The increasing need to control HIVDR in low-resource settings (LRS) requires the implementation of efficient and rapid approaches to limit the emergence of preventable HIVDR, among which a population-based survey, such as EWI evaluations, could yield relevant evidences based-recommendations for best clinical practices. Overall, this is a paper on a topic of high importance in HIV medicine, transmitted drug resistance, as well as the methods for detecting it in a LRS where genotyping is not available, and remains challenging and clinically important issues to all the stakeholders who are involved in the global scale up of ART, particularly in Africa.
Physicians’ prescribing practices (EWI1) remained nationwide in conformity with the national guidelines. Interestingly, even sites with the 98-99% performances for EWI1 had no cases of dual- or mono-ARV prescriptions, which are more likely to select for drug resistant HIV rather than an inappropriate prescribing of drugs such as boosted protease inhibitors, abacavir, or tenofovir (which may not be appearing on several guidelines) which likely have less significance related to HIVDR. This good practice was mainly due to the use of standardized ART regimens and the institution of a consortium agreement (therapeutic committee) for every treatment initiation. This is a weekly consortium body made up of health staff all trained in HIV/AIDS management (medical doctors, nurses, medical biologists/laboratory technicians, medical counselors, pharmacists/pharmacy clerks, data manager and/or community relay agents; a practice which merits to be encouraged. Globally, 75% of clinics monitored worldwide met the WHO-recommended target on prescribing practices . Specifically, other African countries (Malawi, Namibia, and others) also reported good practices [18–24], while poor performances were observed out of Africa (Central American, Caribbean, Asian, Oceanic and Western Pacific: from 38 to 75%) [23–31]. Lack of evaluation overtime in the above mentioned studies could not enable in-depth comparison to ours. Still, the use of a therapeutic committee as well as continuous training may be vital practices to maintain and/or improve good ARV prescriptions.
The high and increasing rates of lost-to-follow-up are indicative of a growing rate of patients harboring potential drug resistant viruses within the national context, which in turns supports a growing risk of HIVDR emergence in Cameroon. These would have been favored by the observed heavy workload, and also probably due to termination of working contracts for community relay agents (CRA). Thus, task shifting (from medical doctors to nurses), and probably community empowerment (by allocating resources to CRAs), as well as free consultations and reduced laboratory costs in such poor settings, may help in reducing the rate of missing patients. Indeed, the numbers of required health care workers to provide ART in LRS (1–2 physicians/1000 patients, 2–7 nurses/1000 patients, <1-3 pharmacy staff/1000 patients, and wider ranges for other health-allied staffs) estimated by Hirschhorn et al. , was based on the WHO-3by5 target (i.e. treatment of 5 million patients by 2005), and currently need to be revised in order to match the growing ART coverage (presently >8 millions) . With restriction to the WHO-protocol, a direct evidence-based evaluation has not yet been conducted to investigate on the real impact of CRA’s disengagement on lost to follow-up. Globally, 69% of clinics monitored worldwide met the WHO-recommended target . Particularly, in other African countries, lost-to-follow-up is also challenging (40 to 75%) [18–24], whereas out of Africa higher performances were recorded (54 to 100%) [23–31]. Furthermore, the impact of distance to the clinic, waiting time prior to medical consultation, stigma and patient educational level, are factors that may help in reducing lost patients . Indeed, ART uptake has been negatively associated with distance from the nearest primary healthcare [34, 35], thus indicating a possible need for creating new ART clinics to foster adherence.
The gradual poor retention of patients on first line ART after 12 months ART may be indicating a rapid switch to second line regimens that could be explained by numerous other factors (wider availability of HIV Viral Load testing, greater clinician experience/awareness on identifying treatment failure, a preexisting drug resistant mutation, etc.). Further studies are therefore needed to determine the time-to-treatment, to implement measures toward long term efficacy of first line ART and to limit events of inappropriate switch to second line ART in these settings. Furthermore, failure to be on first line therapy one year after initiation might in fact not necessarily be a negative indicator, since it might indicate a correct and necessary treatment switch to second line. This observation makes questionable the overall utility of EWI3, which would likely need to be revised for better utility in future. Globally, 67% of clinics monitored worldwide met the WHO-recommended target . More interestingly, our performances in 2008 (70%) were similar to those found in other African settings (among which Malawi: 53% and Namibia: 67%) [18–24], while higher performances (62-90%) were recorded out of Africa [23–31]. Since first line ARV drugs (≈$100/patient/year) are about 4 times less costly than second line, an effective retention on first line is economical  and may regulate the current fast switch to second line ARV (2% of total patients on ART in 2006, to 13% of total patients on ART in 2009) in Cameroon . These analyses are consistent with the different HIVDR rates to NRTI and NNRTI in 2003 (before ART scale-up: 5.6%M184V and 6.1%Y181C) and thereafter (following ART scale-up: 16.3%M184V and 63.7%Y181C) . Despite the higher rate of transmitted HIVDR in Latin America (12-20%), sub-Saharan Africa, though with only 4-9% of transmitted HIVDR, is experiencing a rapid scale-up of ART associated with an increasing rate of transmitted HIVDR (38% increasing risk of HIVDR per year): this important fact urgently needs a regular HIVDR surveillance system [14, 16, 38].
The overall delay in drug pick-up strongly supports a national revision of the community engagement strategy to support patient adherence to ART programmes. This poor/decreasing performance in drug pick-up (EWI4), together with EWI2 and 3, clearly placed patient non-adherence as the main factor with high risks of HIVDR development and spread within the community. However, it should be noted that EWI4 itself seems problematic and may not be entirely practical to address adherence issues. Indeed, in our setting, clients may present one-to-two day(s) after their required drug pick-up appointment date and still maintain 100% ART adherent, due to availability of remaining pills from the previous appointment. Thus, as for EWI3, the overall utility of EWI4 may also be brought into question, and would likely require expert review or reconsideration. Thus, the low scores found in our study are partly explained by the rigidity of this indicator, which has further being recently modified in the 2012 HIVDR report . Globally, 70% of clinics monitored worldwide met the WHO-recommended target for timely drug keep-up . Detail analysis also reports lower timely drug pick-ups in other African settings (between 17% and 41%) [18–24], against settings out of Africa (73-100%) [23–31]. Thus, in African AIDS programmes, issues such as “time spent by patient for pharmacy service”, “service quality rendered by pharmacy staff”, “pharmacy localization”, may be partly explained by delays in drug pick-up. As suggested by El-Khatib et al. in 2011, adherence to drug-refill (pill count) may also be a useful EWI of virologic and immunologic failure on first-line ART in African settings .
The gradual poor performances in drug supply present EWI5 as the main programmatic setback in the national ART performance. Despite the provision of alternative ART (by replacing shortage of efavirenz with nevirapine or lopinavir/ritonavir) in case of drug discontinuity, stock outs still negatively impact patient adherence with non-negligible risks of HIVDR due to potential suboptimal drug levels. Drug supply machinery should be urgently revised. Our findings could be strengthened by conducting further investigations to as to why these stock outs are occurring; targeting specifically the supply lines, trade agreements specific to Cameroon, land versus air versus sea route issues, or in-country distribution network problems. Globally, 65% of clinics monitored worldwide met the WHO-recommended target for drug supply. Geographically, the procurement systems were successful (100%) in Malawi (cross-sectional study) , and with an increasing performance in the Caribbean (31.3%-94%, from 2007–2009) [23, 24]. Aggregated data showed poorer performance in sub-Saharan Africa (42%-47%), as compared to non-African countries (32-90%) [20–31]. Thus, African settings are more in need of further investigations to improve their drug supply system.
Lessons learnt from the three year survey
This study has effectively identified some strengths and weakness of the national ART programme, amongst which the encouraging prescribing practices, and corrective measures been addressed for other EWIs. Indeed, the performance of these later EWIs has decreased over time rather than staying steady or improving (as would have been hoped). Thus, this result is also very interesting, and if taken at face value, is a serious indictment of the overall implementation strategies underway in Cameroon, and a crucial cause for concern for generation of drug resistance. Therefore, tasks shifting/decentralization (to alleviate the heavy workload) and community re-empowerment are underway [4, 39]. A specific algorithm (in form of posters and hand-outs) presenting overall performances and addressing adapted corrective actions, has been provided to guide healthcare providers working at the ART clinic (see Additional file 1). Also, advocacy, addressed to health authorities (ministry and heads of health facilities), boosted the implementation of the above corrective measures. Additionally, a bottom-to-top approach, through consideration of associations of people living with HIV, would allow patients to participate as key players in the success of the national ART performance [33, 35, 36, 39]. Site supervision is also essential for an effective integration of HIVDR activities in the routine clinical practices, to make EWI an instrumental in prioritizing measures and allocating resources for clinics. Our analyses suggest that ART programmes in other LRS may be experiencing similar declining performances, and thus need relevant measures.
Challenges resulting from our findings
A successful and sustainable ART programme performance should be accompanied by scalable EWI survey in the country; the major setback relies on the regular availability of the required resources . Secondly, despite the availability of external support, additional fund raising is still needed to optimize patient healthcare. Continuous staff training is essential to sustain good practices; brain drain makes the heavy workload persistent, thereby calling for policies to train and retain qualified personnel, especially with the need/creation of new ART clinics in the country to ensure scaling-up of the treatment programmes . More importantly, recent studies in Cameroon showed low to moderate levels of transmitted HIVDR , and increasing levels of acquired HIVDR after 12 and 24 months , thus predicting growing risks of treatment failure and HIVDR to the commonly used drugs, due to a broad range of factors [35, 39]. Without attempting to create a direct temporal relationship, the increasing rate of transmitted and acquired HIVDR in Cameroon, alongside the increasing/widely availability of ARV treatment, supports also a growing need of affordable viral load and HIVDR testing, and a more regular surveillance of HIVDR in this country [8, 38]. Pediatric HIVDR surveillance is of prime importance, and needs to be implemented . Of note, as observed in other countries, Fokam et al. also found low (4.9%) and high (90%) rates of HIVDR among drug-naïve and first-line ART failing children in Cameroon, respectively . Finally, the emerging HIV co-infections with tuberculosis, malaria, viral hepatitis, require setting-up an antimicrobial drug resistance strategic plan and working group to preserve active drugs for the next generation [44, 45].
Despite restrictions to WHO-standards, our study limitations could not allow greater/meaningful statistical analysis, due to the limited number of sampled ART sites. Furthermore, difficulties in evaluating other factors that could potentially affect ART performances (disengagement of CRAs, task shifting, distance to clinic, stigma/discrimination, educational level, bottle nets in the drug supply system, etc.) also limited the strengths of our recommendations.