Articles tagged as "United States of America"

Changing norms: lessons from HIV advocacy for NCDs prevention

Ability of HIV advocacy to modify behavioral norms and treatment impact: a systematic review.

Sunguya BF, Munisamy M, Pongpanich S, Yasuoka J, Jimba M. Am J Public Health. 2016 Aug;106(8):e1-e8. Epub 2016 Jun 16.

Background: HIV advocacy programs are partly responsible for the global community's success in reducing the burden of HIV. The rising wave of the global burden of noncommunicable diseases (NCDs) has prompted the World Health Organization to espouse NCD advocacy efforts as a possible preventive strategy. HIV and NCDs share some similarities in their chronicity and risky behaviors, which are their associated etiology. Therefore, pooled evidence on the effectiveness of HIV advocacy programs and ideas shared could be replicated and applied during the conceptualization of NCD advocacy programs. Such evidence, however, has not been systematically reviewed to address the effectiveness of HIV advocacy programs, particularly programs that aimed at changing public behaviors deemed as risk factors.

Objectives: To determine the effectiveness of HIV advocacy programs and draw lessons from those that are effective to strengthen future noncommunicable disease advocacy programs.

Search methods: We searched for evidence regarding the effectiveness of HIV advocacy programs in medical databases: PubMed, The Cumulative Index to Nursing and Allied Health Literature Plus, Educational Resources and Information Center, and Web of Science, with articles dated from 1994 to 2014.

Search criteria. The review protocol was registered before this review. The inclusion criteria were studies on advocacy programs or interventions. We selected studies with the following designs: randomized controlled design studies, pre-post intervention studies, cohorts and other longitudinal studies, quasi-experimental design studies, and cross-sectional studies that reported changes in outcome variables of interest following advocacy programs. We constructed Boolean search terms and used them in PubMed as well as other databases, in line with a population, intervention, comparator, and outcome question. The flow of evidence search and reporting followed the standard Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Data collection and analysis: We selected 2 outcome variables (i.e., changing social norms and a change in impact) out of 6 key outcomes of advocacy interventions. We assessed the risk of bias for all selected studies by using the Cochrane risk-of-bias tool for randomized studies and using the Risk of Bias for Nonrandomized Observational Studies for observational studies. We did not grade the collective quality of evidence because of differences between the studies, with regard to methods, study designs, and context. Moreover, we could not carry out meta-analyses because of heterogeneity and the diverse study designs; thus, we used a narrative synthesis to report the findings.

Main results: A total of 25 studies were eligible, of the 1463 studies retrieved from selected databases. Twenty-two of the studies indicated a shift in social norms as a result of HIV advocacy programs, and 3 indicated a change in impact. We drew 6 lessons from these programs that may be useful for noncommunicable disease advocacy: (1) involving at-risk populations in advocacy programs, (2) working with laypersons and community members, (3) working with peer advocates and activists, (4) targeting specific age groups and asking support from celebrities, (5) targeting several, but specific, risk factors, and (6) using an evidence-based approach through formative research.

Author conclusions: HIV advocacy programs have been effective in shifting social norms and facilitating a change in impact.

Public health implications: The lessons learned from these effective programs could be used to improve the design and implementation of future noncommunicable disease advocacy programs.

Abstract access

Editor’s notes: This article presents the results of a systematic review to answer a question about the effectiveness of HIV advocacy in changing social norms and changing impact among key populations. The review was conducted to learn from effective HIV advocacy and apply similar strategies for the prevention and reduction of the global burden of non-communicable diseases. The review included quantitative research only. After searching 3320 articles, 25 articles met the inclusion criteria. The HIV advocacy activities reviewed ranged from local and mass campaigns using a variety of media, to social marketing, celebrities, drama, promotional activities and counselling. Changes in social norms were assessed using six specific variables, for example testing behaviour change or HIV-associated stigma. Changes in impact were analysed in two aspects, changes in HIV transmission and in adherence to antiretroviral therapy. The review has found significant evidence of the effect of HIV advocacy on the outcomes of interest. The authors highlight lessons from HIV advocacy that might be useful for future non-communicable diseases advocacy. These included the vital role of peer-educator and of lay members of the community and the involvement of key populations in programmes that focus on them.  In addition, there is a need to tailor programmes to specific (rather than multiple) risks using local and salient evidence. 

Africa, Northern America, Oceania
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Taking account of the human factor when introducing new technology – a cautionary tale

Unintended adverse consequences of electronic health record introduction to a mature universal HIV screening program.

Medford-Davis LN, Yang K, Pasalar S, Pillow MT, Miertschin NP, Peacock WF, Giordano TP, Hoxhaj S. AIDS Care. 2016 May;28(5):566-73. doi: 10.1080/09540121.2015.1127319. Epub 2016 Jan 5.

Early HIV detection and treatment decreases morbidity and mortality and reduces high-risk behaviors. Many Emergency Departments (EDs) have HIV screening programs as recommended by the Centers for Disease Control and Prevention. Recent federal legislation includes incentives for electronic health record (EHR) adoption. Our objective was to analyze the impact of conversion to EHR on a mature ED-based HIV screening program. A retrospective pre- and post-EHR implementation cohort study was conducted in a large urban, academic ED. Medical records were reviewed for HIV screening rates from August 2008 through October 2013. On 1 November 2010, a comprehensive EHR system was implemented throughout the hospital. Before EHR implementation, labs were requested by providers by paper orders with HIV-1/2 automatically pre-selected on every form. This universal ordering protocol was not duplicated in the new EHR; rather it required a provider to manually enter the order. Using a chi-squared test, we compared HIV testing in the 6 months before and after EHR implementation; 55 054 patients presented before, and 50 576 after EHR implementation. Age, sex, race, acuity of presenting condition, and HIV seropositivity rates were similar pre- and post-EHR, and there were no major patient or provider changes during this period. Average HIV testing rate was 37.7% of all ED patients pre-, and 22.3% post-EHR, a 41% decline (p < 0.0001), leading to 167 missed new diagnoses after EHR. The rate of HIV screening in the ED decreased after EHR implementation, and could have been improved with more thoughtful inclusion of existing human processes in its design.

Abstract access

Editor’s notes: The introduction of Electronic Health Records is beneficial for sharing patient information between health care providers in large health care settings. However, as the authors of this paper illustrate with this thoughtful case study, the introduction of electronic health records in some settings may worsen rather than improve care. In this case, the electronic health record system which was introduced did not faithfully mimic the manual system it replaced. HIV-screening which had previously been an ‘opt out’ option for laboratory testing, became an ‘opt-in’ option in the new system.  As a result, testing rates went down. Interestingly, a similar electronic system was introduced in another hospital nearby. The effect on testing rates was noticed there and a manual workaround put in place. The nursing director in that institution ‘was a very strong personal advocate and champion for the HIV screening programme there’.  The authors point to the importance of testing new systems carefully and checking for unintended consequences on patient care.

Northern America
United States of America
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Minimal evidence for serious adverse events resulting from in utero ARV exposure

The PHACS SMARTT Study: assessment of the safety of in utero exposure to antiretroviral drugs.

Van Dyke RB, Chadwick EG, Hazra R, Williams PL, Seage GR, 3rd. Front Immunol. 2016 May 23;7:199. doi: 10.3389/fimmu.2016.00199. eCollection 2016.

The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.

Abstract  Full-text [free] access 

Editor’s notes: The SMARTT study set out to determine the safety of in utero exposure to antiretroviral (ARV) therapy using a trigger-based surveillance design to identify adverse events in a cohort of HIV-positive mothers and their HIV-exposed but HIV-negative children in the United States of America and Puerto Rico. A ‘trigger’ was set off if participants met a predefined clinical or laboratory threshold, with additional specified evaluations to determine if they met a predefined adverse event “case” definition.  After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain, such as growth and development or language etc.) with exposure to combination ARVs or any ARV class. No single ARV prophylaxis was associated with an increased risk of overall case status on adjusted analysis. However, several ARVs had significant associations in unadjusted analysis, namely between (1) maternal PI-based ARV prophylaxis during pregnancy and premature delivery and low birth weight; and (2) exposure to atazanavir and a twofold-higher risk of congenital anomalies. Overall the results from this study are reassuring, but some of the findings warrant further evaluation.

Latin America, Northern America
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Partner’s knowledge of HIV suppression among male couples in San Francisco

Relationship dynamics and partner beliefs about viral suppression: a longitudinal study of male couples living with HIV/AIDS (the duo project).

Conroy AA, Gamarel KE, Neilands TB, Dilworth SE, Darbes LA, Johnson MO. AIDS Behav. 2016 May 5. [Epub ahead of print]

Accurate beliefs about partners' viral suppression are important for HIV prevention and care. We fit multilevel mixed effects logistic regression models to examine associations between partners' viral suppression beliefs and objective HIV RNA viral load tests, and whether relationship dynamics were associated with accurate viral suppression beliefs over time. Male couples (N = 266 couples) with at least one HIV-positive partner on antiretroviral therapy completed five assessments over 2 years. Half of the 407 HIV-positive partners were virally suppressed. Of the 40% who had inaccurate viral load beliefs, 80% assumed their partner was suppressed. The odds of having accurate viral load beliefs decreased over time (OR = 0.83; p = 0.042). Within-couple differences in dyadic adjustment (OR = 0.66; p < 0.01) and commitment (OR = 0.82; p = 0.022) were negatively associated with accurate viral load beliefs. Beliefs about a partner's viral load may factor into sexual decision-making and social support. Couple-based approaches are warranted to improve knowledge of partners' viral load.

Abstract access

Editor’s notes: This study with male couples in San Francisco examined how accurate a partner’s knowledge about their partner’s viral load status was, and if this changes over time. The study was the first of its kind. The research team enrolled 266 male couples where at least one of the couple was HIV-positive and on ART for >30 days. Most couples (72%) were seroconcordant (both HIV-positive) and 28% were serodiscordant. Participants were mostly white, middle-aged men with low-income levels. Eighty percent were living with their partner. The couples had been together on average 6.6 years. Thus, this sample may differ substantially from other studies with gay men and other men who have sex with men. Approximately 50% of men living with HIV on ART were virally suppressed at each of three visits. However, between 24% (visit one) and 40% (visit three) of men had inaccurate knowledge about their partner’s viral suppression, with most of these people wrongly believing their partner’s viral load to be suppressed when it was not. Surprisingly, these results were similar among serodiscordant and seroconcordant couples. Results did not differ significantly according to most relationship characteristics (relationship satisfaction; commitment; intimacy; equality; constructive communication).

The results are interesting because inaccuracy in partner’s beliefs about viral load suppression may translate into poor decision making around the safety of condomless anal intercourse. In addition, having accurate knowledge of partner viral suppression is important for the provision of social support associate with HIV care and treatment. Qualitative studies are necessary to understand why many men in this study had an inaccurate knowledge about their partner’s viral suppression. And why this inaccuracy increased over time. Understanding these issues and how they translate to other populations will be useful for developing programmes among male couples to reduce HIV transmission and increase partner’s social support associated with HIV care and treatment. 

Northern America
United States of America
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Oral PrEP reduces risk of HIV and does not result in riskier sex

Effectiveness and safety of oral HIV pre-exposure prophylaxis (PrEP) for all populations: A systematic review and meta-analysis.

Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O'Reilly K R, Koechlin FM, Rodolph M, Hodges-Mameletzis I, Grant RM. AIDS. 2016 May 5. [Epub ahead of print]

Objective: Pre-exposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate (TDF) as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes.

Design: Rigorous systematic review and meta-analysis.

Methods: A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis.

Results: Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared to placebo. Trials with PrEP use >70% demonstrated the highest PrEP effectiveness (RR = 0.30, 95% CI: 0.21-0.45, p < 0.001) compared to placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness.

Conclusion: PrEP is protective against HIV infection across populations, presents few significant safety risks, and no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV-risk.

Abstract access

Editor’s notes: This systematic review is the first to aggregate data from across oral pre-exposure prophylaxis (PrEP) studies, including randomized control trials and observational studies, to present clear evidence on the effectiveness of oral PrEP use. The findings confirm that oral PrEP significantly reduces the risk of acquiring HIV if taken consistently and correctly across populations, countries, and most age groups. Differences in efficacy directly correlate with adherence, which accounts for the lower efficacy seen in some subgroups. Perhaps two of the most compelling analyses presented in this paper relate to resistance and behavioural disinhibition. The risk of resistance was shown to be quite low, and study participants exhibiting resistant HIV either enrolled in the studies during an acute infection stage or acquired resistant strains during the course of the research. Regarding behavioural disinhibition, indicators measured such as rates of sexually transmitted infections revealed that PrEP use in the efficacy trials was not associated with behavioural disinhibition and in some studies, resulted in even safer sexual behaviour than what was reported at baseline. Recently completed demonstration projects have reported increased rates of STIs among gay men and other men who have sex with men. However, in the open-label extensions included in this review, where counselling was more intensive, safer sex practices were maintained, thus suggesting that counselling can be effective in preventing behavioural disinhibition. 

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What works to link people living with HIV to care - a review

Facilitators and barriers in HIV linkage to care interventions: a qualitative evidence review.

Tso LS, Best J, Beanland R, Doherty M, Lackey M, Ma Q, Hall BJ, Yang B, Tucker JD. AIDS. 2016 Apr 6. [Epub ahead of print]

Objective: To synthesize qualitative evidence on linkage to care interventions for people living with HIV.

Design: Systematic literature review.

Methods: We searched nineteen databases for studies reporting qualitative evidence on linkage interventions. Data extraction and thematic analysis were used to synthesize findings. Quality was assessed using the CASP tool and certainty of evidence was evaluated using the CERQual approach.

Results: Twenty-five studies from eleven countries focused on adults (24 studies), adolescents (8 studies), and pregnant women (4 Facilitators included community-level factors (i.e. task-shifting, mobile outreach, integrated HIV and primary services, supportive cessation programs for substance users, active referrals, and dedicated case management teams) and individual-level factors (encouragement of peers/family and positive interactions with healthcare providers in transitioning into care). One key barrier for people living with HIV was perceived inability of providers to ensure confidentiality as part of linkage to care interventions. Providers reported difficulties navigating procedures across disparate facilities and having limited resources for linkage to care interventions.

Conclusions: Our findings extend the literature by highlighting the importance of task-shifting, mobile outreach, and integrated HIV and primary services. Both community and individual level factors may increase the feasibility and acceptability of HIV linkage to care interventions. These findings may inform policies to increase the reach of HIV services available in communities.

Abstract access  

Editor’s notes: As the authors of this paper observe, most evaluations of linkage to care programmes have focused on quantitative assessment. This useful paper provides a thorough overview of the findings from 25 studies which used qualitative methods for assessment. Linkage-to- care programmes feasible in different country settings were identified in this review.  The authors also highlight gaps, most notably a lack of information on linkage-to-care programmes for men. They also note the need for longitudinal assessments that look at changes over time.

This paper is a useful synthesis of findings. But it is also an excellent example of how to carry out a systematic review of qualitative research. The description of the qualitative meta-synthesis the authors performed adds additional value to this paper. 

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What works to link people living with HIV to care - a review

Facilitators and barriers in HIV linkage to care interventions: a qualitative evidence review.

Tso LS, Best J, Beanland R, Doherty M, Lackey M, Ma Q, Hall BJ, Yang B, Tucker JD. AIDS. 2016 Apr 6. [Epub ahead of print]

Objective: To synthesize qualitative evidence on linkage to care interventions for people living with HIV.

Design: Systematic literature review.

Methods: We searched nineteen databases for studies reporting qualitative evidence on linkage interventions. Data extraction and thematic analysis were used to synthesize findings. Quality was assessed using the CASP tool and certainty of evidence was evaluated using the CERQual approach.

Results: Twenty-five studies from eleven countries focused on adults (24 studies), adolescents (8 studies), and pregnant women (4 Facilitators included community-level factors (i.e. task-shifting, mobile outreach, integrated HIV and primary services, supportive cessation programs for substance users, active referrals, and dedicated case management teams) and individual-level factors (encouragement of peers/family and positive interactions with healthcare providers in transitioning into care). One key barrier for people living with HIV was perceived inability of providers to ensure confidentiality as part of linkage to care interventions. Providers reported difficulties navigating procedures across disparate facilities and having limited resources for linkage to care interventions.

Conclusions: Our findings extend the literature by highlighting the importance of task-shifting, mobile outreach, and integrated HIV and primary services. Both community and individual level factors may increase the feasibility and acceptability of HIV linkage to care interventions. These findings may inform policies to increase the reach of HIV services available in communities.

Abstract access  

Editor’s notes: As the authors of this paper observe, most evaluations of linkage to care programmes have focused on quantitative assessment. This useful paper provides a thorough overview of the findings from 25 studies which used qualitative methods for assessment. Linkage-to- care programmes feasible in different country settings were identified in this review.  The authors also highlight gaps, most notably a lack of information on linkage-to-care programmes for men. They also note the need for longitudinal assessments that look at changes over time.

This paper is a useful synthesis of findings. But it is also an excellent example of how to carry out a systematic review of qualitative research. The description of the qualitative meta-synthesis the authors performed adds additional value to this paper. 

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Shorter treatment for latent TB infection?

Three months of weekly rifapentine plus isoniazid for treatment of M. tuberculosis infection in HIV co-infected persons. 

Sterling TR, Scott NA, Miro JM, Calvet G, La Rosa A, Infante R, Chen MP, Benator DA, Gordin F, Benson CA, Chaisson RE, Villarino ME, Tuberculosis Trials Consortium, the AIDS Clinical Trials Group for the PREVENT TB Trial (TBTC Study 26 ACTG 5259). AIDS. 2016 Mar 17. [Epub ahead of print]

Objective: Compare the effectiveness, tolerability, and safety of three months of weekly rifapentine plus isoniazid under direct observation (3HP) vs. 9 months of daily isoniazid (9H) in HIV-infected persons.

Design: prospective, randomized, open-label non-inferiority trial.

Setting: U.S., Brazil, Spain, Peru, Canada, and Hong Kong.

Participants: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases.

Intervention: 3HP vs. 9H.

Main outcome measures: The effectiveness endpoint was tuberculosis; the non-inferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation due to adverse drug reaction.

Results: Median baseline CD4+ counts were 495 (IQR: 389-675) and 538 (IQR: 418-729) cells/mm3 in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention to treat analysis, there were two tuberculosis cases among 206 persons (517 person-years (p-y) of follow-up) in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01% vs. 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval (CI) of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation due to an adverse drug reaction was similar (3% vs. 4%; P = 0.79) in 3HP and 9H, respectively.

Conclusions: Among HIV-infected persons with median CD4+ count of approximately 500 cells/mm3, 3HP was as effective and safe for treatment of latent M. tuberculosis infection as 9H, and better tolerated.

Abstract access 

Editor’s notes: People with HIV are at higher risk of reactivation of latent tuberculosis (TB). The standard treatment for latent TB, with six to nine months of daily isoniazid, is effective, but treatment completion rates are typically low, and implementation has been poor. Shorter, effective regimens to treat latent TB are therefore necessary, and rifapentine and isoniazid, given weekly for 12 weeks, is one such candidate regimen. The analysis reported in this paper is a sub-study of a larger trial which was reported in 2011 (Sterling et al, NEJM 2011;365:2155). The main trial was open to people regardless of HIV status, but few HIV-positive people were enrolled. Trial enrolment was therefore continued for HIV-positive people, and this paper reports outcomes among this group.

Although the number of tuberculosis events was very small in this sub-study (two versus six people developed tuberculosis in the rifapentine-isoniazid versus isoniazid only arms), the rifapentine-isoniazid regimen, given directly-observed, was non-inferior to self-administered isoniazid, similar to the results of the main trial. Treatment completion was substantially better with the rifapentine-isoniazid regimen, as expected for a shorter regimen given under direct observation. The rifapentine-isoniazid regimen was equally well-tolerated to the isoniazid-only regimen.

This study provides evidence that rifapentine-isoniazid has potential as an alternative to isoniazid for the treatment of latent tuberculosis among HIV-positive people. Several questions remain. Weekly directly-observed therapy could be difficult to implement in resource-limited settings, especially if people are required to travel to health centres to receive their weekly dose, and the effectiveness of this regimen is uncertain when self-administered. The weekly dose represents a substantial pill burden unless combination tablets are available, and there are potential drug interactions between rifapentine and some antiretroviral agents. Further research is necessary to establish whether, in settings where the risk of tuberculosis reinfection is high, a single 12-week course of rifapentine-isoniazid has a long-lasting effect.

Comorbidity, HIV Treatment
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Tenofovir resistance – need for caution but not panic

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.

TenoRes Study Group. Lancet Infect Dis. 2016 Jan 28. pii: S1473-3099(15)00536-8. doi: 10.1016/S1473-3099(15)00536-8. [Epub ahead of print]

Background: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.

Methods: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.

Findings: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per µL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]).

Interpretation: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial.

Abstract  Full-text [free] access 

Editor’s notes: Global surveillance for tenofovir (TDF) resistance is important at a time of expanding use of TDF-containing regimens for treatment and prevention. This collaborative analysis used data collated from several small studies in different settings. Overall, around one in three people who had failed on TDF-containing treatment had evidence of TDF resistance, although this frequency varied between 20% in Europe to almost 60% in Africa. Mutations associated with NNRTIs and lamivudine/emtricitabine resistance were more common overall and were present in most people with TDF resistance.

The regional variation probably reflects differences in clinical practice and study inclusion criteria. All European studies involved cohorts with frequent viral load monitoring, whereas half of the African cohorts had no routine viral load monitoring. All European studies included people with virologic failure but with low-level viraemia (viral load <1000 copies/ml) whereas almost all African studies included only people with viral load >1000 copies/ml.

While these data provide useful estimates of the frequency of drug resistance mutations in people with virologic failure on first-line ART, there should be caution about extrapolating beyond this. Reports from cohort studies with an accurate denominator of all people starting TDF-containing first-line ART would be useful to give more reliable estimates of overall incidence of acquired TDF resistance. Moreover, there remains a need for representative population-based surveillance for acquired and transmitted drug resistance. So far, global surveillance has detected limited evidence of transmitted TDF-associated mutations, but this needs to be monitored closely, especially in high incidence settings.

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Abacavir: a safe first line drug for children

Adverse events associated with abacavir use in HIV-infected children and adolescents: a systematic review and meta-analysis.

Jesson J, Dahourou DL, Renaud F, Penazzato M, Leroy V. Lancet HIV. 2016 Feb;3(2):e64-75. doi: 10.1016/S2352-3018(15)00225-8. Epub 2015 Dec 7.

Background: Concerns exist about the toxicity of drugs used in the implementation of large-scale antiretroviral programmes, and documentation of antiretroviral toxicity is essential. We did a systematic review and meta-analysis of adverse events among children and adolescents receiving regimens that contain abacavir, a widely used antiretroviral drug.

Methods: We searched bibliographic databases and abstracts from relevant conferences from Jan 1, 2000, to March 1, 2015. All experimental and observational studies of HIV-infected patients aged 0-18 years who used abacavir, were eligible. Incidence of adverse outcomes in patients taking abacavir (number of new events in a period divided by population at risk at the beginning of the study) and relative risks (RR) compared with non-abacavir regimens were pooled with random effects models.

Findings: Of 337 records and 21 conference abstracts identified, nine studies (eight full-text articles and one abstract) collected information about 2546 children, of whom 1769 (69%) were on abacavir regimens. Among children and adolescents taking abacavir, hypersensitivity reactions (eight studies) had a pooled incidence of 2.2% (95% CI 0.4-5.2); treatment switching or discontinuation (seven studies) pooled incidence was 10.9% (2.1-24.3); of grade 3-4 adverse events (six studies) pooled incidence was 9.9% (2.4-20.9); and adverse events other than hypersensitivity reaction (six studies) pooled incidence was 21.5% (2.8-48.4). Between-study inconsistency was significant for all outcomes (p<0.0001 for all inconsistencies). Incidence of death (four studies) was 3.3% (95% CI 1.5-5.6). In the three randomised clinical trials with comparative data, no increased risk of hypersensitivity reaction (pooled RR 1.08; 95% CI 0.19-6.15), grade 3 or 4 events (0.79 [0.44-1.42]), or death (1.72 [0.77-3.82]) was noted for abacavir relative to non-abacavir regimens. None of the reported deaths were related to abacavir.

Interpretation: Abacavir-related toxicity occurs early after ART initiation and is manageable. Abacavir can be safely used for first-line or second-line antiretroviral regimens in children and adolescents, especially in sub-Saharan Africa where HLA B5701 genotype is rare.

Abstract access

Editor’s notes: Abacavir is a nucleoside reverse transciptase inhibitor (NRTI), available as a paediatric formulation. Abacavir in combination with lamivudine is the preferred NRTI backbone for children aged three to ten years and for adolescents weighing under 35 kilograms. It is thus part of both first- and second-line antiretroviral therapy (ART) regimens recommended for children by World Health Organization (WHO), American and European guidelines.  

In the context of implementation of large-scale ART programmes where abacavir is recommended as the NRTI of choice, understanding its toxicity is crucial. In adults the main concern is the increased risk of hypersensitivity reactions, particularly among people with the HLA B5701 genotype, and of myocardial infarction. Children have specific characteristics that affect both the pharmacokinetic profiles of drugs, and also drug tolerability in the short and the long term. Despite the widespread use of abacavir, there has been no systematic evaluation of the toxicity profile of abacavir in children. 

This systematic review of nine studies conducted between 2000 and 2015 demonstrates that there is a low risk of hypersensitivity reactions, especially for children living in sub-Saharan Africa, where 90% of children with HIV live. This is consistent with studies in adults which illustrates that the frequency of the HLAB5701 allele genotype in African populations is low, estimated to be less than two percent.

Other adverse events such as gastrointestinal symptoms and laboratory abnormalities were common. Rates of adverse events should be interpreted with caution as these could depend on factors such as other drugs in the regimen, adherence and so on. Furthermore, data on adverse events were obtained from cohort studies that were not blinded and selection or recall bias cannot be excluded.

Notwithstanding this, most adverse events occurred early after initiation of abacavir, were no more common than with other NRTI regimens, and were manageable. Importantly, there were no deaths associated with abacavir in any of the reported studies. This study supports the use of abacavir as a preferred drug in the NRTI backbone for treatment of children living with HIV. 

HIV Treatment
Africa, Europe, Latin America
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