Durability of First Line Antiretroviral Therapy : Reasons and

Predictive Factors for Treatment Modifications in a Swaziland

Cohort

Simbarashe Takuva 1, 2 , Goedele Louwagie 1 , Khangelani Zuma 1, 3 , Velephi Okello 2

1 School of Health Systems & Public Health, Faculty of Health Sciences , University of Pretoria2 Ministry of Health and Social Welfare, Mbabane, Swaziland3 Human Sciences Research Council , Pretoria, South Africa

BACKGROUND

High burden of HIV / AIDS in sub-Saharan Africa

Swaziland has highest prevalence in the world

ART has reduced morbidity and mortality

W.H.O 3 x 5 initiative resulted in rapid scale up

At least 35 000 on treatment by beginning of 2009

No data available for drug tolerability and durability

BACKGROUND : Rationale

Optimizing initial ART regimens in terms of durability and

efficacy is paramount for the prognosis of patients initiating

treatment

Where drug options are limited, it is important to understand

the reasons and risk factors that may lead to poor tolerability

of ART

This will help to individualize drug regimens among patients

Most studies done in resourceful settings. Generalizability

difficult

BACKGROUND : SOPs

Initiation of ART based on CD4 counts and WHO staging

FBC, AST/ALT and CD4 count done at baseline

First line options:

NVP-3TC-d4T

NVP-3TC-AZT

Visits – 2weeks,1, 2, 3 months and then 6 monthly

Patients screened by nurses at all visits

BACKGROUND : Aim of the study

To identify reasons for first line antiretroviral

modifications

• To examine risk factors for first line antiretroviral

modifications

METHODS : Study setting

The Mbabane Government Hospital ART Unit is the largest HIV

outpatient clinic in Swaziland.

Currently 15 800 patients, of which 7 000 are presently on ART [2009]

Standard WHO adapted treatment and care guidelines are followed

Clinic records are kept both in a paper-based form and in an electronic

database

A home-based follow-up system is currently undergoing finalization

METHODS : Study design and population

• We conducted a retrospective cohort study

• We included patients who met the following criteria :

1. HIV-infected adults older than 18 years

2. Initiated 1st line ART between 1 March 2006 and 31 May 2008

3. ART naive

4. The end-date for the follow-up was 31 December 2008

5. At least 2 recorded visits

6. Available essential patient information

METHODS : Data issues

Three main data sources

1. Database (an excel database structure recently introduced)

2. Patient clinical notes

3. Patient handheld booklet (used for pharmacy refills)

Data entered into Epi-Data (with double data entry)

Missing values – patients with missing values listed and files

excluded

Data Epi-Data exported from Epi-Data TM to STATA version 10 for

analysis

METHODS : Statistical analysis

Categorical data – proportions and continuous data – medians and

means for non-normally distributed data

Study time – date of ART initiation to the date of ART modification or

censorship

Patients were censored at the date of lost to follow up, last visit date ,

death or date of transfer out

Log – rank test and Kaplan-Meier plots were used to compare survival

time between any 2 compared groups

• Piecewise Cox proportional hazards regression model used for the multivariate analysis (proportionality violation)

METHODS : Ethical considerations

Ethics approval from the Ministry of Health and Social Welfare

Ethics Committee, Swaziland and also from the Ethics Committee

of the University of Pretoria’s Faculty of Health Sciences

RESULTS :Baseline Characteristics

RESULTS: Outcome Data

Specific Drug Modifications

RESULTS: Outcome Data

RESULTS: Outcome Data

Regimen Incidence rate

d4T-based regimen 11.3 per 1 000 person-years of follow-up

AZT-based regimen 6.1 per 1 000 person-years of follow-up

NVP-based regimen 9.5 per 1 000 person-years of follow-up

EFV-based regimen 6.0 per 1 000 person-years of follow-up

Time on treatment Probability modifying treatment (95% CI)

6 months 0.04 (0.03-0.06)

12 months 0.08 (0.06-0.10)

18 months 0.12 (0.10-0.15)

24 months 0.18 (0.15-0.22)

36 months 0.33 (0.27-0.40)

Incidence rates for treatment change by regimen

Probability of modification according to time on treatment

RESULTS : Cumulative hazard estimates for modification

Fig 2: Cumulative proportion modifying ART regimen by baseline CD4 category statusFig 1: Cumulative proportion modifying ART regimen

Fig 3: Cumulative proportion modifying ART regimen by baseline weight category status

Fig 4: Cumulative proportion modifying ART regimen by baseline NTRI regimen status

RESULTS : Univariate analysis

Risk factor crude HR (95% CI) p

Female vs male 1.34 (0.93-1.95) 0.12

Weight > 60kg vs weight < 60kg 1.82 (1.26-2.65) 0.002

Age (years) 1.01 (0.99-1.03) 0.31

CD4< 200 vs > 200 3.38 (1.72–6.65) < 0.001

WHO stage II/III/IV vs stage I 1.40 (0.91 –2.17) 0.13

NVP in regimen vs EFV 1.53 (0.98-2.38) 0.06

d4T in regimen vs AZT / TDF 1.62 (1.14-2.30) 0.007

RESULTS: Multivariate analysis

Multivariate piecewise Cox proportional hazards model

Risk factor Adjusted Hazard Ratios (95% CI)

duration < 11 months duration > 11 months

d4T in regimen vs AZT / TDF in regimen 1.41 (0.82 – 2.44) 2.64 (1.56 – 4.46)

Weight > 60kg vs weight < 60kg 1.22 (0.71 – 2.11) 2.40 (1.43 – 4.04)

CD4< 200 cells/mm3 vs > 200 cells/mm3 1.14 (0.45 – 2.90) 4.42 (1.62 – 12.1)

Gender 1.26 (0.59 – 2.70) 1.56 (0.86 – 2.85)

Age 0.98 (0.95 – 1.02) 1.03 (1.00 – 1.05)

DISCUSSION

overall, a high proportion of patients are able to tolerate their initial

antiretroviral regimen

lack of alternative treatment options in a RLS

current guidelines are rigid 1

less informed patients

1. World Health Organization , 2006.

DISCUSSION

Toxicity related reasons resulted in most modifications

gastrointestinal toxicities – the most commonly reported toxicities

resulting in treatment modification, especially in resource-rich

cohorts 1-4

burden of peripheral neuropathy and lipodystrophy related to

d4T use was of major concern. Similar findings in Cape Town 5

1. Youle M, et al. AIDS 1998. 2. Hansel A,et al. J Acquir Immune Defic Syndr. 2001. 3.Mocroft A, et al. AIDS 2001. 4. Jeanne P, et al. AIDS 2002. 5. Coetzee D, et al. AIDS 2004.

DISCUSSION

modification due to anaemia related to AZT toxicity were

significant (7.3 % of the modifications). DART trial similar 1

NVP in a treatment regimen was well tolerated, accounting for

less than 10% of the reasons for modification.

The latter is in contrast to resource-rich settings (NVP) 2,3

1. Ssali F, et al. Antiviral Ther 11:741-749. 2. MMWR Morb Mortal Wkly Rep 2001. 3. Wit FWNM, et al. J Infect Dis 2002.

DISCUSSION

Another concern : significant number of modifications due to starting

TB therapy (13%) and incident pregnancy (6.6% of reasons)

clearly emphasizes the burden of TB in this setting and brings

out the need for more aggressive TB screening in patients

initiating ART

family planning programmes also need to be routinely integrated

into routine HIV care, to prevent unplanned and unwanted

pregnancies. Patients most likely to become pregnant need to be

identified early on during their treatment

DISCUSSION

Patients initiating ART with lower CD4 cell counts had poor regimen

durability (almost 4 X likely to modify) 1,2

Weight at initiating ART was also a very strong risk factor for

modification (weight over 60 kg: almost 3 x the hazards).

may have been on the d4T 40mg regimen.

heavier patients have also been shown by some studies to be

more susceptible to mitochondrial-related toxicities 3,4

1. IAS , 2008. 2.Ssali F, et al. Antiviral Ther 2009. 3. Moh R ,et al. Antivir Ther 2005. 4.Youle M,et al. AIDS 1998.

DISCUSSION : Limitations

Lots of data with missing values – don’t know if this was influential

on our outcome or was data MCAR

Misclassification bias – information not recorded accurately during

clinic visits

The analysis of a single treatment site may just reflect practices at

this particular site

Informative censoring bias – underestimates outcome

DISCUSSION : Recommendations

1. Early initiation of ART , at higher CD4 cell counts

2. Avoiding drugs with poor toxicity profiles especially Stavudine

(d4T)

3. Before ART initiation, those individuals who may require therapy

for TB or who may become pregnant must be identified promptly

and the appropriate regimen started

4. Develop simple evidence-based algorithms to individualize patient

ART regimens

Acknowledgements

• This study is dedicated to the patients of the Mbabane

Government Hospital Antiretroviral Therapy Unit

• Dr Marian Calnan for conceptual discussions

• Data collection team : Sicelo Zondo, Delisile Mavimbela,

Muzomuhle Stewart and Sicelo Dlamini

• The School of Health Systems and Public Health, Faculty of

Health Sciences , University of Pretoria

• Clinical staff of the study site and the Ministry of Health and Social

Welfare, Swaziland