**5. Treatment**

A cervical cancer screening program cannot be effective unless there is an effective intervention to prevent the development of cervical cancer. Excisional or ablative treatment is indicated for the presence of high grade lesions, which encompasses a diagnosis of moderate-severe cervical dysplasia or carcinoma-in-situ and are the immediate precursors of invasive cervical cancer (ICC). Hysterectomy should not be used as a primary treatment for high-grade cervical dysplasia without first ruling out the presence of invasive cancer with an excisional procedure. The most common procedures used for treatment are loop electrosurgical excisional procedure (LEEP), cryotherapy or cervical conization. Table 2 summarizes the key characteristics of each treatment option.


\*Effectiveness figures cited based on studies in general populations. In HIV + women, the effectiveness is expected to be lower for all techniques.

Table 2. Comparison of treatment methods for cervical dysplasia.

Cervical conization requires regional or general anesthesia and removes a larger volume of tissue. There are higher complication rates after the procedure, including postoperative bleeding (5–15%), infection (02–6.8%), cervical stenosis (approximately 8%) and increased risk of preterm delivery (Hoffman and Mann 2010; Arbyn et al. 2008). This procedure is typically used when lesions are entirely within the cervical canal (based on pathologic analysis of endocervical curettage), are thought to extend high into the cervical canal or when invasive cancer is suspected, so that accurate pathological examination can be performed and, when preinvasive, the entire lesion can be removed.

LEEP has supplanted cervical conization in many situations, including lesions that are believed to extend more superficially into the canal. LEEP utilizes a thin wire in the shape of

HPV+ to assess the presence of disease and the feasibility of treatment. Those who are HPVnegative would receive no further screening. Alternatively, VIA could be the initial screen,

A cervical cancer screening program cannot be effective unless there is an effective intervention to prevent the development of cervical cancer. Excisional or ablative treatment is indicated for the presence of high grade lesions, which encompasses a diagnosis of moderate-severe cervical dysplasia or carcinoma-in-situ and are the immediate precursors of invasive cervical cancer (ICC). Hysterectomy should not be used as a primary treatment for high-grade cervical dysplasia without first ruling out the presence of invasive cancer with an excisional procedure. The most common procedures used for treatment are loop electrosurgical excisional procedure (LEEP), cryotherapy or cervical conization. Table 2

**Cervical Conization LEEP Cryotherapy** 

Electrical generator, wire loops (different sizes)

Intermediate: dependent on amount of tissue removed; excessive bleeding during or after procedure most common

Yes Yes No

Highest Intermediate Lowest–nurses, midwives

Cryoprobes (different sizes), CO2 tank

can safely and effectively perform

Lowest: <1–2%, generally minor

General or regional Local None

with those who are VIA+ having HPV testing to improve PPV.

summarizes the key characteristics of each treatment option.

Operating room supplies, instruments, personnel, anesthetics

stenosis, adverse pregnancy outcomes most common

Table 2. Comparison of treatment methods for cervical dysplasia.

performed and, when preinvasive, the entire lesion can be removed.

**Complications** Highest: bleeding,

is expected to be lower for all techniques.

**Effectiveness \*** 96%+ 96%+ 88%

**Cost** Highest Intermediate Lowest

\*Effectiveness figures cited based on studies in general populations. In HIV + women, the effectiveness

Cervical conization requires regional or general anesthesia and removes a larger volume of tissue. There are higher complication rates after the procedure, including postoperative bleeding (5–15%), infection (02–6.8%), cervical stenosis (approximately 8%) and increased risk of preterm delivery (Hoffman and Mann 2010; Arbyn et al. 2008). This procedure is typically used when lesions are entirely within the cervical canal (based on pathologic analysis of endocervical curettage), are thought to extend high into the cervical canal or when invasive cancer is suspected, so that accurate pathological examination can be

LEEP has supplanted cervical conization in many situations, including lesions that are believed to extend more superficially into the canal. LEEP utilizes a thin wire in the shape of

**5. Treatment** 

**Anesthesia required** 

**Technical difficulty** 

**Pathologic specimen** 

**Other resources needed** 

a loop and electrosurgical generators; the loops are available in a variety of sizes and can also be passed through tissue with several passes if needed to remove the entire area of abnormality, therefore tailoring the procedure to the size of the lesion on the extocervix. The depth of excision can be fairly precisely determined and controlled. LEEP can be performed under local anesthesia and removes less tissue than conization. Complications are less common than after conization (postoperative bleeding 0–8%, infection 0–2%, cervical stenosis 4.3–7.7%; preterm delivery-no increased risk) (Hoffman and Mann 2010; Arbyn et al. 2008).

Cryotherapy uses nitrous oxide or carbon dioxide to freeze the cervix and destroy precancerous tissues and can be performed without anesthesia or electricity. Freezing is done in two cycles of three minutes with five minutes of thawing in between (Sellors 2003). Mid-level providers have been trained successfully to perform cryotherapy safely and with a high degree of acceptability (Bradley 2006; Nene et al. 2008). Carbon dioxide (CO2) provides a less expensive alternative to nitrous oxide and produces equally low temperatures (Sirivongrangson 2007). However, some studies report that CO2 may cause cryotherapy blockage up to 50% (Sirivongrangson 2007; Winkler 2010). The quality of cryotherapy devices rather than gas could be responsible for variant temperature (Winkler 2010). The freeze-clear-freeze technique, often employed to reduce gas blockage, may also produce temperatures not sufficiently low enough for treatment to be effective (Winkler 2010). It is important for providers to give adequate treatment by paying attention to visual cues that confirm freezing. Cryotherapy does not provide a tissue specimen. For cryotherapy to be optimally effective, the entire lesion and ideally the entire transformation zone must be visible and the lesion should occupy less than three-fourths of the transformation zone (Sankaranarayanan 2008). Adverse effects after cryotherapy are relatively uncommon and generally minor, reported in 1–2% of women (Cirisano 1999; Sankaranarayanan 2007; Nene 2008). Discomfort usually resolves within a week after treatment (Chamot 2010; Bradley 2006). Significant bleeding after cryotherapy is uncommon. After cryotherapy, watery discharge generally continues for several weeks. Post-treatment infection and pelvic inflammatory disease for LEEP and cryotherapy are both rare (Chamot 2010). The risk of cervical stenosis after cryotherapy is low (<1%) (Loobuyck and Duncan 1993) and the risk of obstetric complications, particularly preterm delivery, is lower after cryotherapy than after excisional procedures. Complications after cryotherapy do not differ among developed and developing countries.

In lower resource areas, the advantages of cryotherapy are significant: the ability to perform the procedure without anesthesia, lack of need for electricity, the lower level of technical expertise required to perform the procedure and lower costs. A significant advantage of LEEP is the ability to examine a tissue sample histologically; however, in areas with few resources, pathological evaluation is usually not available. Studies have generally found LEEP to be associated with somewhat higher cure rates (absence of persistent or recurrent disease) than cryotherapy (Melnikow et al. 2009). A randomized clinical trial of cryotherapy and LEEP for treatment of histologically confirmed high-grade cervical dysplasia found that LEEP had higher overall cure rate of 96.4% as compared to 88.3% for cryotherapy (p=0.026) (Chirenje et al. 2001). Treatment methods are generally consistent among high-income and low-income countries (Luciani 2008). Cryotherapy is less effective in older women, where the transformation zone and any cervical lesions are more likely to recede into the cervical

Cervical Cancer Screening and Prevention for HIV-Infected Women in the Developing World 245

VIA results are important to further refine screening and treatment protocols and inform guidelines on appropriate screening strategies and intervals. Integration of cervical cancer screening for HIV+ women requires testing of different models for training, implementation and data collection. Given the information currently available of the interaction of HPV and

Will screening earlier in the course of HIV, when there is less immunosuppression, be

Will ART and associated immune reconstitution make a difference in rates of VIA

How will VIA and HPV testing be best integrated to enhance test performance,

How will cervical cancer prevention be taken to scale in low and middle income

Given the millions of new HPV infections/ year in 14-44 year olds primary prevention of HPV infections should be a priority. Consistent and correct use of condoms has been associated with reduction in risk for acquisition of genital HPV infection, including genital warts, CIN and cervical cancer (Winer et al. 2006; Vaccarella et al. 2006; Manhart and Koutsky 2002) although data are limited in the HIV setting. Male circumcision (MC) has been shown to reduce by reduce the risk of sexual HIV transmission from female to male by 60% (http://www.who.int/hiv/topics/malecircumcision/en/index.html) in randomized clinical trials. MC was also associated with a lower incidence of multiple high-risk HPV types and increased clearance of HR-HPVs as compared to controls (14.8% vs 22.3%, respectively) in Uganda (Gray et al. 2010); however, MC was not associated with decreased incidence or increased clearance of HR-HPV in the female partners of circumcised men 24 months after the procedure, as compared to partners of men in the control group (Tobian et al. 2011) However, MC has long been associated with reduced risk of cervical cancer in the

Finally, two HPV preventive vaccines are now available, one quadrivalent, providing protection against HPV types 16, 18, 6, 11, and the second bivalent, protecting against HPV types 16 and 18 only. In the initial trials of these vaccines, there was >95% -100% protection against incident infection with vaccine subtypes in women not previously infected with those subtypes and in CIN2 or greater related to HPV-16 or 18 (FUTURE II Study Group, 2007; Villa et al. 2005; Paavonen et al. 2009, Garland et al. 2007) vaccine effectiveness was maintained through over 7 years of follow-up (FUTURE I/II Study Group 2010). Although there are other high risk HPV types, types 16 and 18 are responsible for approximately 70% of invasive cervical cancers worldwide (de Sanjose et al. 2010). Recent HPV seroprevalence studies in HIV+ African women found that 65% were seropositive for one of the vaccine subtypes (Firnhaber 2011), suggesting that early vaccination may provide significant

What is the relative efficacy and safety of LEEP vs cryotherapy in HIV+ women?

HIV infections and the epidemiology of HIV:

positivity and lesion size?

feasibility and scale-up?

countries?

associated with smaller and more treatable lesions?

Are HIV+ women more likely to accept SVA than HIV- women?

What are appropriate models of care and what is their feasibility?

How often should screening occur in HIV+ women?

**7. Primary prevention of HPV/cervical cancer** 

wives of circumcised men; therefore further study is warranted.

canal and is less effective with large lesions. This raises potential concerns in the management of HIV+ women, who may have lesions occupying a larger volume of the cervix.

One of the treatment effects with either cryotherapy or LEEP may be stimulation of the immune response, promoting clearance of HPV after treatment, even if the entire lesion or the entire transformation zone is not excised or ablated, although one small study failed to show an effect of cryotherapy on HPV clearance one year after treatment (Taylor 2010; Chumworathayi et al. 2010).

HIV-positive women have an increased incidence of persistence or recurrence after treatment, with some studies documenting >50% recurrence rate (Tebeu et al. 2006). Recurrence rates are increased in the following situations:


Most recurrences in HIV+ women appear to be low-grade disease, which may be associated with new HPV infections (Massad et al. 2007) but re-excision may be necessary in some cases (Holcomb et al. 1999; Gingelmaier et al. 2007). Follow-up with cervical cytology alone or cytology and colposcopy together at 6-month intervals over the first year after treatment is recommended (CDC 2009; Wright et al. 2007).

There remain limited data on the use of LEEP and cryotherapy in the setting of HIV, especially related to efficacy. A study of HIV-infected and –uninfected women in Zimbabwe, cryotherapy had a 40.5% failure rate among HIV+ women at one year of followup, compared to 15.8% failure rate among HIV- women; in the same study, LEEP had 14% and 0% failure rates, respectively, among HIV+ and HIV- women (CHirenje 2003). However, over 50% of failures were low-grade lesions. LEEP was associated with higher complication rates, including excessive bleeding,and discharge, than cryotherapy. A study from Zambia of cryotherapy-ineligible women (many of whom were HIV+), referred for further management, LEEP (performed by physicians) was feasible and safe, with low levels of complications that can be managed locally (Pfaendler et al. 2008).

Abstinence should be emphasized until complete healing has occurred after treatment for cervical dysplasia, since the treatment has been shown to dramatically increase genital tract HIV shedding (Wright 2001) and may increase risk of sexual transmission of HIV. However, a recent study from Kenya found no increase in detectable cervical HIV-1 RNA among HIVpositive women (most on ART) after cryotherapy. (Chung et al. 2011).
