Articles tagged as "Uganda"

Disbelief, stigma, ‘strong blood’ and inevitability affect seroconversion among HIV serodiscordant couples in Uganda

'People say that we are already dead much as we can still walk': a qualitative investigation of community and couples' understanding of HIV serodiscordance in rural Uganda.

Kim J, Nanfuka M, Moore D, Shafic M, Nyonyitono M, Birungi J, Galenda F, King R. BMC Infect Dis. 2016 Nov 10;16(1):665.

Background: Stable, co-habiting HIV serodiscordant couples are a key population in terms of heterosexual transmission in sub-Saharan Africa. Despite the wide availability of antiretroviral treatment and HIV educational programs, heterosexual transmission continues to drive the HIV epidemic in Africa. To investigate some of the factors involved in transmission or maintenance of serodiscordant status, we designed a study to examine participants' understanding of HIV serodiscordance and the implications this posed for their HIV prevention practices.

Methods: In-depth interviews were conducted with 28 serodiscordant couples enrolled in a treatment-as-prevention study in Jinja, Uganda. Participants were asked questions regarding sexual behaviour, beliefs in treatment and prevention, participants' and communities' understanding and context around HIV serodiscordance. Qualitative framework analysis capturing several main themes was carried out by a team of four members, and was cross-checked for consistency.

Results: It was found that most couples had difficulty explaining the phenomenon of serodiscordance and tended to be confused regarding prevention. Many individuals still held beliefs in pseudoscientific explanations for HIV susceptibility such as blood type and blood "strength". The participants' trust of treatment and medical services were well established. However, the communities' views of both serodiscordance and treatment were more pessimistic and wrought with mistrust. Stigmatization of serodiscordance and HIV-positive status were reported frequently.

Conclusions: The results indicate that despite years of treatment and prevention methods being available, stigmatization and mistrust persist in the communities of HIV-affected individuals and may directly contribute to new cases and seroconversion. We suggest that to optimize the effects of HIV treatment and prevention, clear education and support of such methods are sorely needed in sub-Saharan African communities.

Abstract  Full-text [free] access 

Editor’s notes: Expanded access to antiretroviral treatment has significantly reduced HIV-associated mortality. It has also contributed to reduced HIV incidence including in the most highly affected region of sub-Saharan Africa. Most new infections in this region are due to heterosexual transmission, with transmission within HIV serodiscordant couples in marriage or cohabitation thought to account for most new infections. This qualitative study explores the perceptions of members of HIV serodiscordant couples in terms of their understanding of serodiscordance or eventual seroconversion. The authors also explore how this understanding affects their sexual behaviour and adherence to antiretroviral therapy (for people living with HIV).

This sub-study was part of the Highly Active Antiretroviral therapy as Prevention (HAARP) study of treatment as prevention (TasP) among serodiscordant couples. In-depth interviews were conducted between June 2013 and August 2014.  All couples were initially serodiscordant upon recruitment into treatment. Over the course of the study, 14 HIV seronegative participants seroconverted. These individuals and their partners were selected for the sub-study and gender-matched to control subjects who were HIV seropositive participants whose partners did not seroconvert during the study.

The results of the HPTN 052 trial demonstrated a 96% reduction in HIV transmission within serodisordant couples associated with early use of antiretroviral therapy.  In this rural Ugandan setting, the phenomenon of serodiscordance remains poorly understood by people affected by it and the communities surrounding them. Despite extensive education campaigns and communication about HIV prevention various factors affect understanding of serodiscordance. Medication, confusion, mistrust, stigma, and a resulting sense of inevitability may negatively affect couples’ understanding and belief in the phenomenon of serodiscordance. For a variety of reasons, some serodisordant couples also report lack of consistent condom use. This is of particular concern where abstinence has proved to be an unachievable option for many couples. Improved education regarding serodiscordance and ART treatment will be required to address heterosexual transmission and ensure the maintenance of serodiscordance in affected couples.

Africa
Uganda
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Using HIV testing infrastructure for other diseases can be very low cost

Implementation and operational research: cost and efficiency of a hybrid mobile multidisease testing approach with high HIV testing coverage in east Africa.

Chang W, Chamie G, Mwai D, Clark TD, Thirumurthy H, Charlebois ED, Petersen M, Kabami J, Ssemmondo E, Kadede K, Kwarisiima D, Sang N, Bukusi EA, Cohen CR, Kamya M, Havlir DV, Kahn JG. J Acquir Immune Defic Syndr. 2016 Nov 1;73(3):e39-e45.

Background: In 2013-2014, we achieved 89% adult HIV testing coverage using a hybrid testing approach in 32 communities in Uganda and Kenya (SEARCH: NCT01864603). To inform scalability, we sought to determine: (1) overall cost and efficiency of this approach; and (2) costs associated with point-of-care (POC) CD4 testing, multidisease services, and community mobilization.

Methods: We applied microcosting methods to estimate costs of population-wide HIV testing in 12 SEARCH trial communities. Main intervention components of the hybrid approach are census, multidisease community health campaigns (CHC), and home-based testing for CHC nonattendees. POC CD4 tests were provided for all HIV-infected participants. Data were extracted from expenditure records, activity registers, staff interviews, and time and motion logs.

Results: The mean cost per adult tested for HIV was $20.5 (range: $17.1-$32.1) (2014 US$), including a POC CD4 test at $16 per HIV+ person identified. Cost per adult tested for HIV was $13.8 at CHC vs. $31.7 by home-based testing. The cost per HIV+ adult identified was $231 ($87-$1245), with variability due mainly to HIV prevalence among persons tested (ie, HIV positivity rate). The marginal costs of multidisease testing at CHCs were $1.16/person for hypertension and diabetes, and $0.90 for malaria. Community mobilization constituted 15.3% of total costs.

Conclusions: The hybrid testing approach achieved very high HIV testing coverage, with POC CD4, at costs similar to previously reported mobile, home-based, or venue-based HIV testing approaches in sub-Saharan Africa. By leveraging HIV infrastructure, multidisease services were offered at low marginal costs.

Abstract access  

Editor’s notes: The scale up of HIV testing services over recent years has meant that infrastructure for HIV testing is, in many places, much stronger than that of other diseases. This study assessed the costs and cost-effectiveness of both HIV testing services and additional multi disease testing in 32 communities of Uganda and Kenya. As has been found in other studies, testing people through community health campaigns cost less than home-based testing. However, the cost per HIV positive person identified varied widely according to the underlying HIV prevalence. The costs of including additional disease testing services – for hypertension, diabetes and malaria – were low. A more holistic approach to health testing could lead to substantial health benefits for relatively low cost.

Africa
Kenya, Uganda
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Invasive cervical cancers preventable by HPV vaccines: a comparison of HIV-positive and negative women

Effect of HIV infection on human papillomavirus types causing invasive cervical cancer in Africa.

Clifford GM, de Vuyst H, Tenet V, Plummer M, Tully S, Franceschi S. J Acquir Immune Defic Syndr. 2016 Nov 1;73(3):332-339.

Objectives: HIV infection is known to worsen the outcome of cervical human papillomavirus (HPV) infection and may do so differentially by HPV type.

Design: Twenty-one studies were included in a meta-analysis of invasive cervical cancers (ICC) among women infected with HIV in Africa.

Method: Type-specific HPV DNA prevalence was compared with data from a similar meta-analysis of HIV-negative ICC using prevalence ratios (PR).

Results: HPV detection was similar in 770 HIV-positive (91.2%) and 3846 HIV-negative (89.6%) ICC, but HIV-positive ICC harbored significantly more multiple HPV infections (PR = 1.75, 95% confidence intervals: 1.18 to 2.58), which were significantly more prevalent in ICC tested from cells than from biopsies. HPV16 was the most frequently detected type in HIV-positive ICC (42.5%), followed by HPV18 (22.2%), HPV45 (14.4%), and HPV35 (7.1%). Nevertheless, HIV-positive ICC were significantly less frequently infected with HPV16 than HIV-negative ICC (PR = 0.88, 95% confidence intervals: 0.79 to 0.99). Other high-risk types were significantly more prevalent in HIV-positive ICC, but only for HPV18 was there a significantly higher prevalence of both single and multiple infections in HIV-positive ICC. Increases for other high-risk types were primarily accounted for by multiple infections. The proportion of HPV-positive ICC estimated attributable to HPV16/18 (71.8% in HIV positive, 73.4% in HIV negative) or HPV16/18/31/33/45/52/58 (88.8%, 89.5%) was not affected by HIV.

Conclusions: HIV alters the relative carcinogenicity of HPV types, but prophylactic HPV16/18 vaccines may nevertheless prevent a similar proportion of ICC, irrespective of HIV infection.

Abstract access  

Editor’s notes: Invasive cervical cancer (ICC) is one of the most common cancers in low and middle income countries. In the African region the prevalence of both ICC and HIV are high. Compared to HIV-negative women, HIV-positive women are at increased risk of oncogenic high-risk (HR) human papillomavirus (HPV) incidence and persistence, and cervical lesion incidence and progression. Current HPV vaccines offer potential for cervical cancer prevention by targeting the HR-HPV types associated with ICC. Although there is no data yet available on HPV vaccine efficacy among HIV-positive persons, HPV vaccines have been reported to be safe and immunogenic in HIV-positive children, female adolescents and adults. 

This systematic review compared the HPV type distribution and the HPV vaccine type distribution in ICC biopsy and cervical cell specimens of 770 HIV-positive and 3846 HIV-negative women from 21 studies in 12 African countries.

The authors report that the fraction of ICC attributable to the HPV types included in the current bivalent (HPV16/18) and nonavalent (HPV16/18/31/33/45/52/58) vaccines was similar among HIV-positive and HIV-negative women (bivalent: 61.7% and 67.3%; nonavalent: 88.9% and 89.5%, respectively). However, a non-negligible proportion of ICC from both HIV-positive and HIV-negative women were infected with non-vaccine types in the absence of any of the vaccine types (7.0% and 7.9% of ICC from HIV-positive and HIV-negative women, respectively), and this was highest for HPV35.

These findings confirm that the currently available HPV vaccines could prevent a similar proportion of ICC cases in HIV-positive as in HIV-negative women. ICC remains an important co-morbidity among HIV-positive women even in the antiretroviral era. Given that HIV-positive women are at greater risk of HR-HPV persistence and cervical lesion incidence and faster progression to high-grade cervical lesions, primary prevention of HPV infection through vaccination could reduce HPV infection and HPV-associated disease in Africa. However, cervical cancer screening will continue to remain important for both HIV-positive and HIV-negative women as there remain a proportion of ICC cases that may not be preventable by currently available vaccines. 

Comorbidity, Epidemiology
Africa
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Moving from facility to community-based models of HIV care - will it work?

Community-based interventions to improve and sustain antiretroviral therapy adherence, retention in HIV care and clinical outcomes in low- and middle-income countries for achieving the UNAIDS 90-90-90 targets.

Nachega JB, Adetokunboh O, Uthman OA, Knowlton AW, Altice FL, Schechter M, Galarraga O, Geng E, Peltzer K, Chang LW, Van Cutsem G, Jaffar SS, Ford N, Mellins CA, Remien RH, Mills EJ. Curr HIV/AIDS Rep. 2016 Oct;13(5):241-55. doi: 10.1007/s11904-016-0325-9.

Little is known about the effect of community versus health facility-based interventions to improve and sustain antiretroviral therapy (ART) adherence, virologic suppression, and retention in care among HIV-infected individuals in low- and middle-income countries (LMICs). We systematically searched four electronic databases for all available randomized controlled trials (RCTs) and comparative cohort studies in LMICs comparing community versus health facility-based interventions. Relative risks (RRs) for pre-defined adherence, treatment engagement (linkage and retention in care), and relevant clinical outcomes were pooled using random effect models. Eleven cohort studies and eleven RCTs (N = 97 657) were included. Meta-analysis of the included RCTs comparing community- versus health facility-based interventions found comparable outcomes in terms of ART adherence (RR = 1.02, 95 % CI 0.99 to 1.04), virologic suppression (RR = 1.00, 95 % CI 0.98 to 1.03), and all-cause mortality (RR = 0.93, 95 % CI 0.73 to 1.18). The result of pooled analysis from the RCTs (RR = 1.03, 95 % CI 1.01 to 1.06) and cohort studies (RR = 1.09, 95 % CI 1.03 to 1.15) found that participants assigned to community-based interventions had statistically significantly higher rates of treatment engagement. Two studies found community-based ART delivery model either cost-saving or cost-effective. Community- versus facility-based models of ART delivery resulted in at least comparable outcomes for clinically stable HIV-infected patients on treatment in LMICs and are likely to be cost-effective.

Abstract access  

Editor’s notes: The remarkable global scale-up of antiretroviral therapy (ART) programmes, while much-needed and impressive, has had inevitable consequences. These include overcrowding of health facilities, longer waiting times, reduced time for counselling and care of newly-enrolled people and restricted capacity to provide support for people who do not remain engaged with care. Furthermore, the UNAIDS 90-90-90 treatment target for 2020 to have 90% of people living with HIV know their HIV status, 90% of all diagnosed individuals receiving ART and 90% of people living with HIV on ART to be virally suppressed, will now require an additional 20 million people living with HIV to start treatment.

Community-based programmes to complement facility-based model of HIV care delivery are increasingly being recognised as an important and sustainable approach to address the growing numbers of people accessing care in high-HIV prevalence settings. This review compared outcomes of community-based versus facility-based models of ART delivery and treatment support. There was no statistical difference in optimal ART adherence, virologic suppression or all-cause mortality between participants assigned to community-based ART and facility-based ART in randomised controlled trials (RCTs). When data from RCTs and cohort studies were pooled, participants assigned to community-based ART appeared to have higher rates of retention in care at the end of the follow-up period. Notably, the few studies that did examine cost-effectiveness found community-based programmes to be cost-saving.

The findings demonstrate that community-level programmes are certainly not inferior to facility-based programmes. However, it is important to note some key limitations. Firstly, many of the studies are subject to selection bias, i.e. people at risk of poorer outcomes e.g. sicker people or people with a history of poor adherence may be excluded from receiving community-based programmes. The authors also highlight a high risk of “other forms of bias” in the cohort studies, but these are not specified. Secondly, adherence measures based on self-report may not be reliable. Thirdly, the review compared a heterogeneous set of programmes. Fourthly, as with other systematic reviews, publication bias is highly likely.   

Notwithstanding these limitations, this study suggests that community-based programmes have promise in supporting fragile and overcrowded facility-based healthcare systems in providing HIV care to a growing number of people. There may even be potential for integrating HIV care with care for other chronic conditions.

Well-designed studies are necessary, given the ambitious targets we have set ourselves, to explore the effectiveness and cost-effectiveness of community-based programmes. This is particularly important in under-represented groups with disproportionately poor outcomes such as children, adolescents and pregnant women. Further, for community-based programmes to be effective, it will be critical to ensure that adequate training and mentorship and ongoing monitoring for quality assurance is in place.      

Africa, Asia, Latin America
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Improving programmes: a thematic synthesis of qualitative studies of treatment adherence programmes

Barriers and facilitators of interventions for improving antiretroviral therapy adherence: a systematic review of global qualitative evidence.

Ma Q, Tso LS, Rich ZC, Hall BJ, Beanland R, Li H, Lackey M, Hu F, Cai W, Doherty M, Tucker JD. J Int AIDS Soc. 2016 Oct 17;19(1):21166. doi: 10.7448/IAS.19.1.21166. eCollection 2016.

Introduction: Qualitative research on antiretroviral therapy (ART) adherence interventions can provide a deeper understanding of intervention facilitators and barriers. This systematic review aims to synthesize qualitative evidence of interventions for improving ART adherence and to inform patient-centred policymaking.

Methods: We searched 19 databases to identify studies presenting primary qualitative data on the experiences, attitudes and acceptability of interventions to improve ART adherence among PLHIV and treatment providers. We used thematic synthesis to synthesize qualitative evidence and the CERQual (Confidence in the Evidence from Reviews of Qualitative Research) approach to assess the confidence of review findings.

Results: Of 2982 references identified, a total of 31 studies from 17 countries were included. Twelve studies were conducted in high-income countries, 13 in middle-income countries and six in low-income countries. Study populations focused on adults living with HIV (21 studies, n=1025), children living with HIV (two studies, n=46), adolescents living with HIV (four studies, n=70) and pregnant women living with HIV (one study, n=79). Twenty-three studies examined PLHIV perspectives and 13 studies examined healthcare provider perspectives. We identified six themes related to types of interventions, including task shifting, education, mobile phone text messaging, directly observed therapy, medical professional outreach and complex interventions. We also identified five cross-cutting themes, including strengthening social relationships, ensuring confidentiality, empowerment of PLHIV, compensation and integrating religious beliefs into interventions. Our qualitative evidence suggests that strengthening PLHIV social relationships, PLHIV empowerment and developing culturally appropriate interventions may facilitate adherence interventions. Our study indicates that potential barriers are inadequate training and compensation for lay health workers and inadvertent disclosure of serostatus by participating in the intervention.

Conclusions: Our study evaluated adherence interventions based on qualitative data from PLHIV and health providers. The study underlines the importance of incorporating social and cultural factors into the design and implementation of interventions. Further qualitative research is needed to evaluate ART adherence interventions.

Abstract  Full-text [free] access 

Editor’s notes: This is a review of studies using qualitative methods to explore the experiences of people living with HIV and healthcare providers involved in programmes to support antiretroviral treatment adherence. The thematic synthesis is presented in two ways. First, the reviewed studies are categorised by types of adherence programmes, such as task shifting, education, or directly observed therapy. Secondly, the authors present themes that are common across all reviewed studies. These include: the benefits and challenges of employing lay healthcare workers; the need to maintain confidentiality in adherence programmes; the benefits of supporting empowerment and social relationships for people living with HIV; and the need for culturally appropriate information and practice. Overall the review illustrates that adherence programmes can have more impact if they address confidentiality, strengthen social ties among people living with HIV and their communities; provide adequate compensation and training for lay healthcare workers; and sensitively reflect local social, cultural and religious norms and beliefs. 

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Voluntary male circumcision still a cost-effective intervention in the era of 90-90-90

Impact and cost of scaling up voluntary medical male circumcision for HIV prevention in the context of the new 90-90-90 HIV treatment targets.

Kripke K, Reed J, Hankins C, Smiley G, Laube C, Njeuhmeli E. PLoS One. 2016 Oct 26;11(10):e0155734. doi: 10.1371/journal.pone.0155734. eCollection 2016.

Background: The report of the Joint United Nations Programme on HIV/AIDS (UNAIDS) for World AIDS Day 2014 highlighted a Fast-Track Strategy that sets ambitious treatment and prevention targets to reduce global HIV incidence to manageable levels by 2020 and end the AIDS epidemic by 2030. The 90-90-90 treatment targets for 2020 call for 90% of people living with HIV to know their HIV status, 90% of people who know their status to receive treatment, and 90% of people on HIV treatment to be virally suppressed. This paper examines how scale-up of voluntary medical male circumcision (VMMC) services in four priority countries in sub-Saharan Africa could contribute to ending the AIDS epidemic by 2030 in the context of concerted efforts to close the treatment gap, and what the impact of VMMC scale-up would be if the 90-90-90 treatment targets were not completely met.

Methods: Using the Goals module of the Spectrum suite of models, this analysis modified ART (antiretroviral treatment) scale-up coverage from base scenarios to reflect the 90-90-90 treatment targets in four countries (Lesotho, Malawi, South Africa, and Uganda). In addition, a second scenario was created to reflect viral suppression levels of 75% instead of 90%, and a third scenario was created in which the 90-90-90 treatment targets are reached in women, with men reaching more moderate coverage levels. Regarding male circumcision (MC) coverage, the analysis examined both a scenario in which VMMCs were assumed to stop after 2015, and one in which MC coverage was scaled up to 90% by 2020 and maintained at 90% thereafter.

Results: Across all four countries, scaling up VMMC is projected to provide further HIV incidence reductions in addition to those achieved by reaching the 90-90-90 treatment targets. If viral suppression levels only reach 75%, scaling up VMMC leads to HIV incidence reduction to nearly the same levels as those achieved with 90-90-90 without VMMC scale-up. If only women reach the 90-90-90 targets, scaling up VMMC brings HIV incidence down to near the levels projected with 90-90-90 without VMMC scale-up. Regarding cost, scaling up VMMC increases the annual costs during the scale-up phase, but leads to lower annual costs after the MC coverage target is achieved.

Conclusions: The scenarios modeled in this paper show that the highly durable and effective male circumcision intervention increases epidemic impact levels over those of treatment-only strategies, including the case if universal levels of viral suppression in men and women are not achieved by 2020. In the context of 90-90-90, prioritizing continued successful scale-up of VMMC increases the possibility that future generations will be free not only of AIDS but also of HIV.

Abstract  Full-text [free] access 

Editor’s notes: Voluntary medical male circumcision (VMMC) has been shown to reduce the risk of female-to-male HIV transmission by up to 60%. It is a highly cost-effective HIV prevention activity. Since 2007, extensive efforts have been made to scale up VMMC in settings with high HIV prevalence and low levels of male circumcision, with the aim of reaching 80% VMMC coverage in 14 priority countries by 2016.  At the end of 2015, more than 11 million men in east and southern Africa had received VMMC.  In this modelling study, the authors look at the impact of scaling up VMMC to 90% coverage in four priority countries. The paper illustrates that VMMC scale-up can achieve additional reductions in HIV incidence above reductions achieved through testing and treatment alone. In the scenarios where the UNAIDS 90-90-90 treatment target is not completely met, VMMC scale-up can reduce HIV incidence to levels comparable to what would be achieved with the 90-90-90 treatment target. VMMC scale-up also resulted in lower long-term annual programme costs in all four settings. In 2015, UNAIDS set a target of an additional 27 million men in high-HIV prevalence settings receiving VMMC by 2021. Achieving this target will require new service delivery models, and innovative approaches to overcome current barriers that discourage men from accessing health care. VMMC is only one component in combination HIV prevention. It has advantages in being a single event that does not require ongoing adherence, offers men lifelong benefits, and is a valuable entry point for providing a broader range of health services to men including HIV testing. As this study demonstrates, VMMC remains a cost-effective strategy for reducing HIV incidence, even in the context of universal testing and treatment.  

Africa
Lesotho, Malawi, South Africa, Uganda
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Standard methods underestimate the effect of HIV on fertility

The effects of HIV on fertility by infection duration: evidence from African population cohorts before ART availability: fertility by duration of HIV infection.

Marston M, Nakiyingi-Miiro J, Kusemererwa S, Urassa M, Michael D, Nyamukapa C, Gregson S, Zaba B, Eaton JW. AIDS. 2016 Oct 20. [Epub ahead of print]

Objectives: To estimate the relationship between HIV natural history and fertility by duration of infection in East and Southern Africa before the availability of antiretroviral therapy, and assess potential biases in estimates of age-specific sub-fertility when using retrospective birth histories in cross-sectional studies.

Design: Pooled analysis of prospective population-based HIV cohort studies in Masaka (Uganda) Kisesa (Tanzania), and Manicaland (Zimbabwe).

Methods: Women aged 15-49 who had ever tested for HIV were included. Analyses were censored at antiretroviral treatment roll out. Fertility rate ratios were calculated to see the relationship of duration of HIV infection on fertility, adjusting for background characteristics. Survivorship and misclassification biases on age-specific subfertility estimates from cross-sectional surveys were estimated by reclassifying person time from the cohort data to simulate cross-sectional surveys and comparing fertility rate ratios to true cohort results.

Results: HIV negative and positive women contributed 15 440 births and 86 320 person years; and 1236 births and 11 240 thousand person years respectively to the final dataset. Adjusting for age, study site and calendar year, each additional year since HIV sero conversion was associated with a 0.02 (95%CI 0.01-0.03) relative decrease in fertility for HIV-positive women. Survivorship and misclassification biases in simulated retrospective birth histories resulted in modest underestimates of sub-fertility by 2-5% for age groups 20-39y.

Conclusion: Longer duration of infection is associated with greater relative fertility reduction for HIV-positive women. This should be considered when creating estimates for HIV prevalence among pregnant women and PMTCT need over the course of the HIV epidemic and ART scale-up.

Abstract access 

Editor’s notes: HIV prevalence among antenatal clinic attenders is used to help estimate population HIV prevalence. It is known that figures must be adjusted upwards to reflect the fact HIV reduces fertility, especially in older women. However, older women are also likely to have been living with HIV for longer. The authors investigated whether length of infection changes the effect of HIV on fertility. Using three prospective longitudinal cohorts, they found that time since seroconversion was associated with reduced fertility, even after adjusting for age and age at seroconversion. This result is important because as the epidemic matures and the majority of women living with HIV are not recently infected, the effect of HIV on suppressing fertility will increase. This will cause measurements of HIV prevalence in pregnancy to underestimate the true population prevalence even if they adjust for age. Conversely, women who have been living with HIV for longer are more likely to be taking ART, which increases fertility relative to women who have been diagnosed more recently. Therefore, within an age-group, pregnancy data is likely to overestimate the proportion of HIV positive women on ART. The usual way to measure the age-specific effects of HIV on fertility is to compare the three-year reported fertility of women living with HIV, and women without HIV in a cross-sectional survey. The authors used longitudinal data to simulate a survey and showed that surveys slightly underestimate the size of the fertility effect, for two reasons. Firstly, if women acquire HIV during the three years any pregnancies before infection are misattributed to HIV. Secondly, there is excess mortality of HIV positive women with low fertility who therefore do not appear in the survey.

The reasons for the age-dependent effect of HIV on fertility are both biological and social (older women living with HIV are more likely to be widowed or divorced) and the relationship is not fixed over time. It shifts according to demographic factors, the stage of the epidemic and, availability of treatment. Assumptions must be continually tested as the epidemic evolves. 

Epidemiology
Africa
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Success in accelerating ART initiation in Uganda

Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial.

Amanyire G, Semitala FC, Namusobya J, Katuramu R, Kampiire L, Wallenta J, Charlebois E, Camlin C, Kahn J, Chang W, Glidden D, Kamya M, Havlir D, Geng E. Lancet HIV. 2016 Nov;3(11):e539-e548. pii: S2352-3018(16)30090-X. doi: 10.1016/S2352-3018(16)30090-X. [Epub 2016 Aug 27]

Background: In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation.

Methods: In this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289.

Findings: Between April 11, 2013, and Feb 2, 2015, 12 024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per µL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41.9%, 95% CI 40.1-43.8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group.

Interpretation: A multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale.

Abstract access  

Editor’s notes: As noted in another article in this month’s digest, early mortality remains high among people starting antiretroviral therapy (ART). People with advanced disease are at particularly high risk. Previous research has illustrated that mortality was even higher during the period between entering care and starting ART. ART start may be delayed for many reasons, some attributable to the person and others to the health system. Some of the health system delays date from practice early in ART roll-out. Great emphasis was placed on ART counselling, usually requiring people to attend several counselling sessions prior to initiating treatment, because of concerns about poor adherence. This practice has persisted despite evidence that treatment outcomes are no worse if ART is initiated rapidly with concurrent counselling rather than delaying ART initiation until after counselling has been completed.

In this study, the investigators tested a complex activity aiming to accelerate ART initiation in primary health care clinics in Uganda. This was developed based on health promotion literature, and was a combination of training led by opinion-leaders to counter the widespread belief that delays to ART initiation are not harmful. There was also a more flexible approach to ART counselling and the need for treatment supporters; introduction of point of care CD4 machines so that ART eligibility could be assessed in-session; and feedback to facilities concerning their performance compared to other clinics. The programme was successful in accelerating ART initiation. This approach holds promise as an effective method to implement change in health facilities. However, as more countries adopt the WHO guidance to offer ART regardless of CD4 count, the contribution of point of care CD4 machines in similar approaches may diminish.  This is a common challenge for generalisability from randomised trials at a time of rapid policy changes. Cost and cost-effectiveness analyses will be reported later. The study was not primarily designed to determine the effect of the activity on patient-relevant outcomes, which were measured in a small subset of people, and illustrated no difference in mortality after one year. Of note, mortality was very low in both groups (2% programme versus 3% control), which may be partly explained by the relatively high median CD4 count at enrolment, and around one-quarter of participants being pregnant women. It would be very interesting to see whether this programme has an effect on early mortality in settings and populations where early survival is less good.  

Africa
Uganda
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High mortality persists among people presenting with advanced HIV disease

Mortality in the first 3 months on antiretroviral therapy among HIV-positive adults in low- and middle-income countries: a meta-analysis.

Brennan AT, Long L, Useem J, Garrison L, Fox MP. J Acquir Immune Defic Syndr. 2016 Sep 1;73(1):1-10. doi: 10.1097/QAI.0000000000001112.

Previous meta-analyses reported mortality estimates of 12-month post-antiretroviral therapy (ART) initiation; however, 40%-60% of deaths occur in the first 3 months on ART, a more sensitive measure of averted deaths through early ART initiation. To determine whether early mortality is dropping as treatment thresholds have increased, we reviewed studies of 3 months on ART initiation in low- to middle-income countries. Studies of 3-month mortality from January 2003 to April 2016 were searched in 5 databases. Articles were included that reported 3-month mortality from a low- to middle-income country; nontrial setting and participants were ≥15. We assessed overall mortality and stratified by year using random effects models. Among 58 included studies, although not significant, pooled estimates show a decline in mortality when comparing studies whose enrollment of patients ended before 2010 (7.0%; 95% CI: 6.0 to 8.0) with the studies during or after 2010 (4.0%; 95% CI: 3.0 to 5.0). To continue to reduce early HIV-related mortality at the population level, intensified efforts to increase demand for ART through active testing and facilitated referral should be a priority. Continued financial investments by multinational partners and the implementation of creative interventions to mitigate multidimensional complex barriers of accessing care and treatment for HIV are needed.

Abstract access  

Editor’s notes: Early mortality among people initiating antiretroviral therapy (ART) remains high, presumed to be because many people living with HIV present when already very sick with advanced HIV disease. This systematic review included 43 studies from Africa and 13 from Asia. Its main aim was to see whether the evolution of guidelines recommending ART initiation at progressively higher CD4 counts over this period had reduced early mortality (defined as death within three months of ART start) and, by implication, the proportion of people starting ART who had advanced disease. To investigate this, the authors compared studies where enrolment ended before 2010 with studies that had started later.

Overall early mortality was six percent.  Because of the large numbers lost to follow up this will be an underestimate. The authors attempted to compensate for this, and calculated an adjusted overall figure of more than 10%. There was a fall in early mortality from seven percent to four percent (unadjusted) between the early and late periods but although the trend was consistent the difference was not significant.

In only four of the 58 studies was the median CD4 count at ART initiation above 200x106/l. It seems likely that even when policies to initiate ART at high CD4 counts are adopted, additional efforts will be necessary to promote initiation of ART and retention in care for people who feel well.  This is in order to reduce the number of people starting ART with advanced disease and consequently at very high risk of early death.   

Africa, Asia, Latin America
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Weekends off ART: a strategy to maintain adherence in children and adolescents?

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial.

The BREATHER (PENTA 16) Trial Group. Lancet HIV. 2016 Sep;3(9):e421-30. doi: 10.1016/S2352-3018(16)30054-6. Epub 2016 Jun 20.

Background: For HIV-1-infected young people facing lifelong antiretroviral therapy (ART), short cycle therapy with long-acting drugs offers potential for drug-free weekends, less toxicity, and better quality-of-life. We aimed to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy (continuous ART).

Methods: In this open-label, non-inferiority trial (BREATHER), eligible participants were aged 8-24 years, were stable on first-line efavirenz with two nucleoside reverse transcriptase inhibitors, and had HIV-1 RNA viral load less than 50 copies per mL for 12 months or longer. Patients were randomly assigned (1:1) to remain on continuous therapy or change to short cycle therapy according to a computer-generated randomisation list, with permuted blocks of varying size, stratified by age and African versus non-African sites; the list was prepared by the trial statistician and randomisation was done via a web service accessed by site clinician or one of the three coordinating trials units. The primary outcome was the proportion of participants with confirmed viral load 50 copies per mL or higher at any time up to the 48 week assessment, estimated with the Kaplan-Meier method. The trial was powered to exclude a non-inferiority margin of 12%. Analyses were intention to treat. The trial was registered with EudraCT, number 2009-012947-40, ISRCTN, number 97755073, and CTA, number 27505/0005/001-0001.

Findings: Between April 1, 2011, and June 28, 2013, 199 participants from 11 countries worldwide were randomly assigned, 99 to the short cycle therapy and 100 to continuous therapy, and were followed up until the last patient reached 48 weeks. 105 (53%) were men, median age was 14 years (IQR 12-18), and median CD4 cell count was 735 cells per µL (IQR 576-968). Six percent (6%) patients assigned to the short cycle therapy versus seven percent (7%) assigned to continuous therapy had confirmed viral load 50 copies per mL or higher (difference -1.2%, 90% CI -7.3 to 4.9, non-inferiority shown). 13 grade 3 or 4 events occurred in the short cycle therapy group and 14 in the continuous therapy group (p=0.89). Two ART-related adverse events (one gynaecomastia and one spontaneous abortion) occurred in the short cycle therapy group compared with 14 (p=0.02) in the continuous therapy group (five lipodystrophy, two gynaecomastia, one suicidal ideation, one dizziness, one headache and syncope, one spontaneous abortion, one neutropenia, and two raised transaminases).

Interpretation: Non-inferiority of maintaining virological suppression in children, adolescents, and young adults was shown for short cycle therapy versus continuous therapy at 48 weeks, with similar resistance and a better safety profile. This short cycle therapy strategy is a viable option for adherent HIV-infected young people who are stable on efavirenz-based ART.

Abstract  Full-text [free] access 

Editor’s notes: Increasing number of children born with HIV infection, who would otherwise have died in infancy, are now reaching adolescence because of the scale-up of antiretroviral therapy (ART). Adherence to treatment for chronic illnesses often drops as children approach adolescence, and unfortunately HIV is no exception.  

BREATHER is an open-label, non-inferiority trial comparing continuous daily ART (CT) with short cycle treatment (SCT) enabling two days off treatment every week. The participants were aged 8 to 24 years and had to have been virally suppressed for at least one year prior to enrolment on an ART regimen containing efavirenz. At 48 weeks, 6.1% of children in the SCT arm versus 7.3% in the CT arm had virologic rebound (defined as an HIV viral load > 50 copies/ml), demonstrating that SCT is non-inferior to CT. There was no statistical difference between arms in the proportion who developed major resistance mutations or in proportion of adverse events.

This is the first trial to demonstrate that controlled interruption appears to be safe in terms of maintaining viral suppression and lack of emergence of drug resistance mutations. Notably, the trial was conducted in geographically diverse settings (11 countries) and achieved an impressive retention rate with only one participant being lost to follow-up. In addition, the strategy was highly acceptable to participants, particularly as it provided a legitimate way of missing doses. Children are expected to take ART for 20 years longer on average than adults and strategies that enable time off ART may be an effective way to reduce treatment fatigue. In addition, reduced ART usage may provide potential cost savings. 

A concern, however, is that such a strategy may give out the detrimental message that missing doses is acceptable and may not affect the viral load. Therefore, appropriate counselling is important to ensure that people understand that there is a maximum break in treatment of two designated days per week. It is also important to note that the findings of this study are only generalisable to people who are stable on ART, who have not experienced treatment failure and who are taking efavirenz-based regimens. The trial was carried out with intensive viral load monitoring and further research is required to work out how such a strategy could be safely implemented in settings where routine viral load monitoring may not be available.

Viral suppression is the ultimate goal to improve health outcomes and reduce HIV transmission. Consistent adherence to ART is critical to ensure sustained virologic suppression. Children and adolescents face multiple challenges to adhere to treatment and a number of different approaches to address this are required- this trial now provides an innovative and promising option to offer to children.

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