Kamya MR, Mayanja-Kizza H, Kambugu A, Bakeera-Kitaka S, Semitala F, Mwebaze-Songa P, et al. Predictors of long-term viral failure among Ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):187-93.
To identify predictors of viral failure and document genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART).
This was a longitudinal study in which enrolled patients were followed for 12 months.
The study took place at the Makerere University Infectious Diseases Institute (IDI) in Kampala, Uganda. Care has been provided free of charge since 2004, including HIV counseling, treatment of HIV-related complications, laboratory testing (confirmatory HIV-1 testing, complete blood count [CBC], and CD4 lymphocyte count), cotrimoxazole prophylaxis, and ART for patients with a CD4 count <200 cells/mm3 or WHO clinical stage IV disease.
Study participants were ART-naive patients beginning treatment at a university clinic from April 2004 through June 2005. Convenience sampling was used to enroll adults and children (age 18 and under) with confirmed HIV-1 infection, at least two clinic visits in the preceding six months, stable residence within 20 km of Kampala, willingness to receive care exclusively at the IDI for two years, and informed consent.
The primary outcome measured for this study was virologic failure, defined as an RNA level ≥400 copies/mL 12 months after starting ART or a change to second-line ART after an RNA level ≥400 copies/mL before 12 months. Secondary outcomes included CD4 cell response, weight gain, adherence, mean corpuscular volume change, and drug resistance.
Patients were to receive care exclusively at the IDI for two years, and to follow the treatment regimen there. ART consisted of a generic fixed dose combination of weight-adjusted stavudine (d4T), lamivudine (3TC), and nevirapine (NVP), or combined branded zidovudine (ZDV) and lamivudine plus efavirenz (EFV). Single drug substitutions were made according to WHO guidelines. Adherence was supported by at least three individual and group counseling sessions and encouragement to designate a treatment supporter. Medical care included monthly visits for counseling and prescriptions, at least quarterly physician evaluations, and CBC/CD4 count tests every six months. Because of limited ART choices, regimen changes for clinical, immunologic, or viral failure were postponed to 12 months after starting ART, although adherence was emphasized at antecedent visits. CD4 counts were determined by FACS Count and FACS Caliber (Becton Dickinson), and HIV RNA levels was measured by Amplicor HIV-1 Monitor polymerase chain reaction test (Roche) with a lower limit of detection of 400 copies/ml. CBCs were done by Coulter (Beckman Coulter). Genotypic sequencing was performed by Davis Sequencing at the University of California at Davis, and resistance mutations were analyzed with the Stanford University HIV Drug Resistance Databases.
Patient characteristics: A total of 776 patients were enrolled (526 adults and 250 children). The median CD4 count was 99 cells/mm3 for adults and 8.6% for children. The mean body weight was 55 (±10.5) kg for adults and 20 (±9.6) kg for children. Of the 776 patients followed for 12 months, 79 (10%) died, 50 within the first three months of initiating ART. After loss to follow-up, withdraw of consent, and missing virologic data, a total of 676 patients remained for analysis.
Predictors of viral response: Viral suppression was more common in adults compared to children (392 [86%] of 454 vs. 164 [74%] of 222, p<0.001), although this difference diminished if those who died or were lost to follow-up were counted as ART failures (75% vs. 69%, p=0.11). Overall, 74 (62%) of 120 patients with viral failure had viral loads of >10,000 copies/ml. In adults, the only independent predictor of viral failure was treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (odds ratio [OR] 2.59, 95% confidence interval [CI] 1.2-5.59, p=0.02). In children, independent predictors of viral failure included male gender (OR: 2.44, 95% CI: 1.20-4.93, p=0.01), having a baseline CD4%<5 (OR: 2.69, 95% CI: 1.28-5.63, p=0.009), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR: 2.46, 95% CI: 1.23-4.90, p=0.01). Findings were similar with and without the excluded patients classified as viral failures.
CD4 T-Cell responses: The CD4 count at 12 months was greater than the baseline value in 408 (90%) of 454 adult patients and 173 (98%) of 177 pediatric patients. The mean increase in the CD4 lymphocyte count at 12 months among adult patients with viral suppression (131.4 cells/mm3) was not significantly different from that in patients with viral failure (123 cells/mm3). The mean increase in CD4% at 12 months among children with viral suppression (14.7%) was significantly greater than those with viral failure (11.3%, p=0.01).
Weight gain: Median body weight increases of 5.0 kg (interquartile range [IQR]: 1.0 to 9.0) and 3.5 kg (IQR: 2.1 to 5.1) were seen in adults and children, respectively. There were no significant differences in weight gain in suppressed and unsuppressed patients for both adults and children.
Adherence: Using the visual analog scale, more than 98% of patients reported 100% adherence at six months. In both adults and children, there were no differences in reported levels of adherence between those with viral suppression and those with viral failure at 12 months.
Mean corpuscular volume changes: Adults with viral failure had significantly smaller mean increase in MCV of red blood cells compared to those with viral suppression (5.6±2.4 fL vs 14.5±0.4 fL, p<0.001). This finding was also true for children (8.0±1.2 fL vs 12.0±0.7 fL, p=0.0012).
Drug resistance: Of the 116 participants with detectable viral loads 12 months after ART initiation, eight resistance results were done, and all eight had NNRTI resistance mutations with the most common being K103N (n=5). All also had the 3TC-associated mutation M184V, and two had the thymidine analog mutation (TAM) T215Y. None of the four patients with baseline genotypic testing had detectable antecedent resistant mutations.
The authors conclude that these data demonstrate the effectiveness of ART in a low-resource setting, that the d4T/3TC/NVP drug regimen was associated with higher rates of viral failure in adults and children, and that viral failure occurring six months or more after ART initiation with regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.
Using the relevant aspects of the Newcastle-Ottawa criteria for evaluating the quality of longitudinal observational studies, this study was of high quality. There was very low loss to follow-up (0.8%) and ascertainment of exposure was reliable. The authors note that their results may not be generalizable, as participants received close medical attention at no cost. However, generalizability is supported by the fact that more than 90% of ART in sub-Saharan Africa was initiated within two years of the study cohort and includes the same compounds and patients with similar viral clades. Because the study was not randomized, interpretation of differences in ART regimens should be made with caution. Additionally, laboratory results reflect single, unconfirmed measurements, which may have been erroneous, although strong concordance was seen between the 6- and 12-month results. Genotypic resistance results were also drawn from a small sample and may or may not be representative.
With the unprecedented speed of the rollout of ART in sub-Saharan Africa, clinical monitoring of patients initiating ART is of paramount importance. The WHO recommends immunologic monitoring of treatment efficiency;(1) however, HIV RNA viral load testing is costly and often not available in low-resource settings. The authors sought to identify predictors of virologic failure, as this is the primary endpoint used to guide ART decision-making in the West and the best measure of the risk of viral resistance.(2) Viral suppression rates in this study are consistent with other experiences in resource-limited settings.(3,4,5,6,7,8) Additionally, advanced stage of disease at the initiation of ART has been connected with increased early mortality, and a low CD4 count at ART initiation has been associated with a relatively poor probability of a good virologic response in other studies.(9,10,11)
The authors note that the results of this study highlight two important features of the sub-Saharan Africa ART rollout: high early mortality and high early viral suppression. Because the high early mortality is generally a result of advanced HIV disease at the initiation of treatment, ART distribution programs should focus future efforts on starting treatment earlier. The high viral suppression rates in this resource-limited setting are very encouraging; however, longer follow-up is needed to determine the sustainability of suppression and should include more thorough measures of adherence. Randomized comparison of ART regimens would also be useful, especially given the common use of d4T/3TC/NVP, as would further study of the lower viral suppression rate in boys compared to girls. Additionally, TAMs are known to accumulate in persons with viral failure and continued exposure to d4T and ZDV, leading to the development of drug resistance.Further efforts should thus focus on developing affordable methods for early detection of viral failure and consideration of less expensive drug resistance testing targeted at K103 and M184 mutations.
- World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings: Towards Universal Access. Geneva, Switzerland: World Health Organization; 2006. No abstract available.
- Smith CJ, Staszewski S, Sabin CA, et al. Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals. J Acquir Immune Defic Syndr 2004;37:1155-1159.
- Marins JR, Jamal LF, Chen SY, et al. Dramatic improvement in survival among adult Brazilian AIDS patients. AIDS 2003;17:1675-1682.
- Djomand G, Roels T, Ellerbrock T, et al. Virologic and immunologic outcomes and programmatic challenges of an antiretroviral treatment pilot project in Abidjan, Côte d'Ivoire. AIDS 2003;17(Suppl 3):S5-S15.
- Laurent C, Diakhate N, Gueye NF, et al. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS 2002;16:1363-1370.
- Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, et al. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet 2002 Jul 6;360(9326):34-40.
- Ivers LC, Kendrick D, Doucette K. Efficacy of antiretroviral therapy programs in resource-poor settings: a meta-analysis of the published literature. Clin Infect Dis 2005;41:217-224.
- Etard JF, Ndiaye I, Thierry-Mieg M, et al. Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study. AIDS 2006;20:1181-1189.
- Gadelha AJ, Accacio N, Costa RL, et al. Morbidity and survival in advanced AIDS in Rio de Janeiro, Brazil. Rev Inst Med Trop Sao Paulo 2002;44:179-186.
- Romanelli RM, Pinto JA, Melo LJ, Vasconcelos MA, Pereira Rde M. Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children. J Pediatr (Rio J). 2006;82:260-265.
- Richman DD, Guatelli JC, Grimes J, et al. Detection of mutations associated with zidovudine resistance in human immunodeficiency virus by use of the polymerase chain reaction. J Infect Dis. 1991;164:1075-1081. No abstract available.