Does perinatal antiretroviral therapy create an iatrogenic cancer risk?

Antiretroviral therapy is highly effective in reducing vertical transfer of HIV infection, sparing many thousands of children premature death from AIDS. However, accumulating evidence indicates that perinatal exposure to antiretroviral agents may place them at elevated risk of developing cancer later in life, owing to potential carcinogenic effects of the agents. An initial experimental evaluation clearly demonstrated that AZT was a genotoxin and transplacental carcinogen of intermediate potency in CD-1 mice. This issue of Environmental and Molecular Mutagenesis contains reports of recent studies designed to confirm and extend earlier findings, and to provide further perspective that will facilitate development of strategies through which the adverse effects might be mitigated. The studies focused on various aspects of the genotoxicity and carcinogenicity of antiretroviral agents, including: mutagenesis in several in vitro experimental systems; mutations and clastogenic effects induced by transplacental administration in mice; transplacental carcinogenesis and mutations in oncogenes and tumor suppressor genes in tumors of mice; and genotoxicity and clastogenicity following perinatal exposure of HIV-infected mothers and their uninfected infants. Collectively, the results obtained provide convincing biological plausibility for the postulate that perinatal exposure to nucleoside analogs puts children at elevated risk of developing cancers later in life. They further emphasize the importance of continued surveillance of these children for increased cancer risk and indicate a need for efforts to develop less genotoxic alternative agents.     

Should antiretroviral therapy be started earlier?

Current treatment guidelines recommend that antiretroviral therapy be deferred until the CD4 count has fallen into the 200 to 350 cells/mm³ range. However, treatment has become simpler, less toxic, and more forgiving of missed doses. Longer-term follow-up data from clinical cohorts are now showing better outcomes when therapy is started at higher CD4 cell counts. Therapy initiated early has better virologic and immunologic responses, is better tolerated, and is cost-effective. Recent developments and clinical data support a return to earlier initiation of therapy.     

Can antiretroviral therapy ever be stopped?

A pool of latently infected CD4+ T cells is established within the first few weeks of HIV infection. Because these memory T cells are inactive, the viral DNA integrated into their chromosomes remains invisible to immune surveillance and to antiretrovirals. Research shows that this reservoir of infected memory T cells does not decay in a clinically meaningful time frame--that is, within 60 years--in patients being treated with potent combination antiretrovirals. Even a hypothetical regimen that prevents any new infection of cells would not hasten the decay of this latent reservoir. Treatments that activate this reservoir have been studied in patients with suppressed viremia, but such interventions are highly toxic and have not succeeded so far. Studying rare individuals who manage to control activation of these latent cells may provide important clues to long-term control of HIV infection.     

Does exposure to antiretroviral therapy affect growth in the first 18 months of life in uninfected children born to HIV-infected women?

Uninfected children born to HIV-infected women are exposed antenatally to antiretroviral therapy, but it is uncertain whether this affects growth in early life. We analyzed weight, height, and occipitofrontal circumference (OFC) in 1912 children from a cohort study: 1304 had no or monotherapy exposure and 608 had combination therapy exposure. The mean z-score for birth weight or OFC did not differ by exposure category in 1513 term children or in 78 born at <34 weeks; the 266 born from 34 to 36 weeks were heavier if exposed to combination therapy. Children with combination therapy exposure born at 34 to 36 weeks reached the 25th centile for weight and OFC earlier than those not exposed born at 34 to 36 weeks (median: birth vs. 3 months; P = 0.003 [weight], P = 0.004 [OFC]), whereas children exposed to combination therapy born at <34 weeks reached the 25th centile for OFC later than those born at <34 weeks not exposed (median: 15 vs. 7 months; P = 0.004). Gestational age and maternal illicit drug use were strongly associated with growth, but the effect of combination therapy exposure was marginal (adjusted coefficients: weight, -0.10 [P = 0.019]; height, -0.12 [P = 0.008]; and OFC, -0.14 [P = 0.001]). Although the effect of combination therapy exposure is minimal, long-term monitoring of these children is important.     

Are feelings of responsibility to limit the sexual transmission of HIV associated with safer sex among HIV-positive injection drug users?

We developed a scale among HIV-positive injection drug users (IDUs) to measure self-perceived responsibility to limit HIV transmission during sex. We describe the characteristics of HIV-positive IDUs (n=1114, 62% male, HIV-positive for 9 years on average) who felt responsible for protecting their sexual partners from HIV and evaluated whether such feelings were associated with safer sexual practices. Using this scale (Cronbach alpha=0.83) and audio computer-assisted self-interviewing technology, 75% of this sample felt responsible for protecting their sexual partners from HIV. In cross-sectional multivariate analysis, HIV-positive IDUs who felt responsible were those with greater HIV knowledge (adjusted odds ratio [95% confidence interval]: 1.74 [1.26 to 2.40]), perceived social support (1.77 [1.28 to 2.44]), self-efficacy for safely injecting (1.41 [1.02 to 1.94]), and self-efficacy for using condoms (1.92 [1.38 to 2.68]). Feeling responsible was associated with having relatively fewer sex partners (<10 vs. >or=10, 0.57 [0.34 to 0.96]) and a lower odds of unprotected sex (0.63 [0.45 to 0.89]) but was not associated with safer injection practices. Feelings of responsibility did not vary by demographic characteristics, suggesting that prevention messages that encourage HIV-positive people to play a role in curbing HIV transmission may be acceptable to many HIV-positive IDUs. Working with HIV-positive IDUs to increase or reinforce feelings of responsibility may reduce the sexual transmission of HIV.     

Can antiretroviral therapy ever be stopped? An update

Eradication of virus is not a reasonable goal of anti-HIV therapy because of the latent reservoir of HIV-1 in resting memory CD4+ T cells, which guarantees lifetime persistence of virus. Any drug-resistant viruses that arise and circulate for significant periods can be stored in the reservoir, limiting future treatment options, and mistakes in treatment can be "remembered" by the virus. Wild-type virus is also preserved in the reservoir and can reemerge if therapy is stopped. Since wild-type virus can be more virulent, suppression of this virus is one benefit of continuing therapy in patients who are experiencing treatment failure. If therapy is stopped, the reemergence of wild-type virus does not mean that drug-resistant virus is gone; it is still preserved in the latent reservoir. In patients who have viral suppression to below 50 copies/mL, there is still a low level of virus in the plasma, but it does not appear to be evolving. Thus, in principle, lifelong control of viral replication is possible if suppression of viremia to below 50 copies/mL is maintained.     

Does supplemental creatine prevent herpes recurrences?

While functioning as a general practitioner at the Camp Pendleton Marine Base, the first author treated numerous patients with recurrent genital herpes. Beginning in 1998, a number of these patients failed to return for periodic acyclovir therapy. Inquiries revealed that these patients had all commenced supplemental creatine after their last outbreak, and had experienced no further outbreaks. A literature search uncovered a report that cyclocreatine, a synthetic compound structurally and functionally homologous to creatine, inhibits the replication of cytomegalovirus, varicella-zoster, and herpes simplex types 1 and 2, in low millimolar concentrations; furthermore, dietary cyclocreatine reduces morbidity and mortality in mice infected with HSV-2. The fact that both creatine and cyclocreatine exert neuroprotective and cancer-retardant effects in rodents, encourages the speculation that creatine shares the anti-viral activity of cyclocreatine. Pilot studies to assess the impact of creatine loading on recurrence of oral and genital herpes appear warranted; the impact of creatine on shingles occurrence in high-risk patients could also be explored. Although initially conceived as an aid to athletic performance, creatine loading may prove to have broad preventive and therapeutic applications.     

Should sexual partners of women with bacterial vaginosis receive treatment?

Bacterial vaginosis is the most prevalent infectious cause of vaginitis. It is associated with significant morbidity, particularly in pregnant women and following gynaecological operations. Cure is difficult. There is some controversy over whether treating sexual partners of affected women can improve cure rates. This paper provides a critical appraisal of the evidence for simultaneously treating the male partner of women affected by bacterial vaginosis. Unfortunately, no evidence was found supporting the treatment of partners of women affected by bacterial vaginosis.     

Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

Pharmacogenetics refers to the effect of single nucleotide polymorphisms(SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction(HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus(HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1(MDR1) 3435 C T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.     

Does gene therapy become pharmacotherapy?

Recent progress in molecular and cellular biology has led to the development of numerous effective cardiovascular drugs. However, there are still a number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischaemic heart disease, restenosis after angioplasty, and vascular bypass graft occlusion. Currently, gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease despite its limitations. The first human trial in gene therapy for cardiovascular disease was started at 1994 to treat peripheral vascular disease using vascular endothelial growth factor (VEGF). Then, many different potent angiogenic growth factors were tested in clinical trials to treat peripheral arterial disease and ischaemic heart disease. Improvement of clinical symptoms in peripheral arterial disease and ischaemic heart disease has been reported. This review focuses on the future potential of gene therapy for the treatment of cardiovascular disease. In the future, gene therapy might become a real pharmacotherapy to treat cardiovascular disease.     

Does gastrointestinal Candida albicans prevent ubiquinone absorption?

Ubiquinones (coenzyme Qs (CoQ)) are essential for oxidative phosphorylation in yeasts and humans, although the isomers present in each are different. The human coenzyme Q, CoQ10, is administered orally for the treatment of heart disease and other disorders. Some patients, however, require much higher doses than others to attain a therapeutic CoQ10 blood level. We propose that one possible explanation for this variability is Candida colonization of the GI tract. Many common medical treatments including antibiotics and anti-hyperchlorhydric agents increase the risk of GI tract Candida colonization. Subsequent uptake and utilization of supplemental CoQ10 by the yeast could diminish availability for the human subject. Data from one patient and an in vitro pilot study using two pathogenic strains of C. albicans support this hypothesis. If C. albicans in the GI tract can hinder availability and interfere with therapeutic effects of CoQ10, it could be of clinical significance for large numbers of patients.