Articles tagged as "15 million accessing treatment"

Viral load monitoring could be cost-effective

Sustainable HIV treatment in Africa through viral-load-informed differentiated care.

Working Group on Modelling of Antiretroviral Therapy Monitoring Strategies in Sub-Saharan Africa, Phillips A, Shroufi A, Vojnov L, Cohn J, Roberts T, Ellman T, Bonner K, Rousseau C, Garnett G, Cambiano V, Nakagawa F, Ford D, Bansi-Matharu L, Miners A, Lundgren JD, Eaton JW, Parkes-Ratanshi R, Katz Z, Maman D, Ford N, Vitoria M, Doherty M, Dowdy D, Nichols B, Murtagh M, Wareham M, Palamountain KM, Chakanyuka Musanhu C, Stevens W, Katzenstein D, Ciaranello A, Barnabas R, Braithwaite RS, Bendavid E, Nathoo KJ, van de Vijver D, Wilson DP, Holmes C, Bershteyn A, Walker S, Raizes E, Jani I, Nelson LJ, Peeling R, Terris-Prestholt F, Murungu J, Mutasa-Apollo T, Hallett TB, Revill P. Nature. 2015 Dec 3;528(7580):S68-76. doi: 10.1038/nature16046.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

Abstract Full-text [free] access

 Editor’s notes: There has been much debate concerning how best to monitor antiretroviral therapy (ART) in resource-limited settings. In the early stages of ART roll-out, there were concerns that if ART monitoring required laboratory testing, the high cost would divert resources away from treatment delivery. Guidelines were drawn up to allow monitoring based on clinical features, alone or with CD4 count monitoring. However, clinical and CD4 monitoring proved to be neither sensitive nor specific when compared to viral load monitoring. In practice, the number of people switched to second-line ART in resource-limited settings has been lower than predicted, particularly where monitoring is clinical or CD4-based. This raises concerns that, in the absence of viral load monitoring, some people will acquire resistance to first-line ART, and this will remain undetected, with the person receiving ineffective treatment for a prolonged period, resulting in the accumulation of resistance mutations. This could threaten the effectiveness of future treatment options, and increases the risk of transmission of drug-resistant viruses. In addition, the poor specificity of clinical and CD4-based definitions of “treatment failure” means that if these definitions are used to make decisions about switching to second line ART, many people who, in reality, have virologic suppression may be inappropriately switched to second-line ART.

Increasingly, there are calls for viral load monitoring to be made more widely available. This is technically challenging, particularly in remote areas. Dried blood spot samples are an alternative method for specimen collection and transport which is practical for remote facilities. Viral load monitoring using dried blood spots has been implemented in some settings. Interpretation of results needs to take account of the lower sensitivity and specificity when compared to viral load assays based on plasma.

This study used a mathematical model to explore outcomes and cost-effectiveness of a range of ART monitoring strategies. The authors found that monitoring based on viral load measurements using dried blood spots was cost-effective. The model assumed that in scenarios with clinical and/or CD4 monitoring patient visits would be three-monthly, whereas in the viral load monitoring scenario, individuals with suppressed viral load would attend clinic for monitoring less frequently (hence the term “viral load-informed differentiated care”). The reduction in visit frequency for people with suppressed viral load was the main driver of cost saving in this scenario.

The cost-effectiveness estimates considered only health sector costs and ignored any patient costs.  Even when treatment and care are free of charge, people incur substantial costs to attend clinics for HIV care, particularly because of loss of income and transport costs. If patient costs had been included, the savings due to reduced visit frequency would almost certainly be even greater.

The accuracy of models is inevitably dependent on the underlying assumptions (described in detail and with admirable clarity in the paper’s accompanying on-line supplement). Cost-effectiveness was sensitive to the cost of viral load monitoring, assumed to be $22 per test based on dried blood spots. These results support efforts to increase access to viral load monitoring. As the authors comment, empirical data from programmes employing viral load-informed differentiated care as a monitoring strategy would be very useful. 

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Mechanism found for increased HIV risk in women using injectable progestin-only contraception

Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study.

Byrne EH, Anahtar MN, Cohen KE, Moodley A, Padavattan N, Ismail N, Bowman BA, Olson GS, Mabhula A, Leslie A, Ndung'u T, Walker BD, Ghebremichael MS, Dong KL, Kwon DS. Lancet Infect Dis. 2015 Dec 23. pii: S1473-3099(15)00429-6. doi: 10.1016/S1473-3099(15)00429-6. [Epub ahead of print]

Background: The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract.

Methods: In this prospective cohort, we enrolled HIV-negative South African women aged 18-23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods.

Findings: Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12.06 per 100 person-years, 95% CI 6.41-20.63) than women using no long-term contraception (3.71 per 100 person-years, 1.36-8.07; adjusted hazard ratio [aHR] 2.93, 95% CI 1.09-7.868, p=0.0326). HIV-negative injectable progestin-only contraceptive users had 3.92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0.0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3.25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0.0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives.

Interpretation: Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure.

Abstract access 

Editor’s notes: Several observational studies have reported increased risk of HIV acquisition in women using injectable progestin-only contraception. In this study, injectable progestin-only contraceptive use was associated with a higher frequency of activated CCR5+ CD4 T cells in the cervix. These cells are the target for HIV, and thus an increase in their number may increase the risk of HIV acquisition by accelerating viral dissemination after genital tract exposure to HIV. This study also found a significantly higher frequency of activated cervical target cells during the luteal phase of the menstrual cycle in women who were not using injectable progestin-only contraception. These findings suggest that the increased HIV acquisition risk may be mediated by both exogenous and endogenous progestin exposure. This study provides novel insights into the role of progestins, and provides a potential biological explanation for an increased risk of HIV acquisition among women using injectable progestin-only contraception. This work will hopefully inform the development of biological prophylactics to reduce HIV acquisition in women. Whether these findings will influence recommendations for contraceptive use in women living in high HIV incidence settings remains to be determined.  

South Africa
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HIV contributes to stroke among young people

HIV, antiretroviral treatment, hypertension, and stroke in Malawian adults: A case-control study.

Benjamin LA, Corbett EL, Connor MD, Mzinganjira H, Kampondeni S, Choko A, Hopkins M, Emsley HC, Bryer A, Faragher B, Heyderman RS, Allain TJ, Solomon T. Neurology. 2015 Dec 18. pii: 10.1212/WNL.0000000000002278. [Epub ahead of print]

Objective: To investigate HIV, its treatment, and hypertension as stroke risk factors in Malawian adults.

Methods: We performed a case-control study of 222 adults with acute stroke, confirmed by MRI in 86%, and 503 population controls, frequency-matched for age, sex, and place of residence, using Global Positioning System for random selection. Multivariate logistic regression models were used for case-control comparisons.

Results: HIV infection (population attributable fraction [PAF] 15%) and hypertension (PAF 46%) were strongly linked to stroke. HIV was the predominant risk factor for young stroke (≤45 years), with a prevalence of 67% and an adjusted odds ratio (aOR) (95% confidence interval) of 5.57 (2.43-12.8) (PAF 42%). There was an increased risk of a stroke in patients with untreated HIV infection (aOR 4.48 [2.44-8.24], p < 0.001), but the highest risk was in the first 6 months after starting antiretroviral therapy (ART) (aOR 15.6 [4.21-46.6], p < 0.001); this group had a lower median CD4+ T-lymphocyte count (92 vs 375 cells/mm3, p = 0.004). In older participants (HIV prevalence 17%), HIV was associated with stroke, but with a lower PAF than hypertension (5% vs 68%). There was no interaction between HIV and hypertension on stroke risk.

Conclusions: In a population with high HIV prevalence, where stroke incidence is increasing, we have shown that HIV is an important risk factor. Early ART use in immunosuppressed patients poses an additional and potentially treatable stroke risk. Immune reconstitution inflammatory syndrome may be contributing to the disease mechanisms.

Abstract Full-text [free] access

Editor’s notes: Stroke incidence is increasing across sub-Saharan Africa. Globally, hypertension accounts for most of the strokes. However, in sub-Saharan Africa, stroke is not uncommon among younger people, among whom the prevalence of hypertension is low. Therefore other factors may play a role.

This article reports on a case-control study with prospective recruitment of cases and community controls, examining the role of HIV, antiretroviral therapy, and the interaction between HIV and hypertension as risk factors for stroke in a setting with high HIV prevalence.

The investigators confirmed 86% of their cases with brain imaging, and found that the majority (78%) had findings consistent with ischemic stroke. Not surprisingly they found that overall, hypertension accounted for about half (46%) of the stroke cases. Interestingly only one-quarter of all people with hypertension in the study (cases and controls) were on hypertensive treatment.

However, among younger people (≤45 years) with stroke, HIV infection was the most important risk factor and accounted for 42% of the cases. HIV-positive people experienced the greatest risk of stroke during their first six months after ART initiation.

The HIV-positive stroke cases had a lower CD4 cell count compared to HIV-positive controls on the same duration of ART. Immunosuppression is a risk factor for immune constitution inflammatory syndrome (IRIS), and IRIS could thus be a plausible mechanism of stroke among people initiating ART.

The results of this study reinforce the need to start ART before people have advanced immunosuppression, which will reduce IRIS-associated morbidity. The latest WHO guidelines, ‘Treat all’, which recommend starting all HIV-positive people on antiretroviral therapy as soon after diagnosis as possible, have the potential to contribute to this.  

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Can nevirapine-exposed children switch to efavirenz?

Efavirenz-based antiretroviral therapy among nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial.

Coovadia A, Abrams EJ, Strehlau R, Shiau S, Pinillos F, Martens L, Patel F, Hunt G, Tsai WY, Kuhn L. JAMA. 2015 Nov 3;314(17):1808-17. doi: 10.1001/jama.2015.13631.

Importance: Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission.

Objective: To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure.

Design, setting, and participants: Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization.

Interventions: Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148).

Main outcomes and measures: Risk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points.

Results: The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to infinity) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to infinity). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.

Conclusions and relevance: Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.

Abstract Full-text [free] access

Editor’s notes: For infants and young children (aged under three years), World Health Organization recommends ritonavir-boosted lopinavir therapy as the first-line antiretroviral therapy regimen. This is because of concerns about the increased risk of virologic failure with non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens among infants previously exposed to NNRTIs for prevention of mother-to-child HIV transmission, and better virologic efficacy of a lopinavir-based regimen even in unexposed HIV-positive infants and young children. However, there are several significant issues associated with use of boosted lopinavir therapy in children. Firstly, the syrup form of the drug has an unpleasant taste posing major adherence challenges. Secondly, there are pharmacokinetic constraints restricting its use in children who are also being treated for tuberculosis. Thirdly, there are metabolic toxicities associated with the use of boosted lopinavir therapy.

In this open-labelled non-inferiority trial, the investigators examined whether efavirenz can be used in children aged over three years, previously exposed to nevirapine as part of prevention of mother-to-child HIV transmission, who have achieved virologic suppression with lopinavir-based therapy. Efavirenz was found to be non-inferior for both the trial endpoints, namely risk of viral rebound and risk of virologic failure. There were no differences in CD4 counts or other clinical endpoints such as height- or weight-for age, anaemia or neutropenia, skin reactions or serious elevations in transaminases between the groups. In addition, children randomised to switch to efavirenz had a significantly better lipid profile than people who continued to take lopinavir-based therapy. Children randomised to receive efavirenz had significantly higher rates of neuropsychiatric disturbances, but these did not persist beyond eight weeks and notably there were no differences in proportions with behavioural problems between the two arms at the end of follow-up.

The findings of this study strongly support the switch to efavirenz in children who have achieved virologic suppression. Some caveats of this study are that the findings cannot be generalised to children who are aged under three years or to children failing boosted lopinavir therapy. In addition, it is not clear how long children can be maintained on lopinavir-based therapy before a switch to efavirenz can be made.

There is currently no guidance on managing children aged over three years taking lopinavir therapy. This study provides strong evidence to support the switch to efavirenz among virally-suppressed children aged over three years. This is important given the considerable advantages of efavirenz, including preservation of protease inhibitor-based regimens for second line treatment, harmonising paediatric with adult guidelines that recommend efavirenz as first-line therapy, once-daily dosing, better palatability and lower cost.

South Africa
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Benefits of available ART greater for women than men in South Africa, with many men not engaging with care

Mass HIV treatment and sex disparities in life expectancy: demographic surveillance in rural South Africa.

Bor J, Rosen S, Chimbindi N, Haber N, Herbst K, Mutevedzi T, Tanser F, Pillay D, Bärnighausen T. PLoS Med. 2015 Nov 24;12(11):e1001905. doi: 10.1371/journal.pmed.1001905. eCollection 2015.

Background: Women have better patient outcomes in HIV care and treatment than men in sub-Saharan Africa. We assessed - at the population level - whether and to what extent mass HIV treatment is associated with changes in sex disparities in adult life expectancy, a summary metric of survival capturing mortality across the full cascade of HIV care. We also determined sex-specific trends in HIV mortality and the distribution of HIV-related deaths in men and women prior to and at each stage of the clinical cascade.

Methods and findings: Data were collected on all deaths occurring from 2001 to 2011 in a large population-based surveillance cohort (52 964 women and 45 688 men, ages 15 y and older) in rural KwaZulu-Natal, South Africa. Cause of death was ascertained by verbal autopsy (93% response rate). Demographic data were linked at the individual level to clinical records from the public sector HIV treatment and care program that serves the region. Annual rates of HIV-related mortality were assessed for men and women separately, and female-to-male rate ratios were estimated in exponential hazard models. Sex-specific trends in adult life expectancy and HIV-cause-deleted adult life expectancy were calculated. The proportions of HIV deaths that accrued to men and women at different stages in the HIV cascade of care were estimated annually. Following the beginning of HIV treatment scale-up in 2004, HIV mortality declined among both men and women. Female adult life expectancy increased from 51.3 y (95% CI 49.7, 52.8) in 2003 to 64.5 y (95% CI 62.7, 66.4) in 2011, a gain of 13.2 y. Male adult life expectancy increased from 46.9 y (95% CI 45.6, 48.2) in 2003 to 55.9 y (95% CI 54.3, 57.5) in 2011, a gain of 9.0 y. The gap between female and male adult life expectancy doubled, from 4.4 y in 2003 to 8.6 y in 2011, a difference of 4.3 y (95% CI 0.9, 7.6). For women, HIV mortality declined from 1.60 deaths per 100 person-years (95% CI 1.46, 1.75) in 2003 to 0.56 per 100 person-years (95% CI 0.48, 0.65) in 2011. For men, HIV-related mortality declined from 1.71 per 100 person-years (95% CI 1.55, 1.88) to 0.76 per 100 person-years (95% CI 0.67, 0.87) in the same period. The female-to-male rate ratio for HIV mortality declined from 0.93 (95% CI 0.82-1.07) in 2003 to 0.73 (95% CI 0.60-0.89) in 2011, a statistically significant decline (p = 0.046). In 2011, 57% and 41% of HIV-related deaths occurred among men and women, respectively, who had never sought care for HIV in spite of the widespread availability of free HIV treatment. The results presented here come from a poor rural setting in southern Africa with high HIV prevalence and high HIV treatment coverage; broader generalizability is unknown. Additionally, factors other than HIV treatment scale-up may have influenced population mortality trends.

Conclusions: Mass HIV treatment has been accompanied by faster declines in HIV mortality among women than men and a growing female-male disparity in adult life expectancy at the population level. In 2011, over half of male HIV deaths occurred in men who had never sought clinical HIV care. Interventions to increase HIV testing and linkage to care among men are urgently needed.

Abstract Full-text [free] access

Editor’s notes: In South Africa and many other sub-Saharan African countries, mass treatment with anti-retroviral therapy (ART) has led to dramatic decreases in mortality and increases in life expectancy. South Africa has provided ART free-of-charge since 2004, but HIV-associated diseases remain the leading cause of death in adults. This paper uses clinical and demographic data from a longitudinal cohort in a rural area of KwaZulu-Natal in South Africa to assess how gender differences in adult life expectancy and HIV-associated mortality changed between 2001 and 2011.

Overall life expectancy increased for both genders since 2004 with the effect significantly greater for females than males. The gender differential in life expectancy over the period 2004-2011 increased from 4.4 to 8.6 years. The analysis illustrates that this decrease was due to decreases in HIV-associated mortality rates, as HIV-cause-deleted life expectancy (i.e. life expectancy that would have occurred in the absence of HIV) remained constant over this period.

This study emphasizes the HIV treatment gap for men, with approximately half of all HIV-associated deaths in this population occurred among men who had never sought care. Mortality for men was significantly higher than that for women at each stage of the treatment cascade.

Although this study draws on data from one rural setting, many of the underlying characteristics reflect those seen in many other rural areas of the country. Further work is necessary to understand the underlying social and cultural factors that underlie these findings which could then lead to the development of programmes designed to address them. Such cross-disciplinary research which engages with people designing and implementing HIV programmes will need to be significantly enhanced over the coming decade in order to meet the UNAIDS 90:90:90 targets.

South Africa
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Living with HIV on the move: migrant workers in north India

Complex routes into HIV care for migrant workers: a qualitative study from north India.

Rai T, Lambert HS, Ward H. AIDS Care. 2015 Nov 26:1-6. [Epub ahead of print]

Migrant workers are designated a bridge population in the spread of HIV and therefore if infected, should be diagnosed and treated early. This study examined pathways to HIV diagnosis and access to care for rural-to-urban circular migrant workers and partners of migrants in northern India, identifying structural, social and individual level factors that shaped their journeys into care. We conducted a qualitative study using in-depth interviews with HIV-positive men (n = 20) and women (n = 13) with a history of circular migration, recruited from an antiretroviral therapy centre in one district of Uttar Pradesh, north India. Migrants and partners of migrants faced a complex series of obstacles to accessing HIV testing and care. Employment insecurity, lack of entitlement to sick pay or subsidised healthcare at destination and the household's economic reliance on their migration-based livelihood led many men to continue working until they became incapacitated by HIV-related morbidity. During periods of deteriorating health they often exhausted their savings on private treatments focused on symptom management, and sought HIV testing and treatment at a public hospital only following a medical or financial emergency. Wives of migrants had generally been diagnosed following their husbands' diagnosis or death, with access to testing and treatment mediated via family members. For some, a delay in disclosure of husband's HIV status led to delays in their own testing. Diagnosing and treating HIV infection early is important in slowing down the spread of the epidemic and targeting those at greatest risk should be a priority. However, despite targeted campaigns, circumstances associated with migration may prevent migrant workers and their partners from accessing testing and treatment until they become sick. The insecurity of migrant work, the dominance of private healthcare and gender differences in health-seeking behaviour delay early diagnosis and treatment initiation.

Abstract access

Editor’s notes: Migrant workers who move for work in their own country face challenges in accessing health care and social support. In a country as large and diverse as India internal migration can be particularly taxing. For people living with HIV, or who acquire HIV while migrating for work, the challenges can be immense. This paper sets out concisely the issues these migrants face, trying to access information, treatment and support both in the place they move to and at home. The authors explain how migrant men might delay treatment because of their need to work, and perhaps also to keep their HIV-status secret. For the wives of migrants, this delay can severely affect their own access to health care. Free antiretroviral therapy is available, but as the authors suggest, many migrant workers do not know that. This lack of knowledge highlights the importance of providing better support for migrant workers. Support for access to free, or at least affordable, health care is something many migrant workers require; for migrant workers living with HIV that support is essential.

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Which NRTI backbone is best for children?

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.

Mulenga V, Musiime V, Kekitiinwa A, Cook AD, Abongomera G, Kenny J, Chabala C, Mirembe G, Asiimwe A, Owen-Powell E, Burger D, McIlleron H, Klein N, Chintu C, Thomason MJ, Kityo C, Walker AS, Gibb DM, CHAPAS-3 trial team. Lancet Infect Dis. 2015 Oct 5. pii: S1473-3099(15)00319-9. doi: 10.1016/S1473-3099(15)00319-9. [Epub ahead of print]

Background: WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz.

Methods: In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957.

Findings: Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2.3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2.6 years vs 6.2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0.63; zidovudine vs stavudine: hazard ratio [HR] 0.99 [95% CI 0.75-1.29]; abacavir vs stavudine: HR 0.88 [0.67-1.15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0.58); most ART-experienced children maintained suppression (p=1.00).

Interpretation: All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines.

Abstract  Full-text [free] access

Editor’s notes: Since 2013, the World Health Organization (WHO) has recommended abacavir as the preferred first-line nucleoside reverse transcriptase inhibitor (NRTI) in children. This recommendation was largely based on expert opinion, observational studies and issues such as cost and availability as a fixed dose combinations (FDC).

The CHAPAS-3 open-label trial is the only trial in African children that has conducted a direct head-to-head comparison of the three most relevant NRTIs (abacavir, stavudine and zidovudine) used for paediatric treatment. These were co-formulated in non-NRTI/NRTI generic fixed-dose combination paediatric tablets, with dosing based on WHO drug ratios and weight bands. The other drugs in the triple regimen were lamivudine with either efavirenz or nevirapine.

The primary aim of the trial was a comparison of the toxicity profile of the three NRTIs. The trial found no major difference in any adverse event or toxicity endpoint during nearly two and a half years of follow-up in both ART-naïve and ART-experienced children. There were no hypersensitivity reactions to abacavir, in agreement with other studies that have reported its rarity in Africans. Haemoglobin increased regardless of the NRTI and severe anaemia occurred no more frequently in children who received zidovudine versus children who received either of the two other drugs. This should reassure clinicians that zidovudine substitution is rarely necessary for anaemia among children on ART. However, an important caveat is that severe anaemia was an exclusion criteria in the trial. Clinical lipodystrophy was also rare. This is in contrast to older children and adolescents where lipodystrophy is much more common. At least in young children, stavudine could be safely used if other alternatives are not available, supporting WHO guidelines that stavudine for children should not be discontinued completely.       

Overall, CHAPAS-3 demonstrates that children respond well to all NRTI/non-NRTI recommended FDCs with minimal toxicity. Unlike previous trials, there was no difference in immunological or virologic outcomes between the three drugs. Importantly, choice of the NRTI backbone should not be a barrier to widening treatment access globally for HIV-positive children. Children receiving abacavir in their first-line regimen who had unsuppressed viral load at the end of the study were less likely to have resistance mutations compromising second-line NRTIs. In addition to its excellent tolerability profile, abacavir is the only NRTI available as a once-daily FDC licenced for children. This would support WHO recommendation of abacavir as the first choice NRTI in children. However, it does remain more expensive than the other two NRTIs and further price reductions will be required if abacavir use is to be widened.

Uganda, Zambia
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Relatedness, communication, and care of children living with HIV in eastern Uganda

Communication in the context of family caregiving: an exploratory study of Ugandan children on antiretroviral therapy.

Kajubi P, Katahoire AR, Kyaddondo D, Whyte SR. J Biosoc Sci. 2015 Oct 28:1-22. [Epub ahead of print]

It is important to consider the complexities of family dynamics when deciding when and how to communicate with HIV-infected children about their illness and treatment. Previous research has focused on providers' and caregivers' perspectives on whether, when and how to disclose HIV/AIDS diagnosis and treatment to HIV-infected children. From the perspective of HIV-infected children, communication does not mean just giving information about illness and treatment, but also encompasses emotional and material care. This paper places communication within the broader framework of caregiving in family situations. This exploratory study was conducted in Jinja district, Uganda, between November 2011 and December 2012. Through participant observation and in-depth interviews, communication by, and with, HIV-infected children in the context of family situations was explored from the perspectives of 29 HIV-infected children aged 8-17 years on antiretroviral therapy (ART) using content thematic analysis. Children's communication with caregivers about their illness and treatment varied depending on whom they were living with and the nature of caregiving. Although a mother's care was considered best, children described others who cared 'like a mother'. For some, caregiving was distributed among several relatives and non-relatives, while others felt they had hardly anyone to care for them. Caregiving from the children's perspective involved emotional support, expressed verbally and explicitly in messages of concern, encouragement conveyed in reminders to take medicines, attention when sick and confidential conversations about the challenges of having HIV and taking ART. Caregiving was also communicated implicitly in acts of provision of food/drinks to take with medicines, counting pills to confirm they had taken the medicines and accompanying children to treatment centres. Children's communication about their health and medicines and the care they received was to a large extent shaped by the nature of their relatedness to their caregivers, the extent to which caregiving was dispersed among several people and who else in the household was infected with HIV and on medication.

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Editor’s notes: The majority of children who acquire HIV are infected perinatally. This makes HIV unique among paediatric conditions to the extent that mothers may be ill or deceased. The family plays a vital role in the treatment and care of children, including individuals living with HIV. The family context is an important consideration when supporting children to adhere to care. It also affects decisions on how and when to communicate with children about their illness and treatment. The authors argue that for children living with HIV, communication is not just the transmission of factual information, but also the conveying of concern, feelings of affection and implicit messages of support, as well as their opposites. This is particularly important in the context of loss and family disruption; stigma and discrimination; and dislocation from siblings and other family when children are cared for by new carers.

This qualitative paper draws on ethnographic data collected between 2011 and 2012 in eastern Uganda through in-depth interviews and participant observation. A total of 29 children living with HIV aged between eight and 17 years and on ART were followed up for one year. Children were purposively sampled to include different ages, sexes and family status (residence, orphan status), education levels and disclosure statuses.

The study draws on the concept of ‘relatedness’ in order to understand the meaning of communication in the context of family caregiving. It highlights that communication by, and with children living with HIV, extends beyond the transmission of information to being structured around a much broader relationship of care. This has important implications for treatment centres as the person that a child lives with may not always be their main caregiver. This framing incorporates a broader understanding of caregiving to include both emotional and material support which may be delivered both explicitly and implicitly through words and deeds.

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Routine opt-out HIV testing reduces missed diagnoses in children

The effectiveness of routine opt-out HIV testing for children in Harare, Zimbabwe.

Ferrand RA, Meghji J, Kidia K, Dauya E, Bandason T, Mujuru H, Ncube G, Mungofa S, Kranzer K. J Acquir Immune Defic Syndr. 2015 Oct 12. [Epub ahead of print]

Objective: HIV testing is the entry point to access HIV care. For HIV-infected children who survive infancy undiagnosed, diagnosis usually occurs on presentation to health care services. We investigated the effectiveness of routine opt-out HIV testing (ROOT) compared to conventional opt-in provider-initiated testing and counselling (PITC) for children attending primary care clinics.

Methods: Following an evaluation of PITC services for children aged 6 to 15 years in six primary health care facilities in Harare, Zimbabwe, ROOT was introduced through a combination of interventions. The change in the proportion of eligible children offered and receiving HIV tests, reasons for not testing, and yield of HIV positive diagnoses were compared between the two HIV testing strategies. Adjusted risk ratios for having an HIV test in the ROOT compared to the PITC period were calculated.

Results: There were 2831 and 7842 children eligible for HIV testing before and after the introduction of ROOT. The proportion of eligible children offered testing increased from 76% to 93% and test uptake improved from 71% to 95% in the ROOT compared to the PITC period. The yield of HIV diagnoses increased from 2.9% to 4.5%, and a child attending the clinics post intervention had a 1.99 increased adjusted risk (95% CI 1.85-2.14) of receiving an HIV test in the ROOT period compared to the pre-intervention period.

Conclusion: ROOT increased the proportion of children undergoing HIV-testing, resulting in an overall increased yield of positive diagnoses, compared to PITC. ROOT provides an effective approach to reduce missed HIV diagnosis in this age-group.

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Editor’s notes: The policy and practice of HIV testing in high HIV prevalence settings has evolved over the years, from a more cautious approach in the early years of the HIV epidemic to a more proactive one with the scale up of antiretroviral therapy (ART). Despite a marked increase in HIV testing following the introduction of provider-initiated testing and counselling (PITC) in clinical settings, coverage remains suboptimal. Routine opt-out testing (ROOT) describes a strategy of HIV testing as part of the routine clinical ‘work-up’, unless a person explicitly refuses to test. To date, ROOT has been confined to specialist clinical services, such as prevention of mother-to-child HIV transmission programmes, sexual health clinics and tuberculosis services.

This study in primary care facilities in Harare compared the effectiveness of ROOT with PITC in children aged six to 15 years, a group for whom opportunities to receive HIV testing have been limited. The authors found that a 22% increase in the proportion of eligible children offered testing following the introduction of ROOT; a 34% increase in the proportion of HIV test uptake; and a 55% increase in proportion of children testing HIV positive (yield).  Importantly, the increase in proportion of children to whom testing was offered, test uptake and yield compared to opt-in PITC was sustained over the 1.5 years follow-up period. Factors postulated to have resulted in improved testing and uptake included the removal of the decision of whether to test from the guardian and healthcare worker and decreased stigma associated with opt-out testing. The authors also acknowledge that investment in training and human resource capacity likely contributed to improvements seen. Further, as stated by the authors, HIV testing must be accompanied by effective strategies to ensure linkage to care in order to improve health outcomes in this population.

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Time to promote earlier HIV diagnosis among older adults living with HIV in South Africa

Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study.

Cornell M, Johnson LF, Schomaker M, Tanser F, Maskew M, Wood R, Prozesky H, Giddy J, Stinson K, Egger M, Boulle A, Myer L, International Epidemiologic Databases to Evaluate A-SAC. Lancet HIV. 2015 Sep;2(9):e368-75. doi: 10.1016/S2352-3018(15)00113-7. Epub 2015 Aug 4.

Background: As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the effect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the effect of age on mortality of patients on ART in South Africa and whether this effect is mediated by baseline immunological status.

Methods: In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the first time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDS-Southern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age.

Findings: Between Jan 1, 2004, and Dec 31, 2013, 84 078 eligible adults started ART. Of these, we followed up 83 566 patients for 174 640 patient-years. 8% (1817 of 23 258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2.52 (95% CI 2.01-3.17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per µL, the adjusted mortality hazard ratio was 2.52 (2.04-3.11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per µL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44 909 patients still alive and in care were aged 50 years or older.

Interpretation: Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV.

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Editor’s notes: This article reports on a retrospective cohort analysis that examined the effect of age on mortality of people starting antiretroviral therapy (ART) in South Africa. Previous studies already illustrated higher mortality and lower risk of loss to follow-up in older people compared to younger adults on ART. Older people on ART also experience poorer immunological recovery on ART.

The investigators used data from six South African cohorts. Their dataset, with more than 80 000 people who started ART between 2004 and 2013, included much larger numbers of older adults than previously reported, particularly in low and middle income countries. This enabled the investigators to look at baseline characteristics of older people at ART initiation, such as CD4 count, and their association with mortality, which may not have been possible in analysis of single cohorts.

The authors found increasing proportions of people older than 50 years, initiating ART in successive years, from 6% in 2004 to 10% in 2013. They affirmed findings from previous studies that mortality increased with age at ART initiation, while loss to follow-up did not. They also affirmed that immunological recovery was diminished in older people, with smaller gains in CD4 cell count at older age than at younger ages.

Interestingly they found that the effect of age on mortality was strongest among individuals with the lowest baseline CD4 cell counts (lower than 50 cells/mm3). Older people were 2.5 times more likely to die compared to younger people in this group. In people with higher CD4 cell counts (more than 200 cells/mm3) the effect of age at ART initiation was less strong. Moreover some 15% of people aged 50 years or older started ART at CD4 cell counts of less than 50 cells /mm3, and should thus be prioritised as a key group of people requiring additional attention in ART programmes.

The lack of HIV prevention and testing strategies for older people may be one of the reasons for delayed diagnosis and late ART initiation. In addition, health care workers are less likely to consider an HIV diagnosis in older people.

The authors suggest that some of these older people may be long-term survivors despite the absence of ART, and further research into this could be valuable.

South Africa
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