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1 Center for AIDS Prevention Studies, University of California San Francisco, San Francisco, CA, USA
2 Dept. of Oral Medicine, Pathology, Immunology and Microbiology, GKT Dental Institute, London, UK
3 Division of Infectious Disease, Stanford University School of Medicine, Palo Alto, CA, USA; and
4 Ministry of Health, Kampala, Uganda
Correspondence: * corresponding author, shafer{at}psg.ucsf.edu
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Abstract |
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 TOP Abstract IntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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KEY WORDS: HIV • saliva • breast-feeding • oral mucosa • oral fluid • post-natal transmission
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Introduction |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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Understanding how HIV presents in the oral environment may lead to rapid and accessible HIV diagnosis, and improved prevention and treatment.
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List of Questions |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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Question 2: Can oral fluids be used for diagnostics in the HIV-infected individual?
Question 3: What are the routes of HIV transmission via breast milk (BM)? Are tonsillar and gastrointestinal tissues (GIT) the primary sites of initial infection?
Question 4: How do other conditions in infants and mothers affect post-natal transmission?
Question 5: What are the benefits and safety of ART, especially nevirapine, given to mothers and infants to prevent the transmission of HIV associated with lactation?
Question 6: What is the rate of infectivity of HIV associated with oral sex?
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Oral Fluids and HIV Diagnosis |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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Here, we review some other potential candidates for consideration as oral markers of disease progression that have been considered, including: IgA, calprotectin, secretory leukocyte protease inhibitor (SLPI), Th1/Th2 cytokines, neopterin, and beta-2-microglobulin. Since oral diseases such as candidiasis are also correlated with decreased HIV viral load (Baqui et al., 1999a), the assessment of these markers in the presence or absence of oral disease has been postulated to be useful for assessing disease progression. HIV infection may be associated with a serum IgA hypergammaglobulinaemia; however, conversely, secretory IgA levels appear to be lowered in HIV infection. Further, the correlation between serum total IgA levels and CD4 count is poor, leading researchers to conclude that salivary IgA would be a poor marker of HIV disease progression (Sweet et al., 1995). Salivary calprotectin levels are increased in the presence of candidiasis, presumably as a consequence of local inflammation, leading to suggestions that this marker may be useful. However, by controlling for confounding variables, researchers found that, in the presence of HIV infection, there is an overall decrease in salivary calprotectin concentration levels, but these correlated poorly with CD4 counts (Sweet et al., 2001). SLPI is a well-known inhibitor of HIV in saliva and other mucosal secretions (Shugars et al., 2002). SLPI levels have been shown to increase by 17% in plasma and 10% in saliva in HIV patients, and this increase was more marked in patients with high viral loads (> 10,000 copies/mL) compared with low loads (< 400 copies/mL). However, alterations in SLPI levels could be used to distinguish only broad subject groups and were not sufficient to be used to predict the progression of individuals (Baqui et al., 1999b). The measurement of local mucosal Th1/Th2 cytokines (IL-4, IL-10, IL-2, IFN-.
, IL-12) in saliva may be indicative of oral-associated cell-mediated immunity, which might reflect the susceptibility of HIV patients to oropharyngeal candidiasis (Leigh et al., 1998). These factors have not, to our knowledge, been assessed in oral fluids other than saliva. Other factors that have been considered as markers of HIV disease progression include beta-2-microglobulin, TNF alpha receptor II, and neopterin levels, which have been compared in serum, saliva, and oral mucosal transudates (OMT). Although levels of these factors in OMT correlate with serum better than with saliva (Nishanian et al., 1998), poor correlations with serum levels likely preclude their use. In summary, it is unlikely that any of the factors listed above can be measured in saliva or oral fluids to give a useful and reliable indication of the progression of HIV disease.
Question 2: Can oral fluids be used for diagnostics in the HIV-infected individual?
HIV-1 antibodies are readily detected in saliva collected from HIV-1-seropositive subjects, and several commercial kits are now available for HIV testing with oral fluids. There are several advantages to using saliva rather than blood. Saliva collection is safe, simple, non-invasive and painless, and obviates the occupational risks associated with needle-stick accidents associated with blood collection (Frerichs et al., 1992). Also, because infectious virus is rare in saliva (Barr et al., 1992), samples are more readily disposed of in resource-poor settings where incineration or autoclaving may not be possible.
Some of the problems associated with HIV antibody testing in saliva—such as the low levels of IgG, degradation of IgG by bacterial proteases, and interference of assay techniques by salivary mucins—have been overcome by the collection of oral mucosal transudates. This involves placing an absorbent pad in the buccal sulcus for a few minutes to facilitate collection of IgG as it passes through the oral mucosa. Storage in a preservative diluent greatly facilitates the subsequent testing with assays reportedly achieving sensitivities and specificities of 99.9 to 100% and 99 to 99.9%, respectively (Gallo et al., 1997; Malamud, 1997; Chohan et al., 2001).
An oral fluid-based test for antibodies to human immunodeficiency virus (HIV), equivalent to serum in its accuracy but safer and easier to use, is now available in the United States and elsewhere. The development of the oral test involved overcoming technical obstacles to the use of oral fluid as a testing medium, including low immunoglobulin G (IgG) titers, suboptimal assay performance, protease degradation of IgG, high viscosity, and lack of a standardized method of specimen collection, all of which contribute to suboptimal assay performance. The currently available oral HIV test utilizes a collection device to isolate a mucosal transudate component of oral fluid rich in IgG. A vial containing a preservative solution facilitates the transport of stable, low-viscosity specimens to the laboratory for testing with an ELISA and confirmatory Western blot assay, specifically designed for use with oral fluid. Non-HIV medical conditions and oral pathologies do not appear to affect oral test results. It is hoped that the availability of this patient-friendly, portable diagnostic test for antibodies to HIV will facilitate identification of greater numbers of infected individuals, with the ultimate goals of early identification, early treatment, and prevention of disease transmission.
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Post-natal HIV Transmission |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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Question 3: What are the routes of HIV transmission via breast milk? Are tonsillar and gastrointestinal tissues (GIT) the primary sites of initial infection?
Breast-feeding is commonly practiced by many HIV-positive women in resource-constrained countries, and shedding of HIV-1 in breast milk continues to pose a risk for late post-natal transmission of HIV-1 through cell-free or cell-associated virus (Richardson et al., 2003; John-Stewart et al., 2004). The port of entry in the infants’ GIT is unknown, but may involve breaches in the mucosal surfaces, transport across M cells, or indirect infection of other epithelial cells, such as enterocytes. In the oral cavity, salivary antibodies to HIV can be readily detected, and secretory IgA antibodies can neutralize some strains of HIV. Several anti-HIV factors have been identified in saliva (Shugars et al., 2002); however, these factors have not been compared among the children who get HIV infection through breast-feeding and those who do not breast-feed. Although relatively low levels of HIV-1 RNA are present in breast milk, consumption of 0.5–1.0 liter of BM daily provides continuous exposure to potentially infectious virus through the oral cavity and the gastrointestinal mucosa. The overall probability of transmission via breast-feeding is estimated to be 0.0064 per liter of breast milk, with the average breast-feeding infant consuming ~ 150 liters of breast milk (Richardson et al., 2003).
Question 4: How do other conditions in infants and mothers affect post-natal transmission?
Co-factors associated with post-natal transmission of HIV include the frequency of breast-feeding, maternal characteristics such as poor nutritional status, exposure to or co-infection with other infectious diseases, and factors surrounding delivery (Embree et al., 2000). Most of these potential co-factors are not well-understood, but research in these areas is needed and ongoing in many areas, especially those factors that might provide avenues for intervention. Mastitis, breast tissue inflammation, and nipple lesions have been linked to elevated post-natal HIV risk (Semba and Neville, 1999; Embree et al., 2000; Fawzi et al., 2002). Mastitis is linked to elevated sodium (Na+) levels in BM and has been associated with an increase in HIV-1 RNA viral loads in breast milk, leading to elevated HIV risk (Semba et al., 1999). All of these factors provide potential routes for prevention of MTCT of HCV.
Question 5: What are the benefits and safety of ART, especially nevirapine, given to mothers and infants to prevent the transmission of HIV associated with lactation?
A 200-mg, single dose (SD) of nevirapine (NVP) given to women in labor, followed by 2 mg/kg of SD NVP to the newborn infants within 72 hours of birth, can reduce vertical transmission by almost 50% (Guay et al., 1999; Marseille et al., 1999; Jackson et al., 2003; Moodley et al., 2003). NVP, a potent non-nucleoside reverse-transcriptase inhibitor (NNRTI), is highly lipophilic, rapidly crosses the placenta, and readily enters breast milk (Musoke et al., 1999). NVP has a long half-life, excellent bioavailability, potent antiviral activity, and established safety with SD maternal and neonatal administration (Mirochnick et al., 1998; Shetty et al., 2003). Its low cost increases the potential for this intervention to reduce MTCT in resource-constrained countries.
However, this success is complicated by the risk of development of resistance virus in the mother and in infected infants (Jackson et al., 2000; Cunningham et al., 2002; Kantor et al., 2002; Eshleman et al., 2004).
In an important assessment of risk for breast-feeding infants, plasma and breast milk from 32 women from Chitungwiza, Zimbabwe, who had participated in HTPN 023 and received SD NVP, were assessed for HIV-1 RNA levels and NVP-associated reverse-transcriptase mutations (Lee et al., 2005). At 0, 2, 8, and 20–32 (reported as an average of 24 weeks) weeks after the intervention, plasma and breast-milk HIV-1 RNA levels were measured and NVP-associated mutations identified. Breast-milk sodium levels were measured to examine the correlation between sodium levels (with elevated sodium levels > 3 S.D. from normal thought to be diagnostic of subclinical mastitis) and breast-milk HIV-1 RNA levels.
Plasma HIV-1 RNA levels did not differ significantly at 0, 2, 8, and 24 weeks after SD NVP exposure, with an 8-week median HIV-1 RNA level of 4.56 log10 copies/mL (25–75% range from 3.78–4.91 log10 copies/mL). NNRTI-associated mutations were found in 21/28 (75%) of women at 2 weeks, 11/32 (34%) at 8 weeks, and 5/27 (19%) at 24 weeks following SD NVP. At the 2-week time-point, 10/28 (36%) women had a single mutation and 11/28 (39%) had 2 or more mutations; at 8 weeks, 5/32 (15%) had a single mutation and 6/32 (18%) had 2 or more mutations. Having a plasma NNRTI-associated resistance mutation at 8 weeks was significantly associated with having a lower baseline median CD4+ lymphocyte cell count of 325.5 cells per mm3 compared with a baseline median CD4+ lymphocyte cell count of 408 cells per mm3 in women who did not develop resistance mutations (p = 0.03). The 8-week HIV-1 RNA levels were higher in women who developed mutations, but were not statistically different in women who did not develop resistance (4.72 vs. 4.01 log10 copies/mL, p = 0.06). The mutations that were seen in plasma varied at different time points, with mutations at codon 181 predominating at 2 weeks (57%), but with mutations at codons 103, 106, 188, and 190 also detected, while K103N was the predominant NNRTI-associated resistance mutation at 8 and 24 weeks.
Breast-milk HIV-1 RNA levels were significantly lower at 2 weeks (1.62 and 1.54 log10 copies/mL in the left and right breast, respectively) than at 8 weeks (2.20 and 2.25 log10 copies/mL in the left and right breast, respectively), following SD NVP (p < 0.01). At 8 weeks, paired right and left breast-milk HIV-1 RNA levels were significantly correlated (r = 0.79, p = 0.003), but with higher levels in milk from the right breast (p = 0.002). Elevated sodium levels, indicative of mastitis (> 12 mmol/L), at 8 weeks were seen in 44% of the paired samples tested, but 17/29 (59%) of women had at least one breast-milk sample with an elevated sodium level. The breast-milk HIV-1 RNA level was significantly higher in those with indications of mastitis in the left breast-milk samples (1.69 vs 2.74 log10 copies/mL, p = 0.024), and trending toward significance in right breast-milk samples (1.94 vs. 2.86 log10 copies/mL, p = 0.099). Overall, a breast-milk sodium level > 12 mmol/L was associated with a 6.23 increased odds of viral RNA level higher than the study median of 2.21 log10 copies/mL at 8 weeks (95% CI 2.03–19.17).
There was no significant correlation between plasma and left breast-milk HIV-1 RNA levels (r = 0.04, p = 0.87), but there was some correlation between plasma and right breast HIV-1 RNA levels (r = 0.42, P = 0.066). Overall, plasma HIV-1 RNA levels were higher than paired breast-milk HIV-1 RNA levels (p < 0.0001). Twenty paired breast-milk and plasma samples were available for sequence analysis at the 8-week time-point. Ten pairs (50%) had concordant findings between breast-milk and plasma samples (6 pairs, wild-type (WT); 3 pairs, K103N; 1 pair, K103N and G190A); the other 10 (50%) pairs were discordant (4 pairs with WT in plasma and K103N in breast milk, 1 with WT in breast milk and K103N in plasma, and the remaining 5 pairs with dissimilar resistance mutations in both breast milk and plasma). The presence of an NNRTI-associated mutation in plasma was associated with a 13.5-increased odds of having at least one breast-milk sample with an NNRTI-associated mutation (95% CI = 0.95–687.88).
In summary, the study showed a high frequency of NNRTI-associated resistance mutations in maternal plasma, with a change in the predominant mutation over time. Different levels of HIV-1 RNA, as well as variation in the mutations detected in paired breast-milk and plasma samples, suggest the possibility that these sites represent different compartments. It is unknown where or how these compartmental differences or the NNRTI-associated mutations found in breast milk may be associated with increased transmission risk to infants.
Anti-retroviral drugs, nevertheless, will continue to pose promising effects, and investigations are under way to assess the benefits and risks of this approach toward reducing post-natal transmission (Gaillard et al., 2004; Safrit et al., 2004). Tenofovir diproxil fumarate (tenofovir), a nucleotide reverse-transcriptase inhibitor, has been demonstrated to prevent transmission of simian immunodeficiency virus (SIV) when administered near the time of virus challenge. A low dose of tenofovir (4 mg/kg/d) partially protected newborn macaques inoculated orally with virulent stock of SIVmac251 at a dose of 100,000 TCID50 (Van Rompay et al., 2001). The 4 placebo-treated animals all became persistently infected after a single inoculation. In contrast, 5 of 8 (62%) animals treated with 2 doses of tenofovir at a dose of 4 mg/kg/d remained seronegative. Two different peri-exposure dosing regimens were used that provided protection in 3 of 4 animals (75%) and 2 of 4 animals (50%), which were not statistically different. This study and others in non-human primates are important in the continued assessment of chemoprophylaxis, immunotherapeutic, and vaccine approaches to post-partum HIV prevention in infants (Van Rompay et al., 1998, 2003). Current studies planned or under way, assessing anti-retroviral interventions to reduce PTMCT in resource-constrained settings, include providing anti-retroviral therapy to infected mothers to reduce viral load in plasma and breast milk, and trials assessing the provision of anti-retroviral therapy to HIV-negative infants during periods of breast-feeding (Gaillard et al., 2004). At sites throughout Africa, studies are planned or under way assessing single or dual anti-retroviral therapies, ultrashort regimens, or one-week trials of SD NVP compared with NVP and zidovudine, intermediate duration (6 weeks) interventions of NVP regimens, and prolonged duration (6 months) interventions (reviewed in Gaillard et al., 2004). Trials of maternal treatment as prophylaxis for infants at risk of HIV from lactation using highly active anti-retroviral treatment (HAART) are also in preparation or under way. Since maternal viral load is significantly associated with infection risk in infants in both breast-feeding and non-breast-feeding women (Cooper et al., 2002; Dorenbaum et al., 2002), approaches to reducing maternal viral load during late pregnancy and after delivery are especially promising. As well as reducing transmission risk, there are other benefits, such as improved immune and health status in mothers and resistance profiles lower than those associated with SD NVP. These studies have important challenges as well, assessing safety and toxicity in both mother and child in the short and long term ("Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts," 2000). Indeed, the many potential benefits from anti-retrovirals for PTMCT could be contradicted by potentially significant and not well-quantified adverse events, including premature delivery, perinatal and neonatal mortality, hematological effects, resistance, impact on future therapy options, rare but possibly fatal mitochondrial abnormalities (Barret et al., 2003), and effects of drug exposures on growth and development.
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Oral Acquisition of HIV and Sex |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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Early studies found no independent risk for fellatio in multivariate analyses (Schechter et al., 1986a; Darrow et al., 1987; Kingsley et al., 1987; Winkelstein et al., 1987; Detels et al., 1989); however, the high correlation among multiple sexual practices in most sexually active persons left open the possibility that risk existed but could not be detected in the available data. Subsequently, case reports of HIV transmission in association with oral sex accumulated among men who have sex with men (MSM), and heterosexual couples who denied practicing other risk behaviors, including anogenital, vaginal intercourse, or intravenous drug use (DeGruttola and Mayer, 1987; Lifson, 1988; Rozenbaum et al., 1988; Detels et al., 1989; Lane et al., 1991; Murray et al., 1991). Despite uncertainty about this potential infection route, many researchers accepted that fellatio, while not an efficient route of transmission, potentially posed a small risk of HIV infection (Lyman et al., 1986; Schechter et al., 1986b; DeGruttola and Mayer, 1987; Goldberg et al., 1988; Lifson, 1988; Spitzer and Weiner, 1989; Lane et al., 1991; Chen and Samarasinghe, 1992; Keet et al., 1992; CDC, 1997; Rothenberg et al., 1998). Some quantitative estimates of risk of HIV seroconversion have been published, principally from cohort studies of MSM (Detels et al., 1989; Samuel et al., 1993; Page-Shafer et al., 1997; Vittinghoff et al., 1999). A particularly well-documented study (Detels et al., 1989) identified and attributed only one seroconversion to oral sex (fellatio) among 232 men followed for 9330 person-years of observation. A study pooling data on seroconverters from multiple sites—Amsterdam, San Francisco, and Sydney (Page-Shafer et al., 1997)—found small but significant associations for incident infection in association with oral sex. An important study by Vittinghoff et al.(1999) estimated infectivity in association with various sexual behaviors and condom use among MSM. They found that the per-contact risk among MSM of unprotected receptive fellatio with ejaculation with an HIV-positive or ’unknown HIV status’ partner, estimated at 4/10,000 (95% CI, 0.01%, 0.17%), was slightly lower than the estimated risk of acquiring HIV per act of protected receptive anal sex (0.18%; 95% CI, 0.10%, 0.28%) and much lower than in unprotected insertive anal sex (0.06%; 95% CI, 0.025%, 0.19%). A limitation of these as well as other studies is the possible overestimation of risk due to the inclusion of persons in the analyses who engaged in higher-risk practices, such as anal sex (Page-Shafer et al., 1997; Vittinghoff et al., 1999; Celum et al., 2001). Keet et al.(1992) found that more than half of incident HIV infections attributed to receptive oral sex (fellatio) were misattributed due to response bias, wherein a high proportion of study participants did not report anogenital sex in written questionnaires, but later did report this practice in face-to-face interviews, leading researchers to conclude that oral acquisition of HIV occurs, but its frequency may be overestimated because of reluctance to report more stigmatized practices, including anal sex. Two more recent studies underscore the very low infectivity of HIV in association with oral sex in heterosexual and MSM populations. In a longitudinal study of serodiscordant heterosexual couples, del Romero et al.(2002) found no incident HIV infections in over 19,000 unprotected orogenital contacts with an HIV-infected partner. In a study of MSM HIV testers in San Francisco who practiced only oral sex (Page-Shafer et al., 2002), no prevalent or incident HIV infections were detected in an estimated 1519 person-years of risk exposure (Balls et al., 2004).
Animal models have demonstrated the biologic plausibility of HIV infection from oral exposure to infected semen: Macaques exposed orally and non-traumatically to SIV easily acquire infection (Baba et al., 1996). These studies use high concentrations of SIV and invasive methods of infection which do not approximate human exposure, where infectivity is demonstrably lower. Maher et al.(2004) reported that although HIV binds to oral mucosal, there is limited progression to infection. These authors developed a mucosal model, using human palatine tonsil with intact external epithelium, to study events after oral exposure to HIV. When applied to the external epithelium, semen from an HIV-seropositive patient and cell-free virus both established HIV infection in individual tonsillar cells. However, clusters of infected tonsillar cells were detected where the epithelial surface was damaged. Investigation of the initial events in HIV transmission revealed extensive and stable binding of HIV virions and seminal cells to tonsil epithelium. In experiments modeling physiologically relevant events, the addition of seminal plasma resulted in enhanced virion binding to epithelial cells; however, there was limited progression from binding to primary infection (Maher et al., 2004).
In conclusion, the low probability of infection in oral sex, combined with the high prevalence of this sexual practice, has suggested to many researchers the presence of potential inhibitory or defensive factors in the oral cavity (Shugars et al., 2002). Investigations into these factors continue to be needed to develop protective agents or pathways for HIV prevention.
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Conclusions and Suggestions for Future Research |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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Acknowledgments |
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Authors received funding from the following sources: K. Page-Shafer from the NIDCR (1 R01 DE12911); Simon Sweet from the Department of Oral Medicine, Pathology and Microbiology, Guys, Kings and St Thomas’ Dental Institute, London; Seble Kassaye from the Doris Duke Charitable Foundation (20000648); and Charles Ssali from the NIH/NIMH (5 P50 MH42459). All authors received support from the organizers of the 5th World Workshop on Oral Health and Disease in AIDS.
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References |
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TOPAbstractIntroductionList of QuestionsOral Fluids and HIV...Post-natal HIV TransmissionOral Acquisition of HIV...Conclusions and Suggestions for...References |
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