First-line HIV Treatment Research Articles

Weight Change Following Switch to Dolutegravir for HIV Treatment in Rural Kenya During Country Roll-Out.

Switch to dolutegravir (DTG) in treatment-experienced people living with HIV (PLH) is associated with excess weight gain in some settings; data are limited from rural low-income settings with low obesity prevalence. In rural Kenya, we conducted a retrospective cohort study at 8 HIV clinics and a single-site prospective cohort study including adults switching to DTG during countrywide transition to DTG/tenofovir DF(TDF)/emtricitabine as first-line HIV treatment. In the retrospective analysis, we used preswitch data to model postswitch weight trajectory had each participant not switched to DTG and contrasted observed vs. predicted postswitch weight. In the prospective analysis, we measured weight post-DTG switch and evaluated predictors of 6-month weight change. Our retrospective cohort included 4445 PLH who switched to DTG between 2018 and 2020. Mean 12-month weight change was 0.6 kg preswitch and 0.8 kg postswitch. Among those on TDF throughout (n = 3374; 83% on efavirenz preswitch), 12-month postswitch weight was 0.7 kg more than predicted for women (95% CI: 0.4, 1.0) and similar among men (0.04 kg; 95% CI -0.3, 0.4). In our prospective cohort (n = 135, 100% female), mean 6-month weight change was +0.4 kg (IQR -1.1, 2.0 kg). Predicted gain varied by baseline food insecurity: +1.1 kg (95% CI: 0.34, 1.87) among food secure, -0.09 kg (95% CI -0.71, 0.54) among moderate insecure, and +0.27 kg (95% CI -0.82, 1.36) among severe insecurity. In contrast to some reports of large weight gain following switch to DTG, we observed small weight increases in women and no weight change in men following DTG switch when on TDF throughout. Weight gain may be attenuated by food insecurity, though was modest even among food secure.

Evidence-based Medicine and Mechanistic Evidence: The Case of the Failed Rollout of Efavirenz in Zimbabwe.

Evidence-based medicine (EBM) has long deemphasized mechanistic reasoning and pathophysiological rationale in assessing the effectiveness of interventions. The EBM+ movement has challenged this stance, arguing that evidence of mechanisms and comparative studies should both be seen as necessary and complementary. Advocates of EBM+ provide a combination of theoretical arguments and examples of mechanistic reasoning in medical research. However, EBM+ proponents have not provided recent examples of how downplaying mechanistic reasoning resulted in worse medical results than would have occurred otherwise. Such examples are necessary to make the case that EBM+ responds to a problem in clinical practice that urgently demands a solution. In light of this, we examine the failed rollout of efavirenz as a first-line HIV treatment in Zimbabwe as evidence of the importance of mechanistic reasoning in improving clinical practice and public health policy decisions. We suggest that this case is analogous to examples commonly given to support EBM.

An evaluation of postmarketing reports of hyperglycaemia associated with dolutegravir for treatment of HIV in Eswatini

BackgroundDolutegravir (DTG) is an Integrase Strand Transfer Inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV infection. It is available in a number of pharmaceutical preparations including the fixed-dose combination (TLD) containing tenofovir (300 mg) + lamivudine (300 mg) + dolutegravir (50 mg). In 2018, Eswatini adopted TLD as the preferred first-line HIV treatment regimen for adults and adolescents as per WHO recommendations. From March 2019 to March 2020, the National Pharmacovigilance Center (NPC) in Eswatini received 8 reports of hyperglycaemia associated with the use of DTG. This study was conducted to investigate if Eswatini NPC database included cases suggestive of causality between dolutegravir and hyperglycaemia.MethodA qualitative synthesis of information from the Eswatini national pharmacovigilance database from March 2019 to March 2020 was conducted to investigate a casual association between hyperglycaemia and dolutegravir.ResultsAll reports with dolutegravir containing regimen and suspected Adverse Event of hyperglycaemia in the period of March 2019 to March 2020 were included in the study. Seven of the reports were serious (resulted in hospitalization and one case concerned optic neuritis, leading to blindness). Two patients had a medical history of diabetes while the rest of the patients had never experienced hyperglycaemia before starting dolutegravir. For all the reports, the time to onset of hyperglycaemia ranges from 2–5 months after the initiation of DTG. None of the patients discontinued the use of DTG. All the patients were treated with oral hypoglycaemic medication. In severe cases, patients were treated with intravenous normal saline and ringer lactate as well as rapid-acting insulins. All patients are currently stable on oral hypoglycaemic drugs.ConclusionCases that support causality between dolutegravir containing regimen and hyperglycaemia were found. These cases were mainly serious. Based on these findings it is recommended that healthcare professionals (HCPs) actively screen all patients for risk factors of hyperglycaemia before DTG initiation. In addition, it is important that HCPs are aware of the possible association between DTG and hyperglycaemia.

Dolutegravir for children with HIV-associated tuberculosis

In The Lancet HIV, Anna Turkova and colleagues1 report the findings of a pharmacokinetic and safety substudy nested within the ODYSSEY trial, which provides evidence that twice-daily dolutegravir dosing is safe and effective when used with rifampicin-containing tuberculosis (TB) treatment in children with HIV-associated TB. Their findings support the 2021 WHO HIV recommendations for once-daily dolutegravir as a component of first-line and second-line HIV treatment from age 4 weeks or older, and twice-daily dosing during treatment with rifampicin-based therapy for TB coinfection.

“It’s only fatness, it doesn’t kill”: a qualitative study on perceptions of weight gain from use of dolutegravir-based regimens in women living with HIV in Uganda

BackgroundDolutegravir (DTG)-based regimens have been recommended by the WHO as the preferred first-line and second-line HIV treatment in all populations. Evidence suggests an association with weight gain, particularly among black women. Our study investigated perceptions of weight gain from DTG-based regimen use on body image and adherence of antiretroviral therapy in women living with HIV (WLHIV) in Uganda.MethodsBetween April and June 2021, we conducted semi-structured interviews involving 25 WLHIV (adolescents, women of reproductive potential and post-menopausal women) and 19 healthcare professionals (clinicians, nurses, ART managers and counsellors) purposively selected from HIV clinics in Kampala. The interviews explored perceptions of body weight and image; experiences and management of weight related side effects associated with DTG; and knowledge and communication of DTG-related risks. Data was analysed thematically in NVivo 12 software.ResultsOur findings indicate WLHIV in Uganda commonly disliked thin body size and aspired to gain moderate to high level body weight to improve their body image, social standing and hide their sero-positive status. Both WLHIV and healthcare professionals widely associated weight gain with DTG use, although it was rarely perceived as an adverse event and was unlikely to be reported or to alter medication adherence. Clinical management and pharmacovigilance of DTG-related weight gain were hampered by the limited knowledge of WLHIV of the health risks of being over-weight and obesity; lack of diagnostic equipment and resources; and limited clinical guidance for managing weight gain and associated cardiovascular and metabolic comorbidities.ConclusionsThe study highlights the significance of large body-size in promoting psychosocial wellbeing in WLHIV in Uganda. Although weight gain is recognized as a side effect of DTG, it may be welcomed by some WLHIV. Healthcare professionals should actively talk about and monitor for weight gain and occurrence of associated comorbidities to facilitate timely interventions. Improved supply of diagnostic equipment and support with sufficient guidance for managing weight gain for healthcare professionals in Uganda are recommended.

Predictors of Viral Non-Suppression among Patients Living with HIV under Dolutegravir in Bunia, Democratic Republic of Congo: A Prospective Cohort Study.

The Democratic Republic of the Congo adopted the integrase inhibitor dolutegravir (DTG) as part of its preferred first-line HIV treatment regimen in 2019. This study aimed to identify predictors of viral non-suppression among HIV-infected patients under a DTG-based regimen in the context of ongoing armed conflict since 2017 in the city of Bunia in the DRC. We conducted a cohort study of 468 patients living with HIV under DTG in all health facilities in Bunia. We calculated the proportion of participants with an HIV RNA of below 50 copies per milliliter. About three in four patients (72.8%) in this cohort had a viral load (VL) of <50 copies/mL after 6–12 months. After controlling for the effect of other covariates, the likelihood of having non-suppression remained significantly lower among the 25–34 age group and self-reported naïve patients with a baseline VL of ≥50 copies/mL. The likelihood of having non-suppression remained significantly higher among those who were at advanced stages of the disease, those with abnormal serum creatinine, those with high baseline HIV viremia over 1000 copies/mL, and the Sudanese ethnic group compared to the reference groups. This study suggests that we should better evaluate adherence, especially among adolescents and economically vulnerable populations, such as the Sudanese ethnic group in the city of Bunia. This suggests that an awareness of the potential effects of DTG and tenofovir is important for providers who take care of HIV-positive patients using antiretroviral therapy (ART), especially those with abnormal serum creatinine levels before starting treatment.

Prevalence of pretreatment HIV drug resistance in key populations: a systematic review and meta-analysis.

IntroductionWHO’s 2019 report on HIV drug resistance (HIVDR) documents a high prevalence of pretreatment drug resistance (PDR) among populations initiating first‐line antiretroviral therapy (ART) in low‐ and middle‐income countries (LMIC). However, systematic evidence on the prevalence of PDR among key populations remains limited. We performed a systematic review to characterize levels of PDR in key population groups and compared them to levels of PDR in the “general population” across different geographical regions.MethodsTen electronic databases were searched for papers published until February 2019 that included predefined search terms. We included studies that reported the number of successfully tested genotypes and the number of genotypes with drug resistance mutations among antiretroviral therapy treatment naïve people, recently infected people, or people initiating first‐line ART from key populations. To assess the prevalence of PDR for each key population, we pooled estimates using random‐effects meta‐analysis of proportions. Where possible, we computed the differences in the odds of PDR (any, and by drug class) present in each key population compared to the “general population”. The I2 statistic (a measure of heterogeneity between studies) is reported.Results and discussionA total of 332 datasets (from 218 studies) and 63,111 people with successful HIVDR genotyping were included in the analysis. The pooled prevalence estimate of any PDR was high among men who have sex with men (13.0%, 95% CI 11.0 to 14.0%, I2 = 93.19), sex workers (17.0%, 95% CI 6.0 – 32.0, I2 = 87.31%) and people in prisons (18.0%, 95% CI 11.0 to 25.0, I2 = 70.18%), but less so among people who inject drugs (7.0%, 95% CI 5.0 to 10.0, I2 = 90.23). Overall, men who have sex with men were more likely to carry any PDR compared to the “general population,” a finding which was statistically significant (odds ratio (OR) 1.28, 95% CI 1.13 – 1.46, I2 48.9%).ConclusionsHigh prevalence of PDR found in key populations highlights the need to increase access to effective first‐line HIV treatment. The low prevalence of nucleotide reverse transcriptase inhibitor (NRTI) PDR suggests that current WHO recommendations for pre‐exposure prophylaxis (PrEP) regimens will remain effective and can be scaled up to prevent new HIV infections in high‐risk groups.

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

BackgroundTo inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.MethodsWe searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework.FindingsWe identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92).InterpretationThe evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable.FundingWHO.

First-line HIV treatment outcomes following the introduction of integrase inhibitors in UK guidelines.

Objective:To investigate the characteristics and outcomes of people who initiated different antiretroviral therapy (ART) regimens during the era of integrase strand transfer inhibitors (INSTIs).Design:UK-based observational cohort study.Methods:UK Collaborative HIV Cohort study participants were included if they had started ART between 1 January 2012 and 30 June 2017. Virological failure was defined as the first of two consecutive plasma HIV RNA more than 50 copies/ml, at least 6 months after starting ART. Follow-up was censored at ART discontinuation, class switch or death. The risk of virological failure among those on INSTI, protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens was compared using Kaplan–Meier and Cox regression methods.Results:Of 12 585 participants, 45.6% started a NNRTI, 29.0% a protease inhibitor and 25.4% an INSTI regimen. Over a median follow-up of 20.3 months (interquartile range 7.9–38.9), 7.5% of participants experienced virological failure. Compared with those starting an NNRTI regimen, people receiving INSTIs or protease inhibitors were more likely to experience virological failure: INSTI group adjusted hazard ratio 1.52, 95% confidence interval 1.19–1.95, P = 0.0009; protease inhibitor group adjusted hazard ratio 2.70, 95% confidence interval 2.27–3.21, P less than 0.0001, likelihood ratio test P less than 0.0001.Conclusion:First-line INSTI regimens were associated with a lower risk of virological failure than protease inhibitor regimens but both groups were more likely to experience virological failure than those initiating treatment with a NNRTI. There is likely to be residual channelling bias resulting from selected use of INSTIs and protease inhibitors in specific clinical contexts, including in those with a perceived risk of poor adherence.

Clinical outcomes after first-line HIV treatment failure in South Africa: the next cascade of care.

IntroductionThere is limited literature on the appropriateness of viral load (VL) monitoring and management of detectable VL in public health settings in rural South Africa.MethodsWe analysed data captured in the electronic patient register from HIV‐positive patients ≥ 15 years old initiating antiretroviral therapy (ART) in 17 public sector clinics in rural KwaZulu‐Natal, during 2010–2016. We estimated the completion rate for VL monitoring at 6, 12, and 24 months. We described the cascade of care for those with any VL measurement ≥ 1000 HIV‐1 RNA copies/mL after ≥ 20 weeks on ART, including the following proportions: (1) repeat VL within 6 months; (2) re‐suppressed; (3) switched to second‐line regimen.ResultsThere were 29 384 individuals who initiated ART during the period [69% female, median age 31 years (interquartile range 25–39)]. Of those in care at 6, 12, and 24 months, 40.7% (9861/24 199), 34% (7765/22 807), and 25.5% (4334/16 965) had a VL test at each recommended time‐point, respectively. The VL results were documented at all recommended time‐points for 12% (2730/22 807) and 6.2% (1054/16 965) of ART‐treated patients for 12 and 24 months, respectively. Only 391 (18.3%) of 2135 individuals with VL ≥ 1000 copies/mL on first‐line ART had a repeat VL documenting re‐suppression or were appropriately changed to second‐line with persistent failure. Completion of the treatment failure cascade occurred a median of 338 days after failure was detected.ConclusionWe found suboptimal VL monitoring and poor responses to virologic failure in public‐sector ART clinics in rural South Arica. Implications include increased likelihood of morbidity and transmission of drug‐resistant HIV.

High acceptability and viral suppression of patients on Dolutegravir-based first-line regimens in pilot sites in Uganda: A mixed-methods prospective cohort study.

Uganda adopted the integrase inhibitor dolutegravir (DTG) as part its preferred first-line HIV treatment regimen in 2018. Prior to the national rollout, the Uganda Ministry of Health and Clinton Health Access Initiative (CHAI) launched a pilot study in July 2017 aimed at better understanding patients’ and prescribers’ experience and acceptability of DTG. Patients were enrolled in the study if they were newly initiating treatment or switched from an NNRTI regimen due to intolerance. Patients were followed up for 6 months after initiation onto DTG and acceptability and experiences were assessed through questionnaires at one-month and six-month follow-up visits. In addition to acceptability side effects of patients on DTG regimens were assessed. Analysis was conducted using MS Excel and SAS 9.4 and confidence intervals were adjusted for facility level clustering. A total of 365 patients from 6 study sites were enrolled in the study, of whom 50% were treatment-experienced and 50% treatment naïve. 325 patients completed the 6 months of follow-up. Survey results showed a high level of acceptability (more than 90%) of DTG-containing regimens for both categories of patients during the from one-month and six-months interviews. The rate of self-reported side effects amongst patients was 33% overall and higher for experienced (37%) than naïve (29%) patients at 6 months. Although frequencies declined between month-1 and month-6, the changes were not statistically significant. Almost all patients (94%) were virally suppressed at 6 months. Overall, the study findings showed a very high level of acceptability of Dolutegravir-based regimens across both experienced and naïve patients. The overall viral suppression rate in this cohort was 94% at six months of taking DTG-based regimen.

Nanoformulated Eudragit lopinavir and preliminary release of its loaded suppositories

The development of novel paediatrics formulations is critical towards achieving the UNAIDS 90-90-90 targets. According to the latest UNAIDS reports, the availability of antiretrovirals (ARVs) for children has increased significantly, from 49% in 2015 to 53% in 2017. However, this percentage is considerably lower than the 80% for pregnant women that are currently on treatment. Therefore, there is still an urgent need for an alternative child-friendly delivery system. Lopinavir (LPV) is a protease inhibitor first-line HIV treatment drugs but suffers from low aqueous solubility, bitter state, short half-life leading to a limited dissolution and variable bioavailability upon oral administration. This work focused on the fabrication and characterization of a delivery system entailing Eudragit RSPO-LPV nanoparticles loaded suppositories in two different bases to improve the bioavailability and overcome the problem encountered through oral administration emanating from poor solubility. The prepared nanoparticles by nanoprecipitation method were characterized and compounded into suppositories in fattibase and polyethylene glycol (PEG) bases using a melt fusion method. The suppositories were stored at 5 and 25 °C, and were sampled at 0, 4, 8, 12 weeks. The samples were assessed by particle size, entrapment efficiency (EE), zeta potential and polydispersity index (PDI) variations. The preliminary in vitro release studies were analysed by HPLC. The nanoparticles have an average particle size of 191 nm with spherical morphology, entrapment efficiency, polydispersity index and zeta potential of 79.0 ± 0.5%, 0.224, and 25.87 ± 0.41 mV respectively. The surface analysis of the nanoparticles with FTIR, SEM, PXRD and TGA indicated that the drug was truly encapsulated without any interaction. The in vitro release studies showed that a better release was observed in suppositories formulated with PEG than the fattibase by having higher drug concentration released. Hence, this rectal formulation might serve as an alternative for paediatric HIV treatment upon further investigation.

980. Effects of Integrase Strand-Transfer Inhibitor Use on Lipids, Glycemic Control, and Insulin Resistance in the Women’s Interagency HIV Study (WIHS)

BackgroundIntegrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is recommended first-line HIV treatment. We recently demonstrated increased weight gain associated with INSTI use among women living with HIV (WLH) enrolled in the Women’s Interagency HIV Study (WIHS), raising concern for cardiometabolic consequences. We, therefore, evaluated the effects of INSTI use on lipids, insulin resistance, and glycemic control in WLH.MethodsData from 2008 to 2017 were analyzed from WLH enrolled in WIHS. Women who switched to or added an INSTI to ART (SWAD group) were compared with women who remained on non-INSTI ART (STAY group). Outcomes included changes in fasting total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and glucose; hemoglobin A1c; and incident insulin resistance (defined as homeostatic model assessment of insulin resistance [HOMA] score ≥2). Outcomes were measured 6–12 months before and 6–18 months after INSTI switch/add in the SWAD group with comparable time points in the STAY group. Linear regression models compared change over time in each outcome by SWAD/STAY group, adjusted for age, race, WIHS site, income, smoking status, statin use, and ART regimen at baseline.ResultsIn total, 881 WIHS participants (182 SWAD and 699 STAY) were followed for a mean 1.8 (±1.1) years. Mean age was 49 (±8.8) years, BMI was 31 (±8.2) kg/m2, and 49% were Black. At baseline, SWAD vs. STAY was more likely to report NNRTI (vs. PI)-based ART and statin use (both P < 0.0001), but all baseline lipid and glucose variables were similar. Compared with STAY, the SWAD group experienced significantly greater decreases in HDL (−2.4 vs. +0.09 mg/dL, P = 0.03) and trended toward greater decreases in TC (−2.6 vs. −2.4 mg/dL, P = 0.07) at follow-up, without significant differences in TG or LDL. The SWAD group had significantly greater increases in A1c (+0.08% vs. −0.05%, P = 0.01) but trended toward lower incidence of insulin resistance (19% vs. 32%, P = 0.05).ConclusionDespite reported increases in weight, INSTI use was associated with only modest changes in lipid measurements and glycemic control during short-term follow-up of WLH compared with non-INSTI ART. Research is needed to elucidate long-term cardiometabolic effects. DisclosuresAnandi N. Sheth, MD, MS, Gilead Sciences, Inc.: Research Grant.

First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda

BackgroundOur understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 subtypes have been hindered by the availability of large study cohorts in resource-limited settings. To maximize our statistical power, we combined HIV-1 sequence and clinical data from every available study population associated with the Joint Clinical Research Centre (JCRC) in Uganda. These records were combined with contemporaneous ART-naive records from Uganda in the Stanford HIVdb database.MethodsTreatment failures were defined by the presence of HIV genotype records with sample collection dates after the ART start dates in the JCRC database. Drug resistances were predicted by the Stanford HIVdb algorithm, and HIV subtype classification and recombination detection was performed with SCUEAL. We used Bayesian network analysis to evaluate associations between drug exposures and subtypes, and binomial regression for associations with recombination.ResultsThis is the largest database of first-line treatment failures (n=1724) in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of ge 1.2. In the subset where drug regimen data were available, we observed that use of 3TC was associated with a higher rate of first line treatment failure, whereas regimens containing AZT and TDF were associated with reduced rates of failure. In the complete database, we found limited evidence of associations between HIV-1 subtypes and treatment failure, with the exception of a significantly lower frequency of failures among A/D recombinants that comprised about 7% of the population. First-line treatment failure was significantly associated with reduced numbers of recombination breakpoints across subtypes.ConclusionsExpanding access to first-line ART should confer the anticipated public health benefits in Uganda, despite known differences in the pathogenesis of HIV-1 subtypes. Furthermore, the impact of ART may actually be enhanced by frequent inter-subtype recombination in this region.

Treatment with a fixed dose combination antiretroviral therapy drug containing tenofovir, emtricitabine and efavirenz is associated with cardioprotection in high calorie diet-induced obese rats.

HIV-infection, certain antiretroviral drug classes, especially protease inhibitors (PI), and obesity are associated with increased ischaemic heart disease (IHD) risk. However, the effect of PI-free fixed dose combination (FDC) antiretroviral therapy (ART) on hearts exposed to ischaemia-reperfusion injury (I/R) is unknown, particularly in obesity. This is becoming relevant as World Health Organisation guidelines recommend a FDC ART containing (non-) nucleoside reverse transcriptase inhibitors (tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV)) as first-line HIV treatment. Additionally, obesity rates are rising in HIV-infected populations, not only in ART-experienced individuals, but also at the time of ART initiation, which may further increase the risk of IHD. Therefore, we investigated the effects of PI-free FDC ART in myocardial I/R-exposed hearts from obese rats. Obesity was induced in male wistar rats via a 16-week high calorie diet. At week 10, treatment with a FDC ART drug containing TDF/FTC/EFV was initiated. Biometric and metabolic parameters, as well as myocardial functional recovery and infract size (IS), and myocardial signalling proteins following I/R were assessed after 16 weeks. Obese rats presented with increased body and intraperitoneal fat mass, elevated triglyceride and TBARS levels, whilst the hearts responded to I/R with impaired functional performance and increased IS. The FDC ART treatment did not alter biometric and metabolic parameters in obese rats. In a novel finding, ART protected obese hearts against I/R as shown by improved functional performance and smaller IS vs. untreated obese hearts. Cardioprotection was underscored by increased myocardial phosphorylated endothelial nitric oxide synthase (eNOS) and reduced AMP-kinase levels. In conclusion, these results demonstrate for the first time, that 6-weeks treatment of obese rats with a FDC ART drug specifically containing TDF/FTC/EFV conferred cardioprotection against I/R. The FDC ART-induced cardioprotection was seemingly unrelated to metabolic changes, but rather due to direct cardiac mechanisms including the up-regulation of myocardial eNOS.

Efficacy and safety of novel russian non-nucleoside reverse transcriptase inhibitor elsulfavirine in combination with 2 nucleoside/nucleotide reverse transcriptase inhibitors in first-line HIV treatment – 96-week study

A randomized multicenter 96-week study of an elsulfavirine (ESV), non-nucleoside reverse transcriptase inhibitor (NNRTI) of novel generation, in combination with 2 nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) was conducted in naive HIV adult patients, divided by 2 parts: 1) partially blind comparative to efavirenz (EFV) 48-week study, 2) open-label observational study during additional 48 weeks. High virological and immunological effectiveness maintained during the study: proportion of patients with HIV RNA <50 copies/ml in 48 weeks achieved 81,6%, in 96 weeks – 83,9% (MITT-analysis) and 91% (if patients withdrawn from the study due to other reasons not related to treatment were excluded). No resistance mutations were found in patients with viral replication blips (HIV RNA 50-1300 copies/ml). CD4+-lymphocytes count was increased by 187,5 at week 48 and 251,0 cells/mcl at week 96. Good tolerability and safety were confirmed during second year of treatment: no additional safety data which could influence benefit/risk ratio were recorded as well as withdrawal from the treatment due to adverse events. Serious adverse events, connected with treatment, allergic reactions were not registered during the whole 96-week study. Conclusion. Results of the 96-week study confirm earlier data from 48-week study on high efficacy and safety of ESV. Based on these data ESV was included into “National recommendations on dispensary follow-up and treatment of patients with HIV-infection” as the first-line ART regime in combination with 2 NRTIs.

A Comparison of Effectiveness of Efavirenz and Nevirapine - Based First-Line HIV Treatment in Patients Attending Coast Provincial General Hospital, Kenya

A Comparison of Effectiveness of Efavirenz and Nevirapine - Based First-Line HIV Treatment in Patients Attending Coast Provincial General Hospital, Kenya

Has the time come to abandon efavirenz for first-line antiretroviral therapy?

Efavirenz has been recommended as a preferred third agent together with two nucleos(t)ides for first-line combination antiretroviral therapy (ART) for >15 years. The availability of efavirenz in a fixed-dose combination makes it very attractive. However, because of (i) adverse events associated with efavirenz, (ii) a poorer overall efficacy of efavirenz compared with newer antiretrovirals, (iii) the ranking of efavirenz as FDA Pregnancy Category D and (iv) the relatively high prevalence of transmitted drug-resistance mutations, there is a need to reconsider the role of efavirenz in first-line ART. We review the available evidence that challenges efavirenz's current position in first-line HIV treatment guidelines. Apart from its animal teratogenic potential, and moderate neuropsychiatric adverse events associated with its use, efavirenz has recently been associated with an increased risk of suicidality when compared with other antiretroviral drugs. Most importantly, efavirenz has demonstrated overall inferior efficacy to various comparator drugs, which include rilpivirine, raltegravir and dolutegravir, in antiretroviral-naive patients. Furthermore, epidemiological data indicate that the prevalence of non-nucleoside reverse transcriptase inhibitor resistance has reached 5%-8% in various parts of the world, and minority transmitted non-nucleoside reverse transcriptase inhibitor resistance-associated mutations can have a negative impact on the outcome of first-line efavirenz-based ART. Based on considerations of efficacy, toxicity and resistance, it is time to reconsider the routine use of efavirenz in ART. This, of course, presupposes that other antiretrovirals will be available in place of efavirenz, and may not be applicable in certain developing country settings where this is not the case.

Beyond first-line HIV treatment regimens

With the availability of antiretroviral drugs in resource-limited settings, there is a rapid scale-up of antiretroviral therapy in developing countries. The review focuses on the issues faced while patients are on first-line antiretroviral therapy in the absence of viral load monitoring, and the availability and progress of the second-line antiretroviral drugs and the salvage regimens in resource-limited settings. There is an urgent need for low-cost, low-tech viral load monitoring in resource-limited settings. Fixed-dose combination of antiretrovirals for first-line and second-line therapy will result in better effectiveness. There is a need for newer antiretroviral drugs in resource-limited settings.

First-line HIV treatment: evaluation of backbone choice and its budget impact

OBJECTIVE: The gradual increase of persons living with HIV, mainly due to the reduced mortality achieved with effective antiretroviral therapies, calls for increased rationality and awareness in health resources consumption also during the early illness phases. Aim of this work is the estimation of the budget impact related to the variation in backbone prescribing trends in naïve patients. METHODS: Target population is the number of patients starting antiretroviral therapy each year, according to the Italian HIV surveillance registry, excluding patients receiving non-authorized or non-recommended regimens. We modeled 3-year mortality and durability rates on a dynamic cohort, basing on international literature. A prevalent patients analysis has also been conducted, for which the model is fed by a closed cohort consisting of all the patients without experience of virologic failure. The aim of this collateral analysis is to estimate the difference in current annual expenditures if the past prescription trends for patients starting therapy would have led to the evaluated hypothetical scenarios. Current Italian market shares of triple regimens containing first-choice or alternative backbones (tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine) are compared to three hypothetical scenarios (base-case, minimum and maximum) in which increasing shares of patients eligible to abacavir/lamivudine start first line treatment with this backbone. Annual cost for each regimen comprises drugs acquisition under hospital pricing rules, monitoring exams and preventive tests, valued basing on regional reimbursement tariffs. RESULTS: According to current prescribing trends, in the next three years about 13,000 patients starting HIV therapy will receive tenofovir/emtricitabine (83% of the target population), and minor portions other regimens (9% abacavir/lamivudine, 8% zidovudine/lamivudine). Patients that would be eligible to abacavir/lamivudine are 1.5, 4.5 and 6 thousand more than those presently treated according to the three hypothetical scenarios, leading to a cumulative saving of 850 thousand, 2.4 million and 3.3 million euro, respectively. If in the past the same modification of first line prescription trend was adopted, the annual current cost saving would vary from 922 thousands to 7.3 million euro. Most of this amount is due to reduced acquisition costs and, secondarily, to lower monitoring needs. CONCLUSION: Where patient features don’t force the choice of the backbone, abacavir/lamivudine prescription may induce substantial savings, allowing the release of resources needed to manage more complicated/advanced cases.