Background: The aim of this study was to assess the cost- effectiveness of HIV treatment alternatives – with and without highly active antiretroviral therapy (HAART) – within alternative strata based on the CD4
+T-cell count at the initiation of treatment in a low-resource setting.
Methods: A retrospective observational study was conducted following 286 HIV-positive individuals admitted to the principal teaching hospital in Casablanca, Morocco, between 1995 and 2002. Patients were stratified by CD4
+T-cell count and regression models were fitted to determine risk of opportunistic infection. Data on healthcare resource use were derived from patient records and were evaluated from the hospital perspective.
Results: HAART led to a significant reduction in the number of HIV-related opportunistic infections (P < 0.0001),
extended survival (61.3 versus 55.2 months; P < 0.0001) and reduced hospital stays (P < 0.0001) in comparison with care in the absence of HAART. When medical care and drug costs were considered together, HAART was more costly than providing treatment for opportunistic infections. The incremental cost-effectiveness ratio was lower than gross domestic product (GDP) per capita for patients starting HAART with a CD4
+T-cell count < 200 cells/mm
3, but this increased to nearly three times GDP per capita when HAART was initiated at CD4
+T-cell counts above this threshold.
Conclusions: HAART is more cost-effective than treating HIV-related opportunistic infections and, contrary to conclusions drawn in developed countries, HAART is more cost-effective when the CD4
+T-cell count drops to < 200 cells/mm
3.
Original article
When to initiate highly active antiretroviral therapy in low-resource settings: the Moroccan experience
Sandrine Loubiere
1,2*, Kamal Marhoum el Filal
3, Mustapha Sodqi
3, Anderson Loundou
4, Stéphane Luchini
1,5, Susan Cleary
6, Jean-Paul Moatti
1,2and Hakima Himmich
31
Health and Medical Research National Institute (INSERM), Research Unit UMR 912, Marseilles, France
2
Southeastern Health Regional Observatory (ORS PACA), Marseilles, France
3
Infectious Disease Unit, Hospital Ibn Rochd, 20100 Casablanca, Morocco
4
Department of Public Health, Timone University Hospital, Marseilles, France
5
GREQAM-CNRS, Marseilles, France
6
Health Economics Unit, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa
*Corresponding author: E-mail: loubiere@marseille.inserm.fr
In developed countries, highly active antiretroviral therapy (HAART) for HIV infection is considered to be a cost-effective use of resources [1–5]. However, some experts using modelling approaches have challenged the diffusion of HAART in developing countries by arguing that it is less efficient than alternative uses of resources for HIV care and prevention [6,7]. Recent empirical studies based on data collected from actual programs for scaling-up access to treatment in low- resource settings have, however, suggested that HAART can be cost-effective in such contexts [8–13].
One of the most controversial topics in the medical management of HIV infection remains the optimal time to initiate HAART [14]. An important and
consensual result from developed countries is that it appears more cost-effective to start HAART at an earlier stage of HIV infection: the incremental cost per life-year gained is lower when initiating HAART in patients with CD4
+T-cell counts of 200–349 cells/mm
3or even 350–499 cells/mm
3in comparison to starting with a CD4
+T-cell count < 200 cells/mm
3[2,15–17].
However, official World Health Organization (WHO) guidelines for low-resource settings, and most national guidelines in developing countries, recommend starting antiretroviral treatment in HIV-infected asymptomatic patients only when the CD4
+T-cell count drops below 200 cells/mm
3[18–20]. In practice, patients in low- income settings are identified at a later stage of disease
Introduction
and started on HAART at a lower CD4
+T-cell count than in developed countries, with median CD4
+T-cell counts of 100 cells/mm
3in most programs [21,22].
Results from recent cost-effectiveness studies in South Africa contrast with those previously obtained in developed countries: in this context of limited resources, the strategy likely to be most cost-effective seems to be later initiation of HAART (CD4
+T-cell count < 200 cells/mm
3), although earlier initiation remains more effective [8,23].
It remains to be seen if this result will be confirmed in other resource-limited settings and, if this is the case, it is worthwhile exploring the reasons why the cost- effectiveness of HAART initiation may systematically differ between developed and developing countries despite similar results in terms of clinical effectiveness.
In Morocco, although the spread of the epidemic is now rapidly increasing, prevalence of HIV is still only 0.1% among adults between 15 and 49 years of age [18]. Until recently, the prevailing assumption in Morocco was that the public health sector of the country could not afford the introduction of HAART in routine clinical care. However, with the support of French non-governmental organizations (NGOs) and national sponsors, the Association de Lutte Contre le Sida (ALCS) – one of the more active Moroccan NGOs in the fight against HIV/AIDS and the only one to be directly involved in the management of HIV care – was able to provide funding for access to HAART for HIV- infected patients as early as 1996. This program was developed in close collaboration with a public hospital in Casablanca, the economic capital of the country.
This Moroccan experience offers the opportunity to estimate the cost-effectiveness of HIV treatment alter- natives – with and without HAART and initiated within alternative strata defined by CD4
+T-cell count – based on an observational cohort of HIV-infected patients. It is also possible to determine whether these results are in line with empirical results from the literature and are supportive of current policy recommendations.
Methods
Subjects and setting
The Infectious Diseases Unit in the University Ibnou Rochd Hospital of Casablanca is the major public health- care facility dedicated to the treatment of HIV-1-infected patients in Morocco. It was established in 1981 and serves largely indigent patients who are referred to the hospital from a wide range of primary healthcare facilities across the country.
A total of 369 HIV-infected patients received care in the hospital unit between 1997 and 2002, of whom 286 met two criteria for inclusion in a retrospective
‘intention-to-treat’ analysis: HIV infection diagnosed
by enzyme-linked immunosorbent assay (ELISA) tests and confirmed by western blot; and availability of at least two CD4
+T-cell count values at different points in time. Among these 286 patients, 167 (HAART cohort) benefited from the initiation of a HAART combination during the study period, whereas 119 (the no-HAART
‘control’ cohort) did not access HAART but did receive other HIV-related care including treatment for oppor- tunistic infections (OIs). Patients who only received mono- or dual-therapy were excluded from the study.
Clinical follow-up was every 2–3 months or more frequently if clinically indicated. At each visit, the attending healthcare personnel recorded detailed clinical and immunological data in the patient’s file. WHO clin- ical stages were used to define the patient’s HIV disease.
Owing to resource constraints, viral load measurements were only taken in patients for whom initiation of HAART was planned and were not available for most of the no-HAART group.
HAART regimens
In Morocco, antiretroviral regimens have changed during the period of the study. Between 1996 and 1998, a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen was used, consisting of zidovudine, didanosine and lamivudine. Between 1998 and 2002, patients received a dual NRTI (including zidovudine, didanosine, lamivu- dine and stavudine) together with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz) or a protease inhibitor (PI) (such as indinavir or nelfinavir).
Only patients who received a triple combination therapy comprising two NRTIs plus one NNRTI or two NRTIs plus one PI were included in the HAART cohort.
Treatment of opportunistic infections
Ten different types of OIs (ranging from mild fungal infections to severe bacterial infections) are common in Morocco: cryptococcal infection, oesophageal candidiasis, oral candidiasis, pneumonia, cutaneous bacterial infections, tuberculosis, cerebral toxoplas- mosis, cytomegalovirus (CMV) infection, and Mycobacteriu avium complex (MAC).
OI treatment and prophylaxis included a range of therapies: fluconazole for fungal diseases; isoniazid, rifampicin and pyrazinamide for tuberculosis; cotri- moxazole for bacterial infections and cerebral toxoplasmosis; and ganciclovir and azithromycin for CMV and MAC infections. Both HAART and no- HAART groups received treatment for OIs as well as other HIV-related care.
Main clinical outcomes
The incidence of OIs and overall survival, that is, the
number of life-years gained, was assessed. OI incidence
was defined as the number of new OIs diagnosed in
each group per 100 patient-years of follow up. The analysis was further stratified by the baseline CD4
+T-cell count ( < 100 cells/mm
3, 101–200 cells/mm
3and
> 200 cells/mm
3).
Statistical analysis
Continuous baseline characteristics are described with means and standard errors (
SD), and binary character- istics are described with numbers and percentages.
Differences in categorical variables were compared using the S2 test, and differences in means using Student’s t-test. The non-parametric median test was used to compare continuous non-normally distributed variables. All P-values quoted are two-sided, with a P-value < 0.05 considered as significant.
The Kaplan–Meier technique and the generalized log-rank test were used to construct and compare the predicted survival times of the two groups. Predicted survival time was defined as the time from inclusion to the date of death from any cause, or to the last follow-up visit.
To compare survival in the two cohorts by baseline immunological status, the Kaplan–Meier analysis was further stratified by baseline CD4
+T-cell count, as described above. Interactions were tested by comparing models with the interaction term included with corre- sponding models without the interaction term, using the likelihood ratio test.
We confirmed the results of these tests, while controlling for specific baseline covariates, by exam- ining the relative probability of survival using a Cox proportional hazards model. Only significant variables from the Kaplan–Meier analysis with the statistic P < 0.30 were introduced into the Cox model. Backward elimination was used to reduce the model to the subgroup of factors that independently contributed to the variation in the predicted survival time. Thereafter, a parametric survival distribution, the Weibull distrib- ution, was used to extrapolate survival beyond the observational period. The Weibull distribution was chosen because is the most widely used parametric survival model. Although Weibull and exponential distributions can accommodate both the proportional hazard and acceleration failure time assumptions, the addition of the shape parameter p, which determines the shape of the hazard function, gives the Weibull model greater flexibility than the exponential model [24–26]. Calculations were conducted with SPSS (version 12; SPSS system) and STATA (version 9;
Intercooled Stata) software.
Identifying and measuring costs
The economic assessment was carried out alongside the observational clinical study and was conducted from the point of view of the funding agencies of the healthcare
system. Standardized case report forms were used to collect data on healthcare resources utilized in the care of HIV-infected patients. Data pertaining to laboratory testing, length of stay for initial and subsequent hospi- talizations, follow-up physician visits and consultations and drugs were collected. No-HAART drugs included all drugs other than antiretrovirals (ARVs) dispensed to patients during the course of care, including treatment and prophylaxis for OIs. Mean and 95% confidence intervals (CI) of inpatient and outpatient service use were calculated for the two groups.
Data on average cost per day for an inpatient bed-day (length of stay > 1 day) and day-care admission (length of stay < 1 day), including both hotel and overhead costs, as well as average physician and nurse fees per day, were calculated from accounting information in the hospital.
Average cost per outpatient medical consultation, and the unit cost for laboratory tests and procedures was collected from the same hospital database. Costs of non- ARV drugs are based on Moroccan market prices.
Table 1 outlines unit costs across the main cost parame- ters. Costs were expressed in 2004 prices and were converted from Dirhams (MAD) to Euros using the average exchange rate for 2005 (€1=MAD11.03).
During the study period, procurement strategies for ARVs in Morocco have been diversified. Most patients received government-subsidised ARV drugs. In addi- tion to the governmental supply of free ARV drugs, drug donation is an alternative way to receive free ARV drugs. The ALCS is an example of a local organization
Resources Unit cost, €*
Laboratory testing
CD4
+T-cell count 18.2
Viral load
†100.0
Complete blood count 3.5
Glycaemia 11.0
Lipids 15.5
Inpatient day 68.0
Emergency department visit 118.0
Medical visit 18.0
HAART drugs (annual cost per patient) 346.0–637.0 No-HAART drugs
‡§Ganciclovir 36.0
Pyrazinamide 9.0
Ethambutol 4.0
Bleomycine 27.0
Aciclovir 20.0
*At 2004 prices. †For information only, viral load was not included in the analysis as it was not performed on most patients in the study. ‡Only the most frequently prescribed treatments are reported here. §These costs were estimated from the National Source for pharmaceutical products and are given as the costs per prescription.
Table 1. Unit costs for healthcare resources at the University
Ibnou Rochd Hospital
receiving funding from international organizations, such as the International Therapeutic Solidarity Fund (ITSF) and the Global Fund to Fight AIDS, Tuberculosis and Malaria, which supports ARV drug treatment programs in Morocco. In 1996, the ALCS obtained an exemption from custom charges for ARVs, which enabled the purchase of drugs at wholesale prices. Dramatic reductions in the prices of patented ARVs combined with the availability of cheaper generics has also contributed to the supply of free drugs by the Moroccan government.
Costs of ARVs were taken from observed public sector prices based on their direct purchase from phar- maceutical companies. As a number of different ARV combinations were used, an average annual price of all drug combinations was calculated, which amounted to 637 per person per annum. However, to take into account actual decreases in prices of ARVs, we created an alternative scenario in which costs of ARVs were based on anticipated public sector prices for generic manufactured drugs, which amounted to 346 per person per year [19].
Economic analysis
Incremental cost-effectiveness ratios (ICERs) for the 5-year follow-up period were calculated for the HAART group. Health outcomes were measured as life-years gained, and total annual costs were defined as the intervention cost (for the HAART group only) plus the estimated mean health service use cost (resource use for the HAART and no-HAART control group multi- plied by the unit cost). The ICER gives the cost per additional unit of health outcome gained from the inter- vention relative to the standard (control) approach. A 3% discount rate was used to discount costs and bene- fits beyond the first year [27]. Health benefits were discounted according to Drummond’s recommenda- tions for continuous variables, although there is still controversy regarding this practice [27–29].
Sensitivity analysis
We developed a set of one-way sensitivity analyses to assess the variation in ICER according to changes in key parameters. We varied mortality and OI incidence in each group using 95% confidence intervals. Two changes in costs were explored. The baseline estimate for inpatient and outpatient costs was varied by 50%
in each direction, and the prices of ARVs were varied over plausible ranges. Multiway sensitivity analyses were conducted by modelling optimistic (‘best-case’) and pessimistic (‘worst-case’) scenarios by varying both survival outcomes and ARV prices. In these scenarios, the upper or lower limits of variables as defined under one-way sensitivity analyses were combined in favour or against HAART, respectively.
Results
Baseline population characteristics
The baseline demographic and clinical characteristics of both cohorts are shown in Table 2. Mean age, gender and socioeconomic status in the two groups did not differ significantly, but the proportion of patients without any healthcare insurance was significantly higher in the no- HAART group. There were also no significant differences in HIV disease stage or prevalence of OIs, but the HAART group had lower median CD4
+T-cell counts.
CD4
+T-cell counts and opportunistic infections Mean ( ±
SD) follow-up in the HAART group (37.4
± 13.9 months) was significantly higher than in the no- HAART group (16.9 ± 13.6 months; P < 0.0001).
During follow up, median CD4
+T-cell counts increased in the HAART group, whereas median CD4
+T-cell counts decreased in the no-HAART group; this result was maintained when patients were stratified by baseline CD4
+T-cell count (Table 3).
Nine cases of OI were reported in the HAART cohort compared with 31 cases in the no-HAART cohort (P < 0.0001 using exact test). The difference in the number of OIs remained significant when patients were stratified by baseline CD4
+T-cell count, except for patients with CD4
+T-cell counts between 101 and 200 cells/mm
3(Table 3).
Survival
Mean survival time over the follow-up period was 61.3 months (95% CI 58.5–64.1) in the HAART group and 50.2 months (95% CI 42.2–58.3) in the no-HAART group, and this difference was statistically significant ( χ
2=26.82; P < 0.0001, log-rank test; Figure 1). This difference remained significant for baseline strata of CD4
+T-cell counts < 200 cells/mm
3(for CD4
+T-cell counts < 100 cells/mm
3the difference was 58.8 versus 16.75 months, P < 0.0001; for 101–200 cells/mm
3the difference was 64.8 versus 27.1; P=0.001), but not for patients with CD4
+T-cell counts > 200 cells/mm
3(64.61 versus 54.9 months; P=0.54).
Cox proportional-hazards regression analysis identified three factors that independently predicted statistically higher survival time: survival was higher for patients treated with HAART than without (hazard ratio [HR] 0.25; 95% CI 0.13–0.52;
P < 0.0001); in patients living in the main cities of the country (Casablanca, Rabat, Marrakech and Agadir) compared with patients living in other areas (HR 0.476; 95% CI 0.26–0.88; P=0.018); and in patients without any occurrence of OIs during follow-up (HR 0.42; 95% CI 0.21–0.87; P=0.019).
Finally, we estimated a parametric survival model
based on Cox’s predictive factors. From the Weibull
distribution, the predicted median survival time was 9.3 years in the HAART group compared with 2.6 years in the no-HAART group. For the group of patients without any OIs during follow-up, predicted survival was 25.4 years in the HAART group compared with 7.1 years in the no-HAART group.
Costs
As shown in Table 4, HAART patients had significantly fewer inpatient days than no-HAART patients (1.98 versus 10.5; P < 0.0001), although they had a higher frequency of day care and outpatient consultations due to the monitoring of ARVs and their potential side- effects. The proportion of patients admitted to hospital was significantly higher in the no-HAART group (45.4% versus 19.2%; P < 0.0001), although the propor- tion of patients with repeat hospitalization was similar in the two groups (9.5% in the HAART group versus 11.8% in the no-HAART group).
When costs of ARVs were excluded, there was a statistically significant difference in total costs per person per year in favour of the HAART group (€135
versus €163; P < 0.0001, Mann–Whitney U test). This observation is mainly due to the higher costs related to hospitalizations in the no-HAART group. When costs of ARV drugs are taken into account, annual total costs of care become significantly higher in the HAART group, even when using an alternative hypothesis based on the recent decrease in prices of these drugs.
Incremental cost-effectiveness ratios
Overall, the ICER with HAART, in comparison to HIV care without HAART, was 1,573 per life-year saved (Table 5). The ICER decreases to 552 under the realistic alternative scenario of decreased prices for ARVs. When stratifying the estimates of HAART ICER according to baseline CD4
+stratum, it appears that in this Moroccan context it is more cost-effective to initiate HAART at lower CD4
+T-cell levels: the ICER was 612 per life-year gained for patients with CD4
+T-cell counts < 100 cells/mm
3and 962 for patients with T-cell counts between 101 and 200 cells/mm
3, whereas the ICER was 100 times higher for patients who started HAART with a CD4
+Baseline variable HAART No-HAART Total
P-valueNumber of patients, n 167 119 286 –
Female gender, % (n) 46.7 (78) 42.9 (51) 45.1 (129) 0.519
Mean age, years (±
SD) 35.2 (±8.2) 33.9 (±8.7) 34.6 (±8.5) –
HIV disease stage
Stage 1, % (n) 29.3 (49) 34.5 (41) 31.5 (90) 0.239
Stage 2, % (n) 11.4 (19) 17.6 (21) 14.0 (40) –
Stage 3, % (n) 31.1 (52) 24.4 (29) 28.3 (81) –
Stage 4, % (n) 28.1 (47) 23.5 (28) 26.2 (75) –
Median CD4
+T-cell count (IQR) 113 (50–218) 200 (69–364) 138 (53–280) 0.001
CD4
+T-cell count
≤100 cells/mm3
, % (n) 45.5 (76) 36.1 (43) 41.6 (119)
<0.0001101–200 cells/mm
3, % (n) 26.9 (45) 14.3 (17) 21.7 (62) –
>200 cells/mm3
, % (n) 27.5 (46) 49.6 (59) 36.7 (105) –
Number of patients with OI, % (n) 29.3 (49) 22.7 (27) 26.6 (76) 0.209
Area of origin
Casablanca, % (n) 24 (40) 18.5 (22) 21.7 (62) 0.384
Rabat, Agadir, Marrakech, % (n) 39.5 (66) 37.8 (45) 38.8 (111) –
Other, % (n) 36.5 (61) 43.7 (52) 39.5 (113) –
Socioeconomic status
Mean household income, Dirhams (±
SD) 1,549 (±1,065) 1,424 (±1,066) 1,497 (±1,066) – Education level: <Baccalaureat
(high school diploma), % (n) 73.1 (122) 82.4 (98) 76.9 (220) 0.066
Employment status: unemployed, % (n) 41.9 (70) 40.3 (48) 41.3 (118) 0.789
Living conditions:
alone, % (n) 15.6 (26) 12.6 (15) 14.3 (41) 0.732
couple, % (n) 13.2 (22) 15.1 (18) 14 (40) –
family, % (n) 71.3 (119) 72.3 (86) 71.7 (205) –
Medical insurance, % (n) 26.3 (44) 10.9 (13) 19.9 (57) 0.001
HAART, highly active antiretroviral therapy; IQR, interquartile range; OI, opportunistic infection.
Table 2. Baseline clinical characteristics of HAART- and no-HAART-treated HIV-infected patients in Morocco
T-cell count > 200 cells/mm
3. When using the alternative scenario of lower ARV prices, these estimates were
€340, €598 and €57,349 from the lower to the higher CD4 strata at baseline.
The ICER of HAART is in the range €1,294–3,743 when using the lower or the upper bound of the 95%
confidence intervals for estimations of survival in both groups (ranging between €454–1,313 under the hypoth- esis of decreased ARV prices). With the exception of the prices of ARVs, all other sensitivity analyses (one-way and multiway sensitivity analyses) gave results within this range. If anticipated public sector prices for ARVs were decreased by twofold, the ICER of HAART would be €327 for the entire cohort and €30,740 for patients with CD4
+T-cell counts > 200 cells/mm
3.
Discussion
Contrary to some pessimistic a priori expert judgments, economic evaluation based on the actual experience of scaling up access to HIV/AIDS care has brought growing evidence that antiretroviral treatment, with the use of clinical criteria in combination with CD4
+T-cell count testing to guide the timing of treatment, is a rational health investment in resource-limited settings.
The experience of the ALCS program in Morocco, a lower-middle income country with a relatively low HIV
prevalence, clearly confirms for the first time in North Africa this result already observed in other developing countries [7–9,11]. This experience also suggests that access to HAART is feasible in countries where both low prevalence and cultural and religious traditions may create significant barriers to universal access to an effective package of HIV prevention, care and support.
Indeed, in such cultural contexts, access to effective treatment may be a pre-requisite for developing testing, counselling and prevention programs that will be a key issue in the future for maintaining the current low level of the HIV epidemic in North African and Middle Eastern countries.
The significant effect of HAART on patients’
survival in this Moroccan study is similar to that reported in published studies conducted in developing countries [9,12,30]. As in most other resource-limited settings to date, patients in Morocco usually had advanced HIV disease at the time of HIV diagnosis and most patients in both HAART and no-HAART cohorts had an acute OI at the time of their inclusion.
However, it is noteworthy that prevalence of tubercu- losis was low at inclusion and subsequent incidence remained low in both HAART- and no-HAART- treated groups [31]. Therefore, the protective effect of HAART in reducing tuberculosis incidence, which is one of the major clinical and economic advantages in
Baseline CD4
+T-cell count
Overall
<100 cells/mm3101–200 cells/mm
3 >200 cells/mm3Median at baseline
HAART group, CD4
+T-cells/mm
3113 43 154 327
No-HAART group, CD4
+T-cells/mm
3200 46 129 364
Median at end of follow up
HAART group, CD4
+T-cells/mm
3382 2,856 416 431
No-HAART group, CD4
+T-cells/mm
3137 29 122 262
Change in CD4
+T-cell count between baseline and end of follow up
HAART group, cells/mm
3+269 +242 +262 +104
No-HAART group, cells/mm
3-63 -17 -7 -102
Number of OIs during follow-up
HAART group – 8 1 0
No-HAART group – 20 2 9
Total – 28 3 9
P-value
–
<0.0001NS 0.016
OI incidence per 100 patient-years
HAART group – 3.37 0.71 0
No-HAART group – 38.5 9.8 12.7
OI averted per 100 patient-years – 35.13 9.1 12.7
Increase in median CD4+T-cell count during follow up (1997–2002), incidence of opportunistic infections and cases averted stratified by baseline CD4+T-cell count and incidence of mortality and cases averted stratified by baseline CD4+T-cell count for HIV-infected patients in Morocco (n=286). HAART, highly active antiretroviral therapy; NS, not significant; OI, opportunistic infection.
Table 3. Increase in median CD4
+T-cell count, incidence of opportunistic infections and mortality and incidence of cases
averted stratified by baseline CD4
+T-cell count
studies carried out in other African countries [32,33], has remained limited in the Moroccan context. For the year 2004, the per capita gross domestic product (GDP) in Morocco was €1,395 (MAD15,384). With current prices of ARVs for first-line therapy, the incre- mental cost-effectiveness ratio per life-year gained with HAART is close to this threshold, which is commonly accepted in some developed countries as an undisputable criterion for judging a medical interven- tion to be cost-effective [34]. Reducing public sector prices for ARVs by twofold would make HAART a very cost-effective alternative in Morocco. However, in the context of resource-limited settings, the extent to which such criterion should be applicable remains a matter of debate.
Not surprisingly, in Morocco as in other developing countries, ICERs are sensitive to the level of ARV prices calling attention to the necessity of creating and maintaining long-term supply mechanisms for these drugs at lower differential prices [35]. This issue will
be of increasing importance as growing numbers of patients need to be switched to the costlier second-line regimens. In this Moroccan observational study dating back to the 1997–2002 period, a non-negligible proportion of treated patients (58%) had already benefited at some point from drug combinations including protease inhibitors.
The main result from the Moroccan experience is that despite differences in the natural history of the HIV disease in comparison to sub-Saharan countries, such as the lower incidence of HIV-related tuberculosis, ICERs also tend to increase with an increase in the baseline CD4
+levels. Studies from South Africa also showed that while the incremental cost per life-year gained was lower than GDP per capita for patients starting HAART with a CD4
+T-cell count < 200 cells/mm
3, this ratio increased to close to two or three times GDP per capita when HAART was initiated at levels above this threshold. This result is similar to those obtained in various South African cost- effectiveness studies, but clearly contrasts with the
Proportion with survival Proportion with survival 0.2
0.4 0.6 0.8 1.0
0.0 0
Months
No-HAART HAART
P<0.054
20 40 60 80
0.2 0.4 0.6 0.8 1.0
0.0 0
Months No-HAART
HAART
P<0.001 20
10 30 40 50 60 70
0.2 0.4 0.6 0.8 1.0
0.0 0
Months
Proportion with survival
No-HAART HAART
P<0.0001
20 40 60 80
Proportion with survival 0.2 0.4 0.6 0.8 1.0
0.0
0 10 30
Months No-HAART
HAART
P<0.0001
20 40 50 60 70
Figure 1. Kaplan–Meier probabilities of mean survival of HAART- and no-HAART-treated HIV-infected patients in Morocco (n=286)
(A)All patients. Patients with CD4+T-cell counts (B)<100 cells/mm3, (C)101–200 cells/mm3and (D)>200 cells/mm3.
C D
B
A
conclusions of studies in developed countries. The main explanation is the difference in the structure of costs for both the HAART and no-HAART groups between developing and developed countries. Because patients access HIV care at an advanced stage of HIV infection in developing countries, and because HAART is particu- larly effective in reducing the incidence of OIs in severely immunosuppressed patients, extra costs due to HAART in comparison with prophylaxis and treatment of OIs in the absence of HAART is minimized at lower levels of CD4
+T-cells. Differences in unit costs of inpatient care between developing and developed countries might also play a role. In developing countries, patients have lower access to inpatient care as well as a lower cost per inpatient day. In addition, although mean survival is
higher in patients starting HAART with a CD4
+T-cell count > 200 cells/mm
3in both developed and developing countries (including the present study in Morocco) [21], differences in overall survival between HAART- and no- HAART-treated patients are maximized in the groups with lower CD4
+T-cell counts at baseline. This result may be due to the limited follow-up period.
Some limitations of this Moroccan study should be acknowledged. This study was focused on hospital services provided at the level of a teaching hospital.
Although costs incurred in primary, community or secondary hospitals were excluded, this reflects the configuration of services available to the majority of HIV- infected people in Morocco at the time of the study.
Similarly, costs were restricted to direct healthcare costs
Variable HAART no-HAART
P-valueNumber of inpatient bed days (>1 day), days (95% CI)
Mean 1.98 (0.87–3.09) 10.5 (7.12–13.88)
<0.0001CD4
+T-cell count ≤100 cells/mm
31.70 (0.84– 2.56) 17.00 (9.86–24.16)
<0.0001CD4
+T-cell count 101–200 cells/mm
31.68 (0.02–3.38) 9.00 (0.79–17.34)
<0.0001CD4
+T-cell count >200 cells/mm
32.80 (0.27–5.78) 6.17 (2.56–9.78) 0.045
Number of inpatient day care days (<1 day), days (95% CI)
Mean 1.98 (1.79–2.17) 1.30 (1.05–1.56) 0.006
CD4
+T-cell count ≤100 cells/mm
32.13 (1.85–2.40) 0.98 (0.53–1.43) 0.10
CD4
+T-cell count 101–200 cells/mm
32.03 (1.67–2.38) 1.34 (0.45–1.82) 0.65
CD4
+T-cell count >200 cells/mm
31.70 (1.31–2.09) 1.60 (1.26–1.93) 0.60
Number of outpatient consultations, days (95% CI)
Mean 2.08 (1.81–2.36) 1.15 (0.85–1.44)
<0.0001CD4
+T-cell count ≤100 cells/mm
32.11 (1.67–2.55) 0.71 (0.31–1.10)
<0.0001CD4
+T-cell count 101–200 cells/mm
32.26 (1.72–2.8) 1.63 (0.31–2.95) 0.108
CD4
+T-cell count >200 cells/mm
31.86 (1.4–2.32) 1.33 (0.95–1.72) 0.037
Inpatient and outpatient costs, € (IQR)
Median 45.8 (24.3–78.5) 88.7 (36.3–547.8)
<0.0001CD4
+T-cell count ≤100 cells/mm
354.4 (30.5–126.6) 439.3 (68.9–1,057.0)
<0.0001CD4
+T-cell count 101–200 cells/mm
349.0 (25.4–77.3) 64.2 (19.4–341.1) 0.163
CD4
+T-cell count >200 cells/mm
333.1 (11.6–65.2) 55.9 (30.3–395.2) 0.002
Laboratory test and non-ARV drug costs, € (IQR)
Median 89.1 (27.3–116.8) 74.6 (0–156.8) 0.374
CD4
+T-cell count ≤100 cells/mm
393.2 (22.2–113.4) 73.1 (0–106.6) 0.013
CD4
+T-cell count 101–200 cells/mm
382.7 (46.7–123.2) 73.8 (0–124.1) 0.373
CD4
+T-cell count >200 cells/mm
377.5 (23.6–118.5) 101.2 (54.2–170.2) 0.044
Annual total costs (includes ARV drugs in the HAART group), € (IQR)
Mean 789.3 (680.9–844.2) 260.0 (138.7–731.7)
<0.0001CD4
+T-cell count ≤100 cells/mm
3800.0 (680.7–857.4) 451.4 (213.2–1,057.0) 0.012
CD4
+T-cell count 101–200 cells/mm
3789.3 (703.2–850.7) 207.3 (101.5–551.7)
<0.0001CD4
+T-cell count >200 cells/mm
3764.6 (673.2–812.7) 211.8 (122.9–395.2)
<0.0001Annual total costs (alternative scenario for ARV prices)
†,
€ (IQR)Mean 497.8 (389.5–552.7) 260.0 (138.7–731.7)
<0.0001CD4
+T-cell count ≤100 cells/mm
3508.5 (389.3–565.9) 451.4 (213.2–1,057.0) 0.634
CD4
+T-cell count 101–200 cells/mm
3497.8 (411.7–559.2) 207.3 (101.5–551.7) 0.001
CD4
+T-cell count >200 cells/mm
3473.1 (381.0–521.2) 211.8 (122.9–395.2)
<0.0001*In Euros at 2004 prices. †Anticipated public sector price for generic manufactured drugs, at €346 per person per year. ARV, antiretroviral; CI, confidence interval;
HAART, highly active antiretroviral therapy; IQR, interquartile range.
Table 4. Median costs* of care for HAART- and no-HAART-treated HIV-infected patients in Morocco (n=286)
and benefits were restricted to life-years because data on direct non-healthcare costs, indirect costs and quality of life are currently unavailable in Morocco. In addition, our estimates did not incorporate the costs of providing the infrastructure required to support appropriate HAART provision in rollout programmes. The long-term benefits of expanded antiretroviral use in less-developed countries will rely on improvements in healthcare infra- structure in addition to the availability of ARV drugs.
The observational cohort design of our study should also be discussed. Although, the no-HAART group may have included patients who were not eligible for HAART, either for clinical or socioeconomic reasons, a compar- ison of patients’ characteristics at baseline showed that the two groups were similar, with the exception of the median baseline CD4
+T-cell count, which was higher in the no-HAART group, and the number of patients with medical insurance, which was higher in the HAART group. In our study design, individuals had access to combination antiretroviral therapy free of charge but had to pay for biological and other clinical examinations. Our results are therefore influenced by issues related to access to follow-up care. Not taking these issues into account could have sometimes compromised the interpretation of similar population-based studies or models based on liter- ature using randomized controlled trial data. Secondly, our data were not derived from a randomized controlled trial. In the absence of the controlled envi- ronment typically found in clinical trials including strict criteria for inclusion/exclusion, management and follow up, we might expect that our patients would have higher viral resistance and drug toxicity,
resulting in lower clinical benefits. Finally, because of the recognized survival benefits of HAART, a randomized placebo-controlled trial in patients with advanced HIV disease at high risk of opportunistic infection would not be ethically justifiable.
Cost-effectiveness estimations based on observed data, like this Moroccan study, however, present the advantage of being a lot more ‘realistic’ than previous research based on pure application of hypothetical scenarios to low-resource settings. Most of the previous studies conducted in low-resource settings were model- based evaluations, whereas our study is one of the first based on context-specific observational data. Although modelling exercises provide useful information, they often rely on assumptions, which may or may not reflect the reality in a particular context. It must be empha- sized, however, that actual HIV care to which HAART is compared may be far from optimal: in particular, late diagnosis of HIV, although very common in developing countries, remains a major problem.
Empirical cost-effectiveness arguments, like the ones provided by the South African and Moroccan studies, should therefore not be used to impede current efforts to scale-up access to HIV screening [36] or to improve clinical benefits by starting HAART at higher CD4
+levels. However, both the South African and Moroccan results are supportive of the recommended WHO HAART initiation criterion of CD4
+T-cell counts < 200 cells for patients without AIDS (WHO stage IV) [18].
These results indicate that this criterion is not solely motivated by concerns about limiting the absolute number of eligible patients in resource-poor settings,
Mean survival (discounted) Total cost per patient over follow up period (discounted) ICER Population Months Years Life-years gained S1 Incremental cost S2 Incremental cost S1 S2 All patients
No-HAART 44.51 3.70 – 971 – 971 – – –
HAART 55.04 4.58 0.88 2,356 1,385 1,457 486 1,573 552
CD4
+T-cell count <100
No-HAART 18.10 1.51 – 395 – 395 – – –
HAART 54.40 4.53 3.03 2,251 1,856 1,427 1,032 612 340
CD4
+T-cell count 101–200
No-HAART 26.90 2.24 – 207 – 207 – – –
HAART 58.10 4.84 2.60 2,710 2,503 1,763 1,556 962 598
CD4
+T-cell count >200
No-HAART 51.90 4.33 – 256 – 256 – – –
HAART 52.10 4.34 0.02 2,233 1,977 1,402 1,146 98,881 57,349
*Costs in Euros at 2004 prices. ICER, incremental cost-effectiveness ratio. Scenario 1 (S1), present public sector prices based on the direct purchase of antiretroviral drugs at a cost of €637 per person per year; Scenario 2 (S2), anticipated public sector prices for generic manufactured drugs at €346 per person per year. HAART, highly active antiretroviral therapy.
Table 5. Incremental cost-effectiveness analysis for each strategy and antiretrovirals price scenario*
but rather corresponds to a rational choice in terms of resource allocation, taking into account the specific context of developing countries. This choice might need further discussion, however, in the light of poten- tial evolution in the proportion of patients benefiting from earlier HIV diagnosis and of HAART-treated patients needing to switch to second-line regimens.
Acknowledgements
This study was partly supported by a grant from Sidaction, a French non-governmental organization.
The funding source had no role in the data collection, analysis or interpretation, or in the decision to submit the study for publication. Special thanks go to Rajaa Bensghir MD, for her assistance in data collection from medical files.
Disclosure statement
The authors declare no conflict of interest.
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