Nachega JB, Hislop M, Dowdy DW, Lo M, Omer SB, Regensberg L, Chaisson RE, Maartens G.Adherence to Highly Active Antiretroviral Therapy Assessed by Pharmacy Claims Predicts Survival in HIV-Infected South African Adults. J Acquir Immune Defic Syndr. 2006 Sep;43(1):78-84.
To evaluate the association between highly active antiretroviral therapy (HAART) adherence, as estimated by pharmacy claims and survival, in HIV-1 infected South African adults enrolled in a private-sector AIDS management program.
This prospective cohort study took place from January 1999 to August 2004.
The study was conducted at a private-sector disease-management program available to beneficiaries of contracted medical insurance funds in South Africa.
All adult (18 years or older) HAART-naive patients who claimed at least one month of HAART between January 1999 and March 2003 were enrolled. In an effort to minimize bias due to patients who entered the program with terminal illness, all those who died before completing at least 180 days of HAART were excluded from the primary analysis.
There was no intervention in this study.
All-cause mortality was the primary outcome. Deaths were identified from the attending medical practitioner, the hospital case manager, or the medical fund administrator. Adherence was defined as the number of months with claims, divided by the number of complete months between the date of HAART initiation and either death, withdrawal from the insurance plan, or the study's end. The secondary outcomes included death or loss to follow up, and 12-month adherence, defined as the total months of HAART claimed during the first 12 months of therapy (this was by definition restricted to patients who survived for at least 12 months).
A total of 6288 patients were eligible for the study (11,623 person-years), 61% of whom were female. The median follow-up time was 1.8 years, and the median age was 37. The median CD4 cell count at initiation was 149 cells/µL, and the median HIV-1 RNA level was 5.16 log10 copies/µL. HAART adherence was ≥80% for 3298 patients (52%) and 100% for 1916 patients (30%). High adherence (≥80%) was associated with female gender, older age, and later enrollment in the study. In bivariate analysis, <80% adherence was significantly associated with poorer survival compared to those with high adherence (relative hazard ratio 3.01, CI: 2.2-4.1). Below 80% adherence, there was a dose-response relationship between adherence and survival. At longer lag periods (the time during which deaths and loss to follow-up were ignored after initiating HAART) the point estimate of the association between adherence and survival continued to increase. In multivariate analysis, only adherence <80% (RH 3.23, CI: 2.4-4.4) and CD4 cell count <50 cells/µL (RH 2.54, CI: 1.8-3.6) remained significantly associated with decreased survival. Median 12-month adherence (n=3267) was 83%, and adherence of ≥80% at 12 months was predictive of the same level of adherence at the end of the study, and was significantly predictive of subsequent mortality (adjusted RH: 3.64, CI: 2.3-5.8). Although the interaction terms were not significant, the effect of poor adherence on survival was greatest among those with low CD4 count.
The authors conclude that HAART adherence of ≥80% as measured by pharmacy claims is associated with a three-fold decrease in mortality hazard among HIV-1-infected South African adults. They state that these data suggest that pharmacy claims are valid indicators of HAART adherence and that measures of adherence based on such data may be a useful tool for population monitoring of adherence.
Using the Newcastle-Ottawa (NOS) criteria for evaluating cohort studies based on selection, comparability and outcomes, this study receives an adequate quality rating. The exposed cohort (adherence ≥80%) and the unexposed cohort were drawn from the same population, and potential confounding factors such as CD4 count and HIV viral load were controlled for. The ascertainment of exposure through pharmacy billing records could have resulted in underestimation of adherence if patients acquired medications from other sources or did not submit claims, or in overestimation of adherence if claims were submitted but medications were not ingested. The primary outcome (survival) was assessed independently through physician or insurance reports. The authors did not report on the baseline clinical or demographic characteristics of those lost to follow up (18% of the patients enrolled). In addition to the NOS criteria, the authors mention the following limitations: they did not assess adherence in finer intervals than 20%, so mortality data must be interpreted with caution, as it is assumed to be homogeneous within these 20% intervals; furthermore, it is possible that the data are subject to reverse causation, as patients may stop taking medication for reasons related to poorer survival.
Compared to studies of adherence using pharmacy data in developed countries, and to other studies of adherence in sub-Saharan Africa, adherence rates in this study were relatively low.(1,2,3)
With the influx of funding for HAART in developing countries, monitoring methods are needed for evaluation of distribution programs. While only a minority of Africans have private health insurance, pharmacy data could also be used by public sector programs to track and monitor adherence, as has been done in Brazil.
Hogg RS, Heath K, Bangsberg D, Yip B, Press N, O'Shaughnessy MV, Montaner JS. Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS. 2002 May 3;16(7):1051-8.
- Laurent C, Diakhate N, Gueye NF, Toure MA, Sow PS, Faye MA, Gueye M, Laniece I, Toure Kane C, Liegeois F, Vergne L, Mboup S, Badiane S, Ndoye I, Delaporte E.
The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS. 2002 Jul 5;16(10):1363-70.
Oyugi JH, Byakika-Tusiime J, Charlebois ED, Kityo C, Mugerwa R, Mugyenyi P, Bangsberg DR.
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.