Health Care Worker Hotline in South Africa. AIDS Res Ther. 2016;13:40.
    1. Karamchand S, Leisegang R, Schomaker M, et al. Risk factors for incident diabetes in a cohort taking first-line nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Medicine (Baltimore). 2016;95:e2844.
    1. van Leth F, Phanuphak P, Stroes E, et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med. 2004;1:e19.
    1. Alonso-Villaverde C, Coll B, Gomez F, et al. The efavirenz-induced increase in HDL-cholesterol is influenced by the multidrug resistance gene 1 C3435T polymorphism. AIDS. 2005;19:341–342.
    1. Thamrongwonglert P, Chetchotisakd P, Anunnatsiri S, et al. Improvement of lipid profiles when switching from efavirenz to rilpivirine in HIV-infected patients with dyslipidemia. HIV Clin Trials. 2016;17:12–16.
    1. Dave JA, Levitt NS, Ross IL, et al. Anti-retroviral therapy increases the prevalence of dyslipidemia in South African HIV-infected patients. PLoS One. 2016;11:e0151911.
    1. Mouton JP, Cohen K, Maartens G. Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen. Expert Rev Clin Pharmacol. 2016;9:1493–1503.
    1. British HIV Association. Guidelines for the Treatment of HIV-Positive Adults with Antiretroviral Therapy 2015 (2016 Interim Update); 2016.
    1. Zengin A, Prentice A, Ward KA. Ethnic differences in bone health. Front Endocrinol (Lausanne). 2015;6:24.
    1. Andrieux-Meyer I, Goemaere, Lynch S, et al. Why it's time to say goodbye to stavudine … everywhere: debate. South Afr J HIV Med. 2012;13:17–19.
    1. Group ES, Carey D, Puls R, et al. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15:793–802.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi