Stringer JS, Zulu I, Levy J, Stringer EM, Mwango A, Chi BH, Mtonga V, Reid S, Cantrell RA, Bulterys M, Saag MS, Marlink RG, Mwinga A, Ellerbrock TV, Sinkala M. Rapid Scale-Up of Antiretroviral Therapy at Primary Care Sites in Zambia: Feasibility and Early Outcomes. JAMA. 2006 Aug 16;296(7):782-93.
To report on the feasibility and initial clinical experience of rapid scale-up of HIV/AIDS care and treatment services in Zambia. Scale-up occurred largely in response to US-PEPFAR and Global Fund initiatives.
Data are presented from an open cohort study of antiretroviral-naive adults evaluated at urban primary-care facilities over an 18-month period from 2004-2005. This paper also provides a programmatic description.
18 primary-care facilities in Lusaka, Zambia that provide services using mostly non-physician clinicians.
A total of 21,755 HIV-positive treatment-naive patients were enrolled into HIV care, 74% of whom started antiretroviral therapy (ART). The median age was 35 years and 63% were female. For those who had baseline measurements at entry, mean body mass index (BMI) was 21.0 for females and 19.9 for males; mean CD4 cell count was 197/µL; mean hemoglobin (Hg) concentration was 10.9 g/dL (measured among 11,773 patients only).
Antiretroviral therapy was provided according to Zambian national guidelines. Criteria for ART was based on CD4 cell count <200/µL, WHO stage III with CD4 cell count <350/µL, or WHO stage IV. Standard protocols consisted of 3TC, NVP, and (ZDV or d4T). Among those on TB therapy, an EVF-based regimen was used instead of NVP. Cotrimoxazole was given to those in WHO stage IV or with CD4 counts <200/ul. Follow-up was every two weeks for the first three months, and then every three months thereafter. CD4 cell counts were measured every six months, and Hg and adherence were monitored closely. Patients were required to come to the clinic each month to receive medications.
Main outcome measures were survival, regimen failure rate, and CD4 cell response. Treatment failure was clinically defined as worsening WHO stage after at least three months of ART, or return of CD4 cell count to below pretreatment baseline. Adherence was assessed by timeliness of pharmacy attendance.
Overall: Among the 16,198 (74%) of patients who started ART, 7% died, <1% withdrew, and 21% were late to follow-up by the time of analysis. Patients starting a ZDV regimen were significantly more likely to have that drug substituted compared to those starting a d4T-based regimen. The mean CD4 cell count increase was 175/µL among those who had a 12-month measure.
Mortality: Overall mortality was 16.1 deaths/100 person-years; 71% of those who died did so within the first three months of starting therapy. In multivariate analysis, mortality was strongly associated with CD4 cell count <50 /µL or from 50-199/µL compared to >200/uL (adjusted hazard ratio (AHR) =2.2 and 1.4, respectively); WHO stage III disease (AHR=1.8) WHO stage IV disease (AHR=2.9) low BMI (AHR=2.4), severe anemia with Hbg <8.0 g/dL (AHR=3.1), and poor adherence to therapy (AHR=2.9).
Regimen failure: Among 11,714 patients at risk (excluding those who died or were not followed), 861 (7%) failed therapy by clinical criteria. The following were independently associated with regimen failure: severe anemia at entry (AHR=1.4) being male (AHR=1.2), poor adherence (AHR=1.8).
Adherence: Thirty-two percent of patients were never late in collecting their medication, and 11% were late an average of 8.0 days or longer per month. Predictors of poor adherence (defined as being among the 10% least adherent patients) included hemoglobin (<8.0 g/dL (relative risk [RR] =1.4), WHO stage III disease (RR=1.3) and WHO stage IV disease (RR=1.6).
The authors conclude that massive scale-up of HIV and AIDS treatment services with good clinical outcomes is feasible in primary-care settings in sub-Saharan Africa. The authors state that the success of this program is due to four major factors: key government leadership, which included the elimination of medical fees and improved access for women and children; the use of clinical officers and nurses to compensate for a physician shortage; the use of an electronic patient-tracking and clinical monitoring system; and the availability of significant financial support from PEPFAR.
There is no formal quality rating system to be applied to this type of study. However, this cohort analysis was of high quality for the following reasons: attempts were made to bring late patients back into care, rigorous multivariate statistical analysis was performed, and a detailed electronic tracking system was used.
This is the largest evaluated rapid scale-up of ARV provision in a resource-limited setting and in response to PEPFAR. As such, it provides critical and timely information regarding the ability to provide care to the large numbers of HIV-infected person in sub-Saharan Africa. Data on clinical outcomes are comparable to other studies and do not indicate that massive scale-up would result in poor service delivery or suboptimal clinical outcomes. Other studies have found that the majority of HIV-related patient deaths occur within the first three months of ART initiation.(1,2,3,4) The mortality rate after the first 90 days observed here (5.0 deaths per 100 patient-years) is comparable with mortality rates observed in resource-rich settings.(5) Additionally, the increase in CD4 cell count observed in this cohort is also comparable to those among patients in more resource-rich settings.(6,7,8)
This study shows that massive and rapid scale-up of AIDS treatment services is feasible in urban sub-Saharan Africa. Favorable clinical outcomes can occur by using nurses and clinical officers to circumvent physician shortages. In general, first-line treatment was well-tolerated, although longer-term follow-up is still needed. The success of this program was facilitated by the use of an electronic patient tracking and outcomes-monitoring system. This system assists with clinic management, patient care, compliance with protocols and adherence, and identification of patients who need home follow-up. Most mortality occurred within the first three months of initiating treatment, particularly among those with advanced disease. It is possible that some early mortality may be due to undiagnosed opportunistic infections, severe immune reconstitution syndrome, or other causes. Therefore, earlier diagnosis and treatment is likely to be important in reducing mortality rates. Finally, government leadership and large-scale financial support (in this case from PEPFAR) are crucial to the success and logistics of providing large scale HIV/AIDS treatment programs in resource-constrained settings.
Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, Wood R, Laurent C, Sprinz E, Seyler C, Bangsberg DR, Balestre E, Sterne JA, May M, Egger M; Antiretroviral Therapy in Lower Income Countries (ART-LINC) Collaboration; ART Cohort Collaboration (ART-CC) groups. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet. 2006 Mar 11;367(9513):817-24.
- Coetzee D, Hildebrand K, Boulle A, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS. 2004; 18:887-895.
Ferradini L, Jeannin A, Pinoges L, Izopet J, Odhiambo D, Mankhambo L, Karungi G, Szumilin E, Balandine S, Fedida G, Carrieri MP, Spire B, Ford N, Tassie JM, Guerin PJ, Brasher C. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet. 2006 Apr 22;367(9519):1335-42.
Grabar S, Le Moing V, Goujard C, Leport C, Kazatchkine MD, Costagliola D, Weiss L. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy.. Ann Intern Med. 2000 Sep 19;133(6):401-10.
- Kitchen CM, Kitchen SG, Dubin JA, Gottlieb MS. Initial virological and immunologic response to highly active antiretroviral therapy predicts long-term clinical outcome. Clin Infect Dis. 2001 Aug 15;33(4):466-72.
- M. Saag et al., unpublished data, April 2006.
Mocroft A, Madge S, Johnson AM, Lazzarin A, Clumeck N, Goebel FD, Viard JP, Gatell J, Blaxhult A, Lundgren JD. A comparison of exposure groups in the EuroSIDA study: starting highly active antiretroviral therapy (HAART), response to HAART, and survival. J Acquir Immune Defic Syndr. 1999 Dec 1;22(4):369-78.
Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, Hanson D, Ochola D, Mugyenyi P, Mermin J, Samb B, Lackritz E. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet. 2002 Jul 6;360(9326):34-40.