Articles tagged as "15 million accessing treatment"

Negative HIV antibody test results among children living with HIV

Young age at start of antiretroviral therapy and negative HIV antibody results in HIV-infected children when suppressed.

Kuhn L, Schramm DB, Shiau S, Strehlau R, Pinillos F, Technau K, Coovadia A, Abrams EJ, Puren A, Tiemessen CT. AIDS. 2015 Apr 13. [Epub ahead of print]

Background: Negative results on standard HIV antibody tests have been described among HIV-infected children suppressed on antiretroviral therapy (ART) started early in life. Here, we describe the frequency and predictors of this phenomenon in a well characterized cohort of treated children.

Methods: We selected samples from 103 HIV-infected children who started ART 14 months of age or less and from 122 children who started 6 months of age or less followed as part of two sequential clinical trials in Johannesburg, South Africa. Children had attained viral suppression on ART and had received ART for between 3 and 6.4 years (mean 4.3 years) when tested for HIV antibody using a standard ELISA (Genescreen HIV1/2 version 2; Bio-rad).

Results: Only children 6 months of age or less when ART was started had negative antibody results when tested after suppression on ART several years later. Negative or low-positive antibody results were observed in 40.0, 37.0 and 27.8% of children starting ART less than 2 months of age, or starting during month 2 or 3, respectively. This dropped to 5.9, 3.5 and 5.3% if ART was started during month 4, 5 and 6, respectively. Higher CD4 percentage prior to ART initiation and no recorded intermittent viremia also predicted negative antibody results.

Conclusion: Testing negative on standard HIV antibody tests occurs fairly commonly among HIV-infected children who started ART by 3 months of age or less and are virally suppressed. It would be prudent in clinical practice to avoid HIV antibody tests among virally suppressed, early-treated children to prevent unnecessary confusion.

Abstract access 

Editor’s notes: After 18 months of age, HIV antibody tests are used routinely for diagnosis in children, as in adults, with the typical expectation that antibody status does not revert to negative after a positive result.

This study illustrated that 34% of HIV-positive children who had started antiretroviral therapy (ART) by three months of age and were virally suppressed at the time of antibody testing, tested HIV antibody negative and/or had low-positive antibody results when tested several years later.

Negative HIV antibody test results were strongly related to the age of starting ART. The proportion of children who had a negative antibody test result dropped to approximately 5% if they had started ART between three and six months of age. No negative HIV antibody tests were observed among children who started ART after six months of age. Several studies have illustrated that younger age at starting ART is associated with a reduced size of the viral reservoir, and that this may be associated with better longer term outcomes. Assuming that a negative antibody response indicates a smaller viral reservoir, these findings suggest that the benefit of immediate ART after diagnosis may be attenuated in children who start ART after three months of age.

Notably, a higher pre-treatment CD4 percentage was independently associated with a greater likelihood of a negative HIV antibody test. Given that ART is now recommended in infants regardless of clinical and immunological status, it is likely that there may be higher rates of antibody negativity than those reported in this study, as the study cohort started ART before universal treatment guidelines were implemented.

In a clinical setting, a negative HIV antibody test in a child treated with antiretroviral therapy will raise concern among clinicians and parents about whether the child was initially misdiagnosed with HIV infection. Indeed there have been anecdotal reports of healthcare workers stopping ART in children testing HIV antibody negative based on mistaken assumptions. Great attention should be paid to ensuring that the initial diagnosis prior to ART initiation in a child under 18 months of age is based on adequate virological tests. Use of HIV antibody tests in children who initiated ART under six months of age should be avoided, given the high chance of the test being falsely negative and the considerable potential for misinterpretation.

South Africa
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Literacy and technology experience are predictors of a successful mHealth programme

Know your audience: predictors of success for a patient-centered texting app to augment linkage to HIV care in rural Uganda.

Siedner MJ, Santorino D. J Med Internet Res. 2015 Mar 24;17(3):e78. doi: 10.2196/jmir.3859.

Background: Despite investments in infrastructure and evidence for high acceptability, few mHealth interventions have been implemented in sub-Saharan Africa.

Objective: We sought to (1) identify predictors of uptake of an mHealth application for a low-literacy population of people living with HIV (PLWH) in rural Uganda and (2) evaluate the efficacy of various short message service (SMS) text message formats to optimize the balance between confidentiality and accessibility.

Methods: The trial evaluated the efficacy of a SMS text messaging app to notify PLWH of their laboratory results and request return to care for those with abnormal test results. Participants with a normal laboratory result received a single SMS text message indicating results were normal. Participants with an abnormal test result were randomized to 1 of 3 message formats designed to evaluate trade-offs between clarity and privacy: (1) an SMS text message that stated results were abnormal and requested return to clinic ("direct"), (2) the same message protected by a 4-digit PIN code ("PIN"), and (3) the message "ABCDEFG" explained at enrollment to indicate abnormal results ("coded"). Outcomes of interest were (1) self-reported receipt of the SMS text message, (2) accurate identification of the message, and (3) return to care within 7 days (for abnormal results) or on the date of the scheduled appointment (for normal results). We fit regression models for each outcome with the following explanatory variables: sociodemographic characteristics, CD4 count result, ability to read a complete sentence, ability to access a test message on enrollment, and format of SMS text message.

Results: Seventy-two percent (234/385) of participants successfully receiving a message, 87.6% (219/250) correctly identified the message format, and 60.8% (234/385) returned to clinic at the requested time. Among participants with abnormal tests results (138/385, 35.8%), the strongest predictors of reported message receipt were the ability to read a complete sentence and a demonstrated ability to access a test message on enrollment. Participants with an abnormal result who could read a complete sentence were also more likely to accurately identify the message format (AOR 4.54, 95% CI 1.42-14.47, P=.01) and return to clinic appropriately (AOR 3.81, 95% CI 1.61-9.03, P=.002). Those who were sent a PIN-protected message were less likely to identify the message (AOR 0.11, 95% CI 0.03-0.44, P=.002) or return within 7 days (AOR 0.26, 95% CI 0.10-0.66, P=.005). Gender, age, and socioeconomic characteristics did not predict any outcomes and there were no differences in outcomes between those receiving direct or coded messages.

Conclusions: Confirmed literacy at the time of enrollment was a robust predictor of SMS text message receipt, identification, and appropriate response for PLWH in rural Uganda. PIN-protected messages reduced odds of clinic return, but coded messages were as effective as direct messages and might augment privacy.

Abstract  Full-text [free] access

Editor’s notes: The authors of this study tap into the increasingly widespread ownership of mobile phones, individually or shared, in sub-Saharan Africa to examine whether text message reminders can be used as a tool to help keep people in care. This randomised trial from rural Uganda adds to the large literature, largely from high-income settings, on the acceptability of SMS text message programmes among people living with HIV. It is the first to directly assess the impact of literacy and experience with technology on clinical outcomes. The study illustrated that confirmed literacy, the absence of a PIN-code protector, and a demonstrated ability to access a sample SMS text message were good predictors of an appropriate response to an SMS reminder. Further, factors such as educational attainment, income, age and gender were not associated with the outcomes. The results have important implications for future mHealth programmes focussed on low-literacy end-users, illustrating the need to assess literacy and technology experience before implementation. 

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Can a simple risk score predict chronic kidney disease among people living with HIV?

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Mocroft A, Lundgren JD, Ross M, Law M, Reiss P, Kirk O, Smith C, Wentworth D, Neuhaus J, Fux CA, Moranne O, Morlat P, Johnson MA, Ryom L, D:A:D study group, the Royal Free Hospital Clinic Cohort, and the INSIGHT, SMART, and ESPRIT study groups. PLoS Med. 2015 Mar 31;12(3):e1001809. doi: 10.1371/journal.pmed.1001809. eCollection 2015.

Background: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.

Methods and findings: A total of 17 954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR >60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103 185 person-years of follow-up (PYFU; incidence 6.2/1000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score <0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1702 (95% CI 1166-3367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2548 individuals, of whom 94 individuals developed CKD (3.7%) during 18 376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria.

Conclusions: Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.

Abstract  Full-text [free] access

Editor’s notes: The nephrotoxicity of antiretroviral drugs, particularly tenofovir, is of concern, particularly where there is limited access to laboratory monitoring of kidney function. The development of kidney impairment among people with HIV is associated with poor outcomes, and in low resource settings where dialysis is not available this can be catastrophic.

This study, like previous work, attempts to address this problem by developing a risk score for the development of chronic kidney disease (CKD). The strength of this study is the availability of data for over 17 000 men and women living with HIV enrolled in cohort studies for many years, and in over 40 countries globally. The resulting risk score uses nine simple clinical variables which predict CKD both overall, and after starting potentially nephrotoxic antiretrovirals. A short risk score, not including cardiovascular risk factors, which may be more suitable for low resource settings, shows almost as good a prediction of CKD.

So will this risk score become widely used in clinical decision making? For high income countries this tool may be useful to identify people where strategies to prevent cardiovascular and renal disease are best focussed. It may also be useful to identify people at high risk of developing CKD for whom use of tenofovir may be unacceptable, especially when monitoring of kidney function is limited. However, few of the enrolled people were from low and middle income countries, and there was limited information on the race of participants. Therefore, the risk score may need to be validated in low resource settings before it can be widely used. Whether the use of the tool would help to improve clinical outcomes where kidney function is frequently monitored is unclear.

Meanwhile, a new drug formulation, tenofovir alafenamide (TAF), is currently in clinical trials. This appears to be associated with less renal toxicity, and to be safe and well tolerated among adults with decreased kidney function. If future trial results support this evidence, and tenofovir alafenamide becomes widely available, concern about drug nephrotoxicity may become a less pressing clinical issue.

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High risk of death among adolescents while awaiting ART

Risk of death among those awaiting treatment for HIV infection in Zimbabwe: adolescents are at particular risk.

Shroufi A, Ndebele W, Nyathi M, Gunguwo H, Dixon M, Saint-Sauveur JF, Taziwa F, Vinoles MC, Ferrand RA. J Int AIDS Soc. 2015 Feb 23;18(1):19247. doi: 10.7448/IAS.18.1.19247. eCollection 2015.

Introduction: Mortality among HIV-positive adults awaiting antiretroviral therapy (ART) has previously been found to be high. Here, we compare adolescent pre-ART mortality to that of adults in a public sector HIV care programme in Bulawayo, Zimbabwe.

Methods: In this retrospective cohort study, we compared adolescent pre-ART outcomes with those of adults enrolled for HIV care in the same clinic. Adolescents were defined as those aged 10-19 at the time of registration. Comparisons of means and proportions were carried out using two-tailed sample t-tests and chi-square tests respectively, for normally distributed data, and the Mann-Whitney U-tests for non-normally distributed data. Loss to follow-up (LTFU) was defined as missing a scheduled appointment by three or more months.

Results: Between 2004 and 2010, 1382 of 1628 adolescents and 7557 of 11 106 adults who registered for HIV care met the eligibility criteria for ART. Adolescents registered at a more advanced disease stage than did adults (83% vs. 73% WHO stage III/IV, respectively, p<0.001), and the median time to ART initiation was longer for adolescents than for adults [21 (10-55) days vs. 15 (7-42) days, p<0.001]. Among the 138 adolescents and 942 adults who never commenced ART, 39 (28%) of adolescents and 135 (14%) of adults died, the remainder being LTFU. Mortality among treatment-eligible adolescents awaiting ART was significantly higher than among adults (3% vs. 1.8%, respectively, p=0.004).

Conclusions: Adolescents present to ART services at a later clinical stage than adults and are at an increased risk of death prior to commencing ART. Improved and innovative HIV case-finding approaches and emphasis on prompt ART initiation in adolescents are urgently needed. Following registration, defaulter tracing should be used, whether or not ART has been commenced.

Abstract  Full-text [free] access

Editor’s notes: In this article the pre-antiretroviral therapy (ART) outcomes of adolescents (persons between 10 and 19 years) registered in a well-established ART programme in Zimbabwe between 2004 and 2010 are compared to those of adults. The authors found that adolescents living with HIV experience a higher risk of death while awaiting ART initiation. This is most likely due to the more advanced stage of HIV infection at the time of registration. Most adolescents in this study had acquired HIV at birth and underwent HIV testing following an HIV-associated illness. Treatment-eligible adolescents also waited significantly longer than adults to initiate ART. Under-preparedness to start ART, and reduced access to transport among adolescents were cited as possible reasons for this delay. The authors suggest that adolescents may be at higher risk of mortality because of the longer duration of having lived with untreated infection. They are therefore less able to afford further delays before starting ART. The authors therefore suggest prompt ART initiation for treatment-eligible adolescents. They emphasize the need for innovative methods of HIV case-finding for adolescents. Adolescents are often suspicious of health care workers, resulting in reduced uptake of health services, including HIV testing. To provide more effective HIV counselling and testing for adolescents, WHO has recognised adolescents as an important population for HIV prevention, and developed specific HIV testing guidelines in 2013.

Interestingly the authors suggest using 12-month mortality among ART-eligible individuals, whether on ART or not, as a programme indicator. Incorporating pre-ART deaths, which are often unrecorded, and deaths among individuals newly started on ART, which may be partly attributed to pre-ART delays, indicates how well a programme manages people from the time they are registered in care. This could provide a more inclusive estimate of programme quality. 

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Boosted protease inhibitor monotherapy as second-line ART: a strategy for resource-limited settings?

Lopinavir/ritonavir monotherapy as second-line antiretroviral treatment in resource-limited settings - week 104 analysis of ACTG A5230.

Kumarasamy N, Aga E, Ribaudo HJ, Wallis CL, Katzenstein DA, Stevens WS, Norton MR, Klingman KL, Hosseinipour MC, Crump JA, Supparatpinyo K, Badal-Faesen S, Bartlett JA. Clin Infect Dis. 2015 Feb 18. pii: civ109. [Epub ahead of print]

Objective: ACTG A5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure on first-line regimens in Africa and Asia.

Methods: Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000copies/mL. All subjects received LPV/r 400/100mg twice daily. Virologic failure (VF) was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200mg/tenofovir 300mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r-monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models.

Results: 123 subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 /123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39/41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400copies/mL over 104 weeks on LPV/r-monotherapy was 60% [95% CI 50%, 68%]; 80-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level<400 copies/mL at weeks 24, 48 and 104 revealed that 61%, 62% and 65% were suppressed to <40 copies/mL, respectively.

Conclusion: LPV/r monotherapy after first-line virologic failure with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks.

Abstract access 

Editor’s notes: First-line antiretroviral therapy failure is increasingly encountered in resource-limited settings. However limited access to viral load monitoring means that treatment failure is often not recognised until immunological or clinical failure occurs. Late switching can lead to the accumulation of resistance mutations. Resistance to nucleoside reverse transcriptase inhibitors (NRTI) is of particular concern as this class remains a component of second-line, boosted protease inhibitor (bPI)-based regimens. Several studies have now looked at boosted protease inhibitor monotherapy as an alternative strategy. A strategy which aims to limit the toxicity and additional cost associated with NRTIs. In general boosted protease inhibitor monotherapy has been found to have inferior virologic outcomes when compared to bPI plus two NRTIs or bPI plus raltegravir.

In this study, while short term virologic outcomes were favourable (87% probability of continued virologic suppression over 24 weeks); longer term outcomes with bPI monotherapy were less good. However, with frequent viral load monitoring, 4-12 weekly, early detection of virologic failure and intensification with two NRTIs, outcomes in the bPI monotherapy arm improved substantially. This strategy warrants further investigation. But without markedly increasing access to viral load monitoring and lowering the cost to allow frequent testing, it is difficult to see how this strategy could be implemented in practice in resource-constrained settings. 

HIV Treatment
Africa, Asia
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Stigma, alcohol dependence and consulting traditional doctors associated with non-adherence to ART

Incomplete adherence among treatment-experienced adults on antiretroviral therapy in Tanzania, Uganda and Zambia.

Denison JA, Koole O, Tsui S, Menten J, Torpey K, van Praag E, Mukadi YD, Colebunders R, Auld AF, Agolory S, Kaplan JE, Mulenga M, Kwesigabo GP, Wabwire-Mangen F, Bangsberg DR. AIDS. 2015 Jan 28;29(3):361-71. doi: 10.1097/QAD.0000000000000543.

Objectives: To characterize antiretroviral therapy (ART) adherence across different programmes and examine the relationship between individual and programme characteristics and incomplete adherence among ART clients in sub-Saharan Africa.

Design: A cross-sectional study.

Methods: Systematically selected ART clients (≥18 years; on ART ≥6 months) attending 18 facilities in three countries (250 clients/facility) were interviewed. Client self-reports (3-day, 30-day, Case Index ≥48 consecutive hours of missed ART), healthcare provider estimates and the pharmacy medication possession ratio (MPR) were used to estimate ART adherence. Participants from two facilities per country underwent HIV RNA testing. Optimal adherence measures were selected on the basis of degree of association with concurrent HIV RNA dichotomized at less than or greater/equal to 1000 copies/ml. Multivariate regression analysis, adjusted for site-level clustering, assessed associations between incomplete adherence and individual and programme factors.

Results: A total of 4489 participants were included, of whom 1498 underwent HIV RNA testing. Nonadherence ranged from 3.2% missing at least 48 consecutive hours to 40.1% having an MPR of less than 90%. The percentage with HIV RNA at least 1000 copies/ml ranged from 7.2 to 17.2% across study sites (mean = 9.9%). Having at least 48 consecutive hours of missed ART was the adherence measure most strongly related to virologic failure. Factors significantly related to incomplete adherence included visiting a traditional healer, screening positive for alcohol abuse, experiencing more HIV symptoms, having an ART regimen without nevirapine and greater levels of internalized stigma.

Conclusion: Results support more in-depth investigations of the role of traditional healers, and the development of interventions to address alcohol abuse and internalized stigma among treatment-experienced adult ART patients.

Abstract access

Editor’s notes: Antiretroviral therapy (ART) non-adherence is a strong predictor of incomplete viral suppression, disease progression and mortality in people living with HIV. Declining adherence rates over long-term follow-up of people on ART have been illustrated in a number of observational studies in both low- and high-income settings. This multi-country study gives valuable insight into the challenges that treatment-experienced people living with HIV in low-income countries face on a daily basis. Incomplete adherence was found to be associated with a number of social and behavioural factors. These include internalised stigma, alcohol dependence, low levels of social support and consulting a traditional healer/herbalist. The factor most strongly associated with incomplete adherence was visiting a traditional healer because of HIV. The data contribute to the growing evidence on the role that traditional healers may have in care-seeking behaviours and influencing sustained ART adherence. Findings from this study corroborate research from other studies that alcohol abuse and HIV stigma are broad and consistent correlates of ART adherence. The study also highlights the variability of existing adherence measures and the need for accurate programme-level methods for assessing pill-taking behaviour in order to inform programme strategies and assess impact.

Improving adherence and thereby longer-term healthy outcomes for people living with HIV requires programmatic activities to address alcohol dependence and internalised stigma among treatment-experienced adults. Greater understanding of the role that traditional healers/herbalists play in how people living with HIV manage their infection is also needed to support life-long ART adherence in sub-Saharan Africa.

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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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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, 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.

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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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Counsellor-initiated testing doubles the proportion of people in hospital knowing their HIV status

Implementation of routine counselor-initiated opt-out HIV testing on the adult medical ward at Kamuzu Central Hospital, Lilongwe, Malawi.

LaCourse SM, Chester FM, Matoga M, Munthali C, Nsona D, Haac B, Hoffman IF, Hosseinipour MC. J Acquir Immune Defic Syndr. 2015 Jan 23. [Epub ahead of print]

The optimal approach of provider-initiated HIV testing and counseling (PITC) for inpatients in high-burden settings is unknown. We prospectively evaluated the implementation of task-shifting from clinician-referral to counselor-initiated PITC on the medical wards of Kamuzu Central Hospital, Malawi. The majority of patients (1905/3154, 60.4%) had an unknown admission HIV status. Counselors offered testing to 66.6% (1268/1905). HIV prevalence was 39.3%. Counselor-initiated PITC significantly increased HIV testing by 85% (643/2957 vs. 1268/3154), resulting in an almost 2-fold increase in patients with known HIV status (2447/3154 vs. 1249/3154) (both p<.0001), with 17.9% of those tested receiving a new diagnosis of HIV.

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Editor’s notes: UNAIDS estimates that in sub-Saharan Africa more than half of all people living with HIV remain unaware of their status and thus have no opportunity to access HIV care. Provider-initiated testing and counselling has been successful in increasing coverage of HIV testing in antenatal and tuberculosis clinics. In in-patient settings, it is most often the responsibility of a clinician to initiate the offer of HIV testing. Even when the universal offer of HIV testing is policy, many people may be missed.

In this study from a tertiary referral hospital in Malawi, counsellors were given responsibility for offering testing to all in-patients in the short-stay and medical wards. Prior to this programme, only 22% of people in these wards had an HIV test, and 31% of people tested were HIV-positive. During the programme period, some 60% of people admitted had unknown HIV status, of whom 67% were tested by counsellors. The refusal rate was very low, 3.2%. Some 39% of people tested were HIV positive. This seems a very effective way to maximise the number of medical in-patients who know their HIV status, thus allowing people to access appropriate care. Similar task-shifting activities have been undertaken to identify in-patients who are coughing and to ensure that their sputum is tested for tuberculosis. In settings where both HIV and tuberculosis are common, a programme combining counsellor-initiated HIV testing and cough screening could maximise case finding for both diseases. This would enable earlier initiation of treatment and reduce the risk of nosocomial transmission of tuberculosis.

HIV testing
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