Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda
Oyugi, Jessica Ha; Byakika-Tusiime, Jayneb; Ragland, Kathleend; Laeyendecker, Olivere; Mugerwa, Royb; Kityo, Cissyc; Mugyenyi, Peterc; Quinn, Thomas Ce; Bangsberg, David Rd,f
From the aInfectious Diseases Institute, Uganda
bMakerere University, Uganda
cJoint Clinical Research Centre, Kampala, Uganda
dEpidemiology and Prevention Interventions Center, Division of Infectious Diseases, Maryland
eJohns Hopkins University, Baltimore, Maryland
fPositive Health Program, San Francisco General Hospital, UCSF, San Francisco, California.
Received 3 February, 2006
Revised 22 August, 2006
Accepted 6 December, 2006
Correspondence to David R. Bangsberg, MD, MPH, Epidemiology and Prevention Interventions Center, POB 1372, UCSF, San Francisco, CA 94143-1372, USA. E-mail: email@example.com
Objective: To evaluate adherence, treatment interruptions, and outcomes in patients purchasing antiretroviral fixed-dose combination (FDC) therapy.
Design: Ninety-seven participants were recruited into a prospective 24-week observational cohort study of HIV-positive, antiretroviral-naive individuals initiating self-pay Triomune or Maxivir therapy in Kampala, Uganda. Adherence was measured by monthly structured interview, unannounced home pill count, and electronic medication monitors (EMM). Treatment interruptions were measured as continuous intervals greater than 48 h without opening the EMM. The primary outcomes were survival with viral suppression below 400 copies/ml, CD4 cell increases, and genotypic drug resistance at 24 weeks.
Results: The median baseline CD4 cell count was 56 cells/μl and median log10 copies RNA/ml was 5.54; mean adherence ranged from 82 to 95% for all measures but declined significantly over time. In an intent-to-treat analysis, 70 (72%) patients had an undetectable plasma HIV-RNA level at week 24. Sixty-two of 95 (65%) individuals with continuous EMM data had a treatment interruption of greater than 48 h. Treatment interruptions accounted for 90% of missed doses. None of 33 participants who did not interrupt treatment for over 48 h had drug resistance, whereas eight of 62 (13%) participants who did interrupt therapy experienced drug resistance. Antiretroviral resistance was seen in 8% of individuals and overall mortality was 10% at 24 weeks.
Conclusion: 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.
Sub-Saharan Africa hosts more than 70% of the global burden of HIV infection, leading to 8000 HIV-related deaths a day . In Uganda, as in many sub-Saharan African countries, generic fixed-dose combinations (FDC) with lamivudine, stavudine and nevirapine (prescribed as Triomune and Maxivir in Kampala, Uganda) is the first-line antiretroviral regimen. A recent report by Braitstein et al.  indicated that individuals on fully subsidized antiretroviral therapy (ART) have 0.23 less odds of death than patients on self-pay therapy. Estimates suggest that perhaps 1–2% of the 85 000 Ugandans currently on ART purchase generic FDC as Triomune or Maxivir . Self-pay ART was a critical component of early treatment access, and remains a possible approach to accommodate universal access in the absence of donor funding to accommodate free treatment access for all.
We set out to evaluate adherence, immunological and virological treatment outcomes in ART treatment-naive HIV-infected Ugandans initiating self-pay antiretroviral treatment with either Triomune (Cipla Ltd., Mumbai, India manufactured stavudine, lamivudine and nevirapine) or Maxivir (manufactured by Cipla Ltd., and distributed by Okasa Pharmaceuticals Ltd., Vasodara, India). Adherence to therapy was measured by unannounced home pill counts, electronic medication monitoring (EMM; MEMS Track V, Aardex Ltd., Union City, California, USA), and patient report. Survival with viral suppression (plasma HIV-RNA levels < 400 copies/ml) was the primary outcome measure.
Eligibility and recruitment
Individuals initiating self-pay Triomune or Maxivir, at least 18 years of age, residing within 15 km of Kampala city center, and naive to combination HIV ART were recruited into a prospective observational study from pharmacies in Kampala, Uganda, between September 2002 and April 2004. During this time period, the vast majority of patients on ART in Uganda paid for these services. The cost of ART decreased from US$32 to US$17 per month during the study period. Participants received medical care from a variety of clinics in Kampala. As previously described, clients presenting prescriptions for generic ART were consecutively approached by a study research assistant to query interest in participating, assess eligibility criteria, and obtain informed consent . Subsequent data collection including interview, adherence data collection, and phlebotomy was conducted during monthly home visits. All study procedures received ethical approval from Makerere University Faculty of Medicine, the Uganda National Council for Science and Technology, and the University of California San Francisco Institutional Review Board.
Demographic information and psychometric measures
Demographic information and psychometric measures were collected during structured interviews upon enrollment, including the Beck Depression Inventory (BDI) [5,6], the Alcohol Use Disorders Identification Test , and the AIDS Clinical Trials Group symptom severity scale .
Adherence was assessed by EMM, monthly unannounced pill counts conducted at the participants' place of residence, monthly 3-day structured self-report, and monthly 30-day visual analog scale, as previously reported . Participants' antiretroviral medication was placed in the electronic medication monitor upon enrollment. EMM adherence was calculated as one minus the number of pill bottle openings registered/number of doses prescribed between visits. Unannounced pill count was calculated as one minus the number of pills missing between counts/number of pills prescribed between counts. Three-day patient self-report was calculated as one minus the reported number of missed/doses prescribed over the previous 3 days. Thirty-day visual analog scale was estimated from the nearest 5% indicator that the participant marked on a visual analog scale. All adherence data were collected during unscheduled monthly home visits.
Treatment interruption and discontinuation
Treatment interruptions were defined as no recorded openings of the EMM cap for 48 h or longer. Individuals were considered to have discontinued therapy if they did not take any antiretroviral medications for 30 or more days.
Plasma HIV-RNA levels were obtained at baseline, 12 and 24 weeks using the Roche Amplicor assay (Roche Diagnostic Systems Ltd., Branchburg, New Jersey, USA), with a detection limit of 400 copies RNA/ml. CD4 cell count was obtained at baseline and 24 weeks using flow cytometry. Baseline CD4 cell counts were not repeated in patients with documented CD4 cell counts obtained by recognized laboratories within 3 months of treatment initiation. Participants with HIV-RNA levels above 1000 copies/ml at 12 or 24 weeks received genotypic resistance testing using the Trugene assay (Bayer Health Care LLC, Berkeley, California, USA) according to the manufacturer's protocol. Resistance to each antiretroviral medication was determined by entering genotypic changes in the Stanford Resistance Database . Individuals with low, moderate, and high-level resistance were considered resistant for analyses.
Follow-up and retention
After recruitment, a research assistant transported the client home. A hand-drawn map with directions to the participants' residence was created to facilitate follow-up to the participant's home for subsequent data collection. The vehicle used at recruitment and at client follow-up was unmarked and carried no identifying information of the study's activities in attempts to preserve the confidential nature of the visits.
Descriptive statistics and survival rates are reported for the entire cohort. The mean adherence for the cohort is calculated from all available adherence data for each individual alive, active in follow-up, and on ART at 12 and 24 weeks (as treated). Symptoms/side effects are coded as any or none. The prevalence of viral load suppression and antiretroviral resistance was calculated for all individuals alive, active in follow-up, and on ART at 12 and 24 weeks (as treated), as well as for the entire enrolled cohort (intent-to-treat). We defined survival with viral suppression as enrolled in follow-up, alive, and with a viral load of 400 copies RNA/ml or less at 24 weeks. Logistic regression was used to assess predictors of adherence and survival with viral suppression of 400 copies or less at 24 weeks. All variables with P values of 0.25 or less in univariate analysis were included in the multivariate analysis. Items in the AIDS Clinical Trials Group symptom severity scale were coded as any or none. The chi-square test for trend was used to test associations between categorical variables. Based on the work of Spacek et al. , treatment interruptions defined as more than 48 h were used to evaluate the association between treatment interruptions and the risk of resistance. Pearson's correlation coefficient was used to assess the association between adherence and CD4 cell increase at 24 weeks. Adherence at 12 and 24 weeks were compared using a t-test for the difference between 24 and 12 weeks. All data were analysed using the SAS statistical analysis software (SAS Institute, Cary, North Carolina, USA).
A total of 210 individuals were approached for this study. Ninety individuals were excluded because they resided beyond 15 km from Kampala city center. Ten individuals were excluded because they reported previous antiretroviral drug exposure. Six individuals were unable to provide informed consent because of altered mental status. Of 104 eligible individuals, seven (6.7%) declined participation (four people reported being ‘too busy’ and three reported concerns about HIV disclosure) for a total of 97 individuals enrolled. None of the enrolled individuals had received nevirapine as prevention of mother to child transmission or other previous ART.
Demographics and descriptive data at enrollment
Participants initiated therapy at advanced stages of HIV infection with a median CD4 cell count of 56 cells/μl [interquartile range (IQR) ± 130] and median log10 copies RNA/ml of 5.53 (IQR ± 5.76). The majority of the cohort was of Baganda ethnicity (the predominant clan in Kampala district) and female. The mean age was 36 years. Nearly one-quarter of participants were unemployed and paid for therapy by transfers (borrowing money) from other family members or friends. One third of the study participants had completed up to a primary level of education (Table 1).
Survival and retention
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. Five of these participants (50%) died before the second monthly home visit. One participant died as a result of nevirapine-induced hepatotoxicity according to the clinical impression of the treating clinician. The remaining deaths were consistent with complications of advanced AIDS. One participant was lost to follow-up before the second monthly visit because of emigration. After the loss of these 11 patients, the remaining 86 participants had at least 24 weeks of follow-up.
The mean levels of adherence across all measures ranged from 82 to 95% [self-report (93% at 12 weeks and 91% at 24 weeks), 30-day visual analog scale (95% at 12 weeks and 90% at 24 weeks), pill count adherence (90% at 12 weeks and 87% at 24 weeks) and EMM (91% at 12 weeks and 82% at 24 weeks)]. Adherence at 24 weeks was significantly lower than at 12 weeks for 3-day self-report (P = 0.044), 30-day visual analog scale (P = 0.008), pill count (P = 0.002), and EMM (P = < 0.001; Table 2). We did not identify significant predictors of adherence in multivariable analyses including sex, marital status, age, education, employment status, ethnicity, depression, alcohol use, symptom/side-effect severity, household size, income, source of antiretroviral payment, baseline viral load, and baseline CD4 cell count.
Antiretroviral discontinuation and interruption
Seventy participants received FDC ART for 24 weeks. Fourteen participants discontinued or modified therapy by 24 weeks (five switched to a new regimen, six developed tuberculosis and discontinued therapy, two chose to discontinue therapy because of a lack of belief in the drugs, and one discontinued treatment as a result of debilitating peripheral neuropathy). Two died 30 days or more after discontinuing therapy and six individuals re-initiated therapy after a mean discontinuation period of 43.5 days.
Of 95 individuals with continuous EMM data (one was lost to follow-up and one participant had a malfunctioning EMM device), 62 participants (65%) had interruptions of 48 h or greater. On average, there were 2.0 (SD 2.9) interruptions per participant; the average duration for each treatment interruption was 11 days (SD 9.2 days; Table 3). Ninety per cent of all missed doses occurred during a treatment interruption. Forty per cent (25/62) of individuals with treatment interruptions cited financial difficulty obtaining medication during interviews compared with 15% (5/33) of those without interruptions (χ2 6.32; P = 0.02). Otherwise, demographic characteristics, self-reported income, household size, depression, symptom/side-effect severity and alcohol use were not independently associated with treatment interruptions in multivariable analyses.
Client-reported symptom severity
At any time during the 6 months of study follow-up, 33% of participants reported severe symptoms and 73.7% reported moderate to severe symptoms. Cough (68.4%), symptom-defined peripheral neuropathy (65.3%), and self-reported skin rash (69.5%) were the most commonly described symptoms.
Virological and immunological response
The proportion of participants with plasma HIV-RNA levels of 400 copies/ml or less was 81.4% (70/86) and 72.2% (70/97) at 24 weeks for the as-treated and intent-to-treat analyses, respectively. The mean CD4 cell count increase was 116 cells/ml at 24 weeks. At week 24, the proportion of subjects with a plasma HIV-RNA level varied by adherence (96, 84 and 67% of patients had undetectable HIV-RNA levels in the 90–100, 80–89, and 50–79% groups, respectively; Fig. 1). Mean adherence of 90% or greater during 24 weeks follow-up by pill count, visual analog scale and electronic monitoring was significantly associated with plasma HIV-RNA levels below 400 copies RNA/ml (P < 0.0419, P < 0.0237 and P < 0.0410, respectively). The CD4 lymphocyte count increase was also significantly associated with unannounced pill count adherence (P = 0.028).
Survival with viral suppression of 400 copies or less at 24 weeks
For the entire cohort in bivariate analyses, depressive symptoms indicated by a BDI score of 14 or greater [odds ratio (OR) 0.58; 95% confidence interval (CI) 0.23–1.44] and adherence of 90% or greater (OR 7.04; 95% CI 2.61–18.98) had a potential association (P < 0.25) with survival with viral load suppression of 400 copies or less at 24 weeks. Age, sex, pre-treatment viral load, pre-treatment CD4 cell count, and alcohol use were not associated with survival with viral suppression below 400 copies/ml. In multivariate analyses, only adherence (OR 10.75; 95% CI 3.37–34.10) was associated with survival with viral suppression of 400 copies or less.
Genotypic resistance results were obtained for 18 of 19 individuals with a HIV viral loads greater than 1000 copies per ml. Eight individuals had genotypic evidence of antiretroviral drug resistance, corresponding to 8% of those enrolled and 9% among those remaining in follow-up at 24 weeks. All eight individuals had nevirapine resistance (all high level), five had lamivudine resistance (four high level, one intermediate), and three had stavudine resistance (one high level and two low level; Table 4). Additional pre-existing baseline polymorphisms, including M36I in protease and R211K and L214F in reverse transcriptase were also detected in the specimens studied. These polymorphisms are consistent with motifs seen in drug-naive protease and reverse transcriptase from untreated subtype A and D-infected subjects from Uganda .
None of 33 (0%) subjects with continuous treatment (no interruption ≥ 48 h) had drug resistance. This contrasts with eight of 62 subjects (13%) who interrupted therapy for more than 48 h and experienced drug resistance (P = 0.047).
In this prospective study of urban Ugandan patients with advanced AIDS purchasing FDC ART, we found high rates of adherence and viral suppression. Treatment interruptions of more than 48 h, largely as a result of financial or structural barriers of securing treatment, explained 90% of all missed doses and predicted drug resistance. Mortality at 24 weeks was 10% and most deaths occurred shortly after treatment initiation, similar to previously reported results .
During our recruitment period between 2002 and 2004, self-pay ART was the mainstay of HIV treatment and preceded the rapid scale-up of donor-subsidized ART that has since occurred in Uganda. Consistent with other reports [4,13–15], adherence was much higher than generally seen in resource-rich settings [16–19]. Nonetheless, adherence declined significantly over 24 weeks. This decline may be related to difficulties in meeting increasing financial demands of therapy over time [20–22]. It is possible that adherence might decline further after 24 weeks of follow-up as health benefits plateau and long-term toxicities develop .
Treatment interruptions, documented by gaps in continuous electronic monitoring, were significantly associated with drug resistance. Parienti et al.  similarly found that patient-reported interruptions were associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance in a resource-rich setting, and Spacek et al.  found that patient-reported treatment interruptions was associated with virological failure in Uganda. The long half-life of NNRTI may lead to effective monotherapy during a treatment interruption. This may be relevant particularly in individuals of African descent who have single nucleotide polymorphisms associated with decreased NNRTI clearance [25–27]. Byakika-Tusiime et al.  found that treatment interruptions were associated with financial barriers of securing therapy and competing family financial demands such as children's school fees and funeral costs for relatives. These interruptions in treatment, leading to virological rebound and drug resistance, may explain the elevated mortality risk observed for patients on self-pay therapy in resource-limited settings .
Additional treatment interruptions were related to disruptions in drug supply. At one point during the study, confusion between Uganda customs authorities and the National Drug Authority prevented the proper clearance of Triomune from Entebbe International Airport. This resulted in a nationwide shortage and a lack of treatment for individuals picking up refills over a 2-week period. Similar reported shortage of medications and financial constraints were important barriers to sustained self-pay therapy in Malawi .
We previously suggested that financial and logistical barriers to drug access, such as these, should not be considered non-adherence because adherence to therapy presumes access to therapy [20,21,23]. These results suggest that steady and reliable access to medications, in order to avoid treatment interruptions, will be critical to limiting the development of drug resistance in resource-limited settings.
Whereas adherence was closely associated with viral suppression, reliable viral suppression occurred at levels of adherence less than the commonly referenced 95% goal . Eighty-four per cent of individuals were suppressed at 80–90% adherence and 67% of individuals were suppressed at 50–79% adherence. These high rates of viral suppression are probably a result of the combination of an antiretroviral-naive population receiving a potent antiretroviral regimen. Early studies of adherence and viral suppression in resource-rich environments were conducted in largely treatment-experienced populations with partly suppressive regimens. Although we advocate the highest adherence possible to maximize the probability of viral suppression, more potent regimens, including NNRTI, are capable of better viral suppression at moderate (80–90%) adherence [29,30].
We were unable to detect statistically significant predictors of adherence because of the relatively narrow range of adherence and the small sample. Self-reported income, an insensitive measure of household socioeconomic status in resource-limited settings , was not associated with either adherence or treatment interruptions, although financial challenges securing therapy were the most commonly cited reasons for treatment interruptions.
There are several limitations to our study. It is possible that the home visits may have affected adherence behavior. We have, however, been unable to detect an association between receipts of home visits and improved viral suppression in previous studies . Although we found that treatment interruptions of greater than 48 h were associated with drug resistance, we did not have sufficient power to control for potential confounders. Whereas patients frequently reported HIV-related symptoms, including cough, neuropathy and rash, we could not distinguish whether these symptoms existed before antiretroviral treatment and were unrelated to medications. Finally, our results may not be generalizable to rural settings that comprise nearly 90% of Uganda's population or current urban treatment settings. The generalizability of our results is also limited because HIV treatment access in Uganda has changed significantly since this study with the expansion of free ART access provided by donor programmes.
In conclusion, we found that individuals purchasing generic HIV ART had high levels of adherence and viral suppression. Adherence was strongly associated with survival with viral suppression of less than 400 copies/ml at 24 weeks. Although participants demonstrated high levels of adherence, there was a significant decline over time. Treatment interruptions of more than 48 h, largely as a result of patient-reported financial challenges in securing self-pay therapy or interruptions in drug supply were an important predictor of drug resistance. These findings suggest that logistical interventions to ensure steady and reliable access to ART along with behavioral monitoring and support to sustain adherence will be important to minimize HIV drug resistance in resource-limited settings.
The authors would like to thank Dr Steven G. Deeks for comments on the manuscript as well as Annet Kawuma, Mary Kasango, and Irene Zawedde for participant recruitment, data collection and data management.
Sponsorship: This work was supported partly by the National Institutes of Health (NIMHRO-1 54907, NIMHRO-3 66654, NIAAA R-21 014784, NIAAA K-24 015287), the UCSF Center for AIDS Research (P30 MH59037), and the Doris Duke Charitable Foundation.
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Adherence; Africa; antiretroviral treatment; finances; fixed-dose combination; generic; HIV/AIDS; resistance; treatment interruptions
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