Conceived and designed the experiments: AFA FM RWS MS CA LJN TE. Performed the experiments: AFA FM RWS MS CA LJN TE. Analyzed the data: RWS AFA. Contributed reagents/materials/analysis tools: AFA FM RWS MS CA LJN. Wrote the paper: AFA FM RWS MS CA LJN TE.
The authors have declared that no competing interests exist.
In Mozambique during 2004–2007 numbers of adult patients (≥15 years old) enrolled on antiretroviral therapy (ART) increased about 16-fold, from <5,000 to 79,500. All ART patients were eligible for co-trimoxazole. ART program outcomes, and determinants of outcomes, have not yet been reported.
In a retrospective cohort study, we investigated rates of mortality, attrition (death, loss to follow-up, or treatment cessation), immunologic treatment failure, and regimen-switch, as well as determinants of selected outcomes, among a nationally representative sample of 2,596 adults initiating ART during 2004–2007. At ART initiation, median age of patients was 34 and 62% were female. Malnutrition and advanced disease were common; 18% of patients weighed <45 kilograms, and 15% were WHO stage IV. Median baseline CD4+ T-cell count was 153/µL and was lower for males than females (139/µL vs. 159/µL, p<0.01). Stavudine, lamivudine, and nevirapine or efavirenz were prescribed to 88% of patients; only 31% were prescribed co-trimoxazole. Mortality and attrition rates were 3.4 deaths and 19.8 attritions per 100 patient-years overall, and 12.9 deaths and 57.2 attritions per 100 patient-years in the first 90 days. Predictors of attrition included male sex [adjusted hazard ratio (AHR) 1.5; 95% confidence interval (CI), 1.3–1.8], weight <45 kg (AHR 2.1; 95% CI, 1.6–2.9, reference group >60 kg), WHO stage IV (AHR 1.7; 95% CI, 1.3–2.4, reference group WHO stage I/II), lack of co-trimoxazole prescription (AHR 1.4; 95% CI, 1.0–1.8), and later calendar year of ART initiation (AHR 1.5; 95% CI, 1.2–1.8). Rates of immunologic treatment failure and regimen-switch were 14.0 and 0.6 events per 100-patient years, respectively.
ART initiation at earlier disease stages and scale-up of co-trimoxazole among ART patients could improve outcomes. Research to determine reasons for low regimen-switch rates and increasing rates of attrition during program expansion is needed.
Globally, during 2004–2009, the number of HIV-infected patients enrolled on
antiretroviral therapy (ART) increased more than 10-fold, from less than 400,000 to
more than five million, with most new ART patients enrolled in sub-Saharan Africa
In Mozambique, where about 1.6 million people are HIV-infected and about 473,000 need
ART
This study was approved by the Institutional Review Board (IRB) of the United
States Centers for Disease Control and Prevention (CDC) and the Mozambican
Ethics Review Committee (
During 2004–2007, patients diagnosed with World Health Organization (WHO)
stage IV disease, stage III disease with CD4 counts <350/µL, or stage I
or II disease with CD4 counts <200/µL, were eligible for ART
At ART initiation, standardized medical records, recommended by the Ministry of Health (MOH), were completed. These records captured, among other variables: date of visit, sex, age at enrollment, date of birth, marital status, employment status, HIV status of partner, WHO stage, CD4 count, weight, height, hemoglobin level, ART regimen and CTX prescription status. At all subsequent visits, the date of the visit, patient weight, clinical stage and ART regimen prescribed were recorded, while at 6-monthly intervals after ART initiation, hemoglobin measurements, and CD4 counts were recommended to monitor disease progression or improvement. Patients collected medications monthly from clinic pharmacies where the date of scheduled antiretroviral (ARV) pick-up appointments and actual ARV pick-up occurrences were documented.
As in other resource-constrained settings where viral load monitoring is not
routine
Our reported mortality rate represents the number of documented deaths during ART
per 100 person-years of observed therapy. The attrition rate represents the
number of patients lost through attrition (death, LTFU, or stopping ART) per 100
person-years of observed therapy. A patient absent from a health facility in the
90 days preceding data abstraction was considered LTFU, unless the medical
record stated that the patient had died, stopped ART, or transferred. The date
of LTFU was recorded as the date of the most recent visit, or one day after ART
initiation if patients only attended the initiation visit. One-year attrition
proportions are reported to allow comparison with published literature
To allow comparison with other resource-constrained programs
CD4 counts were determined using FlowCount PLG CD4 assay and analyzed with Beckman Coulter Epics XL-MCL Flow Cytometers (both Beckman Coulter, Inc., Johannesburg, South Africa). Blood Hemoglobins were determined with an automated hematology analyzer, Sysmex XT2000i (Sysmex Europe, Inc., Hamburg, Germany) or HemoCue photometer assay (HemoCue AB, Helsingborg, Sweden).
Similar to other cohort studies in resource-constrained settings
A retrospective cohort study design was used. Patient-level data were abstracted from standardized, MOH-recommended medical records onto study questionnaires by trained abstractors in November 2008. Only medical records of adult patients, ≥15 years old at ART initiation, who started ART during 2004–2007, were eligible.
Sample size calculations were performed using Epi Info™ software (CDC, Epi
Info 2008, Version 3.5.1, Atlanta, GA). To achieve a 95% confidence
interval (CI) of ±3.0% around the estimate for 6-month attrition,
assuming a design effect of 1.5, and a conservative (i.e. higher than expected)
6-month attrition proportion of 25%
During study planning in November 2007, MOH-reported data from the end of December 2006 were used to define the clinic sample frame. By December 2006, 43,295 adults had initiated ART at 152 clinics, all of which were managed by the MOH with funding support from several donor agencies including the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). Clinics that had initiated <50 adults on ART by this time were excluded from the sample frame, resulting in 58 clinics, ranging in size from 1–49 adult ART enrollees and supporting only 1,061 adult ART patients, being excluded. Ninety-four clinics, which had each enrolled between 50 and 3,530 adult ART patients, were included in the sample frame; of these clinics, 12 with >1,000 enrollees were selected with certainty, while 18 with 50–1,000 enrollees were selected using probability-proportional-to-size sampling. All 11 provinces in Mozambique were represented by the sample with at least one ART clinic selected from each province. From the 30 selected clinics, ranging in site size from 70–3,530 adult ART enrollees, we aimed to randomly sample 2,600 medical records.
Data were analyzed using SAS 9.2 (SAS Institute Inc., Cary, NC), STATA 10 (StataCorp, 2009, Stata Statistical Software, Release 10, College Station, TX), and SUDAAN (Research Triangle Institute, 2005, SUDAAN, Release 9.0.1. Research Triangle Park, NC). Data were weighted and survey design controlled for, during analysis.
Multiple imputation with chained equations was used to impute missing baseline
demographic and clinical data
As a secondary analysis, mean CD4 count and weight change over time was estimated
to allow comparison with published literature. SAS PROC MIXED was used to fit
unweighted polynomial growth curve models with maximum likelihood (ML)
estimation to the data
Data from medical records of 2,596 eligible, adult ART patients were abstracted
and analyzed.
Original Data | Following MultipleImputation (N = 2,596) | |||||
Un-weighted Frequency of Observations | Un-weighted Total | Weighted Median with IQR |
Weighted Median with IQR |
|||
|
||||||
Both Sexes | 2,596 | 2,596 |
|
(28–42) |
|
(28–42) |
Female | 1,576 | 1, 576 |
|
(27–39) |
|
(27–39) |
Male | 1,020 | 1,020 |
|
(31–45) |
|
(31–45) |
|
1,576 | 2,596 |
|
(59–65%) |
|
(59–65%) |
|
||||||
Employed | 992 | 2,268 |
|
(40–51%) |
|
(40–51%) |
Student | 107 | 2,268 |
|
(3–5%) |
|
(3–5%) |
Unemployed | 1,169 | 2,268 |
|
(45–56%) |
|
(46–56%) |
observations missing data |
328 | 2,596 |
|
|||
|
267 | 2,564 |
|
(9–13%) |
|
(9–13%) |
observations missing data |
32 | 2,596 |
|
|||
|
||||||
I/II | 619 | 1,617 |
|
(32–42%) |
|
(34–45%) |
III | 739 | 1,617 |
|
(43–52%) |
|
(40–50%) |
IV | 259 | 1,617 |
|
(13–18%) |
|
(13–18%) |
observations missing data |
979 | 2,596 |
|
|||
|
||||||
<45 kg | 367 | 2,061 |
|
(14–20%) |
|
(15–21%) |
45–60 kg | 1,224 | 2,061 |
|
(56–61%) |
|
(54–59%) |
> 60 kg | 470 | 2,061 |
|
(21–27%) |
|
(22–28%) |
observations missing data |
535 | 2,596 |
|
|||
|
354 | 1,200 |
|
(23–33%) |
|
(23–33%) |
observations missing data |
1,396 | 2,596 |
|
|||
|
||||||
Both Sexes | 2,254 | 2,596 |
|
(76–231) |
|
(74–231) |
Female | 1,373 | 1,576 |
|
(88–244) |
|
(87–243) |
Male | 881 | 1,020 |
|
(59–213) |
|
(59–213) |
observations missing data |
342 | 2,596 |
|
|||
|
||||||
Both Sexes | 1,899 | 2,596 |
|
(8.8–11.6) |
|
(8.8–11.7) |
Female | 1,182 | 1,576 |
|
(8.6–11.0) |
|
(8.5–11.1) |
Male | 717 | 1,020 |
|
(9.0–12.5) |
|
(9.2–12.5) |
|
||||||
D4T + 3TC + NVP/EFV | 2,315 | 2,596 |
|
(82–94%) |
|
(82–94%) |
AZT + 3TC + NVP/EFV | 240 | 2,596 |
|
(5–16%) |
|
(5–16%) |
D4T/AZT + 3TC + ABC | 17 | 2,596 |
|
(0–1%) |
|
(0–1%) |
Other | 24 | 2,596 |
|
(0–1%) |
|
(0–1%) |
Abbreviations: CI, confidence interval; IQR, interquartile range; TB, tuberculosis; WHO, World Health Organization; Kgs, kilograms; BMI, body mass index; ART, antiretroviral therapy; D4T, stavudine; 3TC, lamivudine; NVP, nevirapine; EFV, efavirenz; AZT, zidovudine; ABC, abacavir; CTX, co-trimoxazole.
*Median and IQR calculated across 20 imputed datasets.
Variables with complete data.
**Unweighted sample estimate.
At ART initiation, median age of patients was 34 years, and 62% were female of whom 16% (95% CI, 6–25%) were pregnant. About 53% (95% CI, 50–57%) of patients were married or in a civil union. Partner sero-status was documented in 13% (95% CI, 11–15%) of all records. In un-weighted analysis, 37 (11%) of 330 tested partners were sero-negative.
Active tuberculosis (TB) was frequent at ART initiation with 11% of patients receiving TB treatment. Many patients were underweight; 18% weighed <45 kilograms (kg) at ART start. Advanced disease was common with 15% of patients diagnosed as having WHO stage IV disease.
Median CD4 count at ART initiation was 153/µL; 16% (95% CI, 14–19%) had counts below 50/µL and 50% (95% CI, 47–54%) had counts ranging from 50–200/µL. Median CD4 counts at ART initiation were lower for males than females (139/µL vs. 159/µL, p<0.01).
Median hemoglobin at ART initiation was 10.3 g/dL. Severe anemia (hemoglobin <8 g/dL) was present in 13% (95% CI, 12–15%) of patients. Median hemoglobin at ART initiation was lower for women than men (9.9 vs. 11.0 g/dL, p<0.01).
Stavudine (d4T), lamivudine (3TC), and nevirapine (NVP) or efavirenz (EFV) comprised 88% of first-line regimens. Only 31% (95% CI, 26–36%) of patients were prescribed CTX at ART initiation; 3% (95% CI, 2–3%) were not prescribed CTX due to allergy.
Of 2,596 patients sampled, 164 died, 564 were LTFU, and 10 stopped ART indefinitely during 4,001 patient-years of follow-up. Median follow-up duration was 1.3 years (interquartile range, 0.7–2.2 years). Of patients who died, 56% (95% CI, 49–63%) died within 90 days of starting ART. Of patients who were LTFU, 41% (95% CI, 35–48%) were lost within 90 days of starting ART.
Mortality rates were 3.4 deaths per 100 patient-years overall (95% CI, 2.8–4.2), 12.9 deaths per 100 patient-years in the first 90 days (95% CI, 9.9–17.1), and 1.8 deaths per 100 patient-years after 90 days (95% CI, 1.3–2.4).
One-year attrition was 21% (95% CI, 17–25%) with 15% LTFU (95% CI, 11–18%), 5% dead (95% CI, 4–6%), and 1% stopping ART (95% CI, 0–3%). Attrition rates were 19.8 attritions per 100 patient-years overall (95% CI, 17.9–21.9), 57.2 attritions per 100 patient-years in the first 90 days (95% CI, 49.5–66.4), and 13.2 attritions per 100 patient-years after 90 days (95% CI, 11.7–15.0).
Male sex was associated with attrition (AHR 1.5; 95% CI, 1.3–1.8)
(
Attrition |
Immunologic Treatment Failure |
|||||||
Original | Following Multiple Imputation (N = 2,596) | Original | Following Multiple Imputation (N = 2,596) | |||||
Rate/100PY | HR (95% CI) | AHR |
Rate/100PY | HR (95% CI) | AHR |
|||
|
||||||||
Female | 1,576 | 17.9 | 1.0 | 1.0 | 1,576 | 13.1 | 1.0 | 1.0 |
Male | 1,020 | 23.0 |
|
|
1,020 | 15.5 |
|
|
|
2,596 | – |
|
|
2,596 | – |
|
|
|
2,596 | – |
|
|
2,596 | – | 1.1 (1.0–1.2) | 1.1 (0.9–1.2) |
|
||||||||
Married/Living together | 1,211 | 21.2 | 1.0 | 1.0 | 1,211 | 12.4 | 1.0 | 1.0 |
Single/Widowed | 1,152 | 18.3 | 0.9 (0.8–1.0) | 0.9 (0.8–1.1) | 1,152 | 15.7 |
|
|
|
||||||||
Yes | 992 | 18.8 | 1.0 | 1.0 | 992 | 13.4 | 1.0 | 1.0 |
Student | 107 | 18.8 | 1.1 (0.7–1.5) | 1.0 (0.7–1.4) | 107 | 15.8 | 1.2 (0.9–1.5) | 1.0 (0.7–1.5) |
No | 1,169 | 20.8 | 1.1 (0.8–1.4) | 1.1 (0.9–1.3) | 1,169 | 14.4 | 1.1 (0.9–1.3) | 1.1 (0.8–1.4) |
|
||||||||
No | 2,297 | 18.9 | 1.0 | 1.0 | 2,297 | 14.0 | 1.0 | 1.0 |
Yes | 267 | 27.9 |
|
1.0 (0.8–1.4) | 267 | 13.9 | 1.0 (0.8–1.3) | 1.0 (0.7–1.3) |
|
||||||||
Stage I/II | 619 | 13.3 | 1.0 | 1.0 | 619 | 14.6 | 1.0 | 1.0 |
Stage III | 739 | 21.7 | 1.1 (0.8–1.6) | 739 | 13.1 | 0.9 (0.7–1.2) | 0.9 (0.6–1.2) | |
Stage IV | 259 | 35.0 |
|
|
259 | 14.7 | 1.0 (0.7–1.4) | 0.9 (0.6–1.3) |
|
||||||||
>60 | 470 | 12.7 | 1.0 | 1.0 | 470 | 11.7 | 1.0 | |
45–60 | 1,224 | 18.1 | 1.4 (1.1– 1.8) | 1.2 (1.0–1.6) | 1,224 | 14.3 | 1.2 (1.0–1.5) | 1.3 (1.0–1.7) |
<45 | 367 | 41.9 | 2.9 (2.2–3.8) |
|
367 | 17.5 | 1.5 (1.0–2.3) | 1.6 (1.0–2.6) |
|
||||||||
>200 | 754 | 18.8 | 1.0 | – | 754 | 16.7 | 1.0 | – |
>50–≤200 | 1,144 | 18.5 | 1.0 (0.8–1.3) | – | 1,144 | 10.2 |
|
– |
<50 | 356 | 25.8 |
|
– | 356 | 22.1 | 1.3 (1.0–1.8) | – |
|
||||||||
≥8.0 g/dL | 1,664 | 17.2 | 1.0 | 1.0 | 1,664 | 14.0 | 1.0 | 1.0 |
<8.0 g/dL | 235 | 40.5 |
|
|
235 | 14.1 | 1.0 (0.7–1.5) | 0.9 (0.6–1.5) |
|
||||||||
Yes | 821 | 15.3 | 1.0 | 1.0 | 821 | 13.7 | 1.0 | 1.0 |
No | 1,775 | 21.9 |
|
|
1,775 | 14.1 | 1.0 (0.9–1.2) | 1.0 (0.9–1.2) |
|
||||||||
≥95% | 1,263 | 17.0 | 1.0 | 1.0 | 1,263 | 13.4 | 1.0 | 1.0 |
<95% | 597 | 28.3 |
|
1.3 (0.8–2.0) | 597 | 15.8 | 1.2 (0.9–1.6) | 1.2 (0.9–1.6) |
|
||||||||
>1,000 patients | 2,109 | 15.9 | 1.0 | 1.0 | 2109 | 13.8 | 1.0 | 1.0 |
≤1,000 patients | 487 | 37.3 |
|
1.5 (0.8–2.6) | 487 | 14.6 | 1.0 (0.7–1.5) | 1.0 (0.6–1.5) |
Abbreviations: Rate/100PY, rate per 100 person-years; HR, hazards ratio; AHR, adjusted hazards ratio; CI, confidence interval; TB, tuberculosis; WHO, World Health Organization; BMI, body mass index; CTX, co-trimoxazole.
*Stratified by CD4+ T-cell count (cells/µL).
All variables listed in this table were included in the multivariate Cox proportional hazards regression model.
**Hazard ratios associated with a 10-year increase in age.
Date of ART initiation was entered into the model; hazard ratios represent a yearly increase rather than a daily increase.
Patients not prescribed CTX were at higher risk for attrition compared with
patients who were prescribed this drug (AHR 1.4; 95% CI, 1.0–1.8)
(
Of 2,596 patients at risk, 486 experienced immunologic treatment failure during 3,481 patient-years of follow-up. The failure rate was 14.0 failures per 100-patient years (95% CI, 13.0-16.0). The regimen-switch rate was 0.6 per 100-patient years (95% CI, 0.4-1.1).
Predictors of immunologic treatment failure included male sex (AHR 1.4; 95% CI, 1.2–1.8) and being single or widowed (AHR 1.3; 95% CI, 1.2–1.5). Risk of immunologic failure decreased as age at ART initiation increased (AHR associated with a 10-year age increase was 0.9; 95% CI, 0.8–1.0).
Modeled mean gains in CD4 count were 173, 186, 237, 273, and 293/µL at 6,
12, 24, 36 and 48 months of follow-up, respectively (
About 71% (95% CI, 66–77%) of patients were ≥95% adherent to ART medicine pick-up appointments during the first six months of therapy. Proportions of female and male ART patients who were ≥95% adherent to ART were not significantly different (72% vs. 70%, p = 0.12).
This study adds to the limited number of nationally representative ART outcome
assessments from sub-Saharan Africa
First, rates of mortality, attrition, and immunologic treatment failure for the study
period are comparable with reports from other ART programs in resource-rich
Meta-analyses of attrition in adult ART programs in sub-Saharan Africa have
reported mean one-year attrition proportions of 25% and 20% for
the review periods of 2000-2007
Since recent reports show that patient death may account for 29–59%
of patients who are LTFU
Similar to other programs
Post 90-day mortality and attrition rates of 1.8 and 13.2 events per 100
patient-years, respectively, are comparable with post 90-day mortality rates
reported from both resource-constrained
Compared with the average regimen-switch rate for resource-constrained programs
(2.4 switches per 100 person-years, 95% CI, 2.2–2.6
Similar to other reports, many patients initiated ART with WHO stage IV disease,
which was a strong predictor of attrition
Similar to other reports
As in other studies, our marker for malnutrition at ART initiation (weight <45
kg
Although CTX prescription is recommended for all ART patients in Mozambique
throughout therapy, few (31%) received this drug at ART initiation during
2004–2007. Reasons for this are unknown but may include CTX supply
shortfalls and clinician concerns about CTX drug resistance development
Although several studies have demonstrated an additional benefit of CTX for ART
patients
Additional in-service training for ART-service providers is planned to rapidly scale-up CTX prescription. Further, CTX procurement and distribution procedures are being reviewed to ensure that all ART delivery sites have adequate CTX supplies.
As the ART program expanded during 2004 through 2007, attrition risk for newly
enrolled adult ART patients increased, a temporal trend which has been observed
in other programs in resource-constrained settings
The low proportion of records with documented partner sero-status is concerning
because partner HIV counseling and testing (HIV-CT) can facilitate entry into
HIV care for infected individuals or appropriate prevention strategies for
uninfected partners
Limitations primarily relate to the fact that these analyses were based on routinely collected data, which were incomplete for certain baseline and follow-up clinical characteristics.
Treatment outcomes were comparable with reports from other ART programs; however, the low ART regimen-switch rates and the increasing attrition rates during program expansion are concerning findings which deserve further research. Immediate public health responses that may improve treatment outcomes include initiation of ART at earlier disease stages, especially among males, scale-up of CTX, and evidence-based interventions for malnourished patients; in addition, scale-up of partner HIV-CT could significantly contribute to national HIV prevention efforts.
The authors would like to acknowledge the health care providers in Mozambique's antiretroviral therapy clinics without whom this study would not have been possible.