To our knowledge, this is one of the first longitudinal HIV immuno-virologic outcome and immuno-virologic discordance study done in large multi-center non-research public health facilities in Nigeria. Although favorable immuno-virologic outcomes could be achieved in this large ART program in which over half of the patients are on TDF-containing first-line, immuno-virologic discordance was observed in a third of the patients. Our findings provide important insights into specific predictors of immuno-virologic outcomes that are important for optimizing treatment strategies.
The patients were predominantly female reflecting the long standing feminization of the HIV epidemic in Nigeria , better health seeking behavior of women and possibly the linkage of treatment sites with the antenatal clinics and the prevention-of-mother-to-child HIV programs. Our study demonstrated that patients with higher baseline CD4 cell counts were statistically significantly more likely to have viral suppression at 12 months; a result in agreement with numerous other studies [19, 20]. This well-known trend of late presentation and poorer male outcomes because of poor health seeking behavior of men  deserves renewed focus as male involvement in health program could improve decision-making not only for the men themselves but also for the women and children who live in male dominated societies. Men may need to be reached by new strategies for HIV voluntary counseling and testing focused on work and leisure sites frequently visited by men, flexible clinic hours for working men in addition to more aggressive mobilization campaigns targeted to men.
While many others had published on virologic outcomes results in Nigeria showing 62%-70% virologic suppression rates, they are mostly derived from a research setting [22–24]. The virologic suppression rate of 77% seen in this analysis is one of the first and the best seen in a large HIV treatment program from Nigeria and is consistent with a large review of 89 studies of antiretroviral programs in sub-Saharan Africa which showed a pooled virologic suppression rate of 76% at 12 months . The robust immunologic response of > 50 cells / mm3 was seen in 77.4% of patients at 12 months with a median CD4 cell count increase of 139 cells / mm3 which is consistent with results obtained in other programs in similar settings [26, 27]. Since more than half of the entire patient cohort were on a Tenofovir-containing regimen which is known for its superiority, convenient dosing, low toxicity and high potency [28–30], we were expecting a lower virologic failure rate than 23%. However, there were no statistically significant differences in virologic suppression by baseline drug regimen among this study cohort. These encouraging results confirm that favorable virologic and immunologic outcomes can be obtained from government-run busy large public health HIV treatment programs through technical assistance of PEPFAR implementing partners.
The finding of a strong association of virologic failure with anemia is noteworthy. Previous studies have associated anemia with poorer survival [31–33] and our findings suggest a 71% increased odds of virologic failure with anemia at baseline in addition to a 80% increased odds of virologic discordance. Apart from anemia caused by HIV itself and malnutrition, malaria and chronic helminthiasis are two most common causes of anemia in adults that respond to potent chemo-therapeutic interventions. Thus identifying and managing adults with anemia at baseline when HAART is being initiated as well as providing anti-helminthics can improve anemia and possibly retention and virologic outcome. A systematic review of 43 studies on the impact of hookworm infestation and anemia showed that treating non-pregnant adults with a combination of albendazole and praziquantel will increase hemoglobin level by a mean of 2.87 g/dl . Based on the strong association of virologic failure and VL-/CD4+ discordance and anemia obtained in our study, chronic infections with anemia may be interfering with immuno-virologic recovery on HAART. We therefore recommend that a comprehensive treatment preparation and nutritional counseling program include anemia screening and management incorporating malaria and chronic helminthiasis treatment and provision of hematinics as a priority around the time of HAART initiation.
Younger age < 30 years was significantly associated with 79% increased odds of virologic failure and 50% increased odds of immunologic failure. A majority of studies including one previous evaluation of the ACTION program in Nigeria demonstrated an association between adherence and improved outcomes increasing with age [35–37]. Young people are more likely to be single, engage in high risk behaviors, lack social capital, financial ability and maturity [38–40] and thus should be prioritized in treatment preparation and adherence support programs.
Most studies including an extensive review of barriers to accessing HIV treatment and negative treatment outcomes suggest that longer distances from treatment sites are associated with poorer outcomes [37, 41]. In our study, it appears that compared to those living less than 50 miles of the treatment site, those who lived 50–100 kilometers away had a 56% significantly decreased odds of virologic failure while those who lived the farthest (> 100 kilometers) had a 37% increased odds of virologic failure that was not significant. Since most Nigerians live close to the more than 300 HIV treatment sites in the country, it appears that adherent patients who travel > 50 kilometers to treatment centers make the personal choice to travel that long distance and are probably more motivated than patients who live close to the clinic. However, the farther the patients reside (> 100 kilometers) the greater the difficulty of handling the logistic and financial challenge of a far residential distance. A sub-analysis of our data confirmed that drug adherence by pharmacy refill visits was significantly best in the category of patients who live 50–100 kilometers from the treatment sites.
Even though socio-economic status have been linked to HIV treatment outcomes [42–44], our study surprisingly did not suggest an association between socio-economic or behavioral predictors to virologic failure. The most important impact of SES on HIV treatment is on the cost of the HIV drugs, laboratory work-up and the commodities. Under PEPFAR, HIV drugs and commodities (nutrition, bed-nets, and laboratory tests) are free in Nigeria; SES does not determine access to drugs and services possibly accounting for the lack of association. This may change in coming years as donors push for more country ownership of programs like PEPFAR with a greater share of costs supported by the public sectors. Educational achievement, particularly post-secondary education which has been previously associated with positive treatment outcomes [37, 45] was associated with a 47% significantly reduced odds of virologic failure and 64% reduced odds of virologic discordance.
Immunologic failure normally occurs after virologic failure and can subsequently co-exist with each other. However, the associations of virologic and immunologic failure can differ since both conditions can also exist independently . In our study, an increased odds of immunologic failure and immunologic discordance was associated with male gender. Male gender has been consistently associated with poor health seeking behaviors [47, 48], lower baseline CD4 count levels and poor HIV treatment outcomes [37, 49]. This underlines again the necessity of making many health care facilities male-friendly and encouraging male peer-support systems as well as investing in research and programs that adequately engage males and seek to positively influence the health-seeking behavior of men.
Immuno-virologic discordance has been defined and studied in multiple settings mainly in resource-rich countries and has been associated with co-infections (especially Cytomegalovirus infections), age, lower baseline CD4 cell count, poor adherence and high mortality [15, 50–52]. In our study, the presence of other viral infections were not tested and only age and educational achievement was associated with immuno-discordance and no associations were seen with tuberculosis history and baseline CD4 counts as expected. Unfortunately, tuberculosis history was not consistently obtained and objective screening tests were not routinely performed as indicated.
In addition, our study results strongly suggest that viral load testing should be incorporated into routine patient care, both at baseline and at least every 6 months. Without viral load results, 16% (n=90) of our study population would be switched to a second line ART regimen on the basis of their CD4 count results even though they had sustained viral suppression. Conversely, 17% (n=94) of our study population who were eligible for second line ART regimen would have continued on first line therapy inappropriately, also based on their CD4 count result only. This confirms the results of many studies that CD4 cell count alone is a poor predictor of virologic and clinical failure and an unreliable guide to appropriate clinical management of HIV infected patients on antiretroviral therapy [53–55]. Viral load and CD4 measurements when done together will help in further identifying and characterizing immuno-virologic discordance which has been associated with increased risk of AIDS events and mortality [50, 56]. In the Development of Antiretroviral Therapy in Africa (DART) trial  which was done in a clinical trials setting unlike the current study, clinical monitoring alone had a 31% increase in disease progression and mortality compared to clinical monitoring with routine laboratory monitoring implying benefit albeit small associated with prompt switching to second-line therapy.
Limitations of this study include less than ideal follow-up time (12 months), issues with measurement error, missing data and possible administrative error in recording variables common in busy government hospitals in resource-constrained settings. We use unimputed data and assumed all missing variables were missing completely at random (MCAR) and confirmed this assumption by doing multiple imputations (using sequential regression multivariate imputation (SRMI) method) which produced similar results. There were no baseline HIV RNA viral load results and all patients are expected to have high viral loads at baseline. However, we expect patients fully adherent on potent HAART regimen to be undetectable at 12 months after commencement of therapy. This study was conducted in non-pregnant adults and may not be generalizable to pregnant women and children. This study has some unique strengths including its clinic-based cohort design with validated immunologic and virologic results even though viral load testing were not routinely performed in this program. The selection of different levels of care and different locations serving different populations improved the generalizability of our findings. In addition, since Tenofovir is not a common first line drug in ART programs in Africa, these results could provide additional information on programs that predominantly use this drug in low and middle income countries.