ࡱ > 5 bjbjcTcT >N > > o- + 8 = $ a D f | ! 7 7 7 j l l l l l l $ Q! # 7 7 $ 7 7 j 7 r : 0 $ : D $ $ ~ n $ : Technical Appendix
Model Parameterisation
Data from the ATHENA national observational cohort were used to estimate the parameters describing the course of HIV plasma viral load over time on first-line treatment [1]. All male patients who acquired HIV through sex with men and who were treatment-nave when beginning combination anti-retroviral therapy (cART) and who began cART after 1 January 1998 were included in the analyses to estimate the parameters (n=3219).
The median time from cART initiation to viral suppression was estimated using the Kaplan-Meier method. Viral suppression was defined as at least two consecutive HIV viral load measurements of less than 50, or less than 500, HIV RNA copies per millilitre, depending on the detection limit of the specific viral load assays used. Time from viral suppression to treatment failure was estimated using the Kaplan-Meier method, and Weibull distributions were fitted (Figure S1). Treatment failure was defined as the first measurement to find viral load detectable after being undetectable, while on cART. The rate of increase in viral load was modelled using a random effects model, with random intercept and random slope for HIV RNA levels.
All of the analyses were stratified by patients adherence (good or not good), which reflected the first measurement of plasma drug levels after treatment initiation. For Protease Inhibitors, good adherence was defined as a plasma concentration ratio above 0.25 ADDIN EN.CITE ADDIN EN.CITE.DATA (1, 2); for the non-nucleosides, good adherence was defined as drug concentrations above 25% of the minimal effective concentration, resulting in a cut-off for efavirenz plasma concentrations of 0.25 mg/l and a cut-off for nevirapine plasma concentrations of 0.8 mg/l.
Figure S1: Modelled distributions of time from viral suppression achieved to failure for individuals classified as (a) good and (b) not good adherence. The thick red lines show the data from the ATHENA cohort, and the blue and green lines show the model fits. In (a), two functional forms are shown for the extrapolation of the survival curve past the data (reflecting longer or shorter expected survival times) which are used in sensitivity analyses (Figure S4).
Figure S2: Assumed functional relationships between plasma viral load and the probability of HIV transmission per sex act (red and blue lines) and an empirical estimate of average MSM transmission without treatment (black square). The blue line is the assumption used by Wilson et al. ADDIN EN.CITE Wilson200877677677617Wilson, D. P.Law, M. G.Grulich, A. E.Cooper, D. A.Kaldor, J. M.National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW, Australia. Dwilson@nchecr.unsw.edu.auRelation between HIV viral load and infectiousness: a model-based analysisLancetLancet314-2037296352008/07/29Anti-Retroviral Agents/*therapeutic useFemaleHIV Infections/blood/*drug therapy/transmissionHumansMale*Models, TheoreticalRNA, Viral/bloodRisk-TakingSexual Behavior*Viral Load2008Jul 261474-547X (Electronic)18657710http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18657710S0140-6736(08)61115-0 [pii]
10.1016/S0140-6736(08)61115-0eng(3). The red line is based on the shape of the Hill function fitted to observational data in a Zambian cohort study by Fraser et al. ADDIN EN.CITE Fraser200767267267217Fraser, C.Hollingsworth, T. D.Chapman, R.de Wolf, F.Hanage, W. P.Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom.From the Cover: Variation in HIV-1 set-point viral load: Epidemiological analysis and an evolutionary hypothesisProc Natl Acad Sci U S AProc Natl Acad Sci U S A17441-6104442007/10/242007Oct 300027-8424 (Print)17954909http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=179549090708559104 [pii]
10.1073/pnas.0708559104eng(4) and rescaled to fit the same observational data as Wilson et al.
Further Results
Figure S3: Relative risk of transmission to partner during first-line therapy, compared to always using condoms, if: (i) condoms are never used; (ii) condoms are used 30% of the time; (iii) condoms are used unless viral load is undetectable at last measurement in the past 6 months. Two assumptions are made about the chance of transmission (Figure S1), following either Fraser et al. ADDIN EN.CITE Fraser200767267267217Fraser, C.Hollingsworth, T. D.Chapman, R.de Wolf, F.Hanage, W. P.Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom.From the Cover: Variation in HIV-1 set-point viral load: Epidemiological analysis and an evolutionary hypothesisProc Natl Acad Sci U S AProc Natl Acad Sci U S A17441-6104442007/10/242007Oct 300027-8424 (Print)17954909http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=179549090708559104 [pii]
10.1073/pnas.0708559104eng(4) or Wilson et al. ADDIN EN.CITE Wilson200877677677617Wilson, D. P.Law, M. G.Grulich, A. E.Cooper, D. A.Kaldor, J. M.National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW, Australia. Dwilson@nchecr.unsw.edu.auRelation between HIV viral load and infectiousness: a model-based analysisLancetLancet314-2037296352008/07/29Anti-Retroviral Agents/*therapeutic useFemaleHIV Infections/blood/*drug therapy/transmissionHumansMale*Models, TheoreticalRNA, Viral/bloodRisk-TakingSexual Behavior*Viral Load2008Jul 261474-547X (Electronic)18657710http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18657710S0140-6736(08)61115-0 [pii]
10.1016/S0140-6736(08)61115-0eng(3). The same qualitative result was generated (Figure S4) using alternative assumptions about the survival times with suppressed viral loads (see Figure S2 for alternative assumptions).
Figure S4: Same as Figure 2 in the main text (Probability of infection during first line therapy, if: (i) condoms are never used; (ii) condoms are used 30% of the time; (iii) condoms are used unless last viral load measurement in last 6 months was undetectable; (iv) condoms are always used) but using the alternative extended survival assumption for time until failure for those with good adherence (see Figure S1).
Figure S5: Probability of HIV infection to partner as a function of the interval between routine viral load measurements, assuming condoms are used unless the individual has had undetectable viral load (i) in last 3 months (blue line with triangles); (ii) in last 6 months (green line with circles); (iii) at last measurement ever (red line with squares).
References
ADDIN EN.REFLIST 1. Burger DM, Hugen PW, Aarnoutse RE, Hoetelmans RM, Jambroes M, Nieuwkerk PT, et al. Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations. Ther Drug Monit. 2003 Feb;25(1):73-80.
2. Burger DM, Hoetelmans RM, Hugen PW, Mulder JW, Meenhorst PL, Koopmans PP, et al. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antivir Ther. 1998;3(4):215-20.
3. Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM. Relation between HIV viral load and infectiousness: a model-based analysis. Lancet. 2008 Jul 26;372(9635):314-20.
4. Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP. From the Cover: Variation in HIV-1 set-point viral load: Epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17441-6.
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