Introduction
Landmark randomized studies in chronic HIV infection have proved the enhanced efficacy of triple drug [1] combination antiretroviral therapy (ART), in comparison with mono [2] or dual therapy [3-6], in inducing sustained viral load suppression [7,8] to < 50 copies HIV RNA/ml. Enabling immune reconstitution [9,10] and reductions in morbidity and mortality [11-14] while minimizing the development of drug resistance [15,16]. Although improvement in immune function can be anticipated on starting ART in chronic HIV infection, this is not universal [9]. HIV-specific CD4+ T-cell immunity, shown to correlate with control of initial viraemia [17] in primary HIV infection (PHI), and delayed disease progression in long-term non-progressors [18-20] often fails to recover [9]. In contrast, initiating ART during PHI has been shown to preserve HIV-specific CD4+ T-cells [21-26] otherwise lost. Randomized studies comparing zidovudine monotherapy [27-29] dual and triple ART [30] with placebo in PHI, report demonstrable but short-lived clinical benefit for the treated groups. Non-randomized small studies employing triple [31-34] and four-drug [35] ART in PHI have reported similar outcomes. Aggressive treatment has therefore been advocated for the management of PHI [32], but its composition and optimal duration remains to be determined [36-39].
In this study we compare the efficacy and tolerability of three different treatment ART regimens in PHI.
Materials and methods
One hundred and five patients with defined PHI were recruited into a prospective non-randomized short course antiretroviral therapy (SCART) intervention study from St Mary's Hospital London between 2000 and 2003. Criteria for acute HIV infection were: (1) the presence of a positive HIV-antibody test and a documented seronegative HIV antibody test within the previous 6 months (n = 53); (2), a positive 'de-tuned' (optical density < 0.6) Abbott (Maidenhead, Berks., UK) enzyme-linked immunosorbent assay (n = 10); (3), positive HIV DNA polymerase chain reaction (PCR) in the absence of an HIV-specific antibody response (n = 22) or (4), the presence of an evolving titre positive HIV antibody test (n = 20). Median time from symptoms to diagnosis of PHI was 78 days (range, 12-98 days). Genotypic viral drug resistance testing was performed in real time at baseline and 4 weeks after discontinuation of SCART. Local Regional Ethics Committee approval was received. Eligible participants gave written informed consent. Patients chose between SCART or no treatment; 90 of 105 chose to take SCART whereas 15 of 105 declined and therefore are not included in subsequent analysis. Patients choosing SCART, were consecutively allocated to first the three-drug regimen: zidovudine 250 mg twice daily, lamivudine 150 mg twice daily (Combivir®, GlaxoSmithKline, Greenford, Middlesex, UK) and nevirapine 200 mg twice daily; second, the four-drug combination: zidovudine 250 mg twice daily, lamivudine and abacavir 300 mg twice daily (Trizivir®, GlaxoSmithKline) and efavirenz 600 mg once daily; and third, the protease inhibitor (PI)-containing regimens; Combivir and lopinavir (Kaletra®, Abbott Laboratories Ltd, Queensborough, Kent, UK) 3 capsules twice daily. Regimens were altered based on medical, genotypic resistance results and patient preferences. SCART was commenced in all cases within 2 weeks of diagnosis and stopped after 12 weeks, or once plasma viral load (pVL) was < 50 copies HIV RNA/ml. If non-nucleoside reverse transcriptase inhibitors (NNRTI) drugs were part of the regimen, the NRTI component was continued for an additional 5 days after NNRTI [40] was stopped.
Decisions not to start SCART were varied, mainly relating to anxiety of poor adherence, drug toxicity and the development of drug resistance, introducing a potential bias towards good adherence in those choosing SCART.
Drug toxicity was analysed and graded in accordance with standard UK clinical trial practices (Datapharm Communication Ltd. Medicines.org.uk). Adherence was addressed at each visit using standard self-reported questionnaires and advice from a clinical nurse specialist.
Measurements
Plasma viral load was quantified using the Chiron 3.0 reverse transcriptase (RT)-polymerase chain reaction (PCR) (Chiron UK Ltd, Southam, Warwks., UK). The range of detection was 50 to > 500 000 HIV RNA copies/ml. HIV genotypic analysis in pol using either Visible Genetics Trugene (Visible Genetics, Evry, France) or the ViroSeq vII HIV Genotyping System (Applied Biosystems, Warrington, Cheshire, UK), according to the manufacturers instructions. HIV subtyping was performed using (NCBI) 'BLAST' algorithm software.(www.ncbi.nlm.nih.gov/retroviruses/subtype/htlm). The impact of codon changes within pol was analysed using the chi-squared and Fisher's exact test for discrete variables.
CD4 cell count measurements
CD4 T-cell subset counts were performed monthly using standard fluorescence-activated cell sorter (FACS) analysis.
Survival analysis
Cox proportional hazards model tested for differences between groups in time to reach undetectable pVL, for baseline viral load and CD4 cell count. Both intend-to-treat (ITT) and on-treatment (OT) analyses were performed. ITT definition in this context was all those sequentially allocated to one of the three treatment regimes chosen at the time of diagnosis; volunteers choosing alternative SCART regimens were excluded from this analysis. No measurements from censured patients were included in the OT analysis. Analyses were performed in STATA (STATA Corp., College Station, Texas, USA).
Mathematical model of viral decay
An empirical biphasic decay curve, based on mechanistic models of viral replication [41,42] was fitted to viral load measurements. The curve is given by the equation for the log10 pVL ν(t) as function of time since start of therapy t:
Equation (Uncited)Image Tools
where ts is the duration of the shoulder prior to the start of rapid viral decay, ν1 is the baseline log10 pVL, δ1 is the rate of pVL decay during the rapid first phase, ν2 is the log10 pVL below which decay enters the slower second phase and δ2 is the rate of second phase decay. Because of infrequent sampling during the first phase of viral decay, it was not possible to estimate the two parameters δ1 and ts that affect the rapid phase of viral decay; these were fixed to the plausible values. The rapid decay rate was fixed to δ1 = 0.7/day corresponding to a half life of rapid turnover virus of approximately 1 day [43,44], and the shoulder was fixed to ts = 1 day. Maximum likelihood estimates for the slow decay rate δ2, the baseline log10 viral load ν1 and the rapid-slow phase transition log10 viral load ν2 were obtained using a mixed effects model [41] and assuming a normal distribution for the log-viral load [42,48]. Here, the model curve is fitted to each patient's data, with patient-specific parameters δ2 and ν1. The likelihood is constructed by assuming that the measured viral load is normally distributed with mean ν(t) and standard deviation σ, and that the parameters ln δ2 and ν2 are drawn from a bivariate normal distribution with standard deviations δInδ2 and δν1 and correlation coefficient r. Allowing for additional random effects in the turning-point viral load ν2 did not improve the fit. When pVL was above or below a limit of detection, a cumulative normal distribution with mean ν(t) was substituted in the likelihood. Since the mathematical models assumed viral decay, they were only fitted to OT data. The models were programmed in SAS (SAS Institute, Cary, North Carolina, USA).
The maximum likelihood estimates for the parameters which did not vary between treatment groups (all but δ2) are ν1 = 4.89, ν2 = 3.19, δInδ2 = 0.58, δν1 = 0.91 and r = 0.49. The remaining random variability in viral load was estimated to have standard deviation σ = 0.51.
Results
Seventy-nine of 90 patients were included in the ITT analysis, 11 patients excluded from ITT analysis received alternative ART for either; personal preferences (n = 7), medical indications (n = 2) or transmitted drug-resistant virus (n = 2). OT analysis was possible on 75 of 90 subjects, initial SCART choices were altered in four volunteers according to clinical indications, or drug toxicities (Table 1).
Tolerability
Eight of 79 experienced toxicities. Two of 29 (7%) receiving three-drug SCART had side effects; one grade IV zidovudine-induced anaemia (SCART was stopped after 10 weeks of therapy), pVL < 50 copies HIV RNA/ml, and nevirapine-induced grade III reactive hepatitis, necessitating a switch to lopinavir/ritonovir at week 4.
Five of 33 (13%) reported toxicities receiving four-drug SCART; three of five described psychological symptoms, two of five has additional skin rashes. Three of five substituted efavirenz with lopinavir/ritonavir, whereas two of five remained on triple nucleoside ('Trizivir') alone.
One of 17 (6%) reported gastrointestinal symptoms in the PI-containing regimen, and stopped SCART at week 10 prior to achieving pVL < 50 copies HIV RNA/ml. We report no significant disturbance of serum lipid profiles with lopinavir/ritonavir [45]. One individual developed erythema nodosum, on Combivir/lopinavir.
Adherence
Reported adherence using standard questionnaires was 95%.
Virological response to initial ART regimen
A powerful method to measure ART efficacy is to fit a mathematical model to viral decay (see methods). The model was fitted using a mixed effects procedure, allowing for individual variation in viral decay profiles within as well as between treatment groups. The best-fit model of pVL decay is illustrated in Fig. 1. The first phase slopes of viral decay could not be estimated due to insufficiently frequent sampling during the start of therapy. Second phase decay was significantly faster in the four-drug arm relative to the other two treatment arms (P = 0.01). The maximum likelihood estimate for the decay rate is δ2 = 0.041 per day for the three-drug arms (half-life 17.0 days) and δ2 = 0.061 per day for the four-drug arm (half-life 11.3 days). As previously reported [36], we found a positive correlation between individual patients' rate of second phase decline δ2 and baseline pVL (r = 0.49), but our test was adjusted for this and baseline CD4 cell count. As the mathematical model assumes viral decay, it was only applied to OT data.
Survival analysis, showed that the time taken to reach an undetectable pVL was shorter but insignificant in the four-drug arm than the other two (P = 0.07, Cox proportional hazards model), but this was not replicated in the ITT analysis. The interpretation of survival analysis applied to longitudinal viral load is however controversial [46].
We found no significant differences between patient groups in CD4 cell count recovery using a mathematical model (not described).
Comparison of virological rebound on stopping therapy
The rate and level of median pVL rebound between the three different treatment arms was comparable. Stopping SCART was not associated with any 'seroconversion-type' syndrome, despite high-level rebound pVL. There was no genotypic evidence of de novo drug resistance.
Discussion
This is the first prospective comparison of virological efficacy comparing three antiretroviral regimens in PHI. We report comparable time to successfully suppress pVL in all three-treatment arms (mean 12 weeks) with no significant difference in the ITT analysis. However, OT analysis of virological response to therapy using Kaplan-Meier plots identified an enhanced fall in pVL and rate of pVL decay with the four-drug combination. Differences between the ITT and the OT analyses may rest with the toxicities encountered with the four-drug arm. Problems with skin and mood-altering effects of efavirenz impacted on NNTRI tolerability in contrast to experience reported by other groups [47].
Employment of a novel mathematical modelling analysis may offer better measures of treatment efficacy than standard statistical methods [41] because these analyses are based on a biological model of the effect of drug action. We embedded our mathematical model within a mixed effects statistical framework [42], which provides substantial technical benefits over patient-specific [41] or grouped [44] methods. This resulted in a more powerful test, and thus provided less ambiguous evidence that the four-drug regimen resulted in more rapid decay in viral load. We also confirm that baseline viral load positively correlated with the rate of decay [49-51] (our test adjusted for this effect).
In contrast to previous reports [52], we report a median time to achieve a pVL of < 50 copies HIV RNA/ml of 13 weeks (95% confidence interval, 9-16) which is comparable with reports of initiating triple therapy in chronic infection [53-56].
The structured treatment interruption approach to management of PHI seems a safe compromise [57-59] but remains controversial [36]. It did not induce de novo resistance, nor did it impair response to ART commenced later for CD4 cell count decline, in agreement with reports of STI in chronic infection [55,59].
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