Tolerability of integrase inhibitors in a real-life setting.

Background: Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them. Aims: We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients. Methods: Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models. Results: Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P = 0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P = 0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P = 0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P = 0.0007) was the only independent risk factor for early discontinuation due to toxicity. Conclusions: Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir.

Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression.

OBJECTIVES: We reviewed the 24 week outcomes of HIV-infected patients from our hospital who had their ART switched to dolutegravir monotherapy on an individual clinical basis. METHODS: Retrospective hospital database assessment of virally suppressed patients in whom the treating physician had switched to 50 mg of dolutegravir once daily due to one or more of the following reasons: antiretroviral-related adverse effects; comorbidities; risk of interactions; or archived resistance. Patients had ≥24 weeks of follow-up. Population, virological and immunological responses and safety and tolerability are described. RESULTS: Thirty-three (22 on PIs, of whom 18 had ritonavir-boosted PI monotherapy) patients were identified: median (IQR) age of 56 (50-62) years, 55% women, median (IQR) of 19 (17-23) years of known HIV infection, 39% prior AIDS events, median (IQR) of 8 (4-13) years with undetectable plasma HIV-1 RNA and median (IQR) CD4 cell count of 596 (420-843) cells/mm(3). Twenty-five (76%) patients had antiretroviral-related adverse effects, 32 (97%) patients had comorbidities, 28 (85%) patients had risk of interactions and 16 (48%) patients had archived resistance. One patient with suboptimal adherence had low-level virological failure through weeks 4-24. HIV RNA genotypic resistance tests detected no integrase mutations at weeks 4 and 24, but 118R was detected in 7% of the integrated HIV DNA at 24 weeks. Patients had significant median decreases in triglycerides (-117 mg/dL), total cholesterol (-36 mg/dL), the total cholesterol/HDL cholesterol ratio (-0.7) and high-sensitivity C-reactive protein (-0.05 mg/dL) (P ≤ 0.007), although the Chronic Kidney Disease Epidemiology Collaboration equation also decreased (-7.1 mL/min) (P < 0.0001). CONCLUSIONS: These data suggest the efficacy of dolutegravir monotherapy as a maintenance strategy to be further confirmed in randomized clinical trials.

[Acute outbreak of hepatitis C in human immunodeficiency virus-infected patients]. / Brote epidémico de hepatitis aguda C en pacientes infectados por el virus de la inmunodeficiencia humana.

BACKGROUND: Recent studies suggest an increased incidence of acute infection with hepatitisC virus (AHC) in men who have sex with men (MSM) co-infected with HIV. Early treatment with interferon-alpha, alone or in combination with ribavirin, significantly reduces the risk of chronic evolution. METHODS: This retrospective study includes all HIV patients with AHC in our centre from 2003 to March 2013. AHC was defined by seroconversion of HCV antibodies and detection of serum HCV RNA. RESULTS: 93 episodes of AHC were diagnosed in 89 patients. All but three were MSM with a history of unprotected sex. Thirty-seven (40%) patients had other associated sexually transmitted disease. The 29% (27) had any symptoms suggestive of AHC. HCV genotype 4 was the most common (41%), followed by genotype1. Seventy patients started treatment with interferon-alfa and weight-adjusted ribavirin. Currently 46 have completed treatment and follow-up, reaching 26 of them (56.5%) sustained viral response. CONCLUSIONS: The incidence of AHC in HIV MSM patients from our centre has increased exponentially in recent years; sexual transmission remains the main route of infection. Early treatment with interferon-alpha and ribavirin achieved a moderate response in these patients.

Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study.

BACKGROUND: Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients. METHODS: This was a prospective cohort study. Virologically suppressed patients on PI or NRTI regimens, with problems of tolerability, safety concerns due to comorbidities or risk of drug interactions for both PIs and NRTIs, were given the opportunity to switch their regimen to etravirine plus raltegravir. Patients were required not to have prior virological failure to raltegravir and if there was prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure, only patients in whom efficacy of etravirine could be anticipated through the Stanford Drug Resistance Database were included. Follow-up was scheduled for at least 48 weeks, unless the patient was lost to follow-up or discontinued therapy. RESULTS: Twenty-five patients were included. Their median age was 54 years; they had a median of 16 years on antiretroviral therapy and a median of nine previous regimens; 21 (84%) patients had previous virological failure; and 15 (60%) patients had a genotypic test that showed three or more NRTI mutations in 9 (36%), four or more PI mutations in 11 (44%) and at least one NNRTI mutation in 8 (32%) patients. At 48 weeks efficacy was 84% (95% CI 65.3%-93.6%) by intent-to-treat analysis and 91.3% (95% CI 73.2%-97.6%) by per-protocol analysis. One (4%) patient died, two (8%) discontinued due to intolerance and one (4%) experienced virological failure. The CD4/CD8 ratio and plasma lipids improved. CONCLUSIONS: Dual therapy with etravirine plus raltegravir was well tolerated and maintained durable viral suppression in selected virologically suppressed patients for whom both PI and NRTI therapy was challenging.

Pharmacokinetic study of dual therapy with raltegravir 400 mg twice daily and Darunavir/Ritonavir 800/100 mg once daily in HIV-1-infected patients.

BACKGROUND: Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients. METHODS: This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits. RESULTS: Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients. CONCLUSIONS: Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.

Pharmacokinetic study of saquinavir 500 mg plus ritonavir (1000/100 mg twice a day) in HIV-positive pregnant women.

Antiretroviral therapy during pregnancy is critical to preventing human immunodeficiency virus vertical transmission. Physiological changes during pregnancy can alter drug kinetics. The aim of this study was to assess the pharmacokinetics (PK) of saquinavir (SQV) boosted with ritonavir during pregnancy and postpartum. Fourteen human immunodeficiency virus-positive pregnant women started SQV 500 mg new tablet formulation plus ritonavir at a dose of 1000/100 mg twice a day + 2 nucleoside retrotranscriptase inhibitors during pregnancy. At weeks 24 and 34 of pregnancy and 6 weeks postpartum, a 12-hour PK study was conducted. PK parameters were calculated using Win Nolin software version 4.1. At week 24, the geometric mean values for SQV area under the plasma concentration-time curve from 0-12 hours (AUC0₋12), the maximum observed plasma concentration (C(max)), trough plasma concentration (C(min)), and the elimination half-life (t(1/2)) were 24.80 mg·h⁻¹·mL⁻¹, 4.66 mg/mL, 0.93 mg/mL, and 4.31 hours, respectively. At week 34, AUC0₋12, C(max), C(min), and t(1/2) were 12.71 mg·h⁻¹·mL⁻¹, 3.23 mg/mL, 0.26 mg/mL, and 4.06 hours, respectively. Finally, at 6 weeks postpartum, mean values for SQV AUC0₋12, C(max), C(min), and t(1/2) were 28.94 mg·h⁻¹·mL⁻¹, 3.92 mg/mL, 0.86 mg/mL, and 3.60 hours, respectively. Although PK parameters in week 24 and postpartum were very similar, those for week 34 showed an important reduction: -71.20%, -30.61%, -48.73%, and -5.81% in C(min), C(max), AUC0₋12, and t(1/2), respectively, compared with week 24, but no statistically significant differences were shown between patients. No vertical transmissions were reported. Therapeutic drug monitoring of SQV during pregnancy should be considered, mainly during the third trimester, to ensure adequate drug exposure throughout the entire pregnancy.

A 24-week pilot study of dual maintenance therapy with raltegravir and lamivudine.

BACKGROUND: There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir and lamivudine would keep HIV-1 suppressed and be well tolerated. METHODS: Virally suppressed HIV-1-infected adults without previous viral failures or known resistance mutations to integrase inhibitors or 3TC/FTC or chronic hepatitis B were randomized 2 : 1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. Primary outcome was the proportion of patients free of therapeutic failure (defined as viral failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death) at week 24. Secondary outcomes were changes in laboratory, body composition, sleep quality, adherence, and adverse effects. RESULTS: There were 75 patients included: men 78%; median age 50 years; median CD4 622/µl. At week 24, 7 (9%) patients had therapeutic failure: raltegravir and lamivudine 2 (4%) vs. control 5 (20%). The difference in proportions of therapeutic failures raltegravir and lamivudine minus control was -0.159 (95% confidence interval: -0.353 to -0.012). There was a trend to more weight gain with raltegravir and lamivudine, but no significant changes in other secondary outcomes. Sixty-four percent of patients in each arm had at least one adverse effect. Two (6%) patients in control arm and 4 (7%) patients in raltegravir and lamivudine arm had severe adverse effects. CONCLUSION: This pilot study suggests that switching to raltegravir along with lamivudine in patients with viral suppression maintains efficacy and is well tolerated. A larger study of longer duration is required to confirm these findings.

Current guidelines on management of HIV-infected pregnant women: impact on mode of delivery.

OBJECTIVE: To evaluate acceptance, feasibility and difficulties in the application of a policy of vaginal delivery in selected cases in HIV-infected women. STUDY DESIGN: HIV-infected women delivering March 2002 to December 2004 and enrolled in a prospective observational study in a University hospital tertiary care center were included. A vaginal delivery was not considered if labor before 36 weeks of pregnancy, preterm premature rupture of membranes, on non-highly active antiretroviral therapy (HAART) or viral load >1000copies/mL. Main outcome measures were mode of delivery, prematurity, acceptance of vaginal delivery and mother-to-child transmission of HIV infection. RESULTS: The study included 91 pregnancies, with a total of 95 fetuses. Eighty percent (n=73) of women knew their HIV infection status before becoming pregnant and 57 (63%) were on HAART at conception. Median gestational age at delivery was 37 weeks (range 22-41). Twelve women delivered a live-born before 36 weeks, all with a caesarean section. Among 74 women who reached 36 weeks gestation, 47 (64%) met the pre-established criteria for vaginal delivery, of whom 21 (45%) delivered vaginally. The most common reason for not having a vaginal delivery was the woman's request for a caesarean section. No cases of HIV vertical transmission occurred (0/90, 95% CI 0-4.02%). CONCLUSION: Recommending vaginal delivery among HIV-infected women in selected cases was well accepted, particularly once the policy became established. Nevertheless, a high proportion of HIV-infected women will continue to require caesarean section delivery.

A maintenance 3-day-per-week schedule with the single tablet regimen efavirenz/emtricitabine/tenofovir disoproxil fumarate is effective and decreases sub-clinical toxicity.

BACKGROUND: Antiretroviral drugs contained in single tablet Atripla have pharmacokinetic properties that could allow for longer than once-daily dosing. We hypothesized that simplifying Atripla once daily to 3-day per week would be feasible, able to maintain viral suppression and less toxic. METHODS: Virologically suppressed (≥2 years) HIV+ adults on Atripla once daily, CD4 greater than 350 cells/µl at inclusion, and no prior documented virological failure or evidence of resistance mutations to efavirenz, tenofovir, or emtricitabine were randomized to maintain their once-daily (OD) regimen or to reduce it to 3 days (Mondays, Wednesdays, and Fridays) a week (3W) (A-TRI-WEEK pilot trial). Primary end-point was the proportion of patients free of treatment failure (noncompleter = failure) at 24 weeks. CD4 and CD8 cells, ultrasensitive HIV-1 RNA, Pittsburg Sleep Quality Index (PSQI), bone mineral density, plasma efavirenz levels, and fasting blood and urine chemistries were measured at baseline and 24 weeks. The study is registered at ClinicalTrials.gov, NCT01778413. RESULTS: Sixty-one patients were randomized. All patients in both arms remained free of treatment failure (estimated difference 0%; 95% confidence interval -14.1 to 14.1). Ultrasensitive plasma HIV-1 RNA below detection threshold showed no difference between arms (70% in the 3W arm vs. 71% in the OD arm, P = 0.933) at 24 weeks. Total cholesterol and femur T-score significantly increased, whereas PSQI, plasma efavirenz, albumin/creatinine and beta-2-microglobulin in urine significantly decreased in the 3W arm relative to OD arm. CONCLUSION: The A-TRI-WEEK study represents a proof of concept for the feasibility of three-day per week Atripla maintenance that should be further confirmed in a larger, well powered clinical trial.

The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients.

BACKGROUND: Stavudine (d4T)-containing regimens are associated with a potential for lipoatrophy and dyslipidaemia. We assessed the safety and efficacy of reducing the dose of stavudine compared with switching to tenofovir or maintaining the standard dose of d4T. METHODS: Clinically stable HIV-infected patients receiving antiretroviral therapy containing stavudine 40 mg twice daily with a plasma HIV RNA < 200 copies/ml for at least 6 months were randomized to maintain stavudine 40 mg twice daily (d4T40 arm), to reduce to 30 mg twice daily (d4T30 arm), or to switch from d4T to tenofovir (TDF arm). RESULTS: Fifty-eight (93% male) patients were included: 22 in the d4T40 arm, 19 in the d4T30 arm and 17 in TDF arm. At baseline, median time on d4T was 6 years (interquartile range [IQR] 2.6-7.1), median age 43 years (IQR 36-51) and median CD4+ T-cell count was 587/mm3 (IQR 329-892). At week 24, median limb fat changes (g) were as follows: d4T40 = -182 (95% CI: -469- -5); d4T30 = 527 (95% CI: -343-694); and TDF = 402 (95% CI: 130-835; d4T40 versus TDF, P = 0.0003). Significant differences between median values of laboratory parameters were detected: triglycerides (mg/dl): d4T40 = 19; d4T30 = -23 and TDF = -79 (d4T40 versus TDF, P = 0.03); and total cholesterol (mg/dl): d4t40 = 22, d4T30 = -4, and TDF = -28 (d4T40 versus TDF, P = 0.04). No significant difference was observed in mitochondrial function assessed in peripheral blood mononuclear cells. CONCLUSIONS: Although both strategies were associated with a trend toward a decrease in plasma lipids and an increase in body fat, the only significant changes were observed among those who switched to tenofovir.

Decreased pregnancy rate after in-vitro fertilization in HIV-infected women receiving HAART.

A study on in-vitro fertilization (IVF) was conducted among HIV-infected women. In these patients, a reduced pregnancy rate after IVF was observed if the patient's own oocytes were used. However, no significant reduction in the pregnancy rate was found if donated oocytes were used. The CD4 lymphocyte count was independently associated with ovarian resistance to hyperstimulation. Subclinical hypogonadism mediated by immunosuppression may explain these observations, suggesting the need to optimize the immunological status of the patient before considering assisted reproduction treatments.

Antiretroviral activity of didanosine in patients with different clusters of reverse transcriptase mutations.

Patterns of mutations associated with didanosine (ddI) resistance are still a controversial issue. The correlation between different clusters of reverse transcriptase mutations with the short-term virological activity of ddI when added to a failing regimen was examined in 40 patients. The median fall in plasma viral load at week 4 was 0.67 log10 copies/ml. There was good correlation between the median fall in plasma HIV RNA levels and the number of nucleoside-associated (P = 0.0152) or thymidine-associated (P = 0.0142) mutations. In conclusion, ddI retained substantial antiretroviral activity when the number of nucleoside-associated or thymidine-associated mutations was less than four.

Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy.

BACKGROUND: Pre-eclampsia and/or fetal death have increased sharply in HIV-infected pregnant women receiving HAART. METHODS: The occurrence of pre-eclampsia or fetal death was analysed in women who delivered after at least 22 weeks of gestation for all women (January 2001 until July 2003) and for HIV-infected women (November 1985 until July 2003). RESULTS: In 2001, 2002 and 2003, the rates per 1000 deliveries of pre-eclampsia and fetal death, respectively, remained stable in all pregnant women at 25.4, 31.9 and 27.7 (P = 0.48) and 4.8, 5.8, and 5.0 (P = 0.89) (n = 8768). In 1985-2000 (n = 390) to 2001-2003 (n = 82), rates per 1000 deliveries in HIV-infected women rose from 0.0 to 109.8 (P < 0.001) for pre-eclampsia and from 7.7 to 61.0 (P < 0.001) for fetal death. In all pregnant women, factors associated with pre-eclampsia or fetal death were multiple gestation [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.3-5.6; P < 0.001], HIV infection (adjusted OR, 4.9; 95% CI, 2.4-10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58-0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46-0.90; P = 0.010). The use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7-18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054-0.627; P = 0.007) were risk factors in HIV-infected women. CONCLUSIONS: HIV infection treated with HAART prior to pregnancy was associated with a significantly higher risk for pre-eclampsia and fetal death.

Prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal anomalies.

OBJECTIVE: This study was undertaken to describe a new prenatal diagnosis program among human immunodeficiency virus (HIV)-infected women, and the perinatal outcome of this program's application over a more than 2-year period. STUDY DESIGN: From June 2000 to December 2003, all HIV-infected women who were booked into the antenatal clinic before 20 weeks were offered a screening for chromosomal anomalies, with midtrimester amniocentesis in the tests that were positive. RESULTS: A total of 116 pregnancies (including 3 sets of twins) were seen: 96 women were offered and accepted screening for chromosomal anomalies. Thirteen pregnancies had a positive screening test and amniocentesis was performed in 10 at median 16.5 gestational weeks: a trisomy 21 and a monosomy X were diagnosed. No vertical transmissions were documented by age 6 months in the 6 liveborn infants who underwent amniocentesis. CONCLUSION: A program of prenatal diagnosis for chromosomal anomalies appears to be effective when applied to HIV-infected women, although safety remains to be proven.

Pregnancy in a renal transplant recipient with HIV-1 infection: a case report.

We report the first case of a pregnancy in a renal transplant recipient with HIV infection. She underwent renal transplantation in 2005 and became pregnant in 2009. The patient underwent vaginal delivery and a healthy full-term, female baby was born. Almost 6 years after delivery, both mother and child were doing well. The management of concurrent renal transplantation, HIV infection and pregnancy was extremely challenging. Women with HIV infection who have undergone renal transplantation should be accurately informed of the potential health risks for them and their offspring. Multidisciplinary teams are mandatory in order to properly manage these patients.

Zidovudine treatment in HIV-infected pregnant women is associated with fetal cardiac remodelling.

OBJECTIVE: To evaluate the cardiac structure and function of the fetuses of pregnant women with HIV infection on combined antiretroviral treatment (cART) and the HIV-related and nonrelated determinants of abnormal findings. DESIGN: A prospective cohort study including 42-noninfected fetuses from HIV pregnant women on cART and 84 fetuses from non-HIV-infected women. METHODS: Fetal echocardiography was performed at 26-32 weeks of pregnancy to assess cardiac structure and function. The impact of maternal and perinatal factors on fetal cardiac remodelling was evaluated by multivariate regression analysis. RESULTS: Fetuses from HIV pregnant women on cART presented larger hearts and pericardial effusion together with thicker myocardial septal walls (mean 3.56 mm (SD 0.88) vs non-HIV mean 2.75 mm (SD 0.77); P = 0.002) and smaller left ventricular cavities (10.81 mm (SD 2.28) vs 12.3 mm (SD 2.54); P = 0.033). Fetuses from HIV women also presented signs of systolic (mitral systolic annular peak velocity 5.85 cm/s (SD 0.77) vs non-HIV 6.25 cm/s (SD 0.97); P = 0.007) and diastolic (isovolumic relaxation time 52 ms (SD 8.91) vs non-HIV 45 ms (SD 7.98); P < 0.001) dysfunction. In the multivariate analysis, maternal treatment with zidovudine was the only factor significantly associated with fetal cardiac changes (P = 0.014). CONCLUSION: Fetuses from HIV-infected mothers on cART have cardiac remodelling and dysfunction, which might explain the cardiovascular changes described in childhood. Fetal cardiac remodelling was essentially associated with maternal treatment with zidovudine which challenges its use during pregnancy.

High rate of virological failure in maintenance antiretroviral therapy with didanosine and tenofovir.

We evaluated the virological outcome of tenofovir plus didanosine-based regimens in 67 HIV-suppressed patients. After a median follow-up of 26 months (IQR 10.5-40.5), 12 (18%) discontinued the therapy because of virological failure. At virological failure 'de novo' selected mutations were identified in 11 of the 12 failing patients, including the K65R mutation in seven patients. These results argue against the use of tenofovir-didanosine not only in naive patients, but also in previously suppressed patients.

Evolution of resistance mutations pattern in HIV-1-infected patients during intensification therapy with a boosted protease inhibitor.

Intensification therapy adding a boosted protease inhibitor (PI) to a failing regimen has the potential to worsen the resistance profile. Sixty-six patients included in four different boosted PI intensification studies were assessed and resistance mutations in the reverse transcriptase and protease genes were evaluated at baseline and 4 weeks after the initiation of the intensification strategy. Only one of the 66 patients developed changes in their pattern of mutations able to generate or increase resistance to new drugs.

Immune Reconstitution in Severely Immunosuppressed Antiretroviral-Naive HIV-1-Infected Patients Starting Efavirenz, Lopinavir-Ritonavir, or Atazanavir-Ritonavir Plus Tenofovir/Emtricitabine: Final 48-Week Results (The Advanz-3 Trial).

BACKGROUND: Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naive, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens. METHODS: Randomized, controlled, open-label, multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naive patients with <100 CD4 cells per cubic millimeter were randomly assigned in a 1:1:1 ratio to efavirenz (n = 29), atazanavir/ritonavir (n = 30), or lopinavir/ritonavir (n = 30) combined with tenofovir plus emtricitabine. The primary outcome was median increase in CD4 cell count at week 48. Secondary end points were the proportion of patients with HIV-1 RNA <50 copies per milliliter, adverse events, disease progression, and death. RESULTS: In the on-treatment analysis, the median (interquartile range) increase in the CD4 count after 48 weeks was +193 (129-349) cells per microliter in the efavirenz arm, +197 (146-238) cells per microliter in the ritonavir-boosted atazanavir arm, and +205 (178-327) cells per microliter in the ritonavir-boosted lopinavir arm (P = 0.73). The percentage of patients achieving viral suppression was similar in all 3 treatment arms at 48 weeks {efavirenz, 85.71% [95% confidence interval (CI): 68.5 to 94.3]; atazanavir, 80% [95% CI: 62.7 to 90.5]; and lopinavir, 82.8% [95% CI: 65.5 to 92.4]; P = 0.88}. Bacterial translocation, inflammation, immune activation, and apoptotic markers, but not D-dimer, declined significantly and similarly in the 3 treatment arms. Adverse events had a similar incidence in all 3 antiretroviral regimens. No patients died. CONCLUSIONS: The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1-infected patients was similar to that induced by a ritonavir-boosted protease inhibitor-based regimen (ClinicalTrials.gov registration number: NCT00532168).

Impact of prior virological failure and nucleos(t)ide genotypic resistance mutations on the efficacy of switching from ritonavir-boosted protease inhibitors to raltegravir.

BACKGROUND: The virological efficacy of switching from a ritonavir-boosted protease inhibitor (PI/r)- to a raltegravir (RAL)-containing regimen remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virological outcome. METHODS: This was a substudy of the prospective, open-label, multicentre SPIRAL study. Demographic, virological variables, prior episodes of virological failures (VF) and archived resistance mutations to nucleos(t)ides were identified from databases and its impact measured by genotypic sensitive scores (GSS) according to the genotypic resistance interpretation algorithm from the Stanford HIV Drug Resistance Database on outcome was analysed. RESULTS: Of 250 patients (128 RAL and 122 PI/r) included in the main SPIRAL study, 74 (30%) had previous VF with prior genotypic resistance tests (GRT). Median time of virological suppression prior to inclusion in SPIRAL study was 63.5 months. GSS for backbone nucleos(t)ides was <1 in 15/38 (39%) in the RAL arm and in 9/36 (25%) in the PI/r arm (P=0.13). Among those with nucleos(t)ides GSS <1, 0/15 (0%) in the RAL versus 2/9 (22%) in the PI/r arm developed VF (P=0.13). Moreover 0/11 subjects with null or residual (GSS≤0.5) backbone activity developed VF in the RAL arm. CONCLUSIONS: The 48-week virological efficacy of switching from a PI/r to RAL in subjects with long-term virological suppression was not compromised by a reduction of the nucleos(t)ide backbone activity.