Purpose: The compliant use of combination antiretroviral therapy has virtually eliminated perinatal HIV transmission. Although antiretroviral drug toxicities in adults have been well documented, the effects of fetal and early childhood exposure to antiretroviral drugs on children of HIV-positive mothers are not well known. Methods: We searched the Pub Med database, reviewed publications, and selected abstracts on the use of antiretroviral agents to prevent HIV transmission and their effects on growth and cardiac endpoints in fetal and postnatal life. Results: The link between nucleoside analogs and mitochondrial dysfunction is controversial, and the association between in utero antiretroviral exposure and mitochondrial dysfunction in children is unclear. In utero exposure to antiretroviral therapy has effects on the heart, regardless of HIV status, including improved cardiac function but also reduced cardiac mass of unclear future clinical significance. Preterm delivery and impaired somatic growth have been reported in infants exposed to antiretrovirals, but results are inconsistent. In utero exposure has also been associated with below-normal hematologic parameters. In HIV-infected children, cumulative postnatal exposure to antiretroviral agents is associated with metabolic disturbances and an increased risk for cardiovascular disease. Conclusion: Antiretroviral therapy is effective in preventing perinatal HIV transmission but may be associated with adverse long-term side effects in exposed infants. Further clinical trials and longitudinal monitoring are needed to understand the long-term effects of in utero exposure to antiretroviral agents.

The introduction of the highly active antiretroviral therapy (HAART) in 1996 has drastically reduced the morbidity and mortality associated with the HIV infection. Although short term toxicities of the antiretroviral drugs are being reported, there’s dearth of data on their long term complications, particularly in sub-Saharan Africa. This study was designed to identify hematological and metabolic toxicities in HAART-experienced patients in our facility from January 2000 to December 2009. Patients on HAART for ≥ 2 weeks, and have at least one abnormal laboratory result (hemoglobin < 10.0 g/dl, white blood count < 4,500/ mm3, absolute neutrophil cell count < 1,400/ mm3, platelets < 150,000/mm3, alanine transaminase > 40 iu/L, creatinine > 130 mmol/L, fasting blood sugar > 6.7mmol/L, fasting cholesterol > 2.5mmol/L, fasting triglyceride > 0.5mmol/L) on follow-up evaluations were studied. Of 3641 patients, 357 (9.8%) comprising 231 females (64.7 %) and 126 males (35.3%) with respective mean ages of 36.16 ± 9.06 years and 42.56 ± 9.36years had hematological and metabolic toxicities, due mainly to zidovudine/lamivudine/nevirapine (51.8 %), stavudine/lamivudine/nevirapine (16.5%), and truvada/nevirapine (10.4%). Common laboratory toxicities were elevated alanine transaminase enzyme (39.8%), leucopenia/neutropenia (38.0%), elevated creatinine level (12.3%), and low hemoglobin (11.5%), although the most severe toxicity was grade 4 anemia. Risk factors for these toxicities were: young age, female gender, pre- and on- ART CD4+ > 250 cells/μL. In conclusion, the current first line antiretroviral regimens produced various forms of hematological and metabolic toxicities, except glucose or lipid abnormalities.

Although the rate of new HIV infections has been declining, AIDS continues to be one of the leading causes of death worldwide. The lack of an effective HIV vaccine makes it necessary to develop alternative strategies, such as the development of topical microbicides, to prevent transmission. Antimicrobial peptides represent promising microbicide candidates. Previously, we succeeded in enhancing the anti-HIV activities of several peptides that form helical structures based on the bioinformatic results learned from the antimicrobial peptide database. This study showed that Lys-to-Arg alterations also improved the HIV inhibitory activity of thanatin which is known to form a β-hairpin structure. Using a previously reported de novo designed HIV inhibitory peptide GLR-19 as the starting template, loop structures of varying sizes were generated by restraining a disulfide bond at different positions. The thanatin-mimicking constructs are referred to as GLRC peptides since they are composed of only four amino acid residues G, L, R, and C. While GLRC-2, the peptide with a medium-sized loop structure, was most potent against HIV-1 and HSV-2, GLRC-3, with the small loop structure, was most potent against Escherichia coli K12. Thus, the efficacy of the GLRC peptides is microbe dependent. Further terminal sequence truncation of GLRC-2 reduced antimicrobial activity against both viruses and bacteria. It appears that the high antiviral potency of GLRC-2 is related to high hydrophobicity, although a wide-range correlation is lacking. In addition, GLRC-2, which is more active against viruses, is also more resistant to the action of chymotrypsin. Therefore, GLRC-2, a novel peptide that acquired not only higher stability but also higher anti-HIV activity than the GLR-19 template, serves as the starting point for additional rounds of peptide engineering.

Viral entry is one of the most important targets for the efficient treatment of Human immunodeficiency virus type 1 (HIV-1)-infected patients. The entry process consists of multiple molecular steps: attachment of viral gp120 to CD4, interaction of gp120 with CCR5 or CXCR4 co-receptors, and gp41-mediated fusion of the viral and cellular membranes. Understanding the sequential steps of the entry process has enabled the production of various antiviral drugs to block each of these steps. Currently, the CCR5 inhibitor, maraviroc, and the fusion inhibitor, enfuvirtide, are clinically available. However, the emergence of HIV-1 strains resistant to entry inhibitors, as commonly observed for other classes of antiviral agents, is a serious problem. In this review, we describe a variety of entry inhibitors targeting different steps of viral entry and escape variants that are generated in vitro and in vivo.

We report the first published case of etravirine induced hypersensitivity reaction leading to fulminant hepatic failure in a 49-year-old female patient with Human Immunodefi ciency Virus. She presented with a life threatening rash and end stage organ damage requiring intensive care unit supportive care. Liver biopsy supported the diagnosis of drug-induced hypersensitivity. The patient recovered after withdrawal of etravirine and the use of systemic corticosteroids. The authors describe etravirine drug hypersensitivity as a clinically important reaction and that early recognition can improve survival.

Adherence to Highly Active Antiretroviral Therapy can be affected by a number of factors limiting the outcome of the treatment. We report the case of a 39 year-old HIV-HCV co-infected woman in stable virologic suppression and immune recovery during a raltegravir plus unboosted atazanavir dual-therapy taken every other day. Measurement of HIV-1 RNA plasma levels (viral load), CD4+ T-cell counts and the therapeutic drug monitoring through validated high-performance liquid chromatography methods, were performed to assess the effectiveness of this regimen. Our data on raltegravir pharmacokinetics in association with atazanavir show adequate minimum effective concentrations of raltegravir throughout 36 and 48 hours despite the every other day intake of the drug. Further studies are recommended in order to identify the determinants that could enable a reduction in antiretroviral dosing frequency in case of difficult management of HIV-infected patients due to low adherence to therapy. By reporting our medical experience, we focused on the utility of performing therapeutic drug monitoring especially in cases of poor adherence, drug and/or alcohol abuse, co morbidities and co-administration of other drugs.