Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 19, No. 3, pp.

A9A18, 2005
doi:10.1016/j.bpobgyn.2005.01.005 available online at http://www.sciencedirect.com

HIV in Obstetrics & Gynaecology Answers to Multiple Choice Questions for Vol. 19, No. 2

1. (a) T

(b) T

(c) T

(a) These drugs in combination cause mitochondrial toxicity. (b) They have overlapping toxicities. (c) It is teratogenic in animals. 2. (a) T (b) F (c) T

(a) Zidovudine initiated at 28 weeks gestation and a booster dose of nevirapine to mother and baby during delivery and birth, respectively, reduces transmission rates. (b) Monotherapy can lead to drug resistance and can only be used to prevent MTCT. (c) A number of recent studies have reported mutant strains, viz. Lallemant et al., 2004. 3. (a) T (b) T (c) F

(a) A threshold level for the quantity of virus in serum has not been dened. MTCT can occur at viral loads less than 1000 copies/ml. (b) A number of studies have shown this. (c) More than two-thirds of the transmission is due to vaginal delivery and breastfeeding. 4. (a) F (b) F (c) T (d) F (e) F

(a) The theory that there is a syndrome of malformation-related HIV infection has not been proven. (b) No studies have indicated that there is an increase in the frequency of birth defects related to HIV infection. (c) Higher rates of perinatal mortality, however, are reported in HIV-infected women from poor countries, with advanced HIV infections being associated with the highest neonatal death rates.
1521-6934/$ - see front matter

A10 Appendix

(d) and (e) Controversies about the outcomes of pregnancy in HIV-infected women still exist. In rich countries, reports do not suggest an increase in the frequency of preterm birth, low birth weight babies, intrauterine growth retardation and stillbirths in comparison with similar groups of HIV non-infected women. 5. (a) F (b) T (c) F (d) T (e) T

(a) Studies in the USA and Europe have not shown pregnancy to have any effect on the progression of HIV disease. Reports from resource-poor countries, however, suggest that progression accelerates with pregnancy, but it is difcult to interpret such reports because the sample sizes are small and the studies are subject to selection bias related to the indications for testing. (b) This emphasizes the importance of early booking, universal screening, the need for cheap anti-retroviral medication, the availability of caesarean section and effective alternatives to breastfeeding. (c) Viral load in cervical vaginal secretions has been shown to correlate with MTCT. (d) Usually, genital tract viral load mirrors the plasma load but discordance may occur, notably in the presence of genital infections or ulceration. (e) There are robust data indicating that initiating ARV therapy in late pregnancy and/or intrapartum, and neonatal prophylaxis, can reduce the risk of MTCT. Efforts should therefore be made to give counselling and use rapid tests, with informed consent, in late pregnancy or early labour, to discern the serostatus of the vulnerable group of women who book late but are considered at high risk. 6. (a) T (b) T (c) F (d) F (e) F

(a) Mastitis due to inammation results in an increase in HIV viral load in the breast milk and as such will result in an increase in the risk of breastfeeding transmission. (b) As HIV viral load is an important risk factor for transmission, lowering the viral load through the use of HAART may very well reduce the transmission risk during breastfeeding. (c) Although over-the-counter immune modulators are becoming popular there is no evidence that immune modulators reduce transmission. (d) The WHO meta-analysis estimated that infants not breastfed in the rst few months are about 5.8 times more likely to die. (e) Although this was originally suggested by a Kenyan study this has since been refuted. 7. (a) F (b) F (c) T (d) T (e) T

(a) The transmission risk is about 15% if an infant is fed for about 24 months not 6 months. (b) The risk of transmission is similar during the early and later breastfeeding periods. (c) Early evidence suggests that infants who receive exclusive breastfeeding in the rst 6 months are likely to have lower transmission as they will experience less gut damage. (d) Because of the transient rise in viral load which is experienced in a new HIV infection, a woman who is newly infected is likely to be at higher risk of transmitting virus during breastfeeding.

Appendix A11

(e) The latest BITS study has shown a risk of about 4% for every 6 months of breastfeeding. 8. (a) T (b) F (c) F (d) F (e) T

(a) The polymerase chain reaction (PCR) test is able to amplify viral genetic material and establish the presence of HIV infection in young infants, and it is now possible to determine the risk of transmission by breastfeeding more accurately. (b) To date there has only been one randomised controlled clinical trial (RCT) of breastfeeding versus formula, but this Kenyan study had a serious limitation in terms of lack of compliance with the assigned feeding mode. For ethical and practical reasons, it seems highly unlikely that any groups in the future will attempt an RCT on feeding practices. (c) The BITS group meta-analysis demonstrated that the risk of transmission was cumulative, and roughly constant throughout the breastfeeding period. A good approximate gure to work with is thus a 4% risk for every 6 months of breastfeeding. (d) The accepted WHO denition of exclusive breastfeeding is dened as breast milk only, with no other solids or liquids. (e) see Refs. [19,20] in Chapter 2. 9. (a) T (b) F (c) T (d) T (e) T

(a)(c) Breastfeeding is important even in developed countries to protect against respiratory tract infections, diarrhoea and late-onset diabetes, CVD, cancer and obesity. (d) See references in Chapter 2. (e) When replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breastfeeding by HIV-infected mothers is recommended. 10. (a) F (b) T (c) T (d) T (e) T

(a)(c) Certain factors, such as low CD4 counts, high viral load, and breast pathology, increase the risk of a mother transmitting HIV during breastfeeding. (d) Mothers who have progressed to AIDS, or whose CD4 counts are below 200, should be encouraged to consider replacement feedingassuming that support will be in place for this to occur safely. (e) HIV-infected mothers who breastfeed should be provided with specic guidance and support when they cease breastfeeding to avoid harmful nutritional and psychological consequences to the infant and to maintain their breast health. 11. (a) F (b) F (c) F (d) T (e) F

(a) If access to health services is poor, governments will not experience the full costs of having to provide care for HIV positive children. This means that implementing a PMTCT programme might cost the health service more than providing care for infected children. (b) PMCTC programmes using AZT have also been shown to reduce health costs, when calculating the total health costs without a PMTCT programme minus the total health costs with a PMTCT programme.

A12 Appendix

(c) With breastfeeding there is less of a cost saving to governments, as more children will be infected. However, the cost of implementing the programme will still be less than the costs of treating HIV positive children, assuming good access to health services. (d) The costs required to treat HIV positive children are higher than the costs of implementing PMTCT, but this assumes that children will actually receive appropriate care from the health services. (e) The DALY allows a comparison of various interventions, but will not indicate whether a particular intervention alone will save governments money or not. The problem with DALYs is that comparison of interventions is hampered by limited evidence of the cost-effectiveness of a full range of interventions. 12. (a) F (b) T (c) T (d) F (e) T

(a) The cost of providing ART in Brazil amounted to slightly more than cost savings on hospitalisation costs. (b) The value of longer life expectancy, increased productivity, fewer orphans and lives saved through lower rates of transmission are omitted in the narrow nancial perspective of the public health sector. (c) Hospital admissions in Brazil fell from 1.65 to 0.28 per patient per year. (d) Although ART has not been shown to pay for itself in the same way that PMTCT does, the broader economic benets outlined in (b) above and evidence that ART goes a long way towards paying for itself make a strong case for implementation. (e) A comprehensive approach towards tackling HIV/AIDS, including prevention, treatment and care, along with impact mitigation, is widely advocated. 13. (a) F (b) F (c) F (d) F (e) T

(a) If HIV positive patients had better access to good quality care, then the costs associated with treatment of these patients would be higher. In many parts of Africa, HIV positive patients are not accessing care and this represents a saving to the health services. Furthermore, current AIDS cases represent a small proportion of the total number of people who are HIV positive, meaning that the number of AIDS cases being seen in future years will be more than the current number. (b) HIV prevalence rates were shown to be 50% in 1990 at a hospital in the DRC and 55.6% in 1994 at a hospital in Uganda. More recent studies in other African countries (and therefore not necessarily comparable) have in fact demonstrated lower HIV prevalence rates among hospital patients. (c) At Kenyatta National Hospital (which has the best time series data to date), the number of AIDS patients admitted over time decreased. Speculation attributed this observation to combination of stigma, the belief that hospitals have little to offer the unwell, as well as the costs associated with hospital admission. (d) If bed occupancy rates are remaining constant in the face of increasing numbers of AIDS patients (as is the case in South Africa), then rationing of care should be suspected. This forces clinicians into an ethical mineeld.

Appendix A13

(e) While absenteeism and attrition of health workers due to HIV/AIDS increases, the capacity to deliver services is going to be slowly eroded. This is an important concern which has not received due consideration in health sector research. 14. (a) T (b) T (c) F (d) F (e) T

Adaptive, or specic immunity to HIV-1 follows exposure to HIV-1. In contrast to innate immunity, adaptive immunity is specic for distinct macromolecules and has memory. Cytotoxic T-lymphocytes (CTLs) recognise internally processed antigen through their presentation on MHC class I molecules, and T helper cells recognise antigen presented on MHC class II molecules. 15. (a) T (b) T (c) F (d) T (e) F

CTL escape occurs through single/point mutations that may correspond to changes in amino acids either within a CTL epitope or anking it. The intra-epitope changes can result in an inability of the mutated epitope to bind to the MHC molecule (anchor position change) or a failure of the MHC-peptide complex to be recognised by the CTL T cell receptor (T cell receptor changes). The anking changes impair an ability of the cellular mechanisms to process larger fragments of peptide into the right size and sequence so that it can be taken up by the MHC complex for presentation at the surface of the infected cell. These are explained in Fig. 1. These escape forms can be transmitted vertically. Neutralizing antibodies to HIV-1 occur early, with rapid evolution of escape from neutralization. 16. (a) T 17. (a) T 18. (a) T 19. (a) F (b) T (b) F (b) F (b) F (c) F (c) F (c) T (c) F (d) F (d) T (d) F (d) T (e) T (e) F (e) F

All these assays are all inferior to HIV RNA viral load. b2-Microglobulin is useful to help determine diagnosis; p24 antigen detection serves as diagnosis before HIV infection prior to antibody seroconversion; HIV isolation methods are too expensive and require restricted HIV isolation laboratory facilities; the technique of neopterin measurement is inferior to HIV RNA viral load. 20. (a) F (b) T (c) T (d) T

Category C%200 cells/mm3; antiretroviral therapy is started according to the IAS-USA guidelines CD4 count !200 cells/mm3 and a viral load O55 000 RNA copies/ml plasma. The CD4 count in Category ACB is O200 cells/mm3. 21. (a) T (b) T (c) T (d) F (e) F (f) F (g) F

Viral phenotypic, genotypic resistance and replicative capacity all measure failure to therapy whereas both HLA haplotype and CCR5 status maybe useful in the future in helping to predict which persons to initiate therapy. HIV culture isolation is not a practical method to be used due to the special P3 laboratory facilities required and the time taken to obtain results.

A14 Appendix

22. (a) F

(b)

T (c)

(d) F

(e) T

(a) It is based on the paternalistic belief that the potential benet to the pregnant fetus and her fetus overrides maternal freedoms. (b) Economic costs to society would be reduced by preventing infection to the fetus, i.e. the greatest good for the greatest number. (c) Clinicians, ethicists and lawmakers have, in the main, declined acceptance of this strategy. (d) In the UK, patients have the right to refuse undergoing a test. (e) All ethical action, when seeking good ends take into consideration all the major ethical principles. This is not the case in this situation because the social and economic risks associated with HIV testing pertaining to stigma and discrimination, together with the potential for an erosion of the physician patient relationship have been largely ignored. 23. (a) F (b) F (c) F (d) T (e) T

(a) Respecting womens reproductive rights would have to be balanced against social and distributive justice arguments and the needs of other patients and society at large. Hence not being able to offer all women infertility treatments would not be an infringement of their reproductive rights. (b) The tremendous advances in medical management of the HIV-infected individual have led to an increase in life expectancy and improvement in quality of life. Hence, the uncertain long-term prognosis of the parent would be a moot argument and can no longer be substantiated ethically. Furthermore, infertility treatments are not denied to women aficted with other chronic diseases during their reproductive years. (c) While a 2% vertical transmission rate can be perceived as a signicant risk, it should be examined against the background context of a 2.5% risk for giving birth to offspring with signicant congenital malformation in the general obstetric non HIV-infected population. Hence, where resources allow, it would be unjust to deny these couples infertility treatment based on the vertical transmission risk. (d) Where there is clearly documented evidence of the benecial effects of advances in technologies and where these advances are affordable by the couples concerned it would be unethical not to offer these treatments. There is the additional concern that should fertility advice and treatments not be made available to these couples, they would engage in unprotected intercourse for the purpose of conception with resultant harms to themselves and their future offspring. Benecence, non-malecence and justice would be negated. (e) The reproductive drive is strong in this group and couples may take risks to have a baby beyond what is reasonable. 24. (a) F (b) T (c) F (d) F (e) T

(a) Treating everyone the same appears to be a sound ethical approach because there is no discrimination. But treating everyone the same without considering his or her specic needs and interests would be unjust. Equality is more to do with applying an equal consideration of interest rather than the same treatment. What may be good in one set of economic, social and cultural circumstance may be

Appendix A15

inappropriate in another. It is also untrue in any event because it treats pregnant women differently to other patients. (b) The principal justication is that it increases detection and reduces vertical transmission and the spread of HIV/AIDS in the community. (c) It is being adopted as part of an opt-out strategy. (d) It is not sufcient ethical ground. An ethical strategy would take account of the prevailing social and cultural context for HIV/AIDS. Women may be differently empowered economically, socially and culturally to make decisions without facing harmful consequences within their families and community. This is one reason why it is considered that both pre- and post-test counselling should be an integral part of an ethical screening strategy in countries such as South Africa. (e) Evidence from the UK, other countries in Europe and elsewhere show an increased detection and reduced vertical transmission where the opt-out approach has been adopted. 25. (a) F (b) F (c) T (d) F (e) T

Several studies have compared cytological performance with colposcopy and histologic verication and no signicant difference is demonstrated in HIV compared to HIV negative women. Numerous studies have shown that the prevalence and incidence of cervical intraepithelial neoplasia (CIN) are signicantly more common in HIV infected women compared to HIV negative women. The threshold for colposcopy referral is lower for HIV positive women starting from those with atypical squamous cells of uncertain signicance (ASCUS) and mild dyskariosis (LGSIL) is an indication for colposcopy assessment, and more frequent cytological surveillance like every six months is recommended. HIV positive women with CIN disease can be treated with either ablative or excisional procedures however recurrence rates are much more frequent than in HIV negative women. HAART results in a signicant response to immune reconstitution that has been observed to regress CIN lesions. 26. (a) T (b) T (c) F (d) F (e) F

The earliest observation in cancer epidemiology was the association of cervical cancer to various aspects of sexual behaviour, with the highest risk occurring with women who initiate intercourse at early age, multiple sexual partners, exposure to oncogenic HPV types 16, 18 (causes 65% of cervical cancers), 31, 33, 35, 39, 45, 51, 52, 56, 58, 68, high parity and cigarette smoking. The relationship between HIV and cervical cancer is unique in that women at risk of both conditions share these common socio-behavioural patterns. 27. (a) T (b) F (c) T (d) T

Invasive cervical cancer stage IB2 (bulky disease R4 cm diameter) is recommended to be treated by concurrent chemo-radiation therapy as rst line treatment even in HIV positive women. Several studies have reported that young women below 35 years with ICC are signicantly more likely to be HIV positive than women O35 years with ICC. US Centers for Disease Control (CDC) in 1993 added ICC to the list of AIDS dening illness although only a modest increment of ICC incidence rates has been recorded on HIV infected women by some studies. Several case reports have reported rapid

A16 Appendix

progression to invasive cervical cancer in HIV infected women. Squamous cell carcinoma is the most common (8090%) histological type even among HIV positive women. 28. (a) T (b) T (c) T (d) T (e) F

(a) Early candidate vaccines were designed to elicit antibodies against the HIV envelope protein (Table 2). This subunit vaccine approach has been successful for other viral vaccines in use today, such as Hepatitis B. However, generating antibodies that neutralise HIV infection has proved extremely difcult. This is primarily due to the structure of the Env protein. Regions of the protein targeted by neutralising antibodies are masked by sugar residues or hidden inside the protein [17]. Furthermore, Env is present in a trimeric structure, and vaccines based on monomers of Env do not elicit antibodies against conformational epitopes found on the trimer. A further difculty is the generation of neutralising antibodies that can act against the diversity of HIV variants. Env is highly variable and neutralising antibodies targeting one viral isolate are rarely capable of preventing infection by another. Developing these broadly cross-neutralising antibodies remains one of the biggest challenges in vaccine development. (b) HIV can differ by as much as 30% different between individuals [2]. A comparison of well characterized regions of the virus targeted by the immune response showed greater conservation within a subtype compared to between subtypes [3]. Genetic differences between the vaccine and potential infecting virus impact on vaccine efciacy as this variation may affect the persons ability to recognise the infecting virus. There is evidence that a person can become infected with a second virus once already HIV-infected and this may have some bearing on whether a vaccine based on a particular HIV subtype will protect against infection by a different subtype or variant. (c) Most vaccines do not block replication but rather prevent disease. However, once HIV becomes established, it is an infection for life and for this reason a vaccine against HIV would need to completely block replication by providing what is referred to as sterilising immunity. Neutralising antibodies, directed at the outer coat protein of the virus, the Envelope (Env) protein, can prevent HIV from entering cells. In animal models, sterilising immunity is very difcult to achieve by vaccination and has only been demonstrated by passively infusing macaques with antibodies that neutralise the virus [79]. See (a). (d) Non-human primate models of HIV infection may provide valuable insights into vaccine approaches, but have their limitations. Rhesus macaques are most commonly used to evaluate the protective efcacy of vaccines [16]. However, HIV-1 does not cause infection in macaques, and thus simian immunodeciency virus (SIV), an ancestor of HIV, or hybrids of HIV-1 and SIV (SHIVs) are used to experimentally infect macaques. The most common of these challenge viruses is SHIV89.6P, a highly pathogenic virus causing rapid disease due to almost complete CD4CT cell destruction and death. This course of rapid disease progression is very different to HIV. In addition, high challenge doses and routes of challenge (such as intravenous) rarely mimic the actual transmission situation for most human infections. Furthermore, the challenge viruses are usually identical to what the vaccine was based upon. The relevance of non-human primate models is therefore limited perhaps to the comparative testing of different vaccine

Appendix A17

concepts, as well as providing safety data. Ultimately, only a Phase III trial in humans will be able to determine the efcacy of an HIV vaccine. (e) Although we do not yet have a vaccine to protect against HIV infection, the past 15 years have seen an impressive global effort to develop a vaccine. The minds and resources that have come together from diverse elds to pursue the goal of developing an HIV vaccine provide an inspiring model of collaboration in science. 29. (a) T (b) T (c) T (d) F (e) F

(a) and (b) Non-human primate models of HIV infection may provide valuable insights into vaccine approaches, but have their limitations. Rhesus macaques are most commonly used to evaluate the protective efcacy of vaccines [16]. However, HIV-1 does not cause infection in macaques, and thus simian immunodeciency virus (SIV), an ancestor of HIV, or hybrids of HIV-1 and SIV (SHIVs) are used to experimentally infect macaques. The most common of these challenge viruses is SHIV89.6P, a highly pathogenic virus causing rapid disease due to almost complete CD4CT cell destruction and death. This course of rapid disease progression is very different to HIV. In addition, high challenge doses and routes of challenge (such as intravenous) rarely mimic the actual transmission situation for most human infections. Furthermore, the challenge viruses are usually identical to what the vaccine was based upon. The relevance of nonhuman primate models is therefore limited perhaps to the comparative testing of different vaccine concepts, as well as providing safety data. Ultimately, only a Phase III trial in humans will be able to determine the efcacy of an HIV vaccine. (c) Phase III trials, involving several thousand volunteers, will determine vaccine efcacy. Results of Phase III trials will inform regulatory authorities on whether a vaccine should be licensed. (d) HIV vaccine approaches use only some of the HIV proteins or genes and therefore there is no risk that they could cause infection. In addition, there is no HIV in the vaccine and therefore they cannot cause HIV or AIDS infection. (e) Pregnant women will not be accepted as volunteers. A pregnancy test is done prior to enrolment into the trial and before each immunization. Women of childbearing age must agree to an adequate method of birth control during their immunization period. 30. (a) T (b) T (c) T (d) F (e) F

(a) and (b) Since traditional vaccine approaches cannot be used in HIV vaccine development, it has been necessary to develop novel vaccine strategies. Many of these approaches use either DNA, viral or bacterial vectors (or vehicles) to deliver the genes. See Table 3. (c) Combining various vaccine approaches appears to be more effective than one approach by itself. These prime-boost strategies have shown promise in animal models. Macaques given DNA vaccines and boosted by recombinant MVA have been able to control virus replication and prevent disease following challenge [18,19]. The combination of DNA and adenovirus expressing HIV genes has also protected macaques from disease [20]. (d) There is a chance that a live attenuated HIV vaccine could cause disease. (e) There is a small risk that preparations of whole killed HIV could still contain active virus.

A18 Appendix

31. (a) T

(b) F

(c) F

(d) T

(e) T

(a) CTLs are important in the control of HIV-1 [6] and their presence in such body uids as cervical secretions [7] and breast milk [8] may be a relevant factor in mother-to-child transmission. (b) CD8Cve T cells detect viral antigens that have been processed intracellularly, cleaved into peptides (of 811 amino acids in length) and presented on the surface of the infected cell by major histocompatibility complex (MHC) class I molecules in association with b2 microglobulin. (c) Both cytolytic and non-cytolitic events are involved: cytolytic events are mediated through perforin and granzymes, and non-cytolyticare mediated through b chemokines, MIP-1-a, MIP-1-b and RANTES, and other soluble factors with antiviral capacity. (d) In large population studies undertaken in individuals infected with subtype B HIV-1 infection, HLA B27 and B57 predicted good control, and HLA B35 poor control of HIV-1. (e) Genetic variability within HIV-1 is generated during reverse transcription of the viral genome by the virally encoded reverse transcription enzyme. This enzyme lacks a 3 0 exonuclease proof-reading capacity, resulting in a high error rate of approximately 1 in 10 000 nucleotides, with point mutations predominating. Rapid replication rates result in an array of polymorphisms generated through error. Some of these resultant viral forms are targeted by the host immune surveillance and will be suppressed, allowing for the propagation of replicationcompetent variant forms that are unrecognised by the immune system. 32. (a) F (b) T (c) F (d) T (e) F

(a) Bacterial vaginosis (BV) is the leading cause of vaginal discharge, and though it has traditionally not been considered a sexually transmitted infection, there is increasing evidence that it is linked to sexual activity. (b) Multiple sexual partners, as well as a recent change in the partner, are associated with risk for the condition, though there is no evidence of a sexually transmitted pathogen. (c) The prevalence rate is 1842%, with the upper limit seen in sexually active individuals, and it is similar in HIV-infected women and uninfected women. (d) Bacterial vaginosis is thought to increase susceptibility to HIV infection by a factor of 1.4, and the risk of seropositivity is directly correlated with the severity of the vaginosis (and therefore the degree of lactobacilli depletion), implying that the high vaginal pH and lack of H2O2 production is favourable for HIV transmission. (e) Up to 50% of women with BV are asymptomatic, and clinical presentation is unaltered in the presence of HIV infection.