Articles tagged as "Thailand"

Identifying people most likely to benefit from HIV pre-exposure prophylaxis

HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial.

Buchbinder SP, Glidden DV, Liu AY, McMahan V, Guanira JV, Mayer KH, Goicochea P, Grant RM. Lancet Infect Dis. 2014 Jun;14(6):468-75. doi: 10.1016/S1473-3099(14)70025-8. Epub 2014 Mar 7.

Background: For maximum effect pre-exposure prophylaxis should be targeted to the subpopulations that account for the largest proportion of infections (population-attributable fraction [PAF]) and for whom the number needed to treat (NNT) to prevent infection is lowest. We aimed to estimate the PAF and NNT of participants in the iPrEx (Pre-Exposure Prophylaxis Initiative) trial.

Methods: The iPrEx study was a randomised controlled efficacy trial of pre-exposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine in 2 499 men who have sex with men (MSM) and transgender women. Participants aged 18 years or older who were male at birth were enrolled from 11 trial sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the USA. Participants were randomly assigned (1:1) to receive either a pill with active pre-exposure prophylaxis or placebo, taken daily. We calculated the association between demographic and risk behaviour during screening and subsequent seroconversion among placebo recipients using a Poisson model, and we calculated the PAF and NNT for risk behaviour subgroups..

Findings: Patients were enrolled between July 10, 2007, and Dec 17, 2009, and were followed up until Nov 21, 2010. Of the 2 499 MSM and transgender women in the iPrEx trial, 1 251 were assigned to pre-exposure prophylaxis and 1 248 to placebo. 83 of 1 248 patients in the placebo group became infected with HIV during follow-up. Participants reporting receptive anal intercourse without a condom seroconverted significantly more often than those reporting no anal sex without a condom (adjusted hazard ratio [AHR] 5.11, 95% CI 1.55-16.79). The overall PAF for MSM and transgender women reporting receptive anal intercourse without a condom was 64% (prevalence 60%). Most of this risk came from receptive anal intercourse without a condom with partners with unknown serostatus (PAF 53%, prevalence 54%, AHR 4.76, 95% CI 1.44-15.71); by contrast, the PAF for receptive anal intercourse without a condom with an HIV-positive partner was 1% (prevalence 1%, AHR 7.11, 95% CI 0.70-72.75). The overall NNT per year for the cohort was 62 (95% CI 44-147). NNTs were lowest for MSM and transgender women self-reporting receptive anal intercourse without a condom (NNT 36), cocaine use (12), or a sexually transmitted infection (41). Having one partner and insertive anal sex without a condom had the highest NNTs (100 and 77, respectively).

Interpretation: Pre-exposure prophylaxis may be most effective at a population level if targeted toward MSM and transgender women who report receptive anal intercourse without a condom, even if they perceive their partners to be HIV negative. Substance use history and testing for STIs should also inform individual decisions to start pre-exposure prophylaxis. Consideration of the PAF and NNT can aid in discussion of the benefits and risks of pre-exposure prophylaxis with MSM and transgender women.

Abstract access 

Editor’s notes: Pre-exposure prophylaxis (PreP) is the only biomedical prevention activity shown to be effective against acquisition of HIV in men who have sex with men (MSM) and transgender women, in a randomised controlled trial. The US Centers for Disease Control (CDC) and WHO recommend PreP for MSM and transgender women at high risk of HIV infection. However, many health care providers have difficulty assessing risk and neither the CDC nor WHO has yet provided specific behavioural criteria for when to use pre-exposure prophylaxis. The purpose of this study was to identify subpopulations of participants within the iPrEx trial, for whom PreP may have the largest effect on HIV prevention. The findings suggest that MSM and transgender women can be screened for potential eligibility for PreP in clinical practice by asking about recent receptive anal intercourse without a condom. Substance use history and testing for sexually transmitted infections should also be considered, to inform individual decisions to start pre-exposure prophylaxis.

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Poor accuracy of self-reported adherence to PrEP versus drug detection in many settings

Study product adherence measurement in the iPrEx placebo-controlled trial: concordance with drug detection.

Amico KR, Marcus JL, McMahan V, Liu A, Koester KA, Goicochea P, Anderson PL, Glidden D, Guanira J, Grant R. J Acquir Immune Defic Syndr. 2014 May 21. [Epub ahead of print]

Objective: To evaluate the concordance between adherence estimated by self-report (in-person interview or computer-assisted self-interview [CASI]), in-clinic pill counts, and pharmacy dispensation records and drug detection among participants in a placebo-controlled, pre-exposure prophylaxis (PrEP) HIV prevention trial (iPrEx).

Design: Cross-sectional evaluation of 510 participants who had drug concentration data and matched adherence assessments from their week-24 study visit.

Methods: Self-reported adherence collected via (1) interview and (2) CASI surveys, (3) adherence estimated by pill count, and (4) medication possession ratio (MPR) were contrasted to having a detectable level of drug concentrations (either tenofovir diphosphate [TFV-DP] or emtricitabine triphosphate [FTC-TP]) as well as to having evidence of consistent dosing (TFV-DP>/=16 fmol/10 cells), focusing on positive predictive values (PPV), overall and by research site.

Results: Overall, self-report and pharmacy records suggested high rates of product use (over 90% adherence); however, large discrepancies between these measures and drug detection were noted, which varied considerably between sites (PPV from 34% to 62%). Measures of adherence performed generally well in the US sites, but had poor accuracy in other research locations. MPR outperformed other measures but still had relatively low discrimination.

Conclusions: The sizable discrepancy between adherence measures and drug detection in certain regions highlights the potential contribution of factors that may have incentivized efforts to appear adherent. Understanding the processes driving adherence reporting in some settings, but not others, is essential for finding effective ways to increase accuracy in measurement of product use and may generalize to promotion efforts for open-label PrEP.

Abstract access 

Editor’s notes: This paper discusses the results of a sub-study conducted as part of the iPrEX randomised placebo-controlled trial. This trial tested the efficacy of once daily oral pre-exposure prophylaxis (PrEP) for HIV prevention for men who have sex with men (MSM) and transgender women, in several sites globally. The iPrEX study was the first PrEP efficacy study providing tenofovir-based PrEP which reported positive results. It found a 44% protection against HIV acquisition. After further analysis, researchers discovered that participants with higher adherence rates as measured by drug concentrations in the blood, achieved higher levels of protection. This finding, coupled with analyses of the other PrEP prevention trials, highlighted the need to understand why participants in the trials did not take the PrEP. The study also emphasised the need to develop optimal measures of adherence, support strategies for adherence, and strategies for delivering the programme to those who are motivated to take PrEP, for future research and implementation purposes. This sub-study specifically examined the optimal strategies for measuring adherence, and found that measures relying on self-reporting and pill counts did not reflect drug level concentrations in the blood. The discrepancies with drug levels varied across sites, with wider discrepancies found in the more resource poor settings. The findings indicate a need for qualitative research to confirm suspicions, and to further understand how best to measure adherence, and encourage it, in future HIV prevention research studies. 

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Meta-analysis finds partial support for elevated HIV prevalence among the military

Systematic review and meta-analysis of HIV prevalence among men in militaries in low income and middle income countries. 

Lloyd J, Papworth E, Grant L, Beyrer C, Baral S. Sex Transm Infect. 2014 Apr 7. doi: 10.1136/sextrans-2013-051463. [Epub ahead of print]

Objectives: To determine whether the current HIV prevalence in militaries of low-income and middle-income countries is higher, the same, or lower than the HIV prevalence in the adult male population of those countries.

Methods: HIV prevalence data from low-income and middle-income countries' military men were systematically reviewed during 2000-2012 from peer reviewed journals, clearing-house databases and the internet. Standardised data abstraction forms were used to collect information on HIV prevalence, military branch and sample size. Random effects meta-analyses were completed with the Mantel-Haenszel method comparing HIV prevalence among military populations with other men in each country.

Results: 2 214 studies were retrieved, of which 18 studies representing nearly 150 000 military men across 11 countries and 4 regions were included. Military male HIV prevalence across the studies ranged from 0.06% (n=22 666) in India to 13.8% (n=2 733) in Tanzania with a pooled prevalence of 1.1% (n=147 591). HIV prevalence in male military populations in sub-Saharan Africa was significantly higher when compared with reproductive age (15-49 years) adult men (OR: 2.8, 95% CI 1.01 to 7.81). HIV prevalence in longer-serving male military populations compared with reproductive age adult men was significantly higher (OR: 2.68, 95% CI 1.65 to 4.35).

Conclusions: Our data reveals that across the different settings, the burden of HIV among militaries may be higher or lower than the civilian male populations. In this study, male military populations in sub-Saharan Africa, low-income countries and longer-serving men have significantly higher HIV prevalence. Given the national security implications of the increased burden of HIV, interventions targeting military personnel in these populations should be scaled up where appropriate.

Abstract access 

Editor’s notes: Men in military service are considered a key population because they spend protracted periods away from home and may engage in casual or other high-risk sex. This is not just a health concern for the armed forces themselves, but countries have in the past refused the assistance of peacekeeping forces because they were deemed a source of new infections. This systematic review concludes that HIV infection rates in the military are not universally higher than among men of reproductive age in the general population. However, significantly elevated prevalence was detected in studies from sub-Saharan Africa and among military who have been in service for over one year. The latter suggests that the relatively high prevalence results from increased exposure during service rather than the disproportional recruitment of men with HIV into service. On the contrary, the prevalence among new recruits is lower than in the general population. Prevention efforts, including HIV testing and counselling, and condom distribution, need to be increased during deployment in settings where exposure to HIV is high.

Africa, Asia, Latin America
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Fewer clinical events with early antiretroviral therapy in a trial among serodiscordant couples

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial.

Grinsztejn B, Hosseinipour MC, Ribaudo HJ, Swindells S, Eron J, Chen YQ, Wang L, Ou SS, Anderson M, McCauley M, Gamble T, Kumarasamy N, Hakim JG, Kumwenda J, Pilotto JH, Godbole SV, Chariyalertsak S, de Melo MG, Mayer KH, Eshleman SH, Piwowar-Manning E, Makhema J, Mills LA, Panchia R, Sanne I, Gallant J, Hoffman I, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Havlir D, Cohen MS, HPTN 052-ACTG Study Team. Lancet Infect Dis. 2014 Apr;14(4):281-90. doi: 10.1016/S1473-3099(13)70692-3. Epub 2014 Mar 4.

Background: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.

Methods: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat.

Findings: 1 763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0.73, 95% CI 0.52-1.03; p=0.074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0.64, 0.43-0.96; p=0.031), tuberculosis developed in 17 versus 34 patients, respectively (0.49, 0.28-0.89, p=0.018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24.9 per 100 person-years, 95% CI 22.5-27.5) versus 585 in the delayed treatment group (29.2 per 100 person-years, 26.5-32.1; p=0.025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.

Interpretation: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.

Abstract access 

Editor’s notes: The HPTN 052 trial has received wide attention for its main result. This shows a large reduction in HIV transmission risk among HIV-serodiscordant couples where HIV-positive partners with CD4 counts between 350 and 550 started immediate antiretroviral therapy (ART). This was compared to deferring treatment until the CD4 count fell below 250 or an AIDS-defining illness occurred. This analysis reports on clinical events in the trial. Despite the trial population having relatively high CD4 counts at baseline, new AIDS-defining events, excluding tuberculosis, were the most common outcome. These were reduced in the early ART arm. Tuberculosis incidence was reduced by half. Non-AIDS events were rare.

For these trial results to translate into population level benefits, more people need to know their HIV status at an early stage, before they develop symptomatic disease. People with positive test results then need to link to care successfully so that treatment can be initiated. Stigma remains a key barrier to testing and accessing care in many settings. Virologic suppression among people in the intervention arm of this trial was very high, implying very good adherence to treatment. Strategies to support excellent adherence and retention are needed as ART programmes expand and include people starting ART earlier.

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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Overcoming logistical barriers to implementing viral load testing


Systematic review of the use of dried blood spots for monitoring HIV viral load and for early infant diagnosis.

Smit PW, Sollis KA, Fiscus S, Ford N, Vitoria M, Essajee S, Barnett D, Cheng B, Crowe SM, Denny T, Landay A, Stevens W, Habiyambere V, Perriens JH, Peeling RW. PLoS One. 2014 Mar 6;9(3):e86461. doi: 10.1371/journal.pone.0086461. eCollection 2014.

Background: Dried blood spots (DBS) have been used as alternative specimens to plasma to increase access to HIV viral load (VL) monitoring and early infant diagnosis (EID) in remote settings. We systematically reviewed evidence on the performance of DBS compared to plasma for VL monitoring and EID.

Methods and findings: Thirteen peer reviewed HIV VL publications and five HIV EID papers were included. Depending on the technology and the viral load distribution in the study population, the percentage of DBS samples that are within 0.5 log of VL in plasma ranged from 52-100%. Because the input sample volume is much smaller in a blood spot, there is a risk of false negatives with DBS. Sensitivity of DBS VL was found to be 78-100% compared to plasma at VL below 1 000 copies/ml, but this increased to 100% at a threshold of 5 000 copies/ml. Unlike a plasma VL test which measures only cell free HIV RNA, a DBS VL also measures proviral DNA as well as cell-associated RNA, potentially leading to false positive results when using DBS. The systematic review showed that specificity was close to 100% at DBS VL above 5 000 copies/ml, and this threshold would be the most reliable for predicting true virologic failure using DBS. For early infant diagnosis, DBS has a sensitivity of 100% compared to fresh whole blood or plasma in all studies.  

Conclusions: Although limited data are available for EID, DBS offer a highly sensitive and specific sampling strategy to make viral load monitoring and early infant diagnosis more accessible in remote settings. A standardized approach for sampling, storing, and processing DBS samples would be essential to allow successful implementation.

Abstract    Full-text [free] access 

Editor’s notes: The World Health Organization recommends that viral load monitoring is used to confirm early infant diagnoses of HIV and to monitor people on antiretroviral therapy for treatment failure. However, viral load monitoring is expensive, technically complex and requires good laboratory infrastructure and highly trained staff. As a result few countries in resource-limited settings have been able to implement these guidelines.

This systematic review evaluates the performance of dried blood spots as compared to plasma for measuring viral load. Dried blood spots (DBS) are an alternative sampling strategy which could be used to overcome some of the logistical barriers to the widespread implementation of viral load testing. They can be performed by lay workers as there is no need for phlebotomy. Whole blood from a finger or heel prick is placed directly onto filter paper and once dried they can be stored with desiccant and transferred to the central laboratory at room temperature. The results of this systematic review confirm that DBS offer a highly sensitive and specific sampling strategy for early infant diagnosis and for detecting virologic failure at a viral load threshold of      >5 000 copies/ml. However, the authors’ stress that in order to compare different methodologies, standardised protocols for sampling, storing and processing samples are needed. DBS do provide a very promising strategy for increasing access to viral load monitoring. However if we are to see an impact on outcomes, the roll out of DBS will need to be accompanied by robust systems to ensure timely turn-around-times for results. Staff training and support to ensure that appropriate action is taken following a raised viral load, are also a must.

Africa, Asia, Europe
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Need for increased focus on mental health among HIV-positive pregnant women

Mental health of HIV-seropositive women during pregnancy and postpartum period: a comprehensive literature review.

Kapetanovic S, Dass-Brailsford P, Nora D, Talisman N. AIDS Behav. 2014 Mar 2. [Epub ahead of print]

With growing numbers of HIV-seropositive (HIV+) women of child-bearing age and increased access to effective clinical protocols for preventing mother-to-child transmission (MTCT) of HIV, mental health-related factors have become increasingly relevant due to their potential to affect the women's quality of life, obstetric outcomes and risk of MTCT. This review synthesizes evidence from 53 peer-reviewed publications examining mental health-related variables in pregnant and postpartum HIV+ women. The presentation of results is organized by the level of socioeconomic resources in the countries where studies were conducted (i.e., high-, middle-, and low-income countries). It is concluded that psychiatric symptoms, particularly depression, and mental health vulnerabilities (e.g., inadequate coping skills) are widespread among pregnant HIV+ women globally and have a potential to affect psychological well-being, quality of life and salient clinical outcomes. The current body of evidence provides rationale for developing and evaluating clinical and structural interventions aimed at improving mental health outcomes and their clinical correlates in pregnant HIV+ women.

Abstract access 

Editor’s notes: The comprehensive review summarises evidence from over fifty studies on a range of mental health variables in pregnant and post-partum HIV-positive women. The results highlight the need to screen for depression among pregnant HIV-positive women, and to provide appropriate referrals and programmes. Five randomised controlled trials were identified (all from low- and middle-income countries), with encouraging results of activities such as culturally-adapted psycho-educational programmes. Future randomised trials are needed to build on this evidence and assess the impact of such programmes not only on mental health outcomes, but also HIV-related factors such as antiretroviral therapy adherence and mother-to-child transmission of HIV. The absence of trials from high-income countries is noticeable, indicating the need for further focus on mental health needs of HIV-positive pregnant women in these settings.

Africa, Asia, Europe, Northern America
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Community-level behavioural programme increases access to HIV testing and counselling

NIMH Project Accept (HPTN 043): results from in-depth interviews with a longitudinal cohort of community members.

Maman S, van Rooyen H, Stankard P, Chingono A, Muravha T, Ntogwisangu J, Phakathi Z, Srirak N, F Morin S; NIMH Project Accept (HPTN 043) study team. PLoS One. 2014 Jan 29;9(1):e87091. doi: 10.1371/journal.pone.0087091. eCollection 2014.

Introduction: NIMH Project Accept (HPTN 043) is a community- randomized trial to test the safety and efficacy of a community-level intervention designed to increase testing and lower HIV incidence in Tanzania, Zimbabwe, South Africa and Thailand. The evaluation design included a longitudinal study with community members to assess attitudinal and behavioral changes in study outcomes including HIV testing norms, HIV-related discussions, and HIV-related stigma.

Methods: A cohort of 657 individuals across all sites was selected to participate in a qualitative study that involved 4 interviews during the study period. Baseline and 30-month data were summarized according to each outcome, and a qualitative assessment of changes was made at the community level over time.

Results: Members from intervention communities described fewer barriers and greater motivation for testing than those from comparison communities. HIV-related discussions in intervention communities were more grounded in personal testing experiences. A change in HIV-related stigma over time was most pronounced in Tanzania and Zimbabwe. Participants in the intervention communities from these two sites attributed community-level changes in attitudes to project specific activities.

Discussion: The Project Accept intervention was associated with more favorable social norms regarding HIV testing, more personal content in HIV discussions in all study sites, and qualitative changes in HIV-related stigma in two of five sites.

Abstract Full-text [free] access 

Editor’s notes: This paper describes a qualitative evaluation of the impact of NIMH Project Accept. The programme sought to determine the safety and efficacy of a community level behavioural intervention in reducing HIV incidence. The programme included: 1) increasing community knowledge about HIV; 2) increasing access to voluntary testing and counselling; and 3) providing post-test support services. Programme communities had higher rates of testing and improved social norms regarding HIV, than comparison communities. There was no impact on HIV-related stigma. The qualitative research collected in this evaluation describes how the quantitative changes found in the main trial happened. This paper highlights the importance of using a mixed methods approach when studying multi-level activities at the community level.  The study determined that programme community participants had fewer barriers and stronger motivation for testing than comparison communities. The qualitative analysis provided a narrative for how the programmes affected the communities. There were more favourable community norms regarding HIV testing in the programme communities. The primary goal of Project Accept was that HIV-related stigma would be reduced but there was little quantitative evidence to support this hypothesis in the study. Qualitative evidence did show some reduction in stigmatizing language over time across all study sites. No meaningful patterns of change in sexual risk behaviour were found across the programme and comparison communities. 

Africa, Asia
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Efavirenz dose reduction could help scale up antiretroviral therapy access

Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial.

ENCORE1 Study Group. Lancet. 2014 Feb 7. pii: S0140-6736(13)62187-X. doi: 10.1016/S0140-6736(13)62187-X. [Epub ahead of print]

Background: The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings.

Methods: ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per µL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment.

Findings: The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per µL (SD 99) and median plasma HIV-RNA was 4.75 log10 copies per mL (IQR 0.88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI -2.1 to 5.79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per µL, 95% CI 6-44; p=0.01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89.1%, efavirenz 600=88.4%; difference 0.75%, 95% CI -4.19 to 5.69; p=0.77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10.5%, 95% CI -18.2 to -2.8; p=0.01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3.96%, 95% CI -6.96 to -0.95; p=0.01).

Interpretation: Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care.

Abstract access

Editor’s notes: Nearly 10 million people in low- and middle-income countries were receiving antiretroviral therapy (ART) by the end of 2012, with plans to expand coverage to 15 million by 2015. Several challenges must be overcome if this target is to be achieved. One of the most pertinent of these is how to fund this expansion in the current economic climate. Significant progress has already been made in reducing the cost of first-line drugs. The authors of this paper propose an alternative approach to lowering drug costs, namely dose reduction.

Evidence supporting the 600mg dose of efavirenz used in clinical practice is weak, with no difference found in the proportion of patients achieving viral suppression in the original dose finding trials of 200mg, 400mg and 600mg (unpublished). This trial in ART-naive individuals found that 400mg was non-inferior to 600mg of efavirenz in terms of viral suppression over 48 weeks of follow-up. Findings were similar when stratified by ethnic group (African, Asian, other) and body mass index, both factors which influence drug concentrations. Furthermore, fewer patients on 400mg reported adverse events which were related to efavirenz, and fewer patients with drug-related side effects on this dose stopped efavirenz. These promising results support a dose reduction strategy. However, longer term outcomes need to be evaluated and efficacy studies in patients with tuberculosis are needed before the 400mg dose is recommended for use in routine clinical practice. Certainly, if drug companies agree to manufacture this dose at scale, preferably in fixed-dose combination tablets, cost-savings could be considerable.  

Africa, Asia, Europe, Latin America
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CD4 counts at antiretroviral therapy start rising globally, but could do better!

Immunodeficiency at the start of combination antiretroviral therapy in low-,  middle-, and high-income countries.

The IeDEA and ART Cohort Collaborations. J Acquir Immune Defic Syndr 2014 Jan 1;65(1):e8-e16. doi: 10.1097/QAI.0b013e3182a39979.

Objective: To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries.

Methods: Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed.

Results: In total, 379 865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/µL between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/µL (76% increase), 88 to 135 cells/µL (53%), and 209 to 274 cells/µL (31%). In 2009, compared with LIC, median counts were 13 cells/µL [95% confidence interval (CI): -56 to +30] lower in LMIC, 22 cells/µL (-62 to +18) lower in UMIC, and 112 cells/µL (+75 to +149) higher in HIC. They were 23 cells/µL (95% CI: +18 to +28 cells/µL) higher in women than men. Median counts were 88 cells/µL (95% CI: +35 to +141 cells/µL) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage.

Conclusions: Median CD4 cell counts at the start of cART increased 2000-2009 but remained below 200 cells/µL in LIC and MIC and below 300 cells/µL in HIC. Earlier start of cART will require substantial efforts and resources globally.

Abstract access 

Editor’s notes: In this multi-cohort analysis spanning six continents, median CD4 counts at initiation of combination antiretroviral therapy were substantially higher in high-income compared to low- or middle-income countries. Median CD4 counts at initiation increased between 2002 and 2009 in most countries studied, but these increases were greater in low- and middle-income than high-income countries and were greater among men than women. Baseline CD4 counts in low- and middle-income countries were higher among countries with national antiretroviral therapy coverage of 80% or above. Nevertheless, despite the massive scale-up of antiretroviral therapy in low-income countries since 2002, the increases in median CD4 count at the start of antiretroviral therapy have been modest. Substantial efforts and resources are needed to achieve earlier implementation of antiretroviral therapy globally.

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Intrauterine infections, but not obstetric complications, more common among pregnant women with HIV

HIV and the Risk of Direct Obstetric Complications: A Systematic Review and Meta-Analysis. 

Calvert C, Ronsmans C. PLoS One. 2013 Oct 4;8(10):e74848. doi:10.1371/journal.pone.0074848.

Background: Women of reproductive age in parts of sub-Saharan Africa are faced both with high levels of HIV and the threat of dying from the direct complications of pregnancy. Clinicians practicing in such settings have reported a high incidence of direct obstetric complications among HIV-infected women, but the evidence supporting this is unclear. The aim of this systematic review is to establish whether HIV-infected women are at increased risk of direct obstetric complications.

Methods and findings: Studies comparing the frequency of obstetric haemorrhage, hypertensive disorders of pregnancy, dystocia and intrauterine infections in HIV-infected and uninfected women were identified. Summary estimates of the odds ratio (OR) for the association between HIV and each obstetric complication were calculated through meta-analyses. In total, 44 studies were included providing 66 data sets; 17 on haemorrhage, 19 on hypertensive disorders, five on dystocia and 25 on intrauterine infections. Meta-analysis of the OR from studies including vaginal deliveries indicated that HIV-infected women had over three times the risk of a puerperal sepsis compared with HIV-uninfected women [pooled OR: 3.43, 95% confidence interval (CI): 2.00-5.85]; this figure increased to nearly six amongst studies only including women who delivered by caesarean (pooled OR: 5.81, 95% CI: 2.42-13.97). For other obstetric complications the evidence was weak and inconsistent.

Conclusions: The higher risk of intrauterine infections in HIV-infected pregnant and postpartum women may require targeted strategies involving the prophylactic use of antibiotics during labour. However, as the huge excess of pregnancy-related mortality in HIV-infected women is unlikely to be due to a higher risk of direct obstetric complications, reducing this mortality will require non obstetric interventions involving access to ART in both pregnant and non-pregnant women.

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Editor’s notes: Women with HIV are thought to have a higher risk of adverse outcomes during pregnancy. This review is valuable in summarizing available data on this topic. Many of the included studies predated the wide availability of antiretroviral therapy. There was a clear association between HIV infection and intrauterine infections, but not with the other obstetric complications, e.g., obstetric haemorrhage, hypertensive disorders of pregnancy, dystocia, examined in the review. Considering individual conditions analysed, HIV infection was associated with antepartum haemorrhage, (but not postpartum haemorrhage). It was also found to be associated with pregnancy-induced hypertension (but not pre-eclampsia or eclampsia), and uterine rupture or prolonged labour (but not other complications of dystocia). The authors note that the studies were generally of low quality, and there were too few studies to examine the effect of antiretroviral therapy on these complications.  

Given the excess of intrauterine infections in women with HIV, the authors suggest that these might be preventable with prophylactic antibiotics. Overall, where causes of maternal mortality are documented, pregnant women with HIV are more likely to die of non-pregnancy related infections, than of obstetric complications. Specifically, non-pregnancy related infections are tuberculosis, pneumonia or meningitis. Pregnant women living with HIV need access to antenatal services and a skilled attendant at delivery. But, the top priority with respect to reducing maternal mortality is effective antiretroviral therapy.

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