Articles tagged as "Latin America"

Substantial drop in opportunistic infections in children with ART

Incidence and prevalence of opportunistic and other infections and the impact of antiretroviral therapy among HIV-infected children in low and middle-income countries: a systematic review and meta-analysis. 

B-Lajoie MR, Drouin O, Bartlett G, Nguyen Q, Low A, Gavriilidis G, Easterbrook P, Muhe L. Clin Infect Dis. 2016 Mar 21. pii: ciw139. [Epub ahead of print]

Background: We conducted a systematic review and meta-analysis to evaluate the incidence and prevalence of 14 opportunistic infections (OIs) and other infections as well as the impact of antiretroviral therapy (ART) among HIV-infected children (<18 years) in low and middle-income countries (LMIC), to understand regional burden of disease, and inform delivery of HIV services.

Methods: Eligible studies described the incidence of OIs and other infections in ART-naive and exposed children from January 1990 to November 2013, using Medline, Global Health, Embase, Cinahl, Web of Knowledge and Lilacs databases. Summary incident risk and prevalent risk for each OI in ART-naive and ART-exposed children were calculated, and unadjusted odds ratios calculated for impact of ART. The number of OI cases and associated costs averted were estimated using the AIM model.

Results: We identified 4542 citations, and 88 studies were included, comprising 55 679 HIV-infected children. Bacterial pneumonia and tuberculosis were the most common incident and prevalent infections in both ART-naive and ART-exposed children. There was a significant reduction in incident risk with ART for the majority of OIs. There was a smaller impact on bacterial sepsis and pneumonia, and an increase observed for varicella zoster. ART initiation based on 2010 WHO guidelines criteria for ART initiation in children was estimated to potentially avert more than 161 000 OIs (2013 UNAIDS data) with estimated cost savings of at least USD $17 million per year.

Conclusion: There is a substantial decrease in the risk of most OIs with ART use in HIV-infected children in LMIC, and estimated large potential cost savings in OIs averted with ART use, although there are greater limitations in paediatric data compared to adults.

Abstract  Full-text [free] access

Editor’s notes: The scale-up of programmes to prevent mother-to-child HIV transmission has resulted in a 60% decline in paediatric HIV infections. The scale-up of antiretroviral therapy (ART), however, has been less successful in children, with only a third of eligible children aged under 15 years receiving ART as of 2014. In high-income countries, there has been a substantial decrease in the incidence of most opportunistic infections (OIs) following the introduction of ART. The impact of ART on burden of OIs in low and middle income countries (LMICs) is much less well-understood.

This meta-analysis estimated the incidence and prevalence of 14 key OIs and other infections in children (aged 0-18 years) before and after the introduction of ART across three geographical regions, namely sub-Saharan Africa, Latin America and the Caribbean, and Asia.

The use of ART has resulted in a decline in incidence of all but three infections, namely tuberculosis, pneumonia and candidiasis. These remain the most common incident and prevalent infections in ART-naïve and ART-exposed children. It is important to note that there is a high incidence of lower respiratory infections in children in LMIC regardless of HIV status.

There is a paucity of well-described or large studies in children compared to in adults. There was significant heterogeneity in the studies included in the review, and few studies reported important confounding factors such as use of co-trimoxazole prophylaxis, age at ART initiation and CD4 count. Also, regional differences could not be examined due to a limited number of studies in Latin America and Asia.

Notwithstanding these limitations, ART has resulted in a substantial cost-saving due to the numbers of OIs averted by use of ART. The 2015 WHO guidelines now recommend ART initiation in all children and this is likely to have an even larger impact on the incidence of OIs and mortality. Along with this, strategies to reduce the burden of TB and pneumonia in children are urgently needed.

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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Empirical TB treatment no better than isoniazid among people with low CD4 counts and negative TB tests

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. 

Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A, Adult ACTGAST. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert® MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2.5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5-7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4-7.8); absolute risk difference of -0.06% (95% CI -3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

Abstract access

Editor’s notes: Tuberculosis (TB) remains the leading cause of death among HIV-positive people worldwide. Existing diagnostic tests for TB lack sensitivity, particularly among HIV-positive people, and autopsy studies consistently illustrate that TB is common at death, but often not identified prior to death. This has led to questions about whether empirical TB treatment, meaning treatment for TB in the absence of bacteriological confirmation, should be more widely used among HIV-positive people.

This trial compared empirical TB treatment to isoniazid preventive therapy among adult outpatients with very low CD4 counts starting antiretroviral therapy (ART). People could be enrolled in the study if they did not have confirmed or suspected TB based on symptoms, locally-accessible diagnostic tests (including chest radiography and sputum smear) and, when available, testing with Xpert® MTB/RIF. There was no difference in mortality at six months between participants given empirical TB treatment compared to isoniazid preventive therapy. Mortality was remarkably low overall, particularly considering that participants had very low CD4 counts. It seems likely that the enrolment criteria excluded people at highest risk of death from participating in the study.

Screening for TB at the time of starting ART could reduce mortality if the tests are sufficiently sensitive, and if people identified to have TB receive effective treatment. However, this study was not designed to address how best to do this in resource-limited settings, where chest radiography and Xpert® MTB/RIF are often not accessible. This study does suggest that isoniazid preventive therapy can be given at the time of ART initiation among people who have been effectively screened for TB. The results of other studies of empirical TB treatment, with different designs in different populations, are awaited. Data from all these studies together may provide evidence to guide the optimal package of care for people presenting with advanced HIV disease. 

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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High TB mortality among people living with HIV in eastern Europe: a growing concern

Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study. 

Podlekareva DN, Efsen AM, Schultze A, Post FA, Skrahina AM, Panteleev A, Furrer H, Miller RF, Losso MH, Toibaro J, Miro JM, Vassilenko A, Girardi E, Bruyand M, Obel N, Lundgren JD, Mocroft A, Kirk O, TB:HIV study group in EuroCoord. Lancet HIV. 2016 Mar;3(3):e120-31. doi: 10.1016/S2352-3018(15)00252-0. Epub 2016 Feb 2.

Background: Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study.

Methods: Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models.

Findings: Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0.0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0.0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0.23 (95% CI 0.16-0.31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3.17; 95% CI 1.83-5.49) as were those who did not have baseline drug-susceptibility tests (2.24; 1.31-3.83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0.0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0.0001).

Interpretation: Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe.

Abstract access

Editor’s notes: Eastern Europe is experiencing one of the fastest growing HIV epidemics globally. Within this, the number of HIV-positive people with tuberculosis (TB) is also rising rapidly, posing a significant public health challenge. The authors have previously reported retrospective data illustrating 30% mortality at one year among HIV-positive people with TB in eastern Europe. This was noted to be at least three times higher than mortality among people from western Europe and Argentina. Within this study they go further to provide prospective data with comparison across multiple regions. They also highlight prognostic markers associated with death.

The study spans across eastern Europe, western Europe and Latin America with a cohort of 1406 people. It robustly demonstrates a significant excess of TB-associated mortality in HIV-positive people with TB receiving care in eastern Europe. The cumulative probability of TB-associated death at 12 months in eastern Europe was 23% (95% confidence interval [CI] 20 – 26), versus 1% (95% CI 0 - 3) in western Europe and 4% (95% CI 2-8) in Latin America. Prognostic markers associated with an increased risk of death included multidrug-resistant TB, disseminated TB and modifiable factors such as choice of initial anti-TB regimen and a lack of baseline drug susceptibility tests.

These findings highlight the hugely detrimental impact of the fragmented system of HIV and TB services within eastern Europe. Such inequality in outcomes emphasises the need for urgent strategic change. Co-ordinated care across HIV and TB services, alongside timely and appropriate diagnostics and treatment, is of paramount importance.

Europe, Latin America
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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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The effects of trauma follow people on the move

A systematic review of HIV risk behaviors and trauma among forced and unforced migrant populations from low and middle-income countries: state of the literature and future directions.

Michalopoulos LM, Aifah A, El-Bassel N. AIDS Behav. 2016 Feb;20(2):243-61. doi: 10.1007/s10461-015-1014-1.

The aim of the current systematic review is to examine the relationship between trauma and HIV risk behaviors among both forced and unforced migrant populations from low and middle income countries (LMIC). We conducted a review of studies published from 1995 to 2014. Data were extracted related to (1) the relationship between trauma and HIV risk behaviors, (2) methodological approach, (3) assessment methods, and (4) differences noted between forced and unforced migrants. A total of 340 records were retrieved with 24 studies meeting inclusion criteria. Our review demonstrated an overall relationship between trauma and HIV risk behaviors among migrant populations in LMIC, specifically with sexual violence and sexual risk behavior. However, findings from 10 studies were not in full support of the relationship. Findings from the review suggest that additional research using more rigorous methods is critically needed to understand the nature of the relationship experienced by this key-affected population.

Abstract access

Editor’s notes: The number of forced and unforced migrants is growing globally. Refugees, asylum seekers, and internally displaced persons (IDP) are forced migrants who often migrate due to political violence or conflict. Labour migrants are seen as unforced migrants who choose to emigrate for economic reasons. About half of labour migrants worldwide are women who are increasingly migrating on their own being the sole income provider for their families. With respect to trauma exposure and HIV risk in settings of long-term political violence and conflict, the distinction between war migrant, non-war migrant, and long-term resident is blurred. This in-depth review of 24 studies related to low-and middle-income countries (LMIC), mostly from sub-Saharan Africa, found findings similar to those from non-migrant populations in high-income countries. These linked traumatic experiences among migrant populations with HIV risk behaviours. Sexual violence was consistently associated with HIV sexual risk behaviours and HIV infection across the studies. But there are big gaps in the scientific literature. For example, the relationship between trauma and HIV risks has been explored for female labour migrants who are sex workers but not among women who have other occupations. Most studies addressed sexual risk and alcohol dependence, but injecting drug risk behaviours and use of any illicit drugs were virtually ignored by most studies. Few studies examined a possible link for trauma that occurred pre-migration and post-migration. Three qualitative studies examined male migrants who have sex with men, finding that violent experiences and discrimination and stigma associated with homophobia, combined with other migrant-associated traumas, can compound their mental health outcomes and subsequent HIV risk behaviours – but all were only conducted in the last four years. No studies were found that focused on HIV prevention programmes to address trauma and HIV risks among migrant workers in LMIC. However, the studies do reveal important factors that prevention programmes would have to consider. For example, concerns among labour migrants about dangerous working conditions may take precedence over HIV risk perceptions and the need for safer sex. This systematic review presents a wealth of information while highlighting the need to improve the quality of scientific research examining the link between HIV and trauma among both forced and unforced migrants in LMIC. 

Africa, Asia, Europe, Latin America
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Sex and drugs: cost-effectiveness of risk reduction programmes for female sex workers who inject drugs in Mexico

Cost-effectiveness of combined sexual and injection risk reduction interventions among female sex workers who inject drugs in two very distinct Mexican border cities.

Burgos JL, Patterson TL, Graff-Zivin JS, Kahn JG, Rangel MG, Lozada MR, Staines H, Strathdee SA. PLoS One. 2016 Feb 18;11(2):e0147719. doi: 10.1371/journal.pone.0147719. eCollection 2016.

Background: We evaluated the cost-effectiveness of combined single session brief behavioral intervention, either didactic or interactive (Mujer Mas Segura, MMS) to promote safer-sex and safer-injection practices among female sex workers who inject drugs (FSW-IDUs) in Tijuana (TJ) and Ciudad-Juarez (CJ) Mexico. Data for this analysis was obtained from a factorial RCT in 2008-2010 coinciding with expansion of needle exchange programs (NEP) in TJ, but not in CJ.

Methods: A Markov model was developed to estimate the incremental cost per quality adjusted life year gained (QALY) over a lifetime time frame among a hypothetical cohort of 1000 FSW-IDUs comparing a less intensive didactic vs. a more intensive interactive format of the MMS, separately for safer sex and safer injection combined behavioral interventions. The cost for antiretroviral therapy was not included in the model. We applied a societal perspective, a discount rate of 3% per year and currency adjusted to US$2014. A multivariate sensitivity analysis was performed. The combined and individual components of the MMS interactive behavioral intervention were compared with the didactic formats by calculating the incremental cost-effectiveness ratios (ICER), defined as incremental unit of cost per additional health benefit (e.g., HIV/STI cases averted, QALYs) compared to the next least costly strategy. Following guidelines from the World Health Organization, a combined strategy was considered highly cost-effective if the incremental cost per QALY gained fell below the gross domestic product per capita (GDP) in Mexico (equivalent to US$ 10 300).

Findings: For CJ, the mixed intervention approach of interactive safer sex/didactic safer injection had an incremental cost-effectiveness ratio (ICER) of US$4360 ($310-$7200) per QALY gained compared with a dually didactic strategy. Using the dually interactive strategy had an ICER of US$5874 ($310-$7200) compared with the mixed approach. For TJ, the combination of interactive safer sex/didactic safer injection had an ICER of US$5921 ($104-$9500) per QALY compared with dually didactic. Strategies using the interactive safe injection intervention were dominated due to lack of efficacy advantage. The multivariate sensitivity analysis showed a 95% certainty that in both CJ and TJ the ICER for the mixed approach (interactive safer sex didactic safer injection intervention) was less than the GDP per capita for Mexico. The dual interactive approach met this threshold consistently in CJ, but not in TJ.

Interpretation: In the absence of an expanded NEP in CJ, the combined-interactive formats of the MMS behavioral intervention is highly cost-effective. In contrast, in TJ where NEP expansion suggests that improved access to sterile syringes significantly reduced injection-related risks, the interactive safer-sex combined didactic safer-injection was highly cost-effective compared with the combined didactic versions of the safer-sex and safer-injection formats of the MMS, with no added benefit from the interactive safer-injection component.

Abstract  Full-text [free] access 

Editor’s notes: Female sex workers who inject drugs are a particularly vulnerable group with potential risks of HIV infection stemming from both condomless sex and use of contaminated injecting equipment. In the northern border towns of Mexico, which are on major drug trafficking routes into the United States, the prevalence of HIV among female sex workers who inject drugs is 12%. This is in comparison with 6% among female sex workers who do not inject drugs and 0.3% among the general population. In this context, the authors conducted a cost-effectiveness analysis of a combined single-session brief behavioural programme. It was either didactic or interactive, to promote safer sexual and injection practices among female sex workers who inject drugs in two Mexican cities: Ciudad Juarez and Tijuana.

The authors found that the programme can be highly cost-effective in reducing HIV risky behaviours, although with varying results. Sensitivity analyses suggested that in both cities, the mixed approach (interactive safer sex/didactic safer injection intervention) was highly cost-effective. The dual interactive approach was highly cost-effective in Ciudad Juarez but not in Tijuana.

This article illustrates the importance of targeting programmes that take into consideration city-level contexts. Although the cities are similar in many ways, the double interactive approach was not highly cost-effective in the Tijuana setting. This is likely to be due to the fact that needle syringe distribution at the community level expanded at the same time, making the interactive safer injection practice component redundant. This supports previous research that community-level programmes, such as needle-exchange programmes, could be potentially more cost-effective than individual-level activities. Individual-level activities may then be best suited for settings where needle-syringe programmes are not available, such as in prisons. 

Latin America
Mexico
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Gender inequity expressed as infidelity and jealousy by Nicaraguan men

Gender-specific jealousy and infidelity norms as sources of sexual health risk and violence among young coupled Nicaraguans.

Boyce S, Zeledon P, Tellez E, Barrington C. Am J Public Health. 2016 Feb 18:e1-e8. [Epub ahead of print]

Gender inequity negatively affects health in Central America. In 2011, we conducted 60 semistructured interviews and 12 photovoice focus groups with young coupled men and women in Leon, Nicaragua, to explore the ways in which social norms around marriage and gender affect sexual health and gender-based violence. Participants' depictions of their experiences revealed gendered norms around infidelity that provided a narrative to justify male expressions of jealousy, which included limiting partner autonomy, sexual coercion, and physical violence against women, and resulted in increased women's risk of sexually transmitted infections, including HIV. By understanding and taking account of these different narratives and normalized beliefs in developing health- and gender-based violence interventions, such programs might be more effective in promoting gender-equitable attitudes and behaviors among young men and women in Nicaragua.

Abstract access

Editor’s notes: This interesting paper explored persistent gender inequity in Nicaragua and its effects on sexual health and experiences of gender-based violence. The authors draw on an understanding that in Nicaragua gender inequity is expressed through local ideas of ‘machismo’, the masculine expectation of dominance over women. This is demonstrated through overemphasized heterosexuality, and aggression, and ‘marianismo’, the feminine expectation of submissiveness, dependence, and sexual naivety. The authors conducted two semi-structured in-depth interviews with 30 young coupled men (n = 15) and women (n = 15) and focus groups with a subsample of women (n= 6) and men (n= 5) who participated in interviews. They also asked these participants to take three photos about a discussion topic, which were discussed at a following session.

Their findings revealed two themes concerning fidelity and jealousy. Participants discussed the social acceptability of infidelity by men, and jealous behaviour by men. Women reported having little power to influence their husbands to remain faithful or to stop being jealous. The authors argue that infidelity and jealousy norms are expressions of gender inequity and impact on women’s risk of sexually transmitted infections, sexual coercion, and violence. These factors reflect constrained female sexuality and economic power. The authors conclude that while gender norms in Nicaragua are changing, progress toward gender equity is slow. Programmes to address gender inequity should frame this in terms of jealousy and infidelity, complemented with structural and systemic programmes to address gender-based social and economic inequities.

Gender
Latin America
Nicaragua
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Routine use of steroids harmful in cryptococcal meningitis

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.

Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN, CryptoDex Investigations. N Engl J Med. 2016 Feb 11;374(6):542-54. doi: 10.1056/NEJMoa1509024.

Background: Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600 000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis.

Methods: In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole.

Results: The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites.

Conclusions: Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.

Abstract  Full-text [free] access 

Editor’s notes: Outcomes from cryptococcal meningitis in people living with HIV are very poor. This was highlighted here. Three out of five people overall had died or were severely disabled ten weeks after enrolment. This clinical trial provides strong evidence that steroids cause more harm than good and therefore routine use should not be recommended. Dexamethasone was not only associated with higher risk of death or disability but also with higher risk of significant adverse events, particularly bacterial sepsis.

The majority of deaths occurred early, in the first three weeks. Most participants were ART naïve and severely immunosuppressed (CD4+ cell count <50 cells/µL) and most deaths look to have occurred prior to the scheduled start of antiretroviral therapy. This may also partly explain the low frequency of immune reconstitution inflammatory syndrome (IRIS) and the lack of any observed benefit of dexamethasone in reducing IRIS.

Although dexamethasone was associated with greater decline in intracranial pressure, this did not translate into improved neurological outcomes. All participants had regular lumbar punctures for pressure monitoring. This might have limited the potential to observe a benefit from dexamethasone. Some explanation for the adverse outcomes might come from the impaired fungal clearance in cerebrospinal fluid – a marker of poor outcomes in previous studies. It should be noted that antifungal treatment in this trial was suboptimal. The combination of amphotericin and flucytosine was not used, despite evidence of improved outcomes and more rapid fungal clearance with this regimen.

While the search should go on for better treatment strategies, the findings in this study emphasise the importance of prevention, focused firmly, on earlier HIV diagnosis and treatment.  

Comorbidity, HIV Treatment
Indonesia, Laos, Malawi, Thailand, Uganda, Viet Nam
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