Articles tagged as "France"

CD4 counts at antiretroviral therapy start rising globally, but could do better!

Immunodeficiency at the start of combination antiretroviral therapy in low-,  middle-, and high-income countries.

The IeDEA and ART Cohort Collaborations. J Acquir Immune Defic Syndr 2014 Jan 1;65(1):e8-e16. doi: 10.1097/QAI.0b013e3182a39979.

Objective: To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries.

Methods: Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed.

Results: In total, 379 865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/µL between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/µL (76% increase), 88 to 135 cells/µL (53%), and 209 to 274 cells/µL (31%). In 2009, compared with LIC, median counts were 13 cells/µL [95% confidence interval (CI): -56 to +30] lower in LMIC, 22 cells/µL (-62 to +18) lower in UMIC, and 112 cells/µL (+75 to +149) higher in HIC. They were 23 cells/µL (95% CI: +18 to +28 cells/µL) higher in women than men. Median counts were 88 cells/µL (95% CI: +35 to +141 cells/µL) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage.

Conclusions: Median CD4 cell counts at the start of cART increased 2000-2009 but remained below 200 cells/µL in LIC and MIC and below 300 cells/µL in HIC. Earlier start of cART will require substantial efforts and resources globally.

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Editor’s notes: In this multi-cohort analysis spanning six continents, median CD4 counts at initiation of combination antiretroviral therapy were substantially higher in high-income compared to low- or middle-income countries. Median CD4 counts at initiation increased between 2002 and 2009 in most countries studied, but these increases were greater in low- and middle-income than high-income countries and were greater among men than women. Baseline CD4 counts in low- and middle-income countries were higher among countries with national antiretroviral therapy coverage of 80% or above. Nevertheless, despite the massive scale-up of antiretroviral therapy in low-income countries since 2002, the increases in median CD4 count at the start of antiretroviral therapy have been modest. Substantial efforts and resources are needed to achieve earlier implementation of antiretroviral therapy globally.

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Dolutegravir-based regimen superior to efavirenz-based regimen in treatment-naive patients

Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G; SINGLE Investigators.  N Engl J Med. 2013 Nov 7;369(19):1807-18. doi: 10.1056/NEJMoa1215541.

Background: Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen.

Methods: We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1 000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance.

Results: A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group.

Conclusions: Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine.

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Editor’s notes: In this 48- week double-blind randomized controlled trial in treatment-naive patients, dolutegravir plus abacavir / lamivudine outperformed efavirenz plus tenofovir / emtricitabine in terms of efficacy (viral suppression at 48 weeks and time to viral suppression), immunological recovery and discontinuation of therapy for adverse events. The difference in virologic response was largely due to higher levels of regimen discontinuation for adverse events in the efavirenz arm. The superior virologic response in the dolutegravir arm was consistent regardless of baseline viral load (above or below 100 000 copies/ml). 4% of patients in both arms developed virologic failure (two consecutive viral load measures >50 copies/ml). As expected, non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations and K65R mutations emerged in patients failing the efavirenz-based regimen; however no mutations emerged amongst patients failing the dolutegravir-based regimen.

 Dolutegravir is clearly an attractive future treatment option: its long half-life supports once a day dosing; there are few relevant drug interactions; trials performed to date show that it is well tolerated; and a fixed drug combination tablet of dolutegravir, abacavir and lamivudine is currently being developed. However, until the cost is lowered we are unlikely to see widespread use of this drug.

Europe, Northern America, Oceania
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Explaining the life expectancy deficit of HIV positives in the era of ART

Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy?

Sabin CA. BMC Med. 2013 Nov 27;11(1):251.

There is evidence that the life expectancy (LE) of individuals infected with the human immunodeficiency virus (HIV) has increased since the introduction of combination antiretroviral therapy (cART). However, mortality rates in recent years in HIV-positive individuals appear to have remained higher than would be expected based on rates seen in the general population. A low CD4 count, whether due to late HIV diagnosis, late initiation of cART, or incomplete adherence to cART, remains the dominant predictor of LE, and thus the individual's disease stage at initiation of cART (or thereafter) certainly contributes to these higher mortality rates. However, individuals with HIV also tend to exhibit lifestyles and behaviors that place them at increased risk of mortality, particularly from non-AIDS causes. Thus, although mortality rates among the HIV population may indeed remain slightly higher than those seen in the general population, they may be no higher than those seen in a more appropriately matched control group. Thus, further improvements in LE may now only be possible if some of the other underlying issues (for example, modification of lifestyle or behavioral factors) are tackled.

Abstract  Full-text [free] access

Editor’s notes: The uptake of antiretroviral therapy (ART) has increased dramatically in recent years, and current ART regimens are more efficacious and more forgiving of minor lapses in adherence. As a result the life expectancy of people living with HIV is approaching that of the general population in both resource-rich and resource-poor settings. However, despite the dramatic improvements, life expectancy for people living with HIV is still lower than the general population. This review shows that late HIV diagnosis and ART initiation, and imperfect retention in care are repeatedly identified as barriers to the normalization of life expectancy in HIV positive individuals. In addition, the review highlights non-HIV related factors that put people living with HIV at a higher mortality risk than the general population. This includes behavioural and lifestyle factors such as smoking, alcohol and recreational drug use, and other sexually transmitted co-infections. This review underscores the importance of early diagnosis and linkage to care for improving programme effectiveness. It also has implications for the design of future studies aiming to quantify the life expectancy deficit in HIV positive individuals such as identifying appropriately matched HIV-negative control populations for comparative mortality estimates. 

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Intrauterine infections, but not obstetric complications, more common among pregnant women with HIV

HIV and the Risk of Direct Obstetric Complications: A Systematic Review and Meta-Analysis. 

Calvert C, Ronsmans C. PLoS One. 2013 Oct 4;8(10):e74848. doi:10.1371/journal.pone.0074848.

Background: Women of reproductive age in parts of sub-Saharan Africa are faced both with high levels of HIV and the threat of dying from the direct complications of pregnancy. Clinicians practicing in such settings have reported a high incidence of direct obstetric complications among HIV-infected women, but the evidence supporting this is unclear. The aim of this systematic review is to establish whether HIV-infected women are at increased risk of direct obstetric complications.

Methods and findings: Studies comparing the frequency of obstetric haemorrhage, hypertensive disorders of pregnancy, dystocia and intrauterine infections in HIV-infected and uninfected women were identified. Summary estimates of the odds ratio (OR) for the association between HIV and each obstetric complication were calculated through meta-analyses. In total, 44 studies were included providing 66 data sets; 17 on haemorrhage, 19 on hypertensive disorders, five on dystocia and 25 on intrauterine infections. Meta-analysis of the OR from studies including vaginal deliveries indicated that HIV-infected women had over three times the risk of a puerperal sepsis compared with HIV-uninfected women [pooled OR: 3.43, 95% confidence interval (CI): 2.00-5.85]; this figure increased to nearly six amongst studies only including women who delivered by caesarean (pooled OR: 5.81, 95% CI: 2.42-13.97). For other obstetric complications the evidence was weak and inconsistent.

Conclusions: The higher risk of intrauterine infections in HIV-infected pregnant and postpartum women may require targeted strategies involving the prophylactic use of antibiotics during labour. However, as the huge excess of pregnancy-related mortality in HIV-infected women is unlikely to be due to a higher risk of direct obstetric complications, reducing this mortality will require non obstetric interventions involving access to ART in both pregnant and non-pregnant women.

Abstract  Full-text [free] access

Editor’s notes: Women with HIV are thought to have a higher risk of adverse outcomes during pregnancy. This review is valuable in summarizing available data on this topic. Many of the included studies predated the wide availability of antiretroviral therapy. There was a clear association between HIV infection and intrauterine infections, but not with the other obstetric complications, e.g., obstetric haemorrhage, hypertensive disorders of pregnancy, dystocia, examined in the review. Considering individual conditions analysed, HIV infection was associated with antepartum haemorrhage, (but not postpartum haemorrhage). It was also found to be associated with pregnancy-induced hypertension (but not pre-eclampsia or eclampsia), and uterine rupture or prolonged labour (but not other complications of dystocia). The authors note that the studies were generally of low quality, and there were too few studies to examine the effect of antiretroviral therapy on these complications.  

Given the excess of intrauterine infections in women with HIV, the authors suggest that these might be preventable with prophylactic antibiotics. Overall, where causes of maternal mortality are documented, pregnant women with HIV are more likely to die of non-pregnancy related infections, than of obstetric complications. Specifically, non-pregnancy related infections are tuberculosis, pneumonia or meningitis. Pregnant women living with HIV need access to antenatal services and a skilled attendant at delivery. But, the top priority with respect to reducing maternal mortality is effective antiretroviral therapy.

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LPV/r mono-therapy: a future option for preventing mother to child transmission?

Lopinavir/Ritonavir monotherapy as a nucleoside analogue-sparing strategy to prevent HIV-1 mother-to-child transmission: The ANRS 135 PRIMEVA phase 2/3 randomized trial.

Tubiana R, Mandelbrot L, Le Chenadec J, Delmas S, Rouzioux C, Hirt D, Treluyer JM, Ekoukou D, Bui E, Chaix ML, Blanche S, Warszawski J; ANRS 135 PRIMEVA (Protease Inhibitor Monotherapy Evaluation)Study Group. Clin Infect Dis. 2013 Sep;57(6):891-902. doi: 10.1093/cid/cit390. Epub 2013 Jun 12.

Background:  Prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) is usually based on zidovudine-containing regimens, despite potential toxicities. This multicenter trial evaluated whether lopinavir/ritonavir (LPV/r) monotherapy in HIV type 1-infected women not requiring antiretrovirals for themselves could control maternal viral load (VL).

Methods:  Overall, 105 pregnant women with baseline VL <30 000 copies/mL and CD4 ≥350 cells/µL were randomized to start open-label LPV/r 400/100 mg twice daily alone (monotherapy group, n = 69) or combined with zidovudine/lamivudine 300/150 mg twice daily (triple therapy group, n = 36) from 26 gestational weeks to delivery. According to a Fleming 2-stage phase 2 design, monotherapy was considered to be efficacious if at least 59 patients achieved VL <200 copies/mL at 8 weeks of treatment (primary endpoint). Secondary endpoints were VL at delivery and tolerance.

Results:  Monotherapy was efficacious as defined: 62 women in the monotherapy group achieved VL <200 copies/mL at 34 weeks' gestation (ie, 8 weeks of treatment; 89.9%; 95% confidence interval [CI], 80.2%-95.8%). At delivery, proportions with VL <200 copies/mL were similar in the monotherapy and triple therapy groups (92.8% vs 97.2%; P = .66); however, fewer had VL <50 copies/mL in the monotherapy group (78.3% vs 97.2%; P = .01). Changes for intolerance were less frequent in the monotherapy than in the triple therapy group (1.4% vs 11.1%, respectively; P = .046). Cesarean delivery and preterm delivery rates did not differ. All children were liveborn; 1 case of HIV-1 transmission occurred in the triple therapy group, none in the monotherapy group (95% CI upper limit = 5.2%).

Conclusions:  LPV/r monotherapy achieved satisfactory virologic efficacy in women treated solely for PMTCT, providing proof of concept for future nucleoside-sparing strategies.

Clinical Trials Registration. NCT00424814; Afssaps AIDS Clinical Trial Group A61176-34.

Abstract access 

Editor’s notes: Treating pregnant mothers with antiretroviral therapy (ART) is an effective strategy for eliminating new HIV infections in children. Currently recommended regimens comprise two nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI). However, as NRTIs’ can cross the placenta and have a natural affinity for mitochondrial and nuclear human DNA, concerns have been raised that children exposed to NRTIs in-utero are at risk of long-term toxicity. In this ‘proof-of-concept’ randomized controlled trial (RCT) the researchers compared a NRTI-sparing regimen (ritonavir boosted lopinavir [LPV/r] mono-therapy) to standard of care (2 NRTIs plus LPV/r) in pregnant women who did not require ART for their own health. Mono-therapy was found to have satisfactory virological efficacy in terms of the primary end-point, maternal viral load (VL) <200 copies/ml at 8 weeks; however these women were more likely to have low level viraemia at birth (78.3% versus 97.2% with VL<50 copies/ml [p=0.01] with only one woman on mono-therapy having VL >400 copies/ml). As the authors state, the implications of low level maternal viraemia at birth are uncertain, with the targets set in national guidelines varying between 1000 copies/ml in USA to 50 copies/ml in UK. These results indicate that NRTI-sparing regimens, such as protease inhibitor (PI) mono-therapy, may be an alternative strategy for preventing mother to child transmission in an immune-competent woman with low viral loads in high-income settings. However, as this strategy requires serial VL monitoring, PI mono-therapy is unlikely to be a viable option for many low- and middle income countries. 

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Better virological outcomes with efavirenz compared to nevirapine

Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a systematic review and meta-analysis.

Pillay P, Ford N, Shubber Z, Ferrand RA., PLoS One. 2013 Jul 22;8(7):e68995. doi: 10.1371/journal.pone.0068995. Print 2013

Introduction: There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz (EFV) and nevirapine (NVP) in first-line antiretroviral therapy (ART).

Methods: We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR) and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2) statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.

Results: Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2) = 0%) and observational studies (RR 0.65 [0.59-0.71] I(2) = 54%). EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2) = 0%) and observational studies (RR 1.06 [1.00-1.12] I(2) = 68%).

Conclusion: EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.

Abstract  Full-text [free] access

Editor’s notes: Efavirenz and nevirapine are key antiretroviral agents, particularly in resource-limited settings. Nevirapine has been widely used, for reasons including safety during pregnancy and lower cost, despite lower potency and a higher risk of hepatotoxicity and severe allergic reactions, than with efavirenz. This article summarizes data on virological outcomes from clinical trials and observational cohort studies comparing efavirenz and nevirapine. The finding that efavirenz is associated with slightly better virological outcomes is not surprising but it is valuable to have the available data summarised. The result, along with recent recommendations allowing efavirenz to be taken throughout pregnancy, and price reductions, supports the move towards efavirenz-based fixed drug combinations as first-line antiretroviral treatment in resource-limited settings.

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If approved, once-daily dolutegravir could form part of an effective new option for treatment of HIV-1 in treatment-naive patients

Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study.

Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. SPRING-2 Study Group. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4. Epub 2013 Jan 8.

BACKGROUND: Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1.

METHODS: SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824.

FINDINGS: 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance.

INTERPRETATION: The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients.

FUNDING: ViiV Healthcare.

Abstract access 

Editor’s notes: Integrase inhibitors are a novel and potent class of antiretroviral drug, however their role in first line therapy has yet to be clearly defined. Use of the two FDA approved integrase inhibitors, raltegravir and elvitegravir, has been limited by the need for twice-daily dosing and the requirement for boosting respectively. Dolutegravir, evaluated in the SPRING-2 study, has a very favourable pharmacokinetic profile which allows once-daily dosing without the need for boosting. Planned co-formulation with ABC/3TC further increases the attractiveness of dolutegravir as a treatment option in treatment-naive patients. In this head to head study dolutegravir was non-inferior to raltegravir in terms of the primary endpoint (viral suppression at 48 weeks), and was well tolerated. Additionally, no evidence of drug resistance was found in the small number of patients with virological failure on dolutegravir treatment, in keeping with prior evidence suggesting a high genetic barrier to resistance. But as the accompanying Lancet editorial noted, some important questions remain unanswered. The study population of predominantly white males and the fact that most study participants had non-advanced disease, with a median baseline CD4 count of 359 cells/µL, makes extrapolation of the results to the areas of the world with the highest disease burdens difficult. Further studies in populations more representative of the global HIV epidemic are needed, but the results of the SPRING study suggest that dolutegravir will be a useful addition to the ART repertoire.

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