Articles tagged as "Nigeria"

Cryptoccal meningitis – the unacceptable consequence of leaving people behind during ART scale up

Editor’s notes: Cryptococcal meningitis is a severe disease that occurs in people with advanced immune suppression.  Its occurrence is an indicator that an HIV treatment programme is not working well, as it is rare in people whose CD4 count is above 100 cells per microlitre.  Rajasingham and colleagues have tried to estimate the current burden of disease.  This is not straightforward, as the number and proportion of people with advanced HIV disease is changing with the increasing scale up of antiretroviral therapy and earlier HIV diagnosis.  Nonetheless, severe immune suppression still occurs in those whose HIV infection remains undiagnosed or is diagnosed too late; among those who are not started on effective ARVs promptly and among those in whom ART fails and who are not managed effectively by the ART treatment programme.  The authors estimate that there could be more than 180 000 deaths from cryptococcal meningitis with the large majority (136 000) in Africa.  This makes Cryptococcus responsible for more than 15% of HIV-related deaths, second only to tuberculosis as a documented cause.  The authors emphasize the need for earlier diagnosis of HIV and better linkage to quality care programmes.  In the meantime, there are also advances in the screening, prophylaxis and treatment of Cryptococcus itself, which require investment in laboratory services and affordable medicines that can save lives until the effects of good ART improves the immune status.

Cassim and colleagues have developed a novel approach to costing different approaches to the roll out of technology for screening for cryptococcal antigen in the blood of people with advanced HIV infection.  Depending on the numbers of samples to be tested in the laboratory, a mix of single use lateral flow assays and automated enzyme immunoassays makes most sense.  The aim is to allow the more cost-effective high-volume sites to subsidize the low volume sites in order to ensure that as many people living with advanced HIV infection as possible can be screened.

Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis

Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A, Boulware DR. Lancet Infect Dis. 2017 Aug;17(8):873-881. doi: 10.1016/S1473-3099(17)30243-8. Epub 2017 May 5.

Background: Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease.

Methods: We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per μL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/μL not on ART, and those with CD4 less than 100 cells per μL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis.

Findings: We estimated an average global cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8-6·2) among people with a CD4 cell count of less than 100 cells per μL, with 278 000 (95% CI 195 500-340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600-282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600-193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400-234 300), with 135 900 (75%; [95% CI 93 900-163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10-19).

Interpretation: Our analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority.

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Estimating the cost-per-result of a national reflexed cryptococcal antigenaemia screening program: Forecasting the impact of potential HIV guideline changes and treatment goals

Cassim N, Coetzee LM, Schnippel K, Glencross DK. PLoS One. 2017 Aug 22;12(8):e0182154. doi: 10.1371/journal.pone.0182154. eCollection 2017.

Introduction: During 2016, the National Health Laboratory Service (NHLS) introduced laboratory-based reflexed Cryptococcal antigen (CrAg) screening to detect early Cryptococcal disease in immunosuppressed HIV+ patients with a confirmed CD4 count of 100 cells/μl or less.

Objective: The aim of this study was to assess cost-per-result of a national screening program across different tiers of laboratory service, with variable daily CrAg test volumes. The impact of potential ART treatment guideline and treatment target changes on CrAg volumes, platform choice and laboratory workflow are considered.

Methods: CD4 data (with counts ≤ 100 cells/μl) from the fiscal year 2015/16 were extracted from the NHLS Corporate Date Warehouse and used to project anticipated daily CrAg testing volumes with appropriately-matched CrAg testing platforms allocated at each of 52 NHLS CD4 laboratories. A cost-per-result was calculated for four scenarios, including the existing service status quo (Scenario-I), and three other settings (as Scenarios II-IV) which were based on information from recent antiretroviral (ART) guidelines, District Health Information System (DHIS) data and UNAIDS 90/90/90 HIV/AIDS treatment targets. Scenario-II forecast CD4 testing offered only to new ART initiates recorded at DHIS. Scenario-III projected all patients notified as HIV+, but not yet on ART (recorded at DHIS) and Scenario-IV forecast CrAg screening in 90% of estimated HIV+ patients across South Africa (also DHIS). Stata was used to assess daily CrAg volumes at the 5th, 10th, 25th, 50th, 75th, 90th and 95th percentiles across 52 CD4-laboratories. Daily volumes were used to determine technical effort/ operator staff costs (% full time equivalent) and cost-per-result for all scenarios.

Results: Daily volumes ranged between 3 and 64 samples for Scenario-I at the 5th and 95th percentile. Similarly, daily volumes ranges of 1-12, 2-45 and 5-100 CrAg-directed samples were noted for Scenario's II, III and IV respectively. A cut-off of 30 CrAg tests per day defined use of either LFA or EIA platform. LFA cost-per-result ranged from $8.24 to $5.44 and EIA cost-per-result between $5.58 and $4.88 across the range of test volumes. The technical effort across scenarios ranged from 3.2-27.6% depending on test volumes and platform used.

Conclusion: The study reported the impact of programmatic testing requirements on varying CrAg test volumes that subsequently influenced choice of testing platform, laboratory workflow and cost-per-result. A novel percentiles approach is described that enables an overview of the cost-per-result across a national program. This approach facilitates cross-subsidisation of more expensive lower volume sites with cost-efficient, more centralized higher volume laboratories, mitigating against the risk of costing tests at a single site.

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Understanding different levels and different models of integration

Editor’s notes: Integration between HIV services and programmes and other services and programmes sounds like common sense.  As people with HIV live longer they are more likely to develop other chronic conditions.  Some of these conditions may also be exacerbated by some anti-retroviral medicines, although modern treatment regimens have much less effect on lipid and insulin metabolism.  Low grade chronic inflammation may continue even in people whose HIV is suppressed and people whose CD4 count sunk to a low level before starting seem to be at greater risk of subsequent cardiovascular disease.  Then there are diseases that are more common among people living with HIV, such as tuberculosis and invasive cervical cancer.  And HIV programmes around the world have established some of the best clinical services for chronic care, with regular appointments, decentralized follow-up, algorithmic approaches to clinical changes and so on.  So it seems sensible to look for the synergies and build on them.

However, research on integration makes it clear that there are many different interpretations of what integration should or could mean.  In different epidemiological settings, the priorities will inevitably be very different.  Two useful systematic reviews this month by the same team, review this territory for cardiovascular diseases, diabetes and cervical cancer. 

Haldane et al. distinguish between the levels of integration.  Micro level integration involves direct patient care and adjusting diagnosis, treatment and support appropriately.  Meso level integration refers to changes made at the clinic or delivery system level, while macro level integration is about programme management, supply chains and systems organisation.  Despite a large literature (over 7600 papers) on the overlaps between HIV and cardiovascular diseases and diabetes, the authors found only 14 studies that allowed aspects of the integration to be assessed, and only one of these evaluated outcomes.  The others were descriptive studies which highlighted many innovative models, almost all at the meso-level.

Similarly for invasive cervical cancer, which is at least four times as common among women living with HIV as seronegative women, Sigfrid et al. found many papers but only 21 that met their inclusion criteria.  Their models of integration could all be said to be at the meso-level, with one stop shops; co-located services or more complex integrated pathways described.  Again, there were no good evaluations of the outcomes of these systematic changes to the way that services are delivered.  In most countries, all women with cervical cancer should at least be offered an HIV test and appropriate linkage to care expedited for those found to be seropositive.  Women living with HIV need regular screening for early cervical cancer and (as discussed last month) screening for human papillomavirus, the underlying cause of cervical cancer.  However, many ART clinics are now busy and crowded so that even if staff are trained, they do not have time or space or privacy to do cervical examinations.  HPV vaccination campaigns need to be carried out in schools before girls become sexually active.  This could be a good time to engage with sexuality education. However, many campaigns have tended to avoid the challenges of discussing sex with girls who are not yet sexually active, preferring to focus on the vaccine as a cancer prevention tool.  So, the lesson from both these papers is that we need to define more rigorously what we want to achieve with integration and then ensure that we evaluate whether or not our interventions achieve it.

Tuberculosis and HIV have been dancing together since the first descriptions of HIV in the 1980s.  The large majority of tuberculosis patients in many countries are now screened for HIV, with appropriate referral and increasing numbers of people living with HIV are screened regularly for the four classic symptoms of tuberculosis (weight loss, cough, night sweats and fever) and referred onwards for diagnosis.  Yet we still find that collaboration between programmes is not always easy. The number of people living with HIV who are also on tuberculosis treatment reported by the HIV programme may not be the same as the number of people on tuberculosis treatment who are also living with HIV reported by the tuberculosis programme.  Osei et al. report from the Volta Region of Ghana that more than 90% of tuberculosis patients had an HIV test recorded in the tuberculosis register, with an HIV prevalence of 18%.  As has been reported frequently elsewhere, the authors found that HIV was commoner in those with smear negative tuberculosis, and the outcome of treatment was less good.  Their recommendation for strengthening the collaboration between tuberculosis and HIV makes sense, although it has been WHO policy for many years.

The WHO guidance on collaborative TB/HIV activities has always included isoniazid preventive therapy.  However, this remains poorly implemented for reasons that are never very clear.  Despite no good evidence, many tuberculosis programme staff and clinicians worry about the risk of generating isoniazid resistant tuberculosis.  Many HIV programme staff feel that isoniazid remains in the realm of the tuberculosis programme, so that although they are happy to promote cotrimoxazole, they are much slower to prescribe isoniazid.  Many also feel that ART alone should be sufficient to prevent tuberculosis, despite randomized trials in high prevalence settings that demonstrate the additional benefits of isoniazid.  Shayo et al. make a strong economic argument for promoting isoniazid in their study in Tanzania.  They base their model on the rates of tuberculosis and mortality seen during the expansion of pilot programmes for isoniazid in Dar es Salaam.  Both tuberculosis and mortality were significantly lower in the clinics which were part of the pilot programme.  In fact, mortality was approximately tenfold lower, which seems unlikely to be simply due to isoniazid.  Some studies such as TEMPRANO have shown a mortality benefit from isoniazid, while many trials have failed to do so.  Given the non-randomized nature of the comparison, the authors do point out that their conclusions must be tentative.  Nonetheless, it is a convincing demonstration that isoniazid preventive therapy can be incorporated into a busy HIV care clinic and there is abundant evidence that this is the right thing to do.

One more tuberculosis study this month was carried out in Germany.  Karo et al. reviewed the immunology of the 139 people who developed tuberculosis among more than 10 000 people living with HIV in the German ClinSurv cohort.  The authors excluded people who already had tuberculosis at the time that HIV was diagnosed, and found that new diagnoses of tuberculosis were most common in the first couple of years after starting ART.  The authors also show that immune restoration was slower in people who developed tuberculosis.  There was still some deficit up to seven years after ART was started.  Again, their conclusion is that we should be using isoniazid to prevent tuberculosis in people living with HIV, especially people who have spent much of their lives in areas of the world, such as sub-Saharan Africa where tuberculosis is much more prevalent than in Europe.  It is often said that Mycobacterium tuberculosis is a very slow growing organism.  We must work harder to ensure that our response to it is not very slow too.  Tuberculosis remains the biggest killer of people with HIV in most of the world, yet for years we have known that a simple, cheap, non-toxic treatment can prevent it. 

 

Integrating cardiovascular diseases, hypertension, and diabetes with HIV services: a systematic review.

Haldane V, Legido-Quigley H, Chuah FLH, Sigfrid L, Murphy G, Ong SE, Cervero-Liceras F, Watt N, Balabanova D, Hogarth S, Maimaris W, Buse K, McKee M, Piot P, Perel P. AIDS Care. 2017 Jul 5:1-13. doi:10.1080/09540121.2017.1344350. [Epub ahead of print]

Non-communicable diseases (NCDs), including cardiovascular diseases (CVD), hypertension and diabetes together with HIV infection are among the major public health concerns worldwide. Health services for HIV and NCDs require health systems that provide for people's chronic care needs, which present an opportunity to coordinate efforts and create synergies between programs to benefit people living with HIV and/or AIDS and NCDs. This review included studies that reported service integration for HIV and/or AIDS with coronary heart diseases, chronic CVD, cerebrovascular diseases (stroke), hypertension or diabetes. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias. 11 057 records were identified with 7 616 after duplicate removal. After screening titles and abstracts, 14 papers addressing 17 distinct interventions met the inclusion criteria. We categorized integration models by diseases (HIV with diabetes, HIV with hypertension and diabetes, HIV with CVD and finally HIV with hypertension and CVD and diabetes). Models also looked at integration from micro (patient focused integration) to macro (system level integrations). Most reported integration of hypertension and diabetes with HIV and AIDS services and described multidisciplinary collaboration, shared protocols, and incorporating screening activities into community campaigns. Integration took place exclusively at the meso-level, with no micro- or macro-level integrations described. Most were descriptive studies, with one cohort study reporting evaluative outcomes. Several innovative initiatives were identified and studies showed that CVD and HIV service integration is feasible. Integration should build on existing protocols and use the community as a locus for advocacy and health services, while promoting multidisciplinary teams, including greater involvement of pharmacists. There is a need for robust and well-designed studies at all levels - particularly macro-level studies, research looking at long-term outcomes of integration, and research in a more diverse range of countries.

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Integrating cervical cancer with HIV healthcare services: A systematic review.

Sigfrid L, Murphy G, Haldane V, Chuah FLH, Ong SE, Cervero-Liceras F, Watt N, Alvaro A, Otero-Garcia L, Balabanova D, Hogarth S, Maimaris W, Buse K, Mckee M, Piot P, Perel P, Legido-Quigley H. PLoS One. 2017 Jul 21;12(7):e0181156. doi: 10.1371/journal.pone.0181156. eCollection 2017.

Background: Cervical cancer is a major public health problem. Even though readily preventable, it is the fourth leading cause of death in women globally. Women living with HIV are at increased risk of invasive cervical cancer, highlighting the need for access to screening and treatment for this population. Integration of services has been proposed as an effective way of improving access to cervical cancer screening especially in areas of high HIV prevalence as well as lower resourced settings. This paper presents the results of a systematic review of programs integrating cervical cancer and HIV services globally, including feasibility, acceptability, clinical outcomes and facilitators for service delivery.

Methods: This is part of a larger systematic review on integration of services for HIV and non-communicable diseases. To be considered for inclusion studies had to report on programs to integrate cervical cancer and HIV services at the level of service delivery. We searched multiple databases including Global Health, Medline and Embase from inception until December 2015. Articles were screened independently by two reviewers for inclusion and data were extracted and assessed for risk of bias.

Main results: 11 057 records were identified initially. 7616 articles were screened by title and abstract for inclusion. A total of 21 papers reporting interventions integrating cervical cancer care and HIV services met the criteria for inclusion. All but one study described integration of cervical cancer screening services into existing HIV services. Most programs also offered treatment of minor lesions, a 'screen-and-treat' approach, with some also offering treatment of larger lesions within the same visit. Three distinct models of integration were identified. One model described integration within the same clinic through training of existing staff. Another model described integration through co-location of services, with the third model describing programs of integration through complex coordination across the care pathway. The studies suggested that integration of cervical cancer services with HIV services using all models was feasible and acceptable to patients. However, several barriers were reported, including high loss to follow up for further treatment, limited human-resources, and logistical and chain management support. Using visual screening methods can facilitate screening and treatment of minor to larger lesions in a single 'screen-and-treat' visit. Complex integration in a single-visit was shown to reduce loss to follow up. The use of existing health infrastructure and funding together with comprehensive staff training and supervision, community engagement and digital technology were some of the many other facilitators for integration reported across models.

Conclusions: This review shows that integration of cervical cancer screening and treatment with HIV services using different models of service delivery is feasible as well as acceptable to women living with HIV. However, the descriptive nature of most papers and lack of data on the effect on long-term outcomes for HIV or cervical cancer limits the inference on the effectiveness of the integrated programs. There is a need for strengthening of health systems across the care continuum and for high quality studies evaluating the effect of integration on HIV as well as on cervical cancer outcomes.

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The burden of HIV on tuberculosis patients in the Volta region of Ghana from 2012 to 2015: implication for tuberculosis control.

Osei E, Der J, Owusu R, Kofie P, Axame WK. BMC Infect Dis. 2017 Jul 19;17(1):504. doi: 10.1186/s12879-017-2598-z.

Background: The impact of HIV on TB, and the implications for TB control, has been acknowledged as a public health challenge. It is imperative therefore to assess the burden of HIV on TB patients as an indicator for monitoring the control efforts of the two diseases in this part of the world. This study aimed at determining the burden of HIV infection in TB patients.

Methods: We conducted a retrospective review of TB registers in five districts of the Volta Region of Ghana. Prevalence of TB/HIV co-infection was determined. Bivariate and multivariate logistic regression were used to identify the predictors of HIV infection among TB patients and statistical significance was set at p-value <0.05.

Results: Of the 1772 TB patients, 1633 (92.2%) were tested for HIV. The overall prevalence of TB/HIV co-infection was (18.2%; 95% CI: 16.4-20.1). The prevalence was significantly higher among females (24.1%; 95%CI: 20.8-27.7), compared to males (15.1%; 95% CI: 13.1-17.4) (p < 0.001) and among children <15 years of age (27.0%; 95% CI: 18.2-38.1), compared to the elderly ≥70 years (3.5%; 95% CI: 1.6-7.4) (p < 0.001). Treatment success rate was higher among patients with only TB (90%; 95% CI: 88.1-91.5) than among TB/HIV co-infected patients (77.0%; 95% CI: 71.7-81.7) (p < 0.001). Independent predictors of HIV infection were found to be: being female (AOR: 1.79; 95% CI: 1.38-2.13; p < 0.001); smear negative pulmonary TB (AOR: 1.84; 95% CI: 1.37-2.47; p < 0.001); and patients registered in Hohoe, Kadjebi, and Kpando districts with adjusted odds ratios of 1.69 (95% CI: 1.13-2.54; p = 0.011), 2.29 (95% CI: 1.46-3.57; p < 0.001), and 2.15 (95% CI: 1.44-3.21; p < 0.001) respectively. Patients ≥70 years of age and those registered in Keta Municipal were less likely to be HIV positive with odds ratios of 0.09 (95% CI: 0.04-0.26; p < 0.001) and 0.62 (95% CI: 0.38-0.99; p = 0.047) respectively.

Conclusion: TB/HIV co-infection rate in five study districts of the Volta region is quite high, occurs more frequently in female patients than males; among smear negative pulmonary TB patients, and children <15 years of age. Findings also demonstrate that HIV co-infection affects TB treatment outcomes adversely. Strengthening the TB/HIV collaborative efforts is required in order to reduce the burden of co-infection in patients.

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Cost-effectiveness of isoniazid preventive therapy among HIV-infected patients clinically screened for latent tuberculosis infection in Dar es Salaam, Tanzania: a prospective cohort study.

Shayo GA, Chitama D, Moshiro C, Aboud S, Bakari M, Mugusi F. BMC Public Health. 2017 Jul 19;18(1):35. doi: 10.1186/s12889-017-4597-9.

Background: One of the reasons why Isoniazid preventive therapy (IPT) for Tuberculosis (TB) is not widely used in low income countries is concerns on cost of excluding active TB. We analyzed the cost-effectiveness of IPT provision in Tanzania having ruled out active TB by a symptom-based screening tool.

Methods: Data on IPT cost-effectiveness was prospectively collected from an observational cohort study of 1283 HIV-infected patients on IPT and 1281 controls; followed up for 24 months. The time horizon for the analysis was 2 years. Number of TB cases prevented and deaths averted were used for effectiveness. A micro costing approach was used from a provider perspective. Cost was estimated on the basis of clinical records, market price or interviews with medical staff. We annualized the cost at a discount of 3%. A univariate sensitivity analysis was done. Results are presented in US$ at an average annual exchange rate for the year 2012 which was Tanzania shillings 1562.4 for 1 US $.

Results: The number of TB cases prevented was 420/100 000 persons receiving IPT. The number of deaths averted was 979/100 000 persons receiving IPT. Incremental cost due to IPT provision was US$ 170 490. The incremental cost-effective ratio was US $ 405.93 per TB case prevented and US $ 174.15 per death averted. These costs were less than 3 times the 768 US $ Gross Domestic Product (GDP) per capita for Tanzania in the year 2014, making IPT provision after ruling out active TB by the symptom-based screening tool cost-effective. The results were robust to changes in laboratory and radiological tests but not to changes in recurrent, personnel, medication and utility costs.

Conclusion: IPT should be given to HIV-infected patients who screen negative to symptom-based TB screening questionnaire. Its cost-effectiveness supports government policy to integrate IPT to HIV/AIDS care and treatment in the country, given the availability of budget and the capacity of health facilities.

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Immunological recovery in tuberculosis/HIV co-infected patients on antiretroviral therapy: implication for tuberculosis preventive therapy.

Karo B, Krause G, Castell S, Kollan C, Hamouda O, Haas W; ClinSurv HIV Study Group. BMC Infect Dis. 2017 Jul 25;17(1):517. doi: 10.1186/s12879-017-2627-y.

Background: Understanding the immune response to combination antiretroviral therapy (cART) is essential for a clear approach to tuberculosis (TB) preventive therapy. We investigated the immunological recovery in cART-treated HIV-infected patients developing TB compared to those who remained free of TB.

Methods: We extracted data of HIV-infected patients from a multicenter cohort for the HIV clinical surveillance in Germany. No patients included in our study had TB at the beginning of the observation. Using a longitudinal mixed model, we assessed the differences in the mean change of biomarkers (CD4+ cell count, CD8+ cell count, CD4:CD8 ratio and viral load) since cART initiation in patients who remained free of TB vs. those developing TB. To detect the best-fit trajectories of the immunological biomarkers, we applied a multivariable fractional polynomials model.

Results: We analyzed a total of 10 671 HIV-infected patients including 139 patients who developed TB during follow-up. The highest TB incidences were observed during the first two years since cART initiation (0.32 and 0.50 per 100 person-years). In an adjusted multivariable mixed model, we found that the average change in CD4+ cell count recovery was significantly greater by 33 cells/μl in patients who remained free of TB compared with those developing TB. After the initial three months of cART, 65.6% of patients who remaining free of TB achieved CD4+ count of ≥400 cells/μl, while only 11.3% of patients developing TB reached this immunological status after the three months of cART. We found no differences in the average change of CD8+ cell count, CD4:CD8 ratio or viral load between the two-patient groups.

Conclusion: All HIV-infected patients responded to cART. However, patients developing TB showed reduced recovery in CD4+ cell count and this might partly explain the incident TB in HIV-infected patients receiving cART. These findings reinforce the importance of adjunctive TB preventive therapy for patients with reduced recovery in CD4+ cell count.

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90-90-90: a clear roadmap for HIV treatment. But each 90 brings with it opportunities and challenges

Editor’s notes: The discovery of effective antiretroviral therapy (ART) will go down in history as the greatest success of biomedical science of the past decades.  Landmark studies have shown that the earlier people living with HIV start ART, not only is their clinical outlook improved, but also their likelihood of transmitting infection to their sexual partners falls dramatically.  People who take their ART effectively and in whom the virus is suppressed to undetectable levels are no longer infectious.  A massive public health and social justice response has led to unprecedented scale up of this miraculous treatment.  There is widespread adoption of the UNAIDS 90-90-90 treatment target.  The target is easy to recite: 90% of people living with HIV know their status; 90% of people who know their status are on ART and 90% of people taking ART have suppressed their viral load.  Many mathematical models show that if these targets are achieved, there should be a substantial impact on the trajectory of the epidemic with a large reduction in new HIV infections and HIV-related deaths, leading to huge cost-savings in the future.

Several large community based studies have been established to examine both the necessary processes to reach these goals and the impact at community level of the wider coverage with effective ART.  We have commented in previous editions on the ANRS Treatment as Prevention (TasP) study in rural Kwazulu-Natal and on papers from the SEARCH study in rural Kenya and Uganda.  Not surprisingly, given the different contexts, approaches, methods and definitions, the studies each shed light on different aspects of the 90-90-90 target.

This month, there are two new papers from the PopART (HPTN071) study, along with an accompanying commentary from the TasP study team.  PopART is the largest of the large community randomized studies of the universal test and treat approach, nested within a broader combination prevention package.  The population covered by the trial is around one million people living in largely urban or peri-urban communities in Zambia and the Western Cape province of South Africa.  The approach used in two of the three arms of the trial, is to deliver HIV testing and other prevention services by means of community health workers.  These so called CHiPs (Community HIV care Providers) also encourage linkage of people either known to be or newly found to be living with HIV to the local government health facilities, where ART is started regardless of CD4 count in one arm of the study, or in line with government guidelines (which is now also regardless of CD4 count in both countries) in the other. In the third arm of the trial, there are no CHiPs and HIV testing and linkage to treatment is performed by routine services, with treatment also offered to all, regardless of CD4 count.

The papers in this month’s edition cover only the four Zambian communities receiving the most intensive package during the first year of the intervention. Shanaube and colleagues focus on the first 90, while Hayes and colleagues focus on the second 90.  The overall conclusion is that the CHiPs approach leads to a very high uptake of HIV testing, but that linkage to care still takes longer than expected.  However, there is a wealth of detail in both the process and the ways to measure these apparently straightforward statistics.  When the CHiPs actually see people, acceptance of HIV testing is very high, unless people have recently had an HIV test.  Even then, almost three quarters of women are happy to have another test four to six months after their most recent negative test, whereas for men, there is somewhat more reluctance.  The main challenges for the CHiPs are that people may need more than one visit to decide to test and that men are often not at home, despite multiple visits and scheduled appointments.  Furthermore, as Iwuju and Newell point out in their slightly pessimistic commentary, people move around and migration makes it hard to define a reliable denominator (a challenge also faced by the SEARCH team in Uganda and Kenya).  Around 20% of the people who knew they were HIV positive were not able to be seen at one year follow-up, so it is not possible to know whether they were linked to care or not.  The TasP study also found that the second 90 was the real challenges, with a very high coverage of HIV testing, but not enough linkage to lead to a reduction in incidence at the community level.

The PopART study is ongoing, and recent presentations suggest that with time, a larger proportion of people are indeed linking to care.  The lesson may be that it requires ongoing and continuing support in an urban and peri-urban community to achieve high levels of coverage.  We await eagerly the next instalments and final results demonstrating whether there is a wider public health impact which will not be available before 2019!

These huge longitudinal studies also remind us that the 90-90-90 target is defined as cross-sectional measurements, and does not take into account directly the length of time that it takes to start treatment or to become virally supressed.  The information from large cross-sectional studies, such as ICAP and PEPFAR’s population-based HIV impact assessments (PHIA) give a direct measurement of 90-90-90.  However, in contrast to PopART and the other community-based studies, gives no insight into the dynamics of the processes through which people decide to get tested, link to care and remain in care.

McCreesh and colleagues used an individual-based mathematical model of the flow through testing, linkage to treatment and retention based on data from Uganda and using a novel method of calibration.  They show that removing the CD4 threshold (as is recommended by WHO and the UNAIDS 90-90-90 target) is very likely to be the most cost-effective approach to reduce the burden of HIV over the years up to 2030.  However, they also found that their model predicts that efforts to improve linkage to and retention in care are likely to be more cost-effective than increased coverage of testing in Uganda.  This is in part because many Ugandans already know their HIV status as a result of previous efforts, so it should not be taken as a general recommendation not to work to improve the first 90 as well as the second two!  The authors state clear conclusions: “Our results strongly suggest that an increase in the rates of HIV testing in the general population in Uganda ….. should not be prioritized above interventions to improve linkage to, and retention in, care…..  In Uganda, interventions to improve retention in and movement through the HIV care pathway should be prioritized over case finding interventions in the general population.”

In rural Kwazulu-Natal, the challenge of retention among populations that are by necessity mobile was also shown in a study by Arnesen and colleagues.  In this study of risk factors for people on ART being lost to follow up they found that more than one quarter of the 3242 people on the treatment register in 15 primary care clinics were thought to be lost.  However, the authors found that one-third of these people labelled as lost were in fact taking treatment at another clinic.  As in other similar studies men were more likely to discontinue treatment, as were people with advanced immunosuppression (who are at high risk of dying in the absence of treatment) and being on ART for less than six months. This is a useful reminder of priorities.  Providing more support to men, and the sickest patients, maintaining closer supervision for the first year, might lead to better programme outcomes and (as predicted by the Ugandan model) save money in the medium term.

By comparison, a large records-based study in the United States of America by Youn and colleagues examined time trends in retention on treatment (persistence in the authors’ terminology).  The author used insurance claims for prescriptions for ART and for other medicines for heart disease, hypertension or diabetes taken regularly over a long time by both HIV positive and HIV-negative people.  They were able to examine persistence in over 40 000 people living with HIV starting treatment in 2001-2003 (when ART was more cumbersome and more toxic) compared to 2004-2006 and 2007-2010.  Persistence improved dramatically over this time period for ART, but hardly changed at all for the other medicines studied.  This demonstrates that the changes were not merely secular trends in the likelihood of remaining on treatment.  Interestingly, in people living with HIV, persistence on the non-HIV related medicines also improved, suggesting that HIV care provided additional benefits in terms of retention and adherence to medicines that went beyond ART. 

There was also good news from Australia, where Medland and colleagues used records from the two largest HIV treatment clinics in the state of Victoria to examine time trends in the delay from HIV diagnosis to starting ART.  Among 729 people started on ART, the proportion of patient in care and on ART within one year of diagnosis increased from 43.4% to 78.9% from 2011 to 2014.  By 2014, 50% of people were starting ART within 77 days of being diagnosed.  The authors point out that this is a key measurement of programme effectiveness that is not routinely captured.  Nor does it form part of the 90-90-90 targets.  Of course, it is important to remember that the period prior to HIV diagnosis is probably even more important in terms of risks of transmission, as there have been numerous studies showing that people who know their HIV status are less likely to transmit HIV.  So we really need to know the period from infection to HIV diagnosis, as well as the time from diagnosis to treatment, and perhaps also the time to become virally supressed.  Viral suppression can take months or even more than a year depending on an individual’s initial virological and immunological state and variations in response to treatment as well as with the choice of ART regimen.

Despite massive scale up of ART, there are still many people living with HIV who present to services late with a CD4 count of <200 cells per ml.  A recent report in MMWR, showed that in 10 PEPFAR supported countries, there are still as many as one third of people presenting late.  Many of these people have opportunistic infections that have characterised HIV infection since the earliest days of the AIDS epidemic.  Botswana has made huge progress towards 90-90-90, but Tenforde and colleagues show that cryptococcal meningitis is still a major health problem.  They were able to collect laboratory based data over the past decade, as well as more detailed records from the two largest referral centres.  Although the number of cases of cryptococcal meningitis has halved since 2004, when the scale up of ART in Botswana really got going, the two referral hospitals still see more than 150 cases per year.  Mortality is still horribly high.  Overall, the authors explored data from more than 5000 episodes of cryptococcal meningitis in 4702 individuals over the period 2004-2014.  For people who could be linked to their clinical medical records, they demonstrate that the risk rises dramatically as the CD4 count falls – people with a CD4 count of < 50 cells per ml have an incidence of around 2000/100 000 person years, whereas the rates of people with 50-100 or 100-200 cells per ml are around 350 and 80 respectively.  More than 90% of the cases identified occurred in people whose CD4 cell count was <200 cells per ml.  As other studies might have predicted, men are more affected, as they tend to present to services later.  The most useful medicines for cryptococcal meningitis, i.e., liposomal Amphotericin and 5 flucytosine, remain too expensive or not available in most African countries.  Not only do we need to bring the prices of these commodities down to affordable levels, but we also need continued efforts to engage men (and other populations who get left behind) earlier in the course of their HIV infection.

The improvements in overall survival and life expectancy for people living with HIV if they have access to effective treatments are well known.  A large collaborative study (the ART Cohort Collaboration) has brought together 18 European and North American cohorts in order to look at the mortality experienced in the first years after starting ART.  They found the biggest improvements in people who started treatment in the last period that they studied (2008-2010).  There were also greater changes in mortality in the second and third years after starting ART.  Even so, they conclude that life expectancy is still not as good as that of HIV negative people.  Previous studies have sometimes been biased towards people who survive longer, partly through not including as many people in the first year after ART when mortality is at its highest.  They propose that much of the improvement seen is due to newer drugs and more options for treatment failure.  They therefore caution against the temptation to save money on cheaper generics as they become available for older medicines that may be less palatable or less effective.

What works-reaching universal HIV testing: lessons from HPTN 071 (PopART) trial in Zambia

Shanaube K, Schaap A, Floyd S, Phiri M, Griffith S, Chaila J, Bock P, Hayes R, Fidler S, Ayles H; HPTN 071 (PopART) Study Team. AIDS. 2017 Jul 17;31(11):1555-1564. doi: 10.1097/QAD.0000000000001514..

Objective: To determine the uptake of home-based HIV counselling and testing (HCT) in four HPTN071 (PopART) trial communities (implementing a 'full' combination HIV prevention package that includes universal HIV testing and treatment) in Zambia. We also explore factors associated with uptake of HCT in these communities.

Design: HPTN071 (PopART) is a 3-arm community-randomized trial in 12 communities in Zambia and 9 communities in South Africa evaluating the impact of a combination HIV prevention package, including universal HIV testing and treatment, on HIV incidence.

Methods: Using a door-to-door approach that includes systematically re-visiting households, individuals were offered participation in the intervention and verbal consent was obtained. Data were analysed for the first 18 months of the intervention, December 2013 to June 2015 for individuals 18 years and older.

Results: Among 121 130 enumerated household members, 101 102 (83.5%) accepted the intervention. HCT uptake was 72.2% (66 894/92 612), similar by sex but varied across communities. HCT uptake was associated with younger age, sex, community, being symptomatic for TB and STI and longer time since previous HIV test. Knowledge of HIV status due to the intervention increased by 36% overall and by 66% among HIV positives; the highest impact was among 18-24 year olds.

Conclusion: Overall acceptance of HIV-testing through offering a door-to-door-based combination HIV prevention package was 72.2%. The intervention increased knowledge of HIV status from 50% to 90%. However, challenges still remain and a one-off intervention is unlikely to be successful but will require repeated visits and multiple strategies.

Abstract access

A universal testing and treatment intervention to improve HIV control: One-year results from intervention communities in Zambia in the HPTN 071 (PopART) cluster-randomised trial

Hayes R, Floyd S, Schaap A, Shanaube K, Bock P, Sabapathy K, Griffith S, Donnell D, Piwowar-Manning E, El-Sadr W, Beyers N, Ayles H, Fidler S; HPTN 071 (PopART) Study Team. PLoS Med. 2017 May 2;14(5):e1002292. doi: 10.1371/journal.pmed.1002292. eCollection 2017 May.

Objective: The Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets require that, by 2020, 90% of those living with HIV know their status, 90% of known HIV-positive individuals receive sustained antiretroviral therapy (ART), and 90% of individuals on ART have durable viral suppression. The HPTN 071 (PopART) trial is measuring the impact of a universal testing and treatment intervention on population-level HIV incidence in 21 urban communities in Zambia and South Africa. We report observational data from four communities in Zambia to assess progress towards the UNAIDS targets after 1 y of the PopART intervention.

Methods and Findings: The PopART intervention comprises annual rounds of home-based HIV testing delivered by community HIV-care providers (CHiPs) who also support linkage to care, ART retention, and other services. Data from four communities in Zambia receiving the full intervention (including immediate ART for all individuals with HIV) were used to determine proportions of participants who knew their HIV status after the CHiP visit; proportions linking to care and initiating ART following referral; and overall proportions of HIV-infected individuals who knew their status (first 90 target) and the proportion of these on ART (second 90 target), pre- and post-intervention. We are not able to assess progress towards the third 90 target at this stage of the study. Overall, 121 130 adults (59 283 men and 61 847 women) were enumerated in 46 714 households during the first annual round (December 2013 to June 2015). Of the 45 399 (77%) men and 55 703 (90%) women consenting to the intervention, 80% of men and 85% of women knew their HIV status after the CHiP visit. Of 6197 HIV-positive adults referred by CHiPs, 42% (95% CI: 40%-43%) initiated ART within 6 mo and 53% (95% CI: 52%-55%) within 12 mo. In the entire population, the estimated proportion of HIV-positive adults who knew their status increased from 52% to 78% for men and from 56% to 87% for women. The estimated proportion of known HIV-positive individuals on ART increased overall from 54% after the CHiP visit to 74% by the end of the round for men and from 53% to 73% for women. The estimated overall proportion of HIV-positive adults on ART, irrespective of whether they knew their status, increased from 44% to 61%, compared with the 81% target (the product of the first two 90 targets). Coverage was lower among young men and women than in older age groups. The main limitation of the study was the need for assumptions concerning knowledge of HIV status and ART coverage among adults not consenting to the intervention or HIV testing, although our conclusions were robust in sensitivity analyses.

Conclusions: In this analysis, acceptance of HIV testing among those consenting to the intervention was high, although linkage to care and ART initiation took longer than expected. Knowledge of HIV-positive status increased steeply after 1 y, almost attaining the first 90 target in women and approaching it in men. The second 90 target was more challenging, with approximately three-quarters of known HIV-positive individuals on ART by the end of the annual round. Achieving higher test uptake in men and more rapid linkage to care will be key objectives during the second annual round of the intervention.

Abstract  Full-text [free] access

Universal test, treat, and keep: improving ART retention is key in cost-effective HIV control in Uganda

McCreesh N, Andrianakis I, Nsubuga RN, Strong M, Vernon I, McKinley TJ, Oakley JE, Goldstein M, Hayes R, White RG. BMC Infect Dis. 2017 May 3;17(1):322. doi: 10.1186/s12879-017-2420-y.

Background: With ambitious new UNAIDS targets to end AIDS by 2030, and new WHO treatment guidelines, there is increased interest in the best way to scale-up ART coverage. We investigate the cost-effectiveness of various ART scale-up options in Uganda.

Methods: Individual-based HIV/ART model of Uganda, calibrated using history matching. 22 ART scale-up strategies were simulated from 2016 to 2030, comprising different combinations of six single interventions (1. increased HIV testing rates, 2. no CD4 threshold for ART initiation, 3. improved ART retention, 4. increased ART restart rates, 5. improved linkage to care, 6. improved pre-ART care). The incremental net monetary benefit (NMB) of each intervention was calculated, for a wide range of different willingness/ability to pay (WTP) per DALY averted (health-service perspective, 3% discount rate).

Results: For all WTP thresholds above $210, interventions including removing the CD4 threshold were likely to be most cost-effective. At a WTP of $715 (1 × per-capita-GDP) interventions to improve linkage to and retention/re-enrolment in HIV care were highly likely to be more cost-effective than interventions to increase rates of HIV testing. At higher WTP (> ~ $1690), the most cost-effective option was 'Universal Test, Treat, and Keep' (UTTK), which combines interventions 1-5 detailed above.

Conclusion: Our results support new WHO guidelines to remove the CD4 threshold for ART initiation in Uganda. With additional resources, this could be supplemented with interventions aimed at improving linkage to and/or retention in HIV care. To achieve the greatest reductions in HIV incidence, a UTTK policy should be implemented.

Abstract  Full-text [free] access

Predictors of loss to follow-up among patients on ART at a rural hospital in KwaZulu-Natal, South Africa.

Arnesen R, Moll AP, Shenoi SV. PLoS One. 2017 May 24;12(5):e0177168. doi: 10.1371/journal.pone.0177168. eCollection 2017

Introduction: Improved HIV outcomes as a result of expanded antiretroviral therapy (ART) access is threatened by increasing rates of loss to follow up (LTFU) among those on ART, largely reported in urban populations. Some reports suggest that LTFU rates are overestimated due to patient movement to other facilities and inadequate medical records.

Study Objective: To define the proportion disengaging from HIV care as well as the characteristics of those LTFU in order to design and implement appropriate interventions to increase retention.

Methods: We performed a retrospective review of patients who discontinued ART at a central hospital ART clinic in rural South Africa and compared with patients receiving care at the 15 primary health clinics (PHCs) to determine the true proportion of those who were LTFU. We also compared those who discontinued ART with those who did not at the central hospital ART clinic to determine predictors of loss to follow up.

Results: Among 3242 patients on ART, 820 were originally marked as LTFU. Among all patients, 272 (8.4%) were found at a clinic on treatment, 56 (1.7%) were found at a clinic from which they had since discontinued treatment, and 10 (0.3%) returned to care between June and July 2016, leaving 475 (14.7%) unaccounted for and thus categorized as 'true' LTFU. Factors found to be associated with discontinuation include being male, age 18-35, having a CD4 count under 200 cells/μL, and being on ART for under six months.

Conclusions: Young men with low CD4 counts early after ART initiation are at highest risk of ART disengagement in this rural South African HIV clinic. Novel interventions targeting this group are needed to improve retention in care.

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Ten-year trends in anti-retroviral therapy persistence among US Medicaid beneficiaries, 2001-2010

Youn B, Shireman TI, Lee Y, Galárraga O, Rana AI, Justice AC, Wilson IB. AIDS. 2017 May 16. doi: 10.1097/QAD.0000000000001541. [Epub ahead of print]

Objective: Whether the rate of HIV antiretroviral therapy (ART) persistence has improved over time in the U.S. is unknown. We examined ART persistence trends between 2001 and 2010, using non-HIV medications as a comparator.

Methods: We conducted a retrospective cohort study using Medicaid claims. We defined persistence as the duration of treatment from the first to the last fill date before a 90-day permissible gap, and used Kaplan-Meier curves and Cox proportional hazard models to assess crude and adjusted non-persistence. The secular trends of ART persistence in 43 598 HIV patients were compared with the secular trends of persistence with angiotensin-converting enzyme inhibitors (ACE) or angiotensin receptor blockers (ARB), statins, and metformin in (1) non-HIV-infected patients and (2) subgroups of HIV patients who started these control medications while using ART.

Results: Median time to ART non-persistence increased from 23.9 months in 2001-2003 to 35.4 months in 2004-2006, and was not reached for those starting ART in 2007-2010. In adjusted models, ART initiators in 2007-2010 had 11% decreased hazards of non-persistence compared with those who initiated in 2001-2003 (p < 0.001). For non-HIV patients initiating ACE/ARB, statins, and metformin, the hazard ratios (HR) for non-persistence comparing 2007-2010 to 2001-2003 were 1.07, 0.94, and 1.02, respectively (all p < 0.001). For HIV patients initiating the three control medications, the HRs of non-persistence comparing 2007-2010 to 2001-2003 were 0.71, 0.65, and 0.63, respectively (all p < 0.001).

Conclusions: Persistence with ART improved between 2001 and 2010. Persistence with control medications improved at a higher rate among HIV patients using ART than HIV-negative controls.

Abstract

Time from HIV diagnosis to commencement of antiretroviral therapy as an indicator to supplement the HIV cascade: Dramatic fall from 2011 to 2015

Medland NA, Chow EP, McMahon JH, Elliott JH, Hoy JF, Fairley CK. PLoS One. 2017 May 16;12(5):e0177634. doi: 10.1371/journal.pone.0177634. eCollection 2017.

Introduction:  The HIV care cascade is increasingly used to evaluate HIV treatment programs at the population level. However, the cascade indicators lack the ability to show changes over time, which reduces their utility to guide health policy. Alternatives have been proposed but are complex or result in a delay in results. We propose a new indicator of ART uptake, the time from HIV diagnosis to commencement of ART, and compare it to the existing cascade indicator of proportion of patients on treatment and the WHO proposed cohort cascade indicator of proportion of patients on treatment within one year of diagnosis.

Methods and Materials: Records from patients from the two largest HIV treatment centres in the state of Victoria, Australia (Melbourne Sexual Health Centre and The Alfred Hospital Department of Infectious Diseases) from 2011 to 2015 were extracted. The intervals between date of diagnosis, entry into care and initiation of ART were compared.

Results and Discussion: From 2011 to 2015 the proportion of in-care patients who were on ART rose from 87% to 93% (p<0.0001). From 2011 to 2014, the proportion of patients in care and on ART within one year of diagnosis increased from 43.4% to 78.9% (p = 0.001). The median time from diagnosis to ART fell from 418 days (IQR: 91-1176) to 77 days (IQR: 39-290)(p<0.001) by calendar year in which ART was commenced.

Conclusions: From 2011 to 2015 there were substantial and clinically important falls in the median time from diagnosis to commencing ART in those that commenced ART. The size of this dramatic change was not apparent when only reporting the proportion of patients on ART. Time to ART is a useful indicator and can be used to supplement existing cascade indicators in measuring progress toward universal ART coverage.

Abstract  Full-text [free] access

Trends in prevalence of advanced HIV disease at antiretroviral therapy enrollment — 10 countries, 2004–2015

Auld AF, Shiraishi RW, Oboho I, Ross C, Bateganya M, Pelletier V, Dee J, Francois K, Duval N, Antoine M, Delcher C, Desforges G, Griswold M, Domercant JW, Joseph N, Deyde V, Desir Y, Van Onacker JD, Robin E, Chun H, Zulu I, Pathmanathan I, Dokubo EK, Lloyd S, Pati R, Kaplan J, Raizes E, Spira T, Mitruka K, Couto A, Gudo ES, Mbofana F, Briggs M, Alfredo C, Xavier C, Vergara A, Hamunime N, Agolory S, Mutandi G, Shoopala NN, Sawadogo S, Baughman AL, Bashorun A, Dalhatu I, Swaminathan M, Onotu D, Odafe S, Abiri OO, Debem HH, Tomlinson H, Okello V, Preko P, Ao T, Ryan C, Bicego G, Ehrenkranz P, Kamiru H, Nuwagaba-Biribonwoha H, Kwesigabo G, Ramadhani AA, Ng'wangu K, Swai P, Mfaume M, Gongo R, Carpenter D, Mastro TD, Hamilton C, Denison J, Wabwire-Mangen F, Koole O, Torpey K, Williams SG, Colebunders R, Kalamya JN, Namale A, Adler MR, Mugisa B, Gupta S, Tsui S, van Praag E, Nguyen DB, Lyss S, Le Y, Abdul-Quader AS, Do NT, Mulenga M, Hachizovu S, Mugurungi O, Barr BAT, Gonese E, Mutasa-Apollo T, Balachandra S, Behel S, Bingham T, Mackellar D, Lowrance D, Ellerbrock TV.MMWR Morb Mortal Wkly Rep. 2017 Jun 2;66(21):558-563. doi: 10.15585/mmwr.mm6621a3.

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies. To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694 138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat-all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence.

Abstract  Full-text [free] access

Advanced HIV disease in Botswana following successful antiretroviral therapy rollout: Incidence of and temporal trends in cryptococcal meningitis

Tenforde MW, Mokomane M, Leeme T, Patel RK, Lekwape N, Ramodimoosi C, Dube B, Williams EA, Mokobela KO, Tawanana E, Pilatwe T, Hurt WJ, Mitchell H, Banda DL, Stone H, Molefi M, Mokgacha K, Phillips H, Mullan PC, Steenhoff AP, Mashalla Y, Mine M, Jarvis JN. Clin Infect Dis. 2017 May 13. doi: 10.1093/cid/cix430. [Epub ahead of print].

Background: Botswana has a well-developed antiretroviral therapy (ART) program which serves as a regional model. With wide ART availability, the burden of advanced HIV and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis, and describe characteristics of cases 2000-2014 and temporal trends at two national referral hospitals.

Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected 2000-2014 to identify cases of cryptococcal meningitis. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers 2004-2014.

Results: 5296 episodes of cryptococcal meningitis were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 cases/100 000 person-years (95%CI 16.6 - 19.2). In the HIV-infected population, incidence was 96.8 cases/100 000 person-years (95%CI 90.0 - 104.0); male predominance was seen across CD4 strata. At national referral hospitals, cases decreased 2007-2009 but stabilized 2010-2014.

Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of cryptococcal meningitis comparable to pre-ART era rates in South Africa. Our findings suggest a key population of individuals, often men, are developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.

Abstract

Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies

Trickey A, May MT, Vehreschild JJ, Obel N, Gill MJ, Crane HM, Boesecke C, Patterson S, Grabar S, Cazanave C, Cavassini M, Shepherd L, Monforte AD, van Sighem A, Saag M, Lampe F, Hernando V, Montero M, Zangerle R, Justice AC, Sterling T, Ingle SM, Sterne JAC (Antiretroviral Therapy Cohort Collaboration). Lancet HIV. 2017 May 10. pii: S2352-3018(17)30066-8. doi: 10.1016/S2352-3018(17)30066-8. [Epub ahead of print]

Background: Health care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost importance to patients, clinicians, and health-care planners. We examined changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013.

Methods: We analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between 1996 and 2010 and had at least 3 years of potential follow-up. We estimated adjusted (for age, sex, AIDS, risk group, CD4 cell count, and HIV-1 RNA at start of ART) all-cause and cause-specific mortality hazard ratios (HRs) for the first year after ART initiation and the second and third years after ART initiation in four calendar periods (1996-99, 2000-03 [comparator], 2004-07, 2008-10). We estimated life expectancy by calendar period of initiation of ART.

Findings: 88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second or third year of ART. Patients starting ART in 2008-10 had lower all-cause mortality in the first year after ART initiation than did patients starting ART in 2000-03 (adjusted HR 0·71, 95% CI 0·61-0·83). All-cause mortality in the second and third years after initiation of ART was also lower in patients who started ART in 2008-10 than in those who started in 2000-03 (0·57, 0·49-0·67); this decrease was not fully explained by viral load and CD4 cell count at 1 year. Rates of non-AIDS deaths were lower in patients who started ART in 2008-10 (vs 2000-03) in the first year (0·48, 0·34-0·67) and second and third years (0·29, 0·21-0·40) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men.

Interpretation: Even in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Prognostic models and life expectancy estimates should be updated to account for these improvements.

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
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How are we going to get to our prevention targets? Old tools, new tools and a more nuanced understanding of transmission dynamics.

Editor’s notes: By 2020, the Fast-Track strategy is aiming to reduce new HIV infections to 200 000 per year.  There is increasing recognition that if we are to succeed, we will need to do much more than simply putting people onto HIV treatment.  Despite the massive impact of ART on infectiousness, the decline in new infections at the community level is still not fast enough, even in countries like Botswana (see above) where 90-90-90 has almost been reached.  Renewed enthusiasm for primary prevention has also followed key trials of biomedical prevention tools including voluntary medical male circumcision and ARV-based prevention.  It is all too easy for us to forget the crucial role that condoms have played from the early days of the epidemic.  More recently, with HIV seen as a less terrifying infection, many programmes suffer from “condom fatigue”.  So it is good to see papers on the key importance of condoms as well as perspectives on how they are perceived by young men.

The magic of ARVs does not end with treatment.  We are finally moving to wider use of pre-exposure prophylaxis (PrEP).  There is no doubt that PrEP works when taken, but there are still plenty of questions for policy-makers about how to adopt it whole-heartedly into their national strategic plans and for financiers about how to pay for it.  Papers this month cover a range of experiences with PrEP from the US, where the huge majority of PrEP users still live, to Europe and Australia, where policies are finally moving towards wider use.  Long acting PrEP remains a key objective for many, as it might improve regular adherence, which has proved the Achilles’ heel of oral and topical PrEP in several of the large studies.

One of the ways to make PrEP most cost-effective is to ensure that it is available to people who are most likely to acquire HIV.  So the hope continues that phylogenetic analyses will allow more sophisticated understanding of the dynamics of the multiple overlapping networks of HIV transmission in communities.  Papers this month cover Australia and the PANGEA consortium of African research sites along with a cautionary comment about establishing the ethical framework for such studies, particularly among populations who are already subject to discrimination and criminalization.

When used correctly and consistently, condoms are highly effective not only to prevent HIV but also to prevent pregnancy and to prevent sexually transmitted infections.  Stover and colleagues have tried to capture all three benefits in one model.  They explore three potential scenarios for condom programming between now and 2030 in 81 countries that are priorities for family planning or HIV programmers or both.  The benefits of greater investment in condoms are huge.  In their most optimistic scenario, the authors suggest that if the entire gap between people who would like to use condoms and people who currently use them was filled (almost 11 billion condoms over the period), this could prevent up to 400 million unwanted pregnancies; 16.8 million new HIV infections and more than 700 million sexually transmitted infections.  The costs are quite modest, and at $115 per DALY averted this is an investment that everyone should support.  There are of course limitations in such a broad brush model, but it provides an excellent starting point.

The challenges in provision of condoms to young people go well beyond the cost and effectiveness considerations that underpin the previous analysis.  In an interesting qualitative study in South Africa, de Bruin and Panday-Soobrayan report their findings from focus group discussions with learners in 33 public schools.  Most of the learners were not in favour of provision of condoms at school, although they were keen on more youth friendly sexual and reproductive health and rights services within the public sector.  Many thought that provision of condoms would lead to earlier and more frequent sexual contacts, despite considerable experience showing that this is not the case in other settings.

Multiple trials have shown that PrEP is extremely effective when it is used consistently and correctly.  Many countries in all continents are now beginning to work out where it fits within their combination prevention package.  To date, the large majority of PrEP users are in the United States of America (USA), where more than 140 000 people have started.  It is much harder to measure how many are still taking it regularly.  Patel and colleagues analysed utilization at three months after the initial prescription of PrEP in three major PrEP clinics in three states in the USA.  18% of the 201 people (90% male) seen at baseline did not use their PrEP and this was strongly predicted by insurance status, with around a four-fold risk of dropping out among those who were not insured.  Although the numbers are small, this is an important study.  The authors suggest that increased insurance cover might make PrEP have a greater impact.  More broadly it raises the challenge that PrEP is often needed most by people least able to access it.  This will be a real challenge in countries where people most at risk, such as gay men and other men who have sex with men and sex workers, are criminalized or discriminated against in many health care settings.

In Australia, PrEP has been provided through large demonstration projects while awaiting decisions about how to include it in routine practice.  Lal and colleagues report results from 114 (one transgender woman, the rest male) people taking PrEP in the Victorian PrEP Demonstration project.  Participants have to pay an equivalent of an insurance co-payment, in order to make the situation more like the “real world”.  The participants were recruited because they were at high risk of HIV engaging in condomless anal sex with partners who were known to be living with HIV or of unknown status.  Adherence to PrEP was excellent as measured by a variety of reported and biological measures.  They observed one seroconversion in a man with exposure two weeks before starting PrEP who was already in the process of seroconverting and whose virus was found to be resistant to emtricitabine.  The only other seroconversion occurred in someone who had not yet started PrEP.  The authors found a substantial increase in rates of gonorrhoea and chlamydia once participants were “stable” on PrEP after three months.  There was also a significant reduction in condom use with both regular and casual partners.  This is one of the first studies to document important risk compensation among PrEP users.  Of course, preventing HIV is a huge benefit that generally outweighs the harms of additional treatment for sexually transmitted infections.  However, the study emphasizes the importance of enhancing sexual health services alongside PrEP and reminds us that people most at risk of HIV are also at high risk of other infections (and also of pregnancy in the context of heterosexual transmission.)  If PrEP is integrated within a broad sexual health service, there could be considerable synergistic benefits.

Gay men and men who have sex with men who enrolled in the PrEP demonstration project in Amsterdam also had high concomitant rates of hepatitis C virus (HCV).  Hoorenborg and colleagues found that around 5% of the 375 men enrolled in the project were co-infected.  The HCV found among these men were genetically similar to those circulating in the population of gay men and other men who have sex with men living with HIV, and more distinct from HCV from other risk groups.  This is good evidence that HCV and HIV both circulate in this population, and emphasizes once again the need for more integrated services, including hepatitis screening.

The ÉCLAIR study is a phase 2a trial of cabotegravir injections in healthy HIV-negative male volunteers.  As noted, adherence is a major challenge in many PrEP trials; although notably less of a problem when people choose to take PrEP in demonstration projects.  It is hoped that cabotegravir could be the first long acting PrEP.  Markowitz and colleagues presented the results of this study at CROI 2017.  The authors point out that although the injections are painful, many men stated that they would be happy to continue if the injections were effective.  No serious safety challenges emerged. The pharmacokinetics suggests that a dose given more frequently will be needed – and subsequent trials will use a two monthly regimen. 

One group for whom PrEP has been recommended by WHO for some years are serodiscordant couples (SDCs).  The Partners PrEP study, which forms one of the cornerstones for the evidence that PrEP works for both men and women, was conducted in SDCs.  The idea is to protect the HIV-negative partner from infection until such time as the partner living with HIV has been on ART consistently and suppressed their viral load.  So a study from the Centers for Disease Control USA is relevant to discussions of PrEP.  Crepaz and colleagues found that around 6000 new HIV infections occur each year in the USA among men and women having heterosexual sex and are aware that their partner is living with HIV.  They point out that viral suppression is achieved by only around 50% of heterosexuals living with HIV and that an additional proportion does not know their HIV status.  So the importance of HIV testing, and of focusing efforts on serodiscordant couples is clear.  Such efforts include both improving HIV treatment effectiveness, and providing a range of prevention choices including PrEP until viral suppression is achieved.

While the study above used traditional epidemiological surveillance reports, phylogenetics may provide additional insights into the dynamics of transmission.  In Australia, where notifications with HIV are rising steadily,  Castley and colleagues have examined the sequence data from almost 5000 viruses collected across the country from 2005-2012.  This sample is drawn from around 1200 new HIV infections per year (and around 27 000 people living with HIV).  The sample is not random, but reflects samples that were sent for sequencing to determine drug resistance.  Around one quarter of sequences are found in tight clusters (pairs, triplets or more) with other sequences, making it likely that they are closely connected by transmission.  Of course, all HIV sequences have been transmitted, so a longer time period and complete sampling would be expected to give a much higher proportion in clusters.  Indeed the more recent samples are around twice as likely to be in clusters as those collected at the start of the time period. Nonetheless, the large sample and the time period of collection allows some clear observations to be made.  In all states, the proportion of non-B subtypes is increasing, which must relate to travel and migration to and from Asia and Africa.  There is little evidence that the C subtypes (originally from Africa) are found in all male clusters suggesting little spill over into the community of gay men and other men having sex with men.  Larger clusters are more common among younger, all male networks. Like most molecular epidemiological studies, there are a small number of large clusters which represent highly active transmission.  These clusters are also most likely to be all male.  Taken together, the results suggest that the steady rise in notifications in Australia is probably due to increasing migration and travel and to ongoing active transmission networks among young gay men.  The challenge is to turn this sort of analysis into clear policy recommendations that can improve HIV prevention.

UNAIDS joined an interesting meeting on the ethics of phylogenetic studies in Africa organised by the PANGEA consortium.  Many of the issues discussed are also covered in a comment by Cohen on the importance of thinking through the risks inherent in these studies.  A key issue is to ensure that systems are reinforced to monitor any unexpected harms and to establish mitigation strategies to minimize them.  The challenges are not necessarily different to traditional epidemiological studies which may highlight networks and locations of groups that are criminalized or discriminated against.  In community consultations, prior to agreeing to go forward with phylogenetic studies, some potential participants even say that they would be keen to “know who infected them” in order to punish them.  This is clearly NOT the aim of such studies and emphasizes the importance of clear information about the limitations of the techniques which cannot usually rule out the possibility of additional links in the transmission chain.  Issues of anonymised information and what to do if clinically relevant results such as drug resistance mutations are uncovered as incidental findings also need to be discussed.

Furthermore, Ratmann and colleagues, reporting on the first 4000 sequences from the PANGEA consortium (largely from the Rakai project in Uganda), also emphasize some of the technical challenges that may lead to erroneous results in creating phylogenies.  There is little doubt that as the cost of sequencing falls and as the technologies and software become increasingly straightforward, we will see more and more studies of sequence data.  It is likely that analysis of these data will lead to more nuanced approaches to HIV prevention, particularly as the overall incidence falls, and sharper tools are needed to dissect the pathways of ongoing transmission.

The case for investing in the male condom

Stover J, Rosen JE, Carvalho MN, Korenromp EL, Friedman HS, Cogan M, Deperthes B. PLoS One. 2017 May 16;12(5):e0177108. doi: 10.1371/journal.pone.0177108. eCollection 2017.

When used correctly and consistently, the male condom offers triple protection from unintended pregnancy and the transmission of sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). However, with health funding levels stagnant or falling, it is important to understand the cost and health impact associated with prevention technologies. This study is one of the first to attempt to quantify the cost and combined health impact of condom use, as a means to prevent unwanted pregnancy and to prevent transmission of STIs including HIV. This paper describes the analysis to make the case for investment in the male condom, including the cost, impact and cost-effectiveness by three scenarios (low in which 2015 condom use levels are maintained; medium in which condom use trends are used to predict condom use from 2016-2030; and high in which condom use is scaled up, as part of a package of contraceptives, to meet all unmet need for family planning by 2030 and to 90% for HIV and STI prevention by 2016) for 81 countries from 2015-2030. An annual gap between current and desired use of 10.9 billion condoms was identified (4.6 billion for family planning and 6.3 billion for HIV and STIs). Under a high scenario that completely reduces that gap between current and desired use of 10.9 billion condoms, we found that by 2030 countries could avert 240 million DALYs. The additional cost in the 81 countries through 2030 under the medium scenario is $1.9 billion, and $27.5 billion under the high scenario. Through 2030, the cost-effectiveness ratios are $304 per DALY averted for the medium and $115 per DALY averted for the high scenario. Under the three scenarios described above, our analysis demonstrates the cost-effectiveness of the male condom in preventing unintended pregnancy and HIV and STI new infections. Policy makers should increase budgets for condom programming to increase the health return on investment of scarce resources.

Abstract  Full-text [free] access

Learners' perspectives on the provision of condoms in South African public schools.

de Bruin WE, Panday-Soobrayan S. AIDS care. 2017 May 16:1-4. doi: 10.1080/09540121.2017.1327647. [Epub ahead of print]

A stubborn health challenge for learners in South African public schools concerns sexual and reproductive health and rights (SRHR). In 2015, the Department of Basic Education (DBE) proposed the provision of condoms and SRHR-services to learners in schools. This study aimed to contribute to the finalisation and implementation of DBE's policy by exploring learners' perspectives on the provision of condoms and SRHR-services in schools. Sixteen focus group discussions were conducted with learners (n = 116) from 33 public schools, to assess their attitudes, social influences, and needs and desires regarding condom provision and SRHR-services in schools. The majority of learners did not support condom provision in schools as they feared that it may increase sexual activity. Contrarily, they supported the provision of other SRHR-services as clinics fail to offer youth-friendly services. Learners' sexual behaviour and access to SRHR-services are strongly determined by their social environment, including traditional norms and values, and social-pressure from peers and adults. Learners' most pressing needs and desires to access condoms and SRHR-services in school concerned respect, privacy and confidentiality of such service provision. Implementation of DBE's policy must be preceded by an evidence-informed advocacy campaign to debunk myths about the risk of increased sexual activity, to advocate for why such services are needed, to shift societal norms towards open discussion of adolescent SRHR and to grapple with the juxtaposition of being legally empowered but socially inhibited to protect oneself from HIV, STIs and early pregnancy. Provision of condoms and other SRHR-services in schools must be sensitive to learners' privacy and confidentiality to minimise stigma and discrimination.

Abstract  Full-text [free] access

Impact of insurance coverage on utilization of pre-exposure prophylaxis for HIV prevention

Patel RR, Mena L, Nunn A, McBride T, Harrison LC, Oldenburg CE, Liu J, Mayer KH, Chan PA.  PLoS One. 2017 May 30;12(5):e0178737 . doi: 10.1371/journal.pone.0178737. eCollection 2017.

Pre-exposure prophylaxis (PrEP) can reduce U.S. HIV incidence. We assessed insurance coverage and its association with PrEP utilization. We reviewed patient data at three PrEP clinics (Jackson, Mississippi; St. Louis, Missouri; Providence, Rhode Island) from 2014-2015. The outcome, PrEP utilization, was defined as patient PrEP use at three months. Multivariable logistic regression was performed to determine the association between insurance coverage and PrEP utilization. Of 201 patients (Jackson: 34%; St. Louis: 28%; Providence: 28%), 91% were male, 51% were White, median age was 29 years, and 21% were uninsured; 82% of patients reported taking PrEP at three months. Insurance coverage was significantly associated with PrEP utilization. After adjusting for Medicaid-expansion and individual socio-demographics, insured patients were four times as likely to use PrEP services compared to the uninsured (OR: 4.49, 95% CI: 1.68-12.01; p = 0.003). Disparities in insurance coverage are important considerations in implementation programs and may impede PrEP utilization.

Abstract  Full-text [free] access

Medication adherence, condom use and sexually transmitted infections in Australian PrEP users: interim results from the Victorian PrEP demonstration project

Lal L, Audsley J, Murphy D, Fairley CK, Stoove M, Roth N, Moore R, Tee BK, Puratmaja N, Anderson PL, Leslie D, Grant RM, De Wit J, Wright E; VicPrEP Study Team. AIDS. 2017 May 1 doi: 10.1097/QAD.0000000000001519. [Epub ahead of print]

Objective: HIV Pre-exposure prophylaxis (PrEP) decreases risk of HIV acquisition however its efficacy is closely dependent on adherence. There is also concern that the preventive effect of PrEP may be offset by risk compensation, notably an increase in condomless anal sex.

Design: Multi-site, open-label demonstration study that recruited people at current or recent risk of HIV infection in Melbourne, Australia.

Methods: Participants were recruited from three general practice clinics and one sexual health clinic in Melbourne and consented to take daily tenofovir/emtricitabine for 30 months. Sexual practice data, HIV and sexually transmitted infection (STI) test results were collected at baseline and 3-monthly during follow up. PrEP adherence was evaluated by self-report at clinical visits, online surveys, refill-based assessments and dried blood spot (DBS) testing. We present a 12-month interim analysis.

Results: 114 people were recruited. We observed a significant decline in condom use which occurred concomitantly with a significant increase in STIs over the first 12 months of PrEP. Incidence (per 100PY) of any STI was 43.2 and 119.8 at m0-3 and M3-12, respectively (IRR 2.77 (1.52, 5.56)). Adherence to PrEP medication was high by all measures, including six month TDF-FTC levels in DBS.

Conclusions: We found significant reduction in condom use and an increase STIs over the first 12 months of follow-up. High medication adherence rates coupled with a decline in condom use and a rise in STIs, suggests that prevention, early detection and treatment of STIs is a chief research priority in the current era of HIV PrEP.

Abstract

Men who have sex with men starting pre-exposure prophylaxis (PrEP) are at risk of HCV infection: evidence from the Amsterdam PrEP study

Hoornenborg E, Achterbergh RC, Van Der Loeff MF, Davidovich U, Hogewoning A, de Vries HJ, Schinkel J, Prins M, Laar TJWV; Amsterdam PrEP Project team in the HIV Transmission Elimination AMsterdam Initiative, MOSAIC study group. AIDS. 2017 May 1. doi: 10.1097/QAD.0000000000001522. [Epub ahead of print].

Objectives and Design: Hepatitis C virus (HCV) has been recognised as an emerging sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). However, HIV-negative MSM at high risk for HIV might also be at increased risk for HCV. We studied the HCV prevalence in HIV-negative MSM who start pre-exposure prophylaxis (PrEP) in Amsterdam. Phylogenetic analysis was used to compare HCV strains obtained from HIV-negative and HIV-positive MSM.

Methods: At enrolment in the Amsterdam PrEP (AMPrEP) demonstration project, HIV-negative MSM were tested for the presence of HCV antibodies and HCV RNA. If positive for HCV RNA, an HCV NS5B gene fragment (709 bp) was sequenced and compared with HCV isolates from HIV-positive MSM (n = 223) and risk groups other than MSM (n = 153), using phylogenetic analysis.

Results: Of 375 HIV-negative MSM enrolled in AMPrEP, 18 (4.8%, 95%CI 2.9%-7.5%) of participants were anti-HCV and/or HCV RNA positive at enrolment; 15/18 (83%) had detectable HCV RNA. HCV genotyping showed genotype 1a (73%), 4d (20%) and 2b (7%). All HCV-positive MSM starting PrEP were part of MSM-specific HCV clusters containing MSM with and without HIV.

Conclusion: HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported. All HIV-negative HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status. Hence, routine HCV testing should be offered to MSM at high risk for HIV, especially for those enrolling in PrEP programs.

Abstract

Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial.

Markowitz M, Frank I, Grant RM, Mayer KH, Elion R, Goldstein D, Fisher C, Sobieszczyk ME, Gallant JE, Van Tieu H, Weinberg W, . Margolis DA, Hudson KJ, Stancil BS, Ford SL, Patel P, Gould E, Rinehart AR, Smith KY, Spreen WR. Lancet HIV. 2017 May 22. pii: S2352-3018(17)30068-1. doi: 10.1016/S2352-3018(17)30068-1. [Epub ahead of print]

Background: Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection.

Methods: We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178.

Findings: Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 μg/mL (95% CI 0·237-0·385), 0·331 μg/mL (0·253-0·435), and 0·387 μg/mL (0·296-0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration.

Interpretation: Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens.

Abstract

Examination of HIV infection through heterosexual contact with partners who are known to be HIV infected in the United States, 2010-2015

Crepaz N, Dong B, Chen M, Hall I. AIDS. 2017 Jul 17;31(11):1641-1644. doi: 10.1097/QAD.0000000000001526.

Using data from the National HIV Surveillance System, we examined HIV infections diagnosed between 2010 and 2015 attributed to heterosexual contact with partners previously known to be HIV infected. More than four in 10 HIV infections among heterosexual males and five in 10 HIV infections among heterosexual women were attributed to this group. Findings may inform the prioritization of prevention and care efforts and resource allocation modeling for reducing new HIV infection among discordant partnerships.

Abstract

A national study of the molecular epidemiology of HIV-1 in Australia 2005–2012

Castley A, Sawleshwarkar S, Varma R, Herring B, Thapa K, Dwyer D, Chibo D, Nguyen N, Hawke K, Ratcliff R, Garsia R, Kelleher A, Nolan D; Australian Molecular Epidemiology Network-HIV (AMEN-HIV).. PLoS One. 2017 May 10;12(5):e0170601. doi: 10.1371/journal.pone.0170601. eCollection 2017.

Introduction: Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia.

Methods: The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4873 patients who had genotypes performed during 2005-2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster).

Results: HIV-1 subtype B represented 74.5% of the 4873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p<0.001), being younger (p<0.001), being male (p = 0.023) and having a B subtype (p = 0.02). Being in a larger cluster (>3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008).

Conclusion: This nationwide HIV-1 study of 4873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia

Abstract  Full-text [free] access

HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences.

Ratmann O, Wymant C, Colijn C, Danaviah S, Essex M, Frost SD, Gall A, Gaiseitsiwe S, Grabowski M, Gray R, Guindon S, von Haeseler A, Kaleebu P, Kendall M, Kozlov A, Manasa J, Minh BQ, Moyo S, Novitsky V, Nsubuga R, Pillay S, Quinn TC, Serwadda D, Ssemwanga D, Stamatakis A, Trifinopoulos J, Wawer M, Leigh Brown A, de Oliveira T, Kellam P, Pillay D, Fraser C.. AIDS Res Hum Retroviruses. 2017 May 25. doi: 10.1089/AID.2017.0061. [Epub ahead of print].

To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
Afghanistan, Angola, Australia, Azerbaijan, Bangladesh, Benin, Bolivia, Botswana, Brazil, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Congo, Côte d'Ivoire, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, Haiti, India, Indonesia, Iran (Islamic Republic of), Iraq, Jamaica, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, Niger, Nigeria, Pakistan, Papua New Guinea, Peru, Philippines, Russian Federation, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Solomon Islands, Somalia, South Africa, South Sudan, Sudan, Swaziland, Tajikistan, Togo, Turkmenistan, Uganda, Ukraine, United Republic of Tanzania, United States of America, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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Increasing HIV testing by sharing the load and updating tasks and traditions for traditional birth attendants and lay providers

Editor’s notes: Nigeria still has the highest number of new HIV infections among children in the world, around 40 000 annually, with the large majority arising from mother to child transmission.  In Nigeria, less than 20% of pregnant women receive HIV testing. This is due to several issues which include a limited number of HIV testing service delivery points and a limited number of deliveries taking place at health facilities.  Around two thirds of deliveries take place at home, traditionally supported by traditional birth attendants (TBAs).  Many TBAs in Nigeria have little knowledge of either the benefits or practice of HIV testing, nor of ways to reduce transmission of HIV to infants.

Chizoba and colleagues have developed and tested a model of antenatal care that aims to integrate TBAs within the government primary health care (PHC) network.  The intervention consisted of PHC clinics identifying a few TBAs who operated in the catchment area of the clinic. Between one and five of these TBAs was invited to the PHC clinic for a one-day training on HIV point of care testing, and asked to refer all women found to be positive to the clinic for confirmation and follow up.  Once a month TBAs came to the clinic for encouragement and to provide data on tests performed.  Once a quarter, the clinic visited the TBAs to provide supervision, mentoring and quality improvement training.  The TBAs were also paid $2 for every pregnant woman whom they tested for HIV, in order to compensate them for any loss of earnings from pregnant women living with HIV who would now be seen in the clinic rather than delivering at home. 

The authors used a quasi-experimental design for this study. Out of the 74 PEPFAR supported PHC clinics that provided HIV services in their antenatal clinics in Ebonyi state of Nigeria, 34 were interested in this new integrated approach, whereas 40 expressed no interest.  20 clinics were chosen at random from each of these categories, to avoid additional selection bias.  (Although as the authors state, there may already be considerable differences between the clinics that were interested and clinics that were not).  Comparisons were made before and after the programme was put in place, and also between clinics in the intervention group and those in the group that had not been interested to integrate services with the TBAs.

Despite this non-randomized design, the results are quite striking with more than twice as many women receiving HIV testing in the intervention clinics in the six months after the intervention began (going up from 2501 to 5346 across the 20 clinics).  There was no such increase in the non-intervention areas (which saw a change from 1770 to 1892 across the 20 clinics).  Furthermore the large majority of the increase was among women who had been tested by the TBAs. 

While this is hugely encouraging and a big increase, it will be important to see if the increase can be sustained as it is a significant change in the way that the TBAs and the PHC clinic staff work.  It is also not clear how much the increase is a result of the integration model and how much it relates to the additional payment that TBAs receive, which seems to amount to around $100 per TBA over the 6 month period of the assessment.

A thorough review of the role of trained lay providers in performing HIV tests was carried out as part of the WHO process that led to the guidance in 2015 that “Lay providers who are trained and supervised to use rapid diagnostic tests (RDTs) can independently conduct safe and effective HIV testing services.” Kennedy and colleagues now present the details of that systematic review.

Many national policies, particularly in African countries allow for HIV testing by trained lay providers using rapid diagnostic tests (RDTs) and even more allow lay providers to perform pre- and post-test counselling (around 80% of African countries in one survey of policies).  However, some countries limit these roles to trained healthcare providers due to concerns about lay providers’ ability to perform the tests accurately and reliably and to deliver high quality pre- and post-test counselling, linkage to appropriate prevention and clinical care services, and coordination with laboratory services to ensure the delivery of correct test results.

Despite widespread use of lay providers, there are actually rather few studies that directly compare the outcomes of testing between lay and professional providers.  The authors reviewed over 6000 titles, abstracts or full articles and found only five that allowed a direct comparison, while an additional six studies allowed the values and preferences of clients and providers to be assessed.

While this evidence base is very limited, findings from the single randomized trial (in the US) and one observational study (in Malawi), that compared pre- and post-intervention time periods, suggest that using trained lay providers can increase HIV testing uptake.  Three studies compared the quality of testing between lay providers and professional providers and found that both can achieve similar testing quality. Unfortunately, no studies measured adverse events following testing, nor linkage to care. The six values and preferences studies, also found support for lay providers.

This is the key evidence that underpins the strong recommendation from WHO and now also from many national authorities, that trained lay providers are an essential component in the efforts to scale up HIV testing in order to reach the first 90.

Increasing HIV testing among pregnant women in Nigeria: evaluating the traditional birth attendant and primary health center integration (TAP-In) model.

Chizoba AF, Pharr JR, Oodo G, Ezeobi E, Ilozumb J, Egharevba J, Ezeanolue EE, Nwandu A. AIDS Care. 2017 Apr 18:1-5. doi: 10.1080/09540121.2017.1317325. [Epub ahead of print]

Engaging Traditional Birth Attendants (TBAs) may be critical to preventing mother-to-child transmission of HIV (PMTCT) in Nigeria. We integrated TBAs into Primary Health Centers (PHCs) and provided the TBAs with HIV counseling and testing (HCT) training for PMTCT (TAP-In). The purpose of this study was to evaluate the impact of TAP-In on HCT uptake among pregnant women. A quasi-experimental design was used for this study. Twenty PHCs were assigned to the intervention group that integrated TAP-In and 20 were assigned to the control group. Data were collected six months prior to the initiation of TAP-In and six months post, using antenatal clinic registries. Intervention PHCs more than doubled the number of pregnant women who received HCT in their catchment area post TAP-In while control PHCs had no significant change. After initiating TAP-In, intervention PHCs provided almost three times more HCT than the control PHCs (p < 0.01) with TBA provided over half of the HCT post TAP-In. The TAP-In model was effective for increasing HCT among pregnant women.

Abstract access 

Should trained lay providers perform HIV testing? A systematic review to inform World Health Organization guidelines.

Kennedy CE, Yeh PT, Johnson C, Baggaley R. AIDS Care. 2017 Apr 24:1-7. doi:10.1080/09540121.2017.1317710. [Epub ahead of print.]

New strategies for HIV testing services (HTS) are needed to achieve UN 90-90-90 targets, including diagnosis of 90% of people living with HIV. Task-sharing HTS to trained lay providers may alleviate health worker shortages and better reach target groups. We conducted a systematic review of studies evaluating HTS by lay providers using rapid diagnostic tests (RDTs). Peer-reviewed articles were included if they compared HTS using RDTs performed by trained lay providers to HTS by health professionals, or to no intervention. We also reviewed data on end-users' values and preferences around lay providers preforming HTS. Searching was conducted through 10 online databases, reviewing reference lists, and contacting experts. Screening and data abstraction were conducted in duplicate using systematic methods. Of 6113 unique citations identified, 5 studies were included in the effectiveness review and 6 in the values and preferences review. One US-based randomized trial found patients' uptake of HTS doubled with lay providers (57% vs. 27%, percent difference: 30, 95% confidence interval: 27-32, p < 0.001). In Malawi, a pre/post study showed increases in HTS sites and tests after delegation to lay providers. Studies from Cambodia, Malawi, and South Africa comparing testing quality between lay providers and laboratory staff found little discordance and high sensitivity and specificity (≥98%). Values and preferences studies generally found support for lay providers conducting HTS, particularly in non-hypothetical scenarios. Based on evidence supporting using trained lay providers, a WHO expert panel recommended lay providers be allowed to conduct HTS using HIV RDTs. Uptake of this recommendation could expand HIV testing to more people globally.

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Africa, Asia
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Short and sweet? Do study participants prefer shorter or longer consent forms? Do they understand the contents?

Editor’s notes: As described above in the HOLA en Grupos study, engagement and partnership is vital if HIV research is to produce useful and relevant results.  The ethics of research involving human subjects continues to evolve but the key principles laid out by Beauchamp and Childress in 1989 remain central.  The principles of autonomy, non-maleficence, beneficence, and justice, have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care.

Autonomy implies that research participants should be able to consent willingly to join a research study and a key part of that informed consent process is usually a written “consent form” that is signed by the participant.  However, a major challenge is often to ensure that on the one hand all relevant information about possible benefits and harms is included in the information and on the other hand that the consent process is manageable and appropriate for the participant.

In the largest study of its kind to date, Grady and colleagues embedded a randomized trial within the larger randomized START trial (comparing immediate with deferred start of antiretroviral medicines in people with early HIV infection).  Around 4000 participants in START were allocated according to their 154 research sites, which were randomly assigned to the original, lengthy and somewhat complicated consent form, or to a simplified, shorter consent form with much more attention paid to ease of comprehension and readability.  The shorter form was still around 1800 words long (compared to the almost 6000 of the original) and was only a little easier to read, because the sponsors of the study needed to be certain that all the information demanded by current guidelines was included.

Surprisingly, there was no overall difference in either the primary outcome (an understanding that participants’ treatment would be randomly allocated) or in overall comprehension of aspects of the study.  In other words, the authors did NOT find the advantages that they were expecting from the modified consent form.

However, various clear trends emerge from the data that are relevant to future research too.  Those with less education were clearly less able to understand the randomization approach.  73% of the 1240 participants who had not attended high school compared to more than 90% of the 935 who had completed a university degree or postgraduate education answered the primary question on randomization correctly. The START study team were diligent in explaining the study to potential participants before presenting the informed consent form, with around a half of participants reporting more than an hour of explanation prior to being asked for consent, and more than 80% of sites reporting that participants understood the study “very well” prior to the consent process.  There was also a clear trend for participants from sites that had been involved in previous HIV research to understand the process better (rising from 69% in those with no previous HIV studies to 85% in those with more than 10).

Increasingly HIV prevention researchers are aiming to work with populations that have high ongoing incidence of HIV.  In a world where treatment is increasingly widespread and overall numbers of infections have fallen somewhat, this means that researchers will tend to be working with more and more disadvantaged populations where many participants may be less well educated and less familiar with research.  This important study makes it clear that the ethical principle of autonomy requires an ongoing process that goes far beyond the choice of words in a consent form.  Research must build trust between researchers and participants.  The research team should explain carefully and in appropriate ways what is involved in the study and what options participants have. Study teams should build a governance process into the research so that participants can have confidence that any risks of the research, both for them as individuals, but also often for the community or group to which they belong, are monitored and mitigated.  In this way potentially vulnerable individuals may still be recruited into important research projects and contribute to the ways in which science can end the epidemic.

A randomized trial comparing concise and standard consent forms in the START trial.

Grady C, Touloumi G, Walker AS, Smolskis M, Sharma S, Babiker AG, Pantazis N, Tavel J, Florence E, Sanchez A, Hudson F, Papadopoulos A, Emanuel E, Clewett M, Munroe D, Denning E; INSIGHT START Informed Consent substudy Group PLoS One. 2017 Apr 26;12(4):e0172607. doi: 10.1371/journal.pone.0172607. eCollection 2017.

Background: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed.

Methods: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin).

Results: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups.

Conclusions: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient.

Trial registration: Informed consent substudy was registered as part of START study in clinicaltrials.gov #NCT00867048, and EudraCT # 2008-006439-12.

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Infectious co-morbidities – why are people still dying of advanced HIV infections?

Editor’s notes: Tuberculosis remains the biggest reported killer of people living with HIV.  Studies from Guangxi, China and Nigeria examine risk factors for tuberculosis.  In the Chinese study, Cui Z and colleagues found almost one in six of 1019 people receiving care for HIV had active tuberculosis.  The risk factors that they found when comparing these 160 people with tuberculosis to matched controls living with HIV but without tuberculosis were well-known (low CD4 cell count, smoking and non-use of ART).  Long duration of HIV infection was also independently associated with developing tuberculosis, emphasising the need for tuberculosis specific measures in addition to ART.  The authors recommend standard approaches that need to be strengthened (active screening and case-finding with early initiation of ART; isoniazid preventive therapy and better infection control).  The most extraordinary statistic is how much higher the rate of tuberculosis is among this group of people receiving HIV care than it is among the general population of Guangxi.  173 times higher is pretty impressive!

The Pathmanathan I et al. study in Nigeria, carried out as part of a broader analysis of the outcomes of a nationally representative sample of people taking ART, is more optimistic.  The incidence rate for tuberculosis once people started on ART was 0.57 per 100 person years, which compares quite favourably with the estimated incidence for Nigeria from the WHO Global Tuberculosis 2016 report [link] of 0.32 per 100 person years.  Furthermore, most of the incident tuberculosis occurred soon after starting ART and (as might be expected) was most common in people with low CD4 count; previous tuberculosis or suspected but not diagnosed tuberculosis on starting ART.  Once people’s CD4 count was above 200 cells per ml, the incidence rate was 0.29 per 100 person-years.  This is encouraging, as it suggests that a good ART programme could have a significant impact on the overall risk of tuberculosis.  The aim of collaborative tuberculosis and HIV programme efforts must be to find people living with HIV before they are so immunocompromised.  In this study, the average CD4 count at enrolment was less than 200 cells per ml and around 5% of people already had tuberculosis at that time.

Late HIV diagnosis was also the subject of a study from Jiangsu province in China.  Hu H and colleagues looked at the trends in HIV testing and presentation to care before the CD4 count fell below 350 cells per ml.  From 2011-2014 in cross-sectional annual community based surveys among around 2500 men who have sex with men (MSM), there was a modest decline in the proportion who had had an HIV test within the last 12 months from 60% to 53%, and late presentation remained stable around 40%.  We have to shift from this plateau and the authors point out that HIV self-tests seem highly acceptable to MSM in China and that social media and internet based advocacy might also help.

There is increasing interest in co-infections with hepatitis B and C viruses in people living with HIV.  Hepatitis B is widespread in many countries in sub-Saharan Africa with “horizontal” transmission occurring in childhood.  Vaccination is now included as part of some countries programmes on expanded immunisation.  Co-infection with HIV and Hepatitis B leads to more rapid progression of liver damage and to liver cancer. Seremba E and colleagues tested stored sera from people living with HIV in the Rakai community and found that around half had already been infected with hepatitis B (in line with the high prevalence of infection in children).  During the follow up samples from people who were hepatitis B negative, new infections with hepatitis B occurred in 39 individuals, giving an incidence rate of 1.2 per 100 person years.  While hepatitis B vaccine is recommended for people living with HIV who are not infected, this study shows that ART is also protective, particularly if it contains lamivudine or tenofovir.  So this may be an added benefit of the wider scale-up of ART.

Despite advance in ART, too many people still die with HIV-associated infections that are only seen at low CD4 cell counts.  An important example is cryptococcal meningitis, which causes an insidious onset of symptoms. By the time patients are seen at the hospital with severe headache and signs of raised intracranial pressure it is often too late to prevent them from dying. This is because the best medicines (liposomal amphotericin and flucytosine) are expensive and often not available.  So WHO recommends pre-emptive treatment for people who are first seen at the health service with CD4 counts less than 100 cells per ml and with cryptococcal antigen (CRAG) detectable in the blood.  A modelling study by Ramachandran A et al. from Uganda and the US considered the likely costs and benefits of using a new lateral flow assay for CRAG for people living with HIV with a low CD4 count, with pre-emptive treatment with fluconazole for people found to be CRAG-positive. The results, including various sensitivity tests, are strongly in favour of widespread implementation of this strategy. The authors calculate that it would cost Uganda around US$650 000 per year and would avert more than a thousand deaths.  Like the tuberculosis discussions above, the real aim is to prevent people living with HIV reaching the stage where “old-fashioned” opportunistic infections can cause such misery.  However in the medium term, we are likely to continue to see many people presenting late in the course of their infections, and CRAG (and tuberculosis) screening and management are key ways to prevent mortality.

Risk factors associated with Tuberculosis (TB) among people living with HIV/AIDS: A pair-matched case-control study in Guangxi, China.

Cui Z, Lin M, Nie S, Lan R. PLoS One. 2017 Mar 30;12(3):e0173976. doi:10.1371/journal.pone.0173976.eCollection 2017.

Background: As one of the poorest provinces in China, Guangxi has a high HIV and TB prevalence, with the annual number of TB/HIV cases reported by health department among the highest in the country. However, studies on the burden of TB-HIV co-infection and risk factors for active TB among HIV-infected persons in Guangxi have rarely been reported.

Objective: To investigate the risk factors for active TB among people living with HIV/AIDS in Guangxi Zhuang autonomous region, China.

Methods: A surveillance survey was conducted of 1019 HIV-infected patients receiving care at three AIDS prevention and control departments between 2013 and 2015. We investigated the cumulative prevalence of TB during 2 years. To analyze risk factors associated with active TB, we conducted a 1:1 pair-matched case-control study of newly reported active TB/HIV co-infected patients. Controls were patients with HIV without active TB, latent TB infection or other lung disease, who were matched with the case group based on sex and age (± 3 years).

Results: A total of 1019 subjects were evaluated. 160 subjects (15.70%) were diagnosed with active TB, including 85 clinically diagnosed cases and 75 confirmed cases. We performed a 1:1 matched case-control study, with 82 TB/HIV patients and 82 people living with HIV/AIDS based on surveillance site, sex and age (±3) years. According to multivariate analysis, smoking (OR = 2.996, 0.992-9.053), lower CD4+ T-cell count (OR = 3.288, 1.161-9.311), long duration of HIV-infection (OR = 5.946, 2.221-15.915) and non-use of ART (OR = 7.775, 2.618-23.094) were independent risk factors for TB in people living with HIV/AIDS.

Conclusion: The prevalence of active TB among people living with HIV/AIDS in Guangxi was 173 times higher than general population in Guangxi. It is necessary for government to integrate control planning and resources for the two diseases. Medical and public health workers should strengthen health education for TB/HIV prevention and treatment and promote smoking cessation. Active TB case finding and early initiation of ART is necessary to minimize the burden of disease among patients with HIV, as is IPT and infection control in healthcare facilities.

Abstract  Full-text [free] access

Incidence and predictors of tuberculosis among HIV-infected adults after initiation of antiretroviral therapy in Nigeria, 2004-2012.

Pathmanathan I, Dokubo EK, Shiraishi RW, Agolory SG, Auld AF, Onotu D, Odafe S, Dalhatu I, Abiri O, Debem HC, Bashorun A, Ellerbrock T. PLoS One. 2017 Mar 10;12(3):e0173309. doi: 10.1371/journal.pone.0173309.eCollection 2017.

Background: Nigeria had the most AIDS-related deaths worldwide in 2014 (170 000), and 46% were associated with tuberculosis (TB). Although treatment of people living with HIV (PLHIV) with antiretroviral therapy (ART) reduces TB-associated morbidity and mortality, incident TB can occur while on ART. We estimated incidence and characterized factors associated with TB after ART initiation in Nigeria.

Methods: We analyzed retrospective cohort data from a nationally representative sample of adult patients on ART. Data were abstracted from 3496 patient records, and analyses were weighted and controlled for a complex survey design. We performed domain analyses on patients without documented TB disease and used a Cox proportional hazard model to assess factors associated with TB incidence after ART.

Results: At ART initiation, 3350 patients (95.8%) were not receiving TB treatment. TB incidence after ART initiation was 0.57 per 100 person-years, and significantly higher for patients with CD4<50/μL (adjusted hazard ratio [AHR]:4.2, 95% confidence interval [CI]: 1.4-12.7) compared with CD4≥200/μL. Patients with suspected but untreated TB at ART initiation and those with a history of prior TB were more likely to develop incident TB (AHR: 12.2, 95% CI: 4.5-33.5 and AHR: 17.6, 95% CI: 3.5-87.9, respectively).

Conclusion: Incidence of TB among PLHIV after ART initiation was low, and predicted by advanced HIV, prior TB, and suspected but untreated TB. Study results suggest a need for improved TB screening and diagnosis, particularly among high-risk PLHIV initiating ART, and reinforce the benefit of early ART and other TB prevention efforts.

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Trends in late HIV diagnosis among men who have sex with men in Jiangsu province, China: Results from four consecutive community-based surveys, 2011-2014.

Hu H, Yan H, Liu X, Xu X, Xu J, Qiu T, Shi LE, Fu G, HuanX, McFarland W, Wei C). PLoS One. 2017 Mar 9;12(3):e0172664. doi:10.1371/journal.pone.0172664.eCollection 2017.

Objectives: To examine trends in HIV testing, late HIV diagnosis and associated factors among men who have sex with men (MSM) in Jiangsu province, China.

Methods: Four consecutive community-based cross-sectional surveys were conducted among MSM from 2011 to 2014 in eight cities in the province. Participants were recruited from MSM venues and via the internet. HIV bio-behavioral surveys were conducted to collect demographic and behavioral data and measure HIV infection. HIV-infected participants with CD4 counts less than 350 cells/µL were defined as having a late HIV diagnosis. Chi-square trend tests were used to compare temporal changes over the years and multivariable logistic regression analyses were used to identify factors associated with late diagnosis.

Results: A total of 2441, 2677, 2591 and 2610 participants were enrolled in 2011, 2012, 2013 and 2014, respectively. Testing for HIV in the last 12 months decreased over the time period, from 59.9% to 52.5% (p<0.001). Late HIV diagnosis remained high and steady, ranging from 33.3% to 44.2% over the years with no significant change over time (p = 0.418). MSM who were older than 24 years (aOR =1.748, p = 0.020 for 25-39 years old; aOR = 3.148, p<0.001 for 40 years old or older), were recruited via internet (aOR = 1.596, p = 0.024), and did not have an HIV test in the past 12 months (aOR = 3.385, p<0.001) were more likely to be late diagnosed.

Conclusions: Our study showed a plateau in HIV testing among MSM in China, in parallel to high levels of late diagnosis. Emerging and innovative strategies such as HIV self-testing and reaching more MSM by internet, both highly acceptable to MSM in China, may reduce late diagnosis.

Abstract  Full-text [free] access 

Hepatitis B incidence and prevention with antiretroviral therapy among HIV-positive individuals in Uganda.

Seremba E, Ssempijja V, Kalibbala S, Gray RH, Wawer MJ, Nalugoda F, Casper C, Phipps W, Ocama P, Serwadda D, Thomas DL, Reynolds SJ. 123. AIDS. 2017 Mar 27;31(6):781-786. doi: 10.1097/QAD.0000000000001399.

Objective: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda.

Methods: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs).

Results: Thirty-nine HBV infections occurred over 3342 person-years, incidence1.17/100 person-years. HBV incidence was significantly lower with ART use: 0.49/100 person-years with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1-0.5, P < 0.001], and with lamivudine (3TC) use: (0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI0.1-0.7, P =  < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2-19.0, P < 0.001); and with age: 15-29 years versus 40-50 years (aHR 3.2, 95% CI 1.2-9.0); 30-39 years versus 40-50 years (aHR 2.1, 95% CI 0.9-5.3).

Conclusion: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa.

Abstract access 

Cost-effectiveness of CRAG-LFA screening for cryptococcal meningitis among people living with HIV in Uganda.

Ramachandran A(1), Manabe Y(1,)(2), Rajasingham R(3), Shah M(4).141. BMC Infect Dis. 2017 Mar 23;17(1):225. doi: 10.1186/s12879-017-2325-9.

Background: Cryptococcal meningitis (CM) constitutes a significant source of mortality in resource-limited regions. Cryptococcal antigen (CRAG) can be detected in the blood before onset of meningitis. We sought to determine the cost-effectiveness of implementing CRAG screening using the recently developed CRAG lateral flow assay in Uganda compared to current practice without screening.

Methods: A decision-analytic model was constructed to compare two strategies for cryptococcal prevention among people living with HIV with CD4 < 100 in Uganda: No cryptococcal screening vs. CRAG screening with WHO-recommended preemptive treatment for CRAG-positive patients. The model was constructed to reflect primary HIV clinics in Uganda, with a cohort of HIV-infected patients withCD4 < 100 cells/µL. Primary outcomes were expected costs, DALYs, and incremental cost-effectiveness ratios (ICERs). We evaluated varying levels of programmatic implementation in secondary analysis.

Results: CRAG screening was considered highly cost-effective and was associated with an ICER of $6.14 per DALY averted compared to no screening (95% uncertainty range: $-20.32 to $36.47). Overall, implementation of CRAG screening was projected to cost $1.52 more per person, and was projected to result in a 40% relative reduction in cryptococcal-associated mortality. In probabilistic sensitivity analysis, CRAG screening was cost-effective in 100% of scenarios and cost saving (ie cheaper and more effective than no screening) in 30% of scenarios. Secondary analysis projected a total cost of $651 454 for 100%implementation of screening nationally, while averting 1228 deaths compared to no screening.

Conclusion: CRAG screening for PLWH with low CD4 represents excellent value for money with the potential to prevent cryptococcal morbidity and mortality in Uganda.

Abstract  Full-text [free] access

Africa, Asia
China, Nigeria, Uganda
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Peer support: not a panacea for poor adherence

Use of peers to improve adherence to antiretroviral therapy: a global network meta-analysis.

Kanters S, Park JJ, Chan K, Ford N, Forrest J, Thorlund K, Nachega JB, Mills EJ. J Int AIDS Soc. 2016 Nov 30;19(1):21141. doi: 10.7448/IAS.19.1.21141. eCollection 2016.

Introduction: It is unclear whether using peers can improve adherence to antiretroviral therapy (ART). To construct the World Health Organization's global guidance on adherence interventions, we conducted a systematic review and network meta-analysis to determine the effectiveness of using peers for achieving adequate adherence and viral suppression.

Methods: We searched for randomized clinical trials of peer-based interventions to promote adherence to ART in HIV populations. We searched six electronic databases from inception to July 2015 and major conference abstracts within the last three years. We examined the outcomes of adherence and viral suppression among trials done worldwide and those specific to low- and middle-income countries (LMIC) using pairwise and network meta-analyses.

Results and discussion: Twenty-two trials met the inclusion criteria. We found similar results between pairwise and network meta-analyses, and between the global and LMIC settings. Peer supporter+Telephone was superior in improving adherence than standard-of-care in both the global network (odds-ratio [OR]=4.79, 95% credible intervals [CrI]: 1.02, 23.57) and the LMIC settings (OR=4.83, 95% CrI: 1.88, 13.55). Peer support alone, however, did not lead to improvement in ART adherence in both settings. For viral suppression, we found no difference of effects among interventions due to limited trials.

Conclusions: Our analysis showed that peer support leads to modest improvement in adherence. These modest effects may be due to the fact that in many settings, particularly in LMICs, programmes already include peer supporters, adherence clubs and family disclosures for treatment support. Rather than introducing new interventions, a focus on improving the quality in the delivery of existing services may be a more practical and effective way to improve adherence to ART.

Abstract  Full-text [free] access 

Editor’s notes: Sustained adherence to antiretroviral therapy (ART) is critical to ensure successful treatment outcomes and prevent drug resistance, AIDS-associated illness, death and onward transmission of HIV infection. In recent years, there has been much enthusiasm for use of peer support as a programme to improve adherence. Most high HIV prevalence settings have limited resources. Stigma influences adherence to treatment, and peer-based support may be a practical solution both in terms of being low cost and a mechanism for addressing stigma.

In this systematic review, the authors evaluated the effectiveness of peer-supporter programmes alone or in combination with other activities, namely telephone calls, device reminders or cognitive behavioural therapy (CBT), globally and in low and middle-income countries (LMIC). The systematic review findings were used to inform the 2015 World Health Organization HIV treatment guidelines.

The study demonstrates that peer support alone did not have any impact on adherence or on viral suppression. It did demonstrate modest improvements on adherence when combined with telephone activities. Several factors need to be considered in interpreting these findings. Firstly, adherence was assessed using a variety of methods including pill counts and the Medication Event Monitoring System (MEMS), which may have introduced heterogeneity. Secondly, few trials (particularly in LMICs) used HIV viral load as an outcome and therefore there may not have been adequate statistical power to detect an effect. Thirdly, populations included in the review were heterogeneous e.g. ART-naïve and experienced, people who inject drugs, non-adherent individuals. Notably, only one trial included children and adolescents among whom adherence is typically poorer. 

Importantly, in many settings particularly in LMICs, programmes already include treatment supporters and adherence clubs and therefore additional peer support would likely not add additional impact. The findings of this study suggest that programmes should focus on improving the quality of existing services rather than introduce new programmes. The review also highlights the need to standardise adherence measures and the need for robust research on adherence, particularly among children.         

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Thymidine analogue mutations associated with extensive resistance in African people failing on tenofovir

Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub-Saharan Africa: a retrospective multi-centre cohort study.

Gregson J, Kaleebu P, Marconi VC, van Vuuren C, Ndembi N, Hamers RL, Kanki P, Hoffmann CJ, Lockman S, Pillay D, de Oliveira T, Clumeck N, Hunt G, Kerschberger B, Shafer RW, Yang C, Raizes E, Kantor R, Gupta RK. Lancet Infect Dis. 2016 Nov 30. pii: S1473-3099(16)30469-8. doi: 10.1016/S1473-3099(16)30469-8. [Epub ahead of print]

Background: HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART.

Methods: We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs.

Findings: Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60.5 cells per µL [IQR 21.0-128.0] in patients with TAMS vs 95.0 cells per µL [37.0-177.0] in patients without TAMs; p=0.007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0.0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0.0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0.0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0.64 (p<0.0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1.29 (1.13-1.47; p<0.0001)

Interpretation: TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains.

Abstract  Full-text [free] access 

Editor’s notes: Since 2012, WHO has recommended that tenofovir should be included in first-line antiretroviral therapy, in place of the thymidine analogues, zidovudine and stavudine, which have more significant adverse effects. When therapy fails to maintain virologic control, tenofovir is associated with characteristic resistance mutations that are different from the thymidine analogue mutations (TAMs) associated with the older drugs. This study looked at the resistance patterns of people in Africa with virologic failure after starting on WHO recommended first-line combination including tenofovir and a non-nucleoside reverse transcriptase inhibitor (NNRTI).  TAMs were surprisingly common (16%) for a group who were not known to have received thymidine analogues. This is not what would be expected from this drug combination. The implication is that TAMs may have been present before tenofovir-containing treatment was started, possibly because of undeclared previous therapy. It is well known that TAMs make subsequent therapy with an NNRTI and nucleoside analogues very much more likely to fail. The presence of TAMs was associated with more extensive resistance to other drugs including lamivudine and NNRTIs, some of which may also have been present before the tenofovir based treatment.

Only people with treatment failure were studied. The total number entering into treatment is not recorded. However, based on other reports in Africa the authors speculate a failure rate of 15 to 35% and that they may therefore have found TAMs in two to six percent of people who started treatment. That seems a realistic figure for undeclared prior treatment and gives some perspective to the scale of this problem.

There is continuing concern about drug resistance in low- and middle-income countries.  As the thymidine analogues are phased out, people receiving them may be switched to tenofovir. In situations where there is no access to viral load monitoring, some people will have unrecognised virologic failure and may have developed resistance including TAMs. They are then likely to fail on tenofovir with additional resistance. Realistic strategies are necessary for the prompt detection of treatment failure.

Africa
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Creating welcoming spaces for men’s active involvement

What do you need to get male partners of pregnant women tested for HIV in resource limited settings? The baby shower cluster randomized trial.

Ezeanolue EE, Obiefune MC, Yang W, Ezeanolue CO, Pharr J, Osuji A, Ogidi AG, Hunt AT, Patel D, Ogedegbe G, Ehiri JE. AIDS Behav. 2016 Dec 8. [Epub ahead of print]

Male partner involvement has the potential to increase uptake of interventions to prevent mother-to-child transmission of HIV (PMTCT). Finding cultural appropriate strategies to promote male partner involvement in PMTCT programs remains an abiding public health challenge. We assessed whether a congregation-based intervention, the Healthy Beginning Initiative (HBI), would lead to increased uptake of HIV testing among male partners of pregnant women during pregnancy. A cluster-randomized controlled trial of forty churches in Southeastern Nigeria randomly assigned to either the HBI (intervention group; IG) or standard of care referral to a health facility (control group; CG) was conducted. Participants in the IG received education and were offered onsite HIV testing. Overall, 2498 male partners enrolled and participated, a participation rate of 88.9%. Results showed that male partners in the IG were 12 times more likely to have had an HIV test compared to male partners of pregnant women in the CG (CG = 37.71% vs. IG = 84.00%; adjusted odds ratio = 11.9; p < .01). Culturally appropriate and community-based interventions can be effective in increasing HIV testing and counseling among male partners of pregnant women.

Abstract  Full-text [free] access

Editor’s notes: Barriers to male partner participation in antenatal care in sub-Saharan Africa include the timing of antenatal services during work hours and negative health care provider attitudes. Importantly, they also include gender norms against male participation that are anchored in deep-seated perceptions that pregnancy is a woman’s affair. This highly successful trial resulted in verified HIV testing by 84% of male partners in the programme group and 38% in the control group, well above the overall HIV testing uptake by males in Nigeria at the time of 23%. What were the elements of the programme that contributed to its success? Critically, it was conducted in communities where religious institutions and their leaders have strong community influence and where nearly 90% of the population attends places of worship. Next, it proposed integrated testing (haemoglobin, malaria, sickle cell genotype, HIV, hepatitis B, and syphilis) to reduce stigma associated with HIV testing. It included the haemoglobin test because men indicated in the formative stages that they wanted this test to find out how strong they were. Then, it engaged the couples publically, with the religious leader inviting all pregnant women and their partners each Sunday to approach the altar for a prayer, accompanied by information about the baby shower programme and the importance of antenatal care. The programme ran baby showers monthly for all participants with the programme group playing an educational game and being offered free integrated HIV testing. The control group was referred to a local health facility for antenatal care and free HIV testing. At baby receptions held every two to three months, the control groups were offered free integrated HIV testing. All in all, HIV testing for male partners was convenient, free, and integrated with other tests that men wanted. It was provided in a family-centred, congregation-based enabling environment that supported men to step forward with their pregnant partners to learn their HIV status. Such a strategy could work in other settings where influential community leaders are prepared to lead the design and implementation of innovative HIV prevention programmes that resonate with community cultural and spiritual values.

Africa
Nigeria
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