Articles tagged as "Zimbabwe"

Late antiretroviral therapy start persists for children under two years of age in low- and middle-income countries

Immunodeficiency in children starting antiretroviral therapy in low-, middle-, and high-income countries.

Koller M, Patel K, Chi BH, Wools-Kaloustian K, Dicko F, Chokephaibulkit K, Chimbetete C, Avila D, Hazra R, Ayaya S, Leroy V, Truong HK, Egger M, Davies MA, IeDEA, NISDI, PHACS and IMPAACT 219C studies.  J Acquir Immune Defic Syndr. 2015 Jan 1;68(1):62-72. doi: 10.1097/QAI.0000000000000380.

Background: The CD4 cell count or percent (CD4%) at the start of combination antiretroviral therapy (cART) is an important prognostic factor in children starting therapy and an important indicator of program performance. We describe trends and determinants of CD4 measures at cART initiation in children from low-, middle-, and high-income countries.

Methods: We included children aged <16 years from clinics participating in a collaborative study spanning sub-Saharan Africa, Asia, Latin America, and the United States. Missing CD4 values at cART start were estimated through multiple imputation. Severe immunodeficiency was defined according to World Health Organization criteria. Analyses used generalized additive mixed models adjusted for age, country, and calendar year.

Results: A total of 34 706 children from 9 low-income, 6 lower middle-income, 4 upper middle-income countries, and 1 high-income country (United States) were included; 20 624 children (59%) had severe immunodeficiency. In low-income countries, the estimated prevalence of children starting cART with severe immunodeficiency declined from 76% in 2004 to 63% in 2010. Corresponding figures for lower middle-income countries were from 77% to 66% and for upper middle-income countries from 75% to 58%. In the United States, the percentage decreased from 42% to 19% during the period 1996 to 2006. In low- and middle-income countries, infants and children aged 12-15 years had the highest prevalence of severe immunodeficiency at cART initiation.

Conclusions: Despite progress in most low- and middle-income countries, many children continue to start cART with severe immunodeficiency. Early diagnosis and treatment of HIV-infected children to prevent morbidity and mortality associated with immunodeficiency must remain a global public health priority.

Abstract access 

Editor’s notes: This article describes trends and determinants of CD4 cell measures at antiretroviral therapy (ART) initiation in about 35 000 children in low, middle, and high-income countries. Temporal trends in CD4 measures at ART initiation are a useful indicator of the health system’s ability to identify and treat eligible children in a timely fashion. They are also a useful measure of responsiveness to guideline changes.

Previous WHO guidelines recommended early ART initiation, regardless of immunologic or clinical thresholds. But the authors found that in 2010, approximately two-thirds of children below two years of age, in low- and middle-income countries were still starting ART with severe immunodeficiency.

Delayed country-level implementation of WHO guidelines, poor access to early infant diagnosis, slow turn-around time of test results, and limited ART availability for infants and young children are all contributing factors to this delayed ART initiation. The authors point out that timely diagnosis of paediatric HIV does not necessarily result in timely ART. The main reasons for this diagnosis to treatment gap include HIV diagnostic tests and paediatric ART being located at separate sites without robust referral mechanisms between services. There are challenges with CD4 measurement to determine eligibility. These include access to tests, turn-around time and interpretation of results and health care worker discomfort with treating children.

Currently, only 22% of children living with HIV in sub-Saharan Africa are receiving ART. To decrease the treatment gap among children, WHO 2013 guidelines recommend universal ART for all children living with HIV, aged below five years of age, irrespective of CD4 count or clinical stage. Removing the requirement for a CD4 measurement also removes the time lag while waiting for CD4 results. Thus the guidelines aim both to increase treatment accessibility and to accelerate treatment initiation for all children. 

HIV Treatment
Africa, Asia, Northern America
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Negotiating the price for safe sex: A study among rural sex workers in Zimbabwe

The price of sex: condom use and the determinants of the price of sex among female sex workers in eastern Zimbabwe.

Elmes J, Nhongo K, Ward H, Hallett T, Nyamukapa C, White PJ, Gregson S. J Infect Dis. 2014 Dec 1;210 Suppl 2:S569-78. doi: 10.1093/infdis/jiu493.

Background: Higher prices for unprotected sex threaten the high levels of condom use that contributed to the decline in Zimbabwe's human immunodeficiency virus (HIV) epidemic. To improve understanding of financial pressures competing against safer sex, we explore factors associated with the price of commercial sex in rural eastern Zimbabwe.

Methods: We collected and analyzed cross-sectional data on 311 women, recruited during October-December 2010, who reported that they received payment for their most-recent or second-most-recent sex acts in the past year. Zero-inflated negative binomial models with robust standard errors clustered on female sex worker (FSW) were used to explore social and behavioral determinants of price.

Results: The median price of sex was $10 (interquartile range [IQR], $5-$20) per night and $10 (IQR, $5-$15) per act. Amounts paid in cash and commodities did not differ significantly. At the most-recent sex act, more-educated FSWs received 30%-74% higher payments. Client requests for condom use significantly predicted protected sex (P < .01), but clients paid on average 42.9% more for unprotected sex.

Conclusions: Within a work environment where clients' preferences determine condom use, FSWs effectively use their individual capital to negotiate the terms of condom use. Strengthening FSWs' preferences for protected sex could help maintain high levels of condom use.

Abstract  Full-text [free] access

Editor’s notes: This study addresses a relatively neglected issue of how payments for commercial sex among rural sex workers are determined, and which factors are important to price negotiations. In this study from Zimbabwe, the participants were grouped into “more professional”, both the last two clients were commercial, (FSW2) and “less professional”, one of the last two clients was commercial (FSW1). The “more professional” sex workers effectively negotiated transactions, with unprotected sex increasing the mean payment by almost a half, compared with protected sex. This differential pricing was not seen for the “less professional” sex workers, perhaps reflecting limited capacity to negotiate with clients. This study demonstrates the importance of strengthening preferences for protected sex, among female sex workers, including among less visible sex workers. Such strategies may include enhancing social capital and collective action, e.g. collective price-fixing to reduce competitive pressure to engage in unsafe sex. 

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Associations between HIV and intimate partner violence in ten African countries

Intimate partner violence and HIV in ten sub-Saharan African countries: what do the Demographic and Health Surveys tell us?

Durevall D, Lindskog A. Lancet Glob Health. 2015 Jan;3(1):e34-43. doi: 10.1016/S2214-109X(14)70343-2. Epub 2014 Nov 21.

Background: Many studies have identified a significant positive relation between intimate partner violence and HIV in women, but adjusted analyses have produced inconsistent results. We systematically assessed the association, and under what condition it holds, using nationally representative data from ten sub-Saharan African countries, focusing on physical, sexual, and emotional violence, and on the role of male controlling behaviour.

Methods: We assessed cross-sectional data from 12 Demographic and Health Surveys from ten countries in sub-Saharan Africa. The data are nationally representative for women aged 15-49 years. We estimated odds ratios using logistic regression with and without controls for demographic and socioeconomic factors and survey-region fixed effects. Exposure was measured using physical, sexual, emotional violence, and male controlling behaviour, and combinations of these. The samples used were ever-married women, married women, and women in their first union. Depending on specification, the sample size varied between 11 231 and 45 550 women.

Findings: There were consistent and strong associations between HIV infection in women and physical violence, emotional violence, and male controlling behaviour (adjusted odds ratios ranged from 1.2 to 1.7; p values ranged from <0.0001 to 0.0058). The evidence for an association between sexual violence and HIV was weaker and only significant in the sample with women in their first union. The associations were dependent on the presence of controlling behaviour and a high regional HIV prevalence rate; when women were exposed to only physical, sexual, or emotional violence, and no controlling behaviour, or when HIV prevalence rates are lower than 5%, the adjusted odds ratios were, in general, close to 1 and insignificant.

Interpretation: The findings indicate that male controlling behaviour in its own right, or as an indicator of ongoing or severe violence, puts women at risk of HIV infection. HIV prevention interventions should focus on high-prevalence areas and men with controlling behaviour, in addition to violence.

Abstract  Full-text [free] access

Editor’s notes: Despite two cohort studies illustrating that exposures to intimate partner violence are associated with incident HIV infection, evidence from cross-sectional analysis of population data is more mixed. Using Demographic and Health Surveys data for women aged 15-49 years from 10 sub-Saharan countries, this paper illustrates that HIV infection is strongly associated with physical violence and/or emotional violence and controlling behaviour, with a weaker association with sexual violence. For all forms of violence, the association was strongest among women who also reported that their partner was controlling, and in settings where HIV prevalence exceeds five percent. This study adds to the growing literature on HIV and intimate partner violence that suggests that risk is not only linked to forced sex, but rather to being in a violent and controlling relationship. The paper highlights the importance of male control as a risk factor for HIV, and supports the need for HIV prevention programmes that focus on reducing intimate partner violence in higher-prevalence settings.

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Increasing transmitted resistance to antiretroviral therapy in low/middle-income countries - highest prevalence in MSM

Global burden of transmitted HIV drug resistance and HIV-exposure categories: a systematic review and meta-analysis.

Pham QD, Wilson DP, Law MG, Kelleher AD, Zhang L. AIDS. 2014 Nov 28;28(18):2751-62. doi: 10.1097/QAD.0000000000000494.

Objectives: Our aim was to review the global disparities of transmitted HIV drug resistance (TDR) in antiretroviral-naive MSM, people who inject drugs (PWID) and heterosexual populations in both high-income and low/middle-income countries.

Design/methods: We undertook a systematic review of the peer-reviewed English literature on TDR (1999-2013). Random-effects meta-analyses were performed to pool TDR prevalence and compare the odds of TDR across at-risk groups.

Results: A total of 212 studies were included in this review. Areas with greatest TDR prevalence were North America (MSM: 13.7%, PWID: 9.1%, heterosexuals: 10.5%); followed by western Europe (MSM: 11.0%, PWID: 5.7%, heterosexuals: 6.9%) and South America (MSM: 8.3%, PWID: 13.5%, heterosexuals: 7.5%). Our data indicated disproportionately high TDR burdens in MSM in Oceania (Australia 15.5%), eastern Europe/central Asia (10.2%) and east Asia (7.8%). TDR epidemics have stabilized in high-income countries, with a higher prevalence (range 10.9-12.6%) in MSM than in PWID (5.2-8.3%) and heterosexuals (6.4-9.0%) over 1999-2013. In low/middle-income countries, TDR prevalence in all at-risk groups in 2009-2013 almost doubled than that in 2004-2008 (MSM: 7.8 vs. 4.2%, P = 0.011; heterosexuals: 4.1 vs. 2.6%, P < 0.001; PWID: 4.8 vs. 2.4%, P = 0.265, respectively). The risk of TDR infection was significantly greater in MSM than that in heterosexuals and PWID. We observed increasing trends of resistance to non-nucleoside reverse transcriptase and protease inhibitors among MSM.

Conclusion: TDR prevalence is stabilizing in high-income countries, but increasing in low/middle-income countries. This is likely due to the low, but increasing, coverage of antiretroviral therapy in these settings. Transmission of TDR is most prevalent among MSM worldwide.

Abstract access 

Editor’s notes: HIV mutates very rapidly, and many early antiretroviral agents had a low genetic barrier to the development of resistance. Thus the emergence of virus resistant to antiretroviral agents, particularly to early drug classes, was inevitable. Surveillance for drug-resistant virus among people with no prior history of taking antiretroviral drugs (transmitted drug resistance) is essential to monitor the spread of drug resistance at population level.

This systematic review aimed to compare transmitted drug resistance in different geographical regions and between subpopulations of HIV-positive people by likely route of transmission. Transmitted resistance was most prevalent in high income settings. This is not surprising given wide use of suboptimal drug regimens before effective triple therapy was available. Reassuringly, the prevalence of transmitted resistance seems to have stabilised in high-income settings. The increase in transmitted resistance in low and middle income countries is of more concern. It is not surprising, given that first-line regimens comprising two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor are vulnerable to the development of resistance if the drug supply is interrupted or adherence is suboptimal. In addition, if viral load monitoring is not available, people remain on failing drug regimens for longer, and thus have more risk of transmitting resistant virus.

Within the subpopulations examined in this review, transmitted resistance was consistently higher in men who have sex with men, suggesting that resistance testing prior to treatment is particularly valuable for this population.

Limitations of the review include exclusion of studies that did not compare transmitted resistance between the specified subpopulations, and small sample size in many subgroups.

Continued surveillance for transmitted drug resistance is critical. This is most important in settings where individualised resistance testing is not available. This will ensure that people starting antiretroviral therapy receive treatment that will suppress their viral load effectively. Wider use of viral load monitoring, combined with access to effective second and third line regimens, will also help limit spread of drug resistance.

HIV Treatment
Angola, Argentina, Australia, Austria, Belgium, Benin, Botswana, Brazil, Burkina Faso, Cambodia, Cameroon, Canada, Central African Republic, Chad, China, Côte d'Ivoire, Croatia, Cuba, Cyprus, Denmark, Dominican Republic, El Salvador, Estonia, Ethiopia, France, Gabon, Georgia, Germany, Greece, Guatemala, Honduras, Hong Kong Special Administrative Region of China, Hungary, India, Indonesia, Ireland, Israel, Italy, Japan, Kazakhstan, Kenya, Latvia, Malawi, Malaysia, Moldova, Mozambique, Netherlands, Peru, Philippines, Poland, Portugal, Republic of Korea, Romania, Russia, Rwanda, Slovenia, South Africa, Spain, Swaziland, Sweden, Switzerland, Taiwan, Thailand, Uganda, United Kingdom of Great Britain and Northern Ireland, United Republic of Tanzania, United States of America, Viet Nam, Zambia, Zimbabwe
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Which activities promote adherence to antiretroviral therapy?

Interventions to promote adherence to antiretroviral therapy in Africa: a network meta-analysis.

Mills EJ, Lester R, Thorlund K, Lorenzi M, Muldoon K, Kanters S, Linnemayr S, Gross R, Calderon Y, Amico KR, Thirumurthy H, Pearson C, Remien RH, Mbuagbaw L, Thabane L, Chung MH, Wilson IB, Liu A, Uthman OA, Simoni J, Bangsberg D, Yaya S, Bärnighausen T, Ford N, Nachega JB, Lancet HIV 2014; 1: e104–11 doi:10.1016/S2352-3018(14)00003-4.

Background: Adherence to antiretroviral therapy (ART) is necessary for the improvement of the health of patients and for public health. We sought to determine the comparative effectiveness of different interventions for improving ART adherence in HIV-infected people living in Africa.

Methods: We searched for randomised trials of interventions to promote antiretroviral adherence within adults in Africa. We searched AMED, CINAHL, Embase, Medline (via PubMed), and from inception to Oct 31, 2014, with the terms “HIV”, “ART”, “adherence”, and “Africa”. We created a network of the interventions by pooling the published and individual patients' data for comparable treatments and comparing them across the individual interventions with Bayesian network meta-analyses. The primary outcome was adherence defined as the proportion of patients meeting trial defined criteria; the secondary endpoint was viral suppression.

Findings: We obtained data for 14 randomised controlled trials, with 7110 patients. Interventions included daily and weekly short message service (SMS; text message) messaging, calendars, peer supporters, alarms, counselling, and basic and enhanced standard of care (SOC). Compared with SOC, we found distinguishable improvement in self-reported adherence with enhanced SOC (odds ratio [OR] 1·46, 95% credibility interval [CrI] 1·06–1·98), weekly SMS messages (1·65, 1·25–2·18), counselling and SMS combined (2·07, 1·22–3·53), and treatment supporters (1·83, 1·36–2·45). We found no compelling evidence for the remaining interventions.

Results: were similar when using viral suppression as an outcome, although the network contained less evidence than that for adherence. Treatment supporters with enhanced SOC (1·46, 1·09–1·97) and weekly SMS messages (1·55, 1·01–2·38) were significantly better than basic SOC.

Interpretation: Several recommendations for improving adherence are unsupported by the available evidence. These findings can inform future intervention choices for improving ART adherence in low-income settings.

Abstract access 

Editor’s notes: To maximise the impact of antiretroviral therapy (ART), people living with HIV should be diagnosed early, enrolled and retained in pre-ART care, initiated on ART and retained in ART care. Long-term adherence to achieve and maintain viral load suppression is the last step in the continuum of HIV care. Engagement along the complete treatment cascade will determine the long-term success of the global response to HIV.

A large number of potential programmes aimed at the improvement of engagement with care are available. While there is an urgent need for research on these programmes and on the effect of combined programmes, there is also the reality of a resource constrained environment. Network meta-analysis is a method to synthesise the evidence of programmes. The meta-analysis uses common comparators when these activities have not been compared head-to-head (resulting in indirect evidence), combined with evidence from head-to-head comparisons (direct evidence).

Using a network meta-analysis of randomized trials of programmes to improve ART adherence in Africa, the authors simultaneously compared eight groups of activities against standard care and against each other. The authors found that standard care augmented with intensified adherence counselling, or enhanced standard care, improved adherence to ART. Also weekly SMS messages, enhanced standard care combined with SMS, and enhanced standard care combined with having a treatment supporter were superior to standard care, with regards to self-reported adherence and viral suppression. The authors speculate that combinations of cognitive and behavioural programmes maximise the activity efficacy. Interestingly, their study found a large benefit for weekly but not for daily SMS messages. However the heterogeneity in the published treatment effects could be attributed to heterogeneity of the implemented programmes, especially of behavioural interventions. For example, the authors point out that there is a wide variability in the definition of standard care, and in the definition of treatment supporters.

The authors also note that several recommendations for improving adherence are unsupported by the evidence they examined using network meta-analysis.

Health care delivery
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Laboratory monitoring of paediatric antiretroviral therapy not found to be cost-effective; but cotrimoxazole prophylaxis is

Opportunities for improving the efficiency of paediatric HIV treatment programmes: lessons from the ARROW trial.

Revill PA, Walker S, Mabugu T, Nathoo KJ, Mugyenyi P, Kekitinwa A, Munderi P, Bwakura-Dangarembizi M, Musiime V, Bakeera-Kitaka S, Nahirya-Ntege P, Walker AS, Sculpher MJ, Gibb DP. AIDS. 2014 Nov 13. [Epub ahead of print]

Objectives: To conduct two economic analyses addressing whether to: routinely monitor HIV-infected children on antiretroviral therapy (ART) clinically or with laboratory tests; continue or stop cotrimoxazole prophylaxis when children become stabilized on ART.

Design and methods: The ARROW randomized trial investigated alternative strategies to deliver paediatric ART and cotrimoxazole prophylaxis in 1206 Ugandan/Zimbabwean children. Incremental cost-effectiveness and value of implementation analyses were undertaken. Scenario analyses investigated whether laboratory monitoring (CD4 tests for efficacy monitoring; haematology/biochemistry for toxicity) could be tailored and targeted to be delivered cost-effectively. Cotrimoxazole use was examined in malaria-endemic and non-endemic settings.

Results: Using all trial data, clinical monitoring delivered similar health outcomes to routine laboratory monitoring, but at a reduced cost, so was cost-effective. Continuing cotrimoxazole improved health outcomes at reduced costs. Restricting routine CD4 monitoring to after 52 weeks following ART initiation and removing toxicity testing was associated with an incremental cost-effectiveness ratio of $6084 per quality-adjusted life-year (QALY) across all age groups, but was much lower for older children (12+ years at initiation; incremental cost-effectiveness ratio = $769/QALY).Committing resources to improve cotrimoxazole implementation appears cost-effective. A healthcare system that could pay $600/QALY should be willing to spend up to $12.0 per patient-year to ensure continued provision of cotrimoxazole.

Conclusion: Clinically driven monitoring of ART is cost-effective in most circumstances. Routine laboratory monitoring is generally not cost-effective at current prices, except possibly CD4 testing amongst adolescents initiating ART. Committing resources to ensure continued provision of cotrimoxazole in health facilities is more likely to represent an efficient use of resources.

Abstract access 

Editor’s notes: The authors set out to compare the cost-effectiveness of laboratory monitoring versus clinical monitoring of paediatric antiretroviral therapy (ART), and to determine the cost-effectiveness of continuing cotrimoxazole prophylaxis on children after being stabilised on ART. Using data from a trial in Uganda and Zimbabwe, they found that delivering ART with laboratory monitoring was generally more costly when compared with clinical monitoring. This was despite the two approaches having similar health outcomes. Laboratory monitoring was found not to be cost-effective, except potentially in cases of adolescents aged 12 and older (and without carrying out associated toxicity tests). The authors also found that discontinuing cotrimoxazole prophylaxis was both more costly and less effective than continuing provision. Reductions in cost of hospitalisations and prescriptions for malaria and other infections exceeded the costs of providing cotrimoxazole itself. Cost-reductions were similar in both malaria-endemic and non-malaria-endemic settings.

The questions addressed by this study are important because of the context of paediatric HIV in sub-Saharan Africa. As of 2013 only about 32% of children in need, in the region received ART. This background of poor health infrastructure and large gaps in paediatric treatment makes decision-making on limited resource allocation all the more important. The findings on the effectiveness of co-delivery of cotrimoxazole are further evidence of the need for governments and funders alike to think of effective and creative ways of integrating HIV care and treatment priorities within the wider health system.

This study should also be observed in light of changing national and international guidelines on detection of treatment failure. As of 2013, WHO has recommended viral load monitoring as the preferred method. When compared to CD4 testing, viral load monitoring tends to lead to better health outcomes but also requires sophisticated laboratory technology and highly trained technicians. Changing from CD4 to viral load monitoring may be unaffordable and logistically unfeasible in many settings.

Additionally, more countries in sub-Saharan Africa are rolling out point-of-care CD4 testing technologies. As more competitors in the field enter the point-of-care market, prices are likely to decrease. Although the authors have accounted for these future possibilities in their analysis, cost-effectiveness of monitoring of paediatric ART ought to be revisited at a later time once the costs related to point-of-care technologies have been more thoroughly understood.

Uganda, Zimbabwe
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More, older people living with HIV, but how many more?

Increasing trends in HIV prevalence among people aged 50 years and older: evidence from estimates and survey data.

Mahy M, Autenrieth CS, Stanecki K, Wynd S. AIDS. 2014 Sep 12. [Epub ahead of print]

Objective: To present the most recent 2013 UNAIDS estimates of HIV prevalence among people aged 50 years and older, and to validate these estimates using data from national household surveys.

Design: Modelled estimates of HIV prevalence were validated against nationally representative household survey measures of HIV prevalence.

Methods: The UNAIDS 2013 HIV estimates were used to compute HIV prevalence and number of people living with HIV aged 50 years and older. Sex-specific HIV-prevalence rates by 5-year age groups were calculated from nationally representative household surveys conducted between 2003 and 2013, and were compared to prevalence rates from the modelled estimates. The ratios of the prevalence rates from the two sources were analysed.

Results: In 2013, an estimated 4.2 million (4.0-4.5 million) people aged 50 years and older were living with HIV. The global HIV prevalence among older individuals more than doubled in almost all the 5-year age groups since 1995. There was a relatively good agreement between the modelled HIV-prevalence rates and the survey-based rates among men and women aged 50-54 years (0.90 and 0.98 median ratio, respectively), whereas for 55-59-year-olds, the differences were more notable (ratios of 0.63 for men and 0.9 for women).

Conclusion: Both data sources suggest HIV-prevalence rates among people aged over 50 have increased steadily in recent years. Care and treatment services need to address the specific needs of older people living with HIV. Action is needed to incorporate older age groups into HIV surveillance systems.

Abstract access 

Editor’s notes: According to the most recent estimates, the global number of people above age 50 years and living with HIV, has more than doubled since the mid-1990s. In southern Africa, it has more than tripled. These numbers are expected to increase further as treatment programmes continue to expand. This study by the UNAIDS secretariat, underscores the numeric importance of this population subgroup. Above all, it highlights how little we know about the epidemic in older adults. The authors compare UNAIDS (modelled) HIV prevalence estimates with those from nationally representative surveys. They find good correspondence among 50-54 year-old men and women. The discrepancy between the two sources are more pronounced above age 54 years where the UNAIDS figures tend to fall short of the empirical estimates. This is particularly the case for men. HIV prevalence estimates among older women are rather scarce as surveys and data collection at antenatal clinics typically focus on women of reproductive age. Longer than expected survival of people living with HIV and higher than anticipated HIV incidence at older ages, could explain the discrepancy between the estimates. But we need more and better data about these age groups to be in a position to adjudicate between these explanations.

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Resistance testing: not cost-effective in determining switches to second-line therapy

Cost-effectiveness of HIV drug resistance testing to inform switching to second line antiretroviral therapy in low income settings.

Phillips A, Cambiano V, Nakagawa F, Magubu T, Miners A, Ford D, Pillay D, De Luca A, Lundgren J, Revill P. PLoS One. 2014 Oct 7;9(10):e109148. doi: 10.1371/journal.pone.0109148. eCollection 2014.

Background: To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations being identified.

Methods: An individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa. Underlying monitoring strategies considered were based on clinical disease, CD4 count or viral load. Within each we considered a strategy in which no further measures are performed, one with a viral load measure to confirm failure, and one with both a viral load measure and a resistance test. Predicted outcomes were assessed over 2015-2025 in terms of viral suppression, first line failure, switching to second line regimen, death, HIV incidence, disability-adjusted-life-years averted and costs. Potential future low costs of resistance tests ($30) were used.

Results: The most effective strategy, in terms of DALYs averted, was one using viral load monitoring without confirmation. The incremental cost-effectiveness ratio for this strategy was $2113 (the same as that for viral load monitoring with confirmation). ART monitoring strategies which involved resistance testing did not emerge as being more effective or cost effective than strategies not using it. The slightly reduced ART costs resulting from use of resistance testing, due to less use of second line regimens, was of similar magnitude to the costs of resistance tests.

Conclusion: Use of resistance testing at the time of first line failure as part of the decision whether to switch to second line therapy was not cost-effective, even though the test was assumed to be very inexpensive.

Abstract  Full-text [free] access

Editor’s notes: The landscape around first-line treatment modification is changing. The price of second-line treatment has dropped substantially in recent years and several new point-of-care monitoring technologies (CD4 count tests and viral load tests) are (or will soon be) on the market. It is within this context that this article looks at whether drug resistance testing could play a key role in antiretroviral therapy (ART) monitoring in low- and middle-income settings. Simulating the progression of the HIV epidemic in adults in Zimbabwe, Phillips et al. examined different combinations of monitoring strategies. These included CD4 count monitoring, viral load monitoring and confirmation, and resistance testing. They found that the most cost effective option involved using viral load monitoring without confirmation. The reduced costs of ART due to a decrease in use of second-line regimes as a result of the implementation of resistance tests were offset by the costs of the resistance tests themselves. However, the authors do not rule out potential cost-effectiveness for resistance testing under certain circumstances. This could be in ART initiation clinics where large numbers of people have resistance to first-line treatment, or in selecting drug regimens for ART-naïve pregnant women (as it is important to maximise the chance of viral suppression at the time of birth). Future modelling exercises on this issue may benefit from including real-life implementation issues such as health worker deviation from guidelines and system delays in returning of results.

HIV Treatment
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Prednisolone does not reduce poor outcomes in TB pericarditis

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

Mayosi BM, Ntsekhe M, Bosch J, Pandie S, Jung H, Gumedze F, Pogue J, Thabane L, Smieja M, Francis V, Joldersma L, Thomas KM, Thomas B, Awotedu AA, Magula NP, Naidoo DP, Damasceno A, Chitsa Banda A, Brown B, Manga P, Kirenga B, Mondo C, Mntla P, Tsitsi JM, Peters F, Essop MR, Russell JB, Hakim J, Matenga J, Barasa AF, Sani MU, Olunuga T, Ogah O, Ansa V, Aje A, Danbauchi S, Ojji D, Yusuf S; IMPI Trial Investigators. N Engl J Med. 2014 Sep 18;371(12):1121-30. doi: 10.1056/NEJMoa1407380. Epub 2014 Sep 1.

Background: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis.

Methods: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.

Results: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer.

Conclusions: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.

Abstract  Full-text [free] access

Editor’s notes: Tuberculous pericarditis remains an important and serious complication of HIV disease. Previous studies have suggested that treatment with steroids, in addition to standard TB treatment, reduces the risk of serious complications such as constrictive pericarditis. However, previous studies have been small, and have included few HIV-positive people.

This randomised controlled trial across eight countries in Africa tested two treatments for people with either definite or probable TB pericarditis. These included high dose steroid treatment, and injections of Mycobacterium indicus pranii. Mycobacterium indicus pranii is an environmental mycobacterium suggested to have a possible effect to reduce inflammation among people with TB. Two-thirds of the 1400 study participants were HIV-positive, most of whom were not taking antiretroviral therapy at the time of enrolment. The median CD4 count at enrolment was around 150 cells/µl. The primary outcome of the study was a composite of death, cardiac tamponade requiring drainage, and constrictive pericarditis. 

The death rate overall was high at 18%, and the main causes of death were considered to be pericarditis, TB, and HIV disease. Immunotherapy with Mycobacterium indicus pranii had no beneficial effects on any outcome. There was no overall difference in the composite primary outcome among people receiving prednisolone compared to placebo. However, people receiving prednisolone were less likely to develop constrictive pericarditis or to be hospitalised. There were more cancers (primarily Kaposi’s sarcoma among HIV-positive people) in people receiving either prednisolone or Mycobacterium indicus pranii, although the absolute rate was low. This is in keeping with previous observations.

Limitations of the study include that most people did not have microbiological confirmation of their TB diagnosis, so could potentially have had other causes of pericarditis for which prednisolone would not be expected to improve outcomes.

The results of this trial suggest that guidelines concerning use of prednisolone for TB pericarditis should be reviewed, particularly for people living with HIV. The poor outcomes among this group of people with TB and advanced HIV disease highlight the need for earlier HIV diagnosis, initiation of antiretroviral therapy, and TB preventive therapy.

Avoid TB deaths
Comorbidity, HIV Treatment
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Counting and classifying global deaths

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Murray CJ, Ortblad KF, Guinovart C, et al. Lancet. 2014 Sep 13;384(9947):1005-70. doi: 10.1016/S0140-6736(14)60844-8. Epub 2014 Jul 22.

Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.

Methods: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

Findings: Globally in 2013, there were 1.8 million new HIV infections (95% uncertainty interval 1.7 million to 2.1 million), 29.2 million prevalent HIV cases (28.1 to 31.7), and 1.3 million HIV deaths (1.3 to 1.5). At the peak of the epidemic in 2005, HIV caused 1.7 million deaths (1.6 million to 1.9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19.1 million life-years (16.6 million to 21.5 million) have been saved, 70.3% (65.4 to 76.1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$ 4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7.5 million (7.4 million to 7.7 million), prevalence was 11.9 million (11.6 million to 12.2 million), and number of deaths was 1.4 million (1.3 million to 1.5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7.1 million (6.9 million to 7.3 million), prevalence was 11.2 million (10.8 million to 11.6 million), and number of deaths was 1.3 million (1.2 million to 1.4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64.0% of cases (63.6 to 64.3) and 64.7% of deaths (60.8 to 70.3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1.2 million deaths (1.1 million to 1.4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31.5% (15.7 to 44.1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

Interpretation: Our estimates of the number of people living with HIV are 18.7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

Abstract  Full-text [free] access

Editor’s notes: The Global Burden of Disease (GBD) study uses standard methods to compare and track over time national distributions of deaths by cause, and the prevalence of disease and disability.  This detailed report focuses on HIV, TB and Malaria. It presents regional summaries of incidence, prevalence and mortality rates, and national estimates of the number of male and female deaths and new infections. Point estimates are shown for 2013, and annualised rates of change for 1990-2000 and 2000-2013. These highlight the contrasting trends in disease impact before and after the formulation of the Millennium Development Goal to combat these diseases.  The global peak of HIV mortality occurred in 2005, but regional annualised rates of change for 2000-2013 indicate that HIV deaths are still increasing significantly in east Asia, southern Africa, and most rapidly in eastern Europe.

The GBD 2013 global estimates of new infections and deaths agree closely with the corresponding estimates made by UNAIDS. But there are significant differences in the respective estimates of the number of people currently living with HIV (UNAIDS estimates are some 18% higher), and historical trends in AIDS deaths, with UNAIDS judging that the recent fall has been steeper. These differences are attributed primarily to methods used in the GBD study to ensure that the sum of deaths from specific causes fits the estimated all cause total, and to varying assumptions about historical survival patterns following HIV infection. 

It may be worthwhile to look at a comment by Michel Sidibé, Mark Dybul, and Deborah Birx in the Lancet on MDG 6 and beyond: from halting and reversing AIDS to ending the epidemic which refers to this study.

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