Download Clinical Associations HIV Increased HIV

Bacterial Vaginosis
Gynecologic and Obstetric Considerations
Reproductive Infectious Disease Seminars
March 29, 2005
Natali Aziz, MD, MS
Reproductive Infectious Disease and Maternal-Fetal Medicine Fellow
Department of Obstetrics, Gynecology and Reproductive Sciences
University of California, San Francisco
Overview
www.superscore.com
•
•
•
•
•
Microbiology
Pathogenesis
Epidemiology
Diagnosis
Treatment
– Non-pregnant
– Pregnant
www.fpnotebook.com
• Clinical Associations
– Gynecologic
– Obstetric
– HIV
• Special Considerations
– Screening in Pregnancy
– Treatment in Pregnancy
– Sexual Transmission
Microbiology
•
•
•
•
•
Lactobacillus acidophilus
Gardnerella vaginalis
Mycoplasma hominis
Mobiluncus species
Anaerobes
Mobiluncus mulieris
www.infek.lu.se
– Bacteroides
(Porphyromonas)
– Peptostreptococcus
– Fusobacterium
– Prevotella
Mycoplasma hominis
www.ksmed.ru
Pathogenesis
• Lactobacilli
www.ulb.ac.be
– Compete with other microorganisms for adherence to
epithelial cells
– Produce antimicrobial compounds such as organic
acids (which lower the vaginal pH), hydrogen peroxide,
and bacteriocin-like substances
• Mechanism by which floral imbalance occurs and
the role of sexual activity in the pathogenesis of
bacterial vaginosis are not clear
Pathogenesis
• Marked reduction in
lactobacillus
– Decreased hydrogen
peroxide production
• Polymicrobial superficial
infection: overgrowth of G.
vaginalis and anaerobic
bacteria
– Lactobacilli predominate
after metronidazole
treatment
– (Spiegel and Holmes 1983)
Lactobacillus
www002.upp.co-net.ne.jp
Epidemiology
• “Nonspecific vaginitis” •
• Most common vaginal
infection in women of
•
childbearing age
• Prevalence 5-60% across
the world
•
• 35-50% of “vaginitis”
• 16% (9-23%) prevalence
in pregnant women in
US
Higher prevalence (2437%) in more sexually
active women
High prevalence in
women who have sex with
women, unlike other STIs
Differs by ethnic group
–
–
–
–
6% in Asians
9% in Caucasians
16 % in Hispanics
23% % in African
Americans
CDC 2000, August 2004; Berg 1984; Hillier 1990;
Eschenbach 1988; Skinner 1996; Fethers 2000; Joesoef 2001; Morris 2001
Epidemiology
• Risk factors
–
–
–
–
–
–
Multiple or new sexual partners
(sexual activity alteration of vaginal pH)
Early age of first sexual intercourse
Douching (Ness 2002, Schwebke 2004)
Cigarette smoking (Joesoef 2001, Morris 2001)
Use of IUD (Joesoef 2001, Morris 2001)
*Although sexual activity is a risk factor for
the infection, bacterial vaginosis can occur in
women who have never had vaginal
intercourse
(Yen 2003)
Clinical Features
• Most cases (50-75%)
asymptomatic or mild
• Musty or fishy odor of vaginal
discharge
• Thin, gray-white, non-clumping,
homogenous vaginal discharge
• Dysuria and dyspareunia rare
• Pruritus and inflammation are
absent
• Absence of inflammation is the
basis of the term "vaginosis"
rather than vaginitis
Clinical Features
Discharge due to bacterial vaginosis has been removed revealing a normal cervix. This
discharge associated with BV is from the vagina - not the cervix.
www.hc-sc.gc.ca
Diagnostic Methods
•
•
•
•
Clinical/Microscopic Criteria
Gram Stain (“Gold Standard”)
Pap Smear
Femcard- detect elevated pH
and increased amine
www.hc-sc.gc.ca
– Sensitivity 87%; Specificity 92%
(Hillier)
• *Culture- poor predictive value
for G. vaginalis as prevalent in
healthy asymptomatic women
• *DNA probes- expensive, poor
predictive value alone
Courtesy of Abner P. Korn, MD
www.superscore.com
Diagnostic Criteria (Amsel’s)
Clinical features necessary for diagnosis
of BV include 3 of 4 clinical criteria
– Clue cells on saline wet mount of vaginal
discharge (on >20% cells)
• Bacteria adhered to epithelial cells; most
reliable single indicator
– Vaginal pH > 4.5
• High sensitivity; Poor specificity (false
positive with mucus, menses, semen)
– Characteristic vaginal discharge: thin,
homogeneous, gray-white, and adherent
consistency (scant, moderate, profuse)
– Positive “whiff” test (Amine Test)
• Release of fishy amine odor on addition of
10% KOH to discharge
• Also observed in Trichomonas infection
Amsel and Holmes et al, 1983
www.rnzcgp.org
Diagnosis by Gram Stain
Treatment Considerations
• Resolves spontaneously in 1/3 of nonpregnant and
pregnant women
• Treat
– Symptomatic infection
– Asymptomatic infection prior to abortion or hysterectomy
• 10 -75% reduction in postoperative infectious complications
(Larsson 1992, 2000; Crowley2001)
– ?Asymptomatic pregnant women with previous preterm
birth controversial
• *No difference in symptoms with treatment of
asymptomatic infection (Shwebke 2000)
Treatment Recommendations
• Oral metronidazole 500 mg bid x 7 days ($5)
– 84-96% cure rate
– Single dose therapy (2g) may be less effective
• Oral Clindamycin 300 mg bid x 7 days ($28)
– Less effective
• Topical treatments (higher recurrence rates)
– Metronidazole gel (0.75%) 5 g PV qhs x 5 days ($30)
• 70-80% cure rate
– Clindamycin cream (2%) 5 g PV qhs x 7 days ($31)
• Less effective
• May lead to Clindamycin resistant anaerobic bacteria
Majeroni 1998
Treatment
Refractory/Resistant Cases
• Metronidazole 500 mg po bid x 14
days ($10)
• Other options
– Povidone-iodine (Betadine) gel/supp
PV bid x 14-28 days ($59)
• *No benefit in treatment of sexual
partner
• *Future approaches: “Probiotics”
– Exogenous lactobacillus (elevated
arginine deaminase activity)
recolonization with suppositories
Treatment
Recurrent Cases
• Up to 30% have recurrence in 3 months
• Treat as refractory case
• Maintenance therapy
– Induction: metronidazole gel (0.75%) qhs x 10
days
– Maintenance (when no clue cells on wet mount
and lower pH):
• Metronidazole gel twice weekly x 3 months
• Treat concurrent Candida (Fluconazole 150
mg qW)
Treatment Recommendations
Pregnancy
• First Trimester
–
–
–
–
Metronidazole 250 mg po tid x 7 days
Clindamycin 300 mg po bid x 7 days
Clindamycin cream PV 5 g PV qhs x 7 days
Metronidazole gel PV bid x 5 days
• Other Trimesters
– Metronidazole 250 mg po tid x 7 days
– Clindamycin 300 mg po bid x 7 days
– Erythromycin 333 mg po tid x 14 days
• Topical therapy (clindamycin vaginal cream) at
14-26 weeks not as effective in pregnancy
– Increased PTD (Joesoef 1995, McGregor 1994)
Safety of Metronidazole in Pregnancy
• Hesitation to use oral metronidazole
in pregnancy remains, especially in
first trimester
• Limited studies
• Theoretic teratogenicity risk
• Meta-analyses report no association
between birth defects and use of
metronidazole during pregnancy
www.accuratepregnancytests.com
(Piper 1993, Ledger 1993, Schwebke 1995, Burtin 1995)
Clinical Associations
Gynecologic
www.uptodate.com
Courtesy of Jack Sobel, MD
• PID
– Post-induced abortion
(Eschenbach 1993)
• Plasma cell
endometritis
– 15x higher in women
with BV (Korn 1995)
• Post-surgical Infection
– Post hyst cuff cellulitis
(Larsson 1991)
• ?CIN
– (Boyle 1999, Frega1997)
• More common in women
with PID
– BUT… Not
independently
responsible for PID
(Soper 1994, Ness 2004)
Clinical Associations
Obstetric
• Approximately 15-20% of pregnant women in US have BV
• Preterm Delivery
– BV association with PTD: 1.8 and 2.2 pooled OR from metaanalyses (Flynn 1999, Leitich 2003)
• Flynn- 19 studies
– Pooled aOR yielded 60% increase in PTD in presence of
BV
• Leitich- 18 studies (over 20,000 patients)
– Two-fold increase in PTD with BV (OR 2.2)
– Early Dx and Tx may be more effective in prevention of
PTD than late second trimester management
– BV dx < 16 weeks: PTD OR 7.55 (1.80-31.65)
– BV dx < 20 weeks: PTD OR 4.20 (2.11-8.39)
– SAB OR 9.91 (1.99-49.34)
– Maternal Infection OR 2.53 (1.26-5.08)
(Hillier 1995, Meis 1995, Hauth 1995)
Clinical Associations
Obstetric
• Potential Mechanism of BV association with PTL/PTD
– Genetic polymorphism in regulation of cytokine
production/TNF-2 with greater pro-inflammatory immune
response to infectious stimuli (BV) (Macones 2004, Romero 2003)
• “Susceptible” genotype (TNf-2 allele) and BV yielded OR 6.1of PTD vs.
OR 2.7 in setting of TNF-2 allele alone (Macones 2004)
– Enhanced cytokine induction possibly leading to PTL or
PPROM
– Women with altered vaginal flora developed elevated IL-1beta
and subsequently are at higher risk of PTB than women with
similar altered flora but no IL-1beta elevation
• Sensitivity of 78%; specificity 51% (Genc 1995)
Clinical Associations
Obstetric
• Chorioamnionitis
– (Eschenbach 1989, Hillier 1988)
• Amniotic fluid infection
– OR 1.85 (1.16-2.9) (Newton 1997)
• Spontaneous abortions
– Increased risk of 1st trimester SAB in IVF aOR 2.03 (1.09-3.78)
– Diagnosed more frequently in women w/ h/o late miscarriage (Llahi-Camp 1995)
– Associated with 2nd trimester loss (McGregor 1995, Hay 199$)
– 2nd trimester loss AB OR 9.91 (1.99-49.34) (Leitich 2003)
• PPROM:
– OR 7.3 (McGregor 19993)
• Postpartum Endometritis
– OR 2.53 (1.26-5.08) (Leitich 2003)
– PP endometritis post c/section: RR 1.4 (Newton); aOR 5.8 (Watts 1990)
Clinical Associations
Pediatric
• Low-birth weight
– In setting of PTD
(Hillier 1995)
• ?Neonatal Infections
Considerations
Screening/Treatment in Pregnancy
• Studies do not show reduction of PTD or other
adverse prenatal outcomes with treatment of
asymptomatic BV in pregnant women
(McDonald 2003, Carey 2000, McDonald1997)
• Cochrane Review 2003:
– 10 trials/>4200 patients
– Abx therapy effective in eradicating infection
– No significant reduction of PTB at < 37 weeks, at < 34
weeks, or <32 weeks (McDonald 2003)
• Screening and treating all pregnant women with
asymptomatic bacterial vaginosis to prevent PTD
NOT RECOMMENDED
(McDonald 2003)
Considerations
Screening/Treatment in Pregnancy
• Cochrane Review 2003 (McDonald 2003)
– Subgroup analysis of women with a history of >1 prior
preterm births
– Detection and treatment of asymptomatic bacterial vaginosis in
this population appeared to markedly reduce the rate of
PPROM (OR 0.14, 95% CI 0.05-0.38) and low birth weight
(OR 0.31, 95% CI 0.13-0.75)
– No significant affect on risk of subsequent preterm birth (OR
0.83, 95% CI 0.59-1.17)
– Lack of reduction in preterm birth was largely due to data
from the largest (n = 1953) trial of screening and treatment of
bacterial vaginosis in pregnant women, which reported an
absence of benefit in both average risk women and in the
subgroup of women at high risk of preterm birth (n = 210) (Carey
2000)
Considerations
Screening/Treatment in Pregnancy
• US Preventive Services Task Force (7 RTC)
Considerations
Screening/Treatment in Pregnancy
• USPSTF
Considerations
Screening/Treatment in Pregnancy
• US PSTF
Considerations
Screening/Treatment in Pregnancy
• Recommendation
*Screening and treatment of bacterial vaginosis
could be considered in women with a previous
preterm birth in order to lower the rate of preterm
premature rupture of membranes and low birth
weight, as these conditions are associated with
maternal and neonatal morbidity
*But still not recommended as standard of care for
women with prior PTD
-Cochrane Review
-Centers for Disease Control and Prevention
-United States Preventive Services Task Force
Considerations
Screening/Treatment in Pregnancy
• Still Unclear
– Optimal choice of
therapy
– Time of therapy
initiation
– Therapy duration
Considerations
Screening/Treatment in Pregnancy
• First three trials demonstrating reduction in preterm birth
in high risk patients had screened patients in the second
trimester
– Women with positive test results were treated with oral
metronidazole or oral metronidazole and erythromycin
(Morales 1994, Hauth 1995, McDonald 1997)
• Seven days of treatment may be more effective than two day
regimens (Leitich 2003)
• Oral clindamycin (300 mg twice daily for five days) or
clindamycin cream (daily per vagina for three to seven days)
given early in pregnancy were effective alternatives
(Ugwumadu 2004, Kiss 2004, Ugwumadu 2003, Lamont 2003)
Considerations
Screening/Treatment in Pregnancy
• CDC
If women with prior PTD is screened in subsequent
pregnancy
– Perform at first PNV
– Initiate treatment at that time if BV diagnosed
– F/U evaluation in 1 month after completion of therapy
CDCP; STD Treatment Guidelines 2002
Considerations
Screening/Treatment in Pregnancy
Clinical Associations
HIV
www.vpul.upenn.edu
• BV more prevalent and more persistent in HIV-infected
women
• Prospective cohort study
– Patients followed over 5 years; exams Q6 months
– Adjusted analyses
– HIV+ women more likely than HIV- women to have
prevalence of BV aOR 1.29 (1.08-1.55)
– HIV+ women more likely than HIV- women to have
persistent BV aOR 1.49 (1.18-1.89)
– HIV+/CD4<200 more likely than HIV+/CD4 >500 to
have prevalence of BV aOR1.29 (1.03-1.60); persistent
BV aOR 1.38 (1.01-1.91); more severe BV aOR 1.50
(1.12-2.0)
Jamieson 2001
Clinical Associations
HIV
• BV-associated
microflora isolated
from female genital
tract activates HIV-1
expression (Al-Harthi
1999; Hashemi 1999;
Hashemi 2000)
• Possible risk factor for
HIV acquisition and
transmission
Clinical Associations
HIV
• BV independently associated with HIV seroprevalence
• Cross sectional study
– 144 female commercial sex workers
– Tested for gonorrhea, Chlamydia, syphilis, Candida,
Trichomonas, HIV, BV (clinical criteria and Gram stain)
– BV association with HIV OR 2.7 (1.3-5.0) by clinical
criteria
– BV association with HIV aOR 4.0 (1.7-9.4)
– Relationship: ?HIV promotion of abnormal vaginal flora
or does BV increase susceptibility of HIV sexual
transmission
– OR intervening variables: BV marker or cofactor of HIV
transmission
Cohen 1995
Clinical Associations
HIV
• Association between BV and HIV-1 among
pregnant and post-natal women
• Prospective cohort
– BV associated with antenatal seroconversion aOR 3.7
– BV associated with postnatal HIV seroconversion aOR
2.3
– Increased risk of HIV seroconversion with increasing
severity of vaginal disturbance
– Attributable risk of BV alone for HIV seroconversion
• Antenatal 23%
• Postnatal 14%
Taha 1998
Clinical Associations
HIV
• Increased HIV-1 infection in women with
abnormal vaginal flora (Sewankambo 1997)
• Prospective cohort study (Martin 1999)
– Absence of vaginal lactobacilli per culture
associated with increase risk acquisition HIV1, HR 2.0 (1.2-3.5); gonorrhea, HR 1.7 (1.2-2.6)
– Presence of abnormal vaginal flora on Gram
stain associated with increased risk acquisition
HIV-1, HR 1.9 (1.1-3.1); Trichomonas, HR 1.8,
(1.3-2.4)
– Controlled for identified RF using multivariate
models
Clinical Associations
HIV
Absence of
Lactobacilli
HIV-1
Presence of
Abnormal
Flora
HR 2.0 (1.2-3.5) HR 1.9 (1.1-3.1)
Gonorrhea
HR 1.7 (1.1-2.6)
NS
NS
HR 1.8 (1.3-2.4)
Trichomonas
Martin et al, 1999
Clinical Associations
HIV
www.wooster.edu
• Bacterial vaginosis associated with HIV-1 RNA
expression in female genital tract of HIV-infected
women
• Cross sectional cohort study
– Assessed for effect of lower GTI on HIV-1 RNA levels
– 108 HIV infected women (136 paired plasma and
cervicovaginal lavage specimens)
– Assessed by BV (Amsel’s), Trichomonas (culture),
Candida (culture and clinical criteria)
– Defined threshold HIV-1 RNA levels >400 copies/ml
– Logistic regression adjusting for plasma VL, ARV, and
CD4 count
Cu-Uvin et al, 2001
Clinical Associations
HIV
Detectable HIV-1 RNA
No HAART
P=0.025
HAART
P=0.176
No BV
34%
23%
BV
78%
67%
Cu-Uvin et al, 2001
Clinical Associations
HIV
Proportion of women with
plasma HIV type 1 (HIV-1)
RNA level >400 copies/mL
from whom cervicovaginal
lavage (CVL) samples were
obtained that had an HIV-1
RNA level >400 copies/mL,
stratified by genital tract
infection status and receipt
of highly active
antiretroviral therapy
(HAART). Vertical bars
represent 95% CIs for the
estimated proportions. Neg,
negative results of tests for
infection; Pos, positive
results of tests for infection.
Cu-Uvin et al, 2001
Clinical Associations
HIV
Any GTI
BV
Candida
3.7 (1.4-10.1)
-
-
BV
-
5.9 (1.4-25.0)
-
Candida
-
-
1.0 (0.3-3.0)
HAART
0.3 (0.1-1.2)
0.3 (0.1-1.3)
0.3 (0.1-1.4)
CD4 <200
3.4 (0.8-14.3)
2.8 (0.7-10.5)
2.5 (0.7-9.2)
Plasma VL
6.6 (2.5-17.3)
6.8 (2.6-17.5)
6.4 (2.7-15.4)
Any GTI
Cu-Uvin et al, 2001
Clinical Associations
HIV
• Conclusion: Cu-Uvin et al, 2001
– BV associated with increased expression of HIV-1 RNA levels
in female genital tract
– Limitation of small sample size of women with genital tract
infections other than BV
– BV may be surrogate marker for other nonspecific
inflammatory states or behavioral/clinical factors increasing
risk of HIV RNA expression
• Plausibility of BV as RF for HIV acquisition and transmission
• BV-associated microflora isolated from female genital tract activates
HIV expression (Al-Harthi 1999; Hashemi 1999; Hashemi 2000)
• In vitro evidence for increased pro-inflammatory cytokines (TNF-alpha
and IL-1) in patients with BV; ?thereby increased risk for HIV
susceptibility associated with BV (Sturm-Ramirez 2000)
Future Considerations
HIV Control
• Studies investigating
treatment/control of BV effect
on reduction of HIV viral
load in genital tract and
ultimately HIV
sexual/perinatal transmission
• Development and evaluation
of vaginal microbicides
consisting of naturally
occurring Lactobacillus
Considerations
Sexual Transmission
• Controversy remains
• Occurs more commonly in women with more than one
sexual partner
– BUT can also occur in women not yet sexually active
– No difference in BV rates between sexually active and
not yet sexually active groups (Bump 1988, Yen 2003)
• Treatment of male partner: no improvement in cure rates
or reduced rate of recurrence (Moi 1989)
– Treatment of sexual partner not recommended
• Variable Co-infection rates
– Chlamydia and gonorrhea increased
– No difference in syphilis or Trichomonas
• Not exclusively STI