To the best of our knowledge, this systematic review represents the first ever to evaluate the burden of HPV infections and ICC in Uganda. It is worth noting that comparison of HPV prevalence and incidence rates across studies was hampered by differences in populations studied, laboratory methods used, and variation in HPV genotypes detected. Nevertheless, consistent with other studies in sub Saharan Africa [28
], the review demonstrated a high burden of HR-HPV genotypes in the general population and in ICC. HPV 16 and 18 were the most common genotypes in ICC similar to the global HPV distribution pattern [29
]. Mathematical models predict that widespread use of preventive HPV vaccines containing genotypes 16/18 have the potential to reduce deaths from ICC by 50% over several decades [30
]. However, the efficacy of these vaccines in countries like Uganda with high prevalence of HIV infection, endemic malnutrition, malaria infection and intestinal worm infestation is not yet known. Our review also found that the third most frequent HPV genotype after HPV 16 and 18 among women with ICC was HPV 45, which differed from the worldwide distribution (HPV 16, 18, 58) [9
]. Variation in HPV genotype distribution in ICC is not new as it has been observed in other regions of the world. It is hypothesized that host immunogenetic factors and biologic interplay between different HPV genotypes or variants are probably responsible [32
]. This variation however, implies that any development of the next generation of multivalent preventive HPV vaccines should contain more HR-HPV genotypes than only 16/18. Based on data contained in this review, multivalent vaccines containing HPV 16/18/45 would potentially prevent approximately 83.1% of ICC in Uganda.
The highest prevalence and incidence rates of HPV infections occurred in young women below 25 years similar to previous studies [23
]. It is important to note that Ugandan women tend to marry and become sexually active at a young age and often have older and more sexually experienced partners, which factors would put them at greater risk for HPV infection. The main risk factors for prevalent and incident HPV infections were age, number of lifetime number of sexual partners and HIV infection consistent with other studies [23
HIV positive individuals had a high burden of HPV infection at the time when their life-spans are being prolonged by expanded access to highly active anti-retroviral therapy (HAART) and medical care. Since 2003, the HIV prevalence in Uganda has stabilized at about 6.4% among adults and by the end of 2010; approximately 1.1 million were living with HIV [34
]. Women were disproportionately affected accounting for about 57% of the total adults living with HIV [34
]. However, the proportion of co-infection with HIV and HPV is not known. Though several studies have consistently shown a high burden of HPV-associated diseases in HIV positive women even in the era of HAART [35
], presently, there is limited or noexistent routine screening services for many HIV positive women. There are advantages to providing routine screening to HIV positive women. In Zambia, for example, routine screening prevented one death from ICC for every 46 HIV positive women screened [36
]. Presently, there is limited data to support or discourage HPV vaccination of HIV positive individuals. To date, immune response to HPV vaccination among HIV positive individuals using the quadrivalent vaccine is limited to a small study of 120 children aged 7-11 years some of whom used anti retroviral therapy, which was conducted in the USA [37
]. The antibodies developed by > 99.5% of the vaccinated children were much lower than in HIV negative historical controls raising concerns of perhaps reduced immunogenicity and efficacy.
In this review, HIV positive women seemed to have multiple and more other HR-HPV genotypes than HPV 16/18 consistent with a previous study where 50% of HIV positive women with HPV 16 and 18 were co-infected with other HR-HPV genotypes [38
]. Consequently, it is unclear whether the current vaccines containing only HPV 16 and 18 genotypes may potentially prevent fewer cases of ICC among HIV positive women [39
]. Fortunately, the current preventive vaccines have shown cross-protection against some non vaccine HR-HPV genotypes and because of this, it is estimated that wide coverage (> 70%) could potentially prevent up to 71% of ICC [40
]. Cross-protection even if limited, may be particularly important in low-resource countries like Uganda where screening programs are limited or nonexistent.
Males had a high burden of HR-HPV infections. Studies have shown that males do not perceive themselves to be susceptible to HPV and do not believe that HPV infection is a severe problem to themselves [41
]. However, the role of men as vectors of HR-HPV genotypes that cause ICC has been extensively evaluated in epidemiological studies [42
]. HPV vaccines have been found to be safe and efficacious in males [45
]. However, vaccinating males does not appear to be economical when assessed from the view of ICC. Moreover, the WHO does not recommend routine male vaccination as the primary target of vaccination. Yet, the concept of herd immunity in public health would tend to suggest that vaccinating males would provide a double benefit to females in that the fewer males with HPV, the fewer females will be exposed [46
Although HPV vaccines hold great promise to reduce ICC-associated mortality and morbidity, it remains unclear whether low-resource countries like Uganda will reap the benefits any time soon. The current high cost of the vaccines, poor health infrastructure and competing health priorities will prevent young girls getting the life saving vaccinations. Uganda's health sector remains considerably under-funded. At less than 10% of total government expenditure in fiscal year 2010/2011, public health expenditure remains far below the Abuja target of 15% that the government of Uganda committed to in 2001 [47
]. Furthermore, presently, there is no known public sector pricing for the HPV vaccines making it difficult to budget for and as such the details of vaccine implementation and cost coverage remain unknown. Fortunately, the Global Alliance for Vaccines and Immunization (GAVI) pledged to consider HPV vaccines in their investment strategy of 2009-2013 [49
]. This may provide the much needed financial help to implement HPV immunization programs in low-resource countries where most of the ICC occur.
For prevention, HPV vaccines must be given before sexual debut to ensure that exposure to HPV has not occurred. Accordingly, the World Health Organization recommended that girls between the ages of 9-13 years should be the primary target of vaccination [50
]. Given the financial impossibility of vaccinating all eligible women in the reproductive age, it is vital that primary prevention by HPV vaccination is integrated with education on risk reducing behaviors and secondary prevention programs via screening and treatment of precancerous lesions and ICC. The availability of new and inexpensive screening techniques for rapid identification of HR-HPV may help facilitate the use of HPV testing in low-resource countries [51