The main OIs before ART were oral or esophageal candidiasis (36.8% of patients), Pneumocystis jiroveci pneumonia (20.5% of all patients and 42.4% of those in category C), and tuberculosis (8.0% of all patients and 16.4% of those in category C, one third with extrapulmonary disease). Characteristics of 2479 ART-naive patients (58.2% of the total) included 53.4% having initiated therapy with a CD4 count <100 cells/mm3 and 30.9% with a CD4 count from 100 to 199 cells/mm3; the mean CD4 count was 96 cells/mm3. Background ART in naive patients has been lamivudine plus zidovudine (84.2%) or stavudine (12.5%) plus nevirapine (29.9%), efavirenz (39.5%), or single or boosted indinavir (21.6%). The choice of efavirenz increased from 26.4% in 2002 to 61.5% in late 2003 (Table 2).
At 6 months of follow-up in 1057 patients12,13 5.3% (5.0%) had died: 5.9% in the ART naive-group and 3.3% in the non-naive-group. Mortality according to baseline CDC classification is shown in Table 3 and Figure 4. Mortality according to baseline CD4 cell count is shown in Table 3 and Figure 5.
At 6 months of follow-up, 83.1% of all patients were still on initial therapy and 63.5% of them had a viral load <80 copies/mL. Clinical progression while on therapy was seen in 31 (2.9%) patients and followed a similar pattern as mortality with regard to baseline CD4 count: 1.3% if the baseline CD4 count was >200 cells/mm3, 1.0% if the baseline CD4 count was 101 to 200 cells/mm3, 3.6% if the baseline CD4 count was 51 to 100 cells/mm3, 4.5% if the baseline CD4 count was 11 to 50 cells/mm3, and 6.8% if the baseline CD4 count was ≤10 cells/mm3. The incidence of OIs at 6 months of therapy is shown in Table 4 in comparison to the baseline cumulative incidence of these complications.
Toxicity was the leading cause for ART discontinuation in that period: 81 patients (7.7%) stopped ART because of toxicity. Severe toxicity was almost twice as high among women (12.6% of women, 6.5% of men). Main toxicities requiring therapy discontinuation are shown in Figure 6.
Discontinuation was also required in 1% of cases because of lactic acidosis from stavudine; in 1.2% of cases because of abacavir hypersensitivity; in 1.2% of cases because of hepatitis from nevirapine; in 1.1% and 0.7% of cases because of efavirenz-induced rash and neurologic symptoms, respectively; and in 1.4% and 1.1% of cases because of nephrolithiasis from unboosted and boosted indinavir, respectively.
We have presented the model of the EAP to ART in a middle-income country (Chile), the national system established to evaluate its results (the ChiAC), and preliminary data on results. In late 2001, the government undertook the task of providing free, potent, state-of-the-art HIV therapy to patients cared for by the PHS with its own resources and aiming at 100% coverage. By mid-2003, and with the financial support of the Global Fund to Fight AIDS, Tuberculosis, and Malaria, a small gap was closed and the aim was reached. There is, however, still no free or subsidized ART for the 15% of the HIV-infected nonindigent population cared for by other systems or without any coverage. New health legislation should soon change this situation.
This is a centralized program trying to unite the complex management of a complex disease in a situation in which many health care providers are not specialists. The program not only provides antiretroviral drugs and monitoring tests but, interestingly, a supplementary budget for special medications involved in the nonantiretroviral care of HIV disease, with the purpose of not forcing hospitals, with already austere budgets, to bear the extra burden of these patients and becoming reluctant to undertake their care. The program is not without difficulties: its centralized nature carries unavoidable bureaucracy and delays, and centers do not have a general uncommitted stock of drugs; instead, drugs are allocated to specific and previously defined patients, with modifications of previously approved regimens requiring further approval. There are still few sites performing monitoring tests, and many samples need to be transported long distances. The ministerial AIDS commission, CONASIDA, is still greatly involved in operational activities, taking time and effort from its main regulatory role. Despite all this, the program has been largely successful; after a short waiting period, PHS patients needing therapy do get their treatment. The program uses no generic drugs, which are less expensive, but through price reductions negotiated by the government, the annual cost of a first-line regimen (zidovudine or lamivudine plus nevirapine or efavirenz) is approximately US $2300 (but US $6000 for other regimens after more than 1 failure). No such price reduction is available to patients not participating in this program. In comparison, the annual cost for similar regimens in Argentina, which also has its own EAP and uses mainly generic drugs, are US $1250 and US $2500, respectively (J. Lazovsky, MD, 2005, personal communication). In Brazil, full generic first-line treatments cost between US $606 and $925 (J. Mendonça, MD, 2005, personal communication).
The central authority has limited capability to evaluate the results of the program beyond gross mortality, AIDS-related hospitalizations, and global use of antiretrovirals. This difficulty may explain the scarcity of reports on the results of this kind of program in middle-income countries that have begun treatment of their patients. To fill this gap, among other goals, the ChiAC was created. Interestingly, health care providers from AIDS care centers responded enthusiastically; at this time, more than 90% of doctors and nurses involved in AIDS care in the PHS are voluntarily participating, having enrolled practically all patients on treatment through the EAP. Participants are highly motivated, and many, especially those living distant from major cities, have manifested their satisfaction at participating in a national project and having their opinion considered. This was an unexpected finding, considering the usual reluctance of people to respond to centrally generated inquiries. The active participation of health care providers has allowed a small and low-budget central administrative office to collect a large amount of data in a relatively short time. The Internet has been used to develop a communication system for the cohort. The interactive nature of the cohort study group, still in its infancy, permits the exchange of information and consultations; in the near future, it is expected that ART requests, laboratory results, and drug stocks may be incorporated into the system. The cost of implementing this has been minimal. This massive participation has reduced enrollment bias to a minimum, which is different from the situation in other large cohorts, with voluntary participants providing information not mandatory from all their patients.
The epidemic in Chile is fairly typical of many middle-income nontropical countries. The major mode of transmission is sexual, affecting mainly adult homosexual or bisexual men, with a growing number of women affected, most of whom are regular, long-term, and exclusive partners of infected men, and the disease remains mainly an urban problem. A major difference may be the small impact of drug abuse as a risk factor for infection (<5%).
More than 4300 patients receiving treatment have been included and have provided complete baseline information, which is a larger number than that of cohorts from many industrialized countries14,15 and involves as many naive patients as other multicountry cohorts.16,17 This cohort is likely to be one of the largest from a middle-income country. Most patients were treatment naive, had advanced disease, and were severely immunosuppressed at the beginning of ART. There are still a large number of symptomatic patients not presently under health care, who, now that they are aware of the program, are seeking treatment; thus, it is expected that advanced disease will still predominate for some time.
Background dual therapy for treatment-naive patients has been zidovudine and lamivudine in more than 80% of cases; severe anemia and/or neutropenia requiring a regimen change occurred only in 6.9%, validating this combination as the first choice. The third drug used varied: indinavir was used much more frequently at the beginning of the program, but efavirenz and, in second place, nevirapine are now the first choices, with the former becoming the leading associated third drug mainly because of its lower incidence of adverse effects observed in this cohort and increasing concerns regarding the safety of the latter. Nevirapine and indinavir (especially if boosted with ritonavir) required discontinuation in more than 10% of patients, and efavirenz required discontinuation in approximately 2%. More toxicity was observed in women than in men; the significance of this finding requires confirmation with more patients and longer follow-up. Preliminary results at 6 months of follow-up, although obtained from a quarter of the cohort population, are numerous enough to foresee trends, and these are similar to those obtained in other large cohorts: low toxicity and important reductions in mortality and opportunistic complications of highly active ART. This first report is from a short follow-up period, but the data are clear enough to set a definitive pattern: prompt reduction of major and frequent complications.
Not surprisingly, mortality and clinical failure were higher in patients with more advanced disease clinically or immunologically, but it is worth pointing out the finding of similar mortality in patients with a wide range of baseline CD4 cell counts and a significant increase only when the count was less than 100 cells/mm3 and, more markedly, less than 50 cells/mm3. Similar findings were previously reported in studies involving a smaller number of naive patients with similarly advanced HIV disease.18,19 In settings in which therapy might not be available to everybody, an approach with priorities for therapy initiation according to this finding may be used. Longer follow-up is underway, immunologic and virologic data are being prepared, and substudies with secondary objectives are being undertaken. The preliminary results have already had an impact on the national program: new guidelines have just been released, which include a stronger recommendation for efavirenz than the previous one, exclusion of indinavir, some nevirapine safety warnings, a CD4 count reduction for consideration of therapy initiation in asymptomatic and non-high-viral-load patients from 350 to 250 cells/mm3, and a fast track for initiating therapy for those patients with CD4 counts <100 cells/mm3.20
In summary, an EAP in middle-income countries with only local resources or some minor foreign aid is possible, and clinical results are more than encouraging.
Proper evaluation of the impact and results of such programs is of the utmost importance. The cohort model presented here may be one of these systems. Results of evaluations such as the one presented here may also be useful in other countries with similar epidemic and economic scenarios that are committed to expanded access to therapy.21 The follow-up standard reporting forms in Spanish are available on the ChiAC Web site (www.sidachile.cl).
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The members of the Chilean AIDS Study Group are Carlos Gallo, Roxana Galvez, David Wachter, Patricia Sarabia, Marcela de Andraca, Patricia Pavez, Patricia Carrasco, Lorena Berna, Carmen Aguayo, Marisol Ayala, Viviana Turi, Luis Montes, Eduardo Hermosilla, Gladys Varela, M. Eugenia Madariaga, Erna Ripoll, Elizabeth Barthel, M. Inés Sánchez, M. Teresa de Mateo, Werner Jensen, Rodrigo Ahumada, Alvaro Covarrubias, Luis Bavestrello, Sylvia Gómez, A. Burdiles, P. Rodas, Katty Zúñiga, Marcelo Wolff (coordinator), Rebeca Northland, Teresa Bidart, Jeanette Dabanch, Claudia Bustamante, Patricia Alvarez, Ingrid Flores, Patricia Vásquez, Marisol Bustos, Claudia Ledesma, Juan Ballesteros, Alexis Diomedi, Rinna Ortega, Jeannette Sobarzo, Jorge Pérez, Martín Lasso, Ana M. Fernández, Aurora Garín, Enna Zunino, Laura Bahamondes, Patricia Olea, Lucía Aguad, M. Moreno, Cristian Montenegro, C. Valdés, Margarita Enberg, J. López de Maturana, R. Pizarro, M. Quezada, Gregorio Ramírez, Johanna Bravo, Erika Molina, Carlos Beltrán (coordinator), Ricardo Morales, David Gallardo, J. M. Arancibia, Amalia Adasme, Miguel Valenzuela, Johanna Huerta, Diana Yanine, Silvia Arredondo, Manuel Amigo, Mauricio Maturana, M. Angélica Olivares, Luis Uribe, Eugenia Rodríguez, Ricardo Vásquez, Eva Woldarsky, Elizabeth Daube, Rodrigo Blamey, M. Eugenia Cancino, M. Elena Novoa, José Carreño, M. Isabel Mendoza, Carolina Chahín, Claudia Molina, Mario Calvo, Mónica Hering, Alicia Rebolledo, Jorge Mardones, Sara Villalobos, Iván Becerra, Ana M. Sáez, Carmen Toro, Lucía Atala, Stanko Karelovic, and Tatiana Navarro as well as Alejandra Valdovinos, Angélica Carrasco, and Omar Morales (staff).
Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
resource-limited countries; cohort studies; antiretroviral therapy; expanded access to therapy; impact evaluation