First-line Antiretroviral Research Articles

Compatibility of next-generation first-line antiretrovirals with rifampicin-based antituberculosis therapy in resource limited settings.

Reduced dose efavirenz, dolutegravir, and/or tenofovir alafenamide (TAF) are likely to be used in the next generation of first-line antiretroviral therapy in resource limited settings, where HIV-associated tuberculosis is common. Rifampicin, which is a key component of first-line antituberculosis therapy, is a potent inducer of many drug transporters and metabolising enzymes. We reviewed the literature for potential or actual drug--drug interactions between these antiretrovirals and rifampicin. Dose adjustments of standard dose efavirenz are not necessary with rifampicin, because auto-induction of CYP2B6 by efavirenz counteracts the induction of rifampicin. However, patients with extensive metabolizer CYP2B6 genotypes have lower efavirenz concentrations and may have less auto-induction of CYP2B6; the additive inducing effects of rifampicin on CYP2B6 could result in clinically significant reductions of efavirenz concentrations. Doubling the dose of dolutegravir overcomes induction by rifampicin. TAF is more prone to be the victim in drug--drug interactions than tenofovir disoproxil fumarate. Interactions between TAF and rifampicin have not been studied, but there is likely to be significant interaction. Further research on drug--drug interactions between rifampicin and the next generation of first-line antiretrovirals will be needed before they can be recommended in patients with HIV-associated tuberculosis.

Viral Suppression and Discontinuation Rates have Improved in HIV Patients with Modern Antiretroviral Therapies

Objective: Rates and determinants of first-line antiretroviral (ARV) discontinuation or change in prescribed regimen were assessed between old (pre-2006) and modern (post-2006) era stratified by dosing frequency [(once daily (QD) versus twice or more daily (BID+)]. Methods: A single-center retrospective cohort study was conducted. All adult HIV patients initiating ARVs from January 1995-November 2015 were included. Patients were stratified by old- or modern-era and by dosing frequency. The primary outcome was rate of ARV therapy discontinuation or change in initial regimen. The secondary outcome was reason for discontinuation. Results: 1,127 patients were included from the old (n=621) and modern era (n=506). Modern-era patients were more likely to receive QD regimens (p<0.001) and had increased viral suppression at the last recorded testing than oldera patients (70.9% vs. 43.2%, p<0.001). Modern-era and QD patients had better adherence and treatment duration. Patients on integrase inhibitor (INSTI)- and NNRTI-based therapy had longer treatment durations and better ARV adherence. Risk factors for treatment switch or discontinuation included old-era therapy, IDU and PI+NRTI treatment. Older ages and immigrants were less likely to discontinue therapy. Common reasons for treatment discontinuation included changing treatments to improve regimen profile, gastrointestinal side effects, and neuropsychological issues. Conclusion: In patients initiating first-line ARV, risk of discontinuation or regimen changes has diminished in the modern-era with QD, INSTI- or NNRTI-based regimens. More attention to high risk patients including IDU is advised in attempts to improve outcomes. These findings provide ‘real world’ support for current clinical practice guidelines.

Drug Resistance Mutations and Genetic Diversity in Patients Treated for HIV Type 1 Infection in Rural Care Centers in Togo

Introduction: Access to antiretroviral treatment (ART) in resource-limited countries has increased signif-icantly but scaling up ART into rural areas is more recent and information on treatment outcome in rural areas is still very limited. We reported here virological outcome and drug resistance in ART in rural settings in Togo. Methods: HIV-1 infected adults (≥18 years) and infants were enrolled in routine medical visit at 12 on first-line ART in three HIV care centers. Epidemiological and demographic information and data on ART history were collected. Viral load (VL) was determined and genotypic drug resistance testing was performed on all samples with viral load above 1000 copies/ml. Results: 102 adult patients and 27 infants were consecutively enrolled. Virological failure was observed in 28 (21.5%) patients. For 25/28 patients, sequencing was successful and drug resistance mutations were observed in 23 (92%) of them. The global prevalence of drug resistance in the study population was thus at least 17.8% (23/129), with 7 (6.9%) patients infected with HIV strains that are resistant to two of the three first-line antiretroviral (ARVs) drugs and 9 (8.3%) to all three first-line ARVs. As expected, the observed drug resistance mutations were mainly associated with the drugs used in first line regimens, zidovudine, lamivudine and effavirenz/nevirapine but several patients accumulated high numbers of mutations and developed also cross-resistance to abacavir, didanosine or the new non-nucleoside reverse transcriptase inhibitor drugs, like etravirine and rilpivirine. Conclusion: The observations on ART treatment outcome from ART clinics in rural areas are the same as observed in previous observations in Lome, the capital city. Although access to viral load will improve treatment outcome, better programme management and implementation of actions to improve factors as patient adherence, drugs stock-outs and lost to follow-up are also essential.

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection.

Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure. AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations. Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI. Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype.

Clinical utility of raltegravir for the treatment of HIV infection in children and adolescents

Clinical utility of raltegravir for the treatment of HIV infection in children and adolescents James Nuttall,1 Tammy Meyers,2 Brian Eley11Paediatric Infectious Diseases Unit, Red Cross War Memorial Children&#39;s Hospital and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa; 2Department of Paediatrics, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaAbstract: Raltegravir (RAL) is the first integrase strand transfer inhibitor and has been shown to provide potent antiretroviral (ARV) activity against human immunodeficiency virus type 1 (HIV-1) in both ARV treatment-na&iuml;ve and treatment-experienced individuals. Following initial US Food and Drug Administration (FDA) approval of RAL for treatment of HIV-1-infected adults in 2007, an ongoing pharmacokinetic, safety, and efficacy study in ARV-experienced children and adolescents led to extension of FDA approval to children and adolescents aged 2&ndash;18 years in 2011. Availability of chewable tablets for children aged 2&ndash;11 years is a significant advantage, and twice-daily dosing is recommended based on pharmacokinetic parameters. Granules for oral suspension in children 4 weeks to 2 years of age are currently under evaluation and clinical trials in neonates are imminent. Coadministration of RAL and the anti-tuberculosis drug rifampin (RIF) results in reduced RAL exposure. Evaluation of a double RAL dosing strategy in children requiring cotreatment with RIF is planned. RAL is generally well tolerated and has a good overall safety profile. Further data is required for children before RAL can be recommended in first-line ARV treatment regimens. RAL is also under investigation for use in preventing mother-to-child transmission both during pregnancy and in the HIV-exposed neonate. Currently, the main therapeutic role for RAL in children is for treatment failure and multi-drug resistant cases where the inclusion of RAL in combination with optimal background therapy has demonstrated successful outcomes. Increased availability of RAL and the introduction of second-generation integrase inhibitors are likely to further extend the utility of this class of ARV drugs.Keywords: antiretroviral therapy, integrase strand transfer inhibitor, raltegravir, HIV-1

Trends in Genotypic HIV-1 Antiretroviral Resistance between 2006 and 2012 in South African Patients Receiving First- and Second-Line Antiretroviral Treatment Regimens

ObjectivesSouth Africa’s national antiretroviral (ARV) treatment program expanded in 2010 to include the nucleoside reverse transcriptase (RT) inhibitors (NRTI) tenofovir (TDF) for adults and abacavir (ABC) for children. We investigated the associated changes in genotypic drug resistance patterns in patients with first-line ARV treatment failure since the introduction of these drugs, and protease inhibitor (PI) resistance patterns in patients who received ritonavir-boosted lopinavir (LPV/r)-containing therapy.MethodsWe analysed ARV treatment histories and HIV-1 RT and protease mutations in plasma samples submitted to the Tygerberg Academic Hospital National Health Service Laboratory.ResultsBetween 2006 and 2012, 1,667 plasma samples from 1,416 ARV-treated patients, including 588 children and infants, were submitted for genotypic resistance testing. Compared with 720 recipients of a d4T or AZT-containing first-line regimen, the 153 recipients of a TDF-containing first-line regimen were more likely to have the RT mutations K65R (46% vs 4.0%; p<0.001), Y115F (10% vs. 0.6%; p<0.001), L74VI (8.5% vs. 1.8%; p<0.001), and K70EGQ (7.8% vs. 0.4%) and recipients of an ABC-containing first-line regimen were more likely to have K65R (17% vs 4.0%; p<0.001), Y115F (30% vs 0.6%; p<0.001), and L74VI (56% vs 1.8%; p<0.001). Among the 490 LPV/r recipients, 55 (11%) had ≥1 LPV-resistance mutations including 45 (9.6%) with intermediate or high-level LPV resistance. Low (20 patients) and intermediate (3 patients) darunavir (DRV) cross resistance was present in 23 (4.6%) patients.ConclusionsAmong patients experiencing virological failure on a first-line regimen containing two NRTI plus one NNRTI, the use of TDF in adults and ABC in children was associated with an increase in four major non- thymidine analogue mutations. In a minority of patients, LPV/r-use was associated with intermediate or high-level LPV resistance with predominantly low-level DRV cross-resistance.

Changes to Antiretroviral Drug Regimens during Integrated TB–HIV Treatment: Results of the Sapit Trial

Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and HIV therapy, as a result of treatment-limiting toxicity or virological failure, is not well established. Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy (ART) either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load >1,000 copies/ml on two occasions, taken ≥4 weeks apart) were assessed in these patients. A total of 501 TB-HIV-coinfected patients were followed for a mean of 16.0 months (95% CI 15.5, 16.6) after ART initiation. The standard first-line antiretrovirals used were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate 2.1 per 100 person-years, 95% CI 1.1, 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate 3.7 per 100 person-years, 95% CI 2.4, 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4, 0.8%), elevated transaminase levels and hyperlactataemia (n=3, 0.6%), and peripheral neuropathy (n=2, 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4(+) T-cell count <50 cells/mm(3) (P<0.001) at ART initiation and body mass index >25 kg/m(2) (P=0.01) at entry into the study. Both drug switches and complete regimen change were uncommon in patients cotreated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change.

Are we conSTRucting the best treatment regimens for all patients with HIV infection?

The British HIV Association (BHIVA) 2012 guidelines for the treatment of HIV recommend patients start combination antiretroviral therapy (ART) containing tenofovir and emtricitabine as the nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone. BHIVA third agent preferred choices comprise efavirenz, boosted atazanavir, boosted darunavir and raltegravir, and the guidelines further state that ‘fixed dose combinations (FDC) of drugs can increase adherence’ [1]. Atripla is currently the only available single-tablet regimen (STR) for the treatment of HIV which contains a combination of BHIVA preferred first-line antiretrovirals (tenofovir, emtricitabine and efavirenz). In addition, studies have shown that Atripla can improve adherence, treatment satisfaction and outcomes for patients infected with HIV [2]. A retrospective case note review was conducted for all HIV-positive patients attending a UK HIV centre and receiving ART. The purpose was to ascertain the proportion of patients receiving BHIVA preferred ART in its simplest dosing format (in this case Atripla) and to investigate whether there were clinically or virologically appropriate reasons why patients not on Atripla were prescribed more complex drug regimens. The total number of patients receiving ART at the time of review was 142, of which 47 (33%) were currently taking Atripla. Of the remaining 95 patients, 30 (32%) had taken Atripla or some of its components in the past and been changed from this for valid clinical or virological reasons. In addition, there were a further 34 cases (36%) where Atripla had never been offered to the patient for appropriate reasons and documentation of 8 instances in which Atripla had been declined by the patient. There remained, however, 28 cases (29%) where there was no documentation of Atripla having been considered or offered, and no apparent contraindications to the STR or its components. This included 4 patients with an elevated cardiovascular risk, all of whom were taking an abacavir-containing ART regimen at the time of review. Despite extensive professional guidance on preferred ART regimens and evidence to suggest that STR can increase adherence and patient satisfaction there remain patients in clinical care taking more complex drug regimens with no clear indication for this. We would encourage physicians to identify such patients and to discuss with them their treatment options in the light of advances in ART combination preparations.

HIV-1 Antiretroviral Resistance

The efficacy of an antiretroviral (ARV) treatment regimen depends on the activity of the regimen’s individual ARV drugs and the number of HIV-1 mutations required for the development of resistance to each ARV — the genetic barrier to resistance. ARV resistance impairs the response to therapy in patients with transmitted resistance, unsuccessful initial ARV therapy and multiple virological failures. Genotypic resistance testing is used to identify transmitted drug resistance, provide insight into the reasons for virological failure in treated patients, and help guide second-line and salvage therapies. In patients with transmitted drug resistance, the virological response to a regimen selected on the basis of standard genotypic testing approaches the responses observed in patients with wild-type viruses. However, because such patients are at a higher risk of harbouring minority drug-resistant variants, initial ARV therapy in this population should contain a boosted protease inhibitor (PI) — the drug class with the highest genetic barrier to resistance.In patients receiving an initial ARV regimen with a high genetic barrier to resistance, the most common reasons for virological failure are nonadherence and, potentially, pharmacokinetic factors or minority transmitted drug-resistant variants. Among patients in whom first-line ARVs have failed, the patterns of drug-resistance mutations and cross-resistance are often predictable. However, the extent of drug resistance correlates with the duration of uncontrolled virological replication. Second-line therapy should include the continued use of a dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing backbone, together with a change in the non-NRTI component, most often to an ARV belonging to a new drug class.The number of available fully active ARVs is often diminished with each successive treatment failure. Therefore, a salvage regimen is likely to be more complicated in that it may require multiple ARVs with partial residual activity and compromised genetic barriers of resistance to attain complete virological suppression. A thorough examination of the patient’s ARV history and prior resistance tests should be performed because genotypic and/or phenotypic susceptibility testing is often not sufficient to identify drug-resistant variants that emerged during past therapies and may still pose a threat to a new regimen. Phenotypic testing is also often helpful in this subset of patients. ARVs used for salvage therapy can be placed into the following hierarchy: (i) ARVs belonging to a previously unused drug class; (ii) ARVs belonging to a previously used drug class that maintain significant residual antiviral activity; (iii) NRTI combinations, as these often appear to retain in vivo virological activity, even in the presence of reduced in vitro NRTI susceptibility; and rarely (iv) ARVs associated with previous virological failure and drug resistance that appear to have possibly regained their activity as a result of viral reversion to wild type. Understanding the basic principles of HIV drug resistance is helpful in guiding individual clinical decisions and the development of ARV treatment guidelines.

Antiretroviral drug supply challenges in the era of scaling up ART in Malawi

The number of people receiving antiretroviral treatment (ART) has increased considerably in recent years and is expected to continue to grow in the coming years. A major challenge is to maintain uninterrupted supplies of antiretroviral (ARV) drugs and prevent stock outs. This article discusses issues around the management of ARVs and prevention of stock outs in Malawi, a low-income country with a high HIV/AIDS burden, and a weak procurement and supply chain management system. This system for ARVs, paid for by the Global Fund to Fight AIDS, Tuberculosis and Malaria, and bypassing the government Central Medical Stores, is in place, using the United Nations Children’s Fund’s (UNICEF’s) procurement services. The system, managed by a handful of people who spend limited time on supply management, is characterized by a centrally coordinated quantification based on verified data from all national ART clinics, parallel procurement through UNICEF, and direct distribution to ART clinics. The model worked well in the first years of the ART programme with a single first-line ARV regimen, but with more regimens becoming available (e.g., alternative first-line, second-line and paediatric regimens), it has become more difficult to administer. Managing supplies through a parallel system has the advantage that weaknesses in the national system have limited influence on the ARV procurement and supply chain management system. However, as the current system operates without a central warehouse and national buffer stock capacity, it diminishes the ability to prevent ARV stock outs. The process of ordering ARVs, from the time that estimates are made to the arrival of supplies in health facilities, takes approximately one year. Addressing the challenges involved in maintaining ARVs through an efficient procurement and supply chain management system that prevents ARV stock outs through the establishment of a dedicated procurement team, a central warehouse and/or national buffer stock is a priority.

Lactic Acidosis and Symptomatic Hyperlactataemia in a Randomized Trial of First-Line Therapy in HIV-Infected Adults in South Africa

Lactic acidosis (LA) is a potentially life-threatening complication of antiretroviral (ARV) therapy. Few randomized prospective studies have compared LA between different ARV regimens. Characterization of cases of LA (serum lactate >5 mmol/l and arterial pH<7.35 or bicarbonate <20 mmol/l) and symptomatic hyperlactataemia (SH; serum lactate >2.2 mmol/l and symptoms) was made in a randomized open-label 2×2 factorial study of stavudine/lamivudine (d4T/3TC)-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz (EFV)-based therapy in 1,771 HIV-infected adults initiating therapy between 2004 and 2008. The LA incident rate was 3.5/1,000 person-years (95% CI 1.8-5.9), and for combined LA/SH was 11.0/1,000 person-years (95% CI 7.9-14.9). There were two deaths (15% mortality) among 13 LA cases; all 11 survivors experienced symptom resolution and started new ARV regimens. LA cases were more likely to be female (OR 7.19, 95% CI 1.84-40.75; P=0.001) and had a higher body mass index (BMI; P<0.0001) compared with non-cases. There was no increase in LA according to ARV regimen, age or CD4(+) T-cell count at randomization. When combined, LA/SH cases (n=41) were more often female (OR 4.76, 95% CI 2.36-10.08; P<0.0001), had increased BMI (P<0.0001), were more likely to be assigned d4T/3TC (OR 3.17, 95% CI 1.50-7.28; P=0.001) and were more likely to be assigned EFV (OR 2.18, 95% CI 1.08-4.61; P=0.026). Female sex and increased BMI were associated with severe LA in this large randomized trial of first-line ARV in South Africa. While female sex, increased BMI and d4T are previously described risk factors for the development of clinically significant lactate elevations, the independent risk associated with EFV is a novel observation warranting further investigation.

Design of a randomized trial to evaluate the influence of mobile phone reminders on adherence to first line antiretroviral treatment in South India - the HIVIND study protocol

BackgroundPoor adherence to antiretroviral treatment has been a public health challenge associated with the treatment of HIV. Although different adherence-supporting interventions have been reported, their long term feasibility in low income settings remains uncertain. Thus, there is a need to explore sustainable contextual adherence aids in such settings, and to test these using rigorous scientific designs. The current ubiquity of mobile phones in many resource-constrained settings, make it a contextually appropriate and relatively low cost means of supporting adherence. In India, mobile phones have wide usage and acceptability and are potentially feasible tools for enhancing adherence to medications. This paper presents the study protocol for a trial, to evaluate the influence of mobile phone reminders on adherence to first-line antiretroviral treatment in South India.Methods/Design600 treatment naïve patients eligible for first-line treatment as per the national antiretroviral treatment guidelines will be recruited into the trial at two clinics in South India. Patients will be randomized into control and intervention arms. The control arm will receive the standard of care; the intervention arm will receive the standard of care plus mobile phone reminders. Each reminder will take the form of an automated call and a picture message. Reminders will be delivered once a week, at a time chosen by the patient. Patients will be followed up for 24 months or till the primary outcome i.e. virological failure, is reached, whichever is earlier. Self-reported adherence is a secondary outcome. Analysis is by intention-to-treat. A cost-effectiveness study of the intervention will also be carried out.DiscussionStepping up telecommunications technology in resource-limited healthcare settings is a priority of the World Health Organization. The trial will evaluate if the use of mobile phone reminders can influence adherence to first-line antiretrovirals in an Indian context.Trial RegistrationTrial registration: ISRCTN79261738.

Discontinuation of standard first‐line antiretroviral therapy in a cohort of 1434 Malawian children

The standard first-line antiretroviral (ART) regimen in Malawi for both adults and children is a fixed-dose combination tablet containing stavudine (d4T), lamivudine (3TC) and nevirapine (NVP). This regimen has been shown to yield satisfactory virologic and immunologic outcomes in children. Published studies have described insights into discontinuation of first-line regimen and toxicities of ART in adults, but similar studies in paediatric populations are lacking.A retrospective cohort study was undertaken to assess reasons for discontinuation of the standard first-line ART regimen (d4T/3TC/NVP) in a paediatric population. In total, 1434 patients met eligibility criteria and were included. The cohort had mean and median age at ART initiation of 4.7 years and 2.9 years, respectively (range: 0.1 months-18.7 years). The gender distribution was 47% female and 53% male. Median follow-up time on ART was 1.8 years (range: 2 weeks-3.9 years). A majority (96.2%) of patients were on the standard first-line ART regimen, while 3.8% (54) were on a different regimen. Twenty-eight patients (2.0%) were on an alternative first-line regimen due to toxicities, 22 patients (1.5%) were on a second-line regimen due to ART failure, and four patients (0.3%) were on a non-standard regimen for other clinical reasons.Of the 28 patients who experienced toxicities requiring ART regimen change, 60.7% (17) were caused by NVP, 39.3% (11) by d4T, and none by 3TC. The median time from first-line ART initiation to alternative first-line ART was two months (range: 10 days-28.1 months); 60.7% of patients on alternative first-line ART were male. Average time on ART until switch to second-line ART regimen was 16.3 months (SD: 9.3 months). The probability of failure after one year on first-line regimen was 1.6% (95% CI: 0.9-2.6).There was no compelling evidence in this cohort, representing approximately 10% of all children on ART in Malawi, to support changing the standard paediatric first-line regimen based on early toxicities or failure. However, experience from the national adult cohort, longer term follow up of the paediatric cohort in this study, emerging data on resistance after single-dose NVP containing mother to child transmission antiretroviral prophylaxis, and new 2009 World Health Organization ART recommendations may influence national policy change to a different first-line regimen.

Intervening in global markets to improve access to HIV/AIDS treatment: an analysis of international policies and the dynamics of global antiretroviral medicines markets

BackgroundUniversal access to antiretroviral therapy (ART) in low- and middle-income countries faces numerous challenges: increasing numbers of people needing ART, new guidelines recommending more expensive antiretroviral (ARV) medicines, limited financing, and few fixed-dose combination (FDC) products. Global initiatives aim to promote efficient global ARV markets, yet little is known about market dynamics and the impact of global policy interventions.MethodsWe utilize several data sources, including 12,958 donor-funded, adult first-line ARV purchase transactions, to describe the market from 2002-2008. We examine relationships between market trends and: World Health Organization (WHO) HIV/AIDS treatment guidelines; WHO Prequalification Programme (WHO Prequal) and United States (US) Food and Drug Administration (FDA) approvals; and procurement policies of the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), US President's Emergency Plan for AIDS Relief (PEPFAR) and UNITAID.ResultsWHO recommended 7, 4, 24, and 6 first-line regimens in 2002, 2003, 2006 and 2009 guidelines, respectively. 2009 guidelines replaced a stavudine-based regimen ($88/person/year) with more expensive zidovudine- ($154-260/person/year) or tenofovir-based ($244-465/person/year) regimens. Purchase volumes for ARVs newly-recommended in 2006 (emtricitabine, tenofovir) increased >15-fold from 2006 to 2008. Twenty-four generic FDCs were quality-approved for older regimens but only four for newer regimens. Generic FDCs were available to GFATM recipients in 2004 but to PEPFAR recipients only after FDA approval in 2006. Price trends for single-component generic medicines mirrored generic FDC prices. Two large-scale purchasers, PEPFAR and UNITAID, together accounted for 53%, 84%, and 77% of market volume for abacavir, emtricitabine, and tenofovir, respectively, in 2008. PEPFAR and UNITAID purchases were often split across two manufacturers.ConclusionsGlobal initiatives facilitated the creation of fairly efficient markets for older ARVs, but markets for newer ARVs are less competitive and slower to evolve. WHO guidelines shape demand, and their complexity may help or hinder achievement of economies of scale in pharmaceutical manufacturing. Certification programs assure ARV quality but can delay uptake of new formulations. Large-scale procurement policies may decrease the numbers of buyers and sellers, rendering the market less competitive in the longer-term. Global policies must be developed with consideration for their short- and long-term impact on market dynamics.

The prevalence of transmitted antiretroviral drug resistance in treatment‐naïve patients and factors influencing first‐line treatment regimen selection

To estimate the prevalence of transmitted antiretroviral (ARV) drug resistance, and to assess whether resistance testing influences first-line ARV regimen selection. Data on patients' characteristics were collected through questionnaires. ARV drug resistance was tested by genotypic methods and defined by Quest-Stanford classification rule. Physicians reported the intended and actual treatments and the factors considered in treatment selection. Two hundred and twenty-eight patients were included. The prevalence of ARV drug resistance was 12.1%, with 9.8% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), 4.5% for nucleoside reverse transcriptase inhibitors and 1.8% for protease inhibitors (PIs). Pill burdens, dosing frequency and physicians' experience with regimens were the major factors considered in treatment selection. The intended and actual treatment differed for 73 and 44% of the patients with and without ARV drug resistance, respectively [odds ratio (95% confidence interval, CI)=3.6 (1.5-9.0), P=0.006]. NNRTI-based regimens were intended for 10 patients with resistance to NNRTIs; these patients were prescribed PI-based regimens after genotypic testing. Transmitted ARV drug resistance was detected in 12.1% of treatment-naïve patients, with resistance to NNRTIs the most common. Resistance-testing results played a partial role in first-line treatment selection. However, resistance to NNRTIs pre-empted NNRTI use.

5. HIV AND WOMEN: THE AFRICAN EXPERIENCE

Africa as a continent has been devastated by the acquired immunodeficiency syndrome epidemic caused by the human immunodeficiency virus (HIV). Women are more likely to acquire HIV/AIDS for a number of reasons and incidence studies show that younger women are particularly at risk of HIV acquisition. Biologically, they are more vulnerable and the acquisition of HIV can be influenced by hormonal contraceptives as well as sexually transmitted infections, which are often more asymptomatic than is the case for men. Women in Africa are also more vulnerable because of cultural issues; in some countries polygamy is accepted practice. Women are often economically disadvantaged and disempowered. It is often hard for them to insist on the use of condoms with husbands and regular partners. Physical and sexual abuse of women, including rape, remains a major problem on the continent, particularly in times of civil war. Many women are forced to work as sex workers or be involved in transactional sex in order to survive. Most countries rely on anonymous antenatal surveys to generate HIV seroprevalence data for women of reproductive age. These data is often used as surrogate markers for HIV prevalence rates in men of a similar age. The seroprevalence of HIV among pregnant women differs remarkably around the continent, with the highest rates being seen in Southern Africa, as high as 30%, and much lower rates being seen in West Africa. These reasons underlying these differences are complex and not completely understood. UNAIDS estimated in 2005 that 470�000 (87%) of the world's 540�000 newly infected children (&lt;15 years old) reside in Sub-Saharan Africa. Prevention of mother to child transmission (PMTCT) of HIV is thus a national priority in many Sub-Saharan African countries. Despite policies, treatment is sometimes not given at the clinic level for several reasons, and when it is, most commonly it is with single dose Nevirapine. Data from South Africa has shown that both mothers and infected babies rapidly acquire nevirapine resistance. It is likely that this will lead to early failure of first line antiretroviral (ARV) therapy among these mothers once they start their ARVs. In South Africa, for example, either efavirenz or nevirapine form the backbone of the first-line ARV regimens. AIDS defining illnesses (ADIs) in women living in Africa are similar to those observed in men. Tuberculosis is the most common ADI but other life-threatening illnesses such as cryptococcal meningitis are relatively common compared to other parts of the world. Cervical cancer and cervical intra-epithelial neoplasia (CIN) lesions are more common in HIV-infected than in non-infected women. Most countries in Africa do not have cervical screening programmes and, even in richer countries such as South Africa, the national policy is to screen women three times in their life at 30, 40 and 50 years of age. Many HIV specialist centres, with additional donor funds, are now attempting to perform annual cervical screening, at least in South Africa.

Comprehension and acceptability of a patient information leaflet (pil) for antiretroviral therapy

The patient information leaflet (PIL) is recognised as playing a key role in informing patients about their medicines. The objectives of this research were to evaluate the readability and understanding of a PIL for the first-line ARV (antiretroviral) regimen available in the South African public health sector, and investigate its acceptability in the target Xhosa population.&#x0D; &#x0D; Opsomming&#x0D; Daar word algemeen aanvaar dat die pasiëntinligtingsblaadjie (PIB) ‘n sleutelrol speel in die oordra van inligting ten opsigte van medikasie aan pasiënte. Die doelwitte van hierdie navorsing was om die leesbaarheid en begrip van ‘n PIB vir die eerste-linie antiretrovirale (ARV) regimen wat in die Suid-Afrikaanse openbare gesondheidsektor beskikbaar is, te evalueer, en om die aanvaarbaarheid daarvan in ‘n teiken-Xhosabevolking te ondersoek.&#x0D; &#x0D; *Please note: This is a reduced version of the abstract. Please refer to PDF for full text.