Articles tagged as "Cancers"

Understanding different levels and different models of integration

Editor’s notes: Integration between HIV services and programmes and other services and programmes sounds like common sense.  As people with HIV live longer they are more likely to develop other chronic conditions.  Some of these conditions may also be exacerbated by some anti-retroviral medicines, although modern treatment regimens have much less effect on lipid and insulin metabolism.  Low grade chronic inflammation may continue even in people whose HIV is suppressed and people whose CD4 count sunk to a low level before starting seem to be at greater risk of subsequent cardiovascular disease.  Then there are diseases that are more common among people living with HIV, such as tuberculosis and invasive cervical cancer.  And HIV programmes around the world have established some of the best clinical services for chronic care, with regular appointments, decentralized follow-up, algorithmic approaches to clinical changes and so on.  So it seems sensible to look for the synergies and build on them.

However, research on integration makes it clear that there are many different interpretations of what integration should or could mean.  In different epidemiological settings, the priorities will inevitably be very different.  Two useful systematic reviews this month by the same team, review this territory for cardiovascular diseases, diabetes and cervical cancer. 

Haldane et al. distinguish between the levels of integration.  Micro level integration involves direct patient care and adjusting diagnosis, treatment and support appropriately.  Meso level integration refers to changes made at the clinic or delivery system level, while macro level integration is about programme management, supply chains and systems organisation.  Despite a large literature (over 7600 papers) on the overlaps between HIV and cardiovascular diseases and diabetes, the authors found only 14 studies that allowed aspects of the integration to be assessed, and only one of these evaluated outcomes.  The others were descriptive studies which highlighted many innovative models, almost all at the meso-level.

Similarly for invasive cervical cancer, which is at least four times as common among women living with HIV as seronegative women, Sigfrid et al. found many papers but only 21 that met their inclusion criteria.  Their models of integration could all be said to be at the meso-level, with one stop shops; co-located services or more complex integrated pathways described.  Again, there were no good evaluations of the outcomes of these systematic changes to the way that services are delivered.  In most countries, all women with cervical cancer should at least be offered an HIV test and appropriate linkage to care expedited for those found to be seropositive.  Women living with HIV need regular screening for early cervical cancer and (as discussed last month) screening for human papillomavirus, the underlying cause of cervical cancer.  However, many ART clinics are now busy and crowded so that even if staff are trained, they do not have time or space or privacy to do cervical examinations.  HPV vaccination campaigns need to be carried out in schools before girls become sexually active.  This could be a good time to engage with sexuality education. However, many campaigns have tended to avoid the challenges of discussing sex with girls who are not yet sexually active, preferring to focus on the vaccine as a cancer prevention tool.  So, the lesson from both these papers is that we need to define more rigorously what we want to achieve with integration and then ensure that we evaluate whether or not our interventions achieve it.

Tuberculosis and HIV have been dancing together since the first descriptions of HIV in the 1980s.  The large majority of tuberculosis patients in many countries are now screened for HIV, with appropriate referral and increasing numbers of people living with HIV are screened regularly for the four classic symptoms of tuberculosis (weight loss, cough, night sweats and fever) and referred onwards for diagnosis.  Yet we still find that collaboration between programmes is not always easy. The number of people living with HIV who are also on tuberculosis treatment reported by the HIV programme may not be the same as the number of people on tuberculosis treatment who are also living with HIV reported by the tuberculosis programme.  Osei et al. report from the Volta Region of Ghana that more than 90% of tuberculosis patients had an HIV test recorded in the tuberculosis register, with an HIV prevalence of 18%.  As has been reported frequently elsewhere, the authors found that HIV was commoner in those with smear negative tuberculosis, and the outcome of treatment was less good.  Their recommendation for strengthening the collaboration between tuberculosis and HIV makes sense, although it has been WHO policy for many years.

The WHO guidance on collaborative TB/HIV activities has always included isoniazid preventive therapy.  However, this remains poorly implemented for reasons that are never very clear.  Despite no good evidence, many tuberculosis programme staff and clinicians worry about the risk of generating isoniazid resistant tuberculosis.  Many HIV programme staff feel that isoniazid remains in the realm of the tuberculosis programme, so that although they are happy to promote cotrimoxazole, they are much slower to prescribe isoniazid.  Many also feel that ART alone should be sufficient to prevent tuberculosis, despite randomized trials in high prevalence settings that demonstrate the additional benefits of isoniazid.  Shayo et al. make a strong economic argument for promoting isoniazid in their study in Tanzania.  They base their model on the rates of tuberculosis and mortality seen during the expansion of pilot programmes for isoniazid in Dar es Salaam.  Both tuberculosis and mortality were significantly lower in the clinics which were part of the pilot programme.  In fact, mortality was approximately tenfold lower, which seems unlikely to be simply due to isoniazid.  Some studies such as TEMPRANO have shown a mortality benefit from isoniazid, while many trials have failed to do so.  Given the non-randomized nature of the comparison, the authors do point out that their conclusions must be tentative.  Nonetheless, it is a convincing demonstration that isoniazid preventive therapy can be incorporated into a busy HIV care clinic and there is abundant evidence that this is the right thing to do.

One more tuberculosis study this month was carried out in Germany.  Karo et al. reviewed the immunology of the 139 people who developed tuberculosis among more than 10 000 people living with HIV in the German ClinSurv cohort.  The authors excluded people who already had tuberculosis at the time that HIV was diagnosed, and found that new diagnoses of tuberculosis were most common in the first couple of years after starting ART.  The authors also show that immune restoration was slower in people who developed tuberculosis.  There was still some deficit up to seven years after ART was started.  Again, their conclusion is that we should be using isoniazid to prevent tuberculosis in people living with HIV, especially people who have spent much of their lives in areas of the world, such as sub-Saharan Africa where tuberculosis is much more prevalent than in Europe.  It is often said that Mycobacterium tuberculosis is a very slow growing organism.  We must work harder to ensure that our response to it is not very slow too.  Tuberculosis remains the biggest killer of people with HIV in most of the world, yet for years we have known that a simple, cheap, non-toxic treatment can prevent it. 

 

Integrating cardiovascular diseases, hypertension, and diabetes with HIV services: a systematic review.

Haldane V, Legido-Quigley H, Chuah FLH, Sigfrid L, Murphy G, Ong SE, Cervero-Liceras F, Watt N, Balabanova D, Hogarth S, Maimaris W, Buse K, McKee M, Piot P, Perel P. AIDS Care. 2017 Jul 5:1-13. doi:10.1080/09540121.2017.1344350. [Epub ahead of print]

Non-communicable diseases (NCDs), including cardiovascular diseases (CVD), hypertension and diabetes together with HIV infection are among the major public health concerns worldwide. Health services for HIV and NCDs require health systems that provide for people's chronic care needs, which present an opportunity to coordinate efforts and create synergies between programs to benefit people living with HIV and/or AIDS and NCDs. This review included studies that reported service integration for HIV and/or AIDS with coronary heart diseases, chronic CVD, cerebrovascular diseases (stroke), hypertension or diabetes. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias. 11 057 records were identified with 7 616 after duplicate removal. After screening titles and abstracts, 14 papers addressing 17 distinct interventions met the inclusion criteria. We categorized integration models by diseases (HIV with diabetes, HIV with hypertension and diabetes, HIV with CVD and finally HIV with hypertension and CVD and diabetes). Models also looked at integration from micro (patient focused integration) to macro (system level integrations). Most reported integration of hypertension and diabetes with HIV and AIDS services and described multidisciplinary collaboration, shared protocols, and incorporating screening activities into community campaigns. Integration took place exclusively at the meso-level, with no micro- or macro-level integrations described. Most were descriptive studies, with one cohort study reporting evaluative outcomes. Several innovative initiatives were identified and studies showed that CVD and HIV service integration is feasible. Integration should build on existing protocols and use the community as a locus for advocacy and health services, while promoting multidisciplinary teams, including greater involvement of pharmacists. There is a need for robust and well-designed studies at all levels - particularly macro-level studies, research looking at long-term outcomes of integration, and research in a more diverse range of countries.

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Integrating cervical cancer with HIV healthcare services: A systematic review.

Sigfrid L, Murphy G, Haldane V, Chuah FLH, Ong SE, Cervero-Liceras F, Watt N, Alvaro A, Otero-Garcia L, Balabanova D, Hogarth S, Maimaris W, Buse K, Mckee M, Piot P, Perel P, Legido-Quigley H. PLoS One. 2017 Jul 21;12(7):e0181156. doi: 10.1371/journal.pone.0181156. eCollection 2017.

Background: Cervical cancer is a major public health problem. Even though readily preventable, it is the fourth leading cause of death in women globally. Women living with HIV are at increased risk of invasive cervical cancer, highlighting the need for access to screening and treatment for this population. Integration of services has been proposed as an effective way of improving access to cervical cancer screening especially in areas of high HIV prevalence as well as lower resourced settings. This paper presents the results of a systematic review of programs integrating cervical cancer and HIV services globally, including feasibility, acceptability, clinical outcomes and facilitators for service delivery.

Methods: This is part of a larger systematic review on integration of services for HIV and non-communicable diseases. To be considered for inclusion studies had to report on programs to integrate cervical cancer and HIV services at the level of service delivery. We searched multiple databases including Global Health, Medline and Embase from inception until December 2015. Articles were screened independently by two reviewers for inclusion and data were extracted and assessed for risk of bias.

Main results: 11 057 records were identified initially. 7616 articles were screened by title and abstract for inclusion. A total of 21 papers reporting interventions integrating cervical cancer care and HIV services met the criteria for inclusion. All but one study described integration of cervical cancer screening services into existing HIV services. Most programs also offered treatment of minor lesions, a 'screen-and-treat' approach, with some also offering treatment of larger lesions within the same visit. Three distinct models of integration were identified. One model described integration within the same clinic through training of existing staff. Another model described integration through co-location of services, with the third model describing programs of integration through complex coordination across the care pathway. The studies suggested that integration of cervical cancer services with HIV services using all models was feasible and acceptable to patients. However, several barriers were reported, including high loss to follow up for further treatment, limited human-resources, and logistical and chain management support. Using visual screening methods can facilitate screening and treatment of minor to larger lesions in a single 'screen-and-treat' visit. Complex integration in a single-visit was shown to reduce loss to follow up. The use of existing health infrastructure and funding together with comprehensive staff training and supervision, community engagement and digital technology were some of the many other facilitators for integration reported across models.

Conclusions: This review shows that integration of cervical cancer screening and treatment with HIV services using different models of service delivery is feasible as well as acceptable to women living with HIV. However, the descriptive nature of most papers and lack of data on the effect on long-term outcomes for HIV or cervical cancer limits the inference on the effectiveness of the integrated programs. There is a need for strengthening of health systems across the care continuum and for high quality studies evaluating the effect of integration on HIV as well as on cervical cancer outcomes.

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The burden of HIV on tuberculosis patients in the Volta region of Ghana from 2012 to 2015: implication for tuberculosis control.

Osei E, Der J, Owusu R, Kofie P, Axame WK. BMC Infect Dis. 2017 Jul 19;17(1):504. doi: 10.1186/s12879-017-2598-z.

Background: The impact of HIV on TB, and the implications for TB control, has been acknowledged as a public health challenge. It is imperative therefore to assess the burden of HIV on TB patients as an indicator for monitoring the control efforts of the two diseases in this part of the world. This study aimed at determining the burden of HIV infection in TB patients.

Methods: We conducted a retrospective review of TB registers in five districts of the Volta Region of Ghana. Prevalence of TB/HIV co-infection was determined. Bivariate and multivariate logistic regression were used to identify the predictors of HIV infection among TB patients and statistical significance was set at p-value <0.05.

Results: Of the 1772 TB patients, 1633 (92.2%) were tested for HIV. The overall prevalence of TB/HIV co-infection was (18.2%; 95% CI: 16.4-20.1). The prevalence was significantly higher among females (24.1%; 95%CI: 20.8-27.7), compared to males (15.1%; 95% CI: 13.1-17.4) (p < 0.001) and among children <15 years of age (27.0%; 95% CI: 18.2-38.1), compared to the elderly ≥70 years (3.5%; 95% CI: 1.6-7.4) (p < 0.001). Treatment success rate was higher among patients with only TB (90%; 95% CI: 88.1-91.5) than among TB/HIV co-infected patients (77.0%; 95% CI: 71.7-81.7) (p < 0.001). Independent predictors of HIV infection were found to be: being female (AOR: 1.79; 95% CI: 1.38-2.13; p < 0.001); smear negative pulmonary TB (AOR: 1.84; 95% CI: 1.37-2.47; p < 0.001); and patients registered in Hohoe, Kadjebi, and Kpando districts with adjusted odds ratios of 1.69 (95% CI: 1.13-2.54; p = 0.011), 2.29 (95% CI: 1.46-3.57; p < 0.001), and 2.15 (95% CI: 1.44-3.21; p < 0.001) respectively. Patients ≥70 years of age and those registered in Keta Municipal were less likely to be HIV positive with odds ratios of 0.09 (95% CI: 0.04-0.26; p < 0.001) and 0.62 (95% CI: 0.38-0.99; p = 0.047) respectively.

Conclusion: TB/HIV co-infection rate in five study districts of the Volta region is quite high, occurs more frequently in female patients than males; among smear negative pulmonary TB patients, and children <15 years of age. Findings also demonstrate that HIV co-infection affects TB treatment outcomes adversely. Strengthening the TB/HIV collaborative efforts is required in order to reduce the burden of co-infection in patients.

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Cost-effectiveness of isoniazid preventive therapy among HIV-infected patients clinically screened for latent tuberculosis infection in Dar es Salaam, Tanzania: a prospective cohort study.

Shayo GA, Chitama D, Moshiro C, Aboud S, Bakari M, Mugusi F. BMC Public Health. 2017 Jul 19;18(1):35. doi: 10.1186/s12889-017-4597-9.

Background: One of the reasons why Isoniazid preventive therapy (IPT) for Tuberculosis (TB) is not widely used in low income countries is concerns on cost of excluding active TB. We analyzed the cost-effectiveness of IPT provision in Tanzania having ruled out active TB by a symptom-based screening tool.

Methods: Data on IPT cost-effectiveness was prospectively collected from an observational cohort study of 1283 HIV-infected patients on IPT and 1281 controls; followed up for 24 months. The time horizon for the analysis was 2 years. Number of TB cases prevented and deaths averted were used for effectiveness. A micro costing approach was used from a provider perspective. Cost was estimated on the basis of clinical records, market price or interviews with medical staff. We annualized the cost at a discount of 3%. A univariate sensitivity analysis was done. Results are presented in US$ at an average annual exchange rate for the year 2012 which was Tanzania shillings 1562.4 for 1 US $.

Results: The number of TB cases prevented was 420/100 000 persons receiving IPT. The number of deaths averted was 979/100 000 persons receiving IPT. Incremental cost due to IPT provision was US$ 170 490. The incremental cost-effective ratio was US $ 405.93 per TB case prevented and US $ 174.15 per death averted. These costs were less than 3 times the 768 US $ Gross Domestic Product (GDP) per capita for Tanzania in the year 2014, making IPT provision after ruling out active TB by the symptom-based screening tool cost-effective. The results were robust to changes in laboratory and radiological tests but not to changes in recurrent, personnel, medication and utility costs.

Conclusion: IPT should be given to HIV-infected patients who screen negative to symptom-based TB screening questionnaire. Its cost-effectiveness supports government policy to integrate IPT to HIV/AIDS care and treatment in the country, given the availability of budget and the capacity of health facilities.

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Immunological recovery in tuberculosis/HIV co-infected patients on antiretroviral therapy: implication for tuberculosis preventive therapy.

Karo B, Krause G, Castell S, Kollan C, Hamouda O, Haas W; ClinSurv HIV Study Group. BMC Infect Dis. 2017 Jul 25;17(1):517. doi: 10.1186/s12879-017-2627-y.

Background: Understanding the immune response to combination antiretroviral therapy (cART) is essential for a clear approach to tuberculosis (TB) preventive therapy. We investigated the immunological recovery in cART-treated HIV-infected patients developing TB compared to those who remained free of TB.

Methods: We extracted data of HIV-infected patients from a multicenter cohort for the HIV clinical surveillance in Germany. No patients included in our study had TB at the beginning of the observation. Using a longitudinal mixed model, we assessed the differences in the mean change of biomarkers (CD4+ cell count, CD8+ cell count, CD4:CD8 ratio and viral load) since cART initiation in patients who remained free of TB vs. those developing TB. To detect the best-fit trajectories of the immunological biomarkers, we applied a multivariable fractional polynomials model.

Results: We analyzed a total of 10 671 HIV-infected patients including 139 patients who developed TB during follow-up. The highest TB incidences were observed during the first two years since cART initiation (0.32 and 0.50 per 100 person-years). In an adjusted multivariable mixed model, we found that the average change in CD4+ cell count recovery was significantly greater by 33 cells/μl in patients who remained free of TB compared with those developing TB. After the initial three months of cART, 65.6% of patients who remaining free of TB achieved CD4+ count of ≥400 cells/μl, while only 11.3% of patients developing TB reached this immunological status after the three months of cART. We found no differences in the average change of CD8+ cell count, CD4:CD8 ratio or viral load between the two-patient groups.

Conclusion: All HIV-infected patients responded to cART. However, patients developing TB showed reduced recovery in CD4+ cell count and this might partly explain the incident TB in HIV-infected patients receiving cART. These findings reinforce the importance of adjunctive TB preventive therapy for patients with reduced recovery in CD4+ cell count.

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Technology is advancing rapidly, but are we making the most of it?

Editor’s notes: HIV self-testing was a key area of discussion in the Paris IAS meeting.  UNITAID signed the next phase of the STAR Initiative that is working with six countries in Southern Africa to transform the market for self-testing and understand the impact of different delivery systems.  The Bill and Melinda Gates Foundation are using their resources to lower prices of self-test kits.  Following WHO’s decision to prequalify an oral fluid test, many countries are including self-test commodities within their PEPFAR Country Operation Plans and Global Fund concept notes. WHO have issued guidance on self-testing and assisted partner notification. So we can expect to see more and more self-tests out there in the field!

In Malawi, Choko et al. reported on qualitative research done prior to a cluster randomized trial that involves providing self-tests to women attending antenatal care (ANC) for them to take home to their partners.  Although couples are welcomed at ANC clinics and couple testing is certainly beneficial, many men still feel that the clinic is not a place for them.  As one participant said: “Considering what happens here at the ANC clinic, I don’t see my husband escorting me anymore because you find he is alone among many women and he has to listen to some things concerning birth. . . .”

In contrast, many women and men engaged in conversations about how providing self-test kits could help communication, stigma, privacy, control and time pressure among other aspects of involving men in HIV testing.  Some concerns were raised around violence and it is clear that this approach will suit some but not all couples, so it needs to be delivered in a way that respects autonomy with no coercion.

In a very different context, Jamil et al. have conducted a randomized trial among Australian gay men and men who have sex with men.  The trial enrolled “high risk” men who reported multiple partners and condomless sex over the past months.  A central premise of public health strategies to control the HIV epidemic is to find people who have acquired HIV as early as possible.  So the trial aimed to determine whether the offer of free oral fluid self-tests led to earlier testing and more frequent testing.  They found that compared with standard care, availability of free oral-fluid self-testing increased testing frequency both in men who had not tested recently and in men who had not tested at all in the past years. Importantly there was no decline in facility-based testing for HIV or sexually transmitted infections, which might have implied replacement.  The men commented that self-testing was highly acceptable and easy to do.

Self-tests are not a panacea.  Oral fluid tests do have a slightly lower sensitivity than blood based tests.  This may be important when HIV-antibody levels are not high, particularly in people taking ART (either as treatment or as PrEP), or early in the course of infection.  Furthermore, both oral fluid and blood based test rely on visual identification of bands on the test strip that may be faint, leading to some people assuming that they are negative or failing to see the positive band.  Curlin et al. examined the performance of oral fluid tests in people seroconverting to HIV during three specific trials.  They found a considerable number of false negative results and a long delay before some individuals became positive on oral fluid tests.  There was also a clear suggestion that some test operators were less good than others at performing the test and the possibility that one batch of the test kits were less sensitive.  Overall they concluded that “caution must be exercised when interpreting a negative oral fluid test in settings where acute infection is likely, and where PrEP use, ART induced viral suppression, or profound immunosuppression may result in low HIV-specific antibody titers.”  However, as an additional screening tool to be used in populations where many of whom are “missing” from the first 90 are to be found, self-tests have much to offer.  Many of these people will have acquired HIV some time ago and by definition will not be taking ART.  So the cautions raised by Curlin et al. may be less relevant for the primary intended purpose of self-tests.  Nonetheless, they make it very clear that oral fluid self-tests are not an appropriate technology to follow people on treatment or on PrEP.  Nor are they recommended for the diagnosis of acute infection.

While self-tests may increase the proportion of adults knowing their HIV status, different technology is needed for infants.  Nucleic acid amplification is used to detect pro-viral DNA or viral RNA in samples from infants.  The technology is more complex and often centralized, leading to delays and loss to follow up in mother-infant pairs.  Several systems now aim to provide testing close to the point of care and the evaluation of the SAMBA HIV-1 Qual Whole Blood Test from Ondiek et al. is an encouraging report.  Sensitivity and specificity were high (98.5% and 99.8% on 745 infant samples) and comparable to the standard approach used in centralized labs.  Samples from those with discrepant results were rechecked by assays based on multiple targets and suggested that the SAMBA test and the standard approach were each responsible for some of the few false positive and negatives seen.  The advantages of the SAMBA system is that it has been designed to be used in peripheral health systems.  All the reagents are freeze dried and stable without refrigeration. Turnaround time is approximately 2 hours with minimal sample handling once the sample is put into the machine.  Costs will still need to come down, but competition with other manufacturers may help.

The SAMBA technology that was evaluated is a qualitative assay aimed at diagnosis of infants.  A larger market is for viral load assays that are central to the monitoring of the effectiveness of HIV treatment and form the indicator for UNAIDS’s third 90.  However, at the moment viral load assays are still too expensive. As a result the optimal strategy for their use remains uncertain within programmes that have to make difficult decisions about where their limited resources should be spent.

Negoescu et al. have built an interesting model to explore the economic trade-offs between different frequencies of performing viral load assays.  More importantly they explore models of adapting the frequency of assays according to characteristics of the person taking ART.  People who have been on treatment for longer periods, or are older, or report fewer problems with adherence could be selected for less frequent assays.  This could save resources, without compromising health outcomes.  However, for countries like Uganda, which was used as the example to calibrate the model, the best approach seems to still be a viral load assay once per year, regardless of other factors.  And indeed, many resource limited countries are having to make difficult choices about how to allocate stretched budgets between expansion of access to viral load assays to the possible detriment of basic prevention programmes such as male circumcision and condoms.  As more resources become available (or as the cost of viral load assays fall) countries may well choose to do more frequent viral load assays.  The authors showed that monthly assays were more expensive but did (unsurprisingly) lead to benefits in terms of earlier detection of virological failure.  Given the renewed attention to drug resistance and the role of late detection of HIV treatment failure in propagating it, such models may become increasingly important.  Adapting the viral load assay frequency to the characteristics of the person taking HIV treatment could be a sensible approach in middle and higher income settings.

For some years, WHO has recommended that nucleic acid amplification should also be used as the first line test for tuberculosis among people living with HIV.  The GeneXpert® system has been taken up quite widely in many countries where HIV is common among people with tuberculosis, most notably in South Africa.  However, Hermans et al. remind us that technology is only one part of the solution.  Although there is no doubt that Xpert is considerably more sensitive than sputum microscopy and considerably quicker than mycobacterial culture, incorporating the technology into routine practice is not always straightforward.  At the Infectious Disease Institute in Kampala, Uganda, where there are well trained clinicians and better resources than in much of the rest of Uganda, Xpert was made available at no cost for the diagnosis of tuberculosis in a one stop combined HIV-TB clinic.  In a cohort of people living with HIV with symptoms suggestive of possible tuberculosis and whose sputum smear microscopy result was negative, many clinicians still preferred to treat on the basis of their clinical judgement and chest radiography.  Xpert™ was requested in less than half the patients.  Similar numbers of people were started on treatment for tuberculosis regardless of whether Xpert was requested (22% vs 21%).  And among those in whom an Xpert™ was performed, more were started on anti-tuberculosis treatment who had had a negative test than a positive one.  So it was not really clear that Xpert was useful in the diagnosis and management of HIV-related tuberculosis in this setting.  Xpert is not 100% sensitive, so many clinicians will choose to treat patients who might have tuberculosis regardless of the results of new technology.  Xpert also give a result that includes resistance to rifampicin, but this was not such a major issue in Kampala and was not an objective of this study.  Those treated without a confirmed test result were more likely to die during the next 12 months, but the authors point out that there are many possible reasons for this.  Many clinicians are aware of the high rates of undiagnosed tuberculosis found at autopsy in people with HIV. Thus, empirical treatment is often given to those who are critically unwell, even when there is no clear evidence of tuberculosis.

GeneXpert® was also the technology used in another study of tuberculosis contact tracing among school children in Swaziland (Ustero et al.).  Despite a rapid and extensive response to look for additional cases in schools where a confirmed case of tuberculosis had been found, no secondary cases were identified.  In household contacts of the same children, they found an additional two cases.  WHO recommends contacts tracing in households of infectious tuberculosis patients.  Although there is still a large and important gap in the estimated number of tuberculosis cases and the number who are notified and treated by national programmes, the best ways to find the missing cases are not well established.  Even in settings where both infections are among the most important causes of mortality, tuberculosis is much less prevalent than HIV.  So the challenge for case-finding and screening approaches for tuberculosis is to select the populations most at risk. An alternative would be to develop tools that are so sensitive, specific and cheap that they can be used for widespread screening. GeneXpert® is not that tool.

While tuberculosis remains the single most important cause of mortality among people living with HIV in low resource settings, there is welcome and increasing attention being paid to human papillomaviruses (HPV).  Certain types of HPV are the cause of cervical cancer.  This is an AIDS-defining illness both because it is more common among women living with HIV and because it has such a high mortality when only detected at the late stages.  At the Paris conference there was a morning session on how to do more about cervical cancer and in particular how to build on the synergies of both HPV and HIV programmes to provide more integrated services for women who are at risk of both infections.  The most important types of HPV that cause cervical cancer can be prevented by vaccination.  However, to be most effective the vaccine has to be given prior to becoming infected with the relevant HPV strain.  So the study by Sudenga et al. in South Africa is useful as it demonstrates how many younger women aged 16-24 years in the Western Cape Province had antibodies against four of the important types included in the quadrivalent vaccine that they were testing.  The majority of participants (64%) had antibodies to two or more types present at enrolment and 12% had antibodies to all four.  Furthermore, among those participants who received placebo injections, the seroconversion rates were alarming high at 23% for HPV16 and 5% for HPV6 over the 7 months of the study among baseline seronegative participants.  South Africa has been a leader in the region in HPV vaccination for schoolgirls.  It is clear that vaccination needs to happen at a young enough age to catch most girls before they become sexually active.  This is in contrast to the offer of pre-exposure prophylaxis, which should be focused on young women who are already sexually active and at higher risk of acquiring HIV.  The specificities of synergies and integration need to be clearly delineated if we are to maximize efficiency.

HPV is also the principal cause of anal carcinoma, which is a significant problem among gay men and men who have sex with men.  Jin et al. have been building on the progress in cervical cancer screening, where new technologies such as nucleic acid detection or oncoprotein detection are leading to big improvements in some settings and replacing cytology as the first line screen for women.  The authors determined whether similar biomarkers including both nucleic acids and cellular markers could be used instead of anal cytology.  As with most advances in diagnostic technology, there is a trade-off between sensitivity and specificity.  Tests that do not miss any cases of neoplastic change are also likely to lead to many people being unnecessarily referred for further assessment and treatment.  However, both new approaches seem to be able to be calibrated in this Australian population to allow fewer referrals while still maintaining a similar sensitivity to the current cytological approach.

Acceptability of woman-delivered HIV self-testing to the male partner, and additional interventions: a qualitative study of antenatal care participants in Malawi.

Choko AT, Kumwenda MK, Johnson CC, Sakala DW, Chikalipo MC, Fielding K, Chikovore J, Desmond N, Corbett EL. J Int AIDS Soc. 2017 Jun 26;20(1):1-10. doi: 10.7448/IAS.20.1.21610.

Introduction: In the era of ambitious HIV targets, novel HIV testing models are required for hard-to-reach groups such as men, who remain underserved by existing services. Pregnancy presents a unique opportunity for partners to test for HIV, as many pregnant women will attend antenatal care (ANC). We describe the views of pregnant women and their male partners on HIV self-test kits that are woman-delivered, alone or with an additional intervention.

Methods: A formative qualitative study to inform the design of a multi-arm multi-stage cluster-randomized trial, comprised of six focus group discussions and 20 in-depth interviews, was conducted. ANC attendees were purposively sampled on the day of initial clinic visit, while men were recruited after obtaining their contact information from their female partners. Data were analysed using content analysis, and our interpretation is hypothetical as participants were not offered self-test kits.

Results: Providing HIV self-test kits to pregnant women to deliver to their male partners was highly acceptable to both women and men. Men preferred this approach compared with standard facility-based testing, as self-testing fits into their lifestyles which were characterized by extreme day-to-day economic pressures, including the need to raise money for food for their household daily. Men and women emphasized the need for careful communication before and after collection of the self-test kits in order to minimize the potential for intimate partner violence although physical violence was perceived as less likely to occur. Most men stated a preference to first self-test alone, followed by testing as a couple. Regarding interventions for optimizing linkage following self-testing, both men and women felt that a fixed financial incentive of approximately USD$2 would increase linkage. However, there were concerns that financial incentives of greater value may lead to multiple pregnancies and lack of child spacing. In this low-income setting, a lottery incentive was considered overly disappointing for those who receive nothing. Phone call reminders were preferred to short messaging service.

Conclusions: Woman-delivered HIV self-testing through ANC was acceptable to pregnant women and their male partners. Feedback on additional linkage enablers will be used to alter pre-planned trial arms.

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Effect of availability of HIV self-testing on HIV testing frequency in gay and bisexual men at high risk of infection (FORTH): a waiting-list randomised controlled trial.

Jamil MS, Prestage G, Fairley CK, Grulich AE, Smith KS, Chen M, Holt M, McNulty AM, Bavinton BR, Conway DP, Wand H, Keen P,Bradley J, Kolstee J, Batrouney C, Russell D, Law M, Kaldor JM, Guy RJ. Lancet HIV. 2017 Jun;4(6):e241-e250. doi: 10.1016/S2352-3018(17)30023-1. Epub 2017 Feb 17.

Background: Frequent testing of individuals at high risk of HIV is central to current prevention strategies. We aimed to determine if HIV self-testing would increase frequency of testing in high-risk gay and bisexual men, with a particular focus on men who delayed testing or had never been tested before.

Methods: In this randomised trial, HIV-negative high-risk gay and bisexual men who reported condomless anal intercourse or more than five male sexual partners in the past 3 months were recruited at three clinical and two community-based sites in Australia. Enrolled participants were randomly assigned (1:1) to the intervention (free HIV self-testing plus facility-based testing) or standard care (facility-based testing only). Participants completed a brief online questionnaire every 3 months, which collected the number of self-tests used and the number and location of facility-based tests, and HIV testing was subsequently sourced from clinical records. The primary outcome of number of HIV tests over 12 months was assessed overall and in two strata: recent (last test ≤2 years ago) and non-recent (>2 years ago or never tested) testers. A statistician who was masked to group allocation analysed the data; analyses included all participants who completed at least one follow-up questionnaire. After the 12 month follow-up, men in the standard care group were offered free self-testing kits for a year. This trial is registered with the Australian New Zealand clinical trials registry, number actrn12613001236785.

Findings: Between Dec 1, 2013, and Feb 5, 2015, 182 men were randomly assigned to self-testing, and 180 to standard care. The analysis population included 178 (98%) men in the self-testing group (174 person-years) and 165 (92%) in the standard care group (162 person-years). Overall, men in the self-testing group had 701 HIV tests (410 self-tests; mean 4·0 tests per year), and men in the standard care group had 313 HIV tests (mean 1·9 tests per year); rate ratio (rr) 2·08 (95% ci 1·82-2·38; p<0·0001). Among recent testers, men in the self-testing group had 627 tests (356 self-tests; mean 4·2 per year), and men in the standard care group had 297 tests (mean 2·1 per year); rr 1·99 (1·73-2·29; p<0·0001). Among non-recent testers, men in the self-testing group had 74 tests (54 self-tests; mean 2·8 per year), and men in the standard care group had 16 tests (mean 0·7 per year); rr 3·95 (2·30-6·78; p<0·0001). The mean number of facility-based HIV tests per year was similar in the self-testing and standard care groups (mean 1·7 vs 1·9 per year, respectively; rr 0·86, 0·74-1·01; P=0·074). No serious adverse events were reported during follow-up.

Interpretation: HIV self-testing resulted in a two times increase in frequency of testing in gay and bisexual men at high risk of infection, and a nearly four times increase in non-recent testers, compared with standard care, without reducing the frequency of facility-based HIV testing. HIV self-testing should be made more widely available to help increase testing and earlier diagnosis.

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Analysis of false-negative human immunodeficiency virus rapid tests performed on oral fluid in 3 international clinical research studies.

Curlin ME, Gvetadze R, Leelawiwat W, Martin M, Rose C, Niska RW, Segolodi TM, Choopanya K, Tongtoyai J, Holtz TH, Samandari T, McNicholl JM; OraQuick Study Group. Clin Infect Dis. 2017 Jun 15;64(12):1663-1669. doi: 10.1093/cid/cix228.

Background: The OraQuick Advance Rapid HIV-1/2 Test is a point-of-care test capable of detecting human immunodeficiency virus (HIV)-specific antibodies in blood and oral fluid. To understand test performance and factors contributing to false-negative results in longitudinal studies, we examined results of participants enrolled in the Botswana TDF/FTC Oral HIV Prophylaxis Trial, the Bangkok Tenofovir Study, and the Bangkok MSM Cohort Study, 3 separate clinical studies of high-risk, HIV-negative persons conducted in Botswana and Thailand.

Methods: In a retrospective observational analysis, we compared oral fluid OraQuick (OFOQ) results among participants becoming HIV infected to results obtained retrospectively using enzyme immunoassay and nucleic acid amplification tests on stored specimens. We categorized negative OFOQ results as true-negative or false-negative relative to nucleic acid amplification test and/or enzyme immunoassay, and determined the delay in OFOQ conversion relative to the estimated time of infection. We used log-binomial regression and generalized estimating equations to examine the association between false-negative results and participant, clinical, and testing-site factors.

Results: Two-hundred thirty-three false-negative OFOQ results occurred in 80 of 287 seroconverting individuals.  Estimated OFOQ conversion delay ranged from 14.5 to 547.5 (median, 98.5) days. Delayed OFOQ conversion was associated with clinical site and test operator (P < .05), preexposure prophylaxis (P = .01), low plasma viral load (P < .02), and time to kit expiration (P < .01). Participant age, sex, and HIV subtype were not associated with false-negative results. Long OFOQ conversion delay time was associated with antiretroviral exposure and low plasma viral load.

Conclusions: Failure of OFOQ to detect HIV-1 infection was frequent and multifactorial in origin. In longitudinal trials, negative oral fluid results should be confirmed via testing of blood samples.

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Multi-country validation of SAMBA - A novel molecular point-of- care test for HIV-1 detection in resource-limited setting.

Ondiek J, Namukaya Z, Mtapuri-Zinyowera S, Balkan S, Elbireer A, Ushiro Lumb I, Kiyaga C, Goel N, Ritchie A, Ncube P, Omuomu K, Ndiege K, Kekitiinwa A,Mangwanya D, Fowler MG, Nadala L, Lee H. J Acquir Immune Defic Syndr. 2017 Jun 9. doi: 10.1097/QAI.0000000000001476. [Epub ahead of print]

Introduction: Early diagnosis of HIV-1 infection and the prompt initiation of antiretroviral therapy are critical to achieving a reduction in the morbidity and mortality of infected infants. The SAMBA HIV-1 Qual Whole Blood Test was developed specifically for early infant diagnosis and prevention of mother-to-child transmission programs implemented at the point-of-care in resource-limited settings.

Methods: We have evaluated the performance of this test run on the SAMBA I semi-automated platform with fresh whole blood specimens collected from 202 adults and 745 infants in Kenya, Uganda, and Zimbabwe. Results were compared with those obtained with the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HIV-1 assay as performed with fresh whole blood or dried blood spots of the same subjects, and discrepancies were resolved with alternative assays.

Results: The performance of the SAMBA and CAP/CTM assays evaluated at five laboratories in the three countries was similar for both adult and infant samples. The clinical sensitivity, specificity, and positive and negative predictive values for the SAMBA test were 100%, 99.2%, 98.7%, and 100%, respectively, with adult samples, and 98.5%, 99.8%, 99.7%, and 98.8%, respectively, with infant samples.

Discussion: Our data suggest that the SAMBA HIV-1 Qual Whole Blood Test would be effective for early diagnosis of HIV-1 infection in infants at point-of care settings in sub-Saharan Africa.

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Differentiated human immunodeficiency virus RNA monitoring in resource-limited settings: an economic analysis.

Negoescu DM, Zhang Z, Bucher HC, Bendavid E; Swiss HIV Cohort Study. Clin Infect Dis. 2017 Jun 15;64(12):1724-1730. doi: 10.1093/cid/cix177.

Background: Viral load (VL) monitoring for patients receiving antiretroviral therapy (ART) is recommended worldwide. However, the costs of frequent monitoring are a barrier to implementation in resource-limited settings. The extent to which personalized monitoring frequencies may be cost-effective is unknown.

Methods: We created a simulation model parameterized using person-level longitudinal data to assess the benefits of flexible monitoring frequencies. Our data-driven model tracked human immunodeficiency virus (HIV)-infected individuals for 10 years following ART initiation. We optimized the interval between viral load tests as a function of patients' age, gender, education, duration since ART initiation, adherence behavior, and the cost-effectiveness threshold. We compared the cost-effectiveness of the personalized monitoring strategies to fixed monitoring intervals every 1, 3, 6, 12, and 24 months.

Results: Shorter fixed VL monitoring intervals yielded increasing benefits (6.034 to 6.221 discounted quality-adjusted life-years [QALYs] per patient with monitoring every 24 to 1 month over 10 years, respectively, standard error = 0.005 QALY), at increasing average costs: US$3445 (annual monitoring) to US$5393 (monthly monitoring) per patient, respectively (standard error = US$3.7). The adaptive policy optimized for low-income contexts achieved 6.142 average QALYs at a cost of US$3524, similar to the fixed 12-month policy (6.135 QALYs, US$3518). The adaptive policy optimized for middle-income resource settings yields 0.008 fewer QALYs per person, but saves US$204 compared to monitoring every 3 months.

Conclusions: The benefits from implementing adaptive vs fixed VL monitoring policies increase with the availability of resources. In low- and middle-income countries, adaptive policies achieve similar outcomes to simpler, fixed-interval policies.

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Treatment decisions and mortality in HIV-positive presumptive smear-negative TB in the Xpert™ MTB/RIF era: a cohort study.

Hermans SM, Babirye JA, Mbabazi O, Kakooza F, Colebunders R, Castelnuovo B, Sekaggya-Wiltshire C, Parkes-Ratanshi R, Manabe YC. BMC Infect Dis. 2017 Jun 16;17(1):433. doi: 10.1186/s12879-017-2534-2.

Background: The Xpert™ MTB/RIF (XP) has a higher sensitivity than sputum smear microscopy (70% versus 35%) for TB diagnosis and has been endorsed by the WHO for TB high burden countries to increase case finding among HIV co-infected presumptive TB patients. Its impact on the diagnosis of smear-negative TB in a routine care setting is unclear. We determined the change in diagnosis, treatment and mortality of smear-negative presumptive TB with routine use of Xpert MTB/RIF (XP).

Methods: Prospective cohort study of HIV-positive smear-negative presumptive TB patients during a 12-month period after XP implementation in a well-staffed and trained integrated TB/HIV clinic in Kampala, Uganda. Prior to testing clinicians were asked to decide whether they would treat empirically prior to Xpert result; actual treatment was decided upon receipt of the XP result. We compared empirical and XP-informed treatment decisions and all-cause mortality in the first year.

Results: Of 411 smear-negative presumptive TB patients, 175 (43%) received an XP; their baseline characteristics did not differ. XP positivity was similar in patients with a pre-XP empirical diagnosis and those without (9/29 [17%] versus 14/142 [10%], P = 0.23). Despite XP testing high levels of empirical treatment prevailed (18%), although XP results did change who ultimately was treated for TB. When adjusted for CD4 count, empirical treatment was not associated with higher mortality compared to no or microbiologically confirmed treatment.

Conclusions: XP usage was lower than expected. The lower sensitivity of XP in smear-negative HIV-positive patients led experienced clinicians to use XP as a "rule-in" rather than "rule-out" test, with the majority of patients still treated empirically.

Keywords: Empirical treatment; HIV Infections/complications; Molecular diagnostic techniques/methods; Tuberculosis, pulmonary/diagnosis; Tuberculosis, pulmonary/epidemiology

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School and household tuberculosis contact investigations in Swaziland: Active TB case finding in a high HIV/TB burden setting.

Ustero PA, Kay AW, Ngo K, Golin R, Tsabedze B, Mzileni B,Glickman J, Wisile Xaba M, Mavimbela G, Mandalakas AM. PLoS One. 2017 Jun 5;12(6):e0178873. doi: 10.1371/journal.pone.0178873.eCollection 2017.

Background: Investigation of household contacts exposed to infectious tuberculosis (TB) is widely recommended by international guidelines to identify secondary cases of TB and limit spread. There is little data to guide the use of contact investigations outside of the household, despite strong evidence that most TB infections occur outside of the home in TB high burden settings. In older adolescents, the majority of infections are estimated to occur in school. Therefore, as part of a project to increase active case finding in Swaziland, we performed school contact investigations following the identification of a student with infectious TB.

Methods: The Butimba Project identified 7 adolescent TB index cases (age 10-20) with microbiologically confirmed disease attending 6 different schools between June 2014 and March 2015. In addition to household contact investigations, Butimba Project staff worked with the Swaziland School Health Programme (SHP) to perform school contact investigations. At 6 school TB screening events, between May and October 2015, selected students underwent voluntary TB screening and those with positive symptom screens provided sputum for TB testing.

Results: Among 2015 student contacts tested, 177 (9%) screened positive for TB symptoms, 132 (75%) produced a sputum sample, of which zero tested positive for TB. Household contact investigations of the same index cases yielded 40 contacts; 24 (60%) screened positive for symptoms; 19 produced a sputum sample, of which one case was confirmed positive for TB. The odds ratio of developing TB following household vs. school contact exposure was significantly lower (OR 0.0, 95% CI 0.0 to 0.18, P = 0.02) after exposure in school.

Conclusion: School-based contact investigations require further research to establish best practices in TB high burden settings. In this case, a symptom-based screening approach did not identify additional cases of tuberculosis. In comparison, household contact investigations yielded a higher percentage of contacts with positive TB screens and an additional tuberculosis case.

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HPV serostatus pre- and post-vaccination in a randomized phase II preparedness trial among young Western Cape, South African women: the EVRI trial.

Sudenga SL, Torres BN, Botha MH, Zeier M, Abrahamsen ME, Glashoff RH, Engelbrecht S, Schim Van der Loeff MF, Van der Laan LE, Kipping S, Taylor D, Giuliano AR. Papillomavirus Res. 2017 Jun;3:50-56. doi: 10.1016/j.pvr.2017.02.001. Epub 2017 Feb 16.

Background: HPV antibodies are a marker of past exposure to the virus. Our objective was to assess HPV serostatus pre- and post-vaccination among HIV-negative women.

Methods: Women aged 16-24 years old were randomized in a placebo controlled trial utilizing the 4-valent HPV (4vHPV) vaccine (NCT01489527, clinicaltrials.gov). Participants (n=389) received the 4vHPV vaccine or placebo following a three dose schedule. Sera were collected at Day 1 and Month 7 for assessment of HPV 6, 11, 16, and 18 neutralizing antibody levels using a multiplex competitive Luminex immunoassay (Merck) based on detecting the L1 capsid antigen for each HPV type.

Results: Seroprevalence was 73% for HPV6, 47% for HPV11, 33% for HPV16, and 44% for HPV18. Seroprevalence for any HPV type did not significantly differ by age or lifetime number of partners. The majority of participants (64%) had two or more 4vHPV antibodies present at enrollment and 12% had antibodies to all four. Among women in the vaccine arm, those that were seropositive for HPV16 at enrollment had higher titers at month 7 compared to women that were seronegative for HPV16 at enrollment; this trend holds for the other HPV types as well. Seroconversion among baseline seronegative participants in the placebo group ranged from 5% for HPV16 to 23% for HPV6.

Conclusion: HPV seroprevalence was high in this population, emphasizing the need to vaccinate prior to sexual debut.

Abstract access

 

The performance of human papillomavirus biomarkers in predicting anal high-grade squamous intraepithelial lesions in gay and bisexual men.

Jin F, Roberts JM, Grulich AE, Poynten IM, Machalek DA, Cornall A, Phillips S, Ekman D, McDonald RL, Hillman RJ, Templeton DJ, Farnsworth A, Garland SM, Fairley CK, Tabrizi SN; SPANC Research Team. AIDS. 2017 Jun 1;31(9):1303-1311. doi: 10.1097/QAD.0000000000001462.

Background: We evaluate the performance of human papillomavirus (HPV) biomarkers in prediction of anal histological high-grade squamous intraepithelial lesions in gay and bisexual men (GBM) in Sydney, Australia.

Design: Baseline analysis of a 3-year cohort study.

Methods: The study of the prevention of anal cancer is natural history study of anal HPV infection in GBM aged at least 35 years. All participants completed cytological and histological assessments. Stored ThinPrep PreservCyt residua were tested for HPV genotyping (Linear Array and Cobas 4800) and viral load, E6/E7 mRNA expression (NucliSENS easyQ HPV v1) and dual cytology staining of p16/Ki 67 antibodies (CINtecPLUS). Performance of each biomarker was compared with liquid-based anal cytology. The hypothetical referral rates were defined as the proportion of men who had abnormal cytology or tested positive to each of the biomarkers.

Results: The median age of the 617 participants was 49 years (range: 35-79), and 35.7% were HIV-positive. All biomarkers were strongly associated with the grade of HPV-associated anal lesions (P < 0.001 for all). High-risk HPV (HR-HPV) viral load with a 33% cut-off and HR-HPV E6/E7 mRNA had similar sensitivity to anal cytology (78.4 and 75.4 vs. 83.2%, respectively), improved specificity (68.0 and 69.4 vs. 52.4%, respectively) and lower referral rates (47.0 and 45.0 vs. 59.2%, respectively). Specificity was significantly higher in the HIV-negative for HR-HPV viral load (72.3 vs. 58.2%, P = 0.005).

Conclusion: HR-HPV viral load and E6/E7 mRNA had similar sensitivity and higher specificity in predicting histological anal high-grade squamous intraepithelial lesion with lower referrals in GBM than anal cytology.

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Africa, Asia, Europe, Oceania
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Where are we heading with the horrible interaction between human papillomavirus (HPV) and HIV?

Editor’s notes: Human papillomavirus (HPV) is the most common sexually transmitted infection in the world.  There are over 200 different strains of HPV, distinguished by genetic typing.  The strains are classified into high-risk and low-risk based on their associations with the development of cervical cancer, but also genital warts and anal cancer.  HPV16 is the most common high-risk strain and is found in about half of cervical cancers and 70% of anal cancers.  Although anal cancer is much less common than cervical cancer among women, there is clear evidence that women living with HIV are at greater risk not only of cervical cancer but also of anal cancer.

In a study in Vitoria, Brazil, Volpini and colleagues collected cervical and anal samples from 126 women living with HIV who had recently had a normal Pap smear, and so did not already have pre-cancerous lesions in the cervix.  They found DNA from HPV in 71% of the women. 39% of women had HPV in cervical samples, while 60% had HPV in anal samples.

HPV16 was the most prevalent type at the cervical and anal sites (9% and 18%, respectively).  Other high risk strains were found in the cervical samples from more than 30% of women and in the anal samples of another 12% of women (some women had multiple strains). All currently available vaccines protect against HPV16 and one also protects against HPV45 and 31 (which accounted for almost half of the remaining high risk strains from the cervical samples).  The vaccine works best when given before any HPV infection, and is therefore recommended for girls before they become sexually active.  However, persistence and clearance of HPV is a dynamic process and the possible benefits of vaccination in those already infected are not yet clear.

Testing for HPV is becoming increasingly sophisticated, with molecular technology becoming available that allows detection of DNA and strain typing.  It seems very probable that women living with HIV with high-risk strains in either cervical or anal samples are at greater risk of developing cancer and therefore need additional more intense screening to detect and treat any pre-cancerous abnormalities in their epithelium prior to the development of invasive cancers.  Current guidelines already recommend that women living with HIV are offered Pap smears more regularly than their HIV-negative peers.  DNA based technology may make it possible to offer a more targeted approach to women at the most risk.

In the meantime, encouraging HPV vaccination among schoolgirls (and eventually boys too) is a long term prevention measure.  Ensuring that HPV screening services and HIV prevention and care services are well co-ordinated or even integrated is something that will have an immediate impact on preventing deaths from cervical cancer.  Incorporating molecular testing might help us to reduce the incidence of anal cancer too.

The high prevalence of HPV and HPV16 European variants in cervical and anal samples of HIV-seropositive women with normal Pap test results.

Volpini LPB, Boldrini NAT, de Freitas LB, Miranda AE, Spano LC. PLoS One. 2017 Apr 20;12(4):e0176422. doi: 10.1371/journal.pone.0176422. eCollection 2017.

Human immunodeficiency virus (HIV)-seropositive women are more likely to have anogenital cancer, and high risk-HPV (HR-HPV) infection is the main associated factor. Between August 2013 and December 2015, we conducted a descriptive study to determine the HPV genotypes and HPV16 variants in cervical and anal samples of HIV-seropositive women with a normal Pap test. The viral DNA was amplified by PCR using the PGMY09/11 set of primers. Reverse line blot (RLB), restriction fragment length polymorphism (RFLP) and sequencing assays were used to determine the HPV genotypes. HPV16 variants were identified by gene sequencing. We found a high frequency of HR-HPV (60.3%; 76/126) at the anogenital site among HIV-seropositive women and without association with anal intercourse. HPV16 and European variant predominated among the HR-HPV. Mixed infections with at least three different HPV types were common, particularly at the anal site. CD4+ T-cell counts below 500 cells/mm3, a HIV viral load above 50 copies/mL and an age of 18 to 35 years old were all related to HPV anal infection. Our study showed a high frequency of HR-HPV in both cervical and anal sites of women with negative cytology belonging to a risk group for the development of anogenital cancer.

Abstract Full-text [free] access 

Cancers, Comorbidity
Europe
Brazil
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Integration of reproductive health and rights

Editor’s notes: Integration of reproductive health services and rights needs to be well coordinated with HIV services, so a randomized trial of integration of family planning services into HIV care clinics in Kenya by Cohen CR and colleagues is encouraging.  In their initial randomized trial, 12 clinics were randomly selected for early integration using resources from the study team, while six were delayed.  Subsequently the Ministry of Health took over the integration and provision of “one stop shop” services at all 18 clinics.  The improvements in contraceptive uptake and decreased pregnancy rates that had been observed in the first phase were maintained during the second phase giving more confidence that it was truly the integrated nature of the services rather than the presence of special study team that had led to the difference.

Another major push for integration or coordination between HIV and sexual and reproductive health and rights services is around the prevention of cervical cancer.  Cervical cancer is caused by long-term infection with specific types of human papilloma virus.  Women living with HIV are at considerably increased risk of cervical cancer compared to their HIV-negative peers.  A large cohort study by Kelly HA et al. in Burkina Faso and South Africa has shown that women living with HIV, attending clinical care services have a high prevalence (59-79% at baseline), incidence (48%) and persistence (up to 70% for some types) of HR-HPV and correspondingly a high prevalence and incidence of cervical neoplasia. There are two HPV vaccines currently available, the first prevents HPV types 16 and 18 (the causes of around 70% of cervical cancer) while the newer (and currently more expensive) vaccine prevents nine types (that cause at least 90% of cervical cancer).  HPV vaccination is recommended to be given before sexual debut, as it gives high protection against the specific types of HPV prior to acquisition.  The dynamics of the many different types of HPV after acquisition is less clear.  The virus is often acquired and they may be cleared or may persist.  So this study provides important background data for understanding the possible role of vaccination and also which types are most associated with pre-cancers (cervical Intra-epithelial neoplasia [CIN]) that can be treated and cured relatively easily.  In particular, in this study, HPV58, which is in the same (alpha-9) family as HPV16 showed the greatest association with CIN2+.  HPV58 is included in the newer nonavalent vaccine, but not the current bi- or quadrivalent vaccine.  Overall this is an area where we need more research on the impact of vaccination and screening programmes for women living with HIV, but in the meantime, HPV vaccination for school girls (and boys) is an investment in the future, since these vaccines are effective ways to stop people dying of cervical (and other HPV-related) cancers.

One of the challenges for integrated reproductive services is to continue to emphasize the importance of condoms for protection against HIV and sexually transmitted infections even if other methods are being used for contraception.  Such “dual protection” is particularly hard to achieve in married or cohabiting couples despite evidence of ongoing risk of HIV infection.  A study in 2388 urban 18-24 year old individuals in Zambia (69% female; 35% married) shows that condom use is still much too low with only 45% reporting that they had used a condom in the last 12 months. As might be anticipated, the study found that the poorest and people who were married were least likely to use condoms while people who discussed contraception and agreed to use condoms were more likely to do so [Pinchoff J et al.] The importance of dual protection, and of promoting broader HIV prevention messages to women through integrated (or at least coordinated) reproductive health and rights services is made even more important given the possibility that depot medroxyprogesterone acetate (DMPA) as a long acting reversible contraceptive may increase the risk of HIV acquisition.  WHO has recently changed their guidance to make such contraceptives grade 2 in the Medical Eligibility for Contraceptives (MEC) guidelines.

Integration of family planning services into HIV care clinics: Results one year after a cluster randomized controlled trial in Kenya.

Cohen CR, Grossman D, Onono M, Blat C, Newmann SJ, Burger RL, Shade SB, Bett N, Bukusi EA. PLoS One. 2017 Mar 22;12(3):e0172992. doi: 10.1371/journal.pone.0172992.eCollection 2017.

Objectives: To determine if integration of family planning (FP) and HIV services led to increased use of more effective contraception (i.e. hormonal and permanent methods, and intrauterine devices) and decreased pregnancy rates.

Design: Cohort analysis following cluster randomized trial, when the Kenya Ministry of Health led integration of the remaining control (delayed integration) sites and oversaw integrated services at the original intervention (early integration) sites.

Setting: Eighteen health facilities in Kenya.

Subjects: Women aged 18-45 receiving care: 5682 encounters at baseline, and 11 628 encounters during the fourth quarter of year 2.

Intervention: "One-stop shop" approach to integrating FP and HIV services.

Main outcome measures: Use of more effective contraceptive methods and incident pregnancy across two years of follow-up.

Results: Following integration of FP and HIV services at the six delayed integration clinics, use of more effective contraception increased from 31.7% to 44.2% of encounters (+12.5%; Prevalence ratio (PR) = 1.39 (1.19-1.63). Among the twelve early integration sites, the proportion of encounters at which women used more effective contraceptive methods was sustained from the end of the first to the second year of follow-up (37.5% vs. 37.0%). Pregnancy incidence including all 18 integrated sites in year two declined in comparison to the control arm in year one (rate ratio: 0.72; 95% CI 0.60-0.87).

Conclusions: Integration of FP services into HIV clinics led to a sustained increase in the use of more effective contraceptives and decrease in pregnancy incidence 24 months following implementation of the integrated service model.

Trial registration: ClinicalTrials.gov NCT01001507.

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Associations of human papillomavirus (HPV) genotypes with high-grade cervical neoplasia (CIN2+) in a cohort of women living with HIV in Burkina Faso and South Africa.

Kelly HA, Ngou J, Chikandiwa A, Sawadogo B, Gilham C, Omar T, Lompo O, Doutre S), Meda N, Weiss HA, Delany-Moretlwe S, Segondy M, Mayaud P; HARP Study Group. PLoS One. 2017 Mar 23;12(3):e0174117. doi: 10.1371/journal.pone.0174117.eCollection 2017.

Objective: To describe associations of high-risk human papillomavirus (HR-HPV) with high-grade cervical intraepithelial neoplasia (CIN2+) in women living with HIV (WLHIV) in Burkina Faso (BF) and South Africa (SA).

Methods: Prospective cohort of WLHIV attending HIV outpatient clinics and treatment centres. Recruitment was stratified by ART status. Cervical HPV genotyping using INNO-LiPA and histological assessment of 4-quadrant cervical biopsies at enrolment and 16 months later.

Results: Among women with CIN2+ at baseline, the prevalence of any HR-HPV genotypes included in the bi/quadrivalent (HPV16/18) or nonavalent (HPV16/18/31/35/45/52/58) HPV vaccines ranged from 37% to 90%. HPV58 was most strongly associated with CIN2+ (aOR = 5.40, 95%CI: 2.77-10.53). At 16-months follow-up, persistence of any HR-HPV was strongly associated with incident CIN2+ (aOR = 7.90, 95%CI: 3.11-20.07), as was persistence of HPV16/18 (aOR = 5.25,95%CI: 2.14-12.91) and the additional HR types in the nonavalent vaccine (aOR =3.23, 95%CI: 1.23-8.54).

Conclusion: HR-HPV persistence is very common among African WLHIV and is linked to incident CIN2+. HPV vaccines could prevent between 37-90% of CIN2+ among African WLHIV.

Abstract  Full-text [free] access

Why don't urban youth in Zambia use condoms? The influence of gender and marriage on non-use of male condoms among young adults.

Pinchoff J, Boyer CB, Mutombo N, Chowdhuri RN, Ngo TD. PLoS One. 2017 Mar 23;12(3):e0172062. doi: 10.1371/journal.pone.0172062.eCollection 2017.

Background: Zambia experiences high unmet need for family planning and high rates of HIV, particularly among youth. While male condoms are widely available and 95%of adults have heard of them, self-reported use in the past 12 months is low among young adults (45%). This study describes factors associated with non-use of male condoms among urban young adults in Zambia.

Methods: A household cross-sectional survey in four urban districts was conducted from November 2015 to January 2016 among sexually active young adults ages 18-24 years. A random walk strategy was implemented in urban areas; eligible, enrolled participants were administered a survey on household characteristics, health access, and knowledge, attitudes and practices related to contraception. Relative risk regression models were built to determine factors associated with the decision to not use a male condom (non-use) at most recent sexual intercourse.

Results: A total of 2388 individuals were interviewed; 69% were female, 35% were married, and average lifetime sex partners was 3.45 (SD±6.15). Non-use of male condoms was 59% at most recent sexual intercourse. In a multivariate model, women were more likely to report non-use of a male condom compared with men (aRR = 1.24[95% CI: 1.11, 1.38]), married individuals were more likely to report non-use compared with unmarried individuals (aRR = 1.59 [1.46, 1.73]), and those residing in the highest poverty wards were more likely to report non-use compared with those in the lowest poverty wards (aRR = 1.31 [1.16, 1.48]). Those with more negative perceptions of male condom use were 6% more likely to report non-use (aRR = 1.06 [1.03, 1.09]). Discussion regarding contraception with a partner decreased non-use 13% (aRR = 0.87 [0.80, 0.95]) and agreement regarding male condom use with a partner decreased non-use 16% (aRR = 0.84 [0.77, 0.91)]).

Discussion: Non-use of male condoms is high among young, married adults, particularly women, who may be interested in contraception for family planning but remain at risk of STI infection. Effective marketing strategy of dual protection methods to this population is critical.

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Africa
Burkina Faso, Kenya, South Africa, Zambia
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Invasive cervical cancer and HIV – young women need access to screening

Implementation and operational research: age distribution and determinants of invasive cervical cancer in a "screen-and-treat" program integrated with HIV/AIDS care in Zambia.

Kapambwe S, Sahasrabuddhe VV, Blevins M, Mwanahamuntu MH, Mudenda V, Shepherd BE, Chibwesha CJ, Pfaendler KS, Hicks ML, Vermund SH, Stringer JS, Parham GP. J Acquir Immune Defic Syndr. 2015 Sep 1;70(1):e20-6. doi: 10.1097/QAI.0000000000000685.

Background: Cervical cancer screening efforts linked to HIV/AIDS care programs are being expanded across sub-Saharan Africa. Evidence on the age distribution and determinants of invasive cervical cancer (ICC) cases detected in such programs is limited.

Methods: We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia, the largest public sector programs of its kind in sub-Saharan Africa. We examined age distribution patterns by HIV serostatus of histologically confirmed ICC cases and used multivariable logistic regression to evaluate independent risk factors for ICC among younger (≤35 years) and older (>35 years) women.

Results: Between January 2006 and April 2010, of 48 626 women undergoing screening, 571 (1.2%) were diagnosed with ICC, including 262 (46%) HIV seropositive (median age: 35 years), 131 (23%) HIV seronegative (median age: 40 years), and 178 (31%) of unknown HIV serostatus (median age: 38 years). Among younger (≤35 years) women, being HIV seropositive was associated with a 4-fold higher risk of ICC [adjusted odds ratio = 4.1 (95% confidence interval: 2.8, 5.9)] than being HIV seronegative. The risk of ICC increased with increasing age among HIV-seronegative women and women with unknown HIV serostatus, but among HIV-seropositive women, the risk peaked around age 35 and nonsignificantly declined with increasing ages. Other factors related to ICC included being married (vs. being unmarried/widowed) in both younger and older women, and with having 2+ (vs. ≤1) lifetime sexual partners among younger women.

Conclusions: HIV infection seems to have increased the risk of cervical cancer among younger women in Zambia, pointing to the urgent need for expanding targeted screening interventions.

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Editor’s notes: Increasingly, HIV care services (includes AIDS) are providing platforms for introduction of cervical cancer screening programmes in sub-Saharan Africa. Screening is often also available for HIV-negative women. This analysis of data from a large routine programme gives a useful indication of the rates of identification of invasive cervical cancer (ICC), and describes the burden and distribution of disease; information relevant to future service provision. The association described of ICC with HIV and sexual behaviour is well-known. The findings highlight the importance of ensuring that younger women (especially if known to be HIV-positive) have access to routine screening. A significant part of the burden is borne by older women. HIV status may not always be known or revealed. Important questions remain concerning the cost-benefit of providing screening services and the effect of ART on risk of ICC. In addition, the potential role of human papilloma virus vaccine, which GAVI is currently implementing in demonstration projects in the region, in influencing the risk of ICC in younger women remains to be determined. 

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Cancers, HIV
Africa
Zambia
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HIV-related cancer risk declines with ART in Botswana and Uganda, but population burden a major concern

Cancer incidence following expansion of HIV treatment in Botswana

Dryden-Peterson S, Medhin H, Kebabonye-Pusoentsi M, Seage GR, 3rd, Suneja G, Kayembe MK, Mmalane M, Rebbeck T, Rider JR, Essex M, Lockman S. PLoS One. 2015 Aug 12;10(8):e0135602. doi: 10.1371/journal.pone.0135602. eCollection 2015.

Background: The expansion of combination antiretroviral treatment (ART) in southern Africa has dramatically reduced mortality due to AIDS-related infections, but the impact of ART on cancer incidence in the region is unknown. We sought to describe trends in cancer incidence in Botswana during implementation of the first public ART program in Africa.

Methods: We included 8479 incident cases from the Botswana National Cancer Registry during a period of significant ART expansion in Botswana, 2003-2008, when ART coverage increased from 7.3% to 82.3%. We fit Poisson models of age-adjusted cancer incidence and counts in the total population, and in an inverse probability weighted population with known HIV status, over time and estimated ART coverage.

Findings: During this period 61.6% of cancers were diagnosed in HIV-infected individuals and 45.4% of all cancers in men and 36.4% of all cancers in women were attributable to HIV. Age-adjusted cancer incidence decreased in the HIV infected population by 8.3% per year (95% CI -14.1 to -2.1%). However, with a progressively larger and older HIV population the annual number of cancers diagnosed remained constant (0.0% annually, 95% CI -4.3 to +4.6%). In the overall population, incidence of Kaposi's sarcoma decreased (4.6% annually, 95% CI -6.9 to -2.2), but incidence of non-Hodgkin lymphoma (+11.5% annually, 95% CI +6.3 to +17.0%) and HPV-associated cancers increased (+3.9% annually, 95% CI +1.4 to +6.5%). Age-adjusted cancer incidence among individuals without HIV increased 7.5% per year (95% CI +1.4 to +15.2%).

Interpretation: Expansion of ART in Botswana was associated with decreased age-specific cancer risk. However, an expanding and aging population contributed to continued high numbers of incident cancers in the HIV population. Increased capacity for early detection and treatment of HIV-associated cancer needs to be a new priority for programs in Africa.

Abstract  Full-text [free] access


 

A population-level evaluation of the effect of antiretroviral therapy on cancer incidence in Kyadondo county, Uganda, 1999-2008.

Mutyaba I, Phipps W, Krantz EM, Goldman JD, Nambooze S, Orem J, Wabinga HR, Casper C. J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):481-6. doi: 10.1097/QAI.0000000000000620.

Background: The introduction of antiretroviral therapy (ART) in the United States and Europe has led to changes in the incidence of cancers among HIV-infected persons, including dramatic decreases in Kaposi sarcoma and non-Hodgkin lymphoma, and increases in Hodgkin lymphoma, liver, and anogenital malignancies. We sought to evaluate whether increasing availability of ART is associated with changing cancer incidence in Uganda.

Methods: Incident cases of 10 malignancies were identified from Kampala Cancer Registry from 1999 to 2008. ART coverage rates for Uganda were abstracted from the Joint United Nations Program on HIV/AIDS reports. Negative binomial and Poisson regression modeled the association between ART coverage and age-adjusted cancer incidence.

Results: ART coverage in Uganda increased from 0% to 43% from 1999 to 2008. With each 10% increase in ART coverage, incidence of Kaposi sarcoma decreased by 5% [incidence rate ratio (IRR) = 0.95, 95% confidence interval: 0.91 to 0.99, P = 0.02] and stomach cancer decreased by 13% [IRR = 0.87 (95% CI: 0.80 to 0.95), P = 0.002]. Conversely, incidence of non-Hodgkin lymphoma increased by 6% [IRR = 1.06 (95% CI: 1 to 1.12), P = 0.05], liver cancer by 12% [IRR = 1.12 (95% CI: 1.04 to 1.21), P = 0.002], prostate cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.10), P = 0.05], and breast cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.11), P = 0.05]. ART coverage was not associated with incidence of invasive cervical cancer, lung, colon, and Hodgkin disease. These findings were similar when restricted to histologically confirmed cases.

Conclusions: Our findings suggest that AIDS-defining malignancies and other malignancies are likely to remain significant public health burdens in sub-Saharan Africa even as ART availability increases.

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Editor’s notes: There is increasing concern about non-communicable diseases, including cancers, in sub-Saharan Africa. The increasing population of people on antiretroviral therapy (ART) may result in increased absolute numbers of people diagnosed with cancer, presenting a major challenge to often under-resourced cancer diagnosis and treatment services. Few African countries have functional cancer registries. This month, we highlight data reported from both Botswanan and Ugandan cancer registries.

The article by Dryden-Petersen et al. presents data from the Botswanan registry from 2003-2008, a time of rapid ART roll-out. Age-adjusted rates of cancer were estimated using population survey denominators which include HIV status. The analysis distinguishes cancers occurring in HIV-positive individuals from those attributable to HIV (includes Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer). Kaposi’s sarcoma, cervix and breast cancer were the most commonly-reported cancers. Overall, against a background of increasing age-adjusted incidence of cancers, the age-adjusted incidence in the HIV-positive population decreased compared to an early peak prior to ART implementation. However, given this expanding population of survivors, the absolute numbers of reported cases remained constant. Different cancers had different trends. Cervical cancer, which affects younger women and which increased over the period studied, may be a particular focus as it is common and relatively easy to identify in the early stages.

The article by Mutyaba et al. presents data from the Ugandan cancer registry for Kyadondo county from 1999-2008, similarly a time of rapid ART roll-out. The analysis uses population denominators, and an ecologic analysis to estimate change in cancer incidence by ART coverage for 10 selected cancers, including Kaposi’s sarcoma, invasive cervical cancer and non-Hodgkin’s lymphoma. Although significant differences in the incidence rate of about half of the cancers were observed over this period, the differences per increase of ART coverage (by 10%) were modest.

These data are now somewhat out of date, but despite the limitations of use of routine data (incomplete and biased ascertainment of cancers, HIV status etc) it is clear that the burden of cancers in these two settings is unlikely to decrease and there are major implications for service provision including screening programmes. 

The findings from the two studies are consistent in showing an important decrease in Kaposi’s sarcoma with ART, but an increase in non-Hodgkin’s lymphoma. However the trends for other cancers (cervical, breast, prostate, liver and lung) are in different directions, which may reflect different ascertainment abilities, ART programmatic differences or different methods of data analysis. Overall both studies highlight that cancer is not declining as ART programmes have been rolled out.

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Africa
Botswana, Uganda
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