Articles tagged as "15 million accessing treatment"

Patient-provider encounters are a key factor in ART usage in the United States

Retained in HIV care but not on antiretroviral treatment: a qualitative patient-provider dyadic study.

Christopoulos KA, Olender S, Lopez AM, Lekas HM, Jaiswal J, Mellman W, Geng E, Koester KA. PLoS Med. 2015 Aug 11;12(8):e1001863. doi: 10.1371/journal.pmed.1001863. eCollection 2015.

Background: Patients retained in HIV care but not on antiretroviral therapy (ART) represent an important part of the HIV care cascade in the United States. Even in an era of more tolerable and efficacious ART, decision making in regards to ART offer and uptake remains complex and calls for exploration of both patient and provider perspectives. We sought to understand reasons for lack of ART usage in patients meeting the Health Resources Services Administration definition of retention as well as what motivated HIV primary care appointment attendance in the absence of ART.

Methods and findings: We conducted a qualitative study consisting of 70 in-depth interviews with ART-naive and ART-experienced patients off ART and their primary care providers in two urban safety-net HIV clinics in San Francisco and New York. Twenty patients and their providers were interviewed separately at baseline, and 15 dyads were interviewed again after at least 3 mo and another clinic visit in order to understand any ART use in the interim. We applied dyadic analysis to our data. Nearly all patients were willing to consider ART, and 40% of the sample went on ART, citing education on newer antiretroviral drugs, acceptance of HIV diagnosis, social support, and increased confidence in their ability to adhere as facilitators. However, the strength of the provider recommendation of ART played an important role. Many patients had internalized messages from providers that their health was too good to warrant ART. In addition, providers, while demonstrating patient-centered care through sensitivity to patients experiencing psychosocial instability, frequently muted the offer of ART, at times unintentionally. In the absence of ART, lab monitoring, provider relationships, access to social services, opiate pain medications, and acute symptoms motivated care. The main limitations of this study were that treatment as prevention was not explored in depth and that participants were recruited from academic HIV clinics in the US, making the findings most generalizable to this setting.

Conclusions: Provider communication with regard to ART is a key focus for further exploration and intervention in order to increase ART uptake for those retained in HIV care.

Abstract  Full-text [free] access

Editor’s notes: This paper draws on qualitative data from two clinics in the United States of America.  It examines the barriers to ART uptake in this new era of ART from the perspectives of people who are retained in clinic care and not currently on ART, and their primary care providers. It further explores factors that have promoted peoples’ regular primary care attendance even in the absence of ART. One of the strengths of this paper is the dyadic approach to the data collection which enabled the authors to compare and contrast the narratives of both care users and providers. The findings of this paper are useful as we reflect on the 90-90-90, an ambitious treatment target recently adopted by UNAIDS to help end the AIDS epidemic.

Recent studies including HPTN 052 and the Strategic Timing of AntirRetroviral Treatment (START) studies have highlighted the individual and public health benefits of early initiation of antiretroviral therapy (ART), regardless of CD4 count. The 90-90-90 target is that by 2020, 90% of all people living with HIV will know their status, 90% of people diagnosed with HIV infection will receive sustained antiretroviral therapy and 90% of people receiving antiretroviral therapy, will have viral suppression.

The findings of this article offer important challenges to sub-Saharan Africa and other resource-poor settings for meeting the 90-90-90 target.  First, although the DART trial illustrated that first-line ART can be delivered safely without routine tests, in this study, many people remained engaged in care because of laboratory monitoring of their health status. Second, many of the people valued strong connections to their healthcare providers which were developed through patient-centred medical care.  This contrasts with treatment contexts such as those in sub-Saharan Africa where people may be less likely to see the same provider continuously or even at consecutive visits. Third, access to additional social and acute care services also motivated some participants to maintain primary care visit attendance. In resource poor contexts, such services are rarely available. Understanding how to retain people on ART in resource-poor settings where economic, social and contextual factors differ, will be an important objective for both individual and public health approaches to managing the epidemic.

Northern America
United States of America
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START trial illustrates benefit of ART start with CD4>500

Initiation of antiretroviral therapy in early asymptomatic HIV infection.

Lundgren J, Babiker A,  Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper D, Fätkenheuer G, Llibre J, Molina J, Munderi P, Schechter M, Wood R, Klingman K, Collins S, Lane H, Phillips A,  Neaton J. INSIGHT START Study Group. N Engl J Med. 2015 Jul 20. [Epub ahead of print]

Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.

Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.

Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12 759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.

Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.

Abstract  Full-text [free] access

Editor’s notes: Guidelines on when to start antiretroviral therapy (ART) are rapidly evolving. The major point of uncertainty, and disagreement between guidelines, has been whether the benefits to individuals of starting ART outweigh the risks for people with high CD4 counts, where the absolute risk of morbidity and mortality is relatively low.

The START study addressed this question among people with CD4 counts greater than 500 cells per µl. Study participants were recruited across the global regions, with the largest number from Europe (33%) followed by Latin America (25%) and Africa (21%). Some 55% were gay men and other men who have sex with men. Retention in the study was very good, and virologic outcomes among people who started ART were excellent (98% and 97% had virologic suppression by 12 months in the immediate versus deferred study arms). There was a 57% reduction in the hazard of the primary outcome, a composite of serious AIDS-associated events, serious non-AIDS associated events or death from any cause. The most common AIDS-associated events were tuberculosis (mostly seen in African participants), malignant lymphoma and Kaposi’s sarcoma. Among the serious non-AIDS events, cancers unrelated to AIDS were reduced by 50%, but interestingly there was no change in cardiovascular events. There was no increase in risk of serious adverse events. Interestingly the magnitude of risk reduction for the primary outcome was similar in high- and low-income countries.

These results will be very important as ART guidelines are reviewed and are likely to lead to recommendations for ART initiation, regardless of CD4 count in most settings. The authors note that, with a relatively low absolute risk of serious events, some people with high CD4 counts may opt to defer treatment, and this trial has produced very useful data to inform this discussion. Benefits from earlier ART initiation are dependent on earlier testing.  With an estimated 50% of people with HIV globally unaware of their status, the uptake of testing by asymptomatic people will need to be increased. In addition, retention in care will need to be optimised if the potential benefits of ART demonstrated by this study are to be realised.

HIV Treatment
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Single dose nevirapine for PMTCT does not jeopardise future NNRTI-based ART in children

Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.

Musoke P, Szubert AJ, Musiime V, Nathoo K, Nahirya-Ntege P, Mutasa K, Williams DE, Prendergast AJ, Spyer M, Walker AS, Gibb DM, and the ARROW Trial Team. AIDS. 2015 Jul 24. [Epub ahead of print]

Objectives: To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response.

Design: Observational analysis within the ARROW randomized trial.

Methods: sdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Viral load was assayed retrospectively over a median 4.1 years of follow-up. Multivariable logistic regression models were used to identify independent predictors of viral load below 80 copies/ml, 48 and 144 weeks after ART initiation (backwards elimination, exit P = 0.1).

Results: Median (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP-exposed children vs. 21 (14-27) months in 289 non-exposed children (36 vs. 20% <12 months). At week 48, 49 of 73 (67%) sdNVP-exposed and 154 of 272 (57%) non-exposed children had viral load below 80 copies/ml [adjusted odds ratio (aOR) 2.34 (1.26-4.34), P = 0.007]; 79 and 77% had viral load below 400 copies/ml. Suppression was significantly lower in males (P = 0.009), those with higher pre-ART viral load (P = 0.001), taking syrups (P = 0.05) and with lower self-reported adherence (P = 0.04). At week 144, 55 of 73 (75%) exposed and 188 of 272 (69%) non-exposed children had less than 80 copies/ml [aOR 1.75 (0.93-3.29), P = 0.08]. There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (P > 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144.

Conclusion: Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.

Abstract access 

Editor’s notes: Universal initiation of antiretroviral therapy (ART) is recommended for all children below the age of five years, regardless of immune or clinical status. World Health Organization recommends initiation with lopinavir/ritonavir-containing ART in children aged below three years. This was prompted by the P1060 trials which showed a poorer virologic response to nevirapine compared to lopinavir-containing regimens among infants exposed and unexposed, to single-dose nevirapine (sd NVP) as prophylaxis against mother-to-child HIV transmission. Previous studies had shown a poorer response to nevirapine-containing combination antiretroviral therapy (ART) subsequently initiated by mothers exposed to sd NVP.

However, lopinavir/ritonavir for young children is only available as a liquid formulation. This has limited availability, is highly unpalatable, has cold chain requirements and is bulky and conspicuous to transport. Where lopinavir-containing ART is not feasible, guidelines suggest non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens as an alternative. The NNRTI of choice is nevirapine, because dosing of efavirenz is problematic in young children. Understanding whether sd NVP is associated with substantially greater risks of virologic failure in children who start nevirapine containing regimens is therefore important.

This study compared the risk of virologic failure in young children (aged between six months and three years) initiating nevirapine-containing ART who had been exposed to single dose NVP, compared to people who had not. The study found no higher risk of virologic failure in people who had been exposed to sd NVP compared to people who had not, either at 48 or at 144 weeks after ART initiation. This remained true regardless of whether viral-load cut-off of 80, 400 or 1000 copies/ml was used to define virologic failure. Furthermore, there was no difference between children with and without sd NVP exposure in the percentage of clinically-significant NRTI or NNRTI resistance mutations.

As expected, a high pre-ART viral load was a strong predictor of poor virologic response. Importantly, receiving ART with syrup compared to tablets also predicted poor virologic response, and was equivalent to initiating ART with a 1 log10 higher viral load. This is a similar magnitude of difference in virologic response as that seen between lopinavir- versus nevirapine- containing regimens in the P1060 trials. As triple-drug nevirapine-based tablets are available for young children, this would imply that a tablet nevirapine-based regimen may have similar virologic response to a syrup lopinavir-based regimen in young children.

The study did not do a randomised comparison and sd NVP exposure was based on self-report. Also, a third of the participants took NNRTI for 36 weeks only, following which they were switched to triple NRTI regimens. However, the results were similar when the analyses were restricted to people who took NNRTI-based regimens throughout the study period.

This study should provide reassurance to healthcare providers in resource-limited settings that nevirapine-based ART is a good alternative to syrup lopinavir-based ART, even when there is prior exposure to sd NVP. 

Health care delivery
Africa
Uganda, Zimbabwe
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ART outcomes not improved by medication monitors plus text message reminders

A randomised controlled trial of real-time electronic adherence monitoring with text message dosing reminders in people starting first-line antiretroviral therapy.

Orrell C, Cohen K, Mauff K, Bangsberg DR, Maartens G, Wood RP. J Acquir Immune Defic Syndr. 2015 Jul 24. [Epub ahead of print]

Background: There are conflicting findings about whether mobile phone text message reminders impact on antiretroviral adherence. We hypothesized that text reminders sent when dosing was late would improve adherence and HIV viral suppression.

Methods: ART-naive participants, from a South African outpatient ART clinic, were randomised to standard of care (SoC, three pre-treatment education sessions), or intervention (SoC and automated text reminders if dosing >30 minutes late). Dosing time was recorded by real-time electronic adherence monitoring devices (EAMD), given to participants at ART start. CD4 cell count and HIV RNA were determined at baseline, 16 and 48 weeks. Primary outcome was cumulative adherence execution by EAMD. HIV-1 viral suppression (<40 copies/ml) at week 48 and count of treatment interruptions (TIs) >72 hours were secondary outcomes. Analysis was by intention to treat (missing=failure). Registration was with the Pan-African Clinical Trials Registry: PACTR201311000641402.

Results: 230 participants were randomly assigned to control (n=115) or intervention (n=115) arms. Median adherence was 82.1% (IQR 56.6-94.6%) in the intervention arm, compared to 80.4% (IQR 52.8-93.8%) for SoC (adjusted odds ratio (aOR) for adherence 1.08, 95%CI:0.77-1.52). Suppressed HIV RNA (<40 copies/ml) occurred in 80 (69.6%) of control and 75 (65.2%) of intervention; aOR for virological failure in intervention arm 0.77, 95%CI:0.42-1.40). In the intervention arm the count of TIs of >72hours was reduced (adjusted incident rate ratio 0.84, 95%CI:0.75-0.94).

Conclusion: Text message reminders linked to late doses detected by real-time adherence monitoring reduced the number of prolonged treatment interruptions, but did not significantly improve adherence or viral suppression.

Abstract access 

Editor’s notes: Maximising adherence to treatment is a key issue for management of chronic disease. In the case of antiretroviral therapy (ART), good adherence is essential not only to optimise treatment outcomes for the individual but also to minimise the emergence of drug-resistant disease. Electronic adherence monitoring devices (EAMD) have been used as a research tool but have been too expensive for routine use. However lower-cost devices are being developed with potential for wider use, and would be very valuable if they are shown to improve treatment outcomes.

In this small trial from Cape Town, South Africa, adults initiating ART were randomised either to receive an EAMD as a simple pillbox, recording box opening but without any reminder function, or an EAMD which sent a text message reminder if the box was not opened within 30 minutes of the scheduled dosing time. This time window for the reminder was selected by study participants, who were mostly taking ART as a single evening dose.

There was no difference in adherence by study arm or in virologic suppression. As might be expected, adherence based on self-reported three-day recall or pill count was higher (median 100% in both arms for both measures) compared to adherence measured by EAMD (82.1% in programme and 80.4% in the control arm, calculated as number of days the device was opened divided by the number of days in care). However in the programme arm there were fewer treatment interruptions exceeding 72 hours, relevant to the risk of developing resistance on a non-nucleoside reverse-transcriptase inhibitors (NNRTI)-based regimen. The authors point out that treatment adherence at this clinic is generally very good, attributed to strong adherence support provided by the clinic, which could have contributed to the negative result.

This study suggests that dose reminders alone are unlikely to improve adherence to ART, which is not surprising given the complexity of adherence behaviours. Further work needs to explore whether other activities based on EAMDs will perform better than text message reminders alone.

HIV Treatment
Africa
South Africa
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Switching to second-line ART – we need to do better

Monitoring and switching of first-line antiretroviral therapy in sub-Saharan Africa: collaborative analysis of adult treatment cohorts.

Haas AD, Keiser O, Balestre E, Brown S, Bissagnene E, Chimbetete C, Dabis F, Davies MA, Hoffmann CJ, Oyaro P, Parkes-Ratanshi R, Reynolds SJ, Sikazwe I, Wools-Kaloustian K, Zannou DM, Wandeler G, Egger M, for IeDea Southern Africa EA, West A. Lancet HIV. 2015 Jul 1;2(7):e271-e278.

Background: HIV-1 viral load testing is recommended to monitor antiretroviral therapy (ART) but is not universally available. The aim of our study was to assess monitoring of first-line ART and switching to second-line ART in sub-Saharan Africa.

Methods: We did a collaborative analysis of cohort studies from 16 countries in east Africa, southern Africa, and west Africa that participate in the international epidemiological database to evaluate AIDS (IeDEA). We included adults infected with HIV-1 who started combination ART between January, 2004, and January, 2013. We defined switching of ART as a change from a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen to one including a protease inhibitor, with adjustment of one or more nucleoside reverse-transcriptase inhibitors (NRTIs). Virological and immunological failures were defined according to WHO criteria. We calculated cumulative probabilities of switching and hazard ratios with 95% CIs comparing routine viral load monitoring, targeted viral load monitoring, CD4 monitoring, and clinical monitoring, adjusting for programme and individual characteristics.

Findings: Of 297 825 eligible patients, 10 352 (3%) switched to second-line ART during 782 412 person-years of follow-up. Compared with CD4 monitoring, hazard ratios for switching were 3·15 (95% CI 2·92–3·40) for routine viral load monitoring, 1·21 (1·13–1·30) for targeted viral load monitoring, and 0·49 (0·43–0·56) for clinical monitoring. Of 6450 patients with confirmed virological failure, 58·0% (95% CI 56·5–59·6) switched by 2 years, and of 15 892 patients with confirmed immunological failure, 19·3% (18·5–20·0) switched by 2 years. Of 10 352 patients who switched, evidence of treatment failure based on one CD4 count or viral load measurement ranged from 86 (32%) of 268 patients with clinical monitoring to 3754 (84%) of 4452 with targeted viral load monitoring. Median CD4 counts at switching were 215 cells per μL (IQR 117–335) with routine viral load monitoring, but were lower with other types of monitoring (range 114–133 cells per μL).

Interpretation: Overall, few patients switched to second-line ART and switching happened late in the absence of routine viral load monitoring. Switching was more common and happened earlier after initiation of ART with targeted or routine viral load testing.

Abstract access 

Editor’s notes: Routine viral load monitoring should allow the early identification of first-line antiretroviral therapy (ART) failure, allowing prompt switch to second-line ART. Prolongation of treatment with a failing regimen compromises future therapeutic options (through the accumulation of drug resistance mutations) and potentially leads to increased morbidity and mortality. Previous reports from Africa have suggested that surprisingly few people switch to second-line therapy, even in programmes with routine viral load monitoring. This raises concerns that there are challenges on the ground with identification and management of ART failure.

This is a comprehensive analysis bringing together data from a number of well-characterised cohorts in Africa. In this analysis, switching to second-line ART was rare (3% over an average of almost three years follow-up). In programmes with routine viral load monitoring, only half of the people with confirmed virologic failure on first-line ART (two viral loads >1000 copies/ml) were recorded as having been switched to second-line ART. Furthermore, half of the people that were switched to a second-line regimen did not have evidence of confirmed virologic failure, suggesting that some may have been switched too early without first attempting adherence programmes which may achieve re-suppression on first-line ART. Unsurprisingly, rates of switching were lower in programmes with CD4+ monitoring (with or without targeted viral load testing) or clinical monitoring alone. 

While guidelines and algorithms around identification and management of first-line ART failure are relatively clear and straightforward, translating this into action on the ground seems to be difficult. At least part of this is likely to be due to the lack of tools to reliably measure adherence and the consequent difficulty that frontline health care workers have in identifying people that truly require a switch to second-line ART. Moreover, most programmes still do not routinely monitor indicators relating to virologic suppression or treatment failure and so this might not be seen as a priority by health care workers and programme managers. There is a need for research to explore how best to maximise virologic suppression in resource-constrained settings, as well as studies to evaluate the impact of programmes such as point-of-care viral load testing.

Africa
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TAF: a new, safer version of tenofovir?

Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials.

Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, Pozniak A, Thompson M, Podzamczer D, Molina JM, Oka S, Koenig E, Trottier B, Andrade-Villanueva J, Crofoot G, Custodio JM, Plummer A, Zhong L, Cao H, Martin H, Callebaut C, Cheng AK, Fordyce MW, McCallister S, GS-US-292-0104/0111 Study Team. Lancet. 2015 Jun 27;385(9987):2606-15. doi: 10.1016/S0140-6736(15)60616-X. Epub 2015 Apr 15.

Background: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens.

Methods: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the US Food and Drug Administration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445.

Findings: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2.0%, 95% CI -0.7 to 4.7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0.08 vs 0.12 mg/dL; p<0.0001), significantly less proteinuria (median % change -3 vs 20; p<0.0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1.30 vs -2.86; p<0.0001) and hip (-0.66 vs -2.95; p<0.0001) at 48 weeks.

Interpretation: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile.

Abstract access 

Editor’s notes: Tenofovir alafenamide fumarate (TAF) is a new antiretroviral agent developed by Gilead Sciences and is closely related to tenofovir disoproxil fumarate (TDF).  TDF is widely used, highly potent, and safe in the majority of people but long-term use has been associated with small risks of decreased kidney function, chronic kidney disease, and decreased bone mineral density.  Both TAF and TDF are prodrugs of tenofovir but TAF achieves highly potent concentrations of tenofovir inside HIV-relevant immune cells with much lower plasma concentrations than TDF.  The lower plasma concentration of tenofovir associated with TAF is hypothesised to reduce the toxic effects with regards to kidney and bone health. TAF is also effective at the lower dose of 10-25 mg, compared with the standard TDF dose of 300mg per day.  This may translate into lower drug costs if the lower dose required means lower manufacturing costs.

The authors report the combined results of two phase III, non-inferiority studies comparing the safety and effectiveness of TAF with TDF, funded by Gilead Sciences. In both studies, TAF was co-formulated into one, once-a-day tablet with elvitegravir, cobicistat and emtricitabine. There was a high rate of virologic suppression with the TAF-containing regimen, which was non-inferior to the TDF regimen. Compared to TDF, TAF had significantly more favourable effects on renal and bone parameters, with smaller decreases in creatinine clearance and bone mineral density and smaller increases in proteinuria. The real-world clinical significance of these findings remains to be seen but TAF-containing regimens may offer meaningful safety and cost benefits over TDF regimens in the long-term. The favourable characteristics of TAF have also led to the development of a sustained-release subcutaneous TAF implant, which has recently been evaluated in dogs. A long-acting TAF implant could have translational potential as a candidate for HIV prophylaxis in vulnerable populations.

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Real-time ART adherence monitoring in rural Uganda

Duration of antiretroviral therapy adherence interruption is associated with risk of virologic rebound as determined by real-time adherence monitoring in rural Uganda.

Haberer JE, Musinguzi N, Boum Y, 2nd, Siedner MJ, Mocello AR, Hunt PW, Martin JN, Bangsberg DR. J Acquir Immune Defic Syndr. 2015 Jun 24. [Epub ahead of print]

Background: Antiretroviral therapy (ART) adherence interruptions have been associated with viral rebound; however, the true risk is unknown because HIV RNA has never been measured during ongoing interruptions.

Methods: The Uganda AIDS Rural Treatment Outcomes Study is an observational longitudinal cohort of adults initiating ART. We monitored adherence with device that wirelessly transmits records of device openings, and routinely assessed HIV RNA quarterly. When 48+ hour lapses between device openings were detected, we made unannounced visits to participants to investigate the cause and assess HIV RNA. Generalized estimating equation logistic regressions were used to assess factors associated with viral rebound.

Results: We followed 479 participants (median 25 months per participant). Most were female (72%), median age was 36 years, median pre-ART CD4 count was 198 cells/µL, median pre-ART HIV RNA level was 5.0 log10 copies/ml, and median duration of prior viral suppression was 13 months. A total of 587 adherence interruptions followed confirmed prior viral suppression, of which 13 (2%) had detectable viral rebound. Viral rebound was associated with duration of adherence interruption (OR 1.25 for each day beyond 48 hours, p=0.007) and 30-day adherence prior to the interruption (OR 0.73, p=0.02).

Discussion: This paper is the first demonstration of HIV RNA rebound during adherence interruptions objectively measured in real-time. Odds of viral rebound increased by 25% with each day beyond 48 hours. Real-time adherence monitoring was feasible in a sub-Saharan African setting. Further research should assess the potential for real-time adherence interventions to sustain adherence to affordable first-line regimens.

Abstract access 

Editor’s notes: As the number of people taking antiretroviral therapy grows, the challenge of supporting retention and adherence to treatment becomes greater. Measuring adherence to treatment is difficult, particularly in resource-constrained settings. It is often based on self-report of missed pills, which lacks sensitivity. This paper reports a study in which adherence was monitored using a battery-operated pill box which electronically monitors each time the box is opened. Box opening is “reported” by short message service (SMS) either immediately or whenever the cellular network is next available. In this study, if the box was not opened for more than 48 hours, an unannounced home visit was made to investigate the cause and take blood for HIV viral load measurement.

Adherence of less than 80%, as measured by the adherence monitoring device, was associated with detectable viral load at the next routine clinic visit. Longer treatment interruptions were associated with increasing risk of HIV viral load being detectable in blood taken at the home visit. These results, based on a very small number of individuals with detectable viral load, are not unexpected. However the methodology is interesting in that these medication monitors have the potential to provide health care providers with real-time alerts concerning individuals missing doses. Medication monitors have previously been too expensive to be used outside research studies. However, there is interest in developing monitors which could be mass-produced at low cost. Such monitors have the potential to assist health workers in identifying individuals with poor adherence much more rapidly than is currently possible, and allowing additional adherence support to be targeted. As such they could play an important role in improving treatment outcomes. 

Africa
Uganda
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Tenofovir-based regimens improve outcomes in HIV-HBV co-infection

Comparison of HBV-active HAART regimens in an HIV-HBV multinational cohort: outcomes through 144 weeks.

Thio CL, Smeaton L, Hollabaugh K, Saulynas M, Hwang H, Saravanan S, Kulkarni S, Hakim J, Nyirenda M, Iqbal HS, Lalloo UG, Campbell TB, Lockman S, Currier JS. AIDS. 2015 Jun 19;29(10):1173-82. doi: 10.1097/QAD.0000000000000686.

Objectives: To explore factors associated with short and long-term hepatitis B virus (HBV) DNA suppression in a multinational cohort of HIV-HBV co-infected patients receiving HBV-active antiretrovirals.

Methods: One hundred and fifteen HIV-HBV co-infected patients participating in one of the two global randomized clinical trials conducted by the Adult AIDS Clinical Trials Group of different antiretroviral regimens received either HBV monotherapy with either lamivudine or emtricitabine (N = 56), or HBV dual therapy with tenofovir disoproxil fumarate (TDF) + lamivudine or emtricitabine (N = 59). Associations of pretreatment characteristics with the primary (HBV DNA <200 IU/ml at 24 weeks) and longitudinal outcomes through 144 weeks were explored using logistic regression. HBV drug-resistance mutations were determined by pol sequencing in those with viral rebound.

Results: The proportion with HBV DNA below 200 IU/ml was 60% (95% confidence interval 50-69%) at 24 weeks and 79% (95% confidence interval 69-88%) at 144 weeks. Pretreatment factors associated with the primary outcome were HBV DNA, CD4 T-cell count, and aspartate aminotransferase, but only pretreatment HBV DNA remained associated with long-term suppression (P < 0.0001). HBV therapy group was not significantly associated with the primary outcome at 24 weeks; however, longitudinally, a greater proportion in the dual-therapy group achieved HBV DNA below 200 IU/ml (P = 0.007). A higher proportion of hepatitis B e antigen-negative patients (n = 57) achieved HBV DNA below 200 IU/ml at any point, regardless of the therapy group. All 12 patients with emergence of lamivudine-resistant mutants were in the monotherapy group.

Conclusions: TDF-based dual HBV-active antiretroviral therapy is preferred to treat HIV-HBV co-infected patients. In resource-limited settings in which TDF may not be universally available, lamivudine or emtricitabine HBV monotherapy is a reasonable option in patients with low HBV replication.

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Editor’s notes: Hepatitis B virus infection remains a leading cause of preventable morbidity and mortality globally, through cirrhosis and liver cancer. In settings with a high prevalence of HIV-HBV coinfection, there is an opportunity to optimise clinical management within the public health approach to antiretroviral therapy. This study adds to the evidence base suggesting that antiretroviral regimens containing lamivudine/emtricitabine and tenofovir are associated with better virologic outcomes than regimens without tenofovir for people co-infected with HIV and HBV. In this study, a post hoc analysis of two multicentre randomised controlled trials, regimens with two HBV-active agents provided more durable virologic suppression and limited the emergence of lamivudine-resistant HBV strains. Although recommendations about the treatment of HIV-HBV coinfection are incorporated into WHO antiretroviral guidelines, testing for HBV infection within antiretroviral programmes is still uncommon and tenofovir is not universally employed in standard first-line antiretroviral regimens. With an increasing number of people switching to second-line antiretroviral regimens, there is the additional challenge of identifying HBV infection in order to maintain HBV-active agents within the second-line regimen. There is now a need for better evidence around how to operationalise these recommendations within national antiretroviral programmes.        

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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Care buddies improve daily life but have no effect on retention and HIV progression among pre-ART persons

Impact of patient-selected care buddies on adherence to HIV care, disease progression and conduct of daily life among pre-antiretroviral HIV-infected patients in Rakai, Uganda: a randomized controlled trial.

Nakigozi G, Makumbi FE, Bwanika JB, Atuyambe L, Reynolds SJ, Kigozi G, Nalugoda F, Chang LW, Kiggundu V, Serwadda D, Wawer MJ, Gray RH, Kamya MR. J Acquir Immune Defic Syndr. 2015 Jun 1. [Epub ahead of print]

Background: Data are limited on effects of household or community support persons ("care buddies") on enrolment into and adherence to pre-antiretroviral HIV care. We assessed the impact of care buddies on adherence to HIV clinic appointments, HIV progression and conduct of daily life among pre-ART HIV-infected individuals in Rakai, Uganda.

Methods: 1209 HIV infected pre-ART patients aged ≥15 years were randomized to standard of care (SOC) (n = 604) or patient-selected care buddy (PSCB) (n= 605) and followed at 6 and 12 months. Outcomes were adherence to clinic visits; HIV disease progression and self-reported conduct of daily life. Incidence and prevalence rate ratios and 95% confidence intervals (95%CI) were used to assess outcomes in the intent-to-treat and as-treated analyses.

Results: Baseline characteristics were comparable. In the ITT analysis both arms were comparable with respect to adherence to CD4 monitoring visits (adjPRR 0.99, 95%CI 0.93-1.04, p=0.625), and ART eligibility (adjPRR=1.00, 95%CI 0.77-1.31, p=0.946). Good conduct of daily life was significantly higher in the PSCB than the SOC arm (adjPRR 1.08, 95%CI 1.03-1.13, p=0.001). More men (61%) compared to women (30%) selected spouses/partners as buddies (p<0.0001.) 22% of PSCB arm participants discontinued use of buddies.

Conclusion: In pre-ART persons, having care buddies improved the conduct of daily life of the HIV infected patients but had no effect on HIV disease progression and only limited effect on clinic appointment adherence.

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Editor’s notes: To maximise the impact of antiretroviral therapy (ART), people living with HIV should be diagnosed early, enrolled and retained in pre-ART care, initiated on ART promptly, and retained in ART care. Long-term adherence to achieve and maintain viral load suppression is the last step in the continuum of HIV care. Engagement along the complete HIV treatment cascade will determine the long-term success of the global response to HIV.

Like this one, the next article reports on the results of randomized trials evaluating programmes to improve enrolment and retention into pre-ART care .

The first randomized trial assessed the impact of trained patient-selected care buddies among people living with HIV not yet on ART. The outcomes were adherence to HIV clinic appointments, HIV progression, and conduct of daily life (participants’ perception of their general health, pain and ability to perform activities of daily living) over a 12-month period. The authors found that having care buddies improved the conduct of life but had no effect on retention in care or HIV disease progression. Their findings indicate that it is not necessary for HIV programmes to delay HIV care while waiting for a patient to identify a care buddy. They also found that 22% of the participants discontinued the use of a care buddy, possibly due to buddy exhaustion after an extended period of time, while 10% of the participants in the control arm utilized the services of trained buddies. This will have diluted the difference between the arms and contributed to the lack of effect seen in the intention to treat analysis.

Interestingly the authors also report that women were less likely to select their spouse as a care buddy, some 30% versus 61% among men, likely because disclosure of HIV often carries adverse consequences for women, including domestic violence, abandonment and divorce.

Africa
Uganda
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Home visits by community workers doubled retention in pre-ARV care

The effect of community support agents on retention of people living with HIV in pre-antiretroviral care - A randomized controlled trial in Eastern Uganda.

Lubega M, Tumwesigye MN, Kadobera D, Marrone G, Wabwire-Mangen F, Peterson S, Reynolds SJ, Ekstrom AM. J Acquir Immune Defic Syndr. 2015 Jun 12. [Epub ahead of print]

Introduction: Over 50% of people living with HIV (PLHIV) in sub-Saharan Africa are lost to follow-up between diagnosis and initiation of antiretroviral treatment during pre-ARV care. The effect of providing home counselling visits by community support agents on 2-year retention in pre-ARV care was evaluated through a randomized controlled trial in eastern Uganda.

Methods: 400 newly screened HIV-positive persons were randomly assigned to receive post test counselling alone (routine arm), or post test counselling and monthly home counselling visits by community support agents to encourage them go back for routine pre-ARV care (intervention arm). The outcome measure was the proportion of new PLHIV in either arm who attended their scheduled pre-ARV care visits for at least six out of the anticipated 8 visits in the first 24 months after HIV diagnosis. The difference between the two study arms was assessed using chi-square and T-tests. Mantel-Haenszel Risk Ratios (MHRR) and multivariate logistic models were used to assess the adjusted effect of the intervention on the outcome.

Findings: In all models generated, participants receiving monthly home counselling visits were 2.5 times more likely to be retained in pre-ARV compared to those in standard care over a period of 24 months (ARR 2.5, 95% CI 2.0-3.0).

Interpretation: Monthly follow-up home visits by community workers more than doubled the retention of PLHIV in pre-ARV care in rural Uganda and can be applicable in similar resource-poor settings.

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Editor’s notes: In this second randomized trial, the impact of repeated home counselling visits by community support agents (CSAs) on retention among patients not yet on ART was assessed.

In contrast to the previous article, the authors found a large effect on retention. Some 82% were retained in the programme arm at two years after a positive HIV test compared to 34% in the control arm (standard of care: clinic-based post-test counselling alone). The authors suggest that the improved health seeking behaviour and retention in care, could be explained by the CSAs acting as primary care linkages as they encouraged participants to go to the nearest health centre for HIV care. They also suggest that the excellent two year retention rates can be explained by the persistent monthly visits by the CSAs to the people living with HIV. The linkage function of the CSAs, which was not a function of the care buddies described in the first article, might further explain the different findings on retention.

The authors also report that clients in the programme arm were twice as likely to disclose their HIV status compared to clients in the control arm.

They conclude that community programmes that encourage status acceptance and disclosure should be further reinforced. 

Africa
Uganda
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