Articles tagged as "Oceania"

Masking diversity – the problems with labels for key populations

'Mobile men with money': HIV prevention and the erasure of difference.

Aggleton P, Bell SA, Kelly-Hanku A. Glob Public Health. 2014;9(3):257-70. doi: 10.1080/17441692.2014.889736. Epub 2014 Mar 4.

Mobile Men with Money is one of the latest risk categories to enter into HIV prevention discourse. Used in countries in Asia, the Pacific and Africa, it refers to diverse groups of men (e.g. businessmen, miners and itinerant wage labourers) who, in contexts of high population movement and economic disparity, find themselves at heightened risk of HIV as members of a 'most-at-risk population', or render others vulnerable to infection. How adequate is such a description? Does it make sense to develop HIV prevention programmes from such understandings? The history of the epidemic points to major weaknesses in the use of terminologies such as 'sex worker' and 'men who have sex with men' when characterising often diverse populations. Each of these terms carries negative connotations, portraying the individuals concerned as being apart from the 'general population', and posing a threat to it. This paper examines the diversity of men classified as mobile men with money, pointing to significant variations in mobility, wealth and sexual networking conducive to HIV transmission. It highlights the patriarchal, heteronormative and gendered assumptions frequently underpinning use of the category and suggests more useful ways of understanding men, masculinity, population movement, relative wealth in relation to HIV vulnerability and risk.

Abstract access 

Editor’s notes: Criticism of the use of labels to identify groups of people considered to be at high risk of HIV infection is not new, but this paper serves as a timely reminder of the dangers of such labels and abbreviations. The authors explain why a term that has entered common usage in recent years ‘mobile men with money’, is inappropriate. They argue that the label plays to stereotypes of men as powerful risk takers and, usually, women as their vulnerable victims. The use of the term hides the diversity of men who move around because of their work and other activities, who may be in very different professions and circumstances. It also suggests that mobility is a negative activity, overlooking the great economic and other benefits of migration. They argue that the term is not helpful for HIV programming or activities.  It is unhelpful because it fails to take account of the structural factors that influence and shape the risks many men and women, face. It is often tempting to make use of abbreviations and catchy phrases in our work. This paper helps to remind us why we need to think carefully about terminology and labelling.

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

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

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

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

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

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

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

Abstract access 

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

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

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

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

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

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

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

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

Abstract access 

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

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

Europe, Northern America, Oceania
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Does global procurement and price negotiation through the Global Fund reduce HIV commodity costs?

Trends in procurement costs for HIV commodities: a seven-year retrospective analysis of Global Fund data across 125 countries. 

Wafula F, Agweyu A, Macintyre K. J Acquir Immune Defic Syndr. 2013 Nov 20. [Epub ahead of print]

Background: Nearly 40% of Global Fund money goes towards procurement. However, no analyses have been published to show how costs vary across regions and time, despite the availability of procurement data collected through the Global Fund's price and quality reporting (PQR) system.

Methodology: We analyzed data for the three most widely procured commodities for the prevention, diagnosis and treatment of HIV. These were male condoms, HIV rapid tests, and the ARV combination of lamivudine/nevirapine/zidovudine. The compared costs, first across time (2005-2012), then across regions, and finally, between individual procurement reported through the PQR and pooled procurement reported through the Global Fund's voluntary pooled procurement (VPP) system. All costs were adjusted for inflation and reported in US dollars.

Key findings: There were 2 337 entries from 578 grants in 125 countries. The procurement cost for the ARV dropped substantially over the period, whereas those for condoms and HIV tests remained relatively stable. None of the commodity prices increased. Regional variations were pronounced for HIV tests, but minimal for condoms and the ARV. The unit cost for the three-table ARV combination, for instance, varied between US$0.15 and US$0.23 in South Asia and the Eastern Europe/Central Asia regions respectively, compared to a range of $0.23 (South Asia) - $1.50 (Eastern Europe/Central Asia) for a single diagnostic test. Pooled procurement lowered costs for condoms, but not the other commodities.

Conclusion: We showed how global procurement costs vary by region and time. Such analyses should be done more often to identify and correct market insufficiencies.

Abstract access 

Editor’s notes: With the flatlining of HIV resources, it is important that HIV investments are optimally used, and achieve good value for money. The Global Fund has played a major role in financing HIV programmes, with over a half of the US$23 billion given since 2002 going to HIV. A large proportion of Global Fund grants go towards the procurement of pharmaceuticals and other health products. The global fund uses its (and partners, such as PEPFAR and Clinton Health Access Initiative) bulk purchasing power to negotiate lower commodity prices for countries.  It has also set up systems to support countries to negotiate costs and identify cheap suppliers. This paper uses information from the Global Fund across time and recipient countries, to explore how costs of 3 HIV related commodities have changed over time, and/or vary regionally. The trends observed reflect a variety of market factors, and the increasingly global nature of commodity markets. The reduction in antiretroviral therapy (ART) costs are likely to result from increased competition across suppliers, the move to generic drug use, and the joint negotiation in cost reductions, and there may be scope for further price reductions. In contrast, the limited variation in costs for HIV tests and male condoms suggest that markets for these commodities have stabilized, leaving limited room for negotiation. 

Africa, Asia, Europe, Latin America, Oceania
South Africa
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An integrated investment approach for women’s and children’s health

Advancing social and economic development by investing in women's and children's health: a new Global Investment Framework.

Stenberg K, Axelson H, Sheehan P, Anderson I, Gülmezoglu AM, Temmerman M, Mason E, Friedman HS, Bhutta ZA, Lawn JE, Sweeny K, Tulloch J, Hansen P, Chopra M, Gupta A, Vogel JP, Ostergren M, Rasmussen B, Levin C, Boyle C, Kuruvilla S, Koblinsky M, Walker N, de Francisco A, Novcic N, Presern C, Jamison D, Bustreo F; on behalf of the Study Group for the Global Investment Framework for Women's Children's Health. Lancet. 2013 Nov 18. doi: S0140-6736(13)62231-X. pii: 10.1016/S0140-6736(13)62231-X. [Epub ahead of print]

A new Global Investment Framework for Women's and Children's Health demonstrates how investment in women's and children's health will secure high health, social, and economic returns. We costed health systems strengthening and six investment packages for: maternal and newborn health, child health, immunisation, family planning, HIV/AIDS, and malaria. Nutrition is a cross-cutting theme. We then used simulation modelling to estimate the health and socioeconomic returns of these investments. Increasing health expenditure by just $5 per person per year up to 2035 in 74 high-burden countries could yield up to nine times that value in economic and social benefits. These returns include greater gross domestic product (GDP) growth through improved productivity, and prevention of the needless deaths of 147 million children, 32 million stillbirths, and 5 million women by 2035. These gains could be achieved by an additional investment of $30 billion per year, equivalent to a 2% increase above current spending.

Abstract access 

Editor’s notes: Over the past 20 years there have been substantial gains in maternal and child health (MCH). However, much still needs to be done – assuming a continuation of current rates of progress, there would nevertheless be shortfalls in the achievement of MDG 4 and 5 targets. Especially in sub-Saharan Africa, HIV is an important underlying cause of maternal and child ill health. This paper models the costs and benefits of an accelerated action on MCH, including for HIV, the prevention of mother to child HIV transmission; first line treatment for pregnant women; cotrimoxazole for children, and the provision of paediatric antiretroviral therapy (ART). These HIV services are complemented by health systems strengthening; increased family planning provision; and packages for malaria, immunisation, and child health. The paper is interesting for many reasons, including both the breadth of its intervention focus, and the detailed modelling of the likely health, social and economic benefits of such investments.

Although the direct HIV related benefits are not described in detail in the main paper, it is likely that these result both from increased contraceptive use (prong 2 for preventing vertical HIV transmission), as well as ART and cotrimoxazole provision. It also illustrates the potential value of developing a cross-disease investment approach, as a means to ensure that services effectively respond to the breadth of women’s and children’s health needs. This more ‘joined up’, integrated perspective on strategies for health investment can support core investments in health systems strengthening. It can also potentially achieve important cross-disease synergies, e.g., ensuring that a child who has not acquired HIV at birth does not then die from malaria. 

Africa, Asia, Latin America, Oceania
Afghanistan, Angola, Azerbaijan, Bangladesh, Benin, Bolivia, Botswana, Brazil, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Congo, Côte d'Ivoire, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, Haiti, India, Indonesia, Iraq, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Nepal, Niger, Nigeria, Pakistan, Papua New Guinea, Peru, Philippines, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Solomon Islands, Somalia, South Africa, Sudan, Swaziland, Tajikistan, Togo, Turkmenistan, Uganda, United Republic of Tanzania, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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Incentivizing HIV/STI testing leads to increased uptake in non-clinical, but not in clinical settings

Incentivizing HIV/STI testing: a systematic review of the literature.

Lee R, Cui RR, Muessig KE, Thirumurthy H, Tucker JD. AIDS Behav. 2013 Sep 26. [Epub ahead of print]

Suboptimal HIV/STI testing uptake has a profound impact on morbidity and mortality. Incentives have been effective in other areas of medicine and may improve HIV/STI testing uptake rates. This study reviewed the effects of incentives on HIV/STI testing uptake. A systematic search of seven databases was undertaken. Testing uptake was defined as test implementation and/or test result retrieval. Incentives were defined as monetary or non-monetary rewards or free-of-charge testing vouchers. Seven studies were included. All seven studies demonstrated higher rates of uptake in an incentivized group. Incentives offered at a non-clinical setting demonstrated more significant differences in uptake rates compared to incentives offered at a clinical setting. Incentivizing HIV/STI testing uptake, especially testing at a non-clinical setting, may be a useful tool to modify health behavior. Further research is needed to understand how incentives could be an effective component within a comprehensive HIV/STI control strategy.

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Editor’s notes: Increasing testing for HIV and other STIs is key to increase treatment uptake and to encourage sexual behaviour changes. This is the first systematic review to look at the effect of offering economic incentives to increase STI testing uptake. Results from the 7 studies identified are consistent and encouraging, especially when testing is offered in a non-clinic setting (e.g. at mobile services).  Further research is needed to better understand the potential role for incentives, including the optimal value of the incentive; monetary versus non-monetary incentives; and the potential for using free-of-charge vouchers for increasing STI testing uptake. Across sub-Saharan Africa, men are less likely to test for HIV than women. This is partly driven by the increase in provider-initiated testing and counselling associated with antenatal care. New community-based interventions, such as home based testing and self-testing are needed to increase access to testing for all. Financial incentives may be an important component of such strategies. 

Africa, Northern America, Oceania
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Better self-reported ART adherence with once-daily regimens in a large clinical trial

Factors associated with adherence amongst 5295 people receiving antiretroviral therapy as part of an international trial.

O'Connor JL, Gardner EM, Mannheimer SB, Lifson AR, Esser S, Telzak EE, Phillips AN., J Infect Dis. 2013 Jul;208(1):40-9. doi: 10.1093/infdis/jis731. Epub 2012 Nov 29.

Background: We assessed factors associated with antiretroviral therapy (ART) adherence, including specific ART medications.

Methods: The Strategies for Management of Antiretroviral Therapy study was an international antiretroviral therapy (ART) strategy trial that compared intermittent ART, using CD4+ T-cell count as a guide, to continuous ART. Adherence during the 7 days before each visit was measured using self-report. We defined high adherence as self-report of taking “all” pills for each prescribed ART medication; all other reports were defined as suboptimal adherence. Factors associated with adherence were assessed using logistic regression with generalized estimating equations.

Results: Participants reported suboptimal adherence at 6 016 of 35 695 study visits (17%). Factors independently associated with suboptimal adherence were black race, protease inhibitor–containing regimens, greater pill burden, higher maximum number of doses per day, and smoking. Factors independently associated with higher adherence were older age, higher education, region of residence, episodic treatment, higher latest (at the time of adherence) CD4+ T-cell count, and being prescribed concomitant drugs (i.e., medications for comorbidities). Of specific drugs investigated, atazanavir, atazanavir/ritonavir, fosamprenavir, indinavir, indinavir/ritonavir, and lopinavir/ritonavir were associated with suboptimal adherence, and tenofovir disoproxil fumarate/emtricitabine was associated with higher adherence.

Conclusions: In this, the largest analysis of ART adherence to date, some protease inhibitor–containing regimens and regimens with >1 dose per day were associated with suboptimal adherence.

Abstract access

Editor’s notes: The SMART study was a large clinical trial which found that continuous ART, compared to intermittent ART (to maintain a CD4+ cell count of ≥250 cells/µl), reduced mortality and HIV disease progression. This analysis explored patient and regimen factors associated with self-reported adherence (based on a five-point rating scale for number of pills taken in the previous seven days). Overall, participants reported taking all of their pills at over 80% of time points, although almost half reported some missed doses for at least one visit during follow-up. Most of the demographic factors associated with adherence were consistent with data from elsewhere. Adherence was best with simpler ART regimens dosed once daily, providing support to current ART policies based on fixed-drug combinations as preferred first-line antiretroviral regimens.

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Better virological outcomes with efavirenz compared to nevirapine

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

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

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

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

FUNDING: ViiV Healthcare.

Abstract access 

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

Europe, Northern America, Oceania
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Comparing adverse effects of nevirapine and efavirenz

Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.

Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Thery F, Shaffer N, Hargreaves S, Mills EJ, Ford N. AIDS. 2013 Jan 22. [Epub ahead of print]

Since 2002, the World Health Organization has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the clinical importance of these toxicities overall is not well established. The authors systematically reviewed adverse events among treatment-naïve HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CI) were calculated and proportions and odds ratios (OR) pooled using fixed-effects meta-analysis. Data was reviewed on 26446 adult and 3975 children from 8 randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95%CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95%CI 2.5-4.2), severe skin toxicity (OR 3.9, 95%CI 2.5-5.4), and severe hypersensitivity reactions (OR 2.4, 95%CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe CNS-events (OR 3.4, 95%CI 2.1-5.4). Similar associations were seen in children. Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move towards efavirenz-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach.

Abstract access 

Editor’s notes: As increased progress is being made towards universal access to treatment, increased attention is being addressed towards retention in care and on treatment. Simpler, less toxic regimens have been a cornerstone of the Treatment 2.0 initiative of UNAIDS and WHO. Nevirapine has been widely utilized as an essential component of three drug antiretroviral therapy, in part due to low cost and safety at a population level. While efavirenz does have a greater incidence of central nervous system side effects (many of them manageable with supportive treatment), the overall discontinuation rate is significantly lower than with nevirapine. This data in combination with the continued reduction in efavirenz price, and incorporation into combination pill form, supports the move towards increased use of efavirenz for first line antiretroviral therapy.

HIV Treatment
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