Articles tagged as "Malaysia"

Short and sweet? Do study participants prefer shorter or longer consent forms? Do they understand the contents?

Editor’s notes: As described above in the HOLA en Grupos study, engagement and partnership is vital if HIV research is to produce useful and relevant results.  The ethics of research involving human subjects continues to evolve but the key principles laid out by Beauchamp and Childress in 1989 remain central.  The principles of autonomy, non-maleficence, beneficence, and justice, have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care.

Autonomy implies that research participants should be able to consent willingly to join a research study and a key part of that informed consent process is usually a written “consent form” that is signed by the participant.  However, a major challenge is often to ensure that on the one hand all relevant information about possible benefits and harms is included in the information and on the other hand that the consent process is manageable and appropriate for the participant.

In the largest study of its kind to date, Grady and colleagues embedded a randomized trial within the larger randomized START trial (comparing immediate with deferred start of antiretroviral medicines in people with early HIV infection).  Around 4000 participants in START were allocated according to their 154 research sites, which were randomly assigned to the original, lengthy and somewhat complicated consent form, or to a simplified, shorter consent form with much more attention paid to ease of comprehension and readability.  The shorter form was still around 1800 words long (compared to the almost 6000 of the original) and was only a little easier to read, because the sponsors of the study needed to be certain that all the information demanded by current guidelines was included.

Surprisingly, there was no overall difference in either the primary outcome (an understanding that participants’ treatment would be randomly allocated) or in overall comprehension of aspects of the study.  In other words, the authors did NOT find the advantages that they were expecting from the modified consent form.

However, various clear trends emerge from the data that are relevant to future research too.  Those with less education were clearly less able to understand the randomization approach.  73% of the 1240 participants who had not attended high school compared to more than 90% of the 935 who had completed a university degree or postgraduate education answered the primary question on randomization correctly. The START study team were diligent in explaining the study to potential participants before presenting the informed consent form, with around a half of participants reporting more than an hour of explanation prior to being asked for consent, and more than 80% of sites reporting that participants understood the study “very well” prior to the consent process.  There was also a clear trend for participants from sites that had been involved in previous HIV research to understand the process better (rising from 69% in those with no previous HIV studies to 85% in those with more than 10).

Increasingly HIV prevention researchers are aiming to work with populations that have high ongoing incidence of HIV.  In a world where treatment is increasingly widespread and overall numbers of infections have fallen somewhat, this means that researchers will tend to be working with more and more disadvantaged populations where many participants may be less well educated and less familiar with research.  This important study makes it clear that the ethical principle of autonomy requires an ongoing process that goes far beyond the choice of words in a consent form.  Research must build trust between researchers and participants.  The research team should explain carefully and in appropriate ways what is involved in the study and what options participants have. Study teams should build a governance process into the research so that participants can have confidence that any risks of the research, both for them as individuals, but also often for the community or group to which they belong, are monitored and mitigated.  In this way potentially vulnerable individuals may still be recruited into important research projects and contribute to the ways in which science can end the epidemic.

A randomized trial comparing concise and standard consent forms in the START trial.

Grady C, Touloumi G, Walker AS, Smolskis M, Sharma S, Babiker AG, Pantazis N, Tavel J, Florence E, Sanchez A, Hudson F, Papadopoulos A, Emanuel E, Clewett M, Munroe D, Denning E; INSIGHT START Informed Consent substudy Group PLoS One. 2017 Apr 26;12(4):e0172607. doi: 10.1371/journal.pone.0172607. eCollection 2017.

Background: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed.

Methods: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin).

Results: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups.

Conclusions: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient.

Trial registration: Informed consent substudy was registered as part of START study in clinicaltrials.gov #NCT00867048, and EudraCT # 2008-006439-12.

Abstract Full-text [free] access 

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Fishing, injection drug use and HIV risk

The association between psychosocial and structural-level stressors and HIV injection drug risk behavior among Malaysian fishermen: a cross-sectional study.

Michalopoulos LM, Jiwatram-Negron T, Choo MK, Kamarulzaman A, El-Bassel N. BMC Public Health. 2016 Jun 2;16(1):464. doi: 10.1186/s12889-016-3125-7.

Background: Malaysian fishermen have been identified as a key-affected HIV population with HIV rates 10 times higher than national rates. A number of studies have identified that psychosocial and structural-level stressors increase HIV injection drug risk behaviors. The purpose of this paper is to examine psychosocial and structural-level stressors of injection drug use and HIV injection drug risk behaviors among Malaysian fishermen.

Methods: The study employs a cross-sectional design using respondent driven sampling methods. The sample includes 406 fishermen from Pahang state, Malaysia. Using multivariate logistic regressions, we examined the relationship between individual (depression), social (adverse interactions with the police), and structural (poverty-related) stressors and injection drug use and risky injection drug use (e.g.., receptive and non-receptive needle sharing, frontloading and back-loading, or sharing drugs from a common container).

Results: Participants below the poverty line had significantly lower odds of injection drug use (OR 0.52, 95 % CI: 0.27-0.99, p = 0.047) and risky injection drug use behavior (OR 0.48, 95 % CI: 0.25-0.93, p = 0.030). In addition, participants with an arrest history had higher odds of injection use (OR 19.58, 95 % CI: 9.81-39.10, p < 0.001) and risky injection drug use (OR 16.25, 95 % CI: 4.73-55.85, p < 0.001). Participants with depression had significantly higher odds of engaging in risky injection drug use behavior (OR 3.26, 95 % 1.39-7.67, p = 0.007). Focusing on participants with a history of injection drug use, we found that participants with depression were significantly more likely to engage in risky drug use compared to participants below the depression cutoff (OR 3.45, 95 % CI: 1.23-9.66, p < 0.02).

Conclusions: Findings underscore the need to address psychosocial and structural-level stressors among Malaysian fishermen to reduce HIV injection drug risk behaviors.

Abstract  Full-text [free] access 

Editor’s notes: There is an increasing amount of research on high rates of HIV infection among people living in fishing communities in parts of Africa and Asia. There is also a lot of information on factors which put people in these fishing communities at risk of HIV infection. This paper is, however, the first study to look in detail at the association between risky injection drug use behaviours and HIV among fishermen. The authors of this fascinating and important paper provide a detailed analysis on the association between, what they call, individual, social and structural factors which contribute to risk. Interestingly, poorer fishermen were at less risk than fishermen who were better off, perhaps because poorer men could not afford the costs of injection drugs. However, the fear of the police, and the risk of arrest, resulted in injection practices which increased the risk of HIV infection. The authors note that the association between symptoms of depression and risky injection drug use may be an outcome of this behaviour rather than the cause. The authors highlight how fishermen using injection drugs to manage stress and risk in their lives, may compound the stress they face by this behaviour. The paper illustrates, very clearly, the complex relationship there often is between individual behaviours and the structural and social context. The authors provide very useful pointers for unpacking risk and HIV-infection in other similar populations. 

Asia
Malaysia
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Expanding ART access: increasing costs

The HIV treatment gap: estimates of the financial resources needed versus available for scale-up of antiretroviral therapy in 97 countries from 2015 to 2020.

Dutta A, Barker C, Kallarakal A. PLoS Med. 2015 Nov 24;12(11):e1001907. doi: 10.1371/journal.pmed.1001907. eCollection 2015.

Background: The World Health Organization (WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless of CD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected the global resources needed for rapid scale-up of ART. Under the Health Policy Project, we conducted modeling analyses for 97 countries to estimate eligibility for and numbers on ART from 2015 to 2020, along with the facility-level financial resources required. We compared the estimated financial requirements to estimated funding available.

Methods and findings: Current coverage levels and future need for treatment were based on country-specific epidemiological and demographic data. Simulated annual numbers of individuals on treatment were derived from three scenarios: (1) continuation of countries' current policies of eligibility for ART, (2) universal adoption of aspects of the WHO 2013 eligibility guidelines, and (3) expanded eligibility as per the WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS "90-90-90" ART targets. We modeled uncertainty in the annual resource requirements for antiretroviral drugs, laboratory tests, and facility-level personnel and overhead.

We estimate that 25.7 (95% CI 25.5, 26.0) million adults and 1.57 (95% CI 1.55, 1.60) million children could receive ART by 2020 if countries maintain current eligibility plans and increase coverage based on historical rates, which may be ambitious. If countries uniformly adopt aspects of the WHO 2013 guidelines, 26.5 (95% CI 26.0 27.0) million adults and 1.53 (95% CI 1.52, 1.55) million children could be on ART by 2020. Under the 90-90-90 scenario, 30.4 (95% CI 30.1, 30.7) million adults and 1.68 (95% CI 1.63, 1.73) million children could receive treatment by 2020. The facility-level financial resources needed for scaling up ART in these countries from 2015 to 2020 are estimated to be US$45.8 (95% CI 45.4, 46.2) billion under the current scenario, US$48.7 (95% CI 47.8, 49.6) billion under the WHO 2013 scenario, and US$52.5 (95% CI 51.4, 53.6) billion under the 90-90-90 scenario. After projecting recent external and domestic funding trends, the estimated 6-y financing gap ranges from US$19.8 billion to US$25.0 billion, depending on the costing scenario and the U.S. President's Emergency Plan for AIDS Relief contribution level, with the gap for ART commodities alone ranging from US$14.0 to US$16.8 billion. The study is limited by excluding above-facility and other costs essential to ART service delivery and by the availability and quality of country- and region-specific data.

Conclusions: The projected number of people receiving ART across three scenarios suggests that countries are unlikely to meet the 90-90-90 treatment target (81% of people living with HIV on ART by 2020) unless they adopt a test-and-offer approach and increase ART coverage. Our results suggest that future resource needs for ART scale-up are smaller than stated elsewhere but still significantly threaten the sustainability of the global HIV response without additional resource mobilization from domestic or innovative financing sources or efficiency gains. As the world moves towards adopting the WHO 2015 guidelines, advances in technology, including the introduction of lower-cost, highly effective antiretroviral regimens, whose value are assessed here, may prove to be "game changers" that allow more people to be on ART with the resources available.

Abstract Full-text [free] access

Editor’s notes: This is a complex and important paper that seeks to understand the financial requirements necessary to: a) continue countries’ current policies of eligibility for ART, b) roll out universal adoption of certain aspects of WHO 2013 eligibility guidelines, and c) expand eligibility as per WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS ‘90-90-90’ targets.

The authors estimated the number of adults and children eligible for and receiving HIV treatment, as well as the cost of providing ART in 97 countries across six regions, covering different income levels. They estimated that 25.7 million adults and 1.57 million children could receive ART by 2020 if countries maintain the current eligibility strategies. If countries adopted WHO 2013 eligibility guidelines, 26.5 million adults and 1.53 million children would be on ART by 2020, and if they adopted the 90-90-90 scenario, 30.4 million adults and 1.68 million children could receive treatment by then. The financial resources necessary for this scale up are estimated to be US$ 45.8 billion under current eligibility, US$ 48.7 billion under WHO 2013 scenario and US$ 52.5 billion under the 90-90-90 scenario. The estimated funding gap for the six year period ranges between US$ 20 and US$ 25 billion. In this study, the costs of commodities were taken directly from data collated by other organisations.  No empirical cost estimates of service delivery were made.  Nor was there an attempt to understand the cost implications of the development synergies and social and programme enablers that may be needed to increase the number of people living with HIV knowing their status.  The new WHO recommendations need to be actively pursued if we are to meet targets, rather than passively continuing with “business as usual”. 

Nonetheless, the findings of this study highlight the gap between guidelines written by WHO and very real programmatic obstacles on the ground. There is evidence to suggest that universal test-and-treat strategies could lead to substantially improved health outcomes at the population level, as well as potentially being cost-saving in the long-term. However, as the authors have illustrated, it would require increased levels of funding. What needs to be explored further now is how to overcome the logistical hurdles of rolling out such an initiative. Changing systems and practices is costly and takes time. Health workers will have to be retrained, data collection strategies will have to be revised. Expanding treatment may also mean increasing the number of health staff working on this initiative, which has an opportunity cost that may reverberate in other parts of the health system. Substantially altering health service provision, particularly in weak health systems, may have knock-on effects with unexpected and unintended consequences.

WHO guidelines serve a vital purpose of giving us a goal to aim for. But studies like this one help us know if and how we can get there. 

Africa, Asia, Europe, Latin America, Oceania
Algeria, Angola, Armenia, Azerbaijan, Bahamas, Bangladesh, Barbados, Belarus, Belize, Benin, Bhutan, Bolivia, Botswana, Bulgaria, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Côte d'Ivoire, Cuba, Democratic Republic of the Congo, Djibouti, Dominican Republic, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Georgia, Ghana, Guatemala, Guinea, Guinea-Bissau, Guyana, Haiti, Honduras, India, Indonesia, Iran (Islamic Republic of), Jamaica, Kazakhstan, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Malaysia, Mali, Mauritania, Mauritius, Moldova, Mongolia, Morocco, Mozambique, Myanmar, Namibia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Papua New Guinea, Philippines, Republic of the Congo, Romania, Russia, Rwanda, Senegal, Serbia and Montenegro, Sierra Leone, Somalia, South Africa, Sri Lanka, Sudan, Suriname, Swaziland, Tajikistan, Thailand, Togo, Trinidad and Tobago, Tunisia, Uganda, Ukraine, United Republic of Tanzania, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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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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Combination harm reduction may be more effective and cost-effective than partial approaches alone

The cost-effectiveness of harm reduction.

Wilson DP, Donald B, Shattock AJ, Wilson D, Fraser-Hurt N. Int J Drug Policy. 2015 Feb;26 Suppl 1:S5-11. doi: 10.1016/j.drugpo.2014.11.007. Epub 2014 Dec 1.

HIV prevalence worldwide among people who inject drugs (PWID) is around 19%. Harm reduction for PWID includes needle-syringe programs (NSPs) and opioid substitution therapy (OST) but often coupled with antiretroviral therapy (ART) for people living with HIV. Numerous studies have examined the effectiveness of each harm reduction strategy. This commentary discusses the evidence of effectiveness of the packages of harm reduction services and their cost-effectiveness with respect to HIV-related outcomes as well as estimate resources required to meet global and regional coverage targets. NSPs have been shown to be safe and very effective in reducing HIV transmission in diverse settings; there are many historical and very recent examples in diverse settings where the absence of, or reduction in, NSPs have resulted in exploding HIV epidemics compared to controlled epidemics with NSP implementation. NSPs are relatively inexpensive to implement and highly cost-effective according to commonly used willingness-to-pay thresholds. There is strong evidence that substitution therapy is effective, reducing the risk of HIV acquisition by 54% on average among PWID. OST is relatively expensive to implement when only HIV outcomes are considered; other societal benefits substantially improve the cost-effectiveness ratios to be highly favourable. Many studies have shown that ART is cost-effective for keeping people alive but there is only weak supportive, but growing evidence, of the additional effectiveness and cost-effectiveness of ART as prevention among PWID. Packages of combined harm reduction approaches are highly likely to be more effective and cost-effective than partial approaches. The coverage of harm reduction programs remains extremely low across the world. The total annual costs of scaling up each of the harm reduction strategies from current coverage levels, by region, to meet WHO guideline coverage targets are high with ART greatest, followed by OST and then NSPs. But scale-up of all three approaches is essential. These interventions can be cost-effective by most thresholds in the short-term and cost-saving in the long-term.

Abstract   Full-text [free] access

Editor’s notes: The spread of HIV among people who inject drugs has driven epidemics throughout regions of eastern Europe, and central and South-East Asia. In eastern Europe and central Asia, the majority of HIV infections have been attributed to injecting drug use. Some countries in the Middle East and North Africa region have also been experiencing rapidly emerging HIV epidemics among people who inject drugs. Harm reduction refers to methods of reducing health risks when eliminating them may not be possible. This paper provides a comprehensive review of evidence on the effectiveness and cost-effectiveness of different harm reduction approaches. These include needle- syringe programmes, opioid substitution therapy (OST), and antiretroviral therapy (ART), when implemented in different settings. Importantly, alongside considering the potential benefits of each approach separately, it makes the case that combination  prevention strategies are synergistic, and may achieve multiple impacts. Sadly still however, the coverage of harm reduction remains very low across the world. An estimated 90% of people who inject drugs worldwide are not accessing needle-syringe programmes, despite this being a highly effective and cost-effective programme. Along with the need for a greater investment in harm reduction, there are socio-political and legislative reasons for poor coverage of harm reduction. This cannot be improved without first addressing the stigma, discrimination and intolerance that restricts the expansion of harm reduction programmes in many settings. Addressing these barriers remains of paramount importance for facilitating effective harm reduction programmes. Encouragingly however, high OST coverage has been reported in Iran, Czech Republic and western Europe, and several countries in Asia and the Middle East have begun to scale-up their programmes. China has recently had the largest OST scale-up programme in the world. Uptake of ART by people living with HIV who inject drugs illustrates the largest disparities with what is required or deemed to be appropriate access. Only 14% of people living with HIV who inject drugs globally, have access to ART, with the largest gaps in ART provision in eastern Europe and central Asia. The further expansion of harm reduction is urgently needed, both to meet WHO targets, and to achieve the UNAIDS 90-90-90 target.

Asia, Europe, Oceania
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Late antiretroviral therapy start persists for children under two years of age in low- and middle-income countries

Immunodeficiency in children starting antiretroviral therapy in low-, middle-, and high-income countries.

Koller M, Patel K, Chi BH, Wools-Kaloustian K, Dicko F, Chokephaibulkit K, Chimbetete C, Avila D, Hazra R, Ayaya S, Leroy V, Truong HK, Egger M, Davies MA, IeDEA, NISDI, PHACS and IMPAACT 219C studies.  J Acquir Immune Defic Syndr. 2015 Jan 1;68(1):62-72. doi: 10.1097/QAI.0000000000000380.

Background: The CD4 cell count or percent (CD4%) at the start of combination antiretroviral therapy (cART) is an important prognostic factor in children starting therapy and an important indicator of program performance. We describe trends and determinants of CD4 measures at cART initiation in children from low-, middle-, and high-income countries.

Methods: We included children aged <16 years from clinics participating in a collaborative study spanning sub-Saharan Africa, Asia, Latin America, and the United States. Missing CD4 values at cART start were estimated through multiple imputation. Severe immunodeficiency was defined according to World Health Organization criteria. Analyses used generalized additive mixed models adjusted for age, country, and calendar year.

Results: A total of 34 706 children from 9 low-income, 6 lower middle-income, 4 upper middle-income countries, and 1 high-income country (United States) were included; 20 624 children (59%) had severe immunodeficiency. In low-income countries, the estimated prevalence of children starting cART with severe immunodeficiency declined from 76% in 2004 to 63% in 2010. Corresponding figures for lower middle-income countries were from 77% to 66% and for upper middle-income countries from 75% to 58%. In the United States, the percentage decreased from 42% to 19% during the period 1996 to 2006. In low- and middle-income countries, infants and children aged 12-15 years had the highest prevalence of severe immunodeficiency at cART initiation.

Conclusions: Despite progress in most low- and middle-income countries, many children continue to start cART with severe immunodeficiency. Early diagnosis and treatment of HIV-infected children to prevent morbidity and mortality associated with immunodeficiency must remain a global public health priority.

Abstract access 

Editor’s notes: This article describes trends and determinants of CD4 cell measures at antiretroviral therapy (ART) initiation in about 35 000 children in low, middle, and high-income countries. Temporal trends in CD4 measures at ART initiation are a useful indicator of the health system’s ability to identify and treat eligible children in a timely fashion. They are also a useful measure of responsiveness to guideline changes.

Previous WHO guidelines recommended early ART initiation, regardless of immunologic or clinical thresholds. But the authors found that in 2010, approximately two-thirds of children below two years of age, in low- and middle-income countries were still starting ART with severe immunodeficiency.

Delayed country-level implementation of WHO guidelines, poor access to early infant diagnosis, slow turn-around time of test results, and limited ART availability for infants and young children are all contributing factors to this delayed ART initiation. The authors point out that timely diagnosis of paediatric HIV does not necessarily result in timely ART. The main reasons for this diagnosis to treatment gap include HIV diagnostic tests and paediatric ART being located at separate sites without robust referral mechanisms between services. There are challenges with CD4 measurement to determine eligibility. These include access to tests, turn-around time and interpretation of results and health care worker discomfort with treating children.

Currently, only 22% of children living with HIV in sub-Saharan Africa are receiving ART. To decrease the treatment gap among children, WHO 2013 guidelines recommend universal ART for all children living with HIV, aged below five years of age, irrespective of CD4 count or clinical stage. Removing the requirement for a CD4 measurement also removes the time lag while waiting for CD4 results. Thus the guidelines aim both to increase treatment accessibility and to accelerate treatment initiation for all children. 

HIV Treatment
Africa, Asia, Northern America
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Increasing transmitted resistance to antiretroviral therapy in low/middle-income countries - highest prevalence in MSM

Global burden of transmitted HIV drug resistance and HIV-exposure categories: a systematic review and meta-analysis.

Pham QD, Wilson DP, Law MG, Kelleher AD, Zhang L. AIDS. 2014 Nov 28;28(18):2751-62. doi: 10.1097/QAD.0000000000000494.

Objectives: Our aim was to review the global disparities of transmitted HIV drug resistance (TDR) in antiretroviral-naive MSM, people who inject drugs (PWID) and heterosexual populations in both high-income and low/middle-income countries.

Design/methods: We undertook a systematic review of the peer-reviewed English literature on TDR (1999-2013). Random-effects meta-analyses were performed to pool TDR prevalence and compare the odds of TDR across at-risk groups.

Results: A total of 212 studies were included in this review. Areas with greatest TDR prevalence were North America (MSM: 13.7%, PWID: 9.1%, heterosexuals: 10.5%); followed by western Europe (MSM: 11.0%, PWID: 5.7%, heterosexuals: 6.9%) and South America (MSM: 8.3%, PWID: 13.5%, heterosexuals: 7.5%). Our data indicated disproportionately high TDR burdens in MSM in Oceania (Australia 15.5%), eastern Europe/central Asia (10.2%) and east Asia (7.8%). TDR epidemics have stabilized in high-income countries, with a higher prevalence (range 10.9-12.6%) in MSM than in PWID (5.2-8.3%) and heterosexuals (6.4-9.0%) over 1999-2013. In low/middle-income countries, TDR prevalence in all at-risk groups in 2009-2013 almost doubled than that in 2004-2008 (MSM: 7.8 vs. 4.2%, P = 0.011; heterosexuals: 4.1 vs. 2.6%, P < 0.001; PWID: 4.8 vs. 2.4%, P = 0.265, respectively). The risk of TDR infection was significantly greater in MSM than that in heterosexuals and PWID. We observed increasing trends of resistance to non-nucleoside reverse transcriptase and protease inhibitors among MSM.

Conclusion: TDR prevalence is stabilizing in high-income countries, but increasing in low/middle-income countries. This is likely due to the low, but increasing, coverage of antiretroviral therapy in these settings. Transmission of TDR is most prevalent among MSM worldwide.

Abstract access 

Editor’s notes: HIV mutates very rapidly, and many early antiretroviral agents had a low genetic barrier to the development of resistance. Thus the emergence of virus resistant to antiretroviral agents, particularly to early drug classes, was inevitable. Surveillance for drug-resistant virus among people with no prior history of taking antiretroviral drugs (transmitted drug resistance) is essential to monitor the spread of drug resistance at population level.

This systematic review aimed to compare transmitted drug resistance in different geographical regions and between subpopulations of HIV-positive people by likely route of transmission. Transmitted resistance was most prevalent in high income settings. This is not surprising given wide use of suboptimal drug regimens before effective triple therapy was available. Reassuringly, the prevalence of transmitted resistance seems to have stabilised in high-income settings. The increase in transmitted resistance in low and middle income countries is of more concern. It is not surprising, given that first-line regimens comprising two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor are vulnerable to the development of resistance if the drug supply is interrupted or adherence is suboptimal. In addition, if viral load monitoring is not available, people remain on failing drug regimens for longer, and thus have more risk of transmitting resistant virus.

Within the subpopulations examined in this review, transmitted resistance was consistently higher in men who have sex with men, suggesting that resistance testing prior to treatment is particularly valuable for this population.

Limitations of the review include exclusion of studies that did not compare transmitted resistance between the specified subpopulations, and small sample size in many subgroups.

Continued surveillance for transmitted drug resistance is critical. This is most important in settings where individualised resistance testing is not available. This will ensure that people starting antiretroviral therapy receive treatment that will suppress their viral load effectively. Wider use of viral load monitoring, combined with access to effective second and third line regimens, will also help limit spread of drug resistance.

HIV Treatment
Angola, Argentina, Australia, Austria, Belgium, Benin, Botswana, Brazil, Burkina Faso, Cambodia, Cameroon, Canada, Central African Republic, Chad, China, Côte d'Ivoire, Croatia, Cuba, Cyprus, Denmark, Dominican Republic, El Salvador, Estonia, Ethiopia, France, Gabon, Georgia, Germany, Greece, Guatemala, Honduras, Hong Kong Special Administrative Region of China, Hungary, India, Indonesia, Ireland, Israel, Italy, Japan, Kazakhstan, Kenya, Latvia, Malawi, Malaysia, Moldova, Mozambique, Netherlands, Peru, Philippines, Poland, Portugal, Republic of Korea, Romania, Russia, Rwanda, Slovenia, South Africa, Spain, Swaziland, Sweden, Switzerland, Taiwan, Thailand, Uganda, United Kingdom of Great Britain and Northern Ireland, United Republic of Tanzania, United States of America, Viet Nam, Zambia, Zimbabwe
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Counting and classifying global deaths

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Murray CJ, Ortblad KF, Guinovart C, et al. Lancet. 2014 Sep 13;384(9947):1005-70. doi: 10.1016/S0140-6736(14)60844-8. Epub 2014 Jul 22.

Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.

Methods: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

Findings: Globally in 2013, there were 1.8 million new HIV infections (95% uncertainty interval 1.7 million to 2.1 million), 29.2 million prevalent HIV cases (28.1 to 31.7), and 1.3 million HIV deaths (1.3 to 1.5). At the peak of the epidemic in 2005, HIV caused 1.7 million deaths (1.6 million to 1.9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19.1 million life-years (16.6 million to 21.5 million) have been saved, 70.3% (65.4 to 76.1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$ 4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7.5 million (7.4 million to 7.7 million), prevalence was 11.9 million (11.6 million to 12.2 million), and number of deaths was 1.4 million (1.3 million to 1.5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7.1 million (6.9 million to 7.3 million), prevalence was 11.2 million (10.8 million to 11.6 million), and number of deaths was 1.3 million (1.2 million to 1.4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64.0% of cases (63.6 to 64.3) and 64.7% of deaths (60.8 to 70.3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1.2 million deaths (1.1 million to 1.4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31.5% (15.7 to 44.1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

Interpretation: Our estimates of the number of people living with HIV are 18.7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

Abstract  Full-text [free] access

Editor’s notes: The Global Burden of Disease (GBD) study uses standard methods to compare and track over time national distributions of deaths by cause, and the prevalence of disease and disability.  This detailed report focuses on HIV, TB and Malaria. It presents regional summaries of incidence, prevalence and mortality rates, and national estimates of the number of male and female deaths and new infections. Point estimates are shown for 2013, and annualised rates of change for 1990-2000 and 2000-2013. These highlight the contrasting trends in disease impact before and after the formulation of the Millennium Development Goal to combat these diseases.  The global peak of HIV mortality occurred in 2005, but regional annualised rates of change for 2000-2013 indicate that HIV deaths are still increasing significantly in east Asia, southern Africa, and most rapidly in eastern Europe.

The GBD 2013 global estimates of new infections and deaths agree closely with the corresponding estimates made by UNAIDS. But there are significant differences in the respective estimates of the number of people currently living with HIV (UNAIDS estimates are some 18% higher), and historical trends in AIDS deaths, with UNAIDS judging that the recent fall has been steeper. These differences are attributed primarily to methods used in the GBD study to ensure that the sum of deaths from specific causes fits the estimated all cause total, and to varying assumptions about historical survival patterns following HIV infection. 

It may be worthwhile to look at a comment by Michel Sidibé, Mark Dybul, and Deborah Birx in the Lancet on MDG 6 and beyond: from halting and reversing AIDS to ending the epidemic which refers to this study.

Epidemiology
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Integrating HIV, malaria and diarrhoea prevention is far more efficient than vertical programmes

Scaling up integrated prevention campaigns for global health: costs and cost-effectiveness in 70 countries. 

Marseille E, Jiwani A, Raut A, Verguet S, Walson J, Kahn JG. BMJ Open. 2014 Jun 26;4(6):e003987. doi: 10.1136/bmjopen-2013-003987.

Objective: This study estimated the health impact, cost and cost-effectiveness of an integrated prevention campaign (IPC) focused on diarrhoea, malaria and HIV in 70 countries ranked by per capita disability-adjusted life-year (DALY) burden for the three diseases.

Methods: We constructed a deterministic cost-effectiveness model portraying an IPC combining counselling and testing, cotrimoxazole prophylaxis, referral to treatment and condom distribution for HIV prevention; bed nets for malaria prevention; and provision of household water filters for diarrhoea prevention. We developed a mix of empirical and modelled cost and health impact estimates applied to all 70 countries. One-way, multiway and scenario sensitivity analyses were conducted to document the strength of our findings. We used a healthcare payer's perspective, discounted costs and DALYs at 3% per year and denominated cost in 2012 US dollars.

Primary and secondary outcomes: The primary outcome was cost-effectiveness expressed as net cost per DALY averted. Other outcomes included cost of the IPC; net IPC costs adjusted for averted and additional medical costs and DALYs averted.

Results: Implementation of the IPC in the 10 most cost-effective countries at 15% population coverage would cost US$583 million over 3 years (adjusted costs of US$398 million), averting 8.0 million DALYs. Extending IPC programmes to all 70 of the identified high-burden countries at 15% coverage would cost an adjusted US$51.3 billion and avert 78.7 million DALYs. Incremental cost-effectiveness ranged from US$49 per DALY averted for the 10 countries with the most favourable cost-effectiveness to US$119, US$181, US$335, US$1 692 and US$8 340 per DALY averted as each successive group of 10 countries is added ordered by decreasing cost-effectiveness.

Conclusions: IPC appears cost-effective in many settings, and has the potential to substantially reduce the burden of disease in resource-poor countries. This study increases confidence that IPC can be an important new approach for enhancing global health.

Abstract  Full-text [free] access

Editor’s notes: Increasingly governments and policy makers are seeking to identify how to invest resources most effectively, to achieve multiple health and development outcomes. This paper presents a cost-effectiveness analysis of an integrated campaign to prevent diarrhoea, malaria and HIV.  

They developed a model to estimate the cost per disability adjusted life year (DALY) averted by this intervention, across 70 countries with high disease burden, assuming 15% coverage. The authors categorise countries by income level and their opportunity index (i.e. the opportunity to avert DALYs by having a high disease burden). The findings suggest that an integrated prevention campaign (IPC) could cost as little as US$7 per DALY averted in Guinea-Bissau, a low income, high opportunity country. As would be expected, the contribution of the different IPC components varied by country, depending on their relative disease burdens. This suggests that further focusing of activities within countries may further improve efficiency.

The model was also used to consider potential roll out strategies across counties. For this, countries were grouped into blocks of 10, and ordered with increasing incremental-cost effectiveness. The authors suggest that reaching the top 40 countries with IPC, even at just 15% coverage, could achieve far greater health benefits, with a substantially lower budget, than requested under PEPFAR for antiretroviral therapy alone.

This paper provides further evidence of the need for a more integrated approach to improve population health across disease areas.

Africa, Asia, Europe, Latin America
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Efavirenz dose reduction could help scale up antiretroviral therapy access

Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial.

ENCORE1 Study Group. Lancet. 2014 Feb 7. pii: S0140-6736(13)62187-X. doi: 10.1016/S0140-6736(13)62187-X. [Epub ahead of print]

Background: The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings.

Methods: ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per µL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment.

Findings: The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per µL (SD 99) and median plasma HIV-RNA was 4.75 log10 copies per mL (IQR 0.88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI -2.1 to 5.79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per µL, 95% CI 6-44; p=0.01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89.1%, efavirenz 600=88.4%; difference 0.75%, 95% CI -4.19 to 5.69; p=0.77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10.5%, 95% CI -18.2 to -2.8; p=0.01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3.96%, 95% CI -6.96 to -0.95; p=0.01).

Interpretation: Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care.

Abstract access

Editor’s notes: Nearly 10 million people in low- and middle-income countries were receiving antiretroviral therapy (ART) by the end of 2012, with plans to expand coverage to 15 million by 2015. Several challenges must be overcome if this target is to be achieved. One of the most pertinent of these is how to fund this expansion in the current economic climate. Significant progress has already been made in reducing the cost of first-line drugs. The authors of this paper propose an alternative approach to lowering drug costs, namely dose reduction.

Evidence supporting the 600mg dose of efavirenz used in clinical practice is weak, with no difference found in the proportion of patients achieving viral suppression in the original dose finding trials of 200mg, 400mg and 600mg (unpublished). This trial in ART-naive individuals found that 400mg was non-inferior to 600mg of efavirenz in terms of viral suppression over 48 weeks of follow-up. Findings were similar when stratified by ethnic group (African, Asian, other) and body mass index, both factors which influence drug concentrations. Furthermore, fewer patients on 400mg reported adverse events which were related to efavirenz, and fewer patients with drug-related side effects on this dose stopped efavirenz. These promising results support a dose reduction strategy. However, longer term outcomes need to be evaluated and efficacy studies in patients with tuberculosis are needed before the 400mg dose is recommended for use in routine clinical practice. Certainly, if drug companies agree to manufacture this dose at scale, preferably in fixed-dose combination tablets, cost-savings could be considerable.  

Africa, Asia, Europe, Latin America
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