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Key clinical trials of non-nucleoside reverse transcriptase inhibitors in the treatment of chronic HIV-1 infection in adults.

INTRODUCTION

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an essential component of triple-drug antiretroviral therapy regimens. As of 2008, three NNRTIs are used routinely for the treatment of HIV infection: efavirenz, nevirapine and etravirine. The latter, at present has regulatory approval only in the USA. Several other NNRTIs have been evaluated but were withdrawn for reasons of either poor efficacy or unacceptable toxicity. New NNRTIs are in development, reflecting the importance of this class in the treatment of patients with HIV-1 infection. This paper reviews the key randomised controlled clinical trials (RCTs) of NNRTIs in the treatment of adult HIV-1 infection, the results of which have significantly influenced clinical practice and led to the primary role of NNRTIs in antiretroviral therapy.

ANTIVIRAL ACTIVITY

Inhibition of HIV-1 replication by NNRTIs was first described in 1990 [1,2]. In vitro studies showed activity against HIV-1 replication but not HIV-2. Phase I/II studies of nevirapine confirmed antiviral activity, but early virus suppression was reversed following rapid emergence of virus that was less susceptible to nevirapine within 8 weeks [3]. These studies were important as they were the first to show the virological consequences of the low genetic barrier to resistance of NNRTIs and establish a relationship between drug resistance and surrogate markers of antiviral activity.

CLINICAL EFFICACY

The first trials to evaluate efficacy also contributed to the establishment of a triple-drug combination therapy as standard of care for the treatment of HIV infection. The INCAS trial compared a combination of zidovudine, didanosine and nevirapine versus zidovudine and didanosine versus zidovudine and nevirapine in treatment-naive patients with a CD4 cell count between 200 and 600 cells/[mm.sup.3] [4]. The results of the trial were reported in 1996 and showed that not only did treatment with the triple-drug regimen result in greater falls in plasma HIV-RNA levels in the first 8 weeks than the two-drug regimens, but that viral suppression was generallymaintained out to 52 weeks of treatment, suggesting that emergence of viral resistance could be delayed. The proportion with undetectable viral loads at 52 weeks was 51% in the triple-drug regimen versus 12% (ZDV+ddI) and 0%, (ZDV+NVP) in the two-drug regimens.

The INCAS trial not only demonstrated for the first time the virological efficacy of a combination regimen containing an NNRTI and two NRTIs in a treatment-naive population but also the importance of combining the NNRTI with two other active drugs to maintain viral suppression and prevent the emergence of viral resistance. Previous studies of nevirapine given either as monotherapy or in combination with zidovudine had shown rapid loss of viral suppression after a few weeks of therapy, coincident with the rapid emergence of viral populations with reduced susceptibility to nevirapine. The importance of combining drugs with low genetic barriers to resistance with at least one or two other active drugs has subsequently been established as an important guiding principle in treatment guidelines.

The DMP006 study evaluated efavirenz, zidovudine and lamivudine versus efavirenz and indinavir versus indinavir, zidovudine and lamivudine in patients with CD4 cell counts greater than 50 cells/[mm.sup.3] in an open-label RCT [5]. Fifteen percent of patients had received treatment with NRTIs other than lamivudine. At the time of this study, the combination containing zidovudine, lamivudine and indinavir was the standard of care for triple therapy. The study showed that a significantly higher proportion of patients treated with efavirenz and two NRTIs had an undetectable viral load at 48 weeks compared to those treated with indinavir and two NRTIs (VL <400 copies/ml: 70% vs. 48%; P<0.001). Of importance was the significantly higher rate of treatment discontinuation for any reason in the indinavir plus two NRTI arm compared to efavirenz plus two NRTIs (43% vs. 27%; P=0.005). Adverse events leading to treatment discontinuation were also significantly higher with indinavir.

The study established efavirenz plus two NRTIs as an effective option for treatment in treatment-naive patients. It also emphasised the importance of treatment tolerability as a significant factor in clinical efficacy of HIV treatment. In an insightful discussion the authors pointed to the long terminal half-life and high ratio of free drug trough levels in plasma to IC90 levels in vitro, as major pharmacokinetic factors in the treatment efficacy of efavirenz despite a low genetic barrier to resistance, characteristics which are common to other NNRTIs.

Although not specifically designed to evaluate the efficacy of an NNRTI-based regimen, the results of several other studies have been important in establishing the major role of NNRTIs in first-line therapies, particularly in re-confirming the efficacy of efavirenz and two NRTIs and in demonstrating long-term efficacy out to more than 3 years of follow-up [6-9]. One of these was important in showing the significantly lower virological efficacy of a triple NRTI regimen compared to efavirenz plus two NRTIs [8]. Secondary analysis of this study also importantly showed that treatment with efavirenz was equally effective in patients with advanced immune deficiency (CD4 cell count <50 copies/[mm.sup.3]) [10].

SUMMARY

The initial trials of NNRTIs helped to confirm the importance of triple-drug regimens in maintaining virological suppression and thus delaying the emergence of resistance, as well as the potential role of NNRTIs in first-line therapy. Subsequent trials of efficacy established the combination of efavirenz plus two NRTIs as one of the preferred options for therapy of treatment-naive patients.

CHOICE OF NNRTI

Having established the efficacy of NNRTI-based triple drug combination regimens in first-line therapy, there was need for randomised controlled trials to compare the efficacy of efavirenz and nevirapine in combination with two NRTIs. The results of cohort studies in clinic populations suggested a better virological outcome with efavirenz. The 2NN study is the key trial to date that has compared the efficacy and safety of efavirenz versus nevirapine in first-line therapy [11]. A small open-label RCT had shown similar virological efficacy but the study was limited to patients with baseline CD4 cell counts >100 cells/mm3 and viral load <100,000 copies/ml [12]. There was a clear need for a definitive Phase III trial.

2NN TRIAL

TRIAL DESIGN

The 2NN trial was an open-label RCT comparing the efficacy and safety of treatment with two NRTIs (stavudine and lamivudine) and either nevirapine once daily, nevirapine twice daily, efavirenz or a combination of efavirenz and nevirapine, in treatment-naive patients with baseline viral load >10,000 copies/ml [11]. The study started initially with the aim of comparing nevirapine once daily, efavirenz and the combination of the two. However, 5 months into the study the twice-daily nevirapine arm was added because of concern that the minimum concentration of nevirapine once daily may be insufficient for maximal efficacy. The design of the study was amended with the aims of evaluating for equivalence nevirapine twice daily versus efavirenz, and for superiority nevirapine once daily versus twice daily. Patients were randomised in a ratio of 1:2:2:1 to nevirapine once daily, nevirapine twice daily, efavirenz, and nevirapine plus efavirenz.

For statistical analysis, equivalence was assumed if the limits of the 95% confidence interval for the difference in number of treatment failures was within 10% of zero with a null hypothesis of at least 10% more treatment failures with nevirapine twice daily than with efavirenz. For all other comparisons of the primary outcome the definition of significance was adjusted to P<0.0125.

OUTCOMES

The primary efficacy outcome was the proportion of patients with treatment failure, defined either as virological failure (a decline of less than 1log10 in plasma HIV-RNA concentration within the first 12 weeks or two consecutive measurements >50 copies/ml from week 24 onwards, or a single plasma HIV-RNA concentration >50 copies/ml at week 48 constituted a failure) or clinical disease progression or change of allocated treatment. Change of NRTI backbone was allowable for toxicity.

The results of the primary and selected secondary outcome measures are detailed in Table 2. There was no statistical difference in the proportion of patients who experienced treatment failure between nevirapine twice daily and efavirenz (P=0.091) but equivalence was not demonstrated (difference 5.9%, 95% CI: -0.9-12.8). There were, however, no significant differences among the study groups in the proportions with plasma HIV-RNA concentrations below 50 copies/ml at week 48 (P=0.193). Although treatment efficacy was similar, the trial was not powered to show non-inferiority between nevirapine once daily and twice daily.

Clinical adverse events, including grade 3 or 4, were more common with nevirapine plus efavirenz than with the other arms.With no increased virological benefit, combining these two drugs is thus not recommended. Nevirapine once daily was associated with significantly more hepatotoxicity compared to nevirapine twice daily and as a consequence should not be used for the initiation of antiretroviral therapy. A once-daily extended release formulation of nevirapine is currently under evaluation and it remains to be seen if this is associated with less hepatotoxicity. There was a trend for a higher frequency and severity of hepatotoxicity and hypersensitivity with nevirapine twice daily than with efavirenz, but this was not statistically different. Of concern was that of 25 observed deaths, two were attributed to nevirapine, one from fulminant hepatitis. As a consequence, despite similar virological efficacy, efavirenz is the NNRTI of choice in first-line antiretroviral regimens. At present, to limit hepatotoxicity, nevirapine should be prescribed only for initial therapy in HIV-positive women with CD4 cell counts <250 cells/[mm.sup.3] and men <400 cells/[mm.sup.3].

In secondary analyses a baseline CD4 count <25 cells/[mm.sup.3] and viral load >100,000 copies/ml was associated with significantly higher risk of virological failure, though there was no difference between nevirapine- and efavirenz-treated patients. A better plasma lipid profile was seen in patients treated with nevirapine than efavirenz with greater increases in HDL cholesterol and falls in the total cholesterol to HDL cholesterol ratio with nevirapine.

SUMMARY

To date the 2NN trial remains the only Phase III trial comparing efavirenz- and nevirapine-based triple regimens. The trial established that once-daily nevirapine and combinations of nevirapine and efavirenz in first-line therapy were not recommended. Although virological efficacy was similar between nevirapine twice daily and efavirenz, equivalence was not demonstrated in terms of the proportion of patients experiencing treatment failure. The results have informed treatment guidelines and the choice of NNRTI in first-line therapies.

NNRTIS VS. BOOSTED PIS

In 1999, the first major Phase III trial of efavirenz plus two NRTIs demonstrated significantly greater viral suppression than indinavir plus two NRTIs [5]. Over the next few years several studies investigated the efficacy and safety of an NNRTI-based regimen versus a single protease inhibitor-based therapy in treatment-naive patients [13-16]. None showed a single PI-based regimen to have greater clinical efficacy or virological potency than an NNRTI-based regimen. As the use of single PI-based regimens was replaced in routine clinical practice by ritonavir-boosted PI regimens, it became increasingly important to determine whether efavirenz or a boosted PI had greater efficacy in first-line therapy. Few trials have addressed this question, the most important was ACTG 5142, which reported in 2006 [17].

ACTG 5142

TRIAL DESIGN

ACTG 5142 was an open-label Phase III randomised-controlled trial of efavirenz plus two NRTIs versus lopinavir/r plus two NRTIs versus lopinavir/r and efavirenz in treatment-naive patients with viral loads >2000 copies/ml and any CD4 cell count. All patients randomised to receive NRTIs were treated with lamivudine and one of the following: stavudine, zidovudine or tenofovir. The choice of the second NRTI was made by the site investigator prior to randomisation. The randomisation allocation ratio was 1:1:1.

The primary objectives were to conduct pair-wise comparisons of the time to virological failure and time to regimen failure among the three study groups. P-values of <0.014 were considered to have statistical significance in the analysis of the primary objectives. Virological failure was defined as a lack of viral load suppression or rebound before 32 weeks or lack of suppression to <200 copies/ml or rebound after 32 weeks. Regimen failure was defined as the first of either virological failure or toxicity-related discontinuation of any component of the initial randomised treatment regimen. Patients who discontinued any therapy because of toxicity were followed for occurrence of virological failure.

OUTCOMES

The time to virological failure was significantly longer in the efavirenz plus two NRTIs group than the lopinavir/r plus two NRTIs group (P=0.006, HR: 0.63, 95% CI: 0.45-0.87) [17]. Of note, this outcome remained the same even when the analysis was restricted to patients who were assessed to have high levels of adherence, suggesting the efavirenz regimen had greater virological potency. There was a trend towards a longer time to regimen failure in the efavirenz group than in the lopinavir/r group, but this did not reach significance (P=0.03, HR: 0.75, 95% CI: 0.57-0.98). This was the first time that an efavirenz-based regimen had shown greater virological efficacy than a boosted PI regimen in first-line therapy.

Secondary analyses showed there was no difference to time to virological failure between the efavirenz and lopinavir/r groups in patients with baseline viral load <100,000 copies/ml, and that the proportion with viral load <50 copies/ml at 96 weeks was significantly greater in the efavirenz group compared to the lopinavir/r group (89% vs. 77%; P=0.003). Of note the lopinavir/r group experienced greater increases in CD4 count at 96 weeks than the efavirenz group, and at virological failure, detection of genotypic mutations associated with resistance was significantly more frequent in the efavirenz group than the lopinavir/r group. No major mutations associated with resistance to PIs, were detected in patients experiencing failure in the lopinavir/r plus two NRTI group.

SUMMARY

This was the first study to show that a combination of efavirenz and two NRTIs was more effective than lopinavir/r and two NRTIs in the initial treatment of HIV infection, although at the time of virological failure, the detection of resistance was more frequent with efavirenz.

NNRTIS IN

TREATMENT-EXPERIENCED PATIENTS

There are limited randomised control trial data evaluating the use of NNRTIs in treatment-experienced patients. The most important and relevant to current clinical practice are the data from the DUET studies [18,19], which were Phase III, double-blind placebo-controlled RCTs. They investigated the safety and efficacy of etravirine in treatment-experienced patients, stable on antiretroviral therapy but with viral load >5000 copies/ml. Patients also had to have three or more primary PI mutations at screening and at least one NNRTI resistance-associated mutation at screening or on historical genotype. Patients were randomised to either etravirine or placebo on a 1:1 ratio. All patients received darunavir/r and investigator-selected NRTIs. Use of enfuvirtide was optional.

At 24 weeks significantly more patients in the etravirine group had achieved a viral load <50 copies/ml than had the placebo group (56% vs. 39%; difference in response rate 17%; 95% CI: 9-25; P=0.005) [18]. These results were maintained out to 48 weeks of follow-up. In vitro, etravirine has activity against viral isolates that have reduced susceptibility to nevirapine and efavirenz. This trial is important as it established that patients previously treated with an NNRTI and with NNRTI-associated resistance may benefit from treatment with a new-generation NNRTI, in this case etravirine. Previously high levels of cross-resistance between nevirapine and efavirenz had precluded sequential use. The trial showed that etravirine had significant antiviral activity in patients with NNRTI resistance.

SUMMARY

There have been multiple clinical trials reported, which have been key to informing the development of this drug class, and clinical guidelines, and both have strongly influenced clinical practice. As a consequence, NNRTIs today have a primary role in the initial treatment of chronic HIV-1 infection in adults, and have contributed significantly to the clinical success of treatment seen over the last few years. More recently, new NNRTIs have shown to have significant clinical efficacy in treatment-experienced patients, emphasising that this drug class has a potentially important role at different times in the treatment of patients with HIV-1 infection.

REFERENCES

[1.] Merluzzi VJ, Hargrave KD, Labadia M et al. Inhibition of HIV-1 replication by a non-nucleoside reverse transcriptase inhibitor. Science, 1990, 250, 1411-1413.

[2.] Koup RA, Merluzzi VJ, Hargrave KD et al. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587. J Infect Dis, 1991, 163, 966-970.

[3.] Cheeseman SH, Havlir D,McLaughlinMMet al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immun Defic Syndr, 1995, 8, 141-145.

[4.] Montaner JS, Reiss P, Cooper D et al. Randomised double blind trial comparing combinations of nevirapine, didanosine and zidovudine for HIV-infected patients: the INCAS Trial. JAMA, 1998, 279, 930-937.

[5.] Staszewski S, Morales-Ramirez J, Tashima KT et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med, 1999, 341, 1865-1873.

[6.] 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.

[7.] Gallant JE, DeJesus E, Jose R et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med, 2006, 354, 251-260.

[8.] Gulick RM, Ribaudo HJ, Shikuma CM et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med, 2004, 50, 1850-1861.

[9.] Gulick RM, Ribaudo HJ, Shikuma CM et al. Three vs four drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA, 2006, 296, 769-781.

[10.] Ribaudo HJ, Daniel R, Kuritzkes DR et al. Efavirenz-based regimens in treatment-naive patients with a range of pretreatment HIV-1 RNA levels and CD4 cell counts. J Infect Dis, 2008, 197, 1006-1010.

[11.] van Leth F, Phanuphak P, Ruxrungtham K et al. 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.

[12.] Nunez M, Soriano V, Martin-Carbonero L et al. SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clin Trials, 2002, 3, 186-194.

[13.] van Leeuwen R, Katlama C, Murphy RL et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS, 2003, 17, 987-999.

[14.] Podzamczer D, Ferrer E, Consiglio E et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther, 2002, 7, 81-90.

[15.] Squires K, Lazzarin A, Gatell JM et al. 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.

[16.] Robbins GK, De Gruttola V, Shafer RW et al., for the AIDS Clinical Trials Group 384 Team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med, 2003, 349, 2293-2303.

[17.] Riddler SA, Haubrich R, DiRienzo AG et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med, 2008, 305, 2095-2106.

[18.] Madruga JV, Cahn P, Grinsztejn B et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind placebo-controlled trial. Lancet, 2007, 370, 29-38.

[19.] Lazzarin A, Campbell T, Clotet B et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet, 2007, 370, 39-48.

Correspondence to: Dr Ian G Williams, Centre for Sexual Health and HIV Research, University College London, Mortimer Market Centre, Off Capper Street, London WC1A 6JB,UK.

Email: iwilliams@gum.ucl.ac.uk
Table 1: Major trials of NNRTI-containing regimens: results
influenced clinical practice

Study [ref] Patient population n

ACTG 164/168 [3] CD4 cell count 62
 <400 cells/[mm.sup.3]

INCAS [4] ART-ndive CD4 cell count 153
 200-600 cells/[mm.sup.3]

DMP006 [5] No prior exposure to 3TC 450
 and any NNRTI or PI,
 CD4 cell count
 >50 cells/[mm.sup.3]

ACTG 5095 [8] ART-ndive 1147
 Any CD4 count

2NN [11] ART-naive 1216
 Any CD4 count

ACTG 5142 [17] ART ndive 757
 Any CD4 count

DUET-1 * [18] Treatment experienced, 612
 at least three major PI
 mutations, at least one
 NNRTI mutation

Study [ref] Study ann

ACTG 164/168 [3] Sequential cohorts of NYP
 12.5, 50, 200 and 400 mg
 alone or with zidovudine

INCAS [4] 1. ZDY+ddl
 2. ZDY+NYP
 3. ZDY+NYP+ddl

DMP006 [5] 1. ZDY+3TC+IDY
 2. ZDY+3TC+EFY
 3. EFY+IDY

ACTG 5095 [8] 1. ZDY+3TC+ABC
 2. ZDY+3TC+EFY
 3. ZDY+3TC+ABC+EFY

2NN [11] 1. NYP once daily
 2. NYP twice daily
 3. EFY
 4. NYP+EFY
 All patients received
 d4T + 3TC

ACTG 5142 [17] 1. EFY+3TC+NRTI
 2. LPY/r+3TC+NR11
 3. LPY/r+EFY

DUET-1 * [18] 1. Etravirine
 2. Placebo
 All patients received
 darunavir/r and
 investigator-selected NRTIs

Study [ref] Comment

ACTG 164/168 [3] Showed antiviral activity of NYP monotherapy in
 viva was not sustained. Loss of viral suppression
 associated with rapid emergence of virus
 resistant to nevirapine

INCAS [4] The first study to show sustained virological
 efficacy in an NNRTI-containing triple regimen
 and delay in emergence of resistance to NNRTIs

DMP006 [5] The first study to show greater clinical
 efficacy of an efavirenz-based triple regimen
 than the standard of care of the time, a single
 PI-containing regimen. Established an important
 role for efavirenz plus two NRTIs in first-line
 therapy

ACTG 5095 [8] Study showed superior virological efficacy of
 efavirenz-based regimens over triple NRTIs

2NN [11] The only major trial to compare efavirenz and
 nevirapine in first-line therapy. Similar
 virological efficacy was seen between nevirapine
 twice daily versus efavirenz

ACTG 5142 [17] The first study to show efavirenz plus two NRTIs
 was more effective than lopinavir/r plus two
 NRTIs as initial treatment

DUET-1 * [18] The first Phase III study to show significant
 sustained virological benefit from the use of
 etravirine (a new generation NNRTI) in
 treatment-experienced patients who had
 NNRTI-associated resistance

ZDV, zidovudine; ddl, didanosine; NVP, nevirapine; 3TC,
lamuvudine; IDV, indinavir; EFV, efavirenz; d4T, stavudine;
NRTI, nucleoside reverse transcriptase inhibitor; LPY/r,
lopinavir/r; ABC, abacavir.

* Similar results were seen in DUET-2 [19].

Table 2: Primary and secondary study outcomes in the
2NN trial [11]

Patients (n = 1216) Nevirapine Nevirapine
 once daily twice daily
 (n = 220) (n = 387)

Primary outcome:

Percentage with treatment 43.6 43.7 (1)
failure (%) (95% CI) (37.0-50.5) (38.7-48.8)

Percentage with viral load 70 65.4
<50 copies/ml at 48 weeks (%) (63.5-76.0) (60.4-70.1)

Percentage with grade 15.0 20.4
3-4 clinical adverse events (%)

Percentage with laboratory 13.6 (2) 8.3
grade 3-4 hepatobiliary adverse
events (%)

Percentage with grade 3-4 1.4 3.6
CNS/psychiatric adverse events
(%) (3)

Patients (n = 1216) Efavirenz EFV/NVP
 (n = 400) (n = 209)

Primary outcome:

Percentage with treatment 38.8 (1) 53.1
failure (%) (95% CI) (33.0-42.7) (46.1-60.0)

Percentage with viral load 70 62.7
<50 copies/ml at 48 weeks (%) (65.2-74.5) (55.7-69.3)

Percentage with grade 18.0 24.4
3-4 clinical adverse events (%)

Percentage with laboratory 4.5 9.1
grade 3-4 hepatobiliary adverse
events (%)

Percentage with grade 3-4 5.5 7.7
CNS/psychiatric adverse events
(%) (3)

(1) No statistical difference between nevirapine twice daily
vs. efavirenz, but equivalence not achieved (95% CI of
difference greater than 0-10%).

(2) Significantly higher (P<0.001) in NVP once daily vs.
twice daily.

(3) Overall, significantly higher in efavirenz-containing
groups (P<0.001).
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Title Annotation:LEADING ARTICLE
Author:Williams, Ian G.
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:4EUUK
Date:Mar 1, 2008
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