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The Safety, Efficacy, and Pharmacokinetic Profile of a Switch in Antiretroviral Therapy to Saquinavir, Ritonavir, and Atazanavir Alone for 48 Weeks and a Switch in the Saquinavir Formulation

  1. Alan Winston1,2,
  2. Patrick W. G. Mallon1,2,
  3. Claudette Satchell1,
  4. Karen MacRae2,
  5. Kenneth M. Williams2,
  6. Malte Schutz3,
  7. Matthew Law1,
  8. David A. Cooper1,2, and
  9. Sean Emery1
  1. 1National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
  2. 2St. Vincent's Hospital, Sydney, Australia
  3. 3Roche, Nutley, New Jersey
  1. Reprints or correspondence: Dr. Alan Winston, HIV Clinical Trials Unit, Winston Churchill Wing, Imperial College, St. Mary's Hospital, Praed St., London W2 1NY, United Kingdom (a.winston{at}imperial.ac.uk).

  • Presented in part: 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, Portugal, 20–22 April 2006 (poster 64).

 
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Abstract

Background. Toxicities observed with current combination antiretroviral therapy (CART) warrant a search for novel options, such as class-sparing regimens. Ritonavir-boosted double—protease inhibitor (PI)–only regimens are such an option but are prone to pharmacokinetic interactions.

Methods. This 48-week randomized study examined the safety and efficacy of a switch in CART to a once-daily regimen of saquinavir (SQV), ritonavir (RTV), and atazanavir (ATV) that did not include nucleoside reverse-transcriptase inhibitors (NRTIs). The study also assessed the pharmacokinetic profile of a change in the SQV formulation, from 200 mg to 500 mg, in 2 regimens (SQV-RTV twice per day plus NRTIs [arm 1] and SQV-RTV-ATV once per day without NRTIs [arm 2]) in human immunodeficiency virus type 1–infected subjects (plasma human immunodeficiency virus RNA level, <50 copies/mL). Patients underwent an initial SQV formulation change or a CART change to SQV-RTV-ATV with intense pharmacokinetic sampling. All patients were subsequently assigned to receive SQV-RTV-ATV (1500, 100, and 300 mg once per day, respectively) without NRTIs for 48 weeks. The primary end point was the percentage of patients who experienced virologic failure.

Results. Of 25 subjects enrolled, scleral icterus was the most common adverse event (3 patients [12.5%]). Three subjects (12.5%) experienced virologic failure; and mean (± standard error of the mean) increase in the CD4+ lymphocyte count was 63 ± 36 cells/µL over 48 weeks (P = .012). The SQV geometric mean area under the time curve parameters were not significantly altered for the 2 SQV formulations (arm 1, 23.32 vs. 18.76 ng × h/mL [geometric mean ratio, 0.80] for the 200-mg vs. 500-mg formulations, respectively; arm 2, 50.31 vs. 44.79 ng × h/mL [geometric mean ratio, 0.88], for the 200-mg vs. 500-mg formulations, respectively).

Conclusions. A CART regimen of SQV-RTV-ATV alone demonstrated sustained virologic efficacy and was associated with significant increases in the CD4+ lymphocyte count.

Current regimens of combination antiretroviral therapy (CART) for HIV-1–infected persons are highly effective [1, 2]. However, durable success is limited by many factors, including drug toxicity and drug intolerance [3, 4]. Cross-class toxicities are associated with the use of antiretrovirals. Metabolic abnormalities, changes in body fat distribution (lipodystrophy) [5], peripheral neuropathy, and discordant responses in CD4+ lymphocyte count are observed with the use of nucleoside reverse-transcriptase inhibitors (NRTIs). These adverse effects may be related to mitochondrial toxicity observed with the use of NRTIs [6].

In view of this, the use of class-sparing CART in simplified regimens is becoming an increasingly popular treatment approach. Ritonavir-boosted, double—protease inhibitor (PI)–only regimens are one such option, but these regimens are prone to unforeseen pharmacokinetic interactions and other toxicity profiles, such as gastrointestinal intolerance and unfavorable metabolic profiles.

Once-daily treatment with ritonavir—boosted saquinavir and atazanavir is one boosted double-PI regimen with a number of potential advantages. Saquinavir-ritonavir-atazanavir constitutes a potent regimen that may limit the virus's ability to develop clinically relevant PI resistance. When administered with saquinavir to healthy volunteers, atazanavir has been shown to have a boosting effect on saquinavir's pharmacokinetics, permitting once-daily administration of saquinavir [7]. In HIV-1–infected subjects, the addition of atazanavir (300 mg once daily) to a regimen of saquinavir and ritonavir (1600 and 100 mg, respectively, once daily) increased saquinavir's total plasma exposure by 60% with no increase in toxicity [8]. With a change in the saquinavir formulation from 200 mg to 500 mg, a regimen of saquinavir, ritonavir, and atazanavir (1500, 100, and 300 mg, respectively, once daily) will considerably reduce the total pill burden to 6 tablets per day.

In healthy volunteers, the 500-mg saquinavir formulation has been shown to have a bioavailability similar to that of the 200-mg formulation [9]; however, to our knowledge, no pharmacokinetic data have been reported for HIV-1–infected subjects. The aims of this study were 2-fold: first, to assess the safety and pharmacokinetic profile of a change in the saquinavir formulation from the 200-mg to 500-mg tablet in 2 regimens (saquinavir and ritonavir twice daily plus NRTIs vs. saquinavir, ritonavir, and atazanavir once daily without NRTIs) in HIV-1–infected individuals; and second, to assess the virologic durability and tolerability of a switch in CART to saquinavir, ritonavir, and atazanavir without NRTIs in HIV-1–infected patients.

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Methods

Subject selection. HIV-1–infected patients who were receiving stable antiretroviral therapy (i.e., therapy that contained NRTIs plus a ritonavir-boosted PI or NRTIs alone) were eligible for this study. Subjects with a history of previous intolerance to or virological failure of atazanavir or saquinavir and subjects with viral isolates with ≥2 primary or secondary PI-associated mutations were excluded from the study [10].

Inclusion required a plasma HIV-1 RNA level of <50 copies/mL. Patients for whom the screening HIV-1 RNA value was ≥50 but <400 copies/mL were eligible if an HIV-1 RNA level was <50 copies/mL during the 3 months before screening. According to the study protocol, patients were not permitted to take nonnucleoside reverse-transcriptase inhibitors or prohibited drugs.

Study design. The first phase of the study was an open-label, 2-cohort design. In one cohort, allocation of patients to study drug arms was performed by random allocation, with cross-over to allow for evaluation of the pharmacokinetic and tolerability profiles of a saquinavir formulation change (from 200-mg to 500-mg doses). The second phase of the study was an open-label, single-arm observational study that evaluated the safety and durability of saquinavir, ritonavir, and atazanavir as once-daily CART. The study was conduced at St. Vincent's Hospital (Sydney, Australia) from October 2004 through July 2006.

Subjects who were receiving stable CART were allocated to 2 groups, as follows: arm 1, receipt of NRTIs plus saquinavir and ritonavir (1000 and 100 mg, respectively, twice daily); and arm 2, receipt of NRTIs plus another PI (figure 1). Subjects in arm 1 switched from the 200-mg saquinavir formulation to the 500-mg formulation on day 1. On day 8, subjects changed antiretroviral therapy to saquinavir, ritonavir, and atazanavir (1500, 100, and 300 mg, respectively, once daily) while receiving the 500-mg saquinavir formulation without NRTIs. Subjects in arm 2 were randomized at a 1 : 1 ratio, stratified by current tenofovir use, to switch antiretroviral therapy on day 0 to saquinavir, ritonavir, and atazanavir at either 1500, 100, and 300 mg, respectively, using the 500-mg saquinavir formulation; or at 1600, 100, and 300 mg, respectively, using the 200-mg saquinavir formulation. All agents were administered once daily, and subjects ceased use of NRTIs. On day 8, subjects switched the saquinavir formulation. On day 15, all subjects were assigned the 500-mg saquinavir formulation.

Figure 1
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Figure 1

Flowchart of the study design. ATV, atazanavir; CART, combination antiretroviral therapy; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor; PK, pharmacokinetics; RTV, ritonavir; SQV, saquinavir.

Detailed pharmacokinetic visits were performed on days 0, 7, and 15 in arm 1 and on days 8 and 16 in arm 2. Serial blood samples were drawn at 0, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration of the dose (a 24-h sample was also obtained for once-daily regimens) for the assessment of the relevant plasma PI concentration.

No changes to antiretroviral therapy were allowed outside of the study protocol. Safety blood parameters (including serum electrolyte levels, liver function test results, complete blood cell counts, and plasma lipid levels), adherence to treatment (as determined using a previously validated questionnaire [11]), recording of adverse clinical advents, plasma HIV-1 RNA level (assay cutoff value, 50 copies/mL), and CD4+ lymphocyte count were evaluated on pharmacokinetic study visits, at week 4, and every 3 months thereafter until week 48. Trough plasma drug concentrations were also reassessed at week 48. On the basis of a clinical decision, subjects who developed scleral icterus while receiving saquinavir, ritonavir, and atazanavir with a documented atazanavir trough plasma concentration >1000 ng/mL were permitted to reduce the atazanavir dosage to 200 mg once daily. This was followed by a detailed pharmacokinetic visit after 7 days. In cases of virologic rebound (defined as a detectable plasma HIV-1 RNA level >400 copies/mL), changes to study treatment were permitted.

Pharmacokinetic sampling. Plasma concentrations of saquinavir, ritonavir, and atazanavir were measured using a validated high-pressure liquid chromatography—tandem mass spectrometry method by the Department of Pharmacology and Toxicology at St. Vincent's Hospital (Sydney). This laboratory participates in an international external quality-assurance program [12].

Pharmacokinetic methods. The following pharmacokinetic parameters were calculated: the trough plasma concentration, the maximum observed plasma concentration, the area under the concentration-time-curve (AUC; from 0–12 h or 0–24 h, as appropriate), and the terminal elimination half-life. All of these pharmacokinetic parameters were calculated using noncompartmental modeling techniques in Topfit software, version 2.0 (Gustav Fischer Verlag).

Statistical analysis. All statistical calculations were performed using SPSS software, version 12.0 (SPSS). In-subject changes in the assessed pharmacokinetic parameters between the 200-mg and 500-mg saquinavir formulations were evaluated by calculating geometric mean ratios and 95% CIs. The 95% CIs were determined using logarithms of the individual geometric mean values; the calculated values were then expressed as linear values. The changes in pharmacokinetic parameters were considered to be significant when the 95% CI did not cross the value 1. Interpatient variability in pharmacokinetic parameters was expressed as a coefficient of variation ([SD/mean] × 100). Changes in interpatient variability associated with a change in saquinavir formulation were assessed by the ratio of SD squared (f test) and the corresponding test of variance. Associations between patient characteristics and plasma drug exposure were assessed using nonparametric analysis (using the Mann-Whitney U test).

Factors associated with virological failure and viral load “blips” (i.e., viral load, 50–400 copies/mL) were assessed in a univariate model by linear regression analysis. Potential factors assessed included patient baseline characteristics (such as age in years), duration of antiretroviral treatment before study entry (years), duration of HIV-1 infection (years), number of previous CART regimens, number of prestudy NRTIs in the regimen, baseline CD4+ lymphocyte count, body mass index (calculated as weight in kilograms divided by the square of height in meters), and trough plasma drug concentrations of atazanavir, saquinavir, and ritonavir at the final intensive pharmacokinetic visit and at week 48.

Assuming a difference between saquinavir formulations of 65% to be clinically significant, a total sample size of 20 patients provided 90% power (2-tailed α = 5%).

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Results

Disposition of Patients

After providing written informed consent, 25 HIV-1–infected patients were enrolled in the study. Eleven and 14 patients were enrolled in arms 1 and 2, respectively. In arm 1, all patients completed the first 2 pharmacokinetic visits, and 10 patients completed the third visit. In arm 2, a total of 12 of the 14 patients successfully completed the 2 pharmacokinetic visits; the other subjects did not attend these study visits.

Twenty-four subjects commenced treatment with atazanavir, saquinavir, and ritonavir, and 1 subject did not switch therapy because of a hepatitis B virus infection that required NRTI therapy. All patients completed 48 weeks of follow-up.

Baseline characteristics and prestudy antiretroviral therapy regimens are presented in table 1. In arm 2, a total of 5 patients were receiving tenofovir in their NRTI backbone. The baseline HIV-1 RNA level was <50 copies/mL for 20 subjects; for the other 5 subjects, HIV-1 RNA was detectable, but the level was <400 copies/mL at screening and <50 copies/mL within 3 months after screening.

Figure 2
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Figure 2

Geometric mean saquinavir plasma concentration-time-curve (95% CI) over the dosing interval for the 2 saquinavir formulations (200 and 500 mg) in a regimen of saquinavir and ritonavir (1000 and 100 mg, respectively, twice daily) with a nucleoside backbone.

Figure 3
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Figure 3

Geometric mean saquinavir plasma concentration-time-curve (95% CI) over the dosing interval for the 2 saquinavir formulations (200 and 500 mg) in a regimen of saquinavir, ritonavir, and atazanavir (at 1600, 100, and 300 mg or 1500, 100, and 300 mg, respectively, once daily).

Figure 4
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Figure 4

Geometric mean atazanavir plasma concentration-time-curve (95% CI) over the dosing interval for the 2 saquinavir formulations (200 and 500 mg) in a regimen of saquinavir, ritonavir, and atazanavir (at 1600, 100, and 300 mg or 1500, 100, and 300 mg, respectively, once daily).

Figure 5
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Figure 5

Chart showing mean changes in CD4+ lymphocyte count (95% CI) from baseline. Mean baseline CD4+ lymphocyte count, 511 cells/µL (95% CI, 372–650 cells/µL).

Table 1
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Table 1

Baseline characteristics of the 25 patients recruited.

Pharmacokinetics

Pharmacokinetics of saquinavir and ritonavir (1000 and 100 mg twice daily, respectively) plus NRTIs. No significant changes were observed in ritonavir pharmacokinetics between saquinavir formulations (table 2). Saquinavir plasma exposure (table 2 and figure 2) was slightly lower with the 500-mg formulation than with the 200-mg formulation for all parameters; however, this difference was not statistically significant. Interpatient variability in total plasma saquinavir exposure was reduced with the 500-mg formulation (coefficient of variation, 61% vs. 82%; f = 3.26; P < .05).

Table 2
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Table 2

Saquinavir and ritonavir pharmacokinetics in a regimen of saquinavir plus ritonavir (1000 and 100 mg, respectively, twice daily) with a nucleoside backbone using the 200-mg and 500-mg formulations of saquinavir.

Pharmacokinetics of once-daily regimens of saquinavir, ritonavir, and atazanavir. No significant differences were observed between saquinavir (figure 3), ritonavir, and atazanavir (figure 4) pharmacokinetic profiles between saquinavir formulations (table 3). No significant changes in PI trough plasma concentrations were observed between those measured during the intensive pharmacokinetic visits and at week 48.

Table 3
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Table 3

Saquinavir, ritonavir, and atazanavir pharmacokinetics in a regimen of saquinavir, ritonavir, and atazanavir (at 1600, 100, and 300 mg or 1500, 100, and 300 mg, respectively, once daily) using the 200-mg and 500-mg formulations of saquinavir.

The atazanavir dosage was reduced from 300 to 200 mg daily for 2 individuals. These patients developed scleral icterus after 7 and 28 days of treatment with saquinavir, ritonavir, and atazanavir, with a trough plasma concentration of atazanavir of >1000 ng/mL at these times. Seven days after an atazanavir dose reduction, the trough plasma concentration of atazanavir was <750 ng/mL, and scleral icterus had resolved in both subjects.

Factors associated with saquinavir and atazanavir plasma concentrations. Body mass index, age, and hepatitis C virus coinfection were not significantly associated with changes in the AUC of saquinavir or atazanavir plasma exposure in all treatment regimens examined in this study (P > .20 for all analyses). No significant differences in the atazanavir AUC or trough plasma concentration after 7 days of therapy were observed between subjects receiving and those not receiving tenofovir before study entry (P > .40 for all analyses; determined using the Mann-Whitney U test).

Virologic and Immunologic Outcomes

Virological response. At 1 year, 20 (83%) of 24 subjects continued to receive saquinavir, ritonavir, and atazanavir as CART, with HIV-1 RNA levels <50 copies/mL. During the 48-week study period, 16 patients (67%) had HIV-1 RNA levels <50 copies/mL for the entire period, 5 (21%) had ≥1 viral load blip of 50–400 copies/mL, and 3 (12%) had confirmed virologic failure.

All 3 cases of virologic failure occurred early (i.e., during study weeks 4–12) and were not associated with the development of any new mutations in the protease. In all 3 cases, trough plasma concentrations of atazanavir were considered to be adequate (i.e., >150 ng/mL), and trough plasma concentrations of saquinavir were considered to be adequate (i.e., >100 ng/mL) in 2 cases. In the remaining subject, the trough plasma concentration of saquinavir was 35 ng/mL. In all cases, resuppression of plasma viremia was achieved by reintroducing an NRTI backbone, plus, for the subject whose plasma concentration was considered to be subtherapeutic, incremental increase in the saquinavir dosage to 2000 mg daily.

The development of virologic failure was not significantly associated with any baseline characteristic or observed plasma drug concentration (P > .20 for all variables). However, the presence of viral load blips was associated with previous duration of antiretroviral therapy (P = .043, for every 1-year increment of antiretroviral therapy before study entry being associated with a 5% reduction in the likelihood of a viral load blip).

Immunological response. Significant increases in the mean CD4+ lymphocyte count (±SEM) were observed from week 24 onwards, with increases from the baseline count of 52 ± 26, 78 ± 23, and 63 ± 36 cells/µL at weeks 24, 36, and 48, respectively (P = .005, .005, and .012, respectively). There were no significant changes observed in the CD4+ lymphocyte counts up to week 12 (figure 5).

Safety, Tolerability, and Adherence

No laboratory or clinical adverse events were recorded with regard to the switch in the saquinavir formulation. No new gastrointestinal adverse events were reported in association with switching to a boosted double-PI regimen. Scleral icterus was a frequent clinical adverse event, occurring in 3 subjects (12.5%; 2 of these subjects underwent atazanavir dose reduction, and 1 discontinued receipt of the study regimen and commenced a triple-nucleoside regimen; HIV-1 RNA remains undetectable in all 3 patients). Changes in serum bilirubin levels are shown in table 4. No significant changes in fasting cholesterol or triglyceride levels were observed and no other laboratory adverse events were recorded (table 4).

Table 4
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Table 4

Changes in laboratory parameters over 48 weeks for 24 patients.

Results of the adherence questionnaire administered at baseline revealed mean adherence rates of 98% at baseline. The mean adherence value did not change over the 48-week study period at any time.

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Discussion

This is the first study, to our knowledge, to assess the pharmacokinetic profile of the 500-mg saquinavir tablet in HIV-1–infected subjects. We observed a significant reduction in interpatient variability in saquinavir plasma exposure associated with a formulation change to the 500-mg tablet when it was administered twice daily with ritonavir and NRTIs.

Although not statistically significant, we did observe slight reductions in total saquinavir plasma exposure associated with the use of the 500-mg formulation in both regimens (20% and 12% reduction for twice-daily administration with ritonavir plus NRTIs and for once-daily administration in a regimen of ritonavir and atazanavir, respectively) and a slight reduction in atazanavir exposure. The small difference in saquinavir plasma exposure observed between formulations with saquinavir, ritonavir, and atazanavir may be explained by the small difference in the saquinavir dosage administered (1600 vs. 1500 mg once daily), depending on the formulation.

This switch in CART to saquinavir, ritonavir, and atazanavir alone was well tolerated in virologically suppressed HIV-1–infected subjects. Rates of scleral icterus in our study are similar to previous reports in subjects receiving regimens containing atazanavir and ritonavir [13]. Virological rebound was observed over 48 weeks in 3 (12.5%) of 24 subjects in this study. Virological rebound has also been described in other studies of switches to PI-only—based regimens. In one study of subjects randomized to receive lopinavir and ritonavir only, after 48 weeks of follow-up, 80% of subjects continued to have undetectable HIV-1 RNA [14]. Interestingly, also in this study, patients who developed virological rebound had no evidence of newly acquired PI resistance, as noted by genotypic resistance testing, and complete virologic suppression occurred with the reintroduction of a NRTI backbone. Studies assessing switches in therapy to other PI-only regimens have reported similar results in 10 of 12 patients treated with indinavir and ritonavir alone in 1 study [15] and in 22 of 24 and 31 of 34 patients treated with atazanavir and ritonavir in 2 other studies [16, 17].

Randomized studies have assessed boosted lopinavir-only therapy, compared with standard dual-class antiretroviral therapies, in both antiretroviral-naive subjects [18, 19] and treatment-experienced subjects undergoing switches in therapy [20]. Promising results have been observed in these studies, with the majority of patients in the boosted PI-only arms achieving or maintaining undetectable virus and with no significant differences to dual-class therapy; however, a greater incidence of low-level viremia (virus load, 50–400 copies/mL) was observed with this treatment strategy. In cases where virological failure occurred, few subjects developed new resistance-associated mutations in protease, and resuppression was achieved by reintroducing the NRTIs. These are similar to the findings of our study. However, prospective, randomized studies are required to compare boosted single-PI therapy versus boosted double-PI therapy without NRTI backbones. Boosted double-PI regimens may have lower failure rates, because this strategy uses 2 different active PIs with differing resistance profiles.

Rebound in virological response may be attributable to several factors, including subtherapeutic trough plasma PI concentration. In our cohort, the trough plasma concentrations of atazanavir (geometric mean, 627 ng/mL; range, 139–3342 ng/mL) were similar to historical data [21]. Atazanavir plasma concentrations >150 ng/mL have been associated with greater virologic response rates [22]. No patients in our cohort had a trough plasma concentration of atazanavir that was less than this level. The trough plasma concentration of saquinavir we observed (geometric mean, 240 ng/mL; range, 35–1428 ng/mL) is comparable to historical data assessing saquinavir, ritonavir, and atazanavir. A minimum effective concentration for saquinavir of 100 ng/mL has been suggested. In our cohort, 5 subjects had a trough plasma concentration of saquinavir that was less than this threshold, but of these, only 1 patient experienced virologic failure.

Interestingly, a significant increase in the CD4+ lymphocyte count was observed from week 24 onwards and was maintained until week 48. Because our study was noncomparative, the question remains as to whether this increase in the CD4+ lymphocyte count was related to the switch in antiretroviral therapy or was a chance observation.

Several factors suggest that this increase in the CD4+ lymphocyte count was associated with the use of a boosted double-PI—only regimen. The cohort comprised subjects who had received antiretroviral therapy for a mean of 8 years (range, 2–16 years) and who had a mean baseline CD4+ lymphocyte count of 520 cells/µL (range, 404–635 cells/µL). Other studies assessing similar groups have reported that changes in the CD4+ lymphocyte count over time were uniform [23] and have reported a more modest increase in the CD4+ lymphocyte count of 2 cells/µL per month [23]. Furthermore, a slowing in the increase in the CD4+ lymphocyte count after 3 years of antiretroviral therapy to a plateau at 4 years and a slight decrease after 5 years has been reported [24]. This is unlike the pattern observed in our study. Of note, no subjects were receiving tenofovir and didanosine—the nucleoside backbone most associated with a blunted immunological response—in our cohort at baseline [25].

Other studies assessing boosted PI-only therapy have not observed significant differences in CD4+ lymphocyte count among subjects randomized to receive only PIs [14, 18–20]. However, in 1 study, an increase in the CD4+ lymphocyte count of 70 cells/µL was observed in the lopinavir-ritonavir—only arm at week 48, compared with an increase of 8 cells/µL in the NRTI-based arm; however, this difference did not reach statistical significance [14]. Other studies of PI-only therapy have focused on the boosted single-PI regimens, which may not be associated with such immunological benefits.

A recent study has reported ongoing HIV-1 viral replication in the CNS in subjects with controlled plasma viremia who are receiving the boosted PI-only regimen of atazanavir and ritonavir [26]. No assessment of viral replication in sites other than blood was made in our study. Future studies should consider assessing different body sites for viral replication, because this may be a limitation of PI-only therapies.

In summary, we assessed atazanavir, ritonavir, and saquinavir as a once-daily, boosted double-PI—only regimen and observed a favorable pharmacokinetic profile, a favorable lipid and tolerability profile, and a sustained virologic response in the majority of subjects, accompanied by significant immunological benefits. Additional comparative studies assessing these potential advantages are justified.

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Acknowledgments

Financial support. Hoffmann—La Roche. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales.

Potential conflicts of interest. All authors: no conflicts.

  • Received December 7, 2006.
  • Accepted January 30, 2007.
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  1. Clin Infect Dis. (2007) 44 (11): 1475-1483. doi: 10.1086/517507
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