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1.  Transitional Probability-Based Model for HPV Clearance in HIV-1-Positive Adolescent Females 
PLoS ONE  2012;7(1):e30736.
Background
HIV-1-positive patients clear the human papillomavirus (HPV) infection less frequently than HIV-1-negative. Datasets for estimating HPV clearance probability often have irregular measurements of HPV status and risk factors. A new transitional probability-based model for estimation of probability of HPV clearance was developed to fully incorporate information on HIV-1-related clinical data, such as CD4 counts, HIV-1 viral load (VL), highly active antiretroviral therapy (HAART), and risk factors (measured quarterly), and HPV infection status (measured at 6-month intervals).
Methodology and Findings
Data from 266 HIV-1-positive and 134 at-risk HIV-1-negative adolescent females from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort were used in this study. First, the associations were evaluated using the Cox proportional hazard model, and the variables that demonstrated significant effects on HPV clearance were included in transitional probability models. The new model established the efficacy of CD4 cell counts as a main clearance predictor for all type-specific HPV phylogenetic groups. The 3-month probability of HPV clearance in HIV-1-infected patients significantly increased with increasing CD4 counts for HPV16/16-like (p<0.001), HPV18/18-like (p<0.001), HPV56/56-like (p = 0.05), and low-risk HPV (p<0.001) phylogenetic groups, with the lowest probability found for HPV16/16-like infections (21.60±1.81% at CD4 level 200 cells/mm3, p<0.05; and 28.03±1.47% at CD4 level 500 cells/mm3). HIV-1 VL was a significant predictor for clearance of low-risk HPV infections (p<0.05). HAART (with protease inhibitor) was significant predictor of probability of HPV16 clearance (p<0.05). HPV16/16-like and HPV18/18-like groups showed heterogeneity (p<0.05) in terms of how CD4 counts, HIV VL, and HAART affected probability of clearance of each HPV infection.
Conclusions
This new model predicts the 3-month probability of HPV infection clearance based on CD4 cell counts and other HIV-1-related clinical measurements.
doi:10.1371/journal.pone.0030736
PMCID: PMC3265500  PMID: 22292027
2.  The impact of highly active antiretroviral therapy on prevalence and incidence of cervical human papillomavirus infections in HIV-positive adolescents 
BMC Infectious Diseases  2010;10:295.
Background
The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial.
Methods
HIV-positive and high-risk HIV-negative female adolescents were enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) longitudinal cohort study. At each semi-annual clinical visit, cervical lavage samples were tested for 30 HPV types. Type-specific and carcinogenic risk-specific HPV prevalence and incidence were compared in 373 eligible participants: 146 HIV-negative female adolescents with a median follow-up of 721.5 [IQR: 483-1301] days and 227 HIV-positive female adolescents. Of the 227 HIV-positive participants, a fixed set (n = 100) were examined both before and after HAART initiation; 70 were examined only before HAART initiation; and 57 were examined only after HAART initiation, with overall median follow-up of 271 [IQR: 86.5-473] and 427.25 [IQR: 200-871] days respectively for before and after HAART initiation.
Results
Of the 373 eligible participants, 262 (70%) were infected with at least one type of HPV at baseline, and 78 of the remaining 111 (70%) became infected with at least one type of HPV by the end of the study. Overall, the incidence and prevalence of HPV types 58, 53/66, 68/70, and 31/33/35 were much higher than the established carcinogenic and HPV vaccine types 16 and 18, especially in HIV-positive females both before and after HAART initiation. Baseline prevalence for individual high-risk HPV types ranged, depending on type, from 0.7-10%, 1-17%, and 1-18% in the HIV-negative group, the HIV-positive before HAART initiation group, and the HIV-positive after HAART initiation group, respectively. Likewise, the incidence ranged, depending on HPV type, from 0.64-9.83 cases/100 PY, 3.00-12.80 cases/100 PY, and 1.49-17.05 cases/100 PY in the three groups, respectively. The patterns of each HPV type infection, clearance, and persistence did not differ considerably before or after the introduction of HAART and were clearly independent of CD4+ change within the short post-HAART follow-up period.
Conclusions
HAART did not immediately affect the incidence of type-specific HPV infections within a short-period follow-up; however, future studies are warranted in larger populations to evaluate HAART's impact over longer periods.
doi:10.1186/1471-2334-10-295
PMCID: PMC2965148  PMID: 20946655
3.  Switching HIV Treatment in Adults Based on CD4 Count Versus Viral Load Monitoring: A Randomized, Non-Inferiority Trial in Thailand 
PLoS Medicine  2013;10(8):e1001494.
Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand.
Please see later in the article for the Editors' Summary
Background
Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.
Methods and Findings
The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50–250/mm3) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm3. The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6–11.4) in VL versus 7.4% (5.1–10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2–8.4) in VL versus 7.5% (5.0–11.1) in CD4 (p = 0.097). Median time from treatment initiation to switch was 11.7 months (7.7–19.4) in VL and 24.7 months (15.9–35.0) in CD4 (p = 0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8–8.0) in VL versus 15.8 months (8.5–20.4) in CD4 (p = 0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.
Conclusions
The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.
Trial registration
ClinicalTrials.gov NCT00162682
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment.
Why Was This Study Done?
At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another.
What Did the Researchers Do and Find?
The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch.
What Do These Findings Mean?
These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494.
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2010 recommendations for antiretroviral therapy for HIV infection in adults and adolescents are available as well as the June 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the global HIV/AIDS epidemic, on HIV and AIDS in Thailand, on universal access to AIDS treatment, and on starting, monitoring and switching HIV treatment (in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS
More information about this trial (the PHPT-3 trial) is available
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about HIV treatment
doi:10.1371/journal.pmed.1001494
PMCID: PMC3735458  PMID: 23940461
4.  Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared 
PLoS Medicine  2008;5(7):e148.
Background
The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland.
Methods and Findings
We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/μl in South Africa and 204 cells/μl in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%–97%) in South Africa and 96% (94%–97%) in Switzerland, and 26% (22%–29%) and 27% (24%–31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81–19.2) during months 1–3 and 1.77 (0.90–3.50) during months 4–24.
Conclusions
Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.
Comparing HIV treatment in Switzerland, where drug selection is individualized, and South Africa, where a programmatic approach is used, Matthias Egger and colleagues find similar virologic outcomes over two years.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first reported case in 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a combination of several antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians provide individually tailored care for HIV-infected people by prescribing combinations of antiretroviral drugs chosen from more than 20 approved medicines. The approach to treatment of HIV in developed countries typically also includes frequent monitoring of the amount of virus in patients' blood (viral load), viral resistance testing (to see whether any viruses are resistant to specific antiretroviral drugs), and regular CD4 cell counts (an indication of immune-system health). Since the implementation of these interventions, the health and life expectancy of people with HIV has improved dramatically in these countries.
Why Was This Study Done?
The history of HIV care in resource-poor countries has been very different. Initially, these countries could not afford to provide HAART for their populations. In 2003, however, governments, international agencies, and funding bodies began to implement plans to increase HAART coverage in developing countries. By December 2006, more than a quarter of the HIV-infected people in low- and middle-income countries who urgently needed treatment were receiving HAART. However, instead of individualized treatment, HAART programs in developing countries follow a public-health approach developed by the World Health Organization. That is, drug regimens, clinical decision-making, and clinical and laboratory monitoring are all standardized. This public-health approach takes into account the realities of under-resourced health systems, but is it as effective as the individualized approach? The researchers addressed this question by comparing virologic responses (the effect of treatment on the viral load), changes to first-line (initial) therapy, and deaths in patients receiving HAART in South Africa (public-health approach) and in Switzerland (individualized approach).
What Did the Researchers Do and Find?
The researchers analyzed data collected since 2001 from more than 2,000 patients enrolled in HAART programs in two townships (Gugulethu and Khayelitsha) in Cape Town, South Africa, and from more than 1,000 patients enrolled in the Swiss HIV Cohort Study, a nationwide study of HIV-infected people. The patients in South Africa, who had a lower starting CD4 cell count and were more likely to have advanced AIDS than the patients in Switzerland, started their treatment for HIV infection with one of four first-line therapies, and about a quarter changed to a second-line therapy during the study. By contrast, 36 first-line regimens were used in Switzerland and half the patients changed to a different regimen. Despite these differences, the viral load was greatly reduced within a year in virtually all the patients and viral rebound (an increased viral load after a low measurement) developed within 2 years in a quarter of the patients in both countries. However, more patients died in South Africa than in Switzerland, particularly during the first 3 months of therapy.
What Do These Findings Mean?
These findings suggest that the public-health approach to HAART practiced in South Africa is as effective in terms of virologic outcomes as the individualized approach practiced in Switzerland. This is reassuring because it suggests that “antiretroviral anarchy” (the unregulated use of antiretroviral drugs, interruptions in drug supplies, and the lack of treatment monitoring), which is likely to lead to the emergence of viral resistance, is not happening in South Africa as some experts feared it might. Thus, these findings support the continued rollout of the public-health approach to HAART in resource-poor countries. Conversely, they also suggest that a more standardized approach to HAART could be taken in Switzerland (and in other industrialized countries) without compromising its effectiveness. Finally, the higher mortality in South Africa than in Switzerland, which partly reflects the many patients in South Africa in desperate need of HAART and their more advanced disease at the start of therapy, suggests that HIV-infected patients in South Africa and in other resource-limited countries would benefit from earlier initiation of therapy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050148.
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for a public-health approach to antiretroviral therapy for HIV infection
More details on the Swiss HIV Cohort Study and on the studies in Gugulethu and Khayelitsha are available
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including detailed information about antiretroviral therapy and links to treatment guidelines for various countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS around the world and on providing AIDS drug treatment for millions
doi:10.1371/journal.pmed.0050148
PMCID: PMC2443185  PMID: 18613745
5.  Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women 
Background
Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities.
Methods
Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction.
Results
HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts >350/μl had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 ≤350/μl (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women.
Conclusion
HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology.
doi:10.1186/1471-2334-14-51
PMCID: PMC3922074  PMID: 24484380
Human papillomavirus; Human immunodeficiency virus; Viral load
6.  Influence of Adherent and Effective Antiretroviral Therapy Use on Human Papillomavirus Infection and Squamous Intraepithelial Lesions in HIV-Positive Women 
Background
The impact of HAART on the natural history of human papillomavirus (HPV) remains uncertain following conflicting reports. Prior studies, however, did not consider patients’ adherence to their regimen, or HAART effectiveness (viral suppression).
Methods
HIV-positive women (N=286) who initiated HAART during follow-up in a prospective cohort were assessed semiannually for HPV (by PCR) and SIL. Adherence was defined as using HAART as prescribed ≥95% of the time, and effective HAART as suppression of HIV replication. The prevalence, incident detection, clearance/persistence of HPV/SIL before versus after HAART initiation were compared (using women as their own comparison group).
Findings
HAART initiation among adherent women was associated with a significant reduction in prevalence (odds ratio [OR] 0.60 [95% CI 0.44–0.81];p=0.001), incident detection of oncogenic HPV (hazard ratio [HR] 0.49 [0.30–0.82];p=0.006), and decreased prevalence and more rapid clearance of oncogenic HPV-positive SIL (HR 2.35 [1.07–5.18];p=0.03). Effects were smaller among non-adherent women. The associations of HPV/SIL with HAART effectiveness were fairly similar to those with HAART adherence.
Conclusions
Effective and adherent HAART use is associated with a significantly reduced burden of HPV and SIL; this may help explain why rates of cervical cancer have not increased during the HAART era, despite greater longevity.
doi:10.1086/650467
PMCID: PMC2818607  PMID: 20105077
HIV; human papillomavirus; HPV; HAART; SIL; cervical neoplasia
7.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
8.  A Population-Based Evaluation of a Publicly Funded, School-Based HPV Vaccine Program in British Columbia, Canada: Parental Factors Associated with HPV Vaccine Receipt 
PLoS Medicine  2010;7(5):e1000270.
Analysis of a telephone survey by Gina Ogilvie and colleagues identifies the parental factors associated with HPV vaccine uptake in a school-based program in Canada.
Background
Information on factors that influence parental decisions for actual human papillomavirus (HPV) vaccine receipt in publicly funded, school-based HPV vaccine programs for girls is limited. We report on the level of uptake of the first dose of the HPV vaccine, and determine parental factors associated with receipt of the HPV vaccine, in a publicly funded school-based HPV vaccine program in British Columbia, Canada.
Methods and Findings
All parents of girls enrolled in grade 6 during the academic year of September 2008–June 2009 in the province of British Columbia were eligible to participate. Eligible households identified through the provincial public health information system were randomly selected and those who consented completed a validated survey exploring factors associated with HPV vaccine uptake. Bivariate and multivariate analyses were conducted to calculate adjusted odds ratios to identify the factors that were associated with parents' decision to vaccinate their daughter(s) against HPV. 2,025 parents agreed to complete the survey, and 65.1% (95% confidence interval [CI] 63.1–67.1) of parents in the survey reported that their daughters received the first dose of the HPV vaccine. In the same school-based vaccine program, 88.4% (95% CI 87.1–89.7) consented to the hepatitis B vaccine, and 86.5% (95% CI 85.1–87.9) consented to the meningococcal C vaccine. The main reasons for having a daughter receive the HPV vaccine were the effectiveness of the vaccine (47.9%), advice from a physician (8.7%), and concerns about daughter's health (8.4%). The main reasons for not having a daughter receive the HPV vaccine were concerns about HPV vaccine safety (29.2%), preference to wait until the daughter is older (15.6%), and not enough information to make an informed decision (12.6%). In multivariate analysis, overall attitudes to vaccines, the impact of the HPV vaccine on sexual practices, and childhood vaccine history were predictive of parents having a daughter receive the HPV vaccine in a publicly funded school-based HPV vaccine program. By contrast, having a family with two parents, having three or more children, and having more education was associated with a decreased likelihood of having a daughter receive the HPV vaccine.
Conclusions
This study is, to our knowledge, one of the first population-based assessments of factors associated with HPV vaccine uptake in a publicly funded school-based program worldwide. Policy makers need to consider that even with the removal of financial and health care barriers, parents, who are key decision makers in the uptake of this vaccine, are still hesitant to have their daughters receive the HPV vaccine, and strategies to ensure optimal HPV vaccine uptake need to be employed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 10% of cancers in women occur in the cervix, the structure that connects the womb to the vagina. Every year, globally, more than a quarter of a million women die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse. There are many types of HPV, a virus that infects the skin and the mucosa (the moist membranes that line various parts of the body, including the cervix). Although most people become infected with HPV at some time in their life, most never know they are infected. However, some HPV types cause harmless warts on the skin or around the genital area and several—in particular, HPV 16 and HPV 18, so-called high-risk HPVs—can cause cervical cancer. HPV infections are usually cleared by the immune system, but about 10% of women infected with a high-risk HPV develop a long-term infection that puts them at risk of developing cervical cancer.
Why Was This Study Done?
Screening programs have greatly reduced cervical cancer deaths in developed countries in recent decades by detecting the cancer early when it can be treated; but it would be better to prevent cervical cancer ever developing. Because HPV is necessary for the development of cervical cancer, vaccination of girls against HPV infection before the onset of sexual activity might be one way to do this. Scientists recently developed a vaccine that prevents infection with HPV 16 and HPV 18 (and with two HPVs that cause genital warts) and that should, therefore, reduce the incidence of cervical cancer. Publicly funded HPV vaccination programs are now planned or underway in several countries; but before girls can receive the HPV vaccine, parental consent is usually needed, so it is important to know what influences parental decisions about HPV vaccination. In this study, the researchers undertake a telephone survey to determine the uptake of the HPV vaccine by 11-year-old girls (grade 6) in British Columbia, Canada, and to determine the parental factors associated with vaccine uptake; British Columbia started a voluntary school-based HPV vaccine program in September 2008.
What Did the Researchers Do and Find?
In early 2009, the researchers contacted randomly selected parents of girls enrolled in grade 6 during the 2008–2009 academic year and asked them to complete a telephone survey that explored factors associated with HPV vaccine uptake. 65.1% of the 2,025 parents who completed the survey had consented to their daughter receiving the first dose of HPV vaccine. By contrast, more than 85% of the parents had consented to hepatitis B and meningitis C vaccination of their daughters. Nearly half of the parents surveyed said their main reason for consenting to HPV vaccination was the effectiveness of the vaccine. Conversely, nearly a third of the parents said concern about the vaccine's safety was their main reason for not consenting to vaccination and one in eight said they had been given insufficient information to make an informed decision. In a statistical analysis of the survey data, the researchers found that a positive parental attitude towards vaccination, a parental belief that HPV vaccination had limited impact on sexual practices, and completed childhood vaccination increased the likelihood of a daughter receiving the HPV vaccine. Having a family with two parents or three or more children and having well-educated parents decreased the likelihood of a daughter receiving the vaccine.
What Do These Findings Mean?
These findings provide one of the first population-based assessments of the factors that affect HPV vaccine uptake in a setting where there are no financial or health care barriers to vaccination. By identifying the factors associated with parental reluctance to agree to HPV vaccination for their daughters, these findings should help public-health officials design strategies to ensure optimal HPV vaccine uptake, although further studies are needed to discover why, for example, parents with more education are less likely to agree to vaccination than parents with less education. Importantly, the findings of this study, which are likely to be generalizable to other high-income countries, indicate that there is a continued need to ensure that the public receives credible, clear information about both the benefits and long-term safety of HPV vaccination.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000270.
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on HPV vaccines (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and about HPV
The UK National Health Service Choices website has pages on cervical cancer and on HPV vaccination
More information about cervical cancer and HPV vaccination is available from the Macmillan cancer charity
ImmunizeBC provides general information about vaccination and information about HPV vaccination in British Columbia
MedlinePlus provides links to additional resources about cervical cancer (in English and Spanish)
doi:10.1371/journal.pmed.1000270
PMCID: PMC2864299  PMID: 20454567
9.  Sex-Specific Immunization for Sexually Transmitted Infections Such as Human Papillomavirus: Insights from Mathematical Models 
PLoS Medicine  2011;8(12):e1001147.
Johannes Bogaards and colleagues use mathematical models to investigate whether vaccinating females only, males only, or both sexes is the best way to achieve the most effective reduction in the population prevalence of sexually-transmitted infections
Background
Sex-specific differences regarding the transmissibility and the course of infection are the rule rather than the exception in the epidemiology of sexually transmitted infections (STIs). Human papillomavirus (HPV) provides an example: disease outcomes differ between men and women, as does the potential for transmission to the opposite sex. HPV vaccination of preadolescent girls was recently introduced in many countries, and inclusion of boys in the vaccination programs is being discussed. Here, we address the question of whether vaccinating females only, males only, or both sexes is the most effective strategy to reduce the population prevalence of an STI like HPV.
Methods and Findings
We use a range of two-sex transmission models with varying detail to identify general criteria for allocating a prophylactic vaccine between both sexes. The most effective reduction in the population prevalence of infection is always achieved by single-sex vaccination; vaccinating the sex with the highest prevaccine prevalence is the preferred strategy in most circumstances. Exceptions arise only when the higher prevaccine prevalence is due to a substantially lower rate of natural immunity, or when natural immunity is lifelong, and a prolonged duration of infectiousness coincides with increased transmissibility. Predictions from simple models were confirmed in simulations based on an elaborate HPV transmission model. Our analysis suggests that relatively inefficient genital transmission from males to females might render male vaccination more effective in reducing overall infection levels. However, most existing HPV vaccination programs have achieved sufficient coverage to continue with female-only vaccination.
Conclusions
Increasing vaccine uptake among preadolescent girls is more effective in reducing HPV infection than including boys in existing vaccination programs. As a rule, directing prophylactic immunization at the sex with the highest prevaccine prevalence results in the largest reduction of the population prevalence.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 10% of cancers in women occur in the cervix, the structure that connects the womb to the vagina. Every year, more than a quarter of a million women (85% of them in developing countries) die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse (HPV is one of more than thirty sexually transmissable organisms that, globally, cause many millions of sexually transmitted infections every year). There are many types of HPV, a virus that infects the skin and the mucosa (the moist membranes that line various parts of the body, including the cervix). Most people become infected with HPV at some time during their life, but most never know they have been infected. Some HPV types cause harmless warts on the skin or around the genital area, and several—in particular HPV16 and HPV18, so-called high-risk HPVs—can cause cervical cancer (and some other cancers, including anal, penile, head, and neck cancers). HPV infections are usually cleared by the immune system, but about 10% of women infected with a high-risk HPV develop a long-term infection that puts them at risk of developing cervical cancer.
Why Was This Study Done?
Screening programs have greatly reduced cervical cancer deaths in developed countries by detecting the cancer early, when it can be treated. However, it would be better to prevent cervical cancer ever developing. Moreover, most women in developing countries do not have access to screening. Because infection with specific HPV types can cause the development of some types of cervical cancer, vaccination of girls against HPV before the onset of sexual activity might be one way to prevent cervical cancer. Scientists recently developed a vaccine that prevents infection with HPV16 and HPV18, and HPV vaccination programs have been introduced in several countries. These programs are currently directed only at girls because HPV-related illness and death are higher among women than men, but should boys also be included in HPV vaccination programs? Men would benefit directly from immunization against HPV-related diseases, but, in addition, vaccination of boys might help to reduce the circulation of HPV in the population, thereby indirectly improving the protection of women through so-called “herd immunity.” In this study, the researchers used mathematical models to investigate whether vaccinating girls only, boys only, or both sexes is the most effective way to reduce the population prevalence of HPV infection (the proportion of the population infected with HPV).
What Did the Researchers Do and Find?
The researchers first used a range of standard two-sex mathematical models of infection and transmission in heterosexual populations to identify general criteria for allocating an HPV vaccine between the sexes. They found that the most effective reduction in the population prevalence of HPV infection was always achieved by single-sex vaccination and that, in most situations, the preferred strategy was to vaccinate the sex with the highest prevaccine prevalence of HPV infection. The researchers confirmed these predictions using a more elaborate HPV transmission model that incorporated differences among individuals in age and level of sexual activity. Importantly, this second analysis also suggested that for existing girl-only vaccination programs, increasing coverage of vaccination among girls would bolster herd immunity more effectively than switching to a policy of vaccinating both sexes.
What Do These Findings Mean?
The findings of this study suggest that increasing vaccine uptake among preadolescent girls is a more effective way to reduce HPV infection than including boys in existing vaccination programs. They also suggest that directing HPV vaccination at the sex with the highest prevaccine prevalence of infection will reduce the population prevalence of HPV most effectively. Although the accuracy of these findings is dependent on the assumptions included in the mathematical transmission models used by the researchers, these findings support a policy of increasing female HPV vaccine coverage as far as possible, within the limits set by vaccine acceptance and economic constraints. More generally, these findings suggest that single-sex preventative interventions might be the best way to reduce heterosexual transmission of other sexually transmitted infections and that targeting the sex with the highest prevalence of infection might achieve the most effective reduction in the population prevalence of these common diseases.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001147.
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on HPV vaccines (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and HPV
The UK National Health Service Choices website has pages on cervical cancer and HPV vaccination (available in several languages and including a short video of girls talking about HPV vaccination)
The PREHDICT project investigates health-economic modeling of prevention strategies for HPV-related diseases in European countries; information about this project is available from the European Cervical Cancer Association
More information about cervical cancer and HPV vaccination is available from Macmillan Cancer Support
Personal stories about cervical cancer are available through the charity Healthtalkonline
MedlinePlus provides links to additional resources about cervical cancer and other sexually transmitted infections (in English and Spanish)
doi:10.1371/journal.pmed.1001147
PMCID: PMC3243713  PMID: 22205887
10.  The Impact of HAART on HPV-Related Cervical Disease 
Current HIV research  2010;8(7):493-497.
Purpose of Review
Highly active antiretroviral therapy (HAART) has had an unequivocally positive impact on morbidity and mortality in HIV-infected individuals. These benefits have clearly extended to some HIV-related malignancies, including Kaposi’s sarcoma and non-Hodgkin’s lymphoma. The impact of HAART on cervical cancer, however, remains uncertain. The objective of this review is to summarize the last ten years of registry-based and clinical research into the impact of HAART on human papillomavirus (HPV) related cervical disease.
Relevant Findings
Compared to their HIV-uninfected counterparts, HIV-infected women have an increased prevalence of HPV infection, increased risk of progression of HPV-related cervical disease, and an increased risk of invasive cervical cancer. While the partial immune reconstitution afforded by HAART might be expected to decrease susceptibility to HPV infection and cervical disease, the local effects of improved immunosurveillance on the cervix are uncertain and the increased longevity of patients on HAART may increase risk of exposure to HPV and provide the time required for progression of cervical disease. Registry-based evidence has been consistent in identifying the lack of decrease in cervical cancer incidence in the HAART era. Clinical research on the subject, however, has produced conflicting evidence with regards to both the effect of HAART on HPV infection and its impact on cervical disease progression/regression.
Summary
The incidence of cervical cancer has not decreased in the HAART-era. Furthermore, clinical research has not shown a clear benefit of HAART in decreasing HPV-related cervical disease in HIV-infected women. A better understanding of this subject will have an impact on cervical disease surveillance practices.
PMCID: PMC3108243  PMID: 20946095
HPV; Human papillomavirus; HAART; Cervical dysplasia; Cervical cancer; HIV
11.  Anal and oral human papillomavirus (HPV) infection in HIV-infected subjects in northern Italy: a longitudinal cohort study among men who have sex with men 
BMC Infectious Diseases  2011;11:150.
Background
A study including 166 subjects was performed to investigate the frequency and persistence over a 6-month interval of concurrent oral and anal Human Papillomavirus (HPV) infections in Human Immunodeficiency Virus (HIV)-infected men who have sex with men (MSM).
Methods
Patients with no previously documented HPV-related anogenital lesion/disease were recruited to participate in a longitudinal study. Polymerase chain reaction (PCR) was performed to detect HPV from oral and anal swabs and to detect Human Herpes Virus 8 (HHV-8) DNA in saliva on 2 separate specimen series, one collected at baseline and the other collected 6 months later. A multivariate logistic analysis was performed using anal HPV infection as the dependent variable versus a set of covariates: age, HIV plasma viral load, CD4+ count, hepatitis B virus (HBV) serology, hepatitis C virus (HCV) serology, syphilis serology and HHV-8 viral shedding. A stepwise elimination of covariates with a p-value > 0.1 was performed.
Results
The overall prevalence of HPV did not vary significantly between the baseline and the follow-up, either in the oral (20.1 and 21.3%, respectively) or the anal specimens (88.6 and 86.3%). The prevalence of high-risk (HR) genotypes among the HPV-positive specimens was similar in the oral and anal infections (mean values 24.3% and 20.9%). Among 68 patients with either a HR, low-risk (LR) or undetermined genotype at baseline, 75% had persistent HPV and the persistence rates were 71.4% in HR infections and 76.7% in LR infections. There was a lack of genotype concordance between oral and anal HPV samples. The prevalence of HR HPV in anus appeared to be higher in the younger patients, peaking (> 25%) in the 43-50 years age group. A decrease of the high level of anal prevalence of all genotypes of HPV in the patients > 50 years was evident. HHV-8 oral shedding was positively related to HPV anal infection (p = 0.0046). A significant correlation was found between the persistence of HHV-8 shedding and HIV viral load by logistic bivariate analysis (Odds Ratio of HHV-8 persistence for 1-log increase of HIV viral load = 1.725 ± 0.397, p = 0.018).
Conclusions
A high prevalence of HPV infection was found in our cohort of HIV-infected MSM, with a negative correlation between anal HPV infection and CD4 cell count.
doi:10.1186/1471-2334-11-150
PMCID: PMC3119070  PMID: 21612634
12.  High Prevalence of Human Papillomavirus Infections in Urine Samples from Human Immunodeficiency Virus-Infected Men 
Journal of Clinical Microbiology  2005;43(12):5936-5939.
Infection with human immunodeficiency virus (HIV) and the resulting immunosuppression are associated with an increased risk for human papillomavirus (HPV) persistence and related malignancies. In the present study we investigated the prevalence of HPV in urine samples from 104 HIV-infected men with low CD4+ cell counts (<100 per mm3) and 115 urine samples from HIV-negative men. A high prevalence of HPV DNA (39.4%) was found in the HIV patients. Most of the HPV types were high risk (81.4%), with HPV 52 as the most prevalent type (12.5%), followed by HPV 18 (6.7%), HPV 35 (5.8%), and HPV 70 (4.8%). Multiple HPV genotypes were observed in 17 (41%) of the 41 HPV- and HIV-positive men. In contrast, only 11 (9.6%) HPV DNA-positive cases were observed among the 115 HIV-uninfected men, and 3 (27.3%) contained multiple genotypes. Quantitative analyses indicated that the HPV viral load, as measured in urine samples, is significantly higher in HIV-positive men compared to HIV-negative men. In the present study we show that urine samples are useful for detecting HPV DNA, there is a high prevalence of HPV in HIV-positive men, and the HPV viral load is substantially higher in HIV-positive than in HIV-negative men. More studies are needed to evaluate the risk and natural development of HPV-related malignancies in HIV-positive men.
doi:10.1128/JCM.43.12.5936-5939.2005
PMCID: PMC1317195  PMID: 16333078
13.  Physical state and viral load as predictive biomarkers for persistence and progression of HPV16-positive cervical lesions: results from a population based long-term prospective cohort study 
Persistent infection with a high risk (hr) human papillomavirus (HPV) has been established as the main cause of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN3). Because most infections are transient, testing for hrHPV lacks specificity and has a low positive predictive value. It has been suggested that additional parameters like viral load and physical status of the viral genome could improve the effectiveness of HPV-based screening. We investigated the association between HPV16 viral load and physical state with viral persistence or risk of incident CIN3 or worse in a population-based prospective cohort study comprising 8656 women (20-29 years). All participants had two gynecological examinations two years apart and were followed through the nationwide Danish Pathology Data Bank (median follow-up: 12.9 yrs). Seventynine cervical swabs from women with a persistent HPV16 infection were available for analysis. For comparison we selected a random age-matched sample of transiently HPV16 infected women (N=91). Persistently infected women with incident CIN3 or cancer (CIN3+; N=31) were compared to women with normal cytology during follow up (non-progressors; N=39). Quantitative real-time PCR for HPV16E6, E2 and IFNb1 was done to determine the HPV16 viral load and the E2/E6 ratio was used as a surrogate marker for integration. Women with normal cytology who became persistently HPV16 infected had a significantly lower HPV16 load at baseline than women who cleared the infection (median 4.72 copies/cell versus median 20.0 copies/cell, respectively; p=0.0003). There was no difference in viral load at enrollment between women who progressed to CIN3+ and women who stayed cytologically normal (p=0.85). At the second examination viral load tended to be higher in women who progressed, but the difference was not statistically significant (p=0.39). The E2/E6 ratio was shown to be lower in the persistently infected group (p<0.0001) already at the first examination, but no difference between non-progressors and CIN3+ cases was observed at any of the two examinations (p=0.61 and 0.86). Lower viral load and integration of the viral genome are predictive for the persistence of HPV16 DNA, but not for the progression of a persistent HPV16 infection to CIN3+ in women with normal cytology.
PMCID: PMC3304573  PMID: 22432058
Cervical cancer; HPV; viral load; viral integration
14.  Human papillomavirus detection in women with and without human immunodeficiency virus infection in Colombia 
BMC Cancer  2014;14:451.
Background
HIV infection leads to a decreasing immune response, thereby facilitating the appearance of other infections, one of the most important ones being HPV. However, studies are needed for determining associations between immunodeficiency caused by HIV and/or the presence of HPV during the course of cervical lesions and their degree of malignancy. This study describes the cytological findings revealed by the Papanicolaou test, laboratory characteristics and HPV molecular profile in women with and without HIV infection.
Methods
A total of 216 HIV-positive and 1,159 HIV-negative women were invited to participate in the study; PCR was used for the molecular detection of HPV in cervical samples. Statistical analysis (such as percentages, Chi-square test and Fisher’s exact test when applicable) determined human papillomavirus (HPV) infection frequency (single and multiple) and the distribution of six types of high-risk-HPV in women with and without HIV infection. Likewise, a logistic regression model was run to evaluate the relationship between HIV-HPV infection and different risk factors.
Results
An association was found between the frequency of HPV infection and infection involving 2 or more HPV types (also known as multiple HPV infection) in HIV-positive women (69.0% and 54.2%, respectively); such frequency was greater than that found in HIV-negative women (44.3% and 22.7%, respectively). Statistically significant differences were observed between both groups (p = 0.001) regarding HPV presence (both in infection and multiple HPV infection). HPV-16 was the most prevalent type in the population being studied (p = 0.001); other viral types had variable distribution in both groups (HIV-positive and HIV-negative). HPV detection was associated with <500 cell/mm3 CD4-count (p = 0.004) and higher HIV-viral-load (p = 0.001). HPV-DNA detection, <200 cell/mm3 CD4-count (p = 0.001), and higher HIV-viral-load (p = 0.001) were associated with abnormal cytological findings.
Conclusions
The HIV-1 positive population in this study had high multiple HPV infection prevalence. The results for this population group also suggested a greater association between HPV-DNA presence and cytological findings. HPV detection, together with low CD4 count, could represent useful tools for identifying HIV-positive women at risk of developing cervical lesions.
doi:10.1186/1471-2407-14-451
PMCID: PMC4067500  PMID: 24942545
Human papillomavirus; Human immunodeficiency virus; Multiple infection; Papanicolaou test; Epidemiology
15.  Kidney and liver organ transplantation in persons with human immunodeficiency virus 
Executive Summary
Objective
The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+)
Clinical Need: Condition and Target Population
Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV−), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV.
With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed.
Evidence-Based Analysis Methods
Research Questions
What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF?
Literature Search
A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009.
Inclusion Criteria
Systematic review with or without a Meta analysis, RCT, Non-RCT with controls
HIV+ population undergoing solid organ transplantation
HIV+ population managed with HAART therapy
Controls include persons undergoing solid organ transplantation who are i) HIV− ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.
Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.
Studies with a minimum (mean or medium) follow up of 1-year.
English language citations
Exclusion Criteria
Case reports and case series were excluded form this review.
Outcomes of Interest
i) Risk of Death after transplantation
ii) Death censored graft survival (DCGS)
iii) HIV disease progression defined as the post transplant incidence of:
- opportunistic infections or neoplasms,
- CD4+ T-cell count < 200mm3, and
- any detectable level of plasma HIV viral load.
iv) Acute graft rejection,
v) Return to dialysis,
vi) Recurrence of HCV infection
Summary of Findings
No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search.
The results of this review are reported for the following comparison cohorts undergoing transplantation:
i) Kidney Transplantation: HIV+ cohort compared with HIV− cohort
ii) Liver Transplantation: HIV+ cohort compared with HIV− negative cohort
iii) Liver Transplantation: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort
Kidney Transplantation: HIV+ vs. HIV−
Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV− cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV− cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV− groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain.
The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV− cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect.
Liver Transplantation: HIV+ vs. HIV−
Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV− cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV− cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain.
Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV− groups
Liver Transplantation: HIV+/HCV+ vs. HCV+
Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available.
Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect.
Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low.
Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.
PMCID: PMC3377507  PMID: 23074407
16.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
Objectives
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
Methods
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
Results
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
Conclusions
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
doi:10.1136/sextrans-2013-051230
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
17.  Human papillomavirus type 16 viral load measurement as a predictor of infection clearance 
The Journal of General Virology  2013;94(Pt 8):1850-1857.
Viral load measurements may predict whether human papillomavirus (HPV) type 16 infections may become persistent and eventually lead to cervical lesions. Today, multiple PCR methods exist to estimate viral load. We tested three protocols to investigate viral load as a predictor of HPV clearance. We measured viral load in 418 HPV16-positive cervical smears from 224 women participating in the Ludwig–McGill Cohort Study by low-stringency PCR (LS-PCR) using consensus L1 primers targeting over 40 known HPV types, and quantitative real-time PCR (qRT-PCR) targeting the HPV16 E6 and L1 genes. HPV16 clearance was determined by MY09/11 and PGMY PCR testing on repeated smears collected over 5 years. Correlation between viral load measurements by qRT-PCR (E6 versus L1) was excellent (Spearman’s rank correlation, ρ = 0.88), but decreased for L1 qRT-PCR versus LS-PCR (ρ = 0.61). Viral load by LS-PCR was higher for HPV16 and related types independently of other concurrent HPV infections. Median duration of infection was longer for smears with high copy number by all three PCR protocols (log rank P<0.05). Viral load is inversely related to HPV16 clearance independently of concurrent HPV infections and PCR protocol.
doi:10.1099/vir.0.051722-0
PMCID: PMC4093775  PMID: 23677791
18.  Association of HIV Viral Load and CD4 with HPV Detection and Clearance in HIV Infected Women Initiating HAART 
HIV medicine  2012;13(6):372-378.
Objectives
The extent to which highly active antiretroviral therapy (HAART) affects HPV acquisition and clearance in HIV-infected women is not well-understood. We sought to describe high risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4+ T-cell count (CD4) using novel statistical methods.
Methods
We conducted retrospective analysis of data from completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high risk HPV types from 2003 and 2009 publications were considered.
Results
There was some evidence that VL>400 copies/mL was marginally associated with higher rate of HPV detection (p=0.068, hazard ratio [HR]=4.67), using the older set of high risk HPV types. Such association was not identified using the latest set of HPV types (p=0.343, HR=2.64). CD4>350 cells/mm3 was significantly associated with more rapid HPV clearance with both sets of HPV types (p=0.001, HR=3.93; p=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 in all analyses.
Conclusions
High risk HPV types vary in studies, and they can affect analysis results. Use of HAART to improve CD4 may have an impact in the control of HPV infection, and the decrease in VL to a lesser degree.
doi:10.1111/j.1468-1293.2011.00979.x
PMCID: PMC3500098  PMID: 22257000
HIV; human papillomavirus; HAART; cervical cancer; Markov models
19.  Epidemiology of HPV genotypes in Uganda and the role of the current preventive vaccines: A systematic review 
Background
Limited data are available on the distribution of human papillomavirus (HPV) genotypes in the general population and in invasive cervical cancer (ICC) in Uganda. Yet, with the advent of preventive HPV vaccines that target HPV 16 and 18 responsible for causing about 70% of ICC cases in the world, such information is crucial to predict how vaccination and HPV-based screening will influence prevention of ICC.
Methods
To review the distribution of HPV infection and prevalent genotypes, electronic databases (e.g. PubMed/MEDLINE and HINARI) were searched for peer reviewed English articles on HPV infection up to November 30, 2010. Eligible studies were selected according to the following criteria: DNA-confirmed cervical or male genital HPV prevalence and genotypes, HPV incidence estimates and HPV seroprevalence among participants.
Results
Twenty studies were included in the review. Among HIV negative adult women, the prevalence of HR-HPV infections ranged from 10.2% -40.0% compared to 37.0% -100.0% among HIV positive women. Among HIV positive young women aged below 25 years, the prevalence of HR-HPV genotypes ranged from 41.6% -75.0% compared to 23.7% -67.1% among HIV negative women. Multiple infections with non vaccine HR-HPV genotypes were frequent in both HIV positive and HIV negative women. The main risk factors for prevalent HPV infections were age, lifetime number of sexual partners and HIV infection. Incident infections with HR-HPV genotypes were more frequent among adult HIV positive than HIV negative women estimated at 17.3 and 7.0 per 100 person-years, respectively. Similarly, incident HR-HPV among young women aged below 25 years were more frequent among HIV positive (40.0 per 100 person-years) than HIV negative women (20.3 per 100 person-years) women. The main risk factor for incident infection was HIV infection. HPV 16 and 18 were the most common genotypes in ICC with HPV 16/18 contributing up to 73.5% of cases with single infections.
Among uncircumcised adult HIV positive males, HR-HPV prevalence ranged from 55.3% -76.6% compared to 38.6% -47.6% in HIV negative males. Incident and multiple HR-HPV infections were frequent in HIV positive males. Being uncircumcised was the main risk factor for both prevalent and incident HPV infection.
Conclusion
Infections with HR-HPV genotypes were very common particularly among HIV positive individuals and young women irrespective of HIV status. Given the high prevalence of HIV infection, HPV-associated conditions represent a major public health burden in Uganda. However, although the most common HPV genotypes in ICC cases in Uganda were those targeted by current preventive vaccines, there were a large number of individuals infected with other HR-HPV genotypes. Technology allowing, these other HR-HPV types should be considered in the development of the next generation of vaccines.
doi:10.1186/1750-9378-6-11
PMCID: PMC3163594  PMID: 21749691
20.  Incidence of cervical disease associated to HPV in human immunodeficiency infected women under highly active antiretroviral therapy 
Background
Women infected with human immunodeficiency virus (HIV) may be at higher risk of developing cervical cancer than non infected women. In a pilot study, we assessed the relationships among cervical cytology abnormalities associated to Human Papillomavirus (HPV), HIV infection and Highly Active Antiretroviral Therapy (HAART) on the development of Squamous Intraepithelial lesions (SILs). Out of the 70 HIV infected women from Douala -Cameroon (Central Africa) that we included in the study, half (35) were under HAART. After obtaining information related to their lifestyle and sexual behaviour, cervicovaginal samples for Pap smears and venous blood for CD4 count were collected and further divided into two groups based upon the presence or absence of cervical cytology abnormalities i.e. those with normal cervical cytology and those with low and high Squamous Intraepithelial lesions (LSIL, HSIL).
Results
Assessment was done according to current antiretroviral regimens available nationwide and CD4 count. It was revealed that 44.3% of HIV-infected women had normal cytology. The overall prevalence of LSIL and HSIL associated to HPV in the studied groups was 24.3% (17/70) and 31.4% (22/70) respectively. Among the 22 HSIL-positive women, 63.6% (14/22) were not on antiretroviral therapy, while 36.4% (8/22) were under HAART. HIV infected women under HAART with positive HSIL, showed a median CD4+ T cell count of 253.7 +/- 31.7 higher than those without therapy (164.7 +/- 26.1). The incidence of HSIL related to HPV infection within the study group independently of HAART initiation was high.
Conclusion
These results suggest the need for extension and expansion of the current study in order to evaluate the incidence of HPV infection and cervical cancer among HIV-infected and non HIV- infected women in Cameroon.
doi:10.1186/1750-9378-4-9
PMCID: PMC2701409  PMID: 19493339
21.  Type-specific incidence, clearance and predictors of cervical human papillomavirus infections (HPV) among young women: a prospective study in Uganda 
Background
While infections with human papillomavirus (HPV) are highly prevalent among sexually active young women in Uganda, information on incidence, clearance and their associated risk factors is sparse. To estimate the incidence, prevalence and determinants of HPV infections, we conducted a prospective follow-up study among 1,275 women aged 12-24 years at the time of recruitment. Women answered a questionnaire and underwent a pelvic examination at each visit to collect exfoliated cervical cells. The presence of 42 HPV types was evaluated in exfoliated cervical cells by a polymerase chain based (PCR) assay (SPF10-DEIA LiPA).
Results
Three hundred and eighty (380) of 1,275 (29.8%) women were followed up for a median time of 18.5 months (inter-quartile range 9.7-26.6). Sixty-nine (69) women had incident HPV infections during 226 person-years of follow-up reflecting an incidence rate of 30.5 per 100 person-years. Incident HPV infections were marginally associated with HIV positivity (RR = 2.8, 95% CI: 0.9 - 8.3). Clearance for HPV type-specific infections was frequent ranging between 42.3% and 100.0% for high- and 50% and 100% for low-risk types. Only 31.2% of women cleared all their infections. Clearance was associated with HIV negativity (Adjusted clearance = 0.2, 95% CI: 0.1 - 0.7) but not with age at study entry, lifetime number of sexual partners and multiplicity of infections. The prevalence of low-grade squamous intraepithelial lesions (LSILs) was 53/365 (14.5%). None of the women had a high-grade cervical lesion (HSIL) or cancer. Twenty-two (22) of 150 (14.7%) HPV negative women at baseline developed incident LSIL during follow-up. The risk for LSIL appeared to be elevated among women with HPV 18-related types compared to women not infected with those types (RR = 3.5, 95% CI: 1.0 - 11.8).
Conclusions
Incident HPV infections and type-specific HPV clearance were frequent among our study population of young women. These results underscore the need to vaccinate pre-adolescent girls before initiation of sexual activity.
doi:10.1186/1750-9378-5-7
PMCID: PMC2873244  PMID: 20380709
22.  Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active antiretroviral therapy in South Africa: a cross-sectional study 
BMC Cancer  2009;9:275.
Background
Cervical cancer and infection with human immunodeficiency virus (HIV) are both important public health problems in South Africa (SA). The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs), high-risk human papillomavirus (HR-HPV), HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV) therapy.
Methods
A cross-sectional survey was conducted at an anti-retroviral (ARV) treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2) test was used to detect HR-HPV. Relative light units (RLU) were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology.
Results
The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene), the median HPV viral load was 181.1 RLU (HC2 positive samples only) and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL). The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 – 57.7) for those that were HC2 positive and had a viral load of ≤ 181.1 RLU (the median HPV viral load), and 33.8 (95% CI 6.4 – 178.9) for those that were HC2 positive with a HPV viral load > 181.1 RLU.
Conclusion
Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need for locally relevant, rigorous screening protocols for the increasing numbers of women accessing ARV therapy so that the benefits of ARVs are not partially offset by an excess risk in cervical cancer.
doi:10.1186/1471-2407-9-275
PMCID: PMC2739859  PMID: 19664216
23.  Pharmacy Refill Adherence Compared with CD4 Count Changes for Monitoring HIV-Infected Adults on Antiretroviral Therapy 
PLoS Medicine  2008;5(5):e109.
Background
World Health Organization (WHO) guidelines for monitoring HIV-infected individuals taking combination antiretroviral therapy (cART) in resource-limited settings recommend using CD4+ T cell (CD4) count changes to monitor treatment effectiveness. In practice, however, falling CD4 counts are a consequence, rather than a cause, of virologic failure. Adherence lapses precede virologic failure and, unlike CD4 counts, data on adherence are immediately available to all clinics dispensing cART. However, the accuracy of adherence assessments for predicting future or detecting current virologic failure has not been determined. The goal of this study therefore was to determine the accuracy of adherence assessments for predicting and detecting virologic failure and to compare the accuracy of adherence-based monitoring approaches with approaches monitoring CD4 count changes.
Methodology and Findings
We conducted an observational cohort study among 1,982 of 4,984 (40%) HIV-infected adults initiating non-nucleoside reverse transcriptase inhibitor-based cART in the Aid for AIDS Disease Management Program, which serves nine countries in southern Africa. Pharmacy refill adherence was calculated as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last refill prior to the endpoint of interest, expressed as a percentage. The main outcome measure was virologic failure defined as a viral load > 1,000 copies/ml (1) at an initial assessment either 6 or 12 mo after cART initiation and (2) after a previous undetectable (i.e., < 400 copies/ml) viral load (breakthrough viremia). Adherence levels outperformed CD4 count changes when used to detect current virologic failure in the first year after cART initiation (area under the receiver operating characteristic [ROC] curves [AUC] were 0.79 and 0.68 [difference = 0.11; 95% CI 0.06 to 0.16; χ2 = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; χ2 = 20.2] respectively at 12 mo; p < 0.001 for both comparisons). When used to detect current breakthrough viremia, adherence and CD4 counts were equally accurate (AUCs of 0.68 versus 0.67, respectively [difference = 0.01; 95% CI −0.06 to 0.07]; χ2 = 0.1, p > 0.5). In addition, adherence levels assessed 3 mo prior to viral load assessments were as accurate for virologic failure occurring approximately 3 mo later as were CD4 count changes calculated from cART initiation to the actual time of the viral load assessments, indicating the potential utility of adherence assessments for predicting future, rather than simply detecting current, virologic failure. Moreover, combinations of CD4 count and adherence data appeared useful in identifying patients at very low risk of virologic failure.
Conclusions
Pharmacy refill adherence assessments were as accurate as CD4 counts for detecting current virologic failure in this cohort of patients on cART and have the potential to predict virologic failure before it occurs. Approaches to cART scale-up in resource-limited settings should include an adherence-based monitoring approach.
Analyzing pharmacy and laboratory records from 1,982 patients beginning HIV therapy in southern Africa, Gregory Bisson and colleagues find medication adherence superior to CD4 count changes in identifying treatment failure.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Combinations of antiretroviral drugs that hold HIV in check (viral suppression) have been available since 1996. Unfortunately, most of the people affected by HIV/AIDS live in developing countries and cannot afford these expensive drugs. As a result, life expectancy has plummeted and economic growth has reversed in these poor countries since the beginning of the AIDS pandemic. Faced with this humanitarian crisis, the lack of access to HIV treatment was declared a global health emergency in 2003. Today, through the concerted efforts of governments, international organizations, and funding bodies, about a quarter of the HIV-positive people in developing and transitional countries who are in immediate need of life-saving, combination antiretroviral therapy (cART) receive the drugs they need.
Why Was This Study Done?
To maximize the benefits of cART, health-care workers in developing countries need simple, affordable ways to monitor viral suppression in their patients—a poor virologic response to cART can lead to the selection of drug-resistant HIV, rapid disease progression, and death. In developed countries, virologic response is monitored by measuring the number of viral particles in patients' blood (viral load) but this technically demanding assay is unavailable in most developing countries. Instead, the World Health Organization recommends that CD4+ T cell (CD4) counts be used to monitor patient responses to cART in resource-limited settings. HIV results in loss of CD4 cells (a type of immune system cell), so a drop in a patient's CD4 count often indicates virologic failure (failure of treatment to suppress the virus). However, falling CD4 counts are often a result of virologic failure and therefore monitoring CD4 counts for drops is unlikely to prevent virologic failure from occurring. Rather, falling CD4 counts are often used only to guide a change to new medicines, which may be even more expensive or difficult to take. On the other hand “adherence lapses”—the failure to take cART regularly—often precede virologic failure, so detecting them early provides an opportunity for improvement in adherence that could prevent virologic failure. Because clinics that dispense cART routinely collect data that can be used to calculate adherence, in this study the researchers investigate whether assessing adherence might provide an alternative, low-cost way to monitor and predict virologic failure among HIV-infected adults on cART.
What Did the Researchers Do and Find?
The Aid for AIDS Disease Management Program provides cART to medical insurance fund subscribers in nine countries in southern Africa. Data on claims for antiretroviral drugs made through this program, plus CD4 counts assessed at about 6 or 12 months after initiating cART, and viral load measurements taken within 45 days of a CD4 count, were available for nearly 2,000 HIV-positive adults who had been prescribed a combination of HIV drugs including either efavirenz or nevirapine. The researchers defined adherence as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last pharmacy refill before a viral load assessment was performed. Virologic failure was defined in two ways: as a viral load of more than 1,000 copies per ml of blood 6 or 12 months after cART initiation, or as a rebound of viral load to similar levels after a previously very low reading (breakthrough viremia). The researchers' statistical analysis of these data shows that at 6 and 12 months after initiation of cART, adherence levels indicated virologic failure more accurately than CD4 count changes. For breakthrough viremia, both measurements were equally accurate. Adherence levels during the first 3 months of cART predicted virologic failure at 6 months as accurately as did CD4 count changes since cART initiation. Finally, the combination of adherence levels and CD4 count changes accurately identified patients at very low risk of virologic failure.
What Do These Findings Mean?
These findings suggest that adherence assessments (based in this study on insurance claims for pharmacy refills) can identify the patients on cART who are at high and low risk of virologic failure at least as accurately as CD4 counts. In addition, they suggest that adherence assessments could be used for early identification of patients at high risk of virologic failure, averting the health impact of treatment failure and the cost of changing to second-line drug regimens. Studies need to be done in other settings (in particular, in public clinics where cART is provided without charge) to confirm the generalizability of these findings. These finding do not change that fact that monitoring CD4 counts plays an important role in deciding when to start cART or indicating when cART is no longer protecting the immune system. But, write the researchers, systematic monitoring of adherence to cART should be considered as an alternative to CD4 count monitoring in patients who are receiving cART in resource-limited settings or as a way to direct the use of viral load testing where feasible.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050109.
This study is discussed further in a PLoS Medicine Perspective by David Bangsberg
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including an article about adherence to antiretroviral therapy
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on providing AIDS drug treatment for millions
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for antiretroviral therapy for HIV infection in adults and adolescents
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS pandemic (in English and Spanish)
doi:10.1371/journal.pmed.0050109
PMCID: PMC2386831  PMID: 18494555
24.  Association of HIV infection with distribution and viral load of HPV types in Kenya: a survey with 820 female sex workers 
Background
Human papillomavirus (HPV) and HIV are each responsible for a considerable burden of disease. Interactions between these infections pose substantial public health challenges, especially where HIV prevalence is high and HPV vaccine coverage low.
Methods
Between July 2005 and January 2006, a cross-sectional community-based survey in Mombasa, Kenya, enrolled female sex workers using snowball sampling. After interview and a gynaecological examination, blood and cervical cytology samples were taken. Quantitative real-time PCR detected HPV types and viral load measures. Prevalence of high-risk HPV was compared between HIV-infected and -uninfected women, and in women with abnormal cervical cytology, measured using conventional Pap smears.
Results
Median age of the 820 participants was 28 years (inter-quartile range [IQR] = 24-36 years). One third of women were HIV infected (283/803; 35.2%) and these women were y more likely to have abnormal cervical cytology than HIV-negative women (27%, 73/269, versus 8%, 42/503; P < 0.001). Of HIV-infected women, 73.3% had high-risk HPV (200/273) and 35.5% had HPV 16 and/or 18 (97/273). Corresponding figures for HIV-negative women were 45.5% (229/503) and 15.7% (79/503). After adjusting for age, number of children and condom use, high-risk HPV was 3.6 fold more common in HIV-infected women (95%CI = 2.6-5.1). Prevalence of all 15 of the high-risk HPV types measured was higher among HIV-infected women, between 1.4 and 5.5 fold. Median total HPV viral load was 881 copies/cell in HIV-infected women (IQR = 33-12,110 copies/cell) and 48 copies/cell in HIV-uninfected women (IQR = 6-756 copies/cell; P < 0.001). HPV 16 and/or HPV 18 were identified in 42.7% of LSIL (32/75) and 42.3% of HSIL (11/26) lesions (P = 0.98). High-risk HPV types other than 16 and 18 were common in LSIL (74.7%; 56/75) and HSIL (84.6%; 22/26); even higher among HIV-infected women.
Conclusions
HIV-infected sex workers had almost four-fold higher prevalence of high-risk HPV, raised viral load and more precancerous lesions. HPV 16 and HPV 18, preventable with current vaccines, were associated with cervical disease, though other high-risk types were commoner. HIV-infected sex workers likely contribute disproportionately to HPV transmission dynamics in the general population. Current efforts to prevent HIV and HPV are inadequate. New interventions are required and improved implementation of existing strategies.
doi:10.1186/1471-2334-10-18
PMCID: PMC2845133  PMID: 20102630
25.  Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study 
Background
Herpes zoster (HZ) is common among HIV-infected individuals, but the impacts of highly active antiretroviral therapy (HAART) and HAART adherence on HZ risk have not been well studied.
Methods
The effects of HAART and HAART adherence on HZ incidence were evaluated by comparing HIV-infected women on HAART (HAART use group) with the HIV-infected women remaining HAART naïve (HAART naïve group) in the Women’s Interagency HIV Study (WIHS). A 1:1 matching with propensity score for predicting HAART initiation was conducted to balance background covariates at index visit, including HIV disease stage. Kaplan-Meier method was used to compare the risk of HZ development between the matched pairs. Cox proportional hazard models were used to assess the effects of HAART and HAART adherence on HZ incidence.
Results
Through propensity score matching, 389 pairs of participants were identified and they contributed 3,909 person years after matching. The background covariates were similar between the matched pairs at the index visit. The participants had a mean age around 39 years old, and about 61% of them were Black and 22% were Latina. No significant difference in HZ risk was observed between the HAART use group and the HAART naïve group during the first year of follow-up in any analyses. In the univariate analysis, the HAART use group had marginally lower HZ risk (Hazard Ratio (HR): 0.72; 95% Confidence Interval (CI): 0.48-1.1) over the entire follow-up period. However, women with a HAART adherence level of ≥95% had significantly lower HZ risk (HR: 0.54; 95% CI: 0.31, 0.94) compared to the HAART naïve women. The association remained significant after adjusting for quality of life score and acyclovir use, but it attenuated and was no longer statistically significant after adjusting for an intermediate variable, either CD4+ T cell counts or HIV viral load.
Conclusions
Among adult women, we observed a significant preventive effect of long-term HAART use on HZ incidence when a HAART adherence level of ≥95% was attained, and this effect was mediated through reduction of HIV viral load and improvement of CD4+ T cell counts.
doi:10.1186/1742-6405-10-34
PMCID: PMC3904465  PMID: 24373482
HAART; Adherence; Herpes zoster; Incidence; Propensity score

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