Antiretroviral drugs are used for the treatment of human immunodeficiency virus, they are used as combination regimens to achieve the highest possible benefit, tolerability, compliance and to diminish the risk of resistance development. Reports from preclinical and clinical studies have linked antiretrovirals with some toxicological effects which could be associated with redox imbalance (oxidative stress). This stimulated us to review relevant literature on the relationship between antiretroviral induced toxicological effects and redox imbalance. Available literature on antiretroviral associated toxicological effects and oxidative stress were comprehensively reviewed. Literature showed that antiretrovirals are associated with toxicological effects which includes hepatotoxicity, cardiotoxicity, hematotoxicity and nephrotoxicity. Reports in animal studies also showed that these toxicological effects could be associated with oxidative stress through the generation of oxidative radicals, depletion of antioxidants and antioxidant enzymes leading to mitochondria damage in the heart, kidney, liver brain and other organs. In humans, studies also showed that antiretrovirals are associated with lipid peroxidation, depletion of antoxidants and antioxidant enzymes which are elements of oxidative stress. Furthermore it was observed that supplementations with some antioxidants mitigated antiretroviral induced oxidative stress, mitochondria damage and toxicological effects. Antiretroviral drugs are associated with toxicological effects which may involve redox imbalance, but more studies are required to correlate antiretroviral toxicities with oxidative stress.

Tenofovir is one of the most commonly used antiretrovirals in adolescents and adults because of its potency and favorable pharmacokinetic and relative safety toxicological profile. It has been combined successfully with antiretroviral drugs from classes such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors to achieve virologic suppression in a high percentage of recipients. Despite its therapeutic success, quite a number of cohorts and clinical studies have associated tenofovir with the development of renal toxicity with few studies on the opposing end. This stimulated us to review reported cohorts and clinical studies on tenofovir renal toxicity. In this study it was observed that literature reported incidence of tenofovir renal toxicity falls within the range of 0.7% -17%. Available studies gave different appellations to tenofovir renaltoxicity, which include fanconis syndrome, proximal tubule dysfunction, acute renal failure, chronic renal failure, chronic kidney disease and nephrogenic diabetes insipidus. Markers of renal toxicity (tubulopathy) which include glycosuria, hyperaminoaciduria, proteinuria, hyperphosphaturia, hyperuricosuria, retinol-binding protein, beta2-microglobulinuria, decreased creatinine clearance and decreased glomerular filtration rate were also reported. In some studies renal biopsy demonstrated cytoplasmic vacuolization, apical localization of nuclei and reduction of the brush border on proximal tubule epithelial cells. This study observed that tenofovir renal toxicity could be reversible on discontinuation of tenofovir therapy despite contrary views by some studies. Regardless of tenofovir reported renal toxicity, it is well tolerated with a relative safety profile but it is advised that renal profile of patients should be evaluated before and routinely during tenofovir therapy.

Fluoroquinolones are known to be safe and well tolerated. They are said to have the widest clinical acceptability when compared with other antibiotics. Their reported side effects include gastrointestinal tract, central nervous system effect and blood disorder. Rare side effects include phototoxicity, hypersensitivity, convulsion, psychosis, tendinitis, hypoglycemia, cardiotoxicity and nephrotoxicity. Some of these side effects have led to the withdrawal of some fluoroquinolones like travofloxacin from clinical use in some countries. Of recent fluoroquinolones induce cardiotoxicity and hepatotoxicity has gain attention. Due to increasing reports on fluoroquinolones associated hepatotoxicity in experimental Animal studies and clinical experience. This study reviews reported hepatotoxicity associated with clinically used fluoroquinolones and their safety profile on liver function. It was observed that some fluoroquinolones may have hepatotoxic potential. Reported fluoroquinolones induce hepatotoxicity manifested as hepatitis, pancreatis, jaundice, liver injury and hepatic failure. Most reported cases of fluoroquinolones induced hepatotoxicity were marked by elevated levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, direct bilirubin, total bilirubin and prolong prothrobin time. In some reported cases liver biopsy revealed hepatocellular damage, necrosis and degeneration. Mixed inflammatory infiltrates containing eosinophils, portal edema, bile ductular proliferation and lobular cholestasis were also observed in some cases. The mechanism of fluoroquinolones induce hepatotoxicity may involve generation of oxidative radicals in the liver during drug metabolism which induces DNA damage, mitochondrial damage and gene regulation leading to hepatocellular damage. This was observed in travofloxacin which enhances hepatic mitochondrial peroxynitrite stress in mice with underlying increased basal levels of super oxide leading to the disruption of critical mitochondrial enzyme and gene regulation. This mechanism could be associated with fluoroquinolones mechanism of action which includes DNA damage. In conclusion fluoroquinolones are well tolerated but some may have hepatotoxic potential. Most clinically used fluoroquinolones are relatively safe but Clinicians should consider patients liver function status before fluoroquinolones clinical recommendation. In some cases biochemical parameters associated with liver function should be monitored in patients with impaired liver function

Antiretroviral drugs containing Lopinavir/ ritonavir (LPV/r) are usually co-administered with sulfamethoxazole / trimethoprim (SMX/TMP) in the management of HIV/AIDS and co infections. The concurrent use of these drugs may place more adverse burden on testicular function because reports have associated these drugs individually with decreased testicular function. This study therefore evaluated the effects of the co-administration of SMX/TMP + LPV/r on reproductive indices of male albino rats. Eighty (80) adult male rats which were divided into five (5) groups A-E were used in this study. Animals in group A which served as the control were treated with 1% ethanol while animals in groups B-E were treated orally with SMX/TMP, (22.4/4.6mg/kg), LPV/r (22.8/5.8mg/kg) and combined doses of SMX/TMP + LPV/r for 2-8 weeks respectively. Animals were sacrificed at the end of treatment, testes were collected and weighed. Sperm count, sperm motility, and morphology were evaluated. Testicular levels of malondialdehyde (MDA), super oxide dismutase (SOD) and histopathological changes were also analyzed. Single doses of LPV/r and SMX/TMP produced significant time dependent decrease in total sperm count and sperm motility, with increase in abnormal sperm morphology. Treatment with single doses of these agents time dependently increased testicular MDA, decreased SOD level and induced abnormal testicular histopathological changes. No significant synergistic effects were observed in all evaluated parameters when these agents were coadministered. Conclusion: Due to lack of significant synergistic effects on all evaluated parameters with the coadministration of these agents, the concurrent use of these agents in the management of HIV and co-infections may not have any deleterious effect on male reproductive function.

Tenofovir is a nucleotide reverse transcriptase inhibitor used as part of antiretroviral regimens. It is well tolerated with relative toxicological effects but recent reports have linked it with renal toxicity which is of clinical concern. This study reviews literary work on tenofovir renal toxicity with more light on case reports. Tenofovir renal toxicity manifests as Fanconi's syndrome, nephrogenic diabetes insipidus and acute renal failure. Fanconi's syndrome is characterised by acidosis, protenuria, albuminuria, aminoaciduria, hyperchloremic, metabolic acidosis, hypouricemia, hypophosphatemia and glycosuria. The presence of urine osmolality, polydipsia and polyuria could give credence totenofovir induced nephrogenic diabetes insipidus. In some cases of tenofovir renal toxicity, renal biopsy revealed sclerosed glomeruli with ischemic injury including portal collapse of capillary loops. Histopathological changes in glumeruli include mild mesangial proliferation, increased mesangial matrix and thickened capillary loops. Moderate degenerative tubular changes, loss of tubular mass, interstitial scarring and scattered cellular infiltrates. Pharmacodynamic and pharmacokinetic interactions may occur with the co administration of tenofovir with non steroidal anti-inflammatory drugs, aminoglycosides and some protease inhibitors which may potentiate renal toxicity. Tenofovir renal toxicity is associated with some risk factors including genetic polymorphism as supported by dichotomy in renal toxicity among different race and the association between ABCC2 gene and tenofovir kidney tubular dysfunction. The pharmacology of tenofovir renal toxicity is unclear but it is attributed to the interaction between tenofovir and theorganic anion transporters (hOAT1, and to a lesser extent, OAT3) favoring intracellular accumulation in renal proximal tubule cells. This may lead to ultrastructural mitochondrial abnormalities and decreased mtDNA levels which could stimulate reactive oxygen species production, depletion of antioxidants and antioxidant enzymes. These processes can stimulate the destruction of biomolecules such as DNA, proteins, and lipids, thus causing the deregulation of redox-sensitive metabolic pathways, signaling pathways, and cell death. Despite tenofovir renal toxicity it has achieved notable therapeutic success nevertheless patients on tenofovir containing regimens should be monitored for renal function parameters. Co administration with potential nephrotoxic drugs should be avoided except when benefit outweighs risk.