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Discontinuation and modification of highly active antiretroviral therapy in HIV-infected Ugandans: prevalence and associated factors
Global Health Sciences Literature Digest
Published July 2, 2007
Journal Article

Kiguba R, Byakika-Tusiime J, Karamagi C, Ssali F, Mugyenyi P, Katabira E. Discontinuation and modification of highly active antiretroviral therapy in HIV-infected Ugandans: prevalence and associated factors. J Acquir Immune Defic Syndr. 2007 Jun 1;45(2):218-23.

Objective

To estimate the prevalence of and identify factors associated with discontinuation of highly active antiretroviral therapy (HAART) among patients in sub-Saharan Africa.

Study Design

This was a cross-sectional study of HIV sero-positive adults who were currently receiving HAART, or who had been on antiretroviral therapy (ART) during the last two years, but had discontinued medication. Clients were evaluated using semi-structured quantitative and qualitative face-to-face interviews. The study was performed from December 2005 to March 2006.

Setting

The study was conducted among patients at the Mulago Hospital and the Joint Clinical Research Centre (JCRC) in Kampala, Uganda. Mulago Hospital is the national referral hospital and provides free ART to approximately 4,300 people. The JCRC specializes in HIV/AIDS care and research, with 19,000 cumulative patients having received ART; access to free therapy became available for poor patients in 2004.

Participants

HIV infected patients >18 years of age currently on treatment were consecutively sampled; those who had been on ART for at least one month during the last two years, but were currently not receiving medication, were identified through medical and pharmacy records and traced. Six hundred eighty-six subjects were identified. Two-thirds of participants were female (65.9%). The median age was 36 years (interquartile range [IQR]: 31-43 years) the median CD4 count (n=478) at last measurement was 175 cells/µL (IQR: 66-298 cells/µL). The largest proportion of the study sample (83.8%) received non-nucleoside reverse transcriptase inhibitor - (NNRTI-) based regimens.

Interventions

There was no intervention.

Primary Outcomes

The primary outcomes were: the proportion of patients discontinuing or modifying their ART, and reasons associated with this. Discontinuation of therapy was defined as stopping all antiretroviral drugs for at least one month, based on a decision by the physician or the patient. Structured treatment interruptions and interruptions based on CD4 counts were not included in the definition. Modification was defined as switching at least one antiretroviral drug used as part of the initial HAART regimen.

Results

Ninety-four of 686 patients (13.7%) had discontinued therapy at some point, and 175/686 (25.5%) had modified their initial HAART regimen. Among those discontinuing therapy, the decision was made by the patient in 45.7% of the cases; among those modifying therapy, the decision was made by the physician in 95.5% of the cases. The most frequently cited reasons for discontinuation were that drugs were too expensive (43%), to avoid side effects and toxicity (21.1%), and drugs out of stock (10.5%). Modification of drugs was based on the physician's decision in the vast majority of cases (95.5%), and the most common reasons (n=103) cited were to avoid side effects (71.8%) and high drug cost (23.3%). Factors independently associated with discontinuation of HAART included: 1. patients who had been on ART prior to starting their current regimen (OR=3.70, 95% CI: 2.13 to 6.25; p<0.001); 2. hospitalization after starting ART (OR=2.36, 95% CI: 1.32 to 4.20 4); 3. use of alternative medicines (OR=2.18, 95% CI: 1.06 to 4.47); and 4. receiving HAART for one year or less (vs. more than one year; OR=11.11, 95% CI: 5.00 to 25.00). Those who lived less than 5km from the clinic were shown as more likely to discontinue medication (OR 1.77, 95% CI=0.99-3.15, p=.053). Neither monthly income nor adherence were associated with stopping treatment. In a separate model, factors independently associated with modification of HAART included: 1. being unmarried (OR=1.64, 95% CI: 1.02 to 2.70); and 2. being on therapy more than three months (OR=3.13, 95% CI: 1.16 to 8.33). Neither having an opportunistic infection or CD4 count <200 cells/µl were independently associated with outcome. Results did not differ when the 15 patients (2.2%) who had been on ART for less than one month were excluded from the analysis.

Conclusions

The authors conclude that the proportions of discontinuation and modification of antiretroviral therapy observed in this study's resource-limited setting pose a challenge to the limited treatment options presently available. Drug cost as a major reason for discontinuation of HAART has important implications for antiretroviral therapy programs that charge fees in resource-limited settings.

Quality Rating

There is no formal rating system for cross-sectional studies such as this one. The study was limited by the lack of detail of the aspects of study design that did not allow assessment of sample representativeness and rigor of data collection, and by the lack of stratified analysis. For example, it is not clear whether all patients currently and previously on therapy at both clinics were recruited into the study, given that the authors state that clients were consecutively sampled; the total number of patients serviced by the clinics was not specified. "Unstructured qualitative interviews- implies that standardized domains of questions were not used, leading to the possibility of inconsistent data collection. Reasons for discontinuation were apparently based only on patient report, and were not verified by chart review-thus there may have been significant recall bias, particularly when reporting whether discontinuation was recommended by the physician. It would have been helpful to have a stratified analysis by clinic site of reasons for discontinuation or modification of treatment, since cost was cited as a major impediment to consistent therapy - ART was free for everyone at one site, but not at the other. In addition, discontinuation of therapy based on a physician decision has different implications than discontinuation initiated by the patient. A stratified analysis of reasons associated with discontinuing medication by physician/patient would have been useful. How adherence was measured was not described. It is not clear why patients who lived closer to the clinics were more likely to discontinue heir therapy, compared to those who lived further away.

In Context

The high proportions of study participants who either stopped taking their medications or changed one or more component of their HAART regimen was similar to results found in other studies.(1,2,3,4,5,6) Drug cost was the most frequently cited reason for discontinuation of ART; this has been known to be a major barrier to utilization of ART in resource-limited settings.(7) Also, the finding that a shorter duration of ART was independently associated with discontinuations of therapy was observed in other studies.(8,9,10,11)

Programmatic Implications

This is an interesting analysis of reasons for modification and discontinuation of therapy among patients in Kampala. Results seem to indicate that cost continues to be an important cited factor for discontinuation. However, multivariate analysis did not show an association between income and discontinuation, and medications were apparently free for all at Mulago Hospital. Furthermore, half the patients discontinued therapy based on physicians' recommendation, and it is hard to know why cost would have been a reason in these cases. Unfortunately, the small sample size did not lend itself to a separate analysis of reasons for discontinuation initiated by the physician compared to the patient. The implications are very different in each circumstance. In one case, it is important to know whether physicians are appropriately or inappropriately recommending discontinuation, and on what basis. Lumping reasons for discontinuation initiated by the patient with those initiated by the physician dilutes the ability to analyze patient reasons. Some additional findings of interest include the uses of local and traditional remedies. Reliance on traditional care and its influence on adherence and drug tolerance should be examined more fully.

References

  1. Kirstein LM, Greenblatt RM, Anastos K, Levine A, French AL, Minkoff H, et al. Prevalence and correlates of highly active antiretroviral therapy switching in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 2002 Apr 15;29(5):495-503.
  2. Ahdieh Grant L, Silverberg MJ, Palacio H, Minkoff H, Anastos K, Young MA, et al. Discontinuation of potent antiretroviral therapy: predictive value of and impact on CD4 cell counts and HIV RNA levels. AIDS 2001 Nov 9;15(16):2101-8.
  3. Kumarasamy N, Vallabhaneni S, Cecelia AJ, Yepthomi T, Balakrishnan P, Saghayam S, et al. Reasons for modification of generic highly active antiretroviral therapeutic regimens among patients in southern India. J Acquir Immune Defic Syndr. 2006 Jan 1;41(1):53-8.
  4. Mocroft A, Phillips AN, Soriano V, Rockstroh J, Blaxhult A, Katlama C, et al. Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. AIDS Res Hum Retroviruses 2005 Sep;21(9):743-52.
  5. Mocroft A, Youle M, Moore A, Sabin CA, Madge S, Lepri AC, et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS 2001 Jan 26;15(2):185-94.
  6. Ripamonti D, Arici C, Pezzotti P, Maggiolo F, Ravasio L, Suter F. Hepatitis C infection increases the risk of the modification of first highly active antiretroviral therapy in HIV-infected patients. AIDS 2004 Jan 23;18(2):334-7.
  7. Byakika-Tusiime J, Oyugi JH, Tumwikirize WA, Katabira ET, Mugyenyi PN, Bangsberg DR. Adherence to HIV antiretroviral therapy in HIV+ Ugandan patients purchasing therapy. Int J STD AIDS 2005 Jan;16(1):38-41.
  8. d'arminio Monforte A, Cozzi-Lepri A, Phillips A, De Luca A, Murri R, Mussini C, et al. Interruption of highly active antiretroviral therapy in HIV clinical practice: results from the Italian Cohort of Antiretroviral-Naive Patients. J Acquir Immune Defic Syndr 2005 Apr 1;38(4):407-16.
  9. Bongiovanni M, Bini T, Capetti A, Trovati S, Di Biagio A, Tordato F, et al. Long-term antiretroviral efficacy and safety of lopinavir/ritonavir in HAART-experienced subjects: 4 year follow-up study. AIDS 2005 Nov 4;19(16):1934-6. (No abstract available.)
  10. d'Arminio Monforte A, Lepri AC, Rezza G, Pezzotti P, Antinori A, Phillips AN, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS 2000 Mar 31;14(5):499-507.
  11. Li X, Margolick JB, Conover CS, Badri S, Riddler SA, Witt MD, et al. Interruption and discontinuation of highly active antiretroviral therapy in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2005 Mar 1;38(3):320-8.