The influence of antiretroviral therapy on HIV-related oral manifestations

PurposeThis review aims to provide primary medical and dental healthcare professionals with the current state of information on the oral manifestations of HIV infection in the era of antiretroviral therapy (ART) advancements.ResultsInfection with the human immunodeficiency virus (HIV) is associated with an increased risk of infectious, neoplastic, and immune-mediated oral complications that are regarded as a major constituent of this global epidemic. HIV-related oral manifestations have been subject to changes in their prevalence with the employment of ART, particularly in this period of enhanced patient accessibility to ART. Available antiretroviral medications (ARVs), the clinical presentation of common HIV-related oral manifestations, and patients and healthcare providers’ perceptions are also discussed.ConclusionsScreening, diagnosing, and treating patients with HIV/Acquired immunodeficiency syndrome (AIDS) has improved drastically since the isolation and characterization of HIV. Oral manifestations have been acknowledged to correlate with treatment responses and disease progression. Healthcare providers should be familiar with HIV-related oral manifestations and comfortable in managing and referring patients with HIV/AIDS, they are also key stakeholders in facilitating the elimination of the stigma associated with the infection.     

Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus

The introduction of combined antiretroviral therapies (HAART) has reversed the fatal course of human immunodeficiency virus (HIV) infection. HAART controls virus production and, in most cases, allows the quantitative and functional immune defects caused by HIV to be reversed. Here, we review T cell homeostatic mechanisms that drive immune recovery. These homeostatic mechanisms, as well as differences in T cell antigen exposure, explain the distinct patterns of recovery for HIV-specific T cells versus T cells specific for other pathogens. Immune restoration during HAART can, however, have adverse effects. Immune restoration syndrome occurs in some patients as a result of successful but unbalanced immunity.     

Transplacental genotoxicity of combined antiretroviral nucleoside analogue therapy in Erythrocebus patas monkeys

Antiretroviral nucleoside analogue drugs are a major constituent of highly active antiretroviral therapy (HAART), the most advanced form of treatment for HIV-1 infection. Currently, HAART combinations that include zidovudine (ZDV) and lamivudine (3TC) are highly effective in preventing HIV-1 vertical transmission; most children are born with no evident adverse clinical effects. However, ZDV is a moderately strong transplacental carcinogen in mice, and potential long-term consequences of fetal exposure to most HAART combinations remain unknown. To model human transplacental ZDV and 3TC exposures, experiments were performed in Erythrocebus patas monkeys given human-equivalent drug exposure protocols. Pregnant monkeys were dosed with either no drug (n = 2), 40.0 mg ZDV/d (about 6 mg/kg body weight/d) for the last 50% (10 weeks) of gestation (n = 3), or with the same regimen of ZDV plus 24.0 mg 3TC/d (about 3.6 mg/kg body weight/d) for the last 20% (4 weeks) of gestation (n = 3). Multiple fetal organs were examined at term for DNA incorporation of ZDV and 3TC using two separate radioimmunoassays (RIAs). Values for ZDV-DNA incorporation were similar in fetuses exposed to ZDV alone and those exposed to ZDV plus 3TC. Values for 3TC-DNA in fetal organs were greater than or equal to values for ZDV-DNA, indicating that the total DNA damage sustained by fetuses exposed to both drugs was at least double that observed in fetuses exposed to ZDV alone. Telomere shortening, determined by Southern blot with a telomeric probe, was observed in most organs of the three animals exposed in utero to ZDV plus 3TC. No telomere shortening was evident in the unexposed fetuses, and occasional telomere shortening was found in fetuses exposed to ZDV alone. Overall, these studies demonstrate that monkey fetuses exposed in utero to the combination ZDV plus 3TC sustain a higher level of drug-DNA incorporation and show evidence of more telomere damage than monkey fetuses exposed to ZDV alone.     

Antiarthritic synergism of combined oral and parenteral chrysotherapy

In comparative clinical studies of auranofin (AF, oral gold) and parenteral gold in the treatment of rheumatoid arthritis, no difference in efficacy was detected. Since the pharmacologic profiles of these compounds are different, we studied their combined effect on adjuvant arthritis (AA). The effect of AF alone and combined with gold sodium thiomalate (GTM) or gold sodium thiosulfate (GTS) on the excretion of urinary hydroxyproline (UHP) and urinary calcium (UCa), and the articular index of arthritic rats was followed during five weeks of treatment. The excretion of UHP and UCa was significantly inhibited (P<0.005) in rats treated with AF combined with GTM or GTS as compared with animals treated with the individual gold compounds. However, the articular index only decreased significantly (P<0.02) in the group of rats treated with AF + GTS. The present studies open the possibility that combined treatment with oral and injectable gold provide a new approach for chrysotherapy with an increased antiarthritic potency.Presented in part at the 3rd International Congress of Inflammation, Paris, September 1984, and at the IX Panamerican Congress of Rheumatology, Buenos Aires, November 1986.This study was supported by a Dr. Martine and Harry Recanati Biomedical Research Grant of Ralli Financial Agency SA, Geneva, Switzerland; a grant from Dr. S. M. Robbins of Cleveland, Ohio; and from the Chief Scientist, Ministry of Health, Government of Israel.     

Antiarthritic synergism of combined oral and parenteral chrysotherapy

We have observed an antiarthritic effect of combined chrysotherapy in adjuvant arthritis. Since superoxide radicals (O2-) are potent mediators of rheumatoid inflammation, we studied the combined effect of auranofin (AF) and injectable golds on luminol-dependent chemiluminescence (LDCL) and O2- generation by cytochrome-c reduction of activated leukocytes by different receptor-mediated stimuli: phorbol myristic acetate, 10(-6) M; f-Met-Leu-Phe, 10(-6) M; and poly-L-histidine, 10(-5) M. AF, 0.6 and 0.9 micrograms Au/ml, inhibited 34 and 58% of O2- generation, respectively; the addition to AF of 0.3 micrograms Au/ml of gold thiosulfate (GTS) increased this inhibition to 84 and 97% of the oxygen burst. Similar synergistic potentiation inhibition was obtained by LDCL. When the inhibition of O2- generation by the combined action of AF and GTS was compared with AF + gold sodium thiomalate (GTM), only GTS showed an activation on AF's inhibition of the oxygen burst of human leukocytes. The ligand thiosulfate in equimolar concentrations to GTS had a statistically significant (P less than 0.01) inhibitory effect on AF's blockade of O2- generation during the first 5 min of the interaction with the PMNs; thiomalate had no effect. Sequential pretreatment of PMNs with AF and GTS on O2- generation revealed that for synergism of combined gold action to take place, the cell membrane had to be subjected first to the action of oral gold or to the simultaneous combined action of oral and parenteral gold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noncontraceptive health benefits of combined oral contraception

Contraception is one of the keystones of reproductive health.The availability of effective contraception has helped to changedramatically the structure of the world’s population duringthe last 50 years, through a demographic transition involvinglower fertility rates and longer survival. As the transitionevolves more slowly in developing countries, different effectson population structures contribute to civil strains. Oral contraception(OC) is an extremely effective method of contraception thatalso confers health benefits beyond pregnancy prevention. Notableeffects on the reproductive system include relief from troublesomesymptoms associated with menstruation such as heavy periods,painful periods and irregular bleeding. Many women also haveimprovement in acne and hirsutism. Moreover, OCs may be usedto treat menorrhagia or symptomatic endometriosis. Use of OCsis associated with a long lasting reduction in the risk of developingcancer of the ovary and the endometrium. The effects on benignbreast disease (BBD), bone health and colon cancer are lessclear and merit further investigation.     

Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients

Massive loss of lamina propria CD4⁺ T cells, changes in the lymphatic architecture, and altered intestinal epithelial barrier leading to microbial translocation are the common features of HIV-1 infection and are not fully restored under combined antiretroviral therapy (cART). To better understand determinants of gut mucosal restoration, we have performed phenotypic and gene expression analyses of the gut from HIV-infected patients, naive or treated with cART initiated either at the early phase of the primary infection or later during the chronic phase. We found a depletion of T helper type 22 (Th22) and interleukin-17-producing cells in naive patients. These populations, except Th22 cells, were not restored under cART. Regulatory T cells/Th17 ratio was significantly increased in HIV-infected patients and was inversely correlated to the restoration of CD4⁺ T cells but not to gut HIV DNA levels. Gene profile analysis of gut mucosal distinguished two groups of patients, which fitted with the timing of cART initiation. In their majority early, but not later treated patients, exhibited conserved intestinal lymphoid structure, epithelial barrier integrity and dendritic cell maturation pathways. Our data demonstrate that early initiation of cART helps to preserve and/or restore lymphoid gut mucosal homeostasis and provide a rationale for initiating cART during the acute phase of HIV infection.     

Azole susceptibility patterns and genetic relationship among oral Candida strains isolated in the era of highly active antiretroviral therapy

We performed a cross-sectional study to analyze patterns of azole susceptibility of oral isolates in the highly active antiretroviral therapy (HAART) era and compared current data with those obtained for isolates from 1994. We further identified patients with relapsing oral pharyngeal candidiasis (OPC) who had been included in a similar study in 1994. For these subjects, we compared the susceptibility pattern for the OPC isolates, and if a modification of azole resistance was observed, we analyzed the genotypic pattern for the 1994 and 2000 isolates to determine whether the dominant strain was closely related. We included 69 consecutive HIV-infected subjects with 137 episodes of OPC who were admitted to our ward from January to June 2000. Ninety-two strains (67%) and 21 non- strains (15%) were isolated. We identified 24 episodes of OPC caused by two different species. Compared with the pre-HAART era, the fluconazole resistance of isolates significantly decreased from 45% to 10% (p <.001). Itraconazole resistance decreased from 37% to 7% (p <.001). Ketoconazole resistance (3% in 1994) was not detected more. Nine patients whose isolate was susceptible to all azole drugs had a previous isolate resistant to all azole drugs. We observed that these isolates exhibited different fingerprint profiles. Our findings demonstrate that most cases of HIV-associated OPC observed in the HAART era are caused by azole-susceptible strains. The reversion of an isolate from azole resistant to azole susceptible is related to strain replacement.     

A diagnostic dilemma in a patient receiving antiretroviral and antituberculosis therapy

A southern Indian HIV-infected man with tuberculosis (TB) presented with worsening pulmonary infiltrates and increased mediastinal lymphadenopathy because of immune reconstitution 10 days after initiation of HAART. This case highlights the importance of developing guidelines for management of concurrent HIV infection and TB in the developing world.     

Benefits and risks of long-term low-dose oral continuous combined hormone therapy

OBJECTIVES: Current recommendations for hormone therapy (HT) are mainly based on findings from studies using standard dose regimens in older women who had a different health profile from those who start HT soon after the onset of menopause. METHODS: We, therefore, reviewed controlled trials assessing the efficacy, safety and tolerability of low-dose oral continuous combined HT (cc-HT) started for treatment of climacteric symptoms. This review is limited to oral cc-HT regimens over sequential regimens as most postmenopausal women prefer not to have a return of uterine bleeding, and to studies of at least 2 years in duration. RESULTS: Low-dose cc-HT is effective in alleviating climacteric symptoms and in maintaining bone density over prolonged periods, although no data were available regarding fracture risk. No increased risk of coronary heart disease, venous thrombo-embolism or stroke during the use of low-dose cc-HT was reported in the long-term studies and no definitive evidence for an increased risk of breast cancer was found. Breakthrough bleeding during the first months of use is less common than with standard dose HT and amenorrhoea is achieved in most women over time. These regimens are safe for the endometrium and are well tolerated, with a low incidence of adverse events compared with standard doses. CONCLUSIONS: Current evidence from controlled trials indicates that low-dose oral cc-HT appears effective and safe. This makes it a good choice for the alleviation of climacteric symptoms, and for this purpose long-term administration of low-dose cc-HT does not seem to impose serious health risks. However, more long-term study data and direct head-to-head comparisons between various low-dose preparations are needed to support or rectify the safety aspects.     

The effects of oral and combined parenteral/oral immunization against an experimental Escherichia coli urinary tract infection in mice

A double oral immunization (PO/PO) with an outer membrane protein (OMP) from a human uropathogenic strain of Escherichia coli, resulted in the partial protection of mice infected per urethrally with the same strain. Complete protection was achieved by immunizing with OMP in Freund's complete adjuvant (FCA), intramuscularly (i.m.), followed by an oral boost (i.m./PO). The PO/PO protocol stimulated mainly local urinary antibody synthesis, particularly IgA, whilst the i.m./PO regimen resulted in the appearance of both serum and urine antibodies. A single dose of OMP, 6 days after infection, rendered the mice resistant to reinfection, in contrast to non-immunized mice, and led to a significant increase in urine, serum and bile IgA anti-OMP levels. Our results confirm previous reports that the urinary tract forms part of the common mucosal immune system and provides further evidence for immunological memory in mucosal immunity. These results also demonstrate that our OMP preparation is a highly effective immunizing antigen, and that such preparations may be suitable as oral vaccines against urinary tract infection in humans.     

Differences in the use of combined oral contraceptives amongst women with and without acne

BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) provides a treatment option for women with acne, hirsutism or polycystic ovary syndrome (PCOS). CPA/EE may be prescribed as an oral contraceptive (OC), but is not licensed as such in the UK. The use of CPA/EE steadily increased after its introduction to the UK market in 1987, but there was a marked increase in its share of the OC market after 1995. METHODS: Using the General Practice Research Database, utilization patterns of CPA/EE and conventional oral contraceptives were compared in women aged 15-39 years, with or without acne or PCOS. RESULTS: Between 1994 and 1998, CPA/EE accounted for an increasing proportion of all OC use. The proportion of CPA/EE prescribed to women with acne declined between 1994 and 1998, whereas that prescribed to women with PCOS remained constant. The age-specific use of CPA/EE by women with acne or PCOS almost doubled. After 1995, there was a marked increase in the use of products containing levonorgestrel by women with acne or PCOS. CONCLUSIONS: A large proportion of CPA/EE is prescribed to women with acne and/or PCOS, although this proportion decreased between 1992 and 1998. This has important implications in CPA/EE risk assessment studies.     

Evaluation of transplanted tissue-engineered oral mucosa equivalents in severe combined immunodeficient mice

The aim of this study was to determine the optimal stage of development at which transplant human ex vivo-produced oral mucosa equivalents (EVPOMEs) in vivo. EVPOMEs were generated in a serum-free culture system, without the use of an irradiated xenogeneic feeder layer, by seeding human oral keratinocytes onto a human cadaveric dermal equivalent, AlloDerm. EVPOMEs were cultured for 4 days submerged and then for 7 or 14 days at an air-liquid interface to initiate stratification before transplantation into SCID mice. AlloDerm, without epithelium, was used as a control. Mice were killed on days 3, 10, and 21 posttransplantation. Epithelium of the transplanted EVPOMEs was evaluated with the differentiation marker keratin 10/13. Dermal microvessel ingrowth was determined by immunohistochemistry with a mouse vascular marker, lectin binding from Triticum vulgaris. The presence and stratification of the epithelium were correlated with revascularization of the underlying dermis. The microvessel density of AlloDerm without epithelium was less than that of EVPOMEs with an epithelial layer. Microvessel density of the dermis varied directly with the degree of epithelial stratification of the EVPOMEs. The EVPOMEs cultured at an air-liquid interface for 7 days had the optimal balance of neoangiogenesis and epithelial differentiation necessary for in vivo grafting.