Articles tagged as "Thailand"

Highly variable virological outcomes in ART programmes in seven countries

Extraordinary Heterogeneity of Virological Outcomes in Patients Receiving Highly Antiretroviral Therapy and Monitored With the World Health Organization Public Health Approach in Sub-Saharan Africa and Southeast Asia.

Aghokeng AF, Monleau M, Eymard-Duvernay S, Dagnra A, Kania D, Ngo-Giang-Huong  N, Toni TD, Touré-Kane C, Truong LX, Delaporte E, Chaix ML, Peeters M, Ayouba A; for the ANRS 12186 Study Group. Clin Infect Dis. 2013 Oct 23. [Epub ahead of print]

Background:  The limited access to virological monitoring in developing countries is a major weakness of the current antiretroviral treatment (ART) strategy in these settings. We conducted a large cross-sectional study in Burkina Faso, Cameroon, Cote d'Ivoire, Senegal, Togo, Thailand, and Vietnam to assess virological failure and drug resistance mutations (DRMs) after 12 or 24 months of ART.

Methods:  Between 2009 and 2011, we recruited adults attending ART centers 10-14 months (the M12 group) or 22-26 months (M24 group) after initiating ART. Demographic and clinical data were collected on site, and viral load was measured. Samples with a viral load of ≥ 1 000 copies/mL, considered as the failure threshold, were genotyped for drug resistance assessment.

Results:  Overall, 3 935 patients were recruited (2 060 at M12 and 1 875 at M24). Median ages varied from 32 to 42 years. Median CD4+ T-cell counts at ART initiation were low (99-172 cells/µL). The main ART regimens included stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. Overall, virological failure frequency was 11.1% for M12 patients and 12.4% for M24 patients, and 71.0% to 86.1% of these patients, respectively, had drug-resistant virus. Across sites, virological failure varied from 2.9% to 20.6% in M12 patients and from 3.7% to 26.0% in M24 patients. Predominant DRMs were associated with ART regimens, but virus in several patients accumulated DRMs to drugs not received, such as abacavir, didanosine, tenofovir, etravirine, and rilpivirine.

Conclusions:  Our findings show heterogeneous virological failure and illustrate that, in addition to routine access to viral load, good management of ART programs is even more critical to improve treatment outcomes in resource-limited countries.

Abstract access 

Editor’s notes: As the number of people taking antiretroviral therapy (ART) increases, more attention will be needed to sustaining programme quality and effectiveness. The proportion of people taking ART who have suppressed HIV viral load is a key measure of treatment success. This survey of ART programmes in seven countries found wide variation in the proportion of patients with HIV viral load ≥1 000 copies per ml. This illustrates the value of viral load monitoring as a measure of programme quality. Among individuals with HIV viral load ≥1 000 copies per ml, most but not all had drug-resistant virus. This illustrates the difficulty of rational management of “treatment failure” where resistance cannot be determined. Of more concern are few patients who had resistance to drugs they apparently had never taken. This underlines the importance of careful ART stewardship to maximize the benefits of ART at population level. 

Africa, Asia
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Evidence lacking to guide timing of ART start for children aged 2-5 years

Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old.

Siegfried N, Davies MA, Penazzato M, Muhe LM, Egger M. Cochrane Database Syst Rev. 2013 Oct 10;10:CD010309. [Epub ahead of print]

Background: The use of combination antiretroviral therapy (cART) comprising three antiretroviral medications from at least two classes of drugs is the current standard treatment for HIV infection in adults and children. Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic thresholds or the clinical condition for all infants (less than one years of age) and children under the age of two years. For children aged two to five years current WHO guidelines recommend (based on low quality evidence) that clinical and immunological thresholds be used to identify those who need to start cART (advanced clinical stage or CD4 counts ≤ 750 cells/mm3 or per cent CD4 ≤ 25%). This Cochrane review will inform the current available evidence regarding the optimal time for treatment initiation in children aged two to five years with the goal of informing the revision of WHO 2013 recommendations on when to initiate cART in children.

Objectives: To assess the evidence for the optimal time to initiate cART in treatment-naive, HIV-infected children aged 2 to 5 years.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the AEGIS conference database, specific relevant conferences, www.clinicaltrials.gov, the World Health Organization International Clinical Trials Registry platform and reference lists of articles. The date of the most recent search was 30 September 2012.

Selection criteria: Randomised controlled trials (RCTs) that compared immediate with deferred initiation of cART, and prospective cohort studies which followed children from enrolment to start of cART and on cART.

Data collection and analysis: Two review authors considered studies for inclusion in the review, assessed the risk of bias, and extracted data on the primary outcome of death from all causes and several secondary outcomes, including incidence of CDC category C and B clinical events and per cent CD4 cells (CD4%) at study end. For RCTs we calculated relative risks (RR) or mean differences with 95% confidence intervals (95% CI). For cohort data, we extracted relative risks with 95% CI from adjusted analyses. We combined results from RCTs using a random effects model and examined statistical heterogeneity.

Main results: Two RCTs in HIV-positive children aged 1 to 12 years were identified. One trial was the pilot study for the larger second trial and both compared initiation of cART regardless of clinical-immunological conditions with deferred initiation until per cent CD4 dropped to <15%. The two trials were conducted in Thailand, and Thailand and Cambodia, respectively. Unpublished analyses of the 122 children enrolled at ages 2 to 5 years were included in this review. There was one death in the immediate cART group and no deaths in the deferred group (RR 2.9; 95% CI 0.12 to 68.9). In the subgroup analysis of children aged 24 to 59 months, there was one CDC C event in each group (RR 0.96; 95% CI 0.06 to 14.87) and 8 and 11 CDC B events in the immediate and deferred groups respectively (RR 0.95; 95% CI 0.24 to 3.73). In this subgroup, the mean difference in CD4 per cent at study end was 5.9% (95% CI 2.7 to 9.1). One cohort study from South Africa, which compared the effect of delaying cART for up to 60 days in 573 HIV-positive children starting tuberculosis treatment (median age 3.5 years), was also included. The adjusted hazard ratios for the effect on mortality of delaying ART for more than 60 days was 1.32 (95% CI 0.55 to 3.16).

Authors' conclusions: This systematic review shows that there is insufficient evidence from clinical trials in support of either early or CD4-guided initiation of ART in HIV-infected children aged 2 to 5 years. Programmatic issues such as the retention in care of children in ART programmes in resource-limited settings will need to be considered when formulating WHO 2013 recommendations. 

Abstract   Full-text [free] access

Editor’s notes: Immediate treatment of HIV infection with antiretroviral therapy (ART), i.e., regardless of immunological thresholds, is recommended for infants and children up to two years of age.  This recommendation followed the findings of the children with HIV early antiretroviral (CHER) trial. The CHER trial showed significantly lower mortality in infants who received immediate ART compared to those who received deferred ART (i.e. ART started only when they met immunological and/or clinical criteria).

This Cochrane review sought to investigate the optimal timing for ART start in the 2-5 year age-group to inform development of the WHO 2013 HIV treatment guidelines. The review included two trials: one was a pilot study for the main trial, and the main trial itself. This included a broader age-group of one to twelve years, and a post-hoc sub-group analysis was required for the 2-5 year age-group. The sample size was small, and there were very few outcome events. The one cohort study included in the review had similar limitations and had a very short follow-up period. Overall, no significant difference was found in mortality or in numbers of clinical events between children who received immediate versus deferred ART.

It is not possible to draw conclusions about the clinical impact of immediate versus deferred ART from these studies. The long term beneficial or adverse effects of ART in this age-group are also not clear. Retention in care and adherence to ART are particularly problematic in this age-group and may countermand any clinical benefits, if they exist. There remains equipoise and trials are needed to address the optimal timing of ART initiation for older children. 

Africa, Asia
Cambodia, South Africa, Thailand
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Combination HIV prevention for MSM needed urgently

The global HIV epidemics in MSM: time to act.

Beyrer C, Sullivan P, Sanchez J, Baral SD, Collins C, Wirtz AL, Altman D, Trapence G, Mayer K. AIDS. 2013 Aug6. [Epub ahead of print]

Epidemics of HIV in MSM continue to expand in most low, middle, and upper income countries in 2013 and rates of new infection have been consistently high among young MSM. Current prevention and treatment strategies are insufficient for this next wave of HIV spread. We conducted a series of comprehensive reviews of HIV prevalence and incidence, risks for HIV, prevention and care, stigma and discrimination, and policy and advocacy options. The high per act transmission probability of receptive anal intercourse, sex role versatility among MSM, network level effects, and social and structural determinants play central roles in disproportionate disease burdens. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiologic data show marked clustering of HIV in MSM networks and high proportions of infections due to transmission from recent infections. Prevention strategies that lower biological risks, including those using antiretrovirals, offer promise for epidemic control, but are limited by structural factors including, discrimination, criminalization, and barriers to healthcare. Sub-epidemics, including among racial and ethnic minority MSM in the United States and UK, are particularly severe and will require culturally tailored efforts. For the promise of new and combined bio-behavioral interventions to be realized, clinically competent healthcare is necessary and community leadership, engagement, and empowerment are likely to be key. Addressing the expanding epidemics of HIV in MSM will require continued research, increased resources, political will, policy change, structural reform, community engagement, and strategic planning and programming, but it can and must be done.

Abstract access

Editor’s notes: This paper provides a useful summary of HIV epidemics among men who have sex with men, highlighting that infection levels continue to rise in most countries – both industrialized and developing, and including countries where HIV treatment is widely available. Drawing upon the findings from a range of comprehensive reviews, the paper presents important summary data on the prevalence of HIV among MSM.  It paints a global picture of the very high prevalence burdens found in the United States, the Caribbean, Peru, multiple African countries, Thailand, Myanmar, and parts of China, with the highest rates among the youngest age groups. The paper discusses options for prevention and treatment, arguing that much more needs to be done. The authors suggest that antiretrovirals – including both early treatment and PrEP, could be important additions for prevention.  However, these interventions will only be effective if strategies address structural barriers, including violence, stigmatization and criminalization. The authors argue that interventions and services need to be better equipped to respond to sub-epidemics in particularly marginalized MSM populations; and that an effective response will only be achieved through political will, community engagement and structural change.

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Better virological outcomes with efavirenz compared to nevirapine

Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a systematic review and meta-analysis.

Pillay P, Ford N, Shubber Z, Ferrand RA., PLoS One. 2013 Jul 22;8(7):e68995. doi: 10.1371/journal.pone.0068995. Print 2013

Introduction: There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz (EFV) and nevirapine (NVP) in first-line antiretroviral therapy (ART).

Methods: We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR) and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2) statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.

Results: Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2) = 0%) and observational studies (RR 0.65 [0.59-0.71] I(2) = 54%). EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2) = 0%) and observational studies (RR 1.06 [1.00-1.12] I(2) = 68%).

Conclusion: EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.

Abstract  Full-text [free] access

Editor’s notes: Efavirenz and nevirapine are key antiretroviral agents, particularly in resource-limited settings. Nevirapine has been widely used, for reasons including safety during pregnancy and lower cost, despite lower potency and a higher risk of hepatotoxicity and severe allergic reactions, than with efavirenz. This article summarizes data on virological outcomes from clinical trials and observational cohort studies comparing efavirenz and nevirapine. The finding that efavirenz is associated with slightly better virological outcomes is not surprising but it is valuable to have the available data summarised. The result, along with recent recommendations allowing efavirenz to be taken throughout pregnancy, and price reductions, supports the move towards efavirenz-based fixed drug combinations as first-line antiretroviral treatment in resource-limited settings.

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Disclosure to children of their HIV status: a model from Thailand

Development of a diagnosis disclosure model for perinatally HIV-infected children in Thailand.

Boon-Yasidhi V, Chokephaibulkit K, McConnell MS, Vanprapar N, Leowsrisook P, Prasitsurbsai W, Durier Y, Klumthanom K, Patel A, Sukwicha W, Naiwatanakul T, Chotpitayasunond T, AIDS Care 2013;25:756-62 doi: 10.1080/09540121.2012.749331

While disclosure of HIV status to perinatally HIV-infected children has become an increasingly important clinical issue, specific disclosure guidelines are lacking. We developed a pediatric HIV diagnosis disclosure model to support caretakers. All HIV-infected children greater than 7-years-old at two participating hospitals in Bangkok, Thailand, and their caretakers, were offered disclosure according to the 4-step protocol: (1) screening; (2) readiness assessment; (3) disclosure; and (4) follow-up. Disclosure occurred after agreement of both providers and caretakers. Among 438 children who were screened, 398 (89%) were eligible. Readiness assessment was completed for 353 (91%) of eligible children and 216 (61%) were determined ready. Disclosure was done for 186 children. The mean age at eligibility screening was 10.5 years (range: 6.8-15.8 years); the mean age at disclosure was 11.7 years (range: 7.6-17.7 years). The mean duration between eligibility screening and disclosure was 15.2 months. There were no significant negative behavioral or emotional outcomes reported in children following disclosure. This HIV diagnosis disclosure model was feasible to implement and had no negative outcomes. As the time for preparation process was over 1 year for most cases, the disclosure process can be initiated as early as age 7 to allow enough time for disclosure to be completed by the age of adolescence.

Abstract access

Editor’s notes: Increasing numbers of HIV-infected children are now surviving into adolescence because of antiretroviral therapy. While disclosure to children of their HIV diagnosis is known to be crucial, this process is very often delayed because caretakers find the process difficult.  In this study, caretakers disclosed to children with support from a care provider before, during and after disclosure.  There were no negative consequences for children once they knew their diagnosis, although the study was not able to determine if this model had any impact on longer-term adherence and psychosocial status.  This care-taker assisted disclosure model provides a practical, systematic and stepwise guide to facilitate paediatric disclosure, as well as being adaptable to the caretakers’ wishes and children’s needs. Preparing the caretaker to disclose can take a long time and care providers should initiate this process when the child is as young as 7 years, to enable disclosure to occur before the child reaches adolescence.  The disclosure manual is available here.  

Asia
Thailand
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Decentralised HIV treatment is no worse than hospital based care, and in some cases better

Decentralising HIV treatment in lower- and middle-income countries.

Kredo T, Ford N, Adeniyi FB, Garner P. Cochrane Database Syst Rev. 2013 Jun 27;6:CD009987. doi: 10.1002/14651858.CD009987.pub2.

Background:  Policy makers, health staff and communities recognise that health services in lower- and middle-income countries need to improve people's access to HIV treatment and retention to treatment programmes. One strategy is to move antiretroviral delivery from hospitals to more peripheral health facilities or even beyond health facilities. This could increase the number of people with access to care, improve health outcomes, and enhance retention in treatment programmes. On the other hand, providing care at less sophisticated levels in the health service or at community-level may decrease quality of care and result in worse health outcomes. To address these uncertainties, we summarised the research studies examining the risks and benefits of decentralising antiretroviral therapy service delivery.

Objectives: To assess the effects of various models that decentralised HIV treatment and care to more basic levels in the health system for initiating and maintaining antiretroviral therapy.

Search methods: We conducted a comprehensive search to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress) from 1 January 1996 to 31 March 2013, and contacted relevant organisations and researchers. The search terms included 'decentralisation', 'down referral', 'delivery of health care', and 'health services accessibility'.

Selection criteria: Our inclusion criteria were controlled trials (randomised and non-randomised), controlled-before and after studies, and cohorts (prospective and retrospective) in which HIV-infected people were either initiated on antiretroviral therapy or maintained on therapy in a decentralised setting in lower- and middle-income countries. We define decentralisation as providing treatment at a more basic level in the health system to the comparator.

Data collection and analysis: Two authors applied the inclusion criteria and extracted data independently. We designed a framework to describe different decentralisation strategies, and then grouped studies against these strategies. Data were pooled using random-effects meta-analysis. Because loss to follow up in HIV programmes is known to include some deaths, we used attrition as our primary outcome, defined as death plus loss to follow-up. We assessed evidence quality with GRADE methodology.

Main results: Sixteen studies met the inclusion criteria, all but one were from Africa, comprising two cluster randomised trials and 14 cohort studies. Antiretroviral therapy started at a hospital and maintained at a health centre (partial decentralisation) probably reduces attrition (RR 0.46, 95% CI 0.29 to 0.71, 4 studies, 39 090 patients, moderate quality evidence). There may be fewer patients lost to care with this model (RR 0.55, 95% CI 0.45 to 0.69, low quality evidence).We are uncertain whether there is a difference in attrition for antiretroviral therapy started and maintained at a health centre (full decentralisation) compared to a hospital at 12 months (RR 0.70, 95% CI 0.47 to 1.02; four studies, 56 360 patients, very low quality evidence), but there are probably fewer patients lost to care with this model (RR 0.3, 95% CI 0.17 to 0.54, moderate quality evidence). When antiretroviral maintenance therapy is delivered at home by trained volunteers, there is probably no difference in attrition at 12 months (RR 0.95, 95% CI 0.62 to 1.46, two trials, 1453 patients, moderate quality evidence).

Authors' conclusions: Decentralisation of HIV care aims to improve patient access and retention in care. Most data were from good quality cohort studies but confounding between site of treatment and outcomes cannot be excluded. Nevertheless, this review found that attrition appears to be lower in partial decentralisation models of treatment, where antiretrovirals were started at hospital and continued in the health centre; with antiretroviral drugs started and continued at health centres, no difference in attrition was detected, but there were fewer patients lost to care. For antiretroviral therapy provided at home by trained volunteers, no difference in outcomes was detected when compared to facility-based care.

Abstract   Full-text [free] access

Editor’s notes: As we aim to reach targets of 15 million people on ART by 2015, there is a great need to expand ART services and make them more accessible and to use models that can be scaled up given the constraints within the health sector. One approach is to decentralise care and provide follow up care to patients in health centres or at home. This is a systematic review of the impact of three models of decentralised care on patient attrition (the sum of lost to follow up and mortality) over time, with varying degree of transferring initiation and follow-up to peripheral service levels (from hospital to health centre or community base care). All three analyses showed that decentralised services are at least as good as more centralised approaches for patient retention; while the two health centre based models appear to significantly improve retention relative to a hospital based model. This provides important evidence the potential of decentralised ART to greatly expand treatment access, in particular to rural areas. 

Africa, Asia
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Efavirenz dose adjustments are probably not required in patients taking concurrent rifampicin

Relationship between weight, efavirenz exposure and virologic suppression in HIV-infected patients on rifampin-based TB treatment in the ACTG A5221 STRIDE study

Luetkemeyer AF, Rosenkranz SL, Lu D, Marzan F, Ive P, Hogg E, et al. Adult AIDS Clinical Trials Group A5221 Study Team. Clinical Infectious Diseases Advance Access published April 19, 2013.

Background: Rifampin (RIF) upregulates CYP 450 isoenzymes potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and HIV virologic suppression in patients on EFV (600 mg) and RIFbased TB treatment as part of a multicenter randomized trial (ACTG A5221)

Methods: EFV Cmin was measured using HPLC 20‐28 hours post‐EFV dose at weeks 4,8,16,24 on‐RIF and weeks 4,8 off‐RIF. Results evaluated with two‐sided Wilcoxon rank‐sum, chi‐square and Fisher's Exact tests and logistic regression (5% Type I error rate).

Results: 780 patients from 11 countries received EFV, 543 provided ≥ 1 EFV Cmin. Median (IQR) weight was 52.8 kg (48.0,59.5), BMI 19.4 kg/m2 (17.5,21.6), age 34 (29,41), 63% male, race Black (74%), Hispanic (20%), non‐Hispanic White (5%), Asian (1%). Median Cmin was 1.96μg/mL onRIF vs. 1.80 offRIF (p=0.067). EFV concentrations were significantly higher onRIF vs. offRIF in Blacks (2.08 vs. 1.75, p=0.005). Weight ≥60 kg onRIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs. 2.02, p=0.021). However, weight ≥60 kg was associated with more frequent HIV RNA<400 copies/mL at week 48, compared to weight <60 kg (81.9% vs. 73.8%, p=0.023).

Conclusions: Coadministration of EFV and RIFbased TB therapy was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone, which was statistically significant in Black patients. Patients weighing ≥60 kg had lower median EFV Cmin vs. those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weightbased dosing of EFV with RIF co-administration.

Abstract access 

Editor’s notes: Effective treatment of HIV-TB co-infection is complicated by drug-drug interactions. Rifampicin, the key component of effective anti-TB therapy, is a potent inducer of the cytochrome P450 enzymes which metabolize many antiretrovirals including efavirenz. Appropriate dosing of efavirenz in patients taking concomitant TB treatment has been debated, with both US and British national treatment guidelines recommending efavirenz dose increases. The WHO does not recommend adjusting dosing. This study, an analysis of efavirenz levels from 543 participants in the STRIDE study of ART timing in TB co-infected patients, suggests that efavirenz dose adjustments are not required in patients taking concurrent rifampicin based TB treatment. Efavirenz levels were not reduced in patients who were taking TB treatment. In fact trough efavirenz levels were slightly increased in patients during TB treatment. This increase in efavirenz levels was most marked in black patients. Virological outcomes with efavirenz based ART in this cohort of patients on TB treatment were good, with 76% fully suppressed at 48 weeks.  Perhaps unsurprisingly, efavirenz levels were slightly lower in patients weighing over 60 kg compared to those below 60 kg, but this did not translate into worse virological outcomes. Given the racial differences seen in efavirenz metabolism in this study there is a question about the generalisability of the study to certain populations, notably Caucasians who only made up 5% of the study population. However the demographics were representative of the vast majority of HIV-TB co-infected patients worldwide. These results strongly suggest that efavirenz at standard doses can be safely used in patients receiving rifampicin based TB treatment, avoiding the need to complicate ART treatment regimens in the large number of individuals receiving TB treatment in resource-limited public health programmes.

Avoid TB deaths
Comorbidity, HIV Treatment
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Adverse events associated with nevirapine use in pregnancy

Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis.

Ford N, Calmy A, Andrieux-Meyer I, Hargreaves S, Mills EJ, Shubber Z. AIDS. 2013 Jan 5. [Epub ahead of print]

The risk of adverse drug events associated with nevirapine is suggested to be greater in pregnant women. The authors conducted a systematic review and meta-analysis of severe adverse events in HIV-positive women who initiated NVP while pregnant. Six databases were searched for studies reporting adverse events among HIV-positive pregnant women who had received nevirapine-based antiretroviral therapy for at least seven days. Data were pooled by the fixed-effects method. Twenty studies (3582 pregnant women) from 14 countries were included in the final review. The pooled proportion of patients experiencing a severe hepatotoxic event was 3.6% (95%CI 2.4-4.8%), severe rash was experienced by 3.3% of patients (95%CI 2.1-4.5%), and 6.2% (95%CI 4.0-8.4%) of patients discontinued nevirapine due to an adverse event. These results were comparable to frequencies observed in the general adult patient population, and to frequencies reported in non-pregnant women within the same cohort. For pregnant women with a CD4 cell count >250 cells/mm there was a non-significant tendency towards an increased likelihood of cutaneous events overall (OR 1.1, 95%CI 0.8-1.6) and severe cutaneous adverse events (OR 1.4, 95%CI 0.8-2.4) and consequently an increased risk of toxicity-driven regimen substitution (OR 1.7, 95%CI 1.1-2.6). These results suggest that the frequency of adverse events associated with nevirapine use in pregnant women, while high, is no higher than reported for nevirapine in the general adult population. Pregnant women with a high CD4 count may be at increased risk of adverse events, but evidence supporting this association is weak.

Abstract access 

Editor’s notes: The selection of antiretroviral drug regimens has been particularly challenging for HIV-positive pregnant women. Adverse events are less frequent for men and women with efavirenz use compared to nevirapine, and increasingly efavirenz is a preferred choice. However, due to concerns about the safety of efavirenz in pregnancy, nevirapine continues to be widely used as a component of antiretroviral treatment for pregnant women. However, there have been suggestions that HIV-positive pregnant women have higher rates of nevirapine-associated adverse events, especially for those women with high CD4, compared to non-pregnant women on nevirapine. This meta-analysis of 20 studies did demonstrate a relatively high frequency of adverse events in women who use nevirapine, but not at rates higher than among non-pregnant women on HIV treatment with nevirapine. The data about efavirenz safety for the fetus is being carefully reviewed to elucidate if widespread use of efavirenz is preferable to nevirapine during pregnancy.

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Comparing adverse effects of nevirapine and efavirenz

Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.

Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Thery F, Shaffer N, Hargreaves S, Mills EJ, Ford N. AIDS. 2013 Jan 22. [Epub ahead of print]

Since 2002, the World Health Organization has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the clinical importance of these toxicities overall is not well established. The authors systematically reviewed adverse events among treatment-naïve HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CI) were calculated and proportions and odds ratios (OR) pooled using fixed-effects meta-analysis. Data was reviewed on 26446 adult and 3975 children from 8 randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95%CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95%CI 2.5-4.2), severe skin toxicity (OR 3.9, 95%CI 2.5-5.4), and severe hypersensitivity reactions (OR 2.4, 95%CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe CNS-events (OR 3.4, 95%CI 2.1-5.4). Similar associations were seen in children. Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move towards efavirenz-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach.

Abstract access 

Editor’s notes: As increased progress is being made towards universal access to treatment, increased attention is being addressed towards retention in care and on treatment. Simpler, less toxic regimens have been a cornerstone of the Treatment 2.0 initiative of UNAIDS and WHO. Nevirapine has been widely utilized as an essential component of three drug antiretroviral therapy, in part due to low cost and safety at a population level. While efavirenz does have a greater incidence of central nervous system side effects (many of them manageable with supportive treatment), the overall discontinuation rate is significantly lower than with nevirapine. This data in combination with the continued reduction in efavirenz price, and incorporation into combination pill form, supports the move towards increased use of efavirenz for first line antiretroviral therapy.

HIV Treatment
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"Start then switch": an interesting option in phasing out d4T

A 72-week randomized study of the safety and efficacy of a stavudine to zidovudine switch at 24 weeks compared to zidovudine or tenofovir disoproxil fumarate when given with lamivudine and nevirapine.

Phanuphak N, Ananworanich J, Teeratakulpisarn N, Jadwattanakul T, Kerr SJ, Chomchey N, Hongchookiat P, Mathajittiphun P, Pinyakorn S, Rungrojrat P, Praihirunyakit P, Gerschenson M, Phanuphak P, Valcour V, Kim JH, Shikuma C; the SEARCH 003 Study Group. Antivir Ther. 2012 Dec 7. doi: 10.3851/IMP2497. [Epub ahead of print]

Background: Due to superior long-term toxicity profiles, zidovudine (AZT) and tenofovir disoproxil fumarate (TDF) are preferred over stavudine (d4T) for first-line antiretroviral regimens. However, short-term d4T use could be beneficial in avoiding AZT-induced anaemia.

Methods: We randomized (1:1:1) 150 treatment-naive Thai HIV-infected adults with CD4(+) T-cell count <350 cells/mm(3) to arm 1 (24-week GPO-VIR S30® [d4T plus lamivudine (3TC) plus nevirapine (NVP)] followed by 48-week GPO-VIR Z250® [AZT plus 3TC plus NVP]), arm 2 (72-week GPO-VIR Z250®) or arm 3 (72-week TDF plus emtricitabine [FTC] plus NVP). Haemoglobin (Hb), dual energy x-ray absorptiometry, neuropathic signs, estimated glomerular filtration rate (eGFR), CD4(+) T-cell count, plasma HIV RNA and adherence were assessed.

Results: In an intention-to-treat analysis, mean Hb decreased from baseline to week 24 in arm 2 compared with arm 1 (-0.19 versus 0.68 g/dl; P=0.001) and arm 3 (0.48 g/dl; P=0.010). Neuropathic signs were more common in arm 2 compared with arm 3 (20.4 versus 4.2%; P=0.028) at week 24. There were no differences in changes in peripheral fat and eGFR from baseline to weeks 24 and 72 among arms. CD4(+) T-cell count increased more in arm 1 than arms 2 and 3 from baseline to week 24 (168 versus 117 and 118 cells/mm(3); P=0.01 and 0.02, respectively) but the increase from baseline to week 72 was similar among arms.

Conclusions: A 24-week d4T lead-in therapy caused less anaemia and greater initial CD4(+) T-cell count increase than initiating treatment with AZT. This strategy could be considered in patients with baseline anaemia or low CD4(+) T-cell count. If confirmed in a larger study, this may guide global recommendations on antiretroviral initiation where AZT is more commonly used than TDF.

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Editor’s notes: The 2010 WHO ART guidelines recommend that initial ART in treatment naive HIV infected adults should contain a NNRTI (either NVP or EFV) plus two NRTIs, one of which should be 3TC (or FTC) and the other AZT or TDF. The next revision of the guidelines may put even higher value on avoiding d4T toxicity, on the need to select regimens that are suitable for use across most patient groups and on the clinical and patient compliance benefits of using fixed dose combinations. Over the last two years, progress on discontinuation of d4T use as the initial option has occurred. However, some countries have made rapid and substantial progress, while others have taken a phased approach (e.g. only new initiations). Indeed, the reasons to phase out d4T in countries with limited resources are numerous, and mainly include the long-term adverse effects of thymidine analogues (AZT and d4T) which became evident after years of widespread use, since the ‘90s, in countries without financial constraints, where these drugs have not been used for many years. Now that the goal is universal access and the target is putting 15 million persons in urgent need on antiretrovirals, avoiding double standards has become an imperative. However, d4T is not a bad drug in terms of virological efficacy, and this randomized study is of some interest, because it proves the relative "safety" of d4T when used for short periods of time. These results may help guide the progressive phasing out of d4T in countries where the newly recommended drugs and combinations may not become immediately available, where TDF cost is still an issue, and where d4T procurement has been substantial.

HIV Treatment
Asia
Thailand
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