Articles tagged as "HIV Treatment"

HIV genotyping to focus prevention efforts

Near real-time monitoring of HIV transmission hotspots from routine HIV genotyping: an implementation case study.

Poon AF, Gustafson R, Daly P, Zerr L, Demlow SE, Wong J, Woods CK, Hogg RS, Krajden M, Moore D, Kendall P, Montaner JS, Harrigan PR. Lancet HIV. 2016 May;3(5):e231-8. doi: 10.1016/S2352-3018(16)00046-1. Epub 2016 Apr 7.

Background: HIV evolves rapidly and therefore infections with similar genetic sequences are likely linked by recent transmission events. Clusters of related infections can represent subpopulations with high rates of transmission. We describe the implementation of an automated near real-time system to monitor and characterise HIV transmission hotspots in British Columbia, Canada.

Methods: In this implementation case study, we applied a monitoring system to the British Columbia drug treatment database, which holds more than 32 000 anonymised HIV genotypes for nearly 9000 residents of British Columbia living with HIV. On average, five to six new HIV genotypes are deposited in the database every day, which triggers an automated reanalysis of the entire database. We extracted clusters of five or more individuals with short phylogenetic distances between their respective HIV sequences. The system generated monthly reports of the growth and characteristics of clusters that were distributed to public health officers.

Findings: In June, 2014, the monitoring system detected the expansion of a cluster by 11 new cases during 3 months, including eight cases with transmitted drug resistance. This cluster generally comprised young men who have sex with men. The subsequent report precipitated an enhanced public health follow-up to ensure linkage to care and treatment initiation in the affected subpopulation. Of the nine cases associated with this follow-up, all had already been linked to care and five cases had started treatment. Subsequent to the follow-up, three additional cases started treatment and most cases achieved suppressed viral loads. During the next 12 months, we detected 12 new cases in this cluster with reduction in the onward transmission of drug resistance.

Interpretation: Our findings show the first application of an automated phylogenetic system monitoring a clinical database to detect a recent HIV outbreak and support the ensuing public health response. By making secondary use of routinely collected HIV genotypes, this approach is cost-effective, attains near real-time monitoring of new cases, and can be implemented in all settings in which HIV genotyping is the standard of care.

Abstract access

Editor’s notes: HIV genetic sequence data have been used retrospectively to characterise transmission patterns and association with risk factors. This is the first report of the use of such data in real-time to monitor transmission and inform a public health response.  Under current treatment guidelines in British Columbia, an HIV genotype test is routinely done on all individuals at the time of diagnosis.  The results are fed in to an automated monitoring system that can be used detect transmission ‘clusters’ and track their development. The case study demonstrates the value of this system in detecting an outbreak of transmitted drug resistance which was prioritised for public health programmes.  The authors acknowledge the ethical dilemmas associated with using HIV sequence data to inform public health actions. Accordingly, all individuals in the cluster were offered counselling, testing and treatment so as not to focus on any one person. One limitation of the monitoring system is that it relies on information from people who have presented for HIV testing, so people who are undiagnosed or not engaged with care are not represented. Although monitoring based on HIV sequence data is only possible in certain settings, it may provide a cost-effective tool for focused HIV prevention in situations where the data are already being collected as part of the standard care.

Northern America
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Strengthening PMTCT implementation through systems engineering

Impact of a systems engineering intervention on PMTCT service delivery in Cote d'Ivoire, Kenya, Mozambique: a cluster randomized trial.

Rustagi AS, Gimbel S, Nduati R, Cuembelo MF, Wasserheit JN, Farquhar C, Gloyd S, Sherr K, with input from the SST. J Acquir Immune Defic Syndr. 2016 Apr 14. [Epub ahead of print]

Background: Efficacious interventions to prevent mother-to-child HIV transmission (PMTCT) have not translated well into effective programs. Prior studies of systems engineering applications to PMTCT lacked comparison groups or randomization.

Methods: Thirty-six health facilities in Cote d'Ivoire, Kenya, and Mozambique were randomized to usual care or a systems engineering intervention, stratified by country and volume. The intervention guided facility staff to iteratively identify and then rectify barriers to PMTCT implementation. Registry data quantified coverage of HIV testing during first antenatal care visit, antiretrovirals (ARVs) for HIV-positive pregnant women, and screening HIV-exposed infants (HEI) for HIV by 6-8 weeks. We compared the change between baseline (January 2013-January 2014) and post-intervention (January-March 2015) periods using t-tests. All analyses were intent-to-treat.

Results: ARV coverage increased 3-fold (+13.3 percentage points [95% CI: 0.5, 26.0] in intervention vs. +4.1 [-12.6, 20.7] in control facilities) and HEI screening increased 17-fold (+11.6 [-2.6, 25.7] in intervention vs. +0.7 [-12.9, 14.4] in control facilities). In pre-specified sub-group analyses, ARV coverage increased significantly in Kenya (+20.9 [-3.1, 44.9] in intervention vs. -21.2 [-52.7, 10.4] in controls; p=0.02). HEI screening increased significantly in Mozambique (+23.1 [10.3, 35.8] in intervention vs. +3.7 [-13.1, 20.6] in controls; p=0.04). HIV testing did not differ significantly between arms.

Conclusions: In this first randomized trial of systems engineering to improve PMTCT, we saw substantially larger improvements in ARV coverage and HEI screening in intervention facilities compared to controls, which were significant in pre-specified sub-groups. Systems engineering could strengthen PMTCT service delivery and protect infants from HIV.

Abstract access

Editor’s notes: Systems engineering is an interdisciplinary approach to optimise complex processes or systems. In this randomised trial of a systems engineering approach to improving prevention  of mother-to-child HIV transmission programmes, the study programme was a five-step, iterative package of systems analysis and quality improvement tools. In lay terms, the systems engineering activity helped facility staff understand implementation barriers to prevention of mother-to-child transmission programme service delivery, identify bottlenecks and patient dropout along the cascade and develop a facility-specific microintervention to address these issues. This was then repeated in a quality improvement iterative cycle with the overall aim to improve the flow of mother-infant pairs through the prevention of mother-to-child HIV transmission cascade. Study findings suggest that a systems engineering approach could markedly increase antiretroviral therapy coverage and HIV-exposed infant screening in prevention of mother-to-child HIV transmission programmes.  Further studies evaluating a systems engineering approach in the context of programmatic HIV care, especially in resource-poor settings, are required.

Côte d'Ivoire, Kenya, Mozambique
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Profound effect of ART on mortality through reduction of opportunistic infections

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

Low A, Gavriilidis G, Larke N, Lajoie MR, Drouin O, Stover J, Muhe L, Easterbrook P. Clin Infect Dis. 2016 Mar 6. pii: ciw125. [Epub ahead of print]

Background: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in HIV-infected adults in low and middle-income countries (LMIC).

Methods: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at CD4 ≥200 cells/µl was estimated using UNAIDS country estimates and global average OI treatment cost per case.

Results: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range 57-91%) except for tuberculosis, and was largest for oral candidiasis, PCP and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, 43.8-49.4).

Conclusions: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

Abstract  Full-text [free] access

Editor’s notes: Opportunistic infections (OIs) remain the major cause of HIV-associated mortality. OIs account for substantially higher mortality in low and middle income countries (LMICs) compared to high income countries (HICs).

This paper describes the results of a systematic review and meta-analysis including about 500 000 people on ART in LMICs across three regions (sub-Saharan Africa, Asia, and Latin America). These large numbers enabled the investigators to look at the effect of ART on the incidence of key OIs during and after the first year of treatment.

Not surprisingly they found that the effect of ART reduced the risk of all OIs during the first year after ART initiation, although the reduction was less for tuberculosis. The authors attribute this to the occurrence of tuberculosis across a wide range of CD4 cell counts, a smaller effect of early immune restoration and the contribution of TB as a manifestation of immune reconstitution syndrome during the first months after ART initiation. Beyond one year after ART initiation, the reduction in tuberculosis was greater.

They conclude that the effect of ART on the incidence of most HIV-associated OIs is the key reason for the global decline in HIV-associated mortality. However, a significant proportion of HIV-positive persons still continue to present with advanced disease. Besides timely ART initiation, additional measures such as CTX prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole prophylaxis should be considered for late presenters. 

Africa, Asia, Latin America
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A new drug for cryptococcal meningitis?

Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study.

Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, Musubire A, Akampurira A, Smith KD, Alhadab A, Williams DA, Abassi M, Bahr NC, Velamakanni SS, Fisher J, Nielsen K, Meya DB, Boulware DR, Team A-CS. Lancet Infect Dis. 2016 Mar 9. pii: S1473-3099(16)00074-8. doi: 10.1016/S1473-3099(16)00074-8. [Epub ahead of print]

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus.

Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with, number NCT01802385. 

Findings: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0.37 colony forming units per mL per day (95% CI -0.41 to -0.33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1.27, 95% CI 0.69-2.32; p=0.45).

Interpretation: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy.

Editor’s notes: Mortality from cryptococcal meningitis remains unacceptably high, especially in low-income settings. This is partly due to high cost and limited availability of effective antifungal agents.  Even when antifungal drugs are available, toxic side effects and suboptimal clearance of cryptococcus from the cerebrospinal fluid (CSF) result in continued morbidity and mortality.  There is an urgent need for new effective antifungal drugs in the treatment of cryptococcal meningitis which improve the rate of CSF sterilisation, have low toxicity, and are readily available.

Sertraline, a commonly used selective serotonin reuptake inhibitor antidepressant with excellent brain parenchymal penetration, has been shown to have potent in vitro and in vivo fungicidal activity against cryptococcus in mice. This is the first clinical study in humans to assess the efficacy of adjunctive sertraline for cryptococcal meningitis, when added to standard amphotericin B and high-dose fluconazole antifungal treatment. Faster cryptococcal CSF clearance and lower incidence of immune reconstitution inflammatory syndrome and relapse were seen in people receiving oral sertraline compared to a historical cohort. Repurposing of sertraline, a drug which is widely available, non-toxic and affordable, as an effective novel adjunctive fungicidal agent shows early promise. It is yet to be seen if improved cryptococcal CSF clearance will translate into better survival.  We will have to wait until 2018 to see the outcome of the Adjunctive Sertraline for the Treatment of Cryptococcal Meningitis (ASTRO-CM) randomised clinical trial.

Comorbidity, HIV Treatment
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Substantial drop in opportunistic infections in children with ART

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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Combining community-based HIV testing methods to achieve high testing coverage

A hybrid mobile approach for population-wide HIV testing in rural east Africa: an observational study. 

Chamie G, Clark TD, Kabami J, Kadede K, Ssemmondo E, Steinfeld R, Lavoy G, Kwarisiima D, Sang N, Jain V, Thirumurthy H, Liegler T, Balzer LB, Petersen ML, Cohen CR, Bukusi EA, Kamya MR, Havlir DV, Charlebois ED. Lancet HIV. 2016 Mar;3(3):e111-9. doi: 10.1016/S2352-3018(15)00251-9. Epub 2016 Jan 26.

Background: Despite large investments in HIV testing, only an estimated 45% of HIV-infected people in sub-Saharan Africa know their HIV status. Optimum methods for maximising population-level testing remain unknown. We sought to show the effectiveness of a hybrid mobile HIV testing approach at achieving population-wide testing coverage.

Methods: We enumerated adult (≥15 years) residents of 32 communities in Uganda (n=20) and Kenya (n=12) using a door-to-door census. Stable residence was defined as living in the community for at least 6 months in the past year. In each community, we did 2 week multiple-disease community health campaigns (CHCs) that included HIV testing, counselling, and referral to care if HIV infected; people who did not participate in the CHCs were approached for home-based testing (HBT) for 1-2 months within the 1-6 months after the CHC. We measured population HIV testing coverage and predictors of testing via HBT rather than CHC and non-testing.

Findings: From April 2, 2013, to June 8, 2014, 168 772 adult residents were enumerated in the door-to-door census. HIV testing was achieved in 131 307 (89%) of 146 906 adults with stable residence. 13 043 of 136 033 (9.6%, 95% CI 9.4-9.8) adults with and without stable residence had HIV; median CD4 count was 514 cells per µL (IQR 355-703). Among 131 307 adults with stable residence tested, 56 106 (43%) reported no previous testing. Among 13 043 HIV-infected adults, 4932 (38%) were unaware of their status. Among 105 170 CHC attendees with stable residence 104 635 (99%) accepted HIV testing. Of 131 307 adults with stable residence tested, 104 635 (80%; range 60-93% across communities) tested via CHCs. In multivariable analyses of adults with stable residence, predictors of non-testing included being male (risk ratio [RR] 1.52, 95% CI 1.48-1.56), single marital status (1.70, 1.66-1.75), age 30-39 years (1.58, 1.52-1.65 vs 15-19 years), residence in Kenya (1.46, 1.41-1.50), and migration out of the community for at least 1 month in the past year (1.60, 1.53-1.68). Compared with unemployed people, testing for HIV was more common among farmers (RR 0.73, 95% CI 0.67-0.79) and students (0.73, 0.69-0.77); and compared with people with no education, testing was more common in those with primary education (0.84, 0.80-0.89).

Interpretation: A hybrid, mobile approach of multiple-disease CHCs followed by HBT allowed for flexibility at the community and individual level to help reach testing coverage goals. Men and mobile populations remain challenges for universal testing.

Abstract access

Editor’s notes: Achieving high levels of HIV testing coverage remains a challenge in many parts of sub-Saharan Africa. Conventional facility-based HIV testing models are insufficient to achieve the UNAIDS 90-90-90 targets and maximise the prevention benefits of treatment. This study was able to achieve extremely high levels of HIV testing coverage in a short period of time by strategically combining two community-based testing approaches. By offering testing through multiple-disease community health campaigns (CHC), followed by focused home-based testing (HBT) for individuals who did not attend the CHCs, nearly 90% of adult stable residents accepted HIV testing. This near-universal coverage was achieved in all 32 communities (range 84%‒95%) across two countries, in a variety of settings with different rates of HIV prevalence and of previous testing. Testing uptake in the CHCs varied considerably across the communities (52%‒82%), demonstrating the value of this hybrid approach to expand coverage. Non-stable residents, who were 13% of the population, had low rates of testing uptake (22%). High rates of mobility remain a particular challenge for universal HIV testing coverage, and additional strategies are necessary to engage this group. A potential limitation of a focused approach to HBT is the need for community enumeration.  Still the results illustrate that achieving high HIV testing coverage is feasible with a combination of community-based approaches.

Kenya, Uganda
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Kenya will have to scale, scale, scale to meet 90-90-90 targets

Progress in reversing the HIV epidemic through intensified access to antiretroviral therapy: results from a nationally representative population-based survey in Kenya, 2012.

Kim AA, Mukui I, N'Gan'ga L, Katana A, Koros D, Wamicwe J, De Cock KM, KAIS Study Group. PLoS One. 2016 Mar 1;11(3):e0148068. doi: 10.1371/journal.pone.0148068. eCollection 2016.

Background: In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) called for 90% of people living with HIV (PLHIV) to know their status, 90% of these to be on antiretroviral therapy (ART), and 90% of these to be virally suppressed by 2020 (90-90-90). It is not clear whether planned ART scale-up in countries whose eligibility criteria for ART initiation are based on recommendations from the 2013 World Health Organization treatment guidelines will be sufficient to meet UNAIDS' new global targets.

Materials and methods: Using data from a nationally representative population-based household survey of persons in Kenya we compared coverage and unmet need associated with HIV diagnosis, ART, and viral suppression among PLHIV aged 15-64 years in 2012 based on criteria outlined in the 2014 national ART guidelines and UNAIDS' 90-90-90 goals. Estimates were weighted to account for sampling probability and nonresponse.

Results: Eight in ten PLHIV aged 15-64 years needed ART based on treatment eligibility. Need for treatment based on the national treatment policy was 97.4% of treatment need based on UNAIDS' 90-90-90 goals, requiring an excess of 24 000 PLHIV to access treatment beyond those eligible for ART to achieve UNAIDS' 90-90-90 treatment target. The gap in treatment coverage was high, ranging from 43.1% nationally to 52.3% in Nyanza among treatment-eligible PLHIV and 44.6% nationally to 52.4% in Nyanza among all PLHIV.

Conclusion: Maintaining the current pace of ART scale-up in Kenya will result in thousands of PLHIV unreached, many with high viral load and at-risk of transmitting infection to others. Careful strategies for reaching 90-90-90 will be instrumental in determining whether intensified access to treatment can be achieved to reach all who require ART.

Abstract  Full-text [free] access 

Editor’s notes: The HIV field is pushing for aggressive scale-up of programmes to stem the HIV epidemic. In this regard, UNAIDS launched the 90-90-90 targets to motivate countries to increase awareness, testing and treatment of people living with HIV. This paper presents an analysis of data collected through the last national Kenya AIDS Indicator Survey (KAIS) which examines the number of people reached with testing and treatment in 2012 as compared with the 90-90-90 targets which the country adopted in 2014. The analysis illustrates that the scale up of testing and treatment will need to dramatically increase to meet the targets. The paper notes the importance of strategizing how best to reach the populations most affected. In Kenya’s case, a geographic approach to scaling up in higher incidence areas is now being implemented. Within the geographical approach, strategies include testing family members of people living with HIV, and community-based testing strategies (such as home-based testing and counselling and self-testing), delivered in settings with high HIV prevalence. Analyses such as the one presented in this paper can help other countries in similar situations to review how best to apply limited resources in order to meet targets. 

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Option B+: the way forward for Malawi

Comparative cost-effectiveness of Option B+ for prevention of mother-to-child transmission of HIV in Malawi.

Tweya H, Keiser O, Haas AD, Tenthani L, Phiri S, Egger M, Estill J. AIDS. 2016 Mar 27;30(6):953-62. doi: 10.1097/QAD.0000000000001009.

Objective: To estimate the cost-effectiveness of prevention of mother-to-child transmission (MTCT) of HIV with lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women ('Option B+') compared with ART during pregnancy or breastfeeding only unless clinically indicated ('Option B').

Design: Mathematical modelling study of first and second pregnancy, informed by data from the Malawi Option B+ programme.

Methods: Individual-based simulation model. We simulated cohorts of 10 000 women and their infants during two subsequent pregnancies, including the breastfeeding period, with either Option B+ or B. We parameterized the model with data from the literature and by analysing programmatic data. We compared total costs of antenatal and postnatal care, and lifetime costs and disability-adjusted life-years of the infected infants between Option B+ and Option B.

Results: During the first pregnancy, 15% of the infants born to HIV-infected mothers acquired the infection. With Option B+, 39% of the women were on ART at the beginning of the second pregnancy, compared with 18% with Option B. For second pregnancies, the rates MTCT were 11.3% with Option B+ and 12.3% with Option B. The incremental cost-effectiveness ratio comparing the two options ranged between about US$ 500 and US$ 1300 per DALY averted.

Conclusion: Option B+ prevents more vertical transmissions of HIV than Option B, mainly because more women are already on ART at the beginning of the next pregnancy. Option B+ is a cost-effective strategy for PMTCT if the total future costs and lost lifetime of the infected infants are taken into account.

Abstract access

Editor’s notes: Nearly a quarter of a million children acquire HIV from their mothers every year. Antiretroviral therapy (ART) in pregnant women greatly reduces the risk of mother-to-child HIV transmission to less than two percent. Malawi was the first country to introduce ‘Option B+’, a programme eliminating new HIV infections among children and keeping their mothers alive, in which all pregnant and breastfeeding women living with HIV start lifelong ART regardless of CD4 count or clinical staging. This study compares the cost-effectiveness of Option B+ in Malawi, with Option B, in which ART is recommended only for the duration of pregnancy or breastfeeding, unless the woman qualifies for ART for her own health. Both options have been recommended by World Health Organisation prevention of mother-to-child HIV transmission strategies.

The model simulated a cohort of 10 000 women pregnant for the first time, from conception to the time when the infants were two years old. The authors found that although the total costs of implementing Option B+ were higher than those of Option B, the former can reduce the costs of HIV care and treatment in the future by preventing new infections. The incremental cost-effectiveness ratio of Option B+ compared to Option B, ranged from USD 500 to USD 1300 per disability-adjusted life-years averted, depending on key assumptions around survival and care. The results support the implementation of Option B+ as it is likely to be a cost-effective strategy in the long term and the authors suggest it should be considered as the preferred strategy in low-income, high-fertility settings.

Like all models, this model has some limitations. It only considers women’s first two pregnancies, but the fertility rate in Malawi is high (5.5 births per woman). The model limits itself to mother-to-child HIV transmission, and does not take into account sexual transmission, which is likely to be lower in Option B+. Further research in these two areas would be worthwhile. The landscape is quickly changing, as World Health Organization guidelines now suggest testing and treatment strategies. However, until that policy is fully implemented and absorbed across the world, Option B+ will remain a key element in the HIV response.

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Empirical TB treatment no better than isoniazid among people with low CD4 counts and negative TB tests

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

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

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

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

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

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

Abstract access

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

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

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

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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ART reduces fertility differences by HIV status among women living in sub-Saharan Africa

Measuring the impact of antiretroviral therapy roll-out on population level fertility in three African countries. 

Marston M, Nakiyingi-Miiro J, Hosegood V, Lutalo T, Mtenga B, Zaba B, and on behalf of the ALPHA network. PLoS One. 2016 Mar 25;11(3):e0151877. doi: 10.1371/journal.pone.0151877. eCollection 2016.

Background: UNAIDS official estimates of national HIV prevalence are based on trends observed in antenatal clinic surveillance, after adjustment for the reduced fertility of HIV positive women. Uptake of ART may impact on the fertility of HIV positive women, implying a need to re-estimate the adjustment factors used in these calculations. We analyse the effect of antiretroviral therapy (ART) provision on population-level fertility in Southern and East Africa, comparing trends in HIV infected women against the secular trends observed in uninfected women.

Methods: We used fertility data from four community-based demographic and HIV surveillance sites: Kisesa (Tanzania), Masaka and Rakai (Uganda) and uMkhanyakude (South Africa). All births to women aged 15-44 years old were included in the analysis, classified by mother's age and HIV status at time of birth, and ART availability in the community. Calendar time period of data availability relative to ART introduction varied across the sites, from 5 years prior to ART roll-out, to 9 years after. Calendar time was classified according to ART availability, grouped into pre ART, ART introduction (available in at least one health facility serving study site) and ART available (available in all designated health facilities serving study site). We used Poisson regression to calculate age adjusted fertility rate ratios over time by HIV status, and investigated the interaction between ART period and HIV status to ascertain whether trends over time were different for HIV positive and negative women.

Results: Age-adjusted fertility rates declined significantly over time for HIV negative women in all four studies. However HIV positives either had no change in fertility (Masaka, Rakai) or experienced a significant increase over the same period (Kisesa, uMkhanyakude). HIV positive fertility was significantly lower than negative in both the pre ART period (age adjusted fertility rate ratio (FRR) range 0.51 95%CI 0.42-0.61 to 0.73 95%CI 0.64-0.83) and when ART was widely available (FRR range 0.57 95%CI 0.52-0.62 to 0.83 95%CI 0.78-0.87), but the difference has narrowed. The interaction terms describing the difference in trends between HIV positives and negatives are generally significant.

Conclusions: Differences in fertility between HIV positive and HIV negative women are narrowing over time as ART becomes more widely available in these communities. Routine adjustment of ANC data for estimating national HIV prevalence will need to allow for the impact of treatment.

Abstract  Full-text [free] access 

Editor’s notes: Antenatal care (ANC) clinics records on demographic characteristics and HIV status of attenders are a major component of primary data used to estimate HIV prevalence in sub-Saharan Africa. Prior to scale-up of antiretroviral therapy (ART), the fertility of women living with HIV was lower than that for people without HIV. This means that prevalence estimates from ANC data were adjusted to avoid underestimating the true population fertility rates.

This paper analyses the changing fertility patterns in four longitudinal community-based cohorts in eastern and southern Africa. The study finds that differences in fertility rates between women living with HIV and women without HIV are narrowing as ART is scaled-up, although substantial differences still exist. There was considerable variation in the patterns between the sites reflecting the differing local epidemic profiles. The authors explain this variation as being due to various factors including biological (increased fertility associated with viral suppression), or behavioural (increased fertility among women experiencing widowhood and then forming new partnerships). The impact of treatment on fertility needs to be incorporated into models of HIV prevalence estimated from ANC data, to inform national policy makers measuring their progress towards HIV elimination targets.

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