Routine Immunization Coverage and Immunization Card Retention in Pakistan: Results From a Cross-sectional National Survey.

BACKGROUND: Immunization is one of the most successful public health interventions available, saving millions of lives from death and disability each year. Therefore, improving immunization coverage is a high priority for the Government of Pakistan and essential to progress toward universal health coverage. This survey reports the national and provincial/regional coverage and determinants of fully, partially, and not-vaccinated children 12-23 months of age, antigen-wise coverage, percentage of home-based vaccination records (HBR) retention, and reasons for nonretention; dropout, timeliness, and prevalence of missed opportunities for simultaneous vaccination (MOSV). METHODS: The survey was a descriptive cross-sectional national household survey carried out across Pakistan. The survey included 110,790 children 12-23 months old and their caregivers. A World Health Organization (WHO)-Expanded Program on Immunization (EPI) Survey questionnaire was adapted to collect information. Data were analyzed using the WHO Vaccination Coverage Quality Indicators (VCQI) software and Stata version 17. RESULTS: Nationally excluding Azad Jammu and Kashmir (AJK) and Gilgit Baltistan (GB), the coverage of fully vaccinated children was 76.5%. The likelihood of being fully vaccinated was higher among children of educated parents who belonged to higher wealth quintiles and resided in any province/region other than Balochistan. The main reasons for unimmunization were no faith in immunization, rumors about vaccines, and distance to the facility. About two-thirds (66.2%) of the children had their HBR available, and the main reasons for not having a card were never visiting a health facility and having no awareness about the importance of a card. Dropout was discernible for later doses of vaccines compared with earlier ones. Higher proportions of children received the last doses late by more than two months. Of the 218,002 vaccination visits documented on HBR in the provinces, MOSVs occurred in 17.6% of the visits. CONCLUSION: The immunization coverage rates provide a direction to strategize the progress to improve the vaccination rates in Pakistan. The country needs to outline the immediate and long-term actions to combat vaccine-preventable diseases, such as escalating integrated immunization campaigns and outreach activities, provision of mobility support, and deploying behavioral interventions as a cross-cutting strategy to improve awareness and reduce misconceptions.

Cost optimisation analysis of the expanded programme for immunisation: balancing equity and coverage in Pakistan.

INTRODUCTION: With limited resources, attaining maximal average health service coverage can be at odds with maximising equity which attempts to promote greater reach among underserved populations. In this study, we examined the trade-offs in immunisation coverage levels and equity for children under 5 years of age in Pakistan across various subpopulations who can be targeted with different combinations of immunisation service modalities. METHODS: We conducted a detailed costing exercise across 16 geographically and demographically diverse districts in Pakistan. These data were the basis for (a) technical efficiency benchmarking via Data Envelopment Analysis to identify potential efficiency gains by location, delivery model and cost ingredient; (b) allocative efficiency optimisation modelling to understand how resource allocations could be optimised and to devise recommended budget allocations and operational metrics. Finally, the hypothetical overall efficiency gains attainable were estimated if available resources were allocated with the optimal emphases, and if service delivery models operated at productivity levels at the benchmarked frontier of efficiency. RESULTS: Benchmarking suggests that ~44% of delivery models are running efficiently and 37% are highly inefficient. While coverage and equity are usually at odds, surprisingly, the optimisation modelling revealed that substantial improvements in equity between subpopulations does not necessarily cost very much in overall immunisation coverage: theoretically, equity can be achieved while still attaining close to maximal immunisation coverage. Overall, analyses suggest greater emphases should be placed on outreach delivery models which particularly target rural areas and slum populations. CONCLUSION: The unit cost differentials within districts are not sufficiently large for there to be a large reduction in potential Fully Immunised Children coverage if one focuses on maximising equity. However, reallocations of programme budgets can have a significant impact on equity outcomes, particularly at current low spending amounts. Therefore, it is recommended to address equity as the key objective in national immunisation programming.

Scaling up of HIV treatment for men who have sex with men in Bangkok: a modelling and costing study.

BACKGROUND: Despite the high prevalence of HIV in men who have sex with men (MSM) in Bangkok, little investment in HIV prevention for MSM has been made. HIV testing and treatment coverage remains low. Through a pragmatic programme-planning approach, we assess possible service linkage and provision of HIV testing and antiretroviral treatment (ART) to MSM in Bangkok, and the most cost-effective scale-up strategy. METHODS: We obtained epidemiological and service capacity data from the Thai National Health Security Office database for 2011. We surveyed 13 representative medical facilities for detailed operational costs of HIV-related services for sexually active MSM (defined as having sex with men in the past 12 months) in metropolitan Bangkok. We estimated the costs of various ART scale-up scenarios, accounting for geographical accessibility across Bangkok. We used an HIV transmission population-based model to assess the cost-effectiveness of the scenarios. FINDINGS: For present HIV testing (23% [95% CI 17-36] of MSM at high risk in 2011) and ART provision (20% of treatment-eligible MSM at high risk on ART in 2011) to be sustained, a US$73·8 million ($51·0 million to $97·0 million) investment during the next decade would be needed, which would link an extra 43,000 (27,900-58,000) MSM at high risk to HIV testing and 5100 (3500-6700) to ART, achieving an ART coverage of 44% for MSM at high risk in 2022. An additional $55·3 million investment would link an extra 46,700 (30,300-63,200) MSM to HIV testing and 12,600 (8800-16,600) to ART, achieving universal ART coverage of this population by 2022. This increased investment is achievable within present infrastructure capacity. Consequently, an estimated 5100 (3600-6700) HIV-related deaths and 3700 (2600-4900) new infections could be averted in MSM by 2022, corresponding to a 53% reduction in deaths and a 35% reduction in infections from 2012 levels. The expansion would cost an estimated $10,809 (9071-13,274) for each HIV-related death, $14,783 (12,389-17,960) per new infection averted, and $351 (290-424) per disability-adjusted life-year averted. INTERPRETATION: Spare capacity in Bangkok's medical facilities can be used to expand ART access for MSM with large epidemiological benefits. The expansion needs increased funding directed to MSM services, but given the epidemiological trends, is probably cost effective. Our modelling approach and outcomes are likely to be applicable to other settings. FUNDING: World Bank Group and Australian National Health and Medical Research Council.

Epidemic impacts of a community empowerment intervention for HIV prevention among female sex workers in generalized and concentrated epidemics.

INTRODUCTION: Sex workers have endured a high burden of HIV infection in and across HIV epidemics. A comprehensive, community empowerment-based HIV prevention intervention emphasizes sex worker organization and mobilization to address HIV risk and often includes community-led peer education, condom distribution, and other activities. Meta-analysis of such interventions suggests a potential 51% reduction in inconsistent condom use. Mathematical modeling exercises provide theoretical insight into potential impacts of the intervention on HIV incidence and burden in settings where interventions have not yet been implemented. METHODS: We used a deterministic model, Goals, to project the impact on HIV infections when the community empowerment interventions were scaled up among female sex workers in Kenya, Thailand, Brazil, and Ukraine. Modeling scenarios included expansion of the comprehensive community empowerment-based HIV prevention intervention from baseline coverage over a 5-year period (5-65% in Kenya and Ukraine; 10-70% in Thailand and Brazil), while other interventions were held at baseline levels. A second exercise increased the intervention coverage simultaneously with equitable access to ART for sex workers. Impacts on HIV outcomes among sex workers and adults are observed from 2012-2016 and, compared to status quo when all interventions are held constant. RESULTS: Optimistic but feasible coverage (65%-70%) of the intervention demonstrated a range of impacts on HIV: 220 infections averted over 5 yrs. among sex workers in Thailand, 1,830 in Brazil, 2,220 in Ukraine, and 10,800 infections in Kenya. Impacts of the intervention for female sex workers extend to the adult population, cumulatively averting 730 infections in Thailand to 20,700 adult infections in Kenya. Impacts vary by country, influenced by HIV prevalence in risk groups, risk behaviors, intervention use, and population size. DISCUSSION: A community empowerment approach to HIV prevention and access to universal ART for female sex workers is a promising human rights-based solution to overcoming the persistent burden of HIV among female sex workers across epidemic settings.

CRF01_AE dominates the HIV-1 epidemic in Indonesia.

BACKGROUND: The HIV epidemic in Indonesia remains concentrated in vulnerable populations, namely injecting drug users (IDUs), commercial sex workers (CSWs) and men who have sex with men (MSM). We aimed to determine the HIV-1 subtypes present in Indonesia and to establish the extent of the viral overlap between individuals with different risk factors. METHODS: Venous blood samples were collected from HIV-positive individuals primarily from sexually transmissible infection clinics and drug rehabilitation centres in Bali and Jakarta, and applied to filter paper. A polymerase chain reaction-based assay designed to amplify a 330-bp region of the HIV-1 envelope was used to determine HIV-1 subtype result and to perform phylogenetic analysis. RESULTS: Of the 175 individuals recruited to the study, a subtype result was obtained for 108 (62%). Four subtypes were found to exist in the population, CRF01_AE (n=96, 88.9%), B (n=10, 9.3%), C (n=1, 0.9%) and G (n=1, 0.9%). Of these 108 individuals, 65 (60%) were IDUs, and the remaining 40% were CSWs, MSM, transgender individuals, people with multiple sexual partners or those with no obvious risk factor. CRF01_AE was found to be more common among IDUs with 100% of individuals infected with this subtype. Subtype B was more common among MSM and CSWs (P=<0.001). Phylogenetic analysis revealed a lack of viral segregation between risk groups. CONCLUSIONS: In Indonesia, CRF01_AE continues to dominate the HIV epidemic, although HIV subtype B is responsible for a significant number of sexually acquired infections.

Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy.

BACKGROUND: In many settings, the benefits of antiretroviral therapy (ART) are reduced by the high early incidence of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). METHODS: We used tuberculin skin testing and the QuantiFERON-TB Gold In-Tube assay to investigate cellular immune responses to purified protein derivative (PPD) and region of difference 1 (RD1) antigens during the first 24 weeks of ART. RESULTS: TB-IRIS and ART-associated tuberculosis occurred in 15 of 75 (20%) and 11 of 231 (4.8%) participants at risk, respectively. Greater increases in interferon gamma (IFN-gamma) and skin test responses to PPD were seen at week 24 and 12 in participants with TB-IRIS (P< or = .04), respectively. Raw IFN-gamma responses to RD1 antigens and PPD corrected for pre-ART CD4(+) T cell counts were higher at all time points in individuals with ART-associated tuberculosis (P<.001) and were associated with areas under receiver operator characteristic curves of 0.90 for RD1 (95% confidence interval [CI], 0.78-1.00) and 0.92 for PPD (95% CI, 0.83-1.00) for the diagnosis of ART-associated tuberculosis. Pre-ART IFN-gamma responses enabled stratification of participants into groups with risks of subsequent tuberculosis of 0.7%, 9.3%, and 30.0%. CONCLUSIONS: Type 1 effector T cell responses are prominent in ART-associated tuberculosis, but additional immune defects may be more important in paradoxical TB-IRIS. IFN-gamma release assays may contribute to the prediction and diagnosis of tuberculosis during early ART.

International health financing and the response to AIDS.

Efforts to finance HIV responses have generated large increases in funding, catalyzed activism and institutional innovation, and brought renewed attention to health issues and systems. The benefits go well beyond HIV programs. The substantial increases in HIV funding are a tiny percentage of overall increases in health financing, with other areas also seeing large absolute increases. Data on health funding suggest an improved "pro-poor" distribution, with Africa benefiting relatively more from increased external flows. A literature review found few evidence-based analyses of the impact of AIDS programs and funding on broader health financing. Conceptual frameworks that would facilitate such analysis are summarized.

Household survey in two provinces in Viet Nam estimates HIV prevalence in an urban and a rural population.

A household-based population study interviewed 2,553 women and 1,984 men aged 15-49 years in urban (Ho Chi Minh City) and rural (Thai Binh) provinces in Viet Nam between July and August 2005. The survey response rate was high--approximately 97% of households and 93% of adults overall, with a >92% acceptance of HIV testing among eligible adults. The unadjusted estimated population HIV prevalence was 0.3% (confidence interval [CI]: 0.1-0.6%) in Thai Binh and 0.7% (CI: 0.3-1.3) in Ho Chi Minh City (HCMC), compared with the national estimates and projections of 0.352% and 1.250%, respectively, for 2005. The ratio of male-to-female prevalence was 10.5:1 in Thai Binh and 1.3:1 in HCMC. A low level of men reported purchasing sex in the last 12 months (2.4%) and there were low self-reports of sexually transmitted infections in all adults (5%). A correct knowledge of HIV/AIDS prevention methods was high in both provinces (83%), although only 24.8% of women knew of the use of antiretroviral therapy to prevent vertical transmission of HIV. The observed population prevalence was consistent with recent projections in Thai Binh, although lower than expected in HCMC, indicating the substantial downward revisions of projected population HIV prevalence may need to be extended. The unequal sex prevalence ratio is consistent with the projected trends of increasing male-to-female sexual transmission in urban areas. The results and experience of this study will inform future population based surveys in Viet Nam and the broader Asian region.

The heterosexual HIV type 1 epidemic in Papua New Guinea is dominated by subtype C.

Papua New Guinea is in the midst of a generalized HIV epidemic. As part of a larger behavioral survey aiming to further characterize the HIV epidemic occurring in PNG, samples were collected from 1175 participants from seven different provinces. Seventy-one (6%) of these samples were HIV-1 positive, and 35 (49%) successfully underwent a double nested RT-PCR that was designed to amplify the C2-V4 region of the HIV-1 envelope. Sequence analysis showed that 33 (94%) samples were subtype C and the remaining 2 (6%) were subtype B. Further phylogenetic analysis demonstrated that there was no province-specific clustering among the samples and that within the global pandemic, PNG subtype C isolates most closely resembled those from East Africa.

Astrocyte specific viral strains in HIV dementia.

We molecularly characterized human immunodeficiency virus type 1 (HIV-1) present in pure populations of astrocytes, macrophages, and multinucleated giant cells isolated using laser capture microdissection from brain tissue of two patients who died with HIV-associated dementia. The V3 region of the HIV-1 envelope (env) gene was amplified from the pure-cell populations, and multiple clones were sequenced. In both patients, the V3 env sequences were distinct in astrocytes compared with neighboring macrophages or multinucleated giant cells and were characteristic of CCR5-using (R5) HIV-1. These results demonstrate cell-specific compartmentalization of distinct R5-like viral strains in the central nervous system microenvironment.

Construction and immunogenicity study of a 297-bp humanized HIV V3 DNA of an approximated last common ancestor in mice.

DNA immunization represents one of the promising HIV-1 vaccine approaches. To overcome the obstacle of genetic variation, we used the last common ancestor (LCA) or "center-of-the-tree" approach to study a DNA fragment of the HIV-1 envelope surrounding the V3 region. A humanized codon of the 297-bp consensus ancestral sequence of the HIV-1 envelope (codons 291-391) was derived from the 80 most recent HIV-1 isolates from the 8 circulating HIV-1 subtypes worldwide. This 297-bp humanized "multi-clade" V3 DNA was amplified by a PCR-based technique. The PCR product was well expressed in vitro whereas the corresponding non-humanized V3 DNA (subtype A/E) could not be expressed. However, both V3 DNA constructs as well as the full-length HIV-1 envelope construct (A/E) were found to be immunogenic in mice by the footpad-swelling assay. Moreover, intracellular and extracellular interferon-gamma could be detected upon in vitro stimulation of spleen cells although the response was relatively weak. Further improvement of our humanized V3 DNA is needed.

The subtypes of human immunodeficiency virus in Australia and Asia.

Worldwide, the human immunodeficiency virus exhibits a great genetic variability, with multiple circulating subtypes of the virus. This variability allows study of the movement of HIV strains within and between human populations but also has implications for diagnosis, treatment and monitoring. The type of HIV causing the epidemic in Australia is changing from being homogeneous subtype B, reflecting a greater regional diversity. In this paper the classification of HIV-1 subtypes and their distribution within the Australasian region are reviewed and the implications of these distribution patterns discussed.

The molecular epidemiology of HIV type 1 among Vietnamese Australian injecting drug users in Melbourne, Australia.

The proportion of human immunodeficiency virus type 1 (HIV-1) among Vietnamese injecting drug users (IDUs) in Melbourne, Australia exceeds that of the background population. To investigate the molecular epidemiology of HIV-1 among this group, the C2-V4 region of the HIV-1 envelope was directly sequenced from 11 Vietnamese Australians and 19 non-Vietnamese Australian controls. A significant difference in the distribution of the HIV-1 subtypes was demonstrated, with greater than 50% of Vietnamese Australian IDU shown to be infected with CRF01_AE-the predominant subtype in Southeast Asia, rather than subtype B, which dominates the Australian epidemic and which was found in 89.5% of the non-Vietnamese controls. The genetic diversity of the CRF01_AE epidemic in Vietnamese Australian IDUs was substantially lower that that of the background subtype B, consistent with a more recent introduction of a limited number of viral strains from Vietnam. These results support public health policy targeting Australian IDUs of Vietnamese ethnicity as a distinct vulnerable population.

Monitoring of human immunodeficiency virus infection in resource-constrained countries.

The reference standards used to monitor human immunodeficiency virus (HIV) infection are flow cytometric analysis of T lymphocyte subsets to provide the CD4+ T cell count and molecular assays to quantify plasma HIV load. Few laboratories in resource-constrained countries can afford to perform these tests. A number of lower-cost assays requiring less expensive equipment may be well-suited to such countries. These include manual CD4 cell assays (Dynal, Coulter, BioRad) and ultrasensitive reverse transcriptase (Cavidi) and p24 (Perkin Elmer Life Sciences) assays to monitor virus load. Quality control and access to quality assurance programs are essential. The total lymphocyte count, although readily available and inexpensive, generally does not correlate as closely with CD4+ T cell counts. Other surrogate markers, such as beta2-microglobulin, are not suitable for routine monitoring of HIV infection. This review discusses the above assays and their role in addition to clinical monitoring in resource-constrained countries.

Rates of transmission of antiretroviral drug resistant strains of HIV-1.

BACKGROUND: It is clear that transmission of drug resistant HIV-1 is possible and occurs regularly. However, there is a lack of clarity concerning the true rate of this transmission in a given population, the impact of combination therapies on this rate, and the contribution of transmitted resistant virus to treatment failure either in an individual or on a population basis. OBJECTIVES: To provide a review of our current understanding of rates of transmission of drug resistant HIV-1 in various populations and to report the results of a study conducted to determine this rate in Sydney, Australia in the years 1992-2000. STUDY DESIGN: A review of the literature combined with a prospective study of antiretroviral drug resistance in 130 individuals who were diagnosed with symptomatic primary infection at St. Vincent's Hospital, Sydney, Australia between 1992 and 2000. Sequencing of reverse transcriptase (RT) and protease (PR) was performed by the TruGene HIV-1 genotyping kit (Visible Genetics Inc.). RESULTS: The results found in the Sydney population contrast with much of the literature. The prevalence of mutations that conferred primary resistance to protease inhibitors (PIs) was only 0.8% at position V82I. Secondary mutations/polymorphisms were seen in the PR at position L10I/V, K20R, M36I, L63P, A71T/V, or V77I in 60%. L63P was the most frequently found mutation (46.3%). The incidence of protease-resistant strains of HIV in primary HIV-1 infection did not change after the introduction of PIs in 1996. The distribution of the most common resistance mutations in the RT was as follows; M41L (8.5%) and T215Y (8.5%) and K70R (4.8%). The frequency of mutations associated with NRTI resistance was significantly lower in the post 1995 samples (43.9 vs. 19.1%, P < 0.05). Moreover, both M41L and K70R, but not T215Y, occurred with significantly decreased frequency in the post 1995 samples. CONCLUSIONS: In contrast to other studies we found no increase in the rate of PR resistance and a decrease in the rate of RT resistance in recently transmitted virus over the period 1992-2000. The reasons for the differences between these results and those reported from elsewhere may relate to treatment regimens used in the transmitting population and may have implications for treatment policies in this country.

No increase in protease resistance and a decrease in reverse transcriptase resistance mutations in primary HIV-1 infection: 1992-2001.

Rates of antiretroviral resistance in recently transmitted virus in Sydney, Australia fluctuated over the past decade, influenced by treatment trends. Current rates of drug resistance are not high in historical terms or compared with those reported. Rates of resistance to reverse transcriptase inhibitors peaked in the mid-1990s, fell dramatically with the introduction of combination therapy and appear to have plateaued at 10-15% over the past 3 years. Primary resistance mutations in the protease gene are still rare.

The molecular epidemiology of HIV-1 in South and East Asia.

Foremost amongst human pathogens, the human immunodeficiency virus (HIV) exhibits a great genetic variability. The resultant fluidity of HIV enzymatic proteins allows them to remain functional whilst simultaneously evading immune surrveillance and antiretroviral therapy. This very variability, however, has been turned to powerful advantage in the study of the movement and evolution of HIV strains within and between human populations. Molecular analyses that estimate the relatedness between viral isolates, conducted in tandem with epidemiological studies, provide a new clarity of insight into the modes and routes of HIV transmission and epidemic spread. In this paper the principles underlying the molecular study of HIV and the achievements of this new field of epidemiology in southern and eastern Asia are reviewed.

Adaptive changes after human immunodeficiency virus type 1 transmission.

Primary HIV-1 infection (PHI) is associated with a period of viremia, the resolution of which generally coincides with the development of both humoral and cellular immune responses. In this study replication-competent quasispecies were derived from virus isolated from an individual before and after seroconversion. Virus was also isolated from the presumed donor. Phenotypic and genotypic analysis of biological clones identified transmission of an R5/M-tropic phenotype. However, the ability of clones derived from the recipient to replicate in primary macrophages and PBMCs was restricted after transmission. This apparent selection process was supported by analysis of molecular clones derived from the isolated virus. Analysis of the ratio of synonymous and nonsynonymous substitutions predicted the existence of selective pressure soon after transmission, coincident with the development of HIV-1-specific antibodies. An Env trans-complementation assay demonstrated that the infectivity of a clone derived from the recipient after seroconversion was enhanced in the presence of a selected neutralizing antibody, indicating that the developing humoral immune response may have at least in part contributed to the selective pressure identified.