At the end of 2008, more than 4 million (3,700,000-4,360,000) people were receiving antiretroviral therapy (ART) in low-income and middle-income countries.1 This number is expected to increase in response to revised public health guidelines published by the World Health Organization (WHO) recommending the initiation of ART at CD4+ T-cell counts <350 copies per cubic millimeter.2 An unintended consequence of treatment scale-up is the possible emergence of HIV drug resistance (HIVDR) in populations even when patient adherence to ART is optimally supported. HIVDR has the potential to undermine the dramatic gains which ART has had in reducing the morbidity and mortality of HIV-infected patients in resource-limited settings (RLS).3
In RLS, viral load and HIVDR testing are not routinely available primarily because of their cost and insufficient local laboratory capacity. Monitoring of ART program factors known to be associated with the emergence of HIVDR, for the purpose improving programmatic functioning, may minimize the emergence of preventable HIVDR. For example, HIVDR testing is not required to predict the emergence of drug-resistant HIV in settings where inappropriate prescribing practices (monotherapy or dualtherapy), treatment interruptions due to suboptimal patient adherence, poor patient retention on ART, or ART supply shortages or stock-outs occur at unacceptably high levels. These factors have been shown to be associated with the development of HIVDR4-10; thus, their monitoring may alert national ART program planners to issues, which may be adjusted to minimize the emergence of HIVDR.
HIVDR Early Warning Indicators
The foundation of the WHO's global HIVDR prevention and assessment strategy,11 which includes laboratory-based surveys of acquired12 and transmitted13 HIVDR, is the monitoring of HIVDR Early Warning Indicators (EWIs). EWIs assess ART site and program factors potentially associated with HIVDR.11 Utilizing data routinely collected in patients' medical and pharmacy records, EWI monitoring is a minimum-resource strategy designed to be integrated into national monitoring and evaluation programs. When monitored annually at all ART sites or a large number of representative sites, EWIs provide countries with evidence to make programatic adjustments at the level of an individual site or at the national level, when necessary.
HIV in Namibia
Namibia is a Southwest African country with a population of 2,108,665 individuals.14 Based on 2008 antenatal serosurveillance data, an estimated 17.8% of Namibians aged 15-49 years are infected with HIV-1.15 The epidemic is predominantly spread via heterosexual contact, and prevalence estimates vary by region with up to 31% infected with HIV-1 in the most heavily affected areas in the north.15
ART has been available in Namibia's private sector since 1997 and in the public sector since 2003. As of 2007, approximately 40,000 patients were receiving ART in the public sector and 12,000 patients in the private sector, representing 88% of patients eligible for ART, one of the highest coverage rates in Sub-Saharan Africa.16 At present, ART is available at all 35 public main ART sites and at an additional 66 satellite/outreach service points.
In the public sector, ART is provided free of charge after a population-based model of care with one first-line regimen and 3 alternate first-line regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTI) combined with a nonnucleoside reverse transcriptase inhibitor. Three second-line regimens are available, consisting of 2 NRTIs with a ritonavir-boosted protease inhibitor. ART initiation is based on WHO clinical staging and/or CD4 cell count <200 cells per cubic millimeter. Where available, viral load testing is performed 6 months after ART initiation and targeted viral load testing is performed to confirm clinical or immunological failure.17 With support from Management Sciences for Health Namibia, a standardized pharmacy record system, the Electronic Dispensing Tool (EDT), has been introduced.
Since its inception, Namibia's ART program has forged strong collaborations with national and international support partners to provide the highest possible quality ART delivery. Namibia has been proactive in minimizing preventable HIVDR by mandating the use of standardized national ART prescribing practices, WHO prequalified drugs, and the use of standardized medical and pharmacy record-keeping systems which facilitate population-based evaluation of ART. In 2009, the Namibia Ministry of Health and Social Services (MoHSS) finalized its national plan for the prevention and assessment of HIVDR after WHO recommendations.11
Early Warning Indicators Selection
Based on a review of available patient records, Namibia chose to pilot the following 5 EWIs: “ART Prescribing practices, Patients lost to follow-up (LTFU) at 12 month, Patient retention on first-line ART at 12 months, On-time antiretroviral (ARV) drug pick-up, and ARV drug-supply continuity.11,18,19” Definitions for these selected EWIs and their respective recommended targets are summarized in Table 1.
Pilot Site Selection and Data Abstraction
Nine pilot sites were chosen at random from among 15 sites that had historical data in EDT available for abstraction. Teams headed by MoHSS abstracted data into an electronic tool provided by WHO. Data validation was performed by reabstracting a minimum of 10% of the variables from different sources.
To make the results generalizable to each site, the sampling strategy was based on calculating a minimum sample size for each indicator at each site, based on the number of eligible patients for each EWI. Two different cohorts of “eligible patients” were formed as follows: (1) patients consecutively initiating ART for the first time on or after January 1, 2007 (ART prescribing practices, patients LTFU at 12 month, and patient retention on first-line ART at 12 months); and (2) Patients consecutively picking up ART on or after October 1, 2007, regardless of duration of regimen (on-time ARV drug pick-up). Sample size calculations were performed to provide a 95% confidence interval of ±7%, assuming a true prevalence of 50% because this provided the most conservative estimate of the sample size required. The sample size for all EWIs at all sites was 180. For ARV drug-supply continuity, data were abstracted on stock-outs of each ARV drug in routine use from January 1, 2008, until December 31, 2008, using site-based pharmacy stock cards.
Namibia piloted abstraction of “ART prescribing practices, patients LTFU at 12 months, and patient retention on first-line ART at 12 month” at 9 sites. Data from 3,240 patients were abstracted and analyzed (Table 2). “On-time ARV drug pick-up and ARV drug-supply continuity” could not be monitored because information entered into existing patient records was found to be incomplete or inaccurate.
ART Prescribing Practices
All patients analyzed from each of the 9 sites were prescribed an initial first-line regimen after national guidelines with100% of sites achieving the target of 100% appropriate prescribing practices18,19 (Table 2).
Patients LTFU at 12 Months
Eight of 9 sites (89%) met the target of ≤20%18,19 of “Patients LTFU at 12 months (Table 2).” The median LTFU was 15% (interquartile range: 12%-17%). Although not classified as LTFU at 12 months, 20.8% (range: 4.6%-44.6%) of ART starters at all sites had a period of absence without documented ART coverage of a median of 2.3 months (range: 1.5-3.9 months) during their first year of treatment.
Patient Retention on First-Line ART at 12 Months
Six of 9 sites (67%) met the target of 0% switched to a second-line regimen 12-months after initiation of therapy. At 2 sites, 1 patient had been switched to an appropriate second-line regimen after virological failure; and at 1 site, 1 patient had been changed to an inappropriate triple NRTI regimen (Table 2).
On-Time ARV Drug Pick-Up
Data for “On-time ARV drug pick-up” was unavailable except at 1 site where the proportion of patients picking up pills on time was 72%, which fell significantly short of the suggested WHO target of ≥90%.18,19
ARV Drug-Supply Continuity
It was not feasible to abstract usable data to assess “ARV drug-supply continuity” at any pilot site.
The monitoring of ART site and program factors potentially associated with the emergence of HIVDR is essential, especially in settings where viral load and HIVDR testing are not widely implemented.
In 2009, Namibia piloted WHO-recommended EWIs, which lead to direct public health action. ART record-keeping systems were strengthened which will lead to better patient management and enabling the monitoring of all 5 nationally chosen EWIs in future years. Moreover, EWI data identified populations vulnerable to the development of HIVDR and lead to the development of operational research proposals and interventions targeted at these most-at-risk populations.
Monitoring of “ART prescribing practices” is important because inappropriate prescribing of monotherapy or dualtherapy or inappropriate drug combinations and/or dosing has been well substantiated to lead to the development of HIVDR in individual patients and at the population level.4,20-23 Importantly, no inappropriate prescribing was observed at any of the nine pilot sites in Namibia, suggesting strong leadership in the public health sector.
Poor retention in treatment programs, like poor adherence to ART, is an important reason for undesirable treatment outcomes among patients receiving ART.24-26 When patients previously LTFU reinitiate ART, they may not achieve the same rates of viral suppression compared with those never LTFU due to previous selection of drug-resistant virus; thus they are at increased risk of morbidity and mortality.27 Furthermore, because patients LTFU are at risk of having acquired HIVDR due to treatment interruptions,5,6 they may transmit drug-resistant HIV to others.28
Although the proportion of “Patients LTFU at 12 months” in Namibia was low and met the WHO target, a large number of ART starters were noted to have had a mean 2.3-month period of absence from their ART site during the first year of treatment. The MoHSS hypothesizes that many of these individuals may be “in transits,” a term used to denote patients who migrate seasonally to other areas of the country for work, possibly continuing ART at a different site, only to return to the site of ART initiation at some point in the future. However, existing record-keeping systems do not permit the tracing of this mobile population at risk for the development of HIVDR. As a result of this pilot, the MoHSS has planned an intensification of existing ART defaulter tracing mechanisms through improvements in EDT, the establishment of a national patient database with unique patient identifiers, and increased mobilization and redistribution of human resources.
Namibia's results for “Patient retention on first-line ART at 12 months” suggest success in managing ARV toxicity and side effects through in-class substitutions rather than switches to regimens using drugs from a different class. These results also highlight general success in maintaining the efficacy of available first-line regimens during the first 12 months of treatment and suggest appropriate identification and management of patients with virological failure.
With the exception of 1 site, data were not able to assess “On-time ARV drug pick-up.” In Namibia, routine pharmacy dispensing practice is meant to include the routine counting of remnant pills (number of pills left over from the previous prescription) and the dispensing of a specified number of days of pills. However, the number of remnant pills was not routinely recorded, thus it was not possible to calculate the actual pill run-out date, necessary to monitor this indicator. At the single site where assessment was feasible, the proportion of patients picking up pills on time fell short of the ≥90% target. Because pharmacy refill adherence has been shown to predict virological failure,29,30 it is reasonable to hypothesize that patients not picking up pills on time may be experiencing intermittent treatment interruptions and may be predisposed to developing drug resistant virus.5,6
ARV drug stock-outs are an important cause of treatment interruptions and HIVDR in RLS.6-8,10 It was not possible to assess “ARV drug-supply continuity” because existing pharmacy records did not capture stock at the level of the site dispensary but rather at a more central level.
EWI monitoring results were extensively discussed with individual sites during interactive feedback sessions. These sessions emphasized how sites can make use of well-maintained medical and pharmacy records to conduct their own quality of care assessments and make meaningful local adjustments in practice.
As a result of this EWI pilot, changes have been made in EDT which will not only improve the quality of patient care but will also permit abstraction of all five selected EWIs in the future. Specifically, EDT was modified to include a pill-count field into which pharmacists will record number of remnant pills at each visit. Because drug-supply continuity at the level of the dispensary was not possible to assess, EDT will be adjusted to capture this information.
One important limitation of this pilot is that data are derived only from patients receiving ART in the public sector. Acknowledging that more than 23% of patients receive ART in the private sector, the MoHSS in collaboration with the private sector are assessing “ART prescribing practices and On-time ARV drug pick-up” in the private sector using insurance company claims databases. An additional limitation of this report is that pediatric patients were not included; however, pediatric EWI monitoring assessing the use and availability of pediatric formulations and weight-based dosing will be implemented. The fact that the ART sites chosen for this pilot may not have been representative of all ART sites in Namibia does not diminish the important public health significance of these results. Over the next 5 years, Namibia plans to scale up monitoring of EWIs to all of its ART sites. Steps have been taken to ensure the long-term sustainability of EWI monitoring by integrating it into the existing national monitoring and evaluation system.
In conclusion, this EWI pilot has given Namibia data that allowed it to identify areas within its national ART program, which could be strengthened to minimize the emergence of preventable HIVDR. As Namibia's HIVDR evidence base grows and is augmented by data generated from WHO-recommended population-based surveys to assess transmitted and acquired HIVDR,12,13 the quality of care for HIV-infected patients in Namibia will be further maximized and the emergence of preventable HIVDR minimized.
The authors thank The Republic of Namibia Ministry of Health and Social Services (Kahijoro Kahuure, Norbert P. Forster, Ella Shihepo), Spanish Government Grant (AF/NAM/BBA/701/XU/08), WHO-Namibia (Magda Robalo), WHO-AFRO (Rui Vaz, Fatim Cham, Richard Banda), Management Sciences for Health/Strengthening Pharmaceutical Systems funded by USAID (David Mabirizi), Namibia Institute of Pathology (Boniface Makumbi), Tufts Medical Center (Nestor G. Villanueva), Tufts University School of Medicine (Christine Wanke, Alice Tang), WHO-Geneva (Silvia Bertagnolio, Karen Kelley), and WHO-Namibia technical staff for critical review of article.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the World Health Organization, the United States Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, or the National Institutes of Health.
3. Hogg RS, Bangsberg DR, Lima VD, et al. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med
4. Vergne L, Malonga-Mouellet G, Mistoul I, et al. Resistance to antiretroviral treatment in Gabon: need for implementation of guidelines on antiretroviral therapy use and HIV-1 drug resistance monitoring in developing countries. J Acquir Immune Defic Syndr
5. Parienti JJ, Massari V, Descamps D, et al. Predictors of virologic failure and resistance in HIV-infected patients treated with nevirapine- or efavirenz-based antiretroviral therapy. Clin Infect Dis
6. Oyugi JH, Byakika-Tusiime J, Ragland K, et al. Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda. AIDS
7. Marcellin F, Boyer S, Prothoggopopescu C, et al. Determinants of unplanned antiretroviral treatment interruptions among people living with HIV in Yaoundé, Cameroon. (EVAL survey, ANRS12-116). Trop Med Int Health
8. Eholie S, Tanon A, Polneau S, et al. Field adherence to highly active antiretroviral therapy in HIV-infected adults in Abidjan, Côte d'Ivoire. J Acquir Immune Defic Syndr
9. Tuller DM, Bangsberg DR, Senkungu J, et al. Transportation costs impede sustained adherence and access to HAART in a clinic population in Southwestern Uganda: a qualitative study. AIDS Behav
10. Van Oosterhout JJ, Bodasing N, Kumwenda JJ, et al. Evaluation of antiretroviral therapy results in a resource-poor setting in Blantyre, Malawi. Trop Med Int Health
12. Jordan MR, Bennett DE, Bertagnolio S, et al. World Health Organization surveys to monitor HIV drug resistance prevention and associated factors in sentinel antiretroviral treatment sites. Antivir Ther
. 2008;13(Suppl 2):15-23. Available at: http://www.who.int/hiv/pub/drugresistance/who_surveys/en/index.html
. Accessed July 20, 2010.
18. World Health Organization. HIV Drug resistance Early Warning Indicator Briefing
. April 2008.
20. Kuritzkes DR, Quinn JB, Benoit SL, et al. Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients. AIDS
21. Havlir DV, Eastman S, Gamst A, et al. Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients. J Virol
22. Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med
23. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team. JAMA
24. Rosen S, Fox MP, Gill CJ. Patient retention in antiretroviral therapy programs in sub-Saharan Africa: A systematic review. PLoS Med
25. Nachega JB, Mills EJ, Schechter M. Antiretroviral therapy adherence and retention in care in middle-income and low-income countries: current status of knowledge and research priorities. Curr Opin HIV AIDS
. 2010;5:70-7. Review.
26. Horstmann E, Brown J, Islam F, et al. Retaining HIV-infected patients in care: where are we? where do we go from here? Clin Infect Dis
27. Ndiaye B, Ould-Kaci K, Salleron J, et al. Characteristics of and outcomes in HIV-infected patients who return to care after loss to follow-up. AIDS
28. Castilla J, Del Romero J, Hernando V, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr
29. Bisson GP, Gross R, Bellamy S, et al. Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy. PLoS Med
30. Nachega JB, Hislop M, Dowdy DW, et al. Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med