Original research article

Antiretroviral treatment failure predicts mortality in rural Tanzania

International Journal of STD & AIDS 2015, Vol. 26(9) 633–639 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414548460 std.sagepub.com

Pernille S Pettersen1, Ida K Brox1, Ezra Naman2, Johan N Bruun3, Anne M Dyrhol-Riise1,4, Marius Trøseid4 and Asgeir Johannessen4,5

Abstract Virological monitoring of HIV-infected patients on antiretroviral treatment (ART) is rarely available in resource-limited settings and many patients experience unrecognized virological failure. We studied the long-term consequences of virological failure in rural Tanzania. Previously, virological efficacy was measured in a cohort treated with ART. In the present study, patients with virological failure (VF; HIV-RNA >400 copies/ml) were followed up and compared to those with virological response (VR; HIV-RNA 400 copies/ml) and were included in our study (Figure 2). For each patient with virological failure, another patient with virological response (VR) was selected by choosing the patient with the closest hospital ID number who had HIV-RNA < 400 copies/ml. The two groups ended up uneven because some patients with presumed VF were excluded post hoc (due to misclassification or unconfirmed treatment failure). Baseline was defined as the date when VF or VR was first confirmed. All patients were followed up until August 2011. Blood samples for viral load testing were collected in July and August 2011, when patients attended their monthly control. For those who died, were transferred out, lost to follow-up or missing, the follow-up time was right-censored at the date of the last known contact with the clinic (Figure 1). Demographic, clinical (death) and immunological (CD4 T-cell counts) data were collected from medical charts at the clinic. Death during the follow-up time was ascertained by homevisitors. All data were typed and stored anonymously in the study database. The National Institute for Medical Research in Tanzania and the Regional Committee for Medical Research Ethics in Norway granted ethical approval, and all patients gave written consent to participate in the study.

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Pettersen et al.

635

236 children and adults obtained viral load in cohort study from 2007-201014,15

180 with viral load 400 copies/ml

8 died 10 transferred out 3 lost to follow-up

1 died 25 transferred out 0 lost to follow-up

35 eligible for viral load tesng

37 eligible for viral load tesng

12 missed

5 missed

25 obtained viral load

30 obtained viral load

18 with viral load >400 copies/ml

12 with viral load 400 copies / ml

20 with viral load 1000 copies/ml were tested. Only drug resistance mutations listed in the Spring 2008 update from the International AIDS Society were considered.12 Resistance profiles to antiretroviral drugs were interpreted according to the Stanford University HIV Drug Resistance Database.13 Plasma samples for virological analyses were centrifuged within 1 h of venipuncture, and frozen at 20 C. The samples were transported at ambient temperature for less than 20 h to the reference laboratories, in accordance with the manufacturer’s instructions.

Statistical methods Mann–Whitney U test was used for comparison of continuous data throughout, since some of the data were

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636

International Journal of STD & AIDS 26(9)

not normally distributed. Continuous data were presented as median values and corresponding interquartile range (IQR). Categorical data were summarized using proportion. The main three endpoints of interest in this study were death, subsequent virological failure and immunological progression. CD4 cell counts were plotted every six months, using the nearest measurement (3 months). Difference in clinical and virological outcome was analysed using Chi-squared test or Fisher’s exact test as appropriate. Risk of mortality was calculated with logistical regression. Differences in progression of CD4 T-cell count between the groups were analysed with Mann–Whitney U test. SPSS version 19.0 (SPSS Inc., Chicago, IL, USA) was used for all the analyses. All tests were two-sided and the level of significance was set at p < 0.05.

(IQR 18–44). Twenty-five of the 56 patients with VF (45%) switched to second-line treatment after recognition of virological failure. None of the patients in the VR group changed to second-line ART. Median time from viral load testing to treatment switch was seven months (IQR 4–11). Reasons for late switching or not switching included delayed reporting of laboratory results, patient’s refusal and clinician’s discretion. All patients switched to a regimen based on a boosted protease inhibitor (lopinavir/ritonavir).

Clinical outcome During the follow-up time, nine patients died (7.6%), three were lost to follow-up for more than 12 months (2.5%) and 35 were transferred to other clinics (29.4%). Seventeen patients (14.3%) still in care did not attend during collection of blood samples. The study profile is presented in Figure 2. The proportion who died in the VF group (8 of 56, 14.3%) was significantly higher than in the VR group (1 of 63, 1.6%; p ¼ 0.009; Table 2), giving an odds ratio (OR) of 10.3 (95% confidence interval [CI] 2.1–85). Multivariate adjustments were not justified due to

Results Population characteristics In total, 119 patients were included in the present study: 56 with VF and 63 with VR. The demographic, clinical and laboratory characteristics of the study population at baseline are presented in Table 1. There were no significant differences between the two groups with regard to gender, ART duration prior to virological testing, or median CD4 T-cell count at the time of virological testing; however, there were significantly more children (15 years) in the VF group (p < 0.001; Table 1). Time on ART before first viral load testing was 29 months for the VF group (IQR 22–36) and 25 months for the VR group (IQR 14–34). Median follow-up time after baseline was 28 months for the VF group (IQR 18–42) and 40 months for the VR group

Table 2. Clinical and virological outcome during follow-up.

N Deaths during follow-up HIV-1 RNA test during follow-up, N With viral suppression

Virological failure

Virological response

56 8 (14.3%) 30

63 1 (1.6%) 25

– 0.009

12 (40%)

20 (80%)

0.003

P

Table 1. Patient characteristics at the time of virological testing.

N Female Age 15 >15 Time on ART prior to virological testing, months (IQR) CD4 count (cells/ml), median (IQR) HIV-1 RNA viral load (copies/ml), median (IQR) Genotypic resistance test, N With drug resistance Switched to 2nd line ART

Virological failure

Virological response

P

56 36 (64%)

63 49 (78%)

– 0.104

18 (32%) 38 (68%) 29 (22–36) 358 (223–635) 13,573 (2326–129,736) 47 34 (72%) 25 (45%)

3 (5%) 60 (95%) 25 (14–34) 499 (290–636) 0 0 0 0

Antiretroviral treatment failure predicts mortality in rural Tanzania.

Virological monitoring of HIV-infected patients on antiretroviral treatment (ART) is rarely available in resource-limited settings and many patients e...
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