Baseline HIV-1 RNA Research Articles

Predicting the magnitude of short-term CD4+ T-cell recovery in HIV-infected patients during first-line highly active antiretroviral therapy

The extent of short-term CD4(+) T-cell recovery in patients tolerating first-line highly active antiretroviral therapy (HAART) and attaining undetectable HIV RNA levels is inadequately defined. We retrospectively analysed patients in four Italian cohorts who started HAART between January 1996 and September 2006. All patients had known HCV coinfection status, did not modify the regimen for 6 months and had <50 HIV RNA copies/ml at the end of the sixth month. The analysis involved 1,488 patients (1,096 males, 73.7%) with a median age of 43 years (interquartile range [IQR] 39-49); 435 (29.2%) were positive for HCV, 71 (4.8%) were positive for hepatitis B surface antigen (HBsAg) and 76 (5.1%) had experienced a previous AIDS-defining event. At baseline, patient CD4(+) T-cell counts were 226 cells/microl (IQR 99-332), CD4(+) T-cell percentages were 14.7% (IQR 8.7-21.2) and HIV RNA levels were 4.91 log(10) copies/ml (IQR 4.38-5.34). Overall, 24-week CD4(+) T-cell recovery was 144 cells/microl (IQR 70-240). At multivariable analysis, T-cell recovery was positively related to the use of a boosted protease inhibitor (P<0.0001) or thymidine analogues (P<0.0001), baseline HIV RNA levels (P<0.0001), the baseline percentage of CD4(+) T-cells (P<0.0001) and the absence of HCV coinfection (P=0.006). Age, gender, baseline CD4(+)/CD8(+) T-cell ratio and a history of AIDS-defining events had no independent effect on CD4(+) T-cell recovery. Among HIV-infected patients tolerating first-line HAART and with undetectable HIV RNA after 6 months, CD4(+) T-cell recovery is significantly greater in those without HCV coinfection, with a high baseline viral load, a high baseline percentage of CD4(+) T-cells and in those treated with a boosted protease inhibitor.

Comparison of Early CD4 T-Cell Count in HIV-1 Seroconverters in Côte d'Ivoire and France: The ANRS PRIMO-CI and SEROCO Cohorts

We compared CD4+ decline among untreated HIV-1-infected seroconverters living in Côte d'Ivoire (CI) and in France. HIV-1-infected adults were enrolled in the ANRS1220 PRIMO-CI (CI, 1997-2006) and ANRSCO2 SEROCO (France, 1988-1995) cohorts. CD4+ count and percentage declines were estimated from enrollment until 24 months of seroconversion by linear random-effect models adjusted for time since seroconversion, age, gender, cell-associated HIV DNA, HIV RNA, and country. Overall 521 seroconverters (CI 148, 62% men; France 373, 77% men) were enrolled after a median of 7.6 months since seroconversion. Median follow-up duration was 12.7 months. Median age was 28 years. Median baseline CD4+ count was 472 and 560 cells per cubic millimeter, respectively. Median baseline HIV RNA was 4.4 and 4.0 log10 copies per milliliter and median HIV DNA was 3.0 and 2.8 log10 copies per 10(6) peripheral blood mononuclear cells, respectively. In adjusted models, CD4+ count and percentage at baseline were lower in CI than in France (P < 0.01), and the difference did not vary during follow-up (P = 0.55). Low HIV RNA and low HIV DNA at baseline were associated with higher CD4+ count at baseline. CD4+ count and percentage were lower in CI than in France. These differences were already observed during early infection and remained similar after adjustment.

Definition of Potential Targets in Mycoplasma Pneumoniae Through Subtractive Genome Analysis

Non-nucleoside reverse transcriptase inhibitor (NNRTI) -based antiretroviral therapy (ART) regimens have been recommended and widely used in resource-limited settings because of their reliable effi cacy, low pill burden, and low cost. This study sought to determine outcomes and toxicities of NNRTI-based ART over a period of 208 weeks. A total of 244 HIV/AIDS Thai patients with a mean (±SD) age of 36 (±8.1) years initiated NNRTI-based ART in 2004. The median (inter-quartile range) baseline CD4 cell counts and HIV RNA levels were 34 (13-101) cells/mm3 and 5.4 (4.96-5.79) log copies/ml, respectively. At week 208, 84.6% of patients achieved HIV RNA loads <50 copies/ml, 88.5% continued NNRTI based regimens, 6.1% developed virologic resistance to NNRTIs, and 3.3% lost to follow up. Baseline CD4<50 cell/mm3 (p=0.019), and viral load ?50 copies/ml at 6 months post-ARV (p<0.001) were associated with treatment failure. At the end of the study, 39.8% lipoatrophy and 35.7% hyperlipidemia were identified. In conclusion, NNRTI-based regimens result in high virologic success; early undetectable viral load is key to predicting long-term virologic success.

Early Viral Suppression Predicting Long-term Treatment Success Among HIV Patients Commencing NNRTI-based Antiretroviral Therapy

Non-nucleoside reverse transcriptase inhibitor (NNRTI) -based antiretroviral therapy (ART) regimens have been recommended and widely used in resource-limited settings because of their reliable effi cacy, low pill burden, and low cost. This study sought to determine outcomes and toxicities of NNRTI-based ART over a period of 208 weeks. A total of 244 HIV/AIDS Thai patients with a mean (±SD) age of 36 (±8.1) years initiated NNRTI-based ART in 2004. The median (inter-quartile range) baseline CD4 cell counts and HIV RNA levels were 34 (13-101) cells/mm3 and 5.4 (4.96-5.79) log copies/ml, respectively. At week 208, 84.6% of patients achieved HIV RNA loads <50 copies/ml, 88.5% continued NNRTI based regimens, 6.1% developed virologic resistance to NNRTIs, and 3.3% lost to follow up. Baseline CD4<50 cell/mm3 (p=0.019), and viral load ?50 copies/ml at 6 months post-ARV (p<0.001) were associated with treatment failure. At the end of the study, 39.8% lipoatrophy and 35.7% hyperlipidemia were identified. In conclusion, NNRTI-based regimens result in high virologic success; early undetectable viral load is key to predicting long-term virologic success.

Low-abundance HIV species and their impact on mutational profiles in patients with virological failure on once-daily abacavir/lamivudine/zidovudine and tenofovir

BackgroundHIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir.MethodsHIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA ≥ 400 copies/mL at 24–48 weeks).ResultsFourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log10 copies/mL, and 4.0 log10 copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) ± M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample.ConclusionsThe majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.

Unsupervised self-initiation of antiretroviral drugs in a newly diagnosed HIV-1 infected haemodialysis patient

A 50-year-old Afro-Caribbean male with underlying hypertenion and chronic kidney disease stage 5 was found to be HIV-1 ntibody positive after annual screening for HIV in the renal unit. e had been expecting this result as his new female partner had een found to be HIV-1 infected having been admitted to hospial recently from the accident and emergency department with uberculosis. He had been on haemodialysis for the preceding years and was active on the national cadaveric kidney translant list, from which he was suspended pending control of his IV infection. His baseline HIV-1 RNA load was 92,400 copies/ml 5.0 log10) with a CD4 count of 251 cells/mm3 (19%). No antiretroiral resistance mutations were found on baseline HIV-1 drug esistance testing. The partner also had wild-type virus on baseine testing. He was booked in to the HIV clinic where he was o be started on combination antiretroviral therapy (cART) but efaulted his first clinic appointment and was seen 3 months after

Abacavir and lamivudine combination

Background: Fixed dose antiretroviral combinations (FDC) may improve therapy adherence with reduced pill burden. Abacavir and lamivudine are well-established nucleoside reverse-transcriptase inhibitors available as a once-daily FDC. Abacavir is currently considered an alternative treatment option in most established treatment guidelines based on associations with cardiovascular events and lesser efficacy in patients with higher baseline viremia. Objective: To summarize rigorous clinical trial data and cohort studies that examine efficacy, safety and tolerability of the individual components and the FDC of abacavir–lamivudine. Methods: Clinical trial data, post-marketing research findings and clinical cohort data were reviewed to assess the efficacy, safety and tolerability of the individual components and the FDC of abacavir–lamivudine along with recommendations from published clinical treatment guidelines. Results/conclusion: The efficacy of abacavir–lamivudine is well documented in numerous clinical studies and treatment guidelines. The introduction of laboratory testing to identify patients at risk for hypersensitivity has decreased the incidence of these reactions. Recent findings suggest that abacavir is an alternative treatment agent with baseline HIV RNA > 100,000 copies/ml. Data related to cardiovascular events associated with abacavir are conflicting. Hepatic function should be monitored closely in HIV/HBV co-infected patients who discontinue lamivudine-containing products as severe acute exacerbations of HBV have been reported.

Factors Associated with Virological Response to Etravirine in Nonnucleoside Reverse Transcriptase Inhibitor-Experienced HIV-1-Infected Patients

To identify factors associated with virological response (VR) to an etravirine (ETR)-based regimen, 243 patients previously treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) were studied. The impact of baseline HIV-1 RNA, CD4 cell count, past NNRTIs used, 57 NNRTI resistance mutations, genotypic sensitivity score (GSS) for nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), and the number of new drugs used with ETR for the first time on the VR to an ETR regimen were investigated. Among the 243 patients, the median baseline HIV-1 RNA level was 4.4 log(10) copies/ml (interquartile range [IQR], 3.7 to 4.9) and the median CD4 count was 175 cells/mm(3) (IQR, 69 to 312). Patients had been previously exposed to a median of 6 NRTIs, 1, NNRTI, and 5 PIs. Overall, 82% of patients achieved a VR at month 2, as defined by a decrease of at least 1.5 log(10) copies/ml and/or HIV-1 RNA level of <50 copies/ml. No difference in VR was observed between patients receiving or not a boosted PI in combination with ETR. Factors independently associated with a better VR to ETR were the number of drugs (among enfuvirtide, darunavir, or raltegravir) used for the first time in combination with ETR and the presence of the K103N mutation at baseline. Mutations Y181V and E138A were independently associated with poor VR, whereas no effect of the Y181C on VR was observed. In conclusion, ETR was associated with high response rates in NNRTI-experienced patients in combination with other active drugs regardless of the therapeutic class used.

Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents

To assess pharmacokinetics, safety and efficacy of darunavir/ritonavir (DRV/r) and optimized background regimen in treatment-experienced patients (6-17 years). Forty-eight-week, open-label, two-part, phase II study. In part I, 44 patients were randomized (1: 1 ratio) to receive a body weight-adjusted, adult-equivalent dose (group A) or a 20-33% higher DRV/r twice daily (b.i.d.) dose (group B). Pharmacokinetics, safety and efficacy were assessed following 2-week dosing (part I), which determined dosing for part II (evaluated 48-week safety and efficacy). In part I, both groups met the protocol-specified criteria for pharmacokinetics and showed favorable tolerability and efficacy. The following body-weight doses were selected: DRV/r 375/50 mg b.i.d. (20-<30 kg), 450/60 mg b.i.d. (30-<40 kg) and 600/100 mg b.i.d. (> or =40 kg); these gave an AUC24h, C0h and Cmax of 102, 114 and 112%, respectively, versus the corresponding mean adult pharmacokinetic parameter. In part II, 80 patients received DRV/r (median age: 14 years, mean baseline HIV-1 RNA: 4.64 log(10)copies/ml). One patient (1%) discontinued (treatment-unrelated grade 3 anxiety). An abnormal mean baseline triglyceride level was normalized at 48 weeks (P < 0.01). At week 48, 65% had at least 1.0 log(10)HIV-1 RNA reduction; 59 and 48% achieved HIV-1 RNA less than 400 and less than 50 copies/ml, respectively (time-to-loss-of-virologic response). Mean age-adjusted weight z-score increased by 0.2 (P = 0.003). In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population.

Antiretroviral Therapy Initiation Before, During, or After Pregnancy in HIV-1-Infected Women: Maternal Virologic, Immunologic, and Clinical Response

BackgroundPregnancy has been associated with a decreased risk of HIV disease progression in the highly active antiretroviral therapy (HAART) era. The effect of timing of HAART initiation relative to pregnancy on maternal virologic, immunologic and clinical outcomes has not been assessed.MethodsWe conducted a retrospective cohort study from 1997–2005 among 112 pregnant HIV-infected women who started HAART before (N = 12), during (N = 70) or after pregnancy (N = 30).ResultsWomen initiating HAART before pregnancy had lower CD4+ nadir and higher baseline HIV-1 RNA. Women initiating HAART after pregnancy were more likely to receive triple-nucleoside reverse transcriptase inhibitors. Multivariable analyses adjusted for baseline CD4+ lymphocytes, baseline HIV-1 RNA, age, race, CD4+ lymphocyte count nadir, history of ADE, prior use of non-HAART ART, type of HAART regimen, prior pregnancies, and date of HAART start. In these models, women initiating HAART during pregnancy had better 6-month HIV-1 RNA and CD4+ changes than those initiating HAART after pregnancy (−0.35 vs. 0.10 log10 copies/mL, P = 0.03 and 183.8 vs. −70.8 cells/mm3, P = 0.03, respectively) but similar to those initiating HAART before pregnancy (−0.32 log10 copies/mL, P = 0.96 and 155.8 cells/mm3, P = 0.81, respectively). There were 3 (25%) AIDS-defining events or deaths in women initiating HAART before pregnancy, 3 (4%) in those initiating HAART during pregnancy, and 5 (17%) in those initiating after pregnancy (P = 0.01). There were no statistical differences in rates of HIV disease progression between groups.ConclusionsHAART initiation during pregnancy was associated with better immunologic and virologic responses than initiation after pregnancy.

HIV suppression with stavudine 30 mg versus 40 mg in adults over 60 kg on antiretroviral therapy in South Africa

In 2007, the WHO recommended a maximum stavudine dose of 30 mg. We compared virologic suppression among patients weighing more than 60 kg and receiving stavudine 30 mg (n = 110) versus 40 mg (n = 508) in community HIV clinics in South Africa, before and after guidelines changed. At 6 months, HIV RNA less than 400 copies/ml was achieved in 79% and 81% receiving 30 and 40 mg stavudine, respectively (chi2, P = 0.6). In regression modeling, including baseline HIV RNA and nonnucleoside reverse transcriptase inhibitor agent, stavudine dose remained unassociated with suppression.

Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment

Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients. Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks. At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups. Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Effects of nucleoside reverse transcriptase inhibitor backbone on the efficacy of first-line boosted highly active antiretroviral therapy based on protease inhibitors: meta-regression analysis of 12 clinical trials in 5168 patients

Tenofovir/emtricitabine (TDF/FTC) and abacavir/lamivudine (ABC/3TC) are widely used with ritonavir (RTV)-boosted protease inhibitors (PIs) as first-line highly active antiretroviral therapy (HAART), but there is conflicting evidence on their relative efficacy. The ACTG 5202 and BICOMBO trials suggested higher efficacy for TDF/FTC, whereas the HEAT trial showed no efficacy difference between the nucleoside reverse transcriptase inhibitor (NRTI) backbones. A systematic MEDLINE search identified 21 treatment arms in 12 clinical trials of 5168 antiretroviral-naïve patients, where TDF/FTC (n=3399) or ABC/3TC (n=1769) was used with RTV-boosted PI. For each NRTI backbone and RTV-boosted PI, the percentage of patients with viral load <50 HIV-1 RNA copies/mL at week 48 by standardized Intent to Treat, Time to Loss of Virological Failure (ITT TLOVR) analysis were combined using inverse-variance weighting. The effect of baseline HIV RNA, CD4 cell count and choice of NRTI backbone were examined using a weighted analysis of covariance. Across all the trials, HIV RNA suppression rates were significantly higher for those with baseline viral load below 100,000 copies/mL (77.2%) vs. above 100,000 copies/mL (70.9%) (P=0.0005). For the trials of lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r) and fosamprenavir/ritonavir (FAPV/r) using either TDF/FTC or ABC/3TC, the HIV RNA responses were significantly lower when ABC/3TC was used, relative to TDF/FTC, for all patients (P=0.0015) and for patients with baseline viral load <100,000 copies/mL (70.1%vs. 80.6%, P=0.0161), and was borderline for those with viral load >100,000 copies/mL (67.5%vs. 71.5%, P=0.0523). This systematic meta-regression analysis suggests higher efficacy for first-line use of a TDF/FTC NRTI backbone with boosted PIs, relative to use of ABC/3TC. However, this effect may be confounded by differences between the trials in terms of baseline characteristics, patient management or adherence.

Pattern and Predictors of Immunologic Recovery in Human Immunodeficiency Virus-Infected Children Receiving Non-Nucleoside Reverse Transcriptase Inhibitor-Based Highly Active Antiretroviral Therapy

Non-nucleoside reverse transcription inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) is the recommended first-line regimen for children in Thailand. This study was aimed to assess pattern and predictors of immune recovery in antiretroviral-naive Thai children starting NNRTI-based HAART. Records were extracted from clinical databases of 2 treatment cohorts in Thailand. The inclusion criteria were HIV-infected naive children who initiated NNRTI-based HAART when CD4 <25%. Immune recovery was defined as achieving a target CD4% of 25. The impact of age, gender, baseline clinical category, CD4 and HIV RNA titer, and regimen on immune recovery to weeks 96 was assessed using multiple logistic regression. There were 274 patients (52% females) with a median baseline age of 7 (Interquartile range [IQR]: 4-9) years and a median CD4% of 5 (IQR: 1-12) who started treatment with nevirapine (66%) or efavirenz (34%) based HAART. Median duration of follow-up was 168 (IQR: 120-192) weeks. The median CD4% increase from baseline was 7% (IQR: 5-11) and 18% (IQR: 12-23) at weeks 24 and 96, respectively. The probability of reaching target CD4% was 51% (95% confidence interval: 45%-57%) by week 96. The predictors of immune recovery at week 96 were younger age, female gender, higher baseline CD4%, and sustained virologic suppression after week 24. In this cohort of children with low baseline CD4, half achieved immune recovery after 96 weeks of HAART. The predictors for immune recovery are younger children, female gender, high baseline CD4%, and long-term virologic suppression.

Virologic Response and Safety of the Abacavir/Lamivudine Fixed-Dose Formulation as Part of Highly Active Antiretroviral Therapy: Analyses of Six Clinical Studies

Objective: We analyzed virologic response and safety data from six recent clinical studies conducted in antiretroviral-naïve subjects treated with ABC/3TC or its components to assess the impact of baseline viral load on efficacy and safety endpoints used in the ACTG5202 protocol. Methods: Primary endpoints were time to virologic failure (confirmed HIV-1 RNA ⩾1,000 copies/mL at 16–24 weeks or ⩾200 copies/mL at ⩾24 weeks) and time to first grade 3 or 4 adverse event or laboratory abnormality that was at least one grade higher than at baseline. The survival distributions of both endpoints were estimated using the Kaplan-Meier method overall and by baseline viral load (<100,000 vs. ⩾100,000 copies/mL). A weighted mean of the virologic response and 95% confidence intervals (CI) were calculated by inverse-variance weighting for baseline viral load ⩾100,000 copies/mL across studies. Results: For subjects with baseline HIV-1 RNA ⩾100,000 copies/mL, the rate of virologic survival ranged from 87% to 95% by 48 weeks. Few subjects treated with ABC/3TC developed grade 3 or 4 adverse events, laboratory toxicities, or changes in lipid levels. The weighted mean (CI) for the pooled virologic response was 91% (87%–96%). Conclusion: Based on the A5202 endpoints, ABC/3TC-containing regimens in this analysis had a high rate of virologic survival and were generally well tolerated in antiretroviral-naïve subjects regardless of baseline viral load. The pooled virologic response for ABC/3TC in our analysis is higher than the A5202 estimate.

A Once-Daily Lopinavir/Ritonavir-Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks

Lopinavir/ritonavir (LPV/r)-dosed twice daily has demonstrated durable efficacy in antiretroviral-naive and protease inhibitor (PI) -experienced patients. Study M05-730 compared LPV/r tablets dosed once daily vs. twice daily in antiretroviral-naive subjects. Six hundred sixty-four subjects were randomized to LPV/r soft gel capsules (SGCs) once daily, SGC twice daily, tablets once daily, and tablets twice daily, all with tenofovir and emtricitabine once daily. At week 8, all SGC-treated subjects were switched to tablets, maintaining randomized dose frequency. The primary efficacy analysis used an intent-to-treat, noncompleter = failure approach to assess noninferiority of the LPV/r once-daily group compared with the twice-daily group. At week 48, 77% of once-daily-dosed subjects vs. 76% of twice-daily-dosed subjects had HIV-1 RNA <50 copies per milliliter (P = 0.715; 95% confidence interval for difference: 5% to 8%). Response rates were numerically similar between the once-daily and twice-daily groups among subjects with baseline HIV-1 RNA > or = 100,000 copies per milliliter (75% once daily vs. 74.6% twice daily; P > 0.999) or when analyzed by baseline CD4+ T-cell count (<50, 50 to <200, and > or = 200 cells/mm3). Rates of discontinuation and adverse events, including diarrhea, were similar between arms. Among subjects with protocol-defined virologic rebound through week 48, no new PI resistance mutations were detected. At 48 weeks, the antiviral response in the LPV/r once-daily group was noninferior to the twice-daily group when coadministered with tenofovir and emtricitabine in antiretroviral-naive subjects. Efficacy was comparable between the once-daily and twice-daily groups regardless of baseline HIV-1 RNA or CD4+ T-cell count. Safety and tolerability of once-daily and twice-daily dosing was also comparable. No new PI resistance mutations were detected upon virologic rebound.

Long-Term Efficacy and Safety of Fosamprenavir plus Ritonavir Versus Lopinavir/Ritonavir in Combination with Abacavir/Lamivudine over 144 Weeks

Purpose: The KLEAN study extension assessed the long-term efficacy and safety of fosamprenavir-ritonavir (FPV/r) and lopinavir-ritonavir (LPV/r), both administered with abacavir/lamivudine (ABC/3TC) fixed dose combination, over 144 weeks. Methods: KLEAN was an open-label, noninferiority study that randomised antiretroviral-naïve patients to FPV/r twice daily (bid) or LPV/r bid with ABC/3TC once daily (qd). Patients with a viral load of <400 copies/mL at Week 48 were eligible to participate in the KLEAN study extension (up to 144 weeks) and continued with their previously randomised therapy. Results: The KLEAN study extension (48 to 144 weeks) randomized 199 patients. The proportion of TLOVR responders (HIV-1 RNA <50 copies/mL) at Week 144 was 73% and 60% in the FPV/r and LPV/r arms, respectively. The proportion of TLOVR responders (<50 copies/mL) was the same irrespective of baseline HIV-1 RNA (>100,000 or ⩽100,000 copies/mL). The Week 144 median (interquartile range) change from baseline CD4+ cell count was 300 (236–433) cells/mm3 and 335 (225–444) cells/mm3 in the FPV/r and LPV/r arms, respectively. Diarrhea was the most frequently reported adverse event. A small proportion of patients (FPV/r, 13%; LPV/r, 9%) discontinued study medication due to adverse events. Three patients (FPV/r, 1; LPV/r, 2) experienced virological failure between Week 48 and Week 144. Conclusion: The findings of the KLEAN study extension (48 to 144 weeks) support durable viral suppression with both FPV/r and LPV/r treatment regimens when used in combination with ABC/3TC irrespective of viral load at baseline. Both regimens were well tolerated and had similar safety profiles.

The ARTEMIS Trial: Once-Daily Darunavir/Ritonavir in the Management of Treatment-Naive, HIV-Infected Patients

The potential for once-daily use of darunavir in combination with low-dose ritonavir (darunavir/ritonavir) in antiretroviral-naive patients has been evaluated in the Phase III ARTEMIS trial. This followed the demonstration of sustained efficacy and a favorable safety profile of darunavir/ritonavir 600/100 mg twice daily in patients with a broad range of treatment experience in the Phase IIb POWER and Phase III TITAN studies. The 48-week primary analysis of ARTEMIS demonstrated that once-daily darunavir/ritonavir 800/100 mg was noninferior to lopinavir/ritonavir, given either 400/100 mg twice daily or 800/200 mg every day, in treatment-naive, HIV-1-infected patients (84 vs 78% of patients, respectively, had confirmed plasma HIV-1 RNA less than 50 copies/ml by per-protocol time-to-loss of virologic response at week 48). In patients with baseline HIV RNA more than 100,000 copies/ml, darunavir/ritonavir achieved higher response rates than lopinavir/ritonavir (79 vs 67%; p &lt;0.05). In addition to being at least as effective as lopinavir/ritonavir, once-daily darunavir/ritonavir had tolerability advantages compared with lopinavir/ritonavir, including lower incidences of grade 2–4 gastrointestinal adverse events (mainly diarrhea), and triglyceride and total cholesterol elevations. These benefits, along with the convenience of once-daily darunavir/ritonavir 800/100 mg and its low propensity to the development of resistance, suggest darunavir/ritonavir is a valuable treatment option for treatment-naive patients.

Replication Capacity in Relation to Immunologic and Virologic Outcomes in HIV-1-Infected Treatment-Naive Subjects

To evaluate the association between baseline (BL) replication capacity (RC) (RCBL) and immunologic/virologic parameters (at BL and after 48 weeks on therapy) in HIV-1-infected subjects initiating antiretroviral therapy. RCBL was determined using a modified Monogram PhenoSense HIV drug susceptibility assay on plasma HIV-1 from 321 treatment-naive subjects from AIDS Clinical Trials Group 384. Univariate and multivariable analyses were performed to determine the association of RCBL with BL and on-therapy virologic and immunologic outcomes. Higher RCBL was associated with lower baseline CD4 (CD4BL) (r = -0.23, P < 0.0001), higher baseline HIV-1 RNA (r = 0.25, P < 0.0001), higher CD4BL activation percent (r = 0.23, P < 0.0001), and lower CD4BL memory count (r = -0.21, P = 0.0002). In a multivariable model, week 48 CD4 increase (DeltaCD448) was associated with lower CD4BL memory count and higher CD4BL-naive percent (P = 0.004, P = 0.015, respectively). The interaction between CD4BL and RCBL was significant (P = 0.018), with a positive association between RCBL and DeltaCD448 in subjects with higher CD4BL and a negative association at lower absCD4BL. At baseline, higher RC was significantly associated with higher HIV-1 RNA, higher CD4 cell activation, lower CD4 cell count, and lower CD4 memory cell count. These factors may interact, directly or indirectly, to modify the extent to which CD4 recovery occurs in patients starting antiretroviral therapy at different CD4BL counts.

Predictors of Loss of Virologic Response in Subjects Who Simplified to Lopinavir/Ritonavir Monotherapy from Lopinavir/Ritonavir Plus Zidovudine/Lamivudine

Previous studies have demonstrated that lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a lopinavir/ritonavir-based combination regimen followed by simplification to lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4(+) T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA <50 copies/ml prior to simplification, and lopinavir concentrations. By the Cox proportional hazards model, higher reported adherence levels and higher baseline CD4(+) T cell counts were associated with a greater likelihood of maintaining virologic suppression while receiving lopinavir/ritonavir monotherapy. Lopinavir concentrations, including trough concentrations, were not significantly associated with virologic outcomes. This analysis suggests that adherence and higher baseline CD4(+) T cell counts may help to predict who will sustain virologic suppression with lopinavir/ritonavir monotherapy. The data also suggest that measuring lopinavir concentrations is not useful in predicting virologic response in these patients.