Decreasing Rate of Multiple Treatment Modifications among Individuals who Initiated Antiretroviral Therapy in 1997

Abstract

Background

We hypothesized that rates and reasons for treatment modifications have changed since the implementation of combination antiretroviral therapy (cART) due to improvements in therapy.

Methods

From a nationwide population-based cohort study we identified all HIV-1-infected adults who initiated cART in Denmark 1997–2009 and were followed ≥1 year. Incidence rate ratios (IRRs) and reasons for treatment modifications were estimated and compared between patients, who initiated treatment in 1997–1999, 2000–2004 and 2005–2009. Rates of discontinuation of individual antiretroviral drugs (ARVs) were evaluated.

Results

A total of 3,107 patients were followed for a median of 7.3 years (IQR 3.8–10.8). Rates of first treatment modification ≤1 year after cART initiation did not change (IRR 0.88 [95% CI 0.78, 1.01] and 1.03 [95% CI 0.90, 1.18] in 2000–2004 and 2005–2009, respectively, compared with 1997–1999). Rates of multiple modifications decreased markedly (2000–2004 IRR 0.60 [95% CI 0.53, 0.67] and 2005–2009 IRR 0.38 [95% CI 0.32, 0.46]). Rates of treatment modifications due to virological failure, toxicity and other/unknown reasons decreased (IRR 0.25 [95% CI 0.14, 0.45], 0.69 [95% CI 0.56, 0.83] and 0.45 [95% CI 0.36, 0.57], respectively, in 2005–2009 compared with 1997–1999), whereas the rate of modifications with the aim of simplification increased (IRR 1.85 [95% CI 1.52, 2.25]).

Conclusions

Rates of first treatment modification ≤1 year after cART initiation have not changed since the early cART era, whereas the risk of multiple modifications has decreased markedly. Modifications due to virological failure and toxicity have decreased substantially, whereas rates of switch to simpler and less toxic regimens have increased.

References

Lohse

, Hansen

A.B.

, Pedersen

Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007; 146: 87–95.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. October 14, 2011; 1–167. (Accessed 18 October 2011.) Available from http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

Camacho

, Teofilo

Antiretroviral therapy in treatment-naive patients with HIV infection. Curr Opin HIV AIDS 2011; 6 Suppl 1: S3–S11.

T.T.

, Ledergerber

, Keiser

Durability and outcome of initial antiretroviral treatments received during 2000–2005 by patients in the Swiss HIV Cohort Study. J Infect Dis 2008; 197: 1685–1694.

Cicconi

, Cozzi-Lepri

, Castagna

Insights into reasons for discontinuation according to year of starting first regimen of highly active antiretroviral therapy in a cohort of antiretroviral-naive patients. HIV Med 2010; 11: 104–113.

Audelin

A.M.

, Lohse

, Obel

, Gerstoft

, Jorgensen

L.B.

The incidence rate of HIV type-1 drug resistance in patients on antiretroviral therapy: a nationwide population-based Danish cohort study 1999-2005. Antivir Ther 2009; 14: 995–1000.

Obel

, Omland

L.H.

, Kronborg

Impact of non-HIV and HIV risk factors on survival in HIV-infected patients on HAART: a population-based nationwide cohort study. PLoS ONE 2011; 6: e22698.

Obel

, Engsig

F.N.

, Rasmussen

L.D.

, Larsen

M.V.

, Omland

L.H.

, Sorensen

H.T.

Cohort profile: the Danish HIV cohort study. Int J Epidemiol 2009; 38: 1202–1206.

Petersen

T.S.

, Andersen

S.E.

, Gerstoft

Adherence to national guidelines for initiation of antiretroviral regimens in HIV patients: a Danish nationwide study. Br J Clin Pharmacol 2011; 72: 116–124.

10.

Mocroft

, Youle

, Moore

Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS 2001; 15: 185–194.

11.

Mocroft

, Phillips

A.N.

, Soriano

Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. AIDS Res Hum Retroviruses 2005; 21: 743–752.

12.

O'Brien

M.E.

, Clark

R.A.

, Besch

C.L.

, Myers

, Kissinger

Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr 2003; 34: 407–414.

13.

Hart

, Curtis

, Wilkins

, Johnson

National review of first treatment change after starting highly active antiretroviral therapy in antiretroviral-naive patients. HIV Med 2007; 8: 186–191.

14.

Braithwaite

R.S.

, Kozal

M.J.

, Chang

C.C.

Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies. AIDS 2007; 21: 1579–1589.

15.

Elzi

, Marzolini

, Furrer

Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008. Arch Intern Med 2010; 170: 57–65.

16.

Kirk

, Gerstoft

, Pedersen

Low body weight and type of protease inhibitor predict discontinuation and treatment-limiting adverse drug reactions among HIV-infected patients starting a protease inhibitor regimen: consistent results from a randomized trial and an observational cohort. HIV Med 2001; 2: 43–51.

17.

Hänsel

, Bucher

H.C.

, Nuesch

, Battegay

Reasons for discontinuation of first highly active antiretroviral therapy in a cohort of proteinase inhibitor-naive HIV-infected patients. J Acquir Immune Defic Syndr 2001; 26: 191–193.

18.

Braithwaite

R.S.

, Kozal

M.J.

, Chang

C.C.

Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies. AIDS 2007; 21: 1579–1589.

19.

Lohse

, Obel

, Kronborg

Declining risk of triple-class antiretroviral drug failure in Danish HIV-infected individuals. AIDS 2005; 19: 815–822.

20.

Phillips

A.N.

, Leen

, Wilson

Risk of extensive virological failure to the three original antiretroviral drugs classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study. Lancet 2007; 370: 1923–1928.

21.

PLATO II project team. COHERE Group. Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes: a cohort study. Lancet Infect Dis 2012; 12: 119–127.

22.

Juday

, Gupta

, Grimm

, Wagner

, Kim

Factors associated with complete adherence to HIV combination antiretroviral therapy. HIV Clin Trials 2011; 12: 71–78.

23.

Boyle

B.A.

, Jayaweera

, Witt

M.D.

, Grimm

, Maa

J.F.

, Seekins

D.W.

Randomization to once-daily stavudine extended release/lamivudine/efavirenz versus a more frequent regimen improves adherence while maintaining viral suppression. HIV Clin Trials 2008; 9: 164–176.

24.

Wittkop

, Gunthard

H.F.

, de Wolf

Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect Dis 2011; 11: 363–371.

25.

Audelin

A.M.

, Gerstoft

, Obel

Molecular phylogenetics of transmitted drug resistance in newly diagnosed HIV Type 1 individuals in Denmark: a nation-wide study. AIDS Res Hum Retroviruses 2011; 27: 1283–1290.

26.

van der Valk

, Casula

, Weverlingz

G.J.

Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy. Antivir Ther 2004; 9: 385–393.

27.

Sax

, Tierney

, Collier

ACTG 5202: shorter time to virologic failure (VF) with abacavir/lamivudine (ABC/3TC) than tenofovir/emtricitabine (TDF/FTC) as part of combination therapy in treatment-naive subjects with screening HIV RNA ≥100,000 c/mL. 17th International AIDS Conference. 3–8 August 2008, Mexico City, Mexico. Abstract THAB0303.

28.

Sabin

, Worm

, Weber

Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D study. 15th Conference on Retroviruses and Opportunistic Infections, 3–6 February 2008, Boston, MA, USA. Abstract 957C.

29.

Sabin

C.A.

, Worm

S.W.

, Weber

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–1426.

30.

Brothers

C.H.

, Hernandez

J.E.

, Cutrell

A.G.

Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr 2009; 51: 20–28.

31.

Cruciani

, Zanichelli

, Serpelloni

Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data. AIDS 2011; 25: 1993–2004.

32.

Turner

, Brenner

B.G.

, Routy

J.P.

, Petrella

, Wainberg

M.A.

Rationale for maintenance of the M184v resistance mutation in human immunodeficiency virus type 1 reverse transcriptase in treatment experienced patients. New Microbiol 2004; 27 Suppl 1: 31–39.

33.

Vieira

M.C.

, Kumar

R.N.

, Jansen

J.P.

Comparative effectiveness of efavirenz, protease inhibitors, and raltegravir-based regimens as first-line treatment for HIV-infected adults: a mixed treatment comparison. HIV Clin Trials 2011; 12: 175–189.

34.

Squires

, Lazzarin

, Gatell

J.M.

Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 2004; 36: 1011–1019.

35.

Markowitz

, Nguyen

B.Y.

, Gotuzzo

Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46: 125–133.

36.

Ortiz

, DeJesus

, Khanlou

Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 1389–1397.

37.

Molina

J.M.

, Ferchal

, Rancinan

Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients. J Infect Dis 2000; 182: 599–602.

38.

Adkins

J.C.

, Noble

Efavirenz. Drugs 1998; 56: 1055–1064.

39.

Clifford

D.B.

, Evans

, Yang

Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 2005; 143: 714–721.

40.

Maggiolo

Efavirenz: a decade of clinical experience in the treatment of HIV. J Antimicrob Chemother 2009; 64: 910–928.

41.

van Leth

, Phanuphak

, Ruxrungtham

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363: 1253–1263.

42.

Soriano

, Arasteh

, Migrone

Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN Trial. Antivir Ther 2011; 16: 339–348.

43.

Baylor

M.S.

, Johann-Liang

Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr 2004; 35: 538–539.

44.

Helleberg

, Engsig

F.N.

, Kronborg

Retention in a public health care system with free access to treatment: a Danish nationwide HIV cohort study. AIDS 2012; 26: 741–748.

Decreasing Rate of Multiple Treatment Modifications among Individuals who Initiated Antiretroviral Therapy in 1997–2009 in the Danish HIV Cohort Study

Abstract

Background

Methods

Results

Conclusions

References