Articles tagged as "Botswana"

Hepatitis B virus co-infection: a challenge to successful ART in sub-Saharan Africa?

Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.

Stabinski L, OʼConnor S, Barnhart M, Kahn RJ, Hamm TE. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S274-85. doi: 10.1097/QAI.0000000000000496.

Background: Screening people living with HIV for hepatitis B virus (HBV) co-infection is recommended in resource-rich settings to optimize HIV antiretroviral therapy (ART) and mitigate HBV-related liver disease. This review examines the need, feasibility, and impact of screening for HBV in resource-limited settings (RLS).

Methods: We searched 6 databases to identify peer-reviewed publications between 2007 and 2013 addressing (1) HIV/HBV co-infection frequency in sub-Saharan Africa (SSA); (2) performance of hepatitis B surface antigen (HBsAg) rapid strip assays (RSAs) in RLS; (3) impact of HBV co-infection on morbidity, mortality, or liver disease progression; and/or (4) impact of HBV-suppressive antiretroviral medications as part of ART on at least one of 5 outcomes (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). We rated the quality of individual articles and summarized the body of evidence and expected impact of each intervention per outcome addressed.

Results: Of 3940 identified studies, 85 were included in the review: 55 addressed HIV/HBV co-infection frequency; 6 described HBsAg RSA performance; and 24 addressed the impact of HIV/HBV co-infection and ART. HIV/HBV frequency in sub-Saharan Africa varied from 0% to >28.4%. RSA performance in RLS showed good, although variable, sensitivity and specificity. Quality of studies ranged from strong to weak. Overall quality of evidence for the impact of HIV/HBV co-infection and ART on morbidity and mortality was fair and good to fair, respectively.

Conclusions: Combined, the body of evidence reviewed suggests that HBsAg screening among people living with HIV could have substantial impact on preventing morbidity and mortality among HIV/HBV co-infected individuals in RLS.

Abstract access 

Editor’s notes: The routes of transmission for hepatitis B virus (HBV) and HIV are the same, and they frequently co-infect individuals in high HIV prevalence settings. HIV has also been shown to accelerate the progression of HBV. This has important implications for ART programmes, given also the potential for hepatotoxicity of ART. The response of both infections to certain antivirals gives an opportunity to treat both infections simultaneously, but also the potential to engender resistant strains of virus if treatment is optimised for one and not the other.

This paper reviews the evidence that might support inclusion of HBV screening as part of HIV care programmes. No clinical trials have been done in this area, so the review is based on observational studies. The data are incomplete and geographically patchy, largely from Nigeria and South Africa. However, this does not prevent the authors from concluding that the co-infection risk is sufficiently high and the consequences of lack of treatment sufficiently severe to consider allocation of scarce resources to identify and manage HBV co-infection in HIV programmes. Appropriate validated screening tools - rapid tests for hepatitis B surface antigen - are available. The potential benefit warrants consideration of this issue in sub-Saharan Africa, and inclusion of HBV surveillance alongside HIV to resolve the paucity of data in most countries. This should be rapidly followed by further consideration of the cost- and risk-benefit of introduction of an HBV screening and treatment programme.

Interested readers might also refer to a review by Matthews et al. (J Clin Virol 2014;6:20-33) which considers similar questions and also discusses hepatitis C co-infection.

Avoid TB deaths
Africa
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Hepatitis B virus co-infection: a challenge to successful ART in sub-Saharan Africa?

Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.

Stabinski L, OʼConnor S, Barnhart M, Kahn RJ, Hamm TE. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S274-85. doi: 10.1097/QAI.0000000000000496.

Background: Screening people living with HIV for hepatitis B virus (HBV) co-infection is recommended in resource-rich settings to optimize HIV antiretroviral therapy (ART) and mitigate HBV-related liver disease. This review examines the need, feasibility, and impact of screening for HBV in resource-limited settings (RLS).

Methods: We searched 6 databases to identify peer-reviewed publications between 2007 and 2013 addressing (1) HIV/HBV co-infection frequency in sub-Saharan Africa (SSA); (2) performance of hepatitis B surface antigen (HBsAg) rapid strip assays (RSAs) in RLS; (3) impact of HBV co-infection on morbidity, mortality, or liver disease progression; and/or (4) impact of HBV-suppressive antiretroviral medications as part of ART on at least one of 5 outcomes (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). We rated the quality of individual articles and summarized the body of evidence and expected impact of each intervention per outcome addressed.

Results: Of 3940 identified studies, 85 were included in the review: 55 addressed HIV/HBV co-infection frequency; 6 described HBsAg RSA performance; and 24 addressed the impact of HIV/HBV co-infection and ART. HIV/HBV frequency in sub-Saharan Africa varied from 0% to >28.4%. RSA performance in RLS showed good, although variable, sensitivity and specificity. Quality of studies ranged from strong to weak. Overall quality of evidence for the impact of HIV/HBV co-infection and ART on morbidity and mortality was fair and good to fair, respectively.

Conclusions: Combined, the body of evidence reviewed suggests that HBsAg screening among people living with HIV could have substantial impact on preventing morbidity and mortality among HIV/HBV co-infected individuals in RLS.

Abstract access 

Editor’s notes: The routes of transmission for hepatitis B virus (HBV) and HIV are the same, and they frequently co-infect individuals in high HIV prevalence settings. HIV has also been shown to accelerate the progression of HBV. This has important implications for ART programmes, given also the potential for hepatotoxicity of ART. The response of both infections to certain antivirals gives an opportunity to treat both infections simultaneously, but also the potential to engender resistant strains of virus if treatment is optimised for one and not the other.

This paper reviews the evidence that might support inclusion of HBV screening as part of HIV care programmes. No clinical trials have been done in this area, so the review is based on observational studies. The data are incomplete and geographically patchy, largely from Nigeria and South Africa. However, this does not prevent the authors to conclude that the co-infection risk is sufficiently high and the consequences of lack of treatment sufficiently severe to consider allocation of scarce resources to identify and manage HBV co-infection in HIV programmes. Appropriate validated screening tools such as rapid tests for hepatitis B surface antigen are available. The potential benefit warrants consideration of this issue in sub-Saharan Africa, and inclusion of HBV surveillance alongside HIV to resolve the paucity of data in most countries. This should be rapidly followed by further consideration of the cost- and risk-benefit of introduction of an HBV screening and treatment programme.

Interested readers might also refer to a review by Matthews et al. (J Clin Virol 2014;6:20-33) which considers similar questions and also discusses hepatitis C co-infection.

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Africa
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Need for further water, sanitation and hygiene programmes among people living with HIV

The impact of water, sanitation, and hygiene interventions on the health and well-being of people living with HIV: a systematic review.

Yates T, Lantagne D, Mintz E, Quick R. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S318-30. doi: 10.1097/QAI.0000000000000487.

Background: Access to improved water supply and sanitation is poor in low-income and middle-income countries. Persons living with HIV/AIDS (PLHIV) experience more severe diarrhea, hospitalizations, and deaths from diarrhea because of waterborne pathogens than immunocompetent populations, even when on antiretroviral therapy (ART).

Methods: We examined the existing literature on the impact of water, sanitation, and hygiene (WASH) interventions on PLHIV for these outcomes: (1) mortality, (2) morbidity, (3) retention in HIV care, (4) quality of life, and (5) prevention of ongoing HIV transmission. Cost-effectiveness was also assessed. Relevant abstracts and articles were gathered, reviewed, and prioritized by thematic outcomes of interest. Articles meeting inclusion criteria were summarized in a grid for comparison.

Results: We reviewed 3355 citations, evaluated 132 abstracts, and read 33 articles. The majority of the 16 included articles focused on morbidity, with less emphasis on mortality. Contaminated water, lack of sanitation, and poor hygienic practices in homes of PLHIV increase the risk of diarrhea, which can result in increased viral load, decreased CD4 counts, and reduced absorption of nutrients and antiretroviral medication. We found WASH programming, particularly water supply, household water treatment, and hygiene interventions, reduced morbidity. Data were inconclusive on mortality. Research gaps remain in retention in care, quality of life, and prevention of ongoing HIV transmission. Compared with the standard threshold of 3 times GDP per capita, WASH interventions were cost-effective, particularly when incorporated into complementary programs.

Conclusions: Although research is required to address behavioral aspects, evidence supports that WASH programming is beneficial for PLHIV.

Abstract access 

Editor’s notes: Researchers, implementers, and policy makers have been examining how to better integrate programmes with overlapping burdens of morbidity and mortality. This paper illustrates how access to clean water and good sanitation practices, or lack thereof, can impact the health of people living with HIV. Water, sanitation, and hygiene (WASH) programmes can improve the negative effects poor water quality and bad sanitation have on people living with HIV. They reduce or even eliminate diarrheal infections, which allow for better absorption of HIV treatment medication that leads to a reduction in viral load and increased CD4 counts. While this systematic review revealed evidence on the reduced burden of morbidity that WASH programmes can confer, little has been done in the way of research linking WASH programmes to mortality in people living with HIV, nor how they may affect adherence or retention in care. Side effects of HIV treatment is a common reason why people stop taking medications, and common side effects are nausea and diarrhoea. It is possible that intestinal issues caused by unsafe drinking water could exacerbate the impact of side effects on people already experiencing them, therefore reducing motivation to continue taking their ARVs. This paper also suggests that synergies in cost sharing and increasing cost effectiveness could be achieved by integrating programmes. However further research is necessary to fully understand the logistical and cost implications.

 

Africa, Asia
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Adolescent adherence to antiretroviral therapy: what matters?

Factors associated with adherence to antiretroviral therapy among adolescents living with HIV/AIDS in low- and middle-income countries: a systematic review.

Hudelson C, Cluver L. AIDS Care. 2015 Feb 23:1-12. [Epub ahead of print]

Adolescents living in low- and middle-income countries (LMICs) are disproportionately burdened by the global HIV/AIDS pandemic. Maintaining medication adherence is vital to ensuring that adolescents living with HIV/AIDS receive the benefits of antiretroviral therapy (ART), although this group faces unique challenges to adherence. Knowledge of the factors influencing adherence among people during this unique developmental period is needed to develop more targeted and effective adherence-promoting strategies. This systematic review summarizes the literature on quantitative observational studies examining correlates, including risk and resilience-promoting factors, of ART adherence among adolescents living with HIV/AIDS in LMICs. A systematic search of major electronic databases, conference-specific databases, gray literature, and reference lists of relevant reviews and documents was conducted in May 2014. Included studies examined relationships between at least one factor and ART adherence as an outcome and were conducted in primarily an adolescent population (age 10-19) in LMICs. The search identified 7948 unique citations from which 15 studies fit the inclusion criteria. These 15 studies identified 35 factors significantly associated with ART adherence representing a total of 4363 participants across nine different LMICs. Relevant studies revealed few consistent relationships between measured factors and adherence while highlighting potentially important themes for ART adherence including the impact of (1) adolescent factors such as gender and knowledge of serostatus, (2) family structure, (3) the burdensome ART regimens, route of administration, and attitudes about medication, and (4) health care and environmental factors, such as rural versus urban location and missed clinic appointments. Rates of adherence across studies ranged from 16% to 99%. This review identifies unique factors significantly related to ART adherence among adolescents living in LMICs. More research using longitudinal designs and rigorous measures of adherence is required in order to identify the range of factors influencing ART adherence as adolescents living with HIV/AIDS in LMICs grow into adulthood.

Abstract access 

Editor’s notes: Expanded access to antiretroviral therapy (ART) and scale-up of programmes to prevent mother-to-child HIV transmission has resulted in the burden of paediatric HIV infection shifting onto adolescents, in low- and middle-income countries. Adolescents and young adults account for 41% of incident infections globally and are the only age group for which AIDS-associated deaths have risen in the past decade.

As the number of adolescents on ART increases, sustaining optimal adherence has emerged as the key challenge. While there are limited adolescent-specific data available, estimates of ART adherence suggest that adolescents have much poorer adherence than adults. This leads to increased risk of disease progression, transmission to sexual partners and antiretroviral drug resistance.

There is a growing body of literature that has examined factors affecting adherence, but to date the focus has been on adults and young children. Therefore, this systematic review of factors associated with good and suboptimal adherence specifically among adolescents aged 10 to 19 years, is timely.

There were a diverse range of factors associated with adherence across the fifteen studies considered. These include knowledge of serostatus, the influence of family structure, burdensome regimens, route of administration (caregiver giving medication versus adolescent self-medicating), and attitudes about medication and missed appointments. These factors likely interact with the complexities faced during adolescence to increase the risk of suboptimal adherence.   

The studies considered in this review had significant weaknesses. Firstly, most studies were cross-sectional. Therefore the extent to which causality between the considered factors and adherence can be inferred is limited. Secondly, not all studies reported on the strengths of the relationship between the factors and adherence or accounted for confounding. Thirdly, the method of measuring adherence varied between studies. Only one study in the review used a gold standard, objective treatment outcome measure, HIV viral load.

Notwithstanding these limitations, this is the first study to examine correlates of adherence to ART in adolescence. Although there were few consistent relationships between these factors and adherence, the study does suggest potential activities to improve adherence.

Given the central role of adolescents in determining the trajectory of the HIV epidemic, there is a need for more rigorous research to define factors affecting adherence behaviours among adolescents. Programmes addressing important risk- and resilience-promoting factors such as caregiver support and less burdensome regimens have potential to improve adherence. 

Africa, Asia, Europe, Latin America
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TB protection from 36 months of isoniazid preventive therapy wanes after IPT stopped in Botswana

Tuberculosis incidence after 36 months' isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis.

Samandari T, Agizew TB, Nyirenda S, Tedla Z, Sibanda T, Mosimaneotsile B, Motsamai OI, Shang N, Rose CE, Shepherd J. AIDS. 2015 Jan 28;29(3):351-9. doi: 10.1097/QAD.0000000000000535.

Objective: Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit.

Design: A 36-month double-blind placebo controlled trial (1:1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011.

Methods: One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months.

Results: In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period.

Conclusion: The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings.

Abstract access

Editor’s notes: Randomised controlled trials have illustrated that isoniazid preventive therapy (IPT) prevents TB among people living with HIV. Limited data from early trials suggested that the protective effect of a six month course of IPT waned over time after the end of the IPT course. The authors conducted a clinical trial among people living with HIV in Botswana, comparing 36 with six months of IPT. They found that TB incidence was lower in the group receiving 36 months of IPT, but this effect was limited to people whose baseline tuberculin skin test (TST) was positive.

In this paper, the authors present additional data from that trial, illustrating TB incidence during extended follow-up of participants after the end of the study. Participants started antiretroviral therapy (ART) according to national guidelines. By the end of follow up in 2011, 72% had started ART. In the post-trial period, i.e. from 36 months after enrolment, TB incidence was around 1%, similar in both arms of the trial. During the 36 months of the trial, the unadjusted hazard of TB was reduced by nearly half in the group taking 36 months of IPT. However, after the end of the trial, this protective effect waned to around 20%. Among participants who were TST positive at enrolment, the protective effect of prolonged IPT was greater during the trial, nearly a 75% reduction in TB. This effect waned to 60% after the end of the trial.

Several recent papers have discussed possible mechanisms for waning protection after a limited course of IPT in settings where TB transmission is common. An obvious explanation would be reinfection with TB, followed by rapid progression to active disease. An alternative could be that IPT does not effectively “sterilise” latent TB infection, resulting in reactivation disease after IPT is stopped. Since diagnostic tests for latent infection are unsatisfactory, it is difficult to distinguish between these possibilities. Whatever the mechanism, HIV-positive people remain at higher risk of TB despite ART. In settings where TB is common, a limited course of IPT does not give lasting protection. The data from this study provide further evidence in support of continuous IPT, particularly for people living with HIV who are TST-positive. Studies are in progress to evaluate alternative preventive therapy regimens which have greater potential to sterilise latent TB infection. Such regimens might be effective in shorter courses, which would be an advantage. But this would need to be balanced against the risk of disease due to reinfection with TB. How best to ensure lasting protection against TB for HIV-positive people remains a critically important question.

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Comorbidity
Africa
Botswana
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Further evidence of an association with the injectable contraceptive, depot-medroxyprogesterone acetate with risk of HIV

Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis.

Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM, Van Damme L, Delany-Moretlwe S, Francis SC, Friedland BA, Hayes RJ, Heffron R, Kapiga S, Karim QA, Karpoff S, Kaul R, McClelland RS, McCormack S, McGrath N, Myer L, Rees H, van der Straten A, Watson-Jones D, van de Wijgert JH, Stalter R, Low N. PLoS Med. 2015 Jan 22;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. eCollection 2015.

Background: Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.

Methods and findings: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37 124 women (43 613 woman-years) and 1830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship.

Conclusions: This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Abstract  Full-text [free] access

Editor’s notes: As seen in the paper published this month by Ralph et al, observational studies have reported that hormonal contraception, in particular injectable progestins depot-medroxyprogesterone acetate (DMPA), may increase risk of HIV infection. This individual patient data meta-analysis adds further to the evidence. A major strength of the study is the large sample size. It provides sufficient power to examine associations between specific contraceptives and HIV risk and to investigate effect modification in pre-specified sub-group analyses. Furthermore, using individual-level data allowed a consistent approach to coding and adjustment for confounding. If the association is real, this has important implications for sexual and reproductive health in areas of sub-Saharan Africa where the incidence of HIV acquisition and unintended pregnancy is high.

 


 

Hormonal contraceptive use and women's risk of HIV acquisition: a meta-analysis of observational studies.

Ralph LJ, McCoy SI, Shiu K, Padian NS. Lancet Infect Dis. 2015 Jan 8. pii: S1473-3099(14)71052-7. doi: 10.1016/S1473-3099(14)71052-7. [Epub ahead of print]

Background: The evidence from epidemiological research into whether use of hormonal contraception increases women's risk of HIV acquisition is inconsistent. We did a robust meta-analysis of existing data to provide summary estimates by hormonal contraceptive method which can be used to inform contraceptive guidelines, models, and future studies.

Methods: We updated a recent systematic review to identify and describe studies that met inclusion criteria. To ensure inclusion of more recent research, we searched PubMed for articles published after December, 2011, using the terms "hormonal contraception", "HIV/acquisition", "injectables", "progestin", and "oral contraceptive pills". We assessed statistical heterogeneity for these studies, and, when appropriate, combined point estimates by hormonal contraception formulation using random-effects models. We assessed publication bias and investigated heterogeneity through subgroup and stratified analyses according to study population and design features.

Findings: We identified 26 studies, 12 of which met inclusion criteria. There was evidence of an increase in HIV risk in the ten studies of depot medroxyprogesterone acetate (pooled hazard ratio [HR] 1.40, 95% CI 1.16-1.69). This risk was lower in the eight studies done in women in the general population (pooled HR 1.31, 95% CI 1.10-1.57). There was substantial between-study heterogeneity in secondary analyses of trials (n=7, I2 51.1%, 95% CI 0-79.3). Although individual study estimates suggested an increased risk, substantial heterogeneity between two studies done in women at high risk of HIV infection (I2 54%, 0-88.7) precluded pooling estimates. There was no evidence of an increased HIV risk in ten studies of oral contraceptive pills (pooled HR 1.00, 0.86-1.16) or five studies of norethisterone enanthate (pooled HR 1.10, 0.88-1.37).

Interpretation: Our findings show a moderate increased risk of HIV acquisition for all women using depot medroxyprogesterone acetate, with a smaller increase in risk for women in the general population. Whether the risks of HIV observed in our study would merit complete withdrawal of depot medroxyprogesterone acetate needs to be balanced against the known benefits of a highly effective contraceptive.

Abstract access

Editor’s notes: This meta-analysis has similar findings to the individual patient data (IPD) meta-analysis by Morrison et al, also published this month. The study finds that depot medroxyprogesterone (DMPA) is associated with a moderate increase in HIV risk, and little evidence of a risk associated with combined oral contraceptives or norethisterone enanthate (NET-EN). The policy implications of this finding are unclear. As with the IPD analysis, this meta-analysis is based on observational studies and does not provide conclusive evidence that DMPA causes the increased risk of HIV. However, it does provide refined estimates for modelling studies to assess the implications of possible withdrawal of DMPA on maternal and HIV-associated mortality, so that context-specific contraceptive policies can be considered.

Africa
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Optimising outcomes on second-line antiretroviral therapy: partner-based modified directly observed therapy is not the answer

Partner-based adherence intervention for second-line antiretroviral therapy (ACTG 5234): a multinational randomised trial.

Gross R, Zheng L, La Rosa A, Sun X, Rosenkrantz SL, Wagner Cardoso S, Ssali F, Camp R, Godfrey C, Cohn SE, Robbins GK, Chisada A, Wallis CL, Reynolds NR, Lu D, Safren SA, Hosey L, Severe P, Collier AC for the ACTG 5234 team. Lancet HIV 2015; 2: e12–19

Background: Adherence is key to the success of antiretroviral therapy. Enhanced partner support might benefit patients with previous treatment failure. We aimed to assess whether an enhanced partner-based support intervention with modified directly observed therapy would improve outcomes with second-line therapy in HIV-infected patients for whom first-line therapy had failed.

Methods: We did a multicentre, international, randomised clinical trial at nine sites in Botswana, Brazil, Haiti, Peru, South Africa, Uganda, Zambia, and Zimbabwe. Participants aged 18 years or older for whom first-line therapy had failed, with HIV RNA concentrations greater than 1000 copies per mL and with a willing partner, were randomly assigned (1:1), via computer-generated randomisation, to receive partner-based modified directly observed therapy or standard of care. Randomisation was stratified by screening HIV RNA concentration (≤10 000 copies per mL vs >10 000 copies per mL). Participants and site investigators were not masked to group assignment. Primary outcome was confirmed virological failure (viral load >400 copies per mL) by week 48. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00608569.

Findings: Between April 23, 2009, and Sept 29, 2011, we randomly assigned 259 participants to the modified directly observed therapy group (n=129) or the standard-of-care group (n=130). 34 (26%) participants in the modified directly observed therapy group achieved the primary endpoint of virological failure by week 48 compared with 23 (18%) participants in the standard-of-care group. The Kaplan-Meier estimated cumulative probability of virological failure by week 48 was 25·1% (95% CI 17·7–32·4) in the modified directly observed therapy group and 17·3% (10·8–23·7) in the standard-of-care group, for a weighted difference in standard of care versus modified directly observed therapy of −6·6% (95% CI −16·5% to 3·2%; p=0·19). 36 (14%) participants reported at least one grade 3 or higher adverse event or laboratory abnormality (n=21 in the modified directly observed therapy group and n=15 in the standard-of-care group).

Interpretation: Partner-based training with modified directly observed therapy had no effect on virological suppression. The intervention does not therefore seem to be a promising strategy to increase adherence. Intensive follow-up with clinic staff might be a viable approach in this setting.

Abstract access

Editor’s notes: High rates of virologic failure on second-line antiretroviral therapy (ART) are reported in resource-limited settings. The main driver of this is thought to be sub-optimal adherence rather than resistance. As many of these settings have limited access to third-line regimens there is an urgent need for evidence-informed programmes to optimise peoples’ adherence, both to first-line and second-line regimens.

The results from this randomised controlled trial provide further evidence that partner-based modified directly observed therapy is not the answer. Interestingly, people enrolled in this trial had far lower rates of virologic failure than have been observed in programmatic settings, regardless of whether they were in the programme or standard-of-care arm. Many factors could account for this, including the fact that all people enrolled in the study had to have disclosed their status to a friend or family member, all received enhanced education and support and all attended regular clinic appointments. Further pragmatic studies which focus on clinic-and patient-level programmes are needed to determine the optimal strategies for maximising peoples’ adherence. 

Africa, Latin America
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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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Which activities promote adherence to antiretroviral therapy?

Interventions to promote adherence to antiretroviral therapy in Africa: a network meta-analysis.

Mills EJ, Lester R, Thorlund K, Lorenzi M, Muldoon K, Kanters S, Linnemayr S, Gross R, Calderon Y, Amico KR, Thirumurthy H, Pearson C, Remien RH, Mbuagbaw L, Thabane L, Chung MH, Wilson IB, Liu A, Uthman OA, Simoni J, Bangsberg D, Yaya S, Bärnighausen T, Ford N, Nachega JB, Lancet HIV 2014; 1: e104–11 doi:10.1016/S2352-3018(14)00003-4.

Background: Adherence to antiretroviral therapy (ART) is necessary for the improvement of the health of patients and for public health. We sought to determine the comparative effectiveness of different interventions for improving ART adherence in HIV-infected people living in Africa.

Methods: We searched for randomised trials of interventions to promote antiretroviral adherence within adults in Africa. We searched AMED, CINAHL, Embase, Medline (via PubMed), and ClinicalTrials.gov from inception to Oct 31, 2014, with the terms “HIV”, “ART”, “adherence”, and “Africa”. We created a network of the interventions by pooling the published and individual patients' data for comparable treatments and comparing them across the individual interventions with Bayesian network meta-analyses. The primary outcome was adherence defined as the proportion of patients meeting trial defined criteria; the secondary endpoint was viral suppression.

Findings: We obtained data for 14 randomised controlled trials, with 7110 patients. Interventions included daily and weekly short message service (SMS; text message) messaging, calendars, peer supporters, alarms, counselling, and basic and enhanced standard of care (SOC). Compared with SOC, we found distinguishable improvement in self-reported adherence with enhanced SOC (odds ratio [OR] 1·46, 95% credibility interval [CrI] 1·06–1·98), weekly SMS messages (1·65, 1·25–2·18), counselling and SMS combined (2·07, 1·22–3·53), and treatment supporters (1·83, 1·36–2·45). We found no compelling evidence for the remaining interventions.

Results: were similar when using viral suppression as an outcome, although the network contained less evidence than that for adherence. Treatment supporters with enhanced SOC (1·46, 1·09–1·97) and weekly SMS messages (1·55, 1·01–2·38) were significantly better than basic SOC.

Interpretation: Several recommendations for improving adherence are unsupported by the available evidence. These findings can inform future intervention choices for improving ART adherence in low-income settings.

Abstract access 

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

A large number of potential programmes aimed at the improvement of engagement with care are available. While there is an urgent need for research on these programmes and on the effect of combined programmes, there is also the reality of a resource constrained environment. Network meta-analysis is a method to synthesise the evidence of programmes. The meta-analysis uses common comparators when these activities have not been compared head-to-head (resulting in indirect evidence), combined with evidence from head-to-head comparisons (direct evidence).

Using a network meta-analysis of randomized trials of programmes to improve ART adherence in Africa, the authors simultaneously compared eight groups of activities against standard care and against each other. The authors found that standard care augmented with intensified adherence counselling, or enhanced standard care, improved adherence to ART. Also weekly SMS messages, enhanced standard care combined with SMS, and enhanced standard care combined with having a treatment supporter were superior to standard care, with regards to self-reported adherence and viral suppression. The authors speculate that combinations of cognitive and behavioural programmes maximise the activity efficacy. Interestingly, their study found a large benefit for weekly but not for daily SMS messages. However the heterogeneity in the published treatment effects could be attributed to heterogeneity of the implemented programmes, especially of behavioural interventions. For example, the authors point out that there is a wide variability in the definition of standard care, and in the definition of treatment supporters.

The authors also note that several recommendations for improving adherence are unsupported by the evidence they examined using network meta-analysis.

Health care delivery
Africa
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