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JOBNAME: joa 00#0 2006 PAGE: 1 OUTPUT: Tuesday November 28 18:36:38 2006tspjoa/131957/QAI200568 Implementation of an Antiretroviral Access Program for HIV-1–Infected Individuals in Resource-Limited Settings Clinical Results From 4 African Countries Papa S. Sow, MD,* Leander F. Otieno, MD,† Emmanuel Bissagnene, MD,‡ Cissy Kityo, MD,§ Ruurd Bennink, MSc,k Philippe Clevenbergh, MD,¶ Ferdinand W. N. M. Wit, MD, PhD,k Esther Waalberg, MSc,# Tobias F. Rinke de Wit, MD, PhD,¶ and Joep M. Lange, MD, PhD¶ on behalf of the Cohort Program to Evaluate Access to Antiretroviral Therapy and Education Project Team follow-up. Non–HIV-related serious adverse events occurred in 55 Background: We assessed the effectiveness and safety of highly patients (26.7%), of whom 13 were diagnosed with severe anemia.
active antiretroviral therapy (HAART) in HIV-1–infected patients Thirty-five patients (17%) changed treatment for toxicity reasons.
in resource-limited African countries. HIV-1 screening, therapy,counseling, monitoring, training, and education were provided free Conclusions: Although a statistically significant difference was observed between sites with respect to virologic success, overallvirologic and immunologic responses to HAART in resource-limited Methods: In an open-label cohort program, 206 antiretroviral-naive African settings can be as good as in Western settings. There were HIV-1–infected patients who could not afford HAART were recruited some difficulties (eg, laboratory, logistics, proper training) during the in 4 urban clinics in Senegal, Coˆte d’Ivoire, Uganda, and Kenya and early phase of the program. Therefore, provision of adequate medical were treated with saquinavir boosted with ritonavir (1600/100 mg care, counseling, proper instruction, and education of patients and once daily), lamivudine (150 mg twice daily), and zidovudine (300 medical staff during the entire study is warranted in such programs, mg twice daily). The primary outcome was a plasma viral load (pVL) with special care in the early phase.
of ,400 copies/mL after 96 weeks of treatment. Secondary analysesincluded CD4 cell count changes and the occurrence of treatment- Key Words: African, comparison with results in Western settings, highly active antiretroviral therapy, HIV, free-of-charge, lessonslearned, resource-limited settings Results: The median age of the patient group was 36 years, 38% (J Acquir Immune Defic Syndr 2006;00:000–000) were male, 35% of the patients had AIDS, the median CD4 count was119 cells/mL, and the median pVL was 304,210 copies/mL. Overall,65%/52% (on treatment [OT]/intent to treat [ITT]) of the patients hada pVL ,400 copies/mL after 96 weeks of follow-up. This proportionvaried significantly between sites, however; although in Nairobi andDakar, 51%/40% and 56%/46% (OT/ITT) were found, respectively, Currently, more than 40 million people worldwide are Abidjan and Kampala showed proportions of 69%/54% and infected with HIV-1, and two thirds of those infected are 83%/69% (OT/ITT), respectively. The median increase in the CD4 living in sub-Saharan Africa.1 In Western countries, the use of count was 198 cells/mL (interquartile range: 86–319 cells/mL), highly active antiretroviral therapy (HAART) has become stan- ranging from 191 to 292 cells/mL between the sites. Fourteen patients dard of care and has effectively reduced HIV-related morbid- (6.8%) died between 8 and 96 weeks of follow-up, whereas 18 (9%) ity and mortality.2,3 Until recently, the provision of HAART developed an AIDS-defining event between 8 and 96 weeks of throughout the public sector in Africa was not realistic.
With the implementation of numerous international pro-grams, however, access to HAART in sub-Saharan Africahas increased, reaching approximately 11% of those who are in Received for publication September 8, 2005; accepted October 16, 2006.
From the *Centre Hospitalier Universitaire de Fann, Dakar, Senegal; †Kenyatta National Hospital, Nairobi, Kenya; ‡Centre Hospitalier The unfolding human and economic disaster in the Universitaire de Treichville, Abidjan, Cote d’Ivoire; §Joint Clinical hardest hit countries has fueled global advocacy, which has Research Center, Kampala, Uganda; kIATEC, Amsterdam, The Nether- helped to facilitate, among other things, significant price lands; {PharmAccess Foundation, Amsterdam, The Netherlands; and reductions for antiretroviral drugs, increased donor funding, and Sponsored by PharmAccess International (Amsterdam, The Netherlands) and an increased political will to improve the situation. This has financially supported by Roche (Basel, Switzerland), with additional enabled several developing countries to initiate programs for the materials provided by Roche Diagnostics. Additional medication provided provision of antiretroviral treatment at cost price or even free of charge.5–7 It could be argued that free HAART programs carry Reprints: Ferdinand W. N. M. Wit, MD, PhD, IATEC BV, Pietersbergweg 9, an increased risk of patient drop-out and doubtful long-term 1105 BM Amsterdam, The Netherlands (e-mail: f.wit@iatec.com).
Copyright Ó 2006 by Lippincott Williams & Wilkins sustainability because of dependence on donors.
J Acquir Immune Defic Syndr  Volume 00, Number 0, Month 0, 2006 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JOBNAME: joa 00#0 2006 PAGE: 2 OUTPUT: Tuesday November 28 18:36:39 2006tspjoa/131957/QAI200568 J Acquir Immune Defic Syndr  Volume 00, Number 0, Month 0, 2006 As access to HIV treatment in developing countries course of the program, saquinavir SGC was replaced by increases, so does the need to evaluate its effectiveness in these saquinavir hard-gel capsule (HGC) at a dose of 1600 mg once settings. So far, data on patients’ response to HAART in daily (Invirase; Roche), because the latter does not require routine clinical practice have come mainly from cohorts in refrigeration, gives a comparable saquinavir exposure, and is Europe and the United States, the results of which do not associated with less gastrointestinal discomfort.13 In case of necessarily apply to the setting of low-income countries. For toxicity, saquinavir (1600 mg of SGC or HGC once daily) instance, differences in the health care infrastructure, provider boosted with ritonavir (100 mg once daily) (SQV/r) could be experience, viral subtype, and patient characteristics may all replaced by HGC SQV/r at a dose of 1000 mg/100 mg twice negatively affect the impact of treatment. Although some daily or by nelfinavir (Viracept; Pfizer, New York, NY) at a dose treatment programs in low-income countries have been eval- of 1250 mg twice daily; lamivudine (3TC) plus azidothymidine uated,8–12 there is still a great need to conduct studies in (AZT) could be replaced by 3TC plus stavudine (d4T) or by low-resource settings. First outcomes show results that are didanosine (ddI) plus d4T. In case of virologic failure on first-line comparable to those of Western settings, but there are still therapy, patients could be switched to a salvage regimen numerous problems that pose substantial challenges.
consisting of 1200/200 mg of SQV/r twice daily, 400 mg of ddI Here, we describe the final results of the Cohort Program once daily, and 40 mg of d4T twice daily. At the time of to Evaluate Access to Antiretroviral Therapy and Education development of the study protocol and during the first months of (CARE) initiative, a treatment program that provides access to this study, the combination of ddI and d4T was still considered to HIV-1 screening, therapy, counseling, and monitoring free of be a valid salvage regimen. During the course of the program, it charge in 4 urban clinics in 4 low-income African countries.
became clear that this combination had an unacceptable toxicityprofile and should be replaced by a different combinationof nucleoside reverse transcriptase inhibitors (NRTIs). Alterna- tive NRTIs were not provided by the CARE program; thus, theyhad to be available at each participating site. The CARE program paid for all salvage regimens used, however. Treatment of The CARE initiative was set up as a 96-week pilot tuberculosis (TB) and prophylaxis for bacterial infections and program funded by Roche (Basel, Switzerland) to provide HIV Pneumocystis jiroveci pneumonia and other infectious diseases treatment and medical care to a cohort of 200 patients from were offered according to local guidelines. After this pilot phase 4 urban clinics in 4 African countries. Participating centers of 96 weeks, arrangements were made so that patients would included the Center Hospitalier Universitaire de Fann, Dakar continue to receive this regimen for free for as long as they (Senegal); the Center Hospitalier Universitaire de Treichville, Abidjan (Coˆte d’Ivoire); the Joint Clinical Research Center inKampala (Uganda); and the Kenyatta National Hospital in Nairobi (Kenya). Patients were recruited from the outpatient To assess patients’ clinical status, provide counseling, clinics of these centers over the period February 2002 to January and assess adherence and quality of life through self- 2003. Antiretroviral treatment–naive HIV-1–infected individuals administered questionnaires, scheduled clinic visits took place aged 18 years and older with a CD4 count of ,350 cells/mL who at screening; at entry; at weeks 2, 4, 8, and 12; and every 12 could not afford to pay for antiretroviral medication themselves weeks thereafter. In addition, plasma viral load (pVL) levels were offered treatment with a standard regimen free of charge.
and CD4 cell counts were assessed by flow cytometry at Reasons for exclusion were pregnancy or breast-feeding, active screening and at weeks 0, 4 (except for CD4 cell counts), 8, 12, ongoing opportunistic infection, hemoglobin level ,8.0 g/dL, 24, 36, 48, 72, and 96. All other laboratory measurements of neutrophil count ,1 3 109/L, aspartate or alanine aminotrans- safety-related parameters were assessed at all visits. All these ferase more than 5.0 times the upper limit of normal, renal failure laboratory measurements were performed locally. pVL levels requiring dialysis, use of rifampin or rifabutin, substance abuse, were measured using an HIV polymerase chain reaction assay inability to store medication at home at a temperature lower than (Amplicor HIV-1 Monitor, version 1.5; Roche). In the centers 25°C or inability to collect antiretroviral medication at the clinic in Dakar and Kampala, this assay was performed using the every month, and likely inability to adhere to the dosing schedule ultrasensitive specimen preparation method, resulting in a and the clinic visit schedule as judged by the investigator. The lower limit of quantification of 50 copies/mL. In Abidjan, the program was approved by the ethical review committees in The assay was performed using the standard specimen preparation Netherlands (Stichting Therapeutische Evaluatie Geneesmiddelen method, with a limit of quantification of 200 copies/mL. In [STEG]) and in the participating centers, and all patients Nairobi, until June 2004, no ultrasensitive technique was used; thus, until June 2004, the lower detection limit was 400 First-line treatment consisted of branded versions of copies/mL, and from June 2004 onward, it was 50 copies/mL.
saquinavir (soft-gel capsule [SGC], Fortovase; Roche, BaselSwitzerland) at a dose of 1600 mg once daily plus ritonavir (Norvir; Abbott Laboratories, Abbott Park, IL) at the pharma- The primary efficacy outcome of this treatment program cokinetic boosting level of 100 mg once daily (SQV/r), in was the percentage of patients with a pVL ,400 copies/mL at combination with 150 mg of lamivudine twice daily plus week 96 (‘‘virologic success’’). Secondary efficacy measures 300 mg of zidovudine twice daily (coformulated as Combivir; included (1) the percentage of patients at week 96 with a pVL GlaxoSmithKline, Research Triangle Park, NC). During the ,50 copies/mL, as assessed in the patient subgroup for which Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JOBNAME: joa 00#0 2006 PAGE: 3 OUTPUT: Tuesday November 28 18:36:40 2006tspjoa/131957/QAI200568 J Acquir Immune Defic Syndr  Volume 00, Number 0, Month 0, 2006 Implementation of Antiretroviral Access Program the detection limit was 50 copies/mL; (2) the percentage of Baseline characteristics were not the same across the 4 patients at week 96 with treatment failure (defined as a pVL clinics (Table 1). In particular, patients from Nairobi seemed to $400 copies/mL), major changes or discontinuations of first- be less severely ill at baseline, as suggested by a lower number line treatment, or a Centers for Disease Control and Prevention of patients in CDC category C, higher CD4 cell counts, and (CDC) category C event or death; and (3) the change in CD4 cell counts between baseline and week 96.
Eighty-four percent of the patients started with the Patients who discontinued all or part of their first-line Fortovase-based regimen and 16% with Invirase-based regimen; treatment or interrupted the use of allocated treatment for more 1 patient started with d4T instead of AZT (see Table 1). Overall, than 3 months were considered to represent treatment failures.
16 patients (7.8%) died in the first 96 weeks of follow-up (3 Only patients who discontinued HAART were considered to patients in the first 8 weeks and 13 thereafter), but all died after represent major protocol violations, however.
they took the first dose of study medication. One patient died Proportions of patients with virologic success were after 96 weeks of follow-up. Thirteen patients were lost to follow-up, 8 patients decided to withdraw from the study 1. On treatment (OT): only patients who had a nonmissing themselves, 2 patients were unable to collect the study medica- pVL measurement were included in the calculation of the tion from the clinic, and 1 patient did not attend the clinic visit proportion; hence, no imputation of missing values was at week 96 (the last visit was at week 84) for an unknown reason. Of the remaining 166 patients (81%), 48 had changed 2. Intent to treat (ITT): all enrolled patients were included in or discontinued their regimen of SQV/r, 3TC, and AZT in the the calculation of the proportion; hence, missing values course of the 96 weeks of follow-up. Because all these 48 could be regarded as virologic failures.
patients remained on a HAART regimen, these medication Because most patients were severely ill at baseline, changes were not considered to be major protocol violations.
deaths and CDC category C events that occurred in the first Hence, 166 (81%) of 206 patients completed the study without 8 weeks of follow-up were disregarded in the analysis.
major protocol violations; 45 (79%) of 57 patients in Abidjan, Laboratory toxicities were graded according to the toxicity 41 (82%) of 50 patients in Dakar, 41 (84%) of 49 patients in scale developed by the Division of AIDS, National Institute of Kampala, and 39 (78%) of 50 patients in Nairobi.
Allergy and Infectious Diseases.14 Each event (this applies tothe adverse events and laboratory toxicities) was only consid-ered once per patient, and the highest laboratory toxicity grade Overall, 108 patients had a pVL ,400 copies/mL at Baseline values of CD4 cell counts were calculated as week 96, resulting in a virologic success rate of 65%/52% the mean of the values before the start of treatment. Baseline (OT/ITT). This success rate varied considerably between the pVL values were determined to be the last nonmissing value clinics, however; whereas in Dakar and Nairobi, it was 56%/46% (23/41 or 23/50) and 51%/40% (20/39 or 20/50), Additionally, for the comparison of proportions, a x2 test respectively, in Abidjan and Kampala, it was 69%/54% (31/45 was used. Continuous variables were compared by means of or 31/57) and 83%/69% (34/41 or 34/49), respectively (Fig. 1).
the Kruskal-Wallis test. For all statistical tests, statistical sig- There was a statistically significant difference between these nificance was assumed at less than a 2-sided a-level of 0.05.
clinics at week 96 (P = 0.0131/0.0217 [OT/ITT]).
Statistical analyses were performed using SAS version 8.02 Limiting the analysis to patients whose pVL was determined with a detection limit of 50 copies/mL showed For safety outcomes, data of all patients who took the that, overall, 59%/48% (48/82 or 48/99) had a pVL ,50 copies/mL at week 96. In Dakar and Kampala, these rates were44%/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 Three hundred nineteen patients were screened, 108 of event occurred between weeks 8 and 96. Taking together the whom violated inclusion or exclusion criteria, such that 211 patients who died or experienced a CDC category C event patients entered the study. Of these 211 patients, 2 withdrew between weeks 8 and 96, patients without virologic success at consent after the screening visit; 1 died between the screening week 96, and patients who had a major change in their first- and baseline visits; and 1 never signed the informed consent line regimen, 111 patients (58%) showed treatment failure at form but was erroneously included in the study, although no week 96: 32 (64%) in Dakar, 33 (61%) in Abidjan, 20 (44%) in data were collected for this patient. Therefore, this patient was Kampala, and 26 (60%) in Nairobi. There were no statistically excluded from the database as soon as this was discovered.
significant differences between the sites with respect to One patient made several visits to the clinic but never took any treatment failure (P = 0.21). There is a statistically significant study medication. Hence, 206 patients entered the study after difference between the treatment failure rate in Kampala screening, all took study medication, and all these patients (44%) and the pooled failure rate of the other sites (62%), were considered for efficacy (ITT) and safety outcomes.
however (P = 0.038). Percentages are based on the number of Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JOBNAME: joa 00#0 2006 PAGE: 4 OUTPUT: Tuesday November 28 18:36:42 2006tspjoa/131957/QAI200568 J Acquir Immune Defic Syndr  Volume 00, Number 0, Month 0, 2006 TABLE 1. Baseline Characteristics of All Patients Who Took Study Medication HIV-1 RNA, log10, copies/mL median (IQR)* AZT, 3TC, ritanovir, saquinavir (Fortovase), % AZT, 3TC, ritanovir, saquinavir (Invirase), % *Significant difference between sites (P , 0.05).
†Presence of hepatitis B virus surface antigen at screening.
‡Presence of antibodies to hepatitis.
BMI indicates body mass index; IQR, interquartile range.
patients with at least 1 valid pVL measurement after intake of and did not develop severe anemia during the study. There was also a statistically significant higher incidence of malaria in The mean increase in the CD4 cell count from baseline patients with anemia (P = 0.01): 7 patients with anemia to week 96 was 213 cells/mL (95% confidence interval [CI]: developed malaria (54% of 13 patients), and 44 patients 184 to 242 cells/mL). There were no statistically significant without anemia developed malaria (23% of 193 patients).
differences between the clinics at scheduled week 96 (Wilcoxonrank sum test, P = 0.43) with respect to the change in the CD4cell count from baseline. The mean increase was 206 cells/mL for Abidjan, 181 cells/mL for Dakar, 215 cells/mL for Kampala, and 251 cells/mL for Nairobi.
The CARE program provides an in-depth evaluation of an African program in which HIV treatment and medical care were In total, 1853 adverse events that were not already provided free of charge. It was observed that 65%/52% present before study medication intake were reported during (OT/ITT) of patients had a pVL ,400 copies/mL after 96 the 96 weeks of follow-up. Overall, 96% of the patients who weeks of treatment, whereas the median CD4 count increase used study medication (n = 206) developed at least 1 adverse was 198 cells/mL. These results indicate that the virologic and event. This number was not the same among the 4 clinics, immunologic responses to HAART in resource-limited settings however; particularly in Nairobi, fewer patients were diag- can be comparable to those observed in a Western setting.
nosed with an adverse event (90%). Thirty-five patients An overview of results from previous clinical trials with (17%) had their initial regimen changed because of toxicity HAART in Western settings showed that the overall percentage reasons. Non–HIV-related serious adverse events (SAEs) were of patients having a pVL ,400 copies/mL at week 48 was reported from 55 patients, describing 121 adverse events.
53%15 using the ITT approach whenever possible; if not In 126 patients, 1 or more abnormal laboratory parameters possible, the OT approach was applied. In the CARE program, were measured during follow-up that were not already abnormal the ITT virologic success rate at week 48 was 47% (96/206), (ie, grade 3 or 4) at baseline. Thirteen patients had at least 1 which is similar to the virologic success rate in Western settings.
hemoglobin measurement indicative of grade 3 or 4 anemia.
A randomized open-label clinical trial with saquinavir- Patients who developed anemia did have a significantly lower based HAART that was conducted in Western clinical centers hemoglobin level at baseline compared with patients who did with a 100-week extension showed higher virologic responses not develop severe anemia during the study (P = 0.02, the (78% virologic success [OT]) than the CARE result (65% corresponding means are 10.03 and 11.51 g/dL, respectively).
virologic success [OT]).16 Patients in the CARE program were There was no statistically significant difference in neutrophil more severely ill at baseline, however, possibly explaining the count and platelet count at baseline between patients who did lower OT result in the CARE program.
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JOBNAME: joa 00#0 2006 PAGE: 5 OUTPUT: Tuesday November 28 18:36:43 2006tspjoa/131957/QAI200568 J Acquir Immune Defic Syndr  Volume 00, Number 0, Month 0, 2006 Implementation of Antiretroviral Access Program the study, errors were observed with respect to the protocols inthe laboratory that measured the pVL. From week 36 onward,however, it can be seen that virologic success rates improvedgreatly at the Nairobi site, although the rates of other sites didnot change (see Fig. 1A). In contrast to the apparent discrepantvirologic success rate, the mean CD4 cell count increaseamong patients from the Nairobi site did not differ from that atthe other sites. Such a discrepancy between the virologic andimmunologic 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 explainedby medication errors that were discovered during the course ofthe study. At this site, many patients changed their medicationat 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 ofritonavir (100 mg) once a day rather than 100 mg of ritonavireach time saquinavir capsules were taken. This error wascorrected after 12 to 24 weeks (patients then used 1600 mg ofsaquinavir 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% ofpatients in earlier studies of SQV/r-based combination therapydiscontinued their initial treatment during the first 24 weeks offollow-up,21–23 compared with 10% of patients in the CAREprogram. Of particular relevance with an AZT-containingregimen are changes in hematologic parameters.24 Indeed, 13patients (6.3%) in this program developed grade 3 or 4 anemia.
FIGURE 1. Virologic success. A, Percentage of patients with Saquinavir Boosted With Ritonavir: Twice Daily virologic success (pVL ,400 copies/mL) over time, accordingto the OT principle. B, Percentage of patients with virologic success (pVL ,400 copies/mL) over time, according to the SQV/r is currently licensed as a twice-daily regimen (1000/100 mg twice daily). In an attempt to increaseadherence, however, patients started with a once-daily regimen(1600/100 mg once daily) in this program. A once-daily Factors That May Have Negatively Affected regimen was also used for more practical reasons, because many people in the African setting only receive a full meal once Several factors may have negatively affected the daily. These initial results are similar to the results of earlier virologic treatment responses results. SGC SQV/r requires studies, which showed that a once-daily regimen is well toler- refrigeration, which may not always be available in resource- ated and effectively suppresses plasma viral replication.25,26 limited settings.17,18 Cool-boxes were supplied for transport of More recent pharmacokinetic data also showed that once-daily SQV/r from the clinic to the patient’s home, but the local dosing of saquinavir results in lower plasma concentrations storage conditions at the patient’s home did not always include and a higher frequency of suboptimal trough levels than twice- adequate cooling facilities (even though this was one of the daily dosing, however.27,28 Thus, additional pharmacokinetic selection criteria). Therefore, during the program, it was analyses may assess whether antiretroviral plasma concen- decided to switch to the HGC formulation of saquinavir, which trations were sufficiently high in all patients in this program.17 does not require refrigeration. There was a low attendance rateof 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 conclusion, this study shows that the virologic and In Nairobi, only 51%/40% (OT/ITT) of patients achieved immunologic responses to HAART in resource-limited African virologic success, which is in contrast to their earlier stage of settings can be as good as in Western settings.
disease, as reflected by their higher CD4 cell counts, lower This conclusion is similar to the findings of a meta- HIV-1 pVLs, and fewer AIDS diagnoses at baseline. The lower analysis that compared a group of cohort studies in high- success rate at the Nairobi site may be explained, of the 2 income settings with a group of cohort studies in low-income factors mentioned previously, by contamination of blood settings.29 Nevertheless, a statistically significant difference samples in the local laboratory. Indeed, in the early phase of between the sites with respect to virologic success was Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JOBNAME: joa 00#0 2006 PAGE: 6 OUTPUT: Tuesday November 28 18:36:46 2006tspjoa/131957/QAI200568 J Acquir Immune Defic Syndr  Volume 00, Number 0, Month 0, 2006 observed. These differences might have been caused by the 13. Cardiello PG, Monhaphol T, Mahanontharit A, et al. Pharmacokinetics of fact that some difficulties were experienced (eg, laboratory, once-daily saquinavir hard-gelatin capsules and saquinavir soft-gelatincapsules boosted with ritonavir in HIV-1–infected subjects. J Acquir logistics, training of study personnel, instruction of patients) Immune Defic Syndr. 2003;32:375–379.
during the early phase of the program.
14. 1993 Revised classification system for HIV infection and expanded The objectives of any access program should be feasible surveillance case definition for AIDS among adolescents and adults.
and agreed on by the provider and the participating clinical centers before the start of the program so as to minimize the 15. Bartlett JA, DeMasi R, Quinn J, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.
risk of problems in the start-up phase of the program. By conducting a pilot program with only a limited number of 16. Greenberg RN, Feinberg J, Goodrich J, et al. Long-term efficacy and patients, any communications, logistic, or practical issues can safety of twice daily saquinavir soft gelatin capsules (SGC), with or be quickly identified and addressed and personnel at the sites without nelfinavir, and three times daily saquinavir-SGC, in triplecombination therapy for HIV infection: 100-week follow-up. Antivir Ther.
can be trained on the job. Close monitoring and evaluation of access programs are required to provide adequate feedback 17. Coakley P, Merry C, Kityo C, et al. The pharmacokinetics (PK) of saquinavir and ritonavir in Ugandan patients receiving ritonavir boostedsaquinavir hard gel and soft gel [poster P277]. Presented at: SeventhInternational Congress on Drug Therapy in HIV Infection; 2004; 18. Penzak SR, Acosta EP, Turner M, et al. Antiretroviral drug content in The authors express their gratitude to all the patients products from developing countries. Clin Infect Dis. 2004;38:1317– who participated in this program and to all the study staff from 19. Wit FW, van Leeuwen R, Weverling GJ, et al. Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of acohort of human immunodeficiency virus type 1-infected persons. J InfectDis. 1999;179:790–798.
1. Joint United Nations Program on HIV/AIDS and World Health 21. Michelet C, Ruffault A, Se´bille V, et al. Ritonavir-saquinavir dual protease Organization. AIDS Epidemic Update. Geneva, Switzerland: Joint United inhibitor compared to ritonavir alone in human immunodeficiency Nations Program on HIV/AIDS and World Health Organization; 2005.
virus-infected patients. Antimicrob Agents Chemother. 2001;45:3393– 2. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus 22. Montager JS, Press N, Harris M, et al. Simplified protease inhibitor trial infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338: (SPRINT): antiviral effect of once daily saquinavir SGC plus ritonavir (SQV/r) vs twice daily indinavir plus ritonavir (IDV/r) [abstract 3. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality TuPeB4488]. Presented at: International AIDS Conference; July 11-16, across Europe in patients infected with HIV-1. EuroSIDA Study Group.
23. Ananworanich J, Ruxrungtham K, Siangphoe U, et al. A prospective 4. World Health Organization, Progress on Global Access to HIV cohort study of efficacy and safety of 2 NRTIs plus once-daily ritonavir Antiretroviral Therapy: An Update on ‘‘3 by 5.’’ Geneva, Switzerland: boosted-saquinavir hard gel capsule (SQV-HGC/r) at 24 weeks [abstract TuPeB4469]. Presented at: International AIDS Conference; July 11-16, 5. Desclaux A, Ciss M, Taverne B, et al. Access to antiretroviral drugs and AIDS management in Senegal. AIDS. 2003;17(Suppl 3):S95–S101.
24. Fellay J, Boubaker K, Ledergerber B, et al. Prevalence of adverse events 6. Susman E. Botswana gears up to treat HIV patients in Africa’s largest associated with potent antiretroviral treatment: Swiss HIV Cohort Study.
program. AIDS. 2004;18(Suppl):N1–N2.
7. Abdool Karim Q. HIV treatment in South Africa: overcoming impedi- 25. Cardiello PG, van Heeswijk RP, Hassink EA, et al. Simplifying protease ments to get started. Lancet. 2004;363:1394.
inhibitor therapy with once-daily dosing of saquinavir soft-gelatin 8. Weidle PJ, Malamba S, Mwebaze R, et al. Assessment of a pilot capsules/ritonavir (1600/100 mg): HIVNAT 001.3 Study. J Acquir antiretroviral drug therapy programme in Uganda: patients’ response, Immune Defic Syndr. 2002;29:464–470.
survival, and drug resistance. Lancet. 2002;360:34–40.
26. Cardiello P, Srasuebkul P, Hassink E, et al. The 48-week efficacy of 9. Laurent C, Diakhate N, Fatou N, et al. The Senegalese government’s once-daily saquinavir/ritonavir in patients with undetectable viral load highly active antiretroviral therapy initiative: an 18-month follow-up after 3 years of antiretroviral therapy. HIV Med. 2000;6:122–128.
27. Autar RS, Ananworanich J, Apateerapong W, et al. Pharmacokinetic 10. Djomand G, Roels T, Ellerbrock T, et al. Virologic and immunologic study of saquinavir hard gel caps/ritonavir in HIV-1-infected patients: outcomes and programmatic challenges of an antiretroviral treatment pilot 1600/100 mg once-daily compared with 2000/100 mg once-daily and project in Abidjan, Cote d’Ivoire. AIDS. 2003;17(Suppl 3):S5–15.
1000/100 mg twice-daily. J Antimicrob Chemother. 2004;54:785–790.
11. Tassie JM, Szumilin E, Calmy A, et al. Highly active antiretroviral therapy 28. Boffito M, Dickinson L, Hill A, et al. Pharmacokinetics of once-daily in resource-poor settings: the experience of Medecins Sans Frontieres.
saquinavir/ritonavir in HIV-infected subjects: comparison with the standard twice-daily regimen. Antivir Ther. 2004;9:423–429.
12. Ivers LC, Kendrick D, Doucette K. Efficacy of antiretroviral therapy 29. Egger M, Dabis F, Schechter M, et al. Mortality of HIV-1-infected patients programs in resource-poor settings: a meta-analysis of the published in the first year of antiretroviral therapy: comparison between low-income literature. Clin Infect Dis. 2005;41:217–224.
and high-income countries. Lancet. 2006;367:817–824.
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