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Treatment interruptions predict resistance in HIV positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda
Global Health Sciences Literature Digest
Published May 24, 2007
Journal Article

Oyugi JH, Byakika-Tusiime J, Ragland K, Laeyendecker O, Mugerwa R, Kityo C, Mugyenyi P, Quinn TC, Bangsberg DR. Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda. AIDS 2007 May 11;21(8):965-971.

Objective

To evaluate adherence and immunological and virological treatment outcomes in antiretroviral treatment (ART)-naive, HIV-infected Ugandans initiating self-pay ART with either Triomune or Maxivir, which are both fixed-dose combinations (FDC) of generic stavudine, lamivudine and nevirapine.

Study Design

Prospective observational cohort study with 24 weeks of follow-up. Participants were recruited from pharmacies in Kampala, Uganda between September 2002 and April 2004.

Setting

Kampala, Uganda (urban setting).

Participants

A total of 210 HIV-positive men and women (≥18 years) were approached for this study, of whom 90 were excluded due to residence beyond 15 km from the Kampala city center, 10 due to reported prior ART exposure, six for altered mental status, seven for declining participation, and three due to concern about HIV disclosure. The remaining 97 individuals were included in the study. The majority of the cohort was of Baganda ethnicity (the predominant clan in Kampala district) and female. The mean CD4 count was 56 (SD 130) and the mean viral load was 5.53 log10 copies/µl.

Interventions

Self-pay ART with either Triomune or Maxivir.

Primary Outcome

The primary outcome measures were survival with viral suppression (plasma HIV-RNA levels <400 copies/µl), CD4 cell increases, and genotypic drug resistance at 24 weeks. Adherence to therapy was also measured by unannounced home pill counts, electronic medication monitoring (EMM) and patient report during monthly home visits. Treatment interruptions were measured by EMM and defined as no recorded openings of the EMM caps for 48 hours or longer. Individuals were considered to have discontinued therapy if they did not take any antiretroviral medications for 30 or more days.

Results

Of the 97 participants enrolled, 10 (10%) died during 24 weeks of follow-up. The mean time to death was 49 days (SD ±32) days. Mean adherence ranged from 82% to 95% for all measures, but declined significantly over time. The mean CD4 cell count increase was 116 cells/ µl at 24 weeks. The proportion of participants with plasma HIV-RNA levels of ≤400 copies/ µl was 81.4% and 72.2% at 24 weeks for the as-treated and intent-to-treat analyses, respectively. The proportion of subjects with a plasma HIV-RNA level varied by adherence: 96, 84 and 67% of patients had undetectable levels in the 90-100, 80-89, and 50-79% groups, respectively. In multivariate analysis, only adherence (OR 10.75; 95% CI 3.37-34.10) was associated with survival with viral suppression of <400 copies/ µl. Antiretroviral resistance was seen in 8% of participants. Of the 95 individuals with continuous EMM data, 62 (65%) had a treatment interruption of >48 hours. Treatment interruptions accounted for 90% of missed doses. None of the 33 participants who did not interrupt treatment for over 48 hours has drug resistance, whereas 8 of 62 (13%) participants who did interrupt therapy experienced drug resistance. Forty percent (25/62) of individuals with treatment interruptions cited financial difficulty obtaining medications compared with 15% (5/33) of those without interruptions (X2 6.32, p=0.02). Treatment interruptions were also the result of interruptions in drug supply and were important predictors of drug resistance.

Conclusions

The authors conclude that HIV-positive individuals purchasing generic FDC antiretroviral therapy have high rates of adherence and viral suppression, low rates of antiretroviral resistance, and robust CD4 cell responses. Adherence is an important predictor of survival with full viral suppression. Treatment interruptions are an important predictor of drug resistance.

Quality Rating

Based on the Ottawa-Newcastle rating system for observational cohorts, this study is of good quality. This study was limited by the following factors: home visits may have affected adherence behavior; the study did not have sufficient power to control for variables that may have confounded the association between treatment interruptions greater than 48 hours and drug resistance; and the results may not be generalizable to rural settings or current urban treatment settings with free ART. Self-pay ART was the mainstay of HIV treatment in Uganda during the recruitment period for this study; however, donor-subsidized ART has since expanded rapidly and only 1-2% of Ugandans currently on ART purchase Triomune or Maxivir.

In Context

Consistent with other studies,(1,2,3,4) this study found that adherence was much higher than generally seen in resource-rich settings,(5,6,7,8) although it declined significantly over time. Treatment interruptions were significantly associated with drug resistance, as has been seen in a resource-rich setting.(9) Similarly, treatment interruptions have been associated with virological failure in Uganda.(10) Additionally, this study found that most deaths occurred shortly after treatment initiation, similar to previously reported results.(11)

Programmatic Implications

The findings of this study suggest that treatment interruptions lead to virological rebound and drug resistance and may explain the elevated mortality risk observed for patients on self-pay therapy in resource-limited settings.(12) Logistical interventions to ensure steady and reliable access to ART will be important to minimize HIV drug resistance in resource-limited settings. Additionally, whereas adherence was closely associated with viral suppression, reliable viral suppression occurred at levels of adherence less than the commonly referenced 95% goal,(6) likely reflecting the potency of Triomune and Maxvir in previously ART-naive individuals. Although encouraging, ongoing behavior monitoring and support is needed to sustain adherence and maximize the likelihood of viral suppression.

References

  1. Oyugi JH, Byakika-Tusiime J, Charlebois ED, Kityo C, Mugerwa R, Mugyenyi P, et al. Multiple validated measures of adherence indicate high levels of adherence to generic HIV antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr 2004 Aug 15;36(5):1100-2.
  2. Mills EJ, Nachega JB, Buchan I, Orbinski J, Altaran A, Singh S, et al. Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a meta-analysis. JAMA. 2006 Aug 9;296(6):679-90. Review.
  3. Orrell C, Bangsberg D, Badri M, Wood R. Adherence is not a barrier to successful antiretroviral therapy in South Africa AIDS. 2003 Jun 13;17(9):1369-75.
  4. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue N, Bourgeois A, Calmy A, et al. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004 Jul 3-9;364(9428):29-34.
  5. Bangsberg DR, Deeks SG. Is average adherence to HIV antiretroviral therapy enough? J Gen Intern Med 2002 Oct;17(10):812-3. No abstract available.
  6. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000 Jul 4;133(1):21-30.
  7. Arnsten JH, Demas PA, Farzadegan H, Grant RW, Gourevitch MN, Chang CJ, et al. Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis 2001 Oct 15;33(8):1417-23.
  8. Liu H, Golin CE, Miller LG, Hays RD, Beck K, Sanandaji S, et al. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med 2001 May 15;134(10):968-77.
  9. Parienti J, Massari V, Descamps D, Vabret A, Bouvet E, Larouze B, et al. Predictors of virologic failure and resistance in HIV-infected patients treated with nevirapine- or efavirenz-based antiretroviral therapy. Clin Infect Dis 2004 May 1;38(9):1311-6.
  10. Spacek LA, Shihab HM, Kamya MR, Mwesigire D, Ronald A, Mayanja H, et al. Response to antiretroviral therapy in HIV-infected patients attending a public, urban clinic in Kampala, Uganda. Clin Infect Dis 2006 Jan 15;42(2):252-9.
  11. Laurent C, Ngom Gueye NF, Ndour CT, Gueye PM, Diouf M, Diakhate N, et al. Long-term benefits of highly active antiretroviral therapy in Senegalese HIV-1-infected adults. J Acquir Immune Defic Syndr 2005 Jan 1;38(1):14-7.
  12. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, et al. 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.