Antiretroviral Program Research Articles

Antiretroviral adherence program in HIV patients: a feasibility study in the Swiss HIV Cohort Study

To evaluate the feasibility of a comprehensive, interdisciplinary adherence program aimed at HIV patients. Two centers of the Swiss HIV Cohort Study: Lausanne and Basel. 6-month, pilot, quasi-experimental, 2-arm design (control and intervention). Patients starting a first or second combined antiretroviral therapy line were invited to participate in the study. Patients entering the intervention arm were proposed a multifactorial intervention along with an electronic drug monitor. It consisted of a maximum of six 30-min sessions with the interventionist coinciding with routine HIV check-up. The sessions relied on individualized semi-structured motivational interviews. Patients in the control arm used directly blinded EDM and did not participate in motivational interviews. Rate of patients' acceptance to take part in the HIV-adherence program and rate of patients' retention in this program assessed in both intervention and control groups. Persistence, execution and adherence. The study was feasible in one center but not in the other one. Hence, the control group previously planned in Basel was recruited in Lausanne. Inclusion rate was 84% (n = 21) in the intervention versus 52% (n = 11) in the control group (P = 0.027). Retention rate was 91% in the intervention versus 82% in the control group (P = ns). Regarding adherence, execution was high in both groups (97 vs. 95%). Interestingly, the statistical model showed that adherence decreased more quickly in the control versus the intervention group (interaction group × time P < 0.0001). The encountered difficulties rely on the implementation, i.e., on the program and the health care system levels rather than on the patient level. Implementation needs to be evaluated further; to be feasible a new adherence program needs to fit into the daily routine of the centre and has to be supported by all trained healthcare providers. However, this study shows that patients' adherence behavior evolved differently in both groups; it decreased more quickly over time in the control than in the intervention group. RCTs are eventually needed to assess the clinical impact of such an adherence program and to verify whether skilled pharmacists can ensure continuity of care for HIV outpatients.

Towards universal ARV access: Achievements and challenges in Free State Province, South Africa

To study the progress and challenges with regard to universal antiretroviral (ARV) access in Free State Province, South Africa. Data from the first 4 years of the public sector ARV roll-out and selected health system indicators were used. Data were collected from the public sector ARV database in Free State Province for new patients on ARVs, average waiting times and median CD4 counts at the start of treatment. Information on staff training, vacancy rates and funding allocations for the ARV roll-out was obtained from official government reports. Projections were made of expected new ARV enrolments for 2008 and 2009 and compared with goals set by the National Strategic Plan (NSP) to achieve universal access to ARVs by 2011. New ARV enrolments increased annually to 25% of the estimated need by the end of 2007. Average waiting times to enrolment decreased from 5.82 months to 3.24 months. Median CD4 counts at enrolment increased from 89 to 124 cells/mm3. There is a staff vacancy rate of 38% in the ARV programme and an inadequate increase in budget allocations. The current vertical model of ARV therapy delivery is unlikely to raise the number of new enrolments sufficiently to achieve the goals of universal access by 2011 as envisaged by the NSP. The Free State is implementing a project (STRETCH trial) to broaden the ARV roll-out in an attempt to increase access to ARVs.

Second‐line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline*

The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second-line ART. We report outcomes for patients evaluated and initiated on second-line treatment in Malawi. Patients meeting Malawi immunological or clinical criteria for ART failure in two large urban ART clinics were evaluated for virological failure (viral load >400 HIV-1 RNA copies/mL) and, if failure was confirmed, initiated on second-line ART (zidovudine/lamivudine/tenofovir/lopinavir/ritonavir). Patients were seen monthly and laboratory evaluations were performed quarterly and as needed. We performed logistic regression modelling to identify factors associated with mortality, mortality or new HIV illnesses, and virological suppression at 12 months. Of the 109 patients with confirmed virological failure, five patients died prior to initiation, three declined switching and 101 patients initiated second-line treatment. Over 12 months, 10 additional patients died, 34 patients experienced 45 HIV-related events, and 19 patients experienced grade 3 or 4 toxicities. Among survivors, 85.2% had HIV-1 RNA<400 copies/mL at 12 months. While power to distinguish differences was limited, response rates were similar regardless of baseline resistance level. The median CD4 count increase was 142 cells/microL. World Health Organization clinical failure at baseline [odds ratio (OR) 3.47; 95% confidence interval (CI) 1.14-10.59] and body mass index <18.5 (OR 4.43; 95% CI 1.15-17.12) were risk factors for death. Baseline CD4 count <50 cells/microL was associated with increased risk for death or morbidity at 12 months (OR 2.57; 95% CI 1.01-6.52). Second-line treatment in Malawi was associated with substantial mortality, morbidity and toxicity but, among survivors, virological outcomes were favourable.

Improving the evidence base of Markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings

BackgroundDespite concerns about affordability and sustainability, many models of the lifetime costs of antiretroviral therapy (ART) used in resource limited settings are based on data from small research cohorts, together with pragmatic assumptions about life-expectancy. This paper revisits these modelling assumptions in order to provide input to future attempts to model the lifetime costs and the costs of scaling up ART.MethodsWe analysed the determinants of costs and outcomes in patients receiving ART in line with standard World Health Organization (WHO) guidelines for resource poor settings in a private sector managed ART programme in South Africa. The cohort included over 5,000 patients with up to 4 years (median 19 months) on ART. Generalized linear and Cox proportional hazards regression models were used to establish cost and outcome determinants respectively.ResultsThe key variables associated with changes in mean monthly costs were: being on the second line regimen; receiving ART from 4 months prior to 4 months post treatment initiation; having a recent or current CD4 count <50 cells/µL or 50-199 cells/µl; having mean ART adherence <75% as determined by monthly pharmacy refill data; and having a current or recent viral load >100,000 copies/mL. In terms of the likelihood of dying, the key variables were: baseline CD4 count<50 cells/µl (particularly during the first 4 months on treatment); current CD4 count <50 cells/µl and 50-199 cells/µl (particularly during later periods on treatment); and being on the second line regimen. Being poorly adherent and having an unsuppressed viral load was also associated with a higher likelihood of dying.ConclusionsWhile there are many unknowns associated with modelling the resources needed to scale-up ART, our analysis has suggested a number of key variables which can be used to improve the state of the art of modelling ART. While the magnitude of the effects associated with these variables would be likely to differ in other settings, the variables influencing costs and survival are likely to be generalizable. This is of direct relevance to those concerned about assessing the long-term costs and sustainability of expanded access to ART.

Differences in antiretroviral scale up in three South African provinces: the role of implementation management

BackgroundSouth Africa’s antiretroviral programme is governed by defined national plans, establishing treatment targets and providing funding through ring-fenced conditional grants. However, in terms of the country’s quasi-federal constitution, provincial governments bear the main responsibility for provision of health care, and have a certain amount of autonomy and therefore choice in the way their HIV/AIDS programmes are implemented.MethodsThe paper is a comparative case study of the early management of ART scale up in three South African provincial governments – Western Cape, Gauteng and Free State – focusing on both operational and strategic dimensions. Drawing on surveys of models of ART care and analyses of the policy process conducted in the three provinces between 2005 and 2007, as well as a considerable body of grey and indexed literature on ART scale up in South Africa, it draws links between implementation processes and variations in provincial ART coverage (low, medium and high) achieved in the three provinces.ResultsWhile they adopted similar chronic disease care approaches, the provinces differed with respect to political and managerial leadership of the programme, programme design, the balance between central standardisation and local flexibility, the effectiveness of monitoring and evaluation systems, and the nature and extent of external support and programme partnerships.ConclusionsThis case study points to the importance of sub-national programme processes and the influence of factors other than financing or human resource capacity, in understanding intervention scale up.

Antiretroviral Program Associated with Reduction in Untreated Prevalent Tuberculosis in a South African Township

In 2005, we reported high prevalence of untreated pulmonary tuberculosis (TB) in a South African community. Prevalent untreated TB is the main source of transmission. In settings with large burdens of human immunodeficiency virus (HIV) and TB, highly active antiretroviral therapy (HAART) may contribute to TB control. To assess the community-level impact of HAART on TB prevalence, we repeated a community-based TB prevalence cross-sectional survey in 2008 following HAART roll-out. A random 10% adult population sample was identified from the community. Participants provided two sputum specimens for acid-fast bacilli microscopy and TB culture. Oral transudate specimen was collected for anonymous HIV testing, linked to TB diagnosis. An interviewer-administered, structured questionnaire identified TB and HIV history and risk factors. In the 2008 survey, 1,250 adults participated (90% response rate); 306 (25%) tested HIV positive, of which 60 (20%) were receiving HAART. A total of 20 TB cases were identified (12 receiving TB treatment), representing a significant decline in prevalence from 3.2 to 1.6% (P = 0.02) between the surveys. TB prevalence in participants not infected with HIV was unchanged (P = 0.90). The decline occurred among participants not infected with HIV, decreasing from 9.2 to 3.6% in 2005 to 2008, respectively (P = 0.003). In participants infected with HIV, prevalence of treated TB declined from 4 to 2.3% (P = 0.06), and untreated TB prevalence from 5.2 to 1.3% (P = 0.02). The proportion of untreated TB in patients receiving HAART decreased significantly, from 22 to 0% (P < 0.001). Prevalence of undiagnosed TB declined significantly over a period of increasing HAART availability. The decline was predominantly in individuals infected with HIV receiving HAART.

Molecular diversity and polymerase gene genotypes of HIV-1 among treatment-naïve Cameroonian subjects with advanced disease

Background The progress of antiretroviral treatment roll-out programs in developing countries requires extensive monitoring of primary drug resistance prior to initiation of therapy. This is particularly relevant for Cameroon where a high HIV diversity has been reported. Objectives To determine HIV diversity in Yaoundé, Cameroon, in a cohort of HIV-infected subjects with advanced disease. To characterize HIV-1 mutations conferring primary drug resistance and to assess primary resistance patterns in the RNase H domain of the reverse transcriptase of these viruses. Study design HIV-1 RNA was extracted from plasma of 59 HIV-1 infected, drug-naïve subjects with CD4 + T-cell counts < 200/μl. HIV-1 pol (PR, RT and RNase H) regions were sequenced for subtyping and for identifying drug resistance mutations in pol (PR, RT and RNase H). Results A complex HIV-1 diversity was seen, with multiple subtypes (A1, A2, C, D, F2, H, group O), CRFs (02_AG, 09_cpx, 11_cpx, 13_cpx, 22_01A1, 30_0206, 43_02G) and URFs. Primary drug resistance was low in PR (2%) and in RT regions (4%). RNase H mutations Q509L and Q547K were found in non-CRF02_AG strains. Conclusions A high HIV-1 diversity was already present in Cameroon in the early 90s, when the subjects were likely infected. Primary HIV-1 drug resistance was low. Occurrence of RNase H mutations with proven phenotypic effect on susceptibility to antiretrovirals encourages further assessment of their impact in treatment outcome in the context of complex HIV genetic diversity and in a subtype-specific fashion.

Varied Patterns of HIV-1 Drug Resistance on Failing First-Line Antiretroviral Therapy in South Africa

The South African national antiretroviral therapy roll-out program is entering its sixth year, with over 570,000 adults accessing treatment. HIV-1 drug resistance is a potential consequence of therapy. This study determined the pattern of HIV-1 drug resistance mutations after failure of first-line treatment regimens in South Africa. Two hundred and twenty-six patients virologically failing first-line regimens were studied to determine resistance patterns. The most common reverse transcriptase mutation was M184V/I (72%; n = 163); 11% of patients (n = 25) had only nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations and 17% (n = 38) had no known resistance mutations. The K65R mutation was detected in 4%. The frequency of thymidine analog mutations was significantly higher with azidothymidine-containing (31 of 57) than stavudine-containing regimens (39 of 169; P < 0.001). The Y181C mutation was more frequent with failure of nevirapine (NVP)-containing (26%) than efavirenz (EFV)-containing therapy (3%; P < 0.001). The V106M mutation was more frequent with EFV (30%) than NVP (4%; P = 0.012). HIV-1 drug resistance patterns varied broadly after failure of first-line therapy, ranging from no known resistance mutations (17%) to multinucleoside reverse transcriptase inhibitor and NNRTI resistance (23%). NNRTI mutation profiles differed for patients on EFV- compared with NVP-containing regimens. Overall, these findings suggest that HIV-1 drug resistance testing would be useful in identifying most appropriate second-line regimens.

NucliSens EasyQ ® HIV-1 V1.2 system: Detection of human plasma-derived background signal

Until recently the NucliSens EasyQ ® HIV-1 V1.2 system has been used throughout South Africa as part of the national antiretroviral roll-out programme for the monitoring of HIV-1 RNA load in patients on antiretroviral treatment. Shortly after changing to a new assay lot number an increased proportion of patient specimens, showing detectable but low viral loads, was observed (<200 IU/ml). The test runs remained valid as the lysis buffer-only no-template controls (NTCs) remained negative. Contamination with amplification product was excluded. Subsequently the same phenomenon was observed in at least three other South African laboratories across different assay lot numbers. When testing aliquots of plasma, freshly obtained from HIV-negative donors, at two of these laboratories, 33/134 aliquots showed detectable values (range 26–370, median: 64 IU/ml), while all NTCs remained negative. These findings emphasize the importance of appropriate specimen controls in all diagnostic assays. In this case HIV-negative human plasma should be included routinely in addition to NTCs, which would allow rapid detection of a background signal.

Anti-retroviral (ARV) rationing schemes in developing countries: a review article on strategies and ethical issues related to the successes and failures of ARV programmes

When a patient receives a counterfeit drug, he/she becomes a victim of fraud medicine and is put at risk of developing adverse effects from unwanted medication that is not prescribed. These individuals health also becomes compromised because they are cheated of both successful treatment regimens and economically. Indeed counterfeit drugs pose many threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. Apart from the pharmaceutical aspect in producing substandard drugs, there area also climatic or environmental factors as well as patients and economic factors. All these need to be addressed when considering any proper rationing strategy for antiretroviral drugs (ARVs) in sub-Saharan countries. Short of that, there is a great danger that the shelf life of ARV will be soon lost and once resistance comes in we will be in big problems.

The role of the pharmacist in the prevention and management of HIV/AIDS: an exploratory study of the establishment of AIDS Resource Centres in pharmacies

Abstract Objective The magnitude of the HIV/AIDS epidemic in South Africa, particularly its rapid growth and the inability of existing health structures to respond to the rising needs for treatment, has had a profound impact on South African society. The epidemic has specifically affected the healthcare services, in that it calls for greater involvement of all health professionals, including pharmacists. There is undoubtedly potential for community pharmacists to be involved in the prevention and treatment of HIV/AIDS, and the fact that many community pharmacies already have private areas for consultation and a designated professional to offer advice renders them an ideal space for these activities. The objective of the study was to explore the role played by pharmacists in the prevention and management of the epidemic. Methods The paper synthesises data from three sources: documentary analysis of official reports; a telephone survey of 112 community pharmacies in Johannesburg; and interviews with three key informants from pharmaceutical organisations and pharmacists involved with the governmental anti-retroviral programme. Key findings The South African Pharmacy Council (SAPC) and the Pharmaceutical Society of South Africa (PSSA) embarked on the process of establishing AIDS Resource Centres in pharmacies. Six months later 55% of the pharmacists interviewed had heard about it and 33% of these knew very little about it. The SAPC and the PSSA have developed strict criteria for the accreditation of pharmacists and AIDS Resource Centres, so that the consumer can be assured of a high quality of service. At the time of the survey, 40% of pharmacists said they intended to apply for accreditation at this stage. Most pharmacists (82%) reported that they were already involved in some HIV/AIDS-related activities, without having acquired additional training and specific accreditation. This paper analyses pharmacists' readiness and ability to develop these services and discusses possible barriers to successful implementation of the programme. Conclusion The HIV/AIDS epidemic generally, and in South Africa in particular, poses challenges for all health professionals. This paper demonstrates the willingness of the professional pharmacy establishment in South Africa to co-operate with the government in order to confront the epidemic and respond to national needs; it also highlights the potential difficulties inherent in the process. Given the nature of the epidemic in South Africa, pharmacy is potentially in a position to rise to the challenges presented and place itself at the centre of the professional team. However the findings of this study show that achieving this will require substantial adjustments in pharmacists' practice, good communication skills between pharmacists and their customers, and considerable goodwill among pharmacists on the ground.

Bacterial community-acquired pneumonia in HIV-infected patients

In this review, we focus on the clinical features, diagnosis, outcome and management of bacterial community-acquired pneumonia (BCAP) in HIV-infected patients, with particular attention to the most recent findings in this area. Clinical features of BCAP are often atypical in HIV-infected individuals, especially when liver cirrhosis is also present. Streptococcus pneumoniae is the most common causative agent and is frequently associated with bacteriemic disease even in low-risk patients according to pneumonia severity index. An etiologic diagnosis is obtained in an average 35% of cases with standard culture methods. In such conditions, urinary antigen test for S. pneumoniae identification may help in reaching a rapid and etiologic diagnosis. CD4 cell count should be carefully considered in HIV patients with BCAP. In consideration of their high mortality risk, patients with a CD4 cell count of less than 200 cells/mul should be hospitalized, whereas those with a CD4 cell count of at least 200 cells/mul could be managed according to pneumonia severity index score. Empiric antibiotic therapy should include a combination of a beta-lactam and a macrolide or a respiratory fluoroquinolone alone. Finally, prevention strategies should include lifestyle modification, highly active antiretroviral therapy access and adherence programs and the implementation of pneumococcal vaccination. A correct diagnosis and management together with a comprehensive approach to preventive measures, including lifestyle modification, highly active antiretroviral therapy access and adherence programs and the implementation of pneumococcal vaccination, are key factors to reduce BCAP incidence and mortality in HIV-infected patients.

Referral success among HIV-infected women and HIV-exposed children referred for monitoring and treatment in Tanga, Tanzania

Long-term retention of patients in the rapidly expanding antiretroviral programs against HIV/AIDS is essential for the success of these programs. Unfortunately, high percentages of patients in need of treatment are lost to follow up in resource-poor settings. From June 2006 to March 2007 269 HIV-infected pregnant women were screened for participation in a Prevention of Mother to Child Transmission (PMTCT) study in Tanga, Tanzania. Ninety-one women were referred to Care and Treatment Center (CTC) for monitoring and antiretroviral therapy regardless of inclusion in the PMTCT study. Both women and HIV-exposed children were traced at CTC from mid-February to mid-March 2008. Follow-up visits for all patients were examined. Only 10% (9/91) of the referred women were still attending CTC by February/March 2008 and 64% (58/91) never attended CTC. Not a single child could be traced at CTC. The largest loss of patients occurs between referral and the first attendance at CTC. Every effort must be made to clarify reasons for loss of patients at this point. Further, measures to improve patient retention must be increased as must initiatives to improve the ability to trace and retain children within the clinics.

The effectiveness of highly active antiretroviral therapy among HIV-infected children in Asian countries

Background: Worldwide, there are 2.1 million children under 15 years of age living with HIV infection. In the past five years, there has been significant progress in providing antiretroviral therapy (ART) to children in resource-limited countries. According to the World Health Organization, an estimated 200,000 children were receiving ART by the end of 2007. Objective: To conduct a general review of pediatric ART effectiveness in Asian countries. Methods: Published articles in PubMed and abstracts from the international HIV conferences were searched for articles related to pediatric ART in Asian countries from 1999 up to 2008. Results: Available reports consistently demonstrated beneficial outcomes of first-line antiretroviral therapy, including significant reductions in mortality and hospitalization rates, and good immunological and virological outcomes. However, there were limited data on the availability of second-line ART and the management of children who failed first-line regimens. There was also a need for improved access to early diagnostic testing and treatment in infancy, and more data on ART selection for children exposed to antiretrovirals for prevention of mother to child transmission. Conclusion: The highly active antiretroviral therapy is effective among HIV-infected children in Asia. Strategies for improved diagnosis and implementation of the life-saving antiretroviral programs including second -line ART, throughout Asia is encouraged.

Nutritional status of HIV-infected adults on antiretroviral therapy and the impact of nutritional supplementation in the Northern Cape Province, South Africa

Objectives: The study aimed to describe the nutritional status and determine the impact of current nutrition intervention strategies on weight changes in adult HIV-infected patients on antiretroviral (ARV) therapy.Design: A descriptive, prospective trial was performed.Setting: The investigation was conducted at ARV roll-out centres in Kimberley, Upington, Kuruman, Prieska and Springbok in the Northern Cape Province of South Africa.Subjects: Adult HIV-infected patients receiving ARV therapy were included in the study.Outcome measures: Each participants’s body mass index (BMI) was determined before and after a four-month intervention period of nutritional supplementation with an instant, enriched maize product.Results: Data from 98 patients (mean age 39.7 years; standard deviation 8.9 years) were assessed. Prior to intervention, the median BMI was 20 kg/m2 (range 12.6–29.7 kg/m2); the patients from Kuruman had a greater incidence of underweight compared to the other towns, with a median BMI of 17.9 kg/m2. Of the 87 patients assessed during the final week, 49.4% experienced weight gain and 40.2% lost weight. Eighteen (20.7%) patients gained more than 5% of their baseline weight, which was significant. Only eight (9.2%) patients lost more than 5% of their baseline weight. Twenty-two patients who presented with a BMI < 18.5 kg/m2 at baseline had a median weight gain of 1.13 kg during the intervention period, while the group with a BMI > 18.5 kg/m2 presented with no change in median weight.Conclusions: Nutritional supplementation, provided according to provincial policy and combined with ARVs, nutritionally benefitted about half of the patients in the ARV programme in the Northern Cape.

Reduced referral and case fatality rates for severe symptomatic hyperlactataemia in a South African public sector antiretroviral programme: a retrospective observational study

BackgroundInterventions to promote prevention and earlier diagnosis of severe symptomatic hyperlactataemia (SHL) were implemented in the Western Cape provincial antiretroviral programme (South Africa) from 2004. Interventions included clinician education, point-of-care lactate meters, switch from stavudine to zidovudine in high risk patients and stavudine dose reduction. This study assessed trends in referral rate, severity at presentation and case fatality rate for severe SHL.MethodsRetrospective study of severe SHL cases diagnosed at a referral facility from 1 January 2003 to 31 December 2008. Severe SHL was defined as patients with compatible symptoms and serum lactate ≥ 5 mmol/l attributable to antiretroviral therapy (ART). Cumulative ART exposure at referring ART clinics was used to calculate referral rates.ResultsThere were 254 severe SHL cases. The referral rate (per thousand patient years [py] ART exposure) peaked in 2005 (20.4/1000py), but fell to 1.3/1000py by 2008 (incidence rate ratio [IRR] = 0.07, 95%CI 0.04-0.11). In 2003, 66.7% of cases presented with a standard bicarbonate (SHCO3) level <15 mmol/l, but this fell to 12.5% by 2008 (p for trend < 0.001). Case fatality rate fell from a peak of 33.3% in 2004 to 0% in 2008 (p for trend = 0.002).ConclusionsThese trends suggest the interventions were associated with reduced referral, less severe metabolic acidosis at presentation and improved survival.

Cost analysis of centralized viral load testing for antiretroviral therapy monitoring in Nicaragua, a low‐HIV prevalence, low‐resource setting

BackgroundHIV viral load testing as a component of antiretroviral therapy monitoring is costly. Understanding the full costs and the major sources of inefficiency associated with viral load testing is critical for optimizing the systems and technologies that support the testing process. The objective of our study was to estimate the costs associated with viral load testing performed for antiretroviral therapy monitoring to both patients and the public healthcare system in a low-HIV prevalence, low-resource country.MethodsA detailed cost analysis was performed to understand the costs involved in each step of performing a viral load test in Nicaragua, from initial specimen collection to communication of the test results to each patient's healthcare provider. Data were compiled and cross referenced from multiple information sources: laboratory records, regional surveillance centre records, and scheduled interviews with the key healthcare providers responsible for HIV patient care in five regions of the country.ResultsThe total average cost of performing a viral load test in Nicaragua varied by region, ranging from US$99.01 to US$124.58, the majority of which was at the laboratory level: $88.73 to $97.15 per specimen, depending on batch size. The average cost to clinics at which specimens were collected ranged from $3.31 to $20.92, depending on the region. The average cost per patient for transportation, food, lodging and lost income ranged from $3.70 to $14.93.ConclusionsThe quantitative viral load test remains the single most expensive component of the process. For the patient, the distance of his or her residence from the specimen collection site is a large determinant of cost. Importantly, the efficiency of results reporting has a large impact on the cost per result delivered to the clinician and utility of the result for patient monitoring. Detailed cost analysis can identify opportunities for removing barriers to effective antiretroviral therapy monitoring programmes in limited-resource countries with low HIV prevalence.

Early versus deferred antiretroviral therapy in children in low-income and middle-income countries

We reviewed current literatures on early and deferred initiation of antiretroviral therapy in HIV-infected infants and children in low-income and middle-income countries. Data from children with HIV antiretroviral (Children with HIV Early Antiretroviral Therapy) study showed a significant reduction of 76% in mortality among infants who received antiretroviral therapy within 3 months of their life as opposed to those on deferred therapy. These data led World Health Organization to promptly revise the guideline to recommend initiation of antiretroviral therapy in all HIV-infected infants regardless of clinical or immunological status. The recommendation for older children is differed between guidelines of developed and developing countries. In general, higher CD4 cell count threshold is used for younger children and similar criteria to those used for adults are used once children are above 5 years of age. The randomized study of when to start antiretroviral therapy in children older than 1 year is ongoing. The current trend is to move toward early treatment to reduce morbidity and mortality, achieve immune recovery, normal growth, and development. Even though the antiretroviral rollout program has been successful in Asia and Africa, the challenges lie in diagnosing infants in a timely manner and maintaining infrastructure and resources to support life-long treatment.

Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline

Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline

Antiretroviral Therapeutic Drug Monitoring in Canada: Current Status and Recommendations for Clinical Practice

Therapeutic drug monitoring (TDM) is a strategy whereby the plasma concentration of one or more drugs is measured and drug doses are adjusted accordingly to achieve concentrations within an acceptable therapeutic range. The goal of TDM is to maximize pharmacologic efficacy and minimize the drug’s toxic effects, and hence to contribute to optimizing the patient’s outcomes. In general, TDM is indicated if the following conditions are present: there is a direct relationship between drug exposure and pharmacologic response, the drug has a narrow therapeutic index and is used to treat a condition for which drug failure or toxicity is associated with substantial morbidity or mortality, and there is limited intrapatient but wide interpatient pharmaco kinetic variation. Differences in pharmacokinetic factors among patients are multifactorial and may include age, sex, ethnic background, pregnancy, and body weight, as well as comorbid conditions causing variations in hepatic function, renal function, drug absorption, and drug disposition. In some cases, genetic polymorphisms in the cytochrome P450 enzymes may explain the large interpatient variability for certain antiretroviral agents. For example, certain CYP2B6 and CYP2A6 polymorphisms are independent predictors of plasma concentrations of efavirenz. Moreover, the potential for complex or unpredictable drug–drug or drug–food interactions can significantly affect plasma drug concentrations. Finally, TDM depends on the availability of an accurate and feasible analytical method for a given drug. Among antiretroviral agents, the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered suitable candidates for TDM. Evidence exists of a relation between exposure to antiretrovirals and virologic response and, in more limited instances, between exposure to the drug and toxic effects. Recent data have suggested that intraindividual variation is limited (19.0% for NNRTIs and 38.1% for protease inhibitors). Preliminary data have also suggested that trough levels of maraviroc, a chemokine (C–C motif) receptor 5 (CCR5) antagonist, are predictive of virologic outcome, although TDM experience with this agent is extremely limited. In retrospective and prospective studies, observed interindividual variability in drug concentrations has been 45% to 112% for protease inhibitors and 75% for NNRTIs. Thus, a given dose of a particular antiretroviral agent may result in unacceptable toxic effects in some patients while yielding subtherapeutic concentrations in others. TDM represents a tool by which the effectiveness of these agents in clinical practice can be optimized through dosage adjustments tailored to patient-specific pharmacokinetic and pharmaco dynamic parameters. The current article reviews the literature on antiretroviral TDM, describes the development of an antiretroviral TDM program in Canada, and illustrates the role of the pharmacist in the clinical application of TDM. Given current evidence and personal experience, the authors support the use of antiretro viral TDM as a clinical tool in special patient populations and for specific clinical situations.