Sow, Papa S MD*; Otieno, Leander F MD†; Bissagnene, Emmanuel MD‡; Kityo, Cissy MD§; Bennink, Ruurd MSc∥; Clevenbergh, Philippe MD¶; Wit, Ferdinand W N M MD, PhD∥; Waalberg, Esther MSc#; Rinke de Wit, Tobias F MD, PhD¶; Lange, Joep M MD, PhD¶ ; on behalf of the Cohort Program to Evaluate Access to Antiretroviral Therapy and Education Project Team
Currently, more than 40 million people worldwide are infected with HIV-1, and two thirds of those infected are living in sub-Saharan Africa.1 In Western countries, the use of highly active antiretroviral therapy (HAART) has become standard of care and has effectively reduced HIV-related morbidity and mortality.2,3 Until recently, the provision of HAART throughout the public sector in Africa was not realistic. With the implementation of numerous international programs, however, access to HAART in sub-Saharan Africa has increased, reaching approximately 11% of those who are in immediate need of treatment.4
The unfolding human and economic disaster in the hardest hit countries has fueled global advocacy, which has helped to facilitate, among other things, significant price reductions for antiretroviral drugs, increased donor funding, and an increased political will to improve the situation. This has enabled several developing countries to initiate programs for the provision of antiretroviral treatment at cost price or even free of charge.5-7 It could be argued that free HAART programs carry an increased risk of patient drop-out and doubtful long-term sustainability because of dependence on donors.
As access to HIV treatment in developing countries increases, so does the need to evaluate its effectiveness in these settings. So far, data on patients' response to HAART in routine clinical practice have come mainly from cohorts in Europe and the United States, the results of which do not necessarily apply to the setting of low-income countries. For instance, differences in the health care infrastructure, provider experience, viral subtype, and patient characteristics may all negatively affect the impact of treatment. Although some treatment programs in low-income countries have been evaluated,8-12 there is still a great need to conduct studies in low-resource settings. First outcomes show results that are comparable to those of Western settings, but there are still numerous problems that pose substantial challenges.
Here, we describe the final results of the Cohort Program to Evaluate Access to Antiretroviral Therapy and Education (CARE) initiative, a treatment program that provides access to HIV-1 screening, therapy, counseling, and monitoring free of charge in 4 urban clinics in 4 low-income African countries.
Program Design and Patients
The CARE initiative was set up as a 96-week pilot program funded by Roche (Basel, Switzerland) to provide HIV treatment and medical care to a cohort of 200 patients from 4 urban clinics in 4 African countries. Participating centers included the Center Hospitalier Universitaire de Fann, Dakar (Senegal); the Center Hospitalier Universitaire de Treichville, Abidjan (Côte d'Ivoire); the Joint Clinical Research Center in Kampala (Uganda); and the Kenyatta National Hospital in Nairobi (Kenya). Patients were recruited from the outpatient clinics of these centers over the period February 2002 to January 2003. Antiretroviral treatment-naive HIV-1-infected individuals aged 18 years and older with a CD4 count of <350 cells/μL who could not afford to pay for antiretroviral medication themselves were offered treatment with a standard regimen free of charge. Reasons for exclusion were pregnancy or breast-feeding, active ongoing opportunistic infection, hemoglobin level <8.0 g/dL, neutrophil count <1 × 109/L, aspartate or alanine aminotransferase more than 5.0 times the upper limit of normal, renal failure requiring dialysis, use of rifampin or rifabutin, substance abuse, inability to store medication at home at a temperature lower than 25°C or inability to collect antiretroviral medication at the clinic every month, and likely inability to adhere to the dosing schedule and the clinic visit schedule as judged by the investigator. The program was approved by the ethical review committees in The Netherlands (Stichting Therapeutische Evaluatie Geneesmiddelen [STEG]) and in the participating centers, and all patients provided written informed consent.
First-line treatment consisted of branded versions of saquinavir (soft-gel capsule [SGC], Fortovase; Roche, Basel Switzerland) at a dose of 1600 mg once daily plus ritonavir (Norvir; Abbott Laboratories, Abbott Park, IL) at the pharmacokinetic boosting level of 100 mg once daily (SQV/r), in combination with 150 mg of lamivudine twice daily plus 300 mg of zidovudine twice daily (coformulated as Combivir; GlaxoSmithKline, Research Triangle Park, NC). During the course of the program, saquinavir SGC was replaced by saquinavir hard-gel capsule (HGC) at a dose of 1600 mg once daily (Invirase; Roche), because the latter does not require refrigeration, gives a comparable saquinavir exposure, and is associated with less gastrointestinal discomfort.13 In case of toxicity, saquinavir (1600 mg of SGC or HGC once daily) boosted with ritonavir (100 mg once daily) (SQV/r) could be replaced by HGC SQV/r at a dose of 1000 mg/100 mg twice daily or by nelfinavir (Viracept; Pfizer, New York, NY) at a dose of 1250 mg twice daily; lamivudine (3TC) plus azidothymidine (AZT) could be replaced by 3TC plus stavudine (d4T) or by didanosine (ddI) plus d4T. In case of virologic failure on first-line therapy, patients could be switched to a salvage regimen consisting of 1200/200 mg of SQV/r twice daily, 400 mg of ddI once daily, and 40 mg of d4T twice daily. At the time of development of the study protocol and during the first months of this study, the combination of ddI and d4T was still considered to be a valid salvage regimen. During the course of the program, it became clear that this combination had an unacceptable toxicity profile and should be replaced by a different combination of nucleoside reverse transcriptase inhibitors (NRTIs). Alternative NRTIs were not provided by the CARE program; thus, they had to be available at each participating site. The CARE program paid for all salvage regimens used, however. Treatment of tuberculosis (TB) and prophylaxis for bacterial infections and Pneumocystis jiroveci pneumonia and other infectious diseases were offered according to local guidelines. After this pilot phase of 96 weeks, arrangements were made so that patients would continue to receive this regimen for free for as long as they benefit from it.
To assess patients' clinical status, provide counseling, and assess adherence and quality of life through self-administered questionnaires, scheduled clinic visits took place at screening; at entry; at weeks 2, 4, 8, and 12; and every 12 weeks thereafter. In addition, plasma viral load (pVL) levels and CD4 cell counts were assessed by flow cytometry at screening and at weeks 0, 4 (except for CD4 cell counts), 8, 12, 24, 36, 48, 72, and 96. All other laboratory measurements of safety-related parameters were assessed at all visits. All these laboratory measurements were performed locally. pVL levels were measured using an HIV polymerase chain reaction assay (Amplicor HIV-1 Monitor, version 1.5; Roche). In the centers in Dakar and Kampala, this assay was performed using the ultrasensitive specimen preparation method, resulting in a lower limit of quantification of 50 copies/mL. In Abidjan, the assay was performed using the standard specimen preparation method, with a limit of quantification of 200 copies/mL. In Nairobi, until June 2004, no ultrasensitive technique was used; thus, until June 2004, the lower detection limit was 400 copies/mL, and from June 2004 onward, it was 50 copies/mL.
The primary efficacy outcome of this treatment program was the percentage of patients with a pVL <400 copies/mL at week 96 (“virologic success”). Secondary efficacy measures included (1) the percentage of patients at week 96 with a pVL <50 copies/mL, as assessed in the patient subgroup for which the detection limit was 50 copies/mL; (2) the percentage of patients at week 96 with treatment failure (defined as a pVL ≥400 copies/mL), major changes or discontinuations of first-line treatment, or a Centers for Disease Control and Prevention (CDC) category C event or death; and (3) the change in CD4 cell counts between baseline and week 96.
Patients who discontinued all or part of their first-line treatment or interrupted the use of allocated treatment for more than 3 months were considered to represent treatment failures. Only patients who discontinued HAART were considered to represent major protocol violations, however.
Proportions of patients with virologic success were determined in 2 ways:
1. On treatment (OT): only patients who had a nonmissing pVL measurement were included in the calculation of the proportion; hence, no imputation of missing values was applied.
2. Intent to treat (ITT): all enrolled patients were included in the calculation of the proportion; hence, missing values could be regarded as virologic failures.
Because most patients were severely ill at baseline, deaths and CDC category C events that occurred in the first 8 weeks of follow-up were disregarded in the analysis. Laboratory toxicities were graded according to the toxicity scale developed by the Division of AIDS, National Institute of Allergy and Infectious Diseases.14 Each event (this applies to the adverse events and laboratory toxicities) was only considered once per patient, and the highest laboratory toxicity grade was included.
Baseline values of CD4 cell counts were calculated as the mean of the values before the start of treatment. Baseline pVL values were determined to be the last nonmissing value before the start of treatment.
Additionally, for the comparison of proportions, a χ2 test was used. Continuous variables were compared by means of the Kruskal-Wallis test. For all statistical tests, statistical significance was assumed at less than a 2-sided α-level of 0.05. Statistical analyses were performed using SAS version 8.02 (SAS Institute, Cary, NC).
For safety outcomes, data of all patients who took the study medication were used.
Patient Disposition and Baseline Characteristics
Three hundred nineteen patients were screened, 108 of whom violated inclusion or exclusion criteria, such that 211 patients entered the study. Of these 211 patients, 2 withdrew consent after the screening visit; 1 died between the screening and baseline visits; and 1 never signed the informed consent form but was erroneously included in the study, although no data were collected for this patient. Therefore, this patient was excluded from the database as soon as this was discovered. One patient made several visits to the clinic but never took any study medication. Hence, 206 patients entered the study after screening, all took study medication, and all these patients were considered for efficacy (ITT) and safety outcomes.
Baseline characteristics were not the same across the 4 clinics (Table 1). In particular, patients from Nairobi seemed to be less severely ill at baseline, as suggested by a lower number of patients in CDC category C, higher CD4 cell counts, and lower pVLs.
Eighty-four percent of the patients started with the Fortovase-based regimen and 16% with Invirase-based regimen; 1 patient started with d4T instead of AZT (see Table 1). Overall, 16 patients (7.8%) died in the first 96 weeks of follow-up (3 patients in the first 8 weeks and 13 thereafter), but all died after they took the first dose of study medication. One patient died after 96 weeks of follow-up. Thirteen patients were lost to follow-up, 8 patients decided to withdraw from the study themselves, 2 patients were unable to collect the study medication from the clinic, and 1 patient did not attend the clinic visit at week 96 (the last visit was at week 84) for an unknown reason. Of the remaining 166 patients (81%), 48 had changed or discontinued their regimen of SQV/r, 3TC, and AZT in the course of the 96 weeks of follow-up. Because all these 48 patients remained on a HAART regimen, these medication changes were not considered to be major protocol violations. Hence, 166 (81%) of 206 patients completed the study without major protocol violations; 45 (79%) of 57 patients in Abidjan, 41 (82%) of 50 patients in Dakar, 41 (84%) of 49 patients in Kampala, and 39 (78%) of 50 patients in Nairobi.
Overall, 108 patients had a pVL <400 copies/mL at week 96, resulting in a virologic success rate of 65%/52% (OT/ITT). This success rate varied considerably between the clinics, however; whereas in Dakar and Nairobi, it was 56%/46% (23/41 or 23/50) and 51%/40% (20/39 or 20/50), respectively, in Abidjan and Kampala, it was 69%/54% (31/45 or 31/57) and 83%/69% (34/41 or 34/49), respectively (Fig. 1). There was a statistically significant difference between these clinics at week 96 (P = 0.0131/0.0217 [OT/ITT]).
Limiting the analysis to patients whose pVL was determined with a detection limit of 50 copies/mL showed that, overall, 59%/48% (48/82 or 48/99) had a pVL <50 copies/mL at week 96. In Dakar and Kampala, these rates were 44%/36% (18/41 or 18/50) and 73%/61% (30/41 or 30/49), respectively. There was a statistically significant difference between the clinics at week 96 (P = 0.0071/0.0120 [OT/ITT]).
Of the 16 deaths that occurred in the first 96 weeks of the program, 13 occurred after week 8. Twenty-four patients developed a CDC category C event; for 18 patients (9%), this event occurred between weeks 8 and 96. Taking together the patients who died or experienced a CDC category C event between weeks 8 and 96, patients without virologic success at week 96, and patients who had a major change in their first-line regimen, 111 patients (58%) showed treatment failure at week 96: 32 (64%) in Dakar, 33 (61%) in Abidjan, 20 (44%) in Kampala, and 26 (60%) in Nairobi. There were no statistically significant differences between the sites with respect to treatment failure (P = 0.21). There is a statistically significant difference between the treatment failure rate in Kampala (44%) and the pooled failure rate of the other sites (62%), however (P = 0.038). Percentages are based on the number of patients with at least 1 valid pVL measurement after intake of study medication (192 patients).
The mean increase in the CD4 cell count from baseline to week 96 was 213 cells/μL (95% confidence interval [CI]: 184 to 242 cells/μL). There were no statistically significant differences between the clinics at scheduled week 96 (Wilcoxon rank sum test, P = 0.43) with respect to the change in the CD4 cell count from baseline. The mean increase was 206 cells/μL for Abidjan, 181 cells/μL for Dakar, 215 cells/μL for Kampala, and 251 cells/μL for Nairobi.
In total, 1853 adverse events that were not already present before study medication intake were reported during the 96 weeks of follow-up. Overall, 96% of the patients who used study medication (n = 206) developed at least 1 adverse event. This number was not the same among the 4 clinics, however; particularly in Nairobi, fewer patients were diagnosed with an adverse event (90%). Thirty-five patients (17%) had their initial regimen changed because of toxicity reasons. Non-HIV-related serious adverse events (SAEs) were reported from 55 patients, describing 121 adverse events.
In 126 patients, 1 or more abnormal laboratory parameters were measured during follow-up that were not already abnormal (ie, grade 3 or 4) at baseline. Thirteen patients had at least 1 hemoglobin measurement indicative of grade 3 or 4 anemia. Patients who developed anemia did have a significantly lower hemoglobin level at baseline compared with patients who did not develop severe anemia during the study (P = 0.02, the corresponding means are 10.03 and 11.51 g/dL, respectively). There was no statistically significant difference in neutrophil count and platelet count at baseline between patients who did and did not develop severe anemia during the study. There was also a statistically significant higher incidence of malaria in patients with anemia (P = 0.01): 7 patients with anemia developed malaria (54% of 13 patients), and 44 patients without anemia developed malaria (23% of 193 patients).
Comparison of the Results With Those of Western Settings
The CARE program provides an in-depth evaluation of an African program in which HIV treatment and medical care were provided free of charge. It was observed that 65%/52% (OT/ITT) of patients had a pVL <400 copies/mL after 96 weeks of treatment, whereas the median CD4 count increase was 198 cells/μL. These results indicate that the virologic and immunologic responses to HAART in resource-limited settings can be comparable to those observed in a Western setting.
An overview of results from previous clinical trials with HAART in Western settings showed that the overall percentage of patients having a pVL <400 copies/mL at week 48 was 53%15 using the ITT approach whenever possible; if not possible, the OT approach was applied. In the CARE program, the ITT virologic success rate at week 48 was 47% (96/206), which is similar to the virologic success rate in Western settings.
A randomized open-label clinical trial with saquinavir-based HAART that was conducted in Western clinical centers with a 100-week extension showed higher virologic responses (78% virologic success [OT]) than the CARE result (65% virologic success [OT]).16 Patients in the CARE program were more severely ill at baseline, however, possibly explaining the lower OT result in the CARE program.
Factors That May Have Negatively Affected the Results
Several factors may have negatively affected the virologic treatment responses results. SGC SQV/r requires refrigeration, which may not always be available in resource-limited settings.17,18 Cool-boxes were supplied for transport of SQV/r from the clinic to the patient's home, but the local storage conditions at the patient's home did not always include adequate cooling facilities (even though this was one of the selection criteria). Therefore, during the program, it was decided to switch to the HGC formulation of saquinavir, which does not require refrigeration. There was a low attendance rate of clinic visits up to week 36. From week 36 onward, however, the monitoring of the project became more intense and, subsequently, attendance at clinic visits improved greatly.
In Nairobi, only 51%/40% (OT/ITT) of patients achieved virologic success, which is in contrast to their earlier stage of disease, as reflected by their higher CD4 cell counts, lower HIV-1 pVLs, and fewer AIDS diagnoses at baseline. The lower success rate at the Nairobi site may be explained, of the 2 factors mentioned previously, by contamination of blood samples in the local laboratory. Indeed, in the early phase of the study, errors were observed with respect to the protocols in the laboratory that measured the pVL. From week 36 onward, however, it can be seen that virologic success rates improved greatly at the Nairobi site, although the rates of other sites did not change (see Fig. 1A). In contrast to the apparent discrepant virologic success rate, the mean CD4 cell count increase among patients from the Nairobi site did not differ from that at the other sites. Such a discrepancy between the virologic and immunologic treatment responses has been described before.19
The results from Dakar are also less favorable (56%/46% [OT/ITT] virologic success at week 96). This is likely explained by medication errors that were discovered during the course of the study. At this site, many patients changed their medication at week 24; they used saquinavir SGC (1600 mg once daily) but later switched to saquinavir HGC (1000 mg twice daily). Unfortunately, patients only received a booster dose of ritonavir (100 mg) once a day rather than 100 mg of ritonavir each time saquinavir capsules were taken. This error was corrected after 12 to 24 weeks (patients then used 1600 mg of saquinavir plus 100 mg of ritonavir [SQV/r] once daily).
The incidence of adverse events in the CARE program is similar to previous experience. Between 5% and 14% of patients in earlier studies of SQV/r-based combination therapy discontinued their initial treatment during the first 24 weeks of follow-up,21-23 compared with 10% of patients in the CARE program. Of particular relevance with an AZT-containing regimen are changes in hematologic parameters.24 Indeed, 13 patients (6.3%) in this program developed grade 3 or 4 anemia.
Saquinavir Boosted With Ritonavir: Twice Daily Compared With Once Daily
SQV/r is currently licensed as a twice-daily regimen (1000/100 mg twice daily). In an attempt to increase adherence, however, patients started with a once-daily regimen (1600/100 mg once daily) in this program. A once-daily regimen was also used for more practical reasons, because many people in the African setting only receive a full meal once daily. These initial results are similar to the results of earlier studies, which showed that a once-daily regimen is well tolerated and effectively suppresses plasma viral replication.25,26 More recent pharmacokinetic data also showed that once-daily dosing of saquinavir results in lower plasma concentrations and a higher frequency of suboptimal trough levels than twice-daily dosing, however.27,28 Thus, additional pharmacokinetic analyses may assess whether antiretroviral plasma concentrations were sufficiently high in all patients in this program.17
In conclusion, this study shows that the virologic and immunologic responses to HAART in resource-limited African settings can be as good as in Western settings.
This conclusion is similar to the findings of a meta-analysis that compared a group of cohort studies in high-income settings with a group of cohort studies in low-income settings.29 Nevertheless, a statistically significant difference between the sites with respect to virologic success was observed. These differences might have been caused by the fact that some difficulties were experienced (eg, laboratory, logistics, training of study personnel, instruction of patients) during the early phase of the program.
The objectives of any access program should be feasible and agreed on by the provider and the participating clinical centers before the start of the program so as to minimize the risk of problems in the start-up phase of the program. By conducting a pilot program with only a limited number of patients, any communications, logistic, or practical issues can be quickly identified and addressed and personnel at the sites can be trained on the job. Close monitoring and evaluation of access programs are required to provide adequate feedback and improve medical care.
The authors express their gratitude to all the patients who participated in this program and to all the study staff from each of the centers involved.
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20. Deleted in press.
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