Among 3508 HIV-infected, ART-naïve adults screened for enrollment to five HIV clinical trials conducted in Lilongwe, Malawi, we found that CrCl<50 ml/min was rare, suggesting that few patients would be excluded from receiving the public provision of TDF-based antiretroviral regimen based on this criteria. The small proportion of patients with low CrCl is comparable to other studies assessing CrCl in HIV positive individuals in populations similar to ours 
Our pooled study population provides the most comprehensive and representative data on CrCl among HIV-infected, ART-naïve patients eligible for PMTCT or ART in Lilongwe, since screening recruitment for each trial had an extensive outreach component targeting PMTCT or ART eligible individuals. The pooled data indicate that most eligible HIV-infected, ART-naïve patients would not be excluded from the proposed TDF-based, first-line ART and PMTCT regimen based on CrCl criteria. Therefore, broad implementation of a fixed-dose, combination tablet as a first-line ART likely does not require assessment of baseline CrCl in resource-constrained settings, particularly for healthy pregnant females.
Many indicators suggest our population is comparable to other HIV-infected, ART-naïve cohorts within Malawi. Studies conducted in the PMTCT populations of Thyolo District Hospital located in rural Malawi have shown the median age of PMTCT study participants is 22 years, making our study sample of comparable age to other Malawian PMTCT cohorts 
. A large study of over 13,000 individuals at two ART clinics in Lilongwe indicated that the majority of individuals seeking care were young females. While our study oversamples females due to using data from the BAN clinical trial, females represent 60% of those seeking ART nationally and higher proportions are expected when PMTCT is used as an entry point to ART.
Our cohort's median CD4 cell count, at 444 cells/ml, is higher than most studies assessing risk factors associated with low creatinine clearance in HIV-infected individuals 
but is typical of CD4 counts among pregnant women attending ANC clinics 
. While a higher CD4 cell count suggests a healthier population, we found a low rate of CrCl<50 ml/min even among those with CD4 counts below 350 cells/mm3
(1.9%), and below 200 cells/mm3
Our study's association between low BMI and CrCl<50 ml/min agrees with the current literature on renal insufficiency among HIV-infected, ART-naïve individuals. A cross-sectional survey of 2588 individuals assessing creatinine clearance in HIV-infected patients in France found that a BMI<22 kg/m2
was associated with both mild and advanced renal insufficiency 
. Other studies have found significant differences in the BMI of individuals with HIV-associated nephropathy and those without 
. Our sensitivity analysis showed CrCl<90 ml/min in pregnant women was associated with being under weight. This suggests that lower BMI is associated with a lower CrCl even after considering the increase in serum creatinine in pregnant women.
Low hemoglobin values are associated with renal insufficiency in people living with HIV. Time to death due to end-stage renal disease in individuals living with HIV is significantly shorter for those with low hemoglobin values compared to normal values 
. Kidney-related morbidities, such as albuminuria and renal hyperfiltration, are also highly correlated with HIV infection and low hemoglobin 
. Both our main models and our sensitivity analysis for the BAN clinical trial found that lower hemoglobin values were associated with increased odds of renal insufficiency. This is consistent with current literature on hemoglobin and kidney function in HIV-infected individuals 
Our findings show increases in hemoglobin and BMI have significant protective affects against CrCl<50 ml/min is consistent with other literature. HIV/AIDS-associated nephropathy (HIVAN) is associated with low hemoglobin levels 
. Additionally, the effect of BMI on renal impairment has been shown to differ with respect to gender (22).
Models stratified by pregnancy show only increases in age to be a significant factor associated with CrCl<50 mg/dl in ART-naïve pregnant individuals, while lower BMI and hemoglobin are associated with a increased likelihood of CrCl<50 mg/dl for non-pregnant individuals. The lack of significant factors associated with CrCl<50 mg/dl and pregnancy could possibly be due to the renal changes that occur during pregnancy 
. BMI, hemoglobin, and serum creatinine levels change during pregnancy 
and these changes could possibly affect creatinine clearance.
While CD4 cell count was not significant in our multivariate models, 20 of the 38 individuals with CrCl<50 ml/min using the CG equation also had CD4 counts less than 200 cells/mm3 (52.6%). Of the 38 individuals, 11 had a BMI under 18.5 (28.9%), and 7 of these also had a hemoglobin <11 g/dl and CD4 <200 cells/mm3. This suggests that when clinically assessing patients for potential CrCl<50 ml/min in a general clinical setting, a disproportionate number of afflicted individuals (18.4%) will have low hemoglobin, BMI, and CD4 cell counts. While we were not able to develop a clinical algorithm for assessing CrCl<50 ml/min due to small numbers of clients with this outcome, developing and validating such an algorithm prospectively with a larger study sample could be possible.
There are some limitations to our study. We recognize that the CG equation does not addresses renal tubular function as can be assessed by evaluating proteinuria through dipstick, urine protein
creatinine ratio, or fractional excretion of phosphate. The clinical trials included in this pooled analysis were all conducted in the urban city of Lilongwe and may not be representative of all the PMTCT and ART populations in Malawi. A recent WHO report suggests that only 17% of Malawi's population live in urban areas 
. However, most HIV infections occur in Malawi's cities 
Enrollment criteria for the respective trials varied, and if CD4 clinic data were available and it precluded patients from the study, they would not have been referred for trial screening. The ACTG 5221 and ACTG 5208 trials did not screen individuals with known high CD4 counts, and the BAN study did not enroll individuals with known CD4<250 cells/µL. Therefore, the pooled population may have oversampled sicker individuals for the ACTG screening population and healthier individuals for the BAN screening population. Such misrepresentation is expected to be minimal as individuals presenting for ART tend to be sicker on average and those presenting for PMTCT tend to be healthier. However, it is possible patients screened for the five clinical trials may not be representative of a routine clinic setting because screened individuals might be healthier than normal.
The majority of our population consists of pregnant women screened through the BAN study. This could potentially create an underrepresentation of HIV-infected, ART-naïve men. However, a main goal of our study is to focus on predictive factors of potential renal failure for pregnant mothers in a PMTCT program. Additionally, regardless of the gender imbalance across studies, the data used in this pooled analysis is, to our knowledge, the only data containing serum creatinine values of HIV-infected, ART-naïve individuals in Malawi. It is possible the CG equation could misrepresent creatinine clearance in our study because the majority of our population is pregnant and the equation requires the weight and gender of each subject. To address this potential limitation, we included a sensitivity analysis using CrCl<90 ml/min in pregnant individuals as an outcome.
Our study suggests that few eligible HIV-infected Malawians would be excluded from a TDF-based ART regimen. Limited resources for measuring serum creatinine should be directed towards individuals with low values for BMI or hemoglobin and who are not pregnant, since these individuals are at the greatest risk for a CrCl<50 ml/m.