CHAPTER 5: GENERAL DISCUSSION AND CONCLUSION
The general objective of the thesis was to improve the understanding of the epidemiology, economic and clinical aspects of Kala-azar and to provide evidence for more rational decision making on V L control i n N epal. T o m eet t his obj ective, w e de veloped f ive r esearch questions: (i) what is the epidemiology of Leishmania donovani infection and disease?, (ii) What ar e t he r isk f actors f or V L among u rban residents an d i s t here possiblilty of ur ban transmission?, (iii) What is the health seeking behaviour and costs of VL from the household perspective?, (iv) What is the treatment outcome and patient adherence to currently used anti- VL drugs, and (v) What are the policy recommendations that can be formulated on the basis of our findings to support the ongoing elimination initiative?
5.1 Epidemiology of Leishmania donovani and disease and possible urban transmission One of the objectives of the thesis was to improve the understanding about the epidemiology and risk factors of L. donovani infection and disease.
In c hapter 4.1, w e documented t he e pidemiology of Leishmania donovani infection and disease. We al so revisited the ri sk fa ctors fo r V L, addressing t he i ssue of pos sible ur ban transmission in Nepal. F or the f irst time infection pr evalence of leishmania donovani has been de scribed i n a n e xtensive c ommunity-based s tudy. The ove rall Leishmania infection prevalence rate w as 9 % b ut there w as w ide v ariation b etween t he cl usters. T he r ate o f infection observed in Nepal is however much lower than that in the neighboring districts in Bihar S tate, India ( Sundar et al. 2009). There are s everal r easons t hat co uld ex plain t he differences in the infection prevalence rate. In India, Kala-azar has been endemic for much longer with several large outbreaks noted since late 19th century (Peters 1981) whereas the earliest report of the endemic transmission of the disease in Nepal was in the mid-20th century (Shrestha & Panta 1994). Therefore, exposure to leishmania has been longer in India than in Nepal, with a possible factor of boosting of acquired immune response with every episode of exposure. Secondly, VL incidence rates in the clusters from Bihar India were higher than in the c lusters in Nepal, resulting in a s maller reservoir f or tr ansmission o f a symptomatic infection. In the area of observation, bed net usage was high, but did not give any protective effect against infection, which is most likely related to non-impregnation with insecticide and poor c ondition of t he n ets. T he r ole of dom estic a nimals i n t he hous eholds c ould not be elucidated in this study; the cow and buffalo ownership was not associated with an increased risk of infection or with a protective effect. Possible control strategies should be implemented
in order to reduce the high burden of infections and disease through the reduction of breeding sites for P. argentipes, the vector for L. donovani using IRS along with distribution of ITNs.
In our study we found a higher L. donovani infection rate in men than in women. This is also the case for incident VL. Although this difference is generally attributed to a more frequent exposure of males than females to sand flies, e.g. as men often spend days away from home for seasonal work in f arms, there co uld al so b e an underdetection of di sease i n w omen i n traditionally male-dominated societies (WHO 2010). Another behavioral-related factor is that women in these communities wear long dresses which could prove to be protective to some degree from sand fly biting.
A s econd e xplanation for t he m ale pr edominance i n t he e pidemiology is th e p hysiological hypothesis: most p arasitic disease, i ncluding leishmaniasis, us ually r esult i n m ore s evere disease in males compared with females. Clinical and epidemiological based reports in the literature show that sex-associated hormones such as estradiol, testosterone and progesterone modulate immune r esponses, and m ales t end t o be m ore s usceptible t o leishmaniasis than females (Snider et al. 2009).
Kala-azar is related to poverty, affecting ‘the poorest of the poor’ (Boelaert et al. 2009). In poor states such as Bihar in India and Nepal, VL affects families in the lowest income groups, who already live on less than US$ 1 per day. The relation between leishmaniasis and poverty is complex: while poverty increases the risk for VL and aggravates disease progression, VL itself leads to further impoverishment of the family due to catastrophic health expenditure, income l oss an d d eath of w age earners (Alvar et al. 2006). Poverty is as sociated w ith ecological f actors t hat i ncrease t he r isk f or i nfection due t o pr oliferation of t he ve ctor or increased human-vector contact (Bern et al. 2000, Joshi et al. 2008, Boelaert et al. 2009). In areas of a nthroponotic pe ridomestic t ransmission, s uch a s t he I ndian s ubcontinent, proliferation of t he v ector i s e nhanced b y poor housing c onditions, s uch a s da mp earthen floors, which prolong the survival of the vector and cracked mud walls, which provide the vector w ith da ytime r esting pl aces. H ousing c onditions ( mud pl astered hous e) a nd t he environment (damp soil and organic debris) in these poor communities provide an excellent breeding site for sandflies (Bern et al. 2010). A number of studies in the Indian subcontinent investigated risk factors for VL, and most of them have been recently reviewed in detail by Bern et al. (2010). Generally risk factors for VL were mainly linked to precarious housing conditions. In our s tudy, t he odds of leishmania donovani infection an d d isease i ncreases with decreases in the asset score group. Decreasing the disease burden would probably also
help to alleviate poverty, while general measures of poverty reduction would definitely help to curb VL incidence.
More r ecently, V L i s b ecoming a peri- urban disease, l inked t o m igration of poor r ural families to major cities and the town in Nepal. Poor environmental sanitation in these settings and e rratic r ubbish collection m ay i ncrease t he r isk f or VL. With a h igh l ikelihood, we observed the outbreak of VL in Dharan town, eastern Nepal, can be attributed to transmission within the town. The epidemiology of VL in Nepal is changing from rural to urban areas. We have documented several VL cases in Dharan town; worst affected were the more peripheral wards of t he town. T hese were t he w ards w ith t ypical r ural-urban in terface w ith mo st residents de pend on da ily m anual l abor f or t heir l ivelihood a nd t herefore V L c ases m ight have b een easily ex posed t o L. donovani infection el sewhere. However, s everal factors pointed to urban transmission of VL in Dharan town. Firstly, clustering of VL cases makes intra-domiciliary ( urban) tr ansmission mo re lik ely th an in fection d ue to mig ration (Albuquerque et al. 2009). Secondly, the risk factors for VL among Dharan residents such as very strong association between VL and certain housing factors, those l iving in a thatched houses w ithout w idows had 3-4 t imes hi gher o dds of VL i n compared t o t hose l iving i n thatched houses with windows and i n brick houses. Sleeping on a bed a nd up- stairs w ere protective r espectively. Proximity t o pr evious VL cases w as a s trong r isk f actor. T hese associations a re a ll c onsistent w ith lo cal transmission. T hirdly, t he e ntomological da ta provide further evidence in support of local transmission of VL inside the town. The vector P. argentipes and the parasite L. donovani have been identified inside the town.
Kala-azar is predominantly a rural disease (Bista 1998, Boelaert et al. 2009). Recently Kala- azar c ases ha ve be en reported f rom B hojpur a nd O khaldhunga di stricts; i n t he hi lly non- endemic region. Many of these were treated at BPKIHS hospital (personal communication, Suman R ijal). B ecause of i ntense m igration, V L cases i n hi lly r egions c ould have b een infected with L. donovani in the Terai, but there is a definite concern about the possibility of local t ransmission f or s everal r easons. T his s hould be ve rified a nd i nvestigated ur gently, because if these cases are the result of local transmission in these hills, then national control programme needs to revise its control strategy urgently.
Moreover, VL typically clusters in marginalized communities of the villages at hamlet level (Ahluwalia et al. 2003, Mondal et al. 2009, Das et al. 2010), such as the mushar community in India (Hasker et al. 2010). In our study 39% of individuals living in a house with at least
one recent VL case were Leishmania infection positive compared to 9% in the overall study population in the same endemic region. This clustering pattern suggests that active VL cases are t he m ain s ource of transmission a nd s haring t he s ame hous ehold i s a n i mportant r isk factor for L.donovani infection. The recent initiatives on a ctive case detection strategy have included an index case based approach. The index case based approach includes the search of new VL and PKDL cases among the households members through house to house visits around a hous e ( radius of 50 m eters or 100 ho useholds) o f a r ecently diagnosed VL c ase (usually in the previous 6 months) (Huda et al. 2012). Given the high degree of clustering of infections, an active case finding strategy targeting family members of cases with VL may help i n t he early d iagnosis an d t reatment. It i s i mportant t o i ncrease t he aw areness o f communities about the disease and its control. Specific, adapted messages of health education should be developed. Community participation is essential in order to maximize the effect of control strategies; in cluding c ase de tection a nd ve ctor c ontrol. G ood di alogue w ith communities must be established. The role of asymptomatic L. donovani infections in the transmission of V L i n t he Indian s ubcontinent is not c lear; t hus, future r esearch i n t his direction is needed from the elimination initiative.
5.2 The health seeking behavior and economic burden of VL on households
During t he p ast f ive years, co nsiderable ef forts w ere m ade b y p ublic h ealth au thorities i n Nepal towards the elimination of VL such as decentralization and provision of free diagnosis and tr eatment with oral dr ug M iltefosine i n t he publ ic he alth s ystem. In c hapter 4.2, w e assessed the health seeking behavior of VL patients and documented household costs for one episode of VL from the patient’s perspective in a Miltefosine-based treatment programme.
The majority of patients had first consulted to a public health providers in Nepal. We found some di fferences w ith previous s tudies c onducted i n t he c ountry t hat ha d s hown t hat traditional providers were most commonly the patient’s first choice of provider (Adhikari &
Maskey 2005, Sharma et al. 2006, Rijal et al. 2006). These studies were carried out nearly a decade ago; a knowledge attitudes and practices survey carried out in 2006/2007 had shown knowledge about VL to be reasonable in VL endemic areas with patients mainly using the public sector, (Koirala et al. 1998, Mondal et al. 2009, Sarnoff et al. 2010), similar to our study. In addition, the presence of BPKIHS hospital in our study area may have influenced the health seeking behavior of households and referral practices of healthcare providers. The BPKIHS is a tertiary care hospital located in Sunsari district that has a widespread reputation in surrounding areas as well as a VL treatment and research center.
The da ta f or t his s tudy was c ollected i n 2011 a nd w e e xamined w hether t he V L control efforts i ntroduced b y t he government r esulted i n a de crease i n hous ehold c osts. T he s tudy was not an experimental (e.g. pr e-post t est design) but descriptive and data were collected from patients that had been treated for VL at public health care facilities and identified from the medical records of the District Public Health Offices of five high VL endemic districts and the BPKIHS. We found that the median total cost of VL was US$ 165 per episode or the economic burden of VL across all households was 11% of annual household income or 57%
of median annual per capita income. These overall costs of a VL episode were one third less compared to the studies carried out prior to the VL elimination initiative in Nepal. Despite the free provision of VL drugs and diagnostics, we found that the direct costs of an episode of VL w ere s till hi gh due t o out -of-pocket e xpenditures on ancillary drugs, i n pa rticular f or households that had visited a private provider prior to receiving VL treatment, as well as food costs during treatment.
Indirect co sts (productive time lo ss d ue to illness) were m easured acco rding t o t he h uman capital method whereby we quantified the loss of productivity in terms of loss of earnings to the patients or other household members taking care of the patient; unpaid household work was excluded. Basically the median number of days lost due to VL illness was multiplied by the median daily income of the individual (either the patient or another household member).
We a lso c onsidered i ntra-household labor substitution w hich is a c ommon s trategy th at households used to mitigate income losses.
Our study showed that direct and indirect costs represented a considerable proportion of total costs (i.e. 47% and 53% respectively). VL is characterized by prolonged fever, weight loss, anemia, fatigue and enlargement o f t he l iver a nd s pleen. As a r esult patients ar e either severely limited or not able at all to carry out their daily activities and need much support from the family members. We found that patients were not able to work for a median number of 57 days. The long inactivity of patients was caused by a combination of the delay between the ons et of s ymptoms and t he time th e p atient is c orrectly d iagnosed f or V L (i.e. pa tient delay). Most of the economically active patients in Nepal were working as daily laborers such as r ickshaw d river o r f arm labor. W hen f alling i ll, t hey w ere r arely replaced b y ot her household members. However, in households with a working patient reporting income losses due to VL illness, indirect costs represented 40% of the total cost of a VL episode.
With the exception of two studies in Nepal (including our study), household expenditure on medical and non-medical items (i.e. direct costs) were catastrophic to households. Combined with income losses due to VL illness, the burden of an episode of VL was very high in all studies. W e d etermined co sts as c atastrophic i f t hey exceeded 1 0% o f an nual h ousehold income ( Ranson 2002) .It i s h ypothesized t hat i f c osts i ncurred b y hous eholds e xceed t his threshold, they will need to cut expenditure on ba sic goods and services, incur debt or sell productive assets which may lead to impoverishment. The economic impact of a VL episode is not limited to direct and indirect costs, but also the strategies they used to cope with the costs of illness added to the burden of VL. These strategies addressed direct costs (e.g. using savings or borrowing) and/or indirect costs (intra-household labor substitution) (Sauerborn et al. 1996). The first and most common strategy used by households was the mobilization of savings or use of available cash. For the majority of the households this was not sufficient to cover the cost of care and 56% of households had also taken a loan and household had to repay on a verage 140% of t he or iginal a mount bor rowed w hen bor rowing f rom e ither a n informal m oney l ender or a vi llage m ember. Furthermore, i n 24 % of ho useholds, c hildren were involved in preserving the income of the households and were removed from school for the duration of illness to replace the VL patient.
The free VL diagnosis and drugs at public health facilitates have been an important policy measures to lower financial barriers and to improve the access to VL diagnosis and care, but the economic burden of VL on household is still considerable because of the long duration of treatment and length of hospitalization. In addition households also incurred substantial costs during t he health s eeking pha se ( prior t o c orrect V L di agnosis) as w ell a s t hrough t he strategies t hey us ed t o cope w ith t he costs of i llness s uch as l oans. Therefore, i ntensified efforts are n eeded t o f urther r educe t he bur den of V L t o a ffected hous eholds. T hese m ay include s hortening t he dur ation of s tay at hos pital, e xpanding de mand s ide f inancing mechanisms a nd i ncentives t o V L pa tients t o c over a w ider r ange o f costs i ncurred b y households. Control strategies that do not take into account the socioeconomic context of this disease will be difficult in the long term.
5.3 Treatment outcomes and patient adherence to Miltefosine treatment
Miltefosine, the only oral drug for VL, is currently the 1st line therapy in the VL elimination programme of the Indian subcontinent. We monitored the clinical outcomes of VL patients treated with miltefosine up to 12 months after completion of therapy, a follow-up which is
not r outinely don e b y t he government a t pr ogramme l evel. All p atients initially r esponded well to the MIL (initial cure rate of 95.8%), but an unexpectedly high number relapsed in the course o f t he 12 months’ fo llow-up thereafter. We f ound the cure rate at 6 m onths af ter treatment w as 82.5% , d ropping fu rther to 73.3% a t 12 m onths a fter t reatment. This i s a n important finding in view of the current consensus of considering the six month cure rate as the f inal e ndpoint i n clinical r esearch. We w ere a lso a ble t o de monstrate t hrough fingerprinting t hat t he r ecrudescence of V L i n our s tudy w ere due t o r elapses, a nd not t o reinfection, a n a rgument of ten us ed t o j ustify t he s ix m onths’ l imit. The f inal cu re r ate observed in our study is much lower than that observed in a similar study from India (90%) (Sundar et al. 2010), but similar to cure rates reported from Bangladesh (85%) (Rahman et al.
2011); both studies assessed outcomes only up to 6 months.
All th e MIL treatment f ailures obs erved i n our study w ere du e t o late relapse after in itial clinical cu re, contrasting w ith th e s ituation in th e sodiumstibogluconate era, w hen many patients were non-responsive during treatment (Rijal et al. 2010). The relapse rate at six and twelve m onths w as 10.8% a nd 20.0% r espectively w hich is a n alarming s ignal f or th e ongoing VL elimination campaign in the Indian subcontinent. The reasons for therapy failure are mu ltiple a nd c an b e r elated to th e h ost, th e drug, or the p arasite, all o f w hich w ere assessed in t he study. With respect t o t he host, we only found one significant clinical risk factors o f r elapse i.e. age < 12 years, w hich w as not a significant ri sk fa ctor fo r sodiumstibogluconate treatment f ailure o f V L in p revious s tudy ( Rijal et al. 2010). This increased relapse could be explained by the fact that the linear dosage of MIL (2.5mg/kg of body weight) apparently results in relatively lower drug exposure in children under 12 years compared t o a dults ( Dorlo et al. 2012a,b). A lso drug cl earance o f M IL v aries m uch i n between individuals (25%, Dorlo et al. 2008) and may be higher in children than in adults.
We al so ex plored t he p otential role o f d rug co mpliance, p arasite d rug resistance, an d r e- infection. P arasite f ingerprints o f p retreatment a nd r elapse b one ma rrow is olates w ithin 8 patients were similar, suggesting that clinical relapses were not due to re-infection with a new strain. The mean promastigote MIL susceptibility (50% inhibitory concentration) of isolates from definite cures was similar to that of relapses. Moreover, MIL blood levels at the end of treatment were s imilar i n cu red an d r elapsed p atients in a sub-sample (n= 31) available at BPKIHS hospital .
We assessed p atient ad herence t o unsupervised s ingle-drug M IL tr eatment f or V L a t th ree different h ealthcare s ettings, a t opic t o w hich little a ttention is g iven b y the government (Hasker et al. 2010, Malaviya et al. 2011). Adherence studies are difficult, as effective tools to measure adherence are missing, and we relied on pa tient interview and pill count, which both are i naccurate and can b e b iased - intentionally or non -intentionally – by the interviewee. Moreover, there is no gold standard to measure adherence, as drug concentration levels i n bl ood m ay va ry largely i n be tween i ndividuals ( Dorlo et al., 2008) . With th ese limitations, we found that patient adherence to MIL treatment in our study population was indeed a problem and the target of 90% of capsules taken was not reached in at least 17% of the enrolled patients. Though not statistically significant, these patients did have a higher risk of relapse. Good adherence is hindered by the side effects of the treatment, treatment fatigue, but also access problems (financial, procurement, quality), conditions-related factors (severe illness, c oncomitant dr ugs), l imited know ledge on t he di sease and i ts c ure a nd o f c ourse limited information provided by the healthcare providers to the patients.
However, we found better adherence in patients who were literate and informed on treatment duration a nd s ide e ffects, c ompared t o t hose w ho w ere not . For V L, t reatment dur ation i s limited to 28 days and treatment is provided free of charge in Nepalese government health facilitates, b ut ad herence r emains a m ajor ch allenge f or p atients an d h ealthcare providers.
There are a number of strategies proposed to optimize adherence, of which the most efficient is directly observed tr eatment ( DOT) as pr omoted s trongly i n t uberculosis pr ograms. T he main obj ection f or s uch s trategy i s t hat pa tients ha ve t o r emain unde r obs ervation f or t he duration of the treatment, i.e. 28 days for MIL-based treatment. This would be contradictory to t he c hosen pol icy of bringing di agnosis and t reatment closer t o t he p atients a nd r educe barriers and d elays, a s well a s in direct tr eatment c osts. C linical s ymptoms te nd to r esolve quite quickly under treatment, i.e. usually within the first week. A number of VL patients can therefor resume their activities while still taking treatment at home.
An alternative DOT, through village health workers, has not been explored yet, though many authors (including our research group) have suggested the potential of involving the FCHVs (Female Community Health Volunteers) or A SHAs (Accredited Social Health Activists) in the management of VL diagnosis and care (Joshi et al. 2009, M alaviya et al.2013, ) In our paper, w e s uggested i mproving adherence through better counseling at th e start of the treatment, i ncluding c omprehensive i nformations on V L a nd on s ide e ffects a nd a ction of MIL, a nd on t he i mportance of f ollow-up vi sits. A dherence t o f ollow-up vi sits a nd t o
completion of treatment can be further improved by financial incentives to motivate patients to return to refill the capsules at hospital.
Post kala-azar dermal leishmaniasis is a cutaneous complication appearing after treatment of VL. PKDL patients are considered infectious to sandflies and may therefore play a role as a reservoir i n t he absence of a ctive V L cases dur ing i nter-epidemic p eriod ( Addy & N andy 1992).
There have been few reports and studies on PKDL from Nepal (Garg et al. 2001, Karki et al.
2003, Rijal et al. 2005, Das et al. 2007), and the frequency and risk factors of PKDL have not been studied previously. When we re-examined the group of patients treated for VL in the previous t en years, w e f ound 2.4% having P KDL. Overall, t he risk t o d evelop P KDL w as 1.4% within 2 years after VL treatment; 2.5% within 4 years and 3.6% within 8 years. PKDL was more common in those with incomplete VL treatment and in settings with little treatment supervision.
Our study shows t hat t he occurrence of P KDL i n patients with past t reated V L i s l ow but existing and related to quality of treatment. This risk is lower than that reported in other VL- endemic a reas i n t he Indian s ubcontinent ( Rahman et al. 2010) . S till, the risk e stimates reported are hard to compare due to the unequal follow up t imes (Mondal et al.2010). We found t hat PKDL was more c ommon in th ose with in complete V L t reatment with s odium stibogluconate and in settings with little treatment supervision. However, in our region only few VL patients attend private clinics for VL treatment because anti-VL drugs are provided free-of-charge i n t he publ ic he alth system and a re n ot av ailable i n p rivate p harmacies. No cases o f f ormer V L t reatment t hrough p rivate practitioners or pha rmacies ha ve e ver be en reported t o t he s taff i n t he V L t reatment c enter a t B PKIHS. T his c ould pos sibly h elp to explain why the prevalence of PKDL in past treated VL patients is lower in Nepal. Though PKDL patients have b een recognized as an i mportant reservoir for infection, it r emains a neglected pa rt of t he c ontrol pr ogramme. Counseling and s upervision of treatment s eems therefore essential to reduce PKDL development in the future, even if sodium stibogluconate is no longer used in Nepal. Policy makers should include surveillance and case management of PKDL in the ongoing VL elimination programme in Nepal.
5.4 General conclusion
With a renewed interest in neglected tropical disease and the implementation of VL control efforts in the Indian subcontinent, the studies presented in this thesis will contribute to the ongoing elimination in itiative for m ore rational V L c ontrol in va rious w ays. W ith the availability o f new t echnologies an d t reatment , t he ev idences generated on e pidemiology, clinical as well as economic aspects of VL will be useful to control the disease in the resource constraints V L en demic countries l ike N epal. Moreover, i ntegration of publ ic he alth interventions and research evidences into the existing health system and improving the access to VL diagnosis and care for the marginalized people will be favorable options to reach the goal of elimination by year 2015.
From my research work, the followings conclusions can be drawn:
• Epidemiology of L. donovani infection is not well documented; role in the transmission of disease is not well understood in the Indian subcontinent.
• Epidemiology of VL is changing; more recently the disease is becoming a peri--urban disease, linked to migration of poor rural families to major cities in Nepal
• Despite VL diagnosis and drugs being provided free, patients and their households still incurred substantial costs.
• Current policy of Miltefosine-based ambulatory treatment is not performing as good as expected: (i) high relapse rate especially in children, (ii) adherence problem
• The occurrence of PKDL is low but existing and related to the quality of treatment.
5.5 Recommendations for policy implications
Though making policy recommendations is beyond the scope of this thesis. However, on the basis of our findings, the following recommendations can be formulated:
• Increase the awareness on the changing epidemiology of VL for effective disease control
• Further e fforts n eed t o be done i n or der t o reduce the breeding s ites f or Phlebotomus argentipes, the vector for L. donovani to curtail the transmission.
• Strengthen the reporting system of VL and investigate t he disease outbreak in the new foci to i nform t he na tional c ontrol p rogramme t o r evise t he d isease control s trategy if required.
• The f ree provision of VL di agnosis a nd d rugs a t publ ic he alth s ystems ha s been an important p olicy measures to lo wer financial ba rriers and i mprove the access t o V L diagnosis and care. However, the economic burden of VL is still considerable and more intensified efforts are needed to further reduce the burden of VL to affected households through shortening t he dur ation of s tay a t t he hos pital, e xpanding t he de mand s ide financing mechanism and incentive to VL patients to cover other costs.
• Regular m onitoring t he e ffectiveness of dr ug r egimens a nd counseling the p atients t o optimize treatment adherence
• Need to improve PKDL surveillance & case management in control programme
5.6 Future research priorities
Several a spects of t he e pidemiology and t ransmission of V L still remain unknown and require further research.
• Research o n risk factors for i nfection and t ransmission are n ecessary, i ncluding s ocial economic and nutritional aspects
• Field s tudies on new foci and outbreaks of V L s hould be l aunched t o determine t he structure of the focus and the feasibility of control
• There is a need to have a better understanding of the process by which patients seek care and present earlier at health facilities.
• Research a nd de velopment of i nnovative tools for vector and reservoir control are needed, including evaluations of the cost, feasibility, acceptability and sustainability of control Strategies
• Clinical research to e valuate ne w dr ugs a nd combinations of dr ugs to r educe t he duration of treatment
• Operational research to i mprove t he c ollection of i nformation a bout t reatment compliance a nd i mplementation of a pha rmacovigilance system is imp ortant to better define algorithms for new treatment regimens
• Social-behavioral research to id entify s ocial d eterminants o f th e u se o f h ealth-care services and healthcare- seeking behavior is important
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